Anti-Tumor Necrosis Factor Treatment for Glomerulopathy: Case Report and Review of Literature

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Article
Changed
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Author(s)
Olcay Y. Jones, MD, PhD
Laura C. Malone, MD
Celina Brunson, MD

Podocytes are terminally differentiated, highly specialized cells located in juxtaposition to the basement membrane over the abluminal surfaces of endothelial cells within the glomerular tuft. This triad structure is the site of the filtration barrier, which forms highly delicate and tightly regulated architecture to carry out the ultrafiltration function of the kidney.1 The filtration barrier is characterized by foot processes that are connected by specialized junctions called slit diaphragms.

Insults to components of the filtration barrier can initiate cascading events and perpetuate structural alterations that may eventually result in sclerotic changes.2 Common causes among children include minimal change disease (MCD) with the collapse of foot processes resulting in proteinuria, Alport syndrome due to mutation of collagen fibers within the basement membrane leading to hematuria and proteinuria, immune complex mediated nephropathy following common infections or autoimmune diseases, and focal segmental glomerulosclerosis (FSGS) that can show variable histopathology toward eventual glomerular scarring.3,4 These children often clinically have minimal, if any, signs of systemic inflammation.3-5 This has been a limiting factor for the commitment to immunomodulatory treatment, except for steroids for the treatment of MCD.6 Although prolonged steroid treatment may be efficacious, adverse effects are significant in a growing child. Alternative treatments, such as tacrolimus and rituximab have been suggested as second-line steroid-sparing agents.7,8 Not uncommonly, however, these cases are managed by supportive measures only during the progression of the natural course of the disease, which may eventually lead to renal failure, requiring transplant for survival.8,9

This case report highlights a child with a variant of uncertain significance (VUS) in genes involved in Alport syndrome and FSGS who developed an abrupt onset of proteinuria and hematuria after a respiratory illness. To our knowledge, he represents the youngest case demonstrating the benefit of targeted treatment against tumor necrosis factor-α (TNF-α) for glomerulopathy using biologic response modifiers.

 

Case Description

This is currently a 7-year-old male patient who was born at 39 weeks gestation to gravida 3 para 3 following induced labor due to elevated maternal blood pressure. During the first 2 years of life, his growth and development were normal and his immunizations were up to date. The patient's medical history included upper respiratory tract infections (URIs), respiratory syncytial virus, as well as 3 bouts of pneumonia and multiple otitis media that resulted in 18 rounds of antibiotics. The child was also allergic to nuts and milk protein. The patient’s parents are of Northern European and Native American descent. There is no known family history of eye, ear, or kidney diseases.

Renal concerns were first noted at the age of 2 years and 6 months when he presented to an emergency department in Fall 2019 (week 0) for several weeks of intermittent dark-colored urine. His mother reported that the discoloration recently progressed in intensity to cola-colored, along with the onset of persistent vomiting without any fever or diarrhea. On physical examination, the patient had normal vitals: weight 14.8 kg (68th percentile), height 91 cm (24th percentile), and body surface area 0.6 m2. There was no edema, rash, or lymphadenopathy, but he appeared pale.
 

 

 

The patient’s initial laboratory results included: complete blood count with white blood cells (WBC) 10 x 103/L (reference range, 4.5-13.5 x 103/L); differential lymphocytes 69%; neutrophils 21%; hemoglobin 10 g/dL (reference range, 12-16 g/dL); hematocrit, 30%; (reference range, 37%-45%); platelets 437 103/L (reference range, 150-450 x 103/L); serum creatinine 0.46 mg/dL (reference range, 0.5-0.9 mg/dL); and albumin 3.1 g/dL (reference range, 3.5-5.2 g/dL). Serum electrolyte levels and liver enzymes were normal. A urine analysis revealed 3+ protein and 3+ blood with dysmorphic red blood cells (RBC) and RBC casts without WBC. The patient's spot urine protein-to-creatinine ratio was 4.3 and his renal ultrasound was normal. The patient was referred to Nephrology.

During the next 2 weeks, his protein-to-creatinine ratio progressed to 5.9 and serum albumin fell to 2.7 g/dL. His urine remained red colored, and a microscopic examination with RBC > 500 and WBC up to 10 on a high powered field. His workup was negative for antinuclear antibodies, antineutrophil cytoplasmic antibody, antistreptolysin-O (ASO) and anti-DNase B. Serum C3 was low at 81 mg/dL (reference range, 90-180 mg/dL), C4 was 13.3 mg/dL (reference range, 10-40 mg/dL), and immunoglobulin G was low at 452 mg/dL (reference range 719-1475 mg/dL). A baseline audiology test revealed normal hearing.

 

 

Percutaneous renal biopsy yielded about 12 glomeruli, all exhibiting mild mesangial matrix expansion and hypercellularity (Figure 1). One glomerulus had prominent parietal epithelial cells without endocapillary hypercellularity or crescent formation. There was no interstitial fibrosis or tubular atrophy. Immunofluorescence studies showed no evidence of immune complex deposition with negative staining for immunoglobulin heavy and light chains, C3 and C1q. Staining for α 2 and α 5 units of collagen was normal. Electron microscopy showed patchy areas of severe basement membrane thinning with frequent foci of mild to moderate lamina densa splitting and associated visceral epithelial cell foot process effacement (Figure 2).

These were reported as concerning findings for possible Alport syndrome by 3 independent pathology teams. The genetic testing was submitted at a commercial laboratory to screen 17 mutations, including COL4A3, COL4A4, and COL4A5. Results showed the presence of a heterozygous VUS in the COL4A4 gene (c.1055C > T; p.Pro352Leu; dbSNP ID: rs371717486; PolyPhen-2: Probably Damaging; SIFT: Deleterious) as well as the presence of a heterozygous VUS in TRPC6 gene (c2463A>T; p.Lys821Asn; dbSNP ID: rs199948731; PolyPhen-2: Benign; SIFT: Tolerated). Further genetic investigation by whole exome sequencing on approximately 20,000 genes through MNG Laboratories showed a new heterozygous VUS in the OSGEP gene [c.328T>C; p.Cys110Arg]. Additional studies ruled out mitochondrial disease, CoQ10 deficiency, and metabolic disorders upon normal findings for mitochondrial DNA, urine amino acids, plasma acylcarnitine profile, orotic acid, ammonia, and homocysteine levels.

Figure 3 summarizes the patient’s treatment response during 170 weeks of follow-up (Fall 2019 to Summer 2023). The patient was started on enalapril 0.6 mg/kg daily at week 3, which continued throughout treatment. Following a rheumatology consult at week 30, the patient was started on prednisolone 3 mg/mL to assess the role of inflammation through the treatment response. An initial dose of 2 mg/kg daily (9 mL) for 1 month was followed by every other day treatment that was tapered off by week 48. To control mild but noticeably increasing proteinuria in the interim, subcutaneous anakinra 50 mg (3 mg/kg daily) was added as a steroid-sparing agent at week 39 and increased to 100mg daily by week 41.His urine proteintocreatinineratiodecreasedfrom 1.720 to 0.575, andserumalbuminnormalizedbyweek 53. At that time, due to the patient’s up-trending proteinuria after a URI, as well as concerns for injection site skin reaction and quality of life on daily subcutaneous treatment, anakinra was substituted with subcutaneous adalimumab 20 mg every 2 weeks.

By week 80,the patient’s urineproteintocreatininerationormalized (< 0.2). Thiswasfollowedbynormalizedurine microalbumintocreatinineratio, andbyweek 130 hismicroscopichematuriaresolved. While onadalimumab, heremainedwellandwasabletomountan immune response to viralinfectionsuneventfully,including COVID-19. He tolerated agradual wean of adalimumab to every 3 weeks by week 139 and discontinuation at week 151. At week 204, the patient has normal renal function and urine findings; his growth parameters are at 20.3 percentile for weight and 15.3percentile for height.

 

 

DISCUSSION

This case describes a child with rapidly progressive proteinuria and hematuria following a URI who was found to have VUS mutations in 3 different genes associated with chronic kidney disease. Serology tests on the patient were negative for streptococcal antibodies and antinuclear antibodies, ruling out poststreptococcal glomerulonephritis, or systemic lupus erythematosus. His renal biopsy findings were concerning for altered podocytes, mesangial cells, and basement membrane without inflammatory infiltrate, immune complex, complements, immunoglobulin A, or vasculopathy. His blood inflammatory markers, erythrocyte sedimentation rate, C-reactive protein, and ferritin were normal when his care team initiated daily steroids.

Overall, the patient’s clinical presentation and histopathology findings were suggestive of Alport syndrome or thin basement membrane nephropathy with a high potential to progress into FSGS.10-12 Alport syndrome affects 1 in 5000 to 10,000 children annually due to S-linked inheritance of COL4A5, or autosomal recessive inheritance of COL4A3 or COL4A4 genes. It presents with hematuria and hearing loss.10 Our patient had a single copy COL4A4 gene mutation that was classified as VUS. He also had 2 additional VUS affecting the TRPC6 and OSGEP genes. TRPC6 gene mutation can be associated with FSGS through autosomal dominant inheritance. Both COL4A4 and TRPC6 gene mutations were paternally inherited. Although the patient’s father not having renal disease argues against the clinical significance of these findings, there is literature on the potential role of heterozygous COL4A4 variant mimicking thin basement membrane nephropathy that can lead to renal impairment upon copresence of superimposed conditions.13 The patient’s rapidly progressing hematuria and changes in the basement membrane were worrisome for emerging FSGS. Furthermore, VUS of TRPC6 has been reported in late onset autosomal dominant FSGS and can be associated with early onset steroid-resistant nephrotic syndrome (NS) in children.14 This concern was voiced by 3 nephrology consultants during the initial evaluation, leading to the consensus that steroid treatment for podocytopathy would not alter the patient’s long-term outcomes (ie, progression to FSGS).

 

Immunomodulation

Our rationale for immunomodulatory treatment was based on the abrupt onset of renal concerns following a URI, suggesting the importance of an inflammatory trigger causing altered homeostasis in a genetically susceptible host. Preclinical models show that microbial products such as lipopolysaccharides can lead to podocytopathy by several mechanisms through activation of toll-like receptor signaling. It can directly cause apoptosis by downregulation of the intracellular Akt survival pathway.15 Lipopolysaccharide can also activate the NF-αB pathway and upregulate the production of interleukin-1 (IL-1) and TNF-α in mesangial cells.16,17

Both cytokines can promote mesangial cell proliferation.18 Through autocrine and paracrine mechanisms, proinflammatory cytokines can further perpetuate somatic tissue changes and contribute to the development of podocytopathy. For instance, TNF-α can promote podocyte injury and proteinuria by downregulation of the slit diaphragm protein expression (ie, nephrin, ezrin, or podocin), and disruption of podocyte cytoskeleton.19,20 TNF-α promotes the influx and activation of macrophages and inflammatory cells. It is actively involved in chronic alterations within the glomeruli by the upregulation of matrix metalloproteases by integrins, as well as activation of myofibroblast progenitors and extracellular matrix deposition in crosstalk with transforming growth factor and other key mediators.17,21,22

For the patient described in this case report, initial improvement on steroids encouraged the pursuit of additional treatment to downregulate inflammatory pathways within the glomerular milieu. However, within the COVID-19 environment, escalating the patient’s treatment using traditional immunomodulators (ie, calcineurin inhibitors or mycophenolate mofetil) was not favored due to the risk of infection. Initially, anakinra, a recombinant IL-1 receptor antagonist, was preferred as a steroid-sparing agent for its short life and safety profile during the pandemic. At first, the patient responded well to anakinra and was allowed a steroid wean when the dose was titrated up to 6 mg/kg daily. However, anakinra did not prevent the escalation of proteinuria following a URI. After the treatment was changed to adalimumab, a fully humanized monoclonal antibody to TNF-α, the patient continued to improve and reach full remission despite experiencing a cold and the flu in the following months.

 

 

Literature Review

There is a paucity of literature on applications of biological response modifiers for idiopathic NS and FSGS.23,24 Angeletti and colleagues reported that 3 patients with severe long-standing FSGS benefited from anakinra 4 mg/kg daily to reduce proteinuria and improve kidney function. All the patients had positive C3 staining in renal biopsy and treatment response, which supported the role of C3a in inducing podocyte injury through upregulated expression of IL-1 and IL-1R.23 Trachtman and colleagues reported on the phase II FONT trial that included 14 of 21 patients aged < 18 years with advanced FSGS who were treated with adalimumab 24 mg/m2, or ≤ 40 mg every other week.24 Although, during a 6-month period, none of the 7 patients met the endpoint of reduced proteinuria by ≥ 50%, and the authors suggested that careful patient selection may improve the treatment response in future trials.24

A recent study involving transcriptomics on renal tissue samples combined with available pathology (fibrosis), urinary markers, and clinical characteristics on 285 patients with MCD or FSGS from 3 different continents identified 3 distinct clusters. Patients with evidence of activated kidney TNF pathway (n = 72, aged > 18 years) were found to have poor clinical outcomes.25 The study identified 2 urine markers associated with the TNF pathway (ie, tissue inhibitor of metalloproteinases-1 and monocyte chemoattractant protein-1), which aligns with the preclinical findings previously mentioned.25

 

Conclusions

The patient’s condition in this case illustrates the complex nature of biologically predetermined cascading events in the emergence of glomerular disease upon environmental triggers under the influence of genetic factors. Observations on this child’s treatment response suggest that downregulation of somatic tissue-driven proinflammatory milieu originating from the constituents of glomerular microenvironment can help in recovery from emerging podocytopathy. The prolonged time span and stepwise resolution of proteinuria, followed by microalbuminuria (data not shown), and finally microscopic hematuria, supports the delicate balance and presence of reciprocal feedback loops between the podocytes and mesangial cells. Within this framework, blocking TNF-α, even temporarily, may allow time for the de novo regenerative process to prevail.

Chronic kidney disease affects 7.7% of veterans annually, illustrating the need for new therapeutics.26 Based on our experience and literature review, upregulation of TNF-α is a root cause of glomerulopathy; further studies are warranted to evaluate the efficacy of anti-TNF biologic response modifiers for the treatment of these patients. Long-term postmarketing safety profile and steroid-sparing properties of adalimumab should allow inclusion of pediatric cases in future trials. Results may also contribute to identifying new predictive biomarkers related to the basement membrane when combined with precision nephrology to further advance patient selection and targeted treatment.25,27

Acknowledgments

The authors thank the patient’s mother for providing consent to allow publication of this case report.

References

1. Arif E, Nihalani D. Glomerular filtration barrier assembly: an insight. Postdoc J. 2013;1(4):33-45.

2. Garg PA. Review of podocyte biology. Am J Nephrol. 2018;47(suppl 1):3-13. doi:10.1159/000481633SUPPL

3. Warady BA, Agarwal R, Bangalore S, et al. Alport syndrome classification and management. Kidney Med. 2020;2(5):639-649. doi:10.1016/j.xkme.2020.05.014

4. Angioi A, Pani A. FSGS: from pathogenesis to the histological lesion. J Nephrol. 2016;29(4):517-523. doi:10.1007/s40620-016-0333-2

5. Roca N, Martinez C, Jatem E, Madrid A, Lopez M, Segarra A. Activation of the acute inflammatory phase response in idiopathic nephrotic syndrome: association with clinicopathological phenotypes and with response to corticosteroids. Clin Kidney J. 2021;14(4):1207-1215. doi:10.1093/ckj/sfaa247

6. Vivarelli M, Massella L, Ruggiero B, Emma F. Minimal change disease. Clin J Am Soc Nephrol. 2017;12(2):332-345.

7. Medjeral-Thomas NR, Lawrence C, Condon M, et al. Randomized, controlled trial of tacrolimus and prednisolone monotherapy for adults with De Novo minimal change disease: a multicenter, randomized, controlled trial. Clin J Am Soc Nephrol. 2020;15(2):209-218. doi:10.2215/CJN.06290420

8. Ye Q, Lan B, Liu H, Persson PB, Lai EY, Mao J. A critical role of the podocyte cytoskeleton in the pathogenesis of glomerular proteinuria and autoimmune podocytopathies. Acta Physiol (Oxf). 2022;235(4):e13850. doi:10.1111/apha.13850

9. Trautmann A, Schnaidt S, Lipska-Ziμtkiewicz BS, et al. Long-term outcome of steroid-resistant nephrotic syndrome in children. J Am Soc Nephrol. 2017;28:3055-3065. doi:10.1681/ASN.2016101121

10. Kashtan CE, Gross O. Clinical practice recommendations for the diagnosis and management of Alport syndrome in children, adolescents, and young adults-an update for 2020. Pediatr Nephrol. 2021;36(3):711-719. doi:10.1007/s00467-020-04819-6

11. Savige J, Rana K, Tonna S, Buzza M, Dagher H, Wang YY. Thin basement membrane nephropathy. Kidney Int. 2003;64(4):1169-78. doi:10.1046/j.1523-1755.2003.00234.x

12. Rosenberg AZ, Kopp JB. Focal segmental glomerulosclerosis. Clin J Am Soc Nephrol. 2017; 12(3):502-517. doi:10.2215/CJN.05960616

13. Savige J. Should we diagnose autosomal dominant Alport syndrome when there is a pathogenic heterozygous COL4A3 or COL4A4 variant? Kidney Int Rep. 2018;3(6):1239-1241. doi:10.1016/j.ekir.2018.08.002

14. Gigante M, Caridi G, Montemurno E, et al. TRPC6 mutations in children with steroid-resistant nephrotic syndrome and atypical phenotype. Clin J Am Soc Nephrol. 2011;6(7):1626-1634. doi:10.2215/CJN.07830910

15. Saurus P, Kuusela S, Lehtonen E, et al. Podocyte apoptosis is prevented by blocking the toll-like receptor pathway. Cell Death Dis. 2015;6(5):e1752. doi:10.1038/cddis.2015.125

16. Baud L, Oudinet JP, Bens M, et al. Production of tumor necrosis factor by rat mesangial cells in response to bacterial lipopolysaccharide. Kidney Int. 1989;35(5):1111-1118. doi:10.1038/ki.1989.98

17. White S, Lin L, Hu K. NF-κB and tPA signaling in kidney and other diseases. Cells. 2020;9(6):1348. doi:10.3390/cells9061348

18. Tesch GH, Lan HY, Atkins RC, Nikolic-Paterson DJ. Role of interleukin-1 in mesangial cell proliferation and matrix deposition in experimental mesangioproliferative nephritis. Am J Pathol. 1997;151(1):141-150.

19. Lai KN, Leung JCK, Chan LYY, et al. Podocyte injury induced by mesangial-derived cytokines in IgA Nephropathy. Nephrol Dial Transplant. 2009;24(1):62-72. doi:10.1093/ndt/gfn441

20. Saleem MA, Kobayashi Y. Cell biology and genetics of minimal change disease. F1000 Res. 2016;5: F1000 Faculty Rev-412. doi:10.12688/f1000research.7300.1

21. Kim KP, Williams CE, Lemmon CA. Cell-matrix interactions in renal fibrosis. Kidney Dial. 2022;2(4):607-624. doi:10.3390/kidneydial2040055

22. Zvaifler NJ. Relevance of the stroma and epithelial-mesenchymal transition (EMT) for the rheumatic diseases. Arthritis Res Ther. 2006;8(3):210. doi:10.1186/ar1963

23. Angeletti A, Magnasco A, Trivelli A, et al. Refractory minimal change disease and focal segmental glomerular sclerosis treated with Anakinra. Kidney Int Rep. 2021;7(1):121-124. doi:10.1016/j.ekir.2021.10.018

24. Trachtman H, Vento S, Herreshoff E, et al. Efficacy of galactose and adalimumab in patients with resistant focal segmental glomerulosclerosis: report of the font clinical trial group. BMC Nephrol. 2015;16:111. doi:10.1186/s12882-015-0094-5

25. Mariani LH, Eddy S, AlAkwaa FM, et al. Precision nephrology identified tumor necrosis factor activation variability in minimal change disease and focal segmental glomerulosclerosis. Kidney Int. 2023;103(3):565-579. doi:10.1016/j.kint.2022.10.023

26. Korshak L, Washington DL, Powell J, Nylen E, Kokkinos P. Kidney Disease in Veterans. US Dept of Veterans Affairs, Office of Health Equity. Updated May 13, 2020. Accessed June 28, 2024. https://www.va.gov/HEALTHEQUITY/Kidney_Disease_In_Veterans.asp

27. Malone AF, Phelan PJ, Hall G, et al. Rare hereditary COL4A3/COL4A4 variants may be mistaken for familial focal segmental glomerulosclerosis. Kidney Int. 2014;86(6):1253-1259. doi:10.1038/ki.2014.305

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Olcay Y. Jones, MD, PhDa; Laura C. Malone, MDa; Celina Brunson, MDb

Correspondence:  Olcay Jones  (olcay.jones@gmail.com)

aWalter Reed National Military Medical Center, Bethesda, Maryland

bChildren’s National Medical Center, Washington, DC

Author disclosures

The authors report no actual or potential conflicts of interest regarding this article.

Disclaimer

The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the US Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review the complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

Ethics and consent

This case report is compliant with the rules and regulations of the Health Insurance Portability and Accountability Act. The content of this report was reviewed and approved by the Walter Reed National Military Medical Center’s Public Affairs Office and approved by its institutional review board (ED)-2020-0493). Verbal and written consent was provided by the parent of this child described in this case report.

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Laura C. Malone, MD
Celina Brunson, MD
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Olcay Y. Jones, MD, PhDa; Laura C. Malone, MDa; Celina Brunson, MDb

Correspondence:  Olcay Jones  (olcay.jones@gmail.com)

aWalter Reed National Military Medical Center, Bethesda, Maryland

bChildren’s National Medical Center, Washington, DC

Author disclosures

The authors report no actual or potential conflicts of interest regarding this article.

Disclaimer

The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the US Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review the complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

Ethics and consent

This case report is compliant with the rules and regulations of the Health Insurance Portability and Accountability Act. The content of this report was reviewed and approved by the Walter Reed National Military Medical Center’s Public Affairs Office and approved by its institutional review board (ED)-2020-0493). Verbal and written consent was provided by the parent of this child described in this case report.

Author and Disclosure Information

Olcay Y. Jones, MD, PhDa; Laura C. Malone, MDa; Celina Brunson, MDb

Correspondence:  Olcay Jones  (olcay.jones@gmail.com)

aWalter Reed National Military Medical Center, Bethesda, Maryland

bChildren’s National Medical Center, Washington, DC

Author disclosures

The authors report no actual or potential conflicts of interest regarding this article.

Disclaimer

The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the US Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review the complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

Ethics and consent

This case report is compliant with the rules and regulations of the Health Insurance Portability and Accountability Act. The content of this report was reviewed and approved by the Walter Reed National Military Medical Center’s Public Affairs Office and approved by its institutional review board (ED)-2020-0493). Verbal and written consent was provided by the parent of this child described in this case report.

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HCV, HBV, and HIV associated with autoimmune kidney diseases

Podocytes are terminally differentiated, highly specialized cells located in juxtaposition to the basement membrane over the abluminal surfaces of endothelial cells within the glomerular tuft. This triad structure is the site of the filtration barrier, which forms highly delicate and tightly regulated architecture to carry out the ultrafiltration function of the kidney.1 The filtration barrier is characterized by foot processes that are connected by specialized junctions called slit diaphragms.

Insults to components of the filtration barrier can initiate cascading events and perpetuate structural alterations that may eventually result in sclerotic changes.2 Common causes among children include minimal change disease (MCD) with the collapse of foot processes resulting in proteinuria, Alport syndrome due to mutation of collagen fibers within the basement membrane leading to hematuria and proteinuria, immune complex mediated nephropathy following common infections or autoimmune diseases, and focal segmental glomerulosclerosis (FSGS) that can show variable histopathology toward eventual glomerular scarring.3,4 These children often clinically have minimal, if any, signs of systemic inflammation.3-5 This has been a limiting factor for the commitment to immunomodulatory treatment, except for steroids for the treatment of MCD.6 Although prolonged steroid treatment may be efficacious, adverse effects are significant in a growing child. Alternative treatments, such as tacrolimus and rituximab have been suggested as second-line steroid-sparing agents.7,8 Not uncommonly, however, these cases are managed by supportive measures only during the progression of the natural course of the disease, which may eventually lead to renal failure, requiring transplant for survival.8,9

This case report highlights a child with a variant of uncertain significance (VUS) in genes involved in Alport syndrome and FSGS who developed an abrupt onset of proteinuria and hematuria after a respiratory illness. To our knowledge, he represents the youngest case demonstrating the benefit of targeted treatment against tumor necrosis factor-α (TNF-α) for glomerulopathy using biologic response modifiers.

 

Case Description

This is currently a 7-year-old male patient who was born at 39 weeks gestation to gravida 3 para 3 following induced labor due to elevated maternal blood pressure. During the first 2 years of life, his growth and development were normal and his immunizations were up to date. The patient's medical history included upper respiratory tract infections (URIs), respiratory syncytial virus, as well as 3 bouts of pneumonia and multiple otitis media that resulted in 18 rounds of antibiotics. The child was also allergic to nuts and milk protein. The patient’s parents are of Northern European and Native American descent. There is no known family history of eye, ear, or kidney diseases.

Renal concerns were first noted at the age of 2 years and 6 months when he presented to an emergency department in Fall 2019 (week 0) for several weeks of intermittent dark-colored urine. His mother reported that the discoloration recently progressed in intensity to cola-colored, along with the onset of persistent vomiting without any fever or diarrhea. On physical examination, the patient had normal vitals: weight 14.8 kg (68th percentile), height 91 cm (24th percentile), and body surface area 0.6 m2. There was no edema, rash, or lymphadenopathy, but he appeared pale.
 

 

 

The patient’s initial laboratory results included: complete blood count with white blood cells (WBC) 10 x 103/L (reference range, 4.5-13.5 x 103/L); differential lymphocytes 69%; neutrophils 21%; hemoglobin 10 g/dL (reference range, 12-16 g/dL); hematocrit, 30%; (reference range, 37%-45%); platelets 437 103/L (reference range, 150-450 x 103/L); serum creatinine 0.46 mg/dL (reference range, 0.5-0.9 mg/dL); and albumin 3.1 g/dL (reference range, 3.5-5.2 g/dL). Serum electrolyte levels and liver enzymes were normal. A urine analysis revealed 3+ protein and 3+ blood with dysmorphic red blood cells (RBC) and RBC casts without WBC. The patient's spot urine protein-to-creatinine ratio was 4.3 and his renal ultrasound was normal. The patient was referred to Nephrology.

During the next 2 weeks, his protein-to-creatinine ratio progressed to 5.9 and serum albumin fell to 2.7 g/dL. His urine remained red colored, and a microscopic examination with RBC > 500 and WBC up to 10 on a high powered field. His workup was negative for antinuclear antibodies, antineutrophil cytoplasmic antibody, antistreptolysin-O (ASO) and anti-DNase B. Serum C3 was low at 81 mg/dL (reference range, 90-180 mg/dL), C4 was 13.3 mg/dL (reference range, 10-40 mg/dL), and immunoglobulin G was low at 452 mg/dL (reference range 719-1475 mg/dL). A baseline audiology test revealed normal hearing.

 

 

Percutaneous renal biopsy yielded about 12 glomeruli, all exhibiting mild mesangial matrix expansion and hypercellularity (Figure 1). One glomerulus had prominent parietal epithelial cells without endocapillary hypercellularity or crescent formation. There was no interstitial fibrosis or tubular atrophy. Immunofluorescence studies showed no evidence of immune complex deposition with negative staining for immunoglobulin heavy and light chains, C3 and C1q. Staining for α 2 and α 5 units of collagen was normal. Electron microscopy showed patchy areas of severe basement membrane thinning with frequent foci of mild to moderate lamina densa splitting and associated visceral epithelial cell foot process effacement (Figure 2).

These were reported as concerning findings for possible Alport syndrome by 3 independent pathology teams. The genetic testing was submitted at a commercial laboratory to screen 17 mutations, including COL4A3, COL4A4, and COL4A5. Results showed the presence of a heterozygous VUS in the COL4A4 gene (c.1055C > T; p.Pro352Leu; dbSNP ID: rs371717486; PolyPhen-2: Probably Damaging; SIFT: Deleterious) as well as the presence of a heterozygous VUS in TRPC6 gene (c2463A>T; p.Lys821Asn; dbSNP ID: rs199948731; PolyPhen-2: Benign; SIFT: Tolerated). Further genetic investigation by whole exome sequencing on approximately 20,000 genes through MNG Laboratories showed a new heterozygous VUS in the OSGEP gene [c.328T>C; p.Cys110Arg]. Additional studies ruled out mitochondrial disease, CoQ10 deficiency, and metabolic disorders upon normal findings for mitochondrial DNA, urine amino acids, plasma acylcarnitine profile, orotic acid, ammonia, and homocysteine levels.

Figure 3 summarizes the patient’s treatment response during 170 weeks of follow-up (Fall 2019 to Summer 2023). The patient was started on enalapril 0.6 mg/kg daily at week 3, which continued throughout treatment. Following a rheumatology consult at week 30, the patient was started on prednisolone 3 mg/mL to assess the role of inflammation through the treatment response. An initial dose of 2 mg/kg daily (9 mL) for 1 month was followed by every other day treatment that was tapered off by week 48. To control mild but noticeably increasing proteinuria in the interim, subcutaneous anakinra 50 mg (3 mg/kg daily) was added as a steroid-sparing agent at week 39 and increased to 100mg daily by week 41.His urine proteintocreatinineratiodecreasedfrom 1.720 to 0.575, andserumalbuminnormalizedbyweek 53. At that time, due to the patient’s up-trending proteinuria after a URI, as well as concerns for injection site skin reaction and quality of life on daily subcutaneous treatment, anakinra was substituted with subcutaneous adalimumab 20 mg every 2 weeks.

By week 80,the patient’s urineproteintocreatininerationormalized (< 0.2). Thiswasfollowedbynormalizedurine microalbumintocreatinineratio, andbyweek 130 hismicroscopichematuriaresolved. While onadalimumab, heremainedwellandwasabletomountan immune response to viralinfectionsuneventfully,including COVID-19. He tolerated agradual wean of adalimumab to every 3 weeks by week 139 and discontinuation at week 151. At week 204, the patient has normal renal function and urine findings; his growth parameters are at 20.3 percentile for weight and 15.3percentile for height.

 

 

DISCUSSION

This case describes a child with rapidly progressive proteinuria and hematuria following a URI who was found to have VUS mutations in 3 different genes associated with chronic kidney disease. Serology tests on the patient were negative for streptococcal antibodies and antinuclear antibodies, ruling out poststreptococcal glomerulonephritis, or systemic lupus erythematosus. His renal biopsy findings were concerning for altered podocytes, mesangial cells, and basement membrane without inflammatory infiltrate, immune complex, complements, immunoglobulin A, or vasculopathy. His blood inflammatory markers, erythrocyte sedimentation rate, C-reactive protein, and ferritin were normal when his care team initiated daily steroids.

Overall, the patient’s clinical presentation and histopathology findings were suggestive of Alport syndrome or thin basement membrane nephropathy with a high potential to progress into FSGS.10-12 Alport syndrome affects 1 in 5000 to 10,000 children annually due to S-linked inheritance of COL4A5, or autosomal recessive inheritance of COL4A3 or COL4A4 genes. It presents with hematuria and hearing loss.10 Our patient had a single copy COL4A4 gene mutation that was classified as VUS. He also had 2 additional VUS affecting the TRPC6 and OSGEP genes. TRPC6 gene mutation can be associated with FSGS through autosomal dominant inheritance. Both COL4A4 and TRPC6 gene mutations were paternally inherited. Although the patient’s father not having renal disease argues against the clinical significance of these findings, there is literature on the potential role of heterozygous COL4A4 variant mimicking thin basement membrane nephropathy that can lead to renal impairment upon copresence of superimposed conditions.13 The patient’s rapidly progressing hematuria and changes in the basement membrane were worrisome for emerging FSGS. Furthermore, VUS of TRPC6 has been reported in late onset autosomal dominant FSGS and can be associated with early onset steroid-resistant nephrotic syndrome (NS) in children.14 This concern was voiced by 3 nephrology consultants during the initial evaluation, leading to the consensus that steroid treatment for podocytopathy would not alter the patient’s long-term outcomes (ie, progression to FSGS).

 

Immunomodulation

Our rationale for immunomodulatory treatment was based on the abrupt onset of renal concerns following a URI, suggesting the importance of an inflammatory trigger causing altered homeostasis in a genetically susceptible host. Preclinical models show that microbial products such as lipopolysaccharides can lead to podocytopathy by several mechanisms through activation of toll-like receptor signaling. It can directly cause apoptosis by downregulation of the intracellular Akt survival pathway.15 Lipopolysaccharide can also activate the NF-αB pathway and upregulate the production of interleukin-1 (IL-1) and TNF-α in mesangial cells.16,17

Both cytokines can promote mesangial cell proliferation.18 Through autocrine and paracrine mechanisms, proinflammatory cytokines can further perpetuate somatic tissue changes and contribute to the development of podocytopathy. For instance, TNF-α can promote podocyte injury and proteinuria by downregulation of the slit diaphragm protein expression (ie, nephrin, ezrin, or podocin), and disruption of podocyte cytoskeleton.19,20 TNF-α promotes the influx and activation of macrophages and inflammatory cells. It is actively involved in chronic alterations within the glomeruli by the upregulation of matrix metalloproteases by integrins, as well as activation of myofibroblast progenitors and extracellular matrix deposition in crosstalk with transforming growth factor and other key mediators.17,21,22

For the patient described in this case report, initial improvement on steroids encouraged the pursuit of additional treatment to downregulate inflammatory pathways within the glomerular milieu. However, within the COVID-19 environment, escalating the patient’s treatment using traditional immunomodulators (ie, calcineurin inhibitors or mycophenolate mofetil) was not favored due to the risk of infection. Initially, anakinra, a recombinant IL-1 receptor antagonist, was preferred as a steroid-sparing agent for its short life and safety profile during the pandemic. At first, the patient responded well to anakinra and was allowed a steroid wean when the dose was titrated up to 6 mg/kg daily. However, anakinra did not prevent the escalation of proteinuria following a URI. After the treatment was changed to adalimumab, a fully humanized monoclonal antibody to TNF-α, the patient continued to improve and reach full remission despite experiencing a cold and the flu in the following months.

 

 

Literature Review

There is a paucity of literature on applications of biological response modifiers for idiopathic NS and FSGS.23,24 Angeletti and colleagues reported that 3 patients with severe long-standing FSGS benefited from anakinra 4 mg/kg daily to reduce proteinuria and improve kidney function. All the patients had positive C3 staining in renal biopsy and treatment response, which supported the role of C3a in inducing podocyte injury through upregulated expression of IL-1 and IL-1R.23 Trachtman and colleagues reported on the phase II FONT trial that included 14 of 21 patients aged < 18 years with advanced FSGS who were treated with adalimumab 24 mg/m2, or ≤ 40 mg every other week.24 Although, during a 6-month period, none of the 7 patients met the endpoint of reduced proteinuria by ≥ 50%, and the authors suggested that careful patient selection may improve the treatment response in future trials.24

A recent study involving transcriptomics on renal tissue samples combined with available pathology (fibrosis), urinary markers, and clinical characteristics on 285 patients with MCD or FSGS from 3 different continents identified 3 distinct clusters. Patients with evidence of activated kidney TNF pathway (n = 72, aged > 18 years) were found to have poor clinical outcomes.25 The study identified 2 urine markers associated with the TNF pathway (ie, tissue inhibitor of metalloproteinases-1 and monocyte chemoattractant protein-1), which aligns with the preclinical findings previously mentioned.25

 

Conclusions

The patient’s condition in this case illustrates the complex nature of biologically predetermined cascading events in the emergence of glomerular disease upon environmental triggers under the influence of genetic factors. Observations on this child’s treatment response suggest that downregulation of somatic tissue-driven proinflammatory milieu originating from the constituents of glomerular microenvironment can help in recovery from emerging podocytopathy. The prolonged time span and stepwise resolution of proteinuria, followed by microalbuminuria (data not shown), and finally microscopic hematuria, supports the delicate balance and presence of reciprocal feedback loops between the podocytes and mesangial cells. Within this framework, blocking TNF-α, even temporarily, may allow time for the de novo regenerative process to prevail.

Chronic kidney disease affects 7.7% of veterans annually, illustrating the need for new therapeutics.26 Based on our experience and literature review, upregulation of TNF-α is a root cause of glomerulopathy; further studies are warranted to evaluate the efficacy of anti-TNF biologic response modifiers for the treatment of these patients. Long-term postmarketing safety profile and steroid-sparing properties of adalimumab should allow inclusion of pediatric cases in future trials. Results may also contribute to identifying new predictive biomarkers related to the basement membrane when combined with precision nephrology to further advance patient selection and targeted treatment.25,27

Acknowledgments

The authors thank the patient’s mother for providing consent to allow publication of this case report.

Podocytes are terminally differentiated, highly specialized cells located in juxtaposition to the basement membrane over the abluminal surfaces of endothelial cells within the glomerular tuft. This triad structure is the site of the filtration barrier, which forms highly delicate and tightly regulated architecture to carry out the ultrafiltration function of the kidney.1 The filtration barrier is characterized by foot processes that are connected by specialized junctions called slit diaphragms.

Insults to components of the filtration barrier can initiate cascading events and perpetuate structural alterations that may eventually result in sclerotic changes.2 Common causes among children include minimal change disease (MCD) with the collapse of foot processes resulting in proteinuria, Alport syndrome due to mutation of collagen fibers within the basement membrane leading to hematuria and proteinuria, immune complex mediated nephropathy following common infections or autoimmune diseases, and focal segmental glomerulosclerosis (FSGS) that can show variable histopathology toward eventual glomerular scarring.3,4 These children often clinically have minimal, if any, signs of systemic inflammation.3-5 This has been a limiting factor for the commitment to immunomodulatory treatment, except for steroids for the treatment of MCD.6 Although prolonged steroid treatment may be efficacious, adverse effects are significant in a growing child. Alternative treatments, such as tacrolimus and rituximab have been suggested as second-line steroid-sparing agents.7,8 Not uncommonly, however, these cases are managed by supportive measures only during the progression of the natural course of the disease, which may eventually lead to renal failure, requiring transplant for survival.8,9

This case report highlights a child with a variant of uncertain significance (VUS) in genes involved in Alport syndrome and FSGS who developed an abrupt onset of proteinuria and hematuria after a respiratory illness. To our knowledge, he represents the youngest case demonstrating the benefit of targeted treatment against tumor necrosis factor-α (TNF-α) for glomerulopathy using biologic response modifiers.

 

Case Description

This is currently a 7-year-old male patient who was born at 39 weeks gestation to gravida 3 para 3 following induced labor due to elevated maternal blood pressure. During the first 2 years of life, his growth and development were normal and his immunizations were up to date. The patient's medical history included upper respiratory tract infections (URIs), respiratory syncytial virus, as well as 3 bouts of pneumonia and multiple otitis media that resulted in 18 rounds of antibiotics. The child was also allergic to nuts and milk protein. The patient’s parents are of Northern European and Native American descent. There is no known family history of eye, ear, or kidney diseases.

Renal concerns were first noted at the age of 2 years and 6 months when he presented to an emergency department in Fall 2019 (week 0) for several weeks of intermittent dark-colored urine. His mother reported that the discoloration recently progressed in intensity to cola-colored, along with the onset of persistent vomiting without any fever or diarrhea. On physical examination, the patient had normal vitals: weight 14.8 kg (68th percentile), height 91 cm (24th percentile), and body surface area 0.6 m2. There was no edema, rash, or lymphadenopathy, but he appeared pale.
 

 

 

The patient’s initial laboratory results included: complete blood count with white blood cells (WBC) 10 x 103/L (reference range, 4.5-13.5 x 103/L); differential lymphocytes 69%; neutrophils 21%; hemoglobin 10 g/dL (reference range, 12-16 g/dL); hematocrit, 30%; (reference range, 37%-45%); platelets 437 103/L (reference range, 150-450 x 103/L); serum creatinine 0.46 mg/dL (reference range, 0.5-0.9 mg/dL); and albumin 3.1 g/dL (reference range, 3.5-5.2 g/dL). Serum electrolyte levels and liver enzymes were normal. A urine analysis revealed 3+ protein and 3+ blood with dysmorphic red blood cells (RBC) and RBC casts without WBC. The patient's spot urine protein-to-creatinine ratio was 4.3 and his renal ultrasound was normal. The patient was referred to Nephrology.

During the next 2 weeks, his protein-to-creatinine ratio progressed to 5.9 and serum albumin fell to 2.7 g/dL. His urine remained red colored, and a microscopic examination with RBC > 500 and WBC up to 10 on a high powered field. His workup was negative for antinuclear antibodies, antineutrophil cytoplasmic antibody, antistreptolysin-O (ASO) and anti-DNase B. Serum C3 was low at 81 mg/dL (reference range, 90-180 mg/dL), C4 was 13.3 mg/dL (reference range, 10-40 mg/dL), and immunoglobulin G was low at 452 mg/dL (reference range 719-1475 mg/dL). A baseline audiology test revealed normal hearing.

 

 

Percutaneous renal biopsy yielded about 12 glomeruli, all exhibiting mild mesangial matrix expansion and hypercellularity (Figure 1). One glomerulus had prominent parietal epithelial cells without endocapillary hypercellularity or crescent formation. There was no interstitial fibrosis or tubular atrophy. Immunofluorescence studies showed no evidence of immune complex deposition with negative staining for immunoglobulin heavy and light chains, C3 and C1q. Staining for α 2 and α 5 units of collagen was normal. Electron microscopy showed patchy areas of severe basement membrane thinning with frequent foci of mild to moderate lamina densa splitting and associated visceral epithelial cell foot process effacement (Figure 2).

These were reported as concerning findings for possible Alport syndrome by 3 independent pathology teams. The genetic testing was submitted at a commercial laboratory to screen 17 mutations, including COL4A3, COL4A4, and COL4A5. Results showed the presence of a heterozygous VUS in the COL4A4 gene (c.1055C > T; p.Pro352Leu; dbSNP ID: rs371717486; PolyPhen-2: Probably Damaging; SIFT: Deleterious) as well as the presence of a heterozygous VUS in TRPC6 gene (c2463A>T; p.Lys821Asn; dbSNP ID: rs199948731; PolyPhen-2: Benign; SIFT: Tolerated). Further genetic investigation by whole exome sequencing on approximately 20,000 genes through MNG Laboratories showed a new heterozygous VUS in the OSGEP gene [c.328T>C; p.Cys110Arg]. Additional studies ruled out mitochondrial disease, CoQ10 deficiency, and metabolic disorders upon normal findings for mitochondrial DNA, urine amino acids, plasma acylcarnitine profile, orotic acid, ammonia, and homocysteine levels.

Figure 3 summarizes the patient’s treatment response during 170 weeks of follow-up (Fall 2019 to Summer 2023). The patient was started on enalapril 0.6 mg/kg daily at week 3, which continued throughout treatment. Following a rheumatology consult at week 30, the patient was started on prednisolone 3 mg/mL to assess the role of inflammation through the treatment response. An initial dose of 2 mg/kg daily (9 mL) for 1 month was followed by every other day treatment that was tapered off by week 48. To control mild but noticeably increasing proteinuria in the interim, subcutaneous anakinra 50 mg (3 mg/kg daily) was added as a steroid-sparing agent at week 39 and increased to 100mg daily by week 41.His urine proteintocreatinineratiodecreasedfrom 1.720 to 0.575, andserumalbuminnormalizedbyweek 53. At that time, due to the patient’s up-trending proteinuria after a URI, as well as concerns for injection site skin reaction and quality of life on daily subcutaneous treatment, anakinra was substituted with subcutaneous adalimumab 20 mg every 2 weeks.

By week 80,the patient’s urineproteintocreatininerationormalized (< 0.2). Thiswasfollowedbynormalizedurine microalbumintocreatinineratio, andbyweek 130 hismicroscopichematuriaresolved. While onadalimumab, heremainedwellandwasabletomountan immune response to viralinfectionsuneventfully,including COVID-19. He tolerated agradual wean of adalimumab to every 3 weeks by week 139 and discontinuation at week 151. At week 204, the patient has normal renal function and urine findings; his growth parameters are at 20.3 percentile for weight and 15.3percentile for height.

 

 

DISCUSSION

This case describes a child with rapidly progressive proteinuria and hematuria following a URI who was found to have VUS mutations in 3 different genes associated with chronic kidney disease. Serology tests on the patient were negative for streptococcal antibodies and antinuclear antibodies, ruling out poststreptococcal glomerulonephritis, or systemic lupus erythematosus. His renal biopsy findings were concerning for altered podocytes, mesangial cells, and basement membrane without inflammatory infiltrate, immune complex, complements, immunoglobulin A, or vasculopathy. His blood inflammatory markers, erythrocyte sedimentation rate, C-reactive protein, and ferritin were normal when his care team initiated daily steroids.

Overall, the patient’s clinical presentation and histopathology findings were suggestive of Alport syndrome or thin basement membrane nephropathy with a high potential to progress into FSGS.10-12 Alport syndrome affects 1 in 5000 to 10,000 children annually due to S-linked inheritance of COL4A5, or autosomal recessive inheritance of COL4A3 or COL4A4 genes. It presents with hematuria and hearing loss.10 Our patient had a single copy COL4A4 gene mutation that was classified as VUS. He also had 2 additional VUS affecting the TRPC6 and OSGEP genes. TRPC6 gene mutation can be associated with FSGS through autosomal dominant inheritance. Both COL4A4 and TRPC6 gene mutations were paternally inherited. Although the patient’s father not having renal disease argues against the clinical significance of these findings, there is literature on the potential role of heterozygous COL4A4 variant mimicking thin basement membrane nephropathy that can lead to renal impairment upon copresence of superimposed conditions.13 The patient’s rapidly progressing hematuria and changes in the basement membrane were worrisome for emerging FSGS. Furthermore, VUS of TRPC6 has been reported in late onset autosomal dominant FSGS and can be associated with early onset steroid-resistant nephrotic syndrome (NS) in children.14 This concern was voiced by 3 nephrology consultants during the initial evaluation, leading to the consensus that steroid treatment for podocytopathy would not alter the patient’s long-term outcomes (ie, progression to FSGS).

 

Immunomodulation

Our rationale for immunomodulatory treatment was based on the abrupt onset of renal concerns following a URI, suggesting the importance of an inflammatory trigger causing altered homeostasis in a genetically susceptible host. Preclinical models show that microbial products such as lipopolysaccharides can lead to podocytopathy by several mechanisms through activation of toll-like receptor signaling. It can directly cause apoptosis by downregulation of the intracellular Akt survival pathway.15 Lipopolysaccharide can also activate the NF-αB pathway and upregulate the production of interleukin-1 (IL-1) and TNF-α in mesangial cells.16,17

Both cytokines can promote mesangial cell proliferation.18 Through autocrine and paracrine mechanisms, proinflammatory cytokines can further perpetuate somatic tissue changes and contribute to the development of podocytopathy. For instance, TNF-α can promote podocyte injury and proteinuria by downregulation of the slit diaphragm protein expression (ie, nephrin, ezrin, or podocin), and disruption of podocyte cytoskeleton.19,20 TNF-α promotes the influx and activation of macrophages and inflammatory cells. It is actively involved in chronic alterations within the glomeruli by the upregulation of matrix metalloproteases by integrins, as well as activation of myofibroblast progenitors and extracellular matrix deposition in crosstalk with transforming growth factor and other key mediators.17,21,22

For the patient described in this case report, initial improvement on steroids encouraged the pursuit of additional treatment to downregulate inflammatory pathways within the glomerular milieu. However, within the COVID-19 environment, escalating the patient’s treatment using traditional immunomodulators (ie, calcineurin inhibitors or mycophenolate mofetil) was not favored due to the risk of infection. Initially, anakinra, a recombinant IL-1 receptor antagonist, was preferred as a steroid-sparing agent for its short life and safety profile during the pandemic. At first, the patient responded well to anakinra and was allowed a steroid wean when the dose was titrated up to 6 mg/kg daily. However, anakinra did not prevent the escalation of proteinuria following a URI. After the treatment was changed to adalimumab, a fully humanized monoclonal antibody to TNF-α, the patient continued to improve and reach full remission despite experiencing a cold and the flu in the following months.

 

 

Literature Review

There is a paucity of literature on applications of biological response modifiers for idiopathic NS and FSGS.23,24 Angeletti and colleagues reported that 3 patients with severe long-standing FSGS benefited from anakinra 4 mg/kg daily to reduce proteinuria and improve kidney function. All the patients had positive C3 staining in renal biopsy and treatment response, which supported the role of C3a in inducing podocyte injury through upregulated expression of IL-1 and IL-1R.23 Trachtman and colleagues reported on the phase II FONT trial that included 14 of 21 patients aged < 18 years with advanced FSGS who were treated with adalimumab 24 mg/m2, or ≤ 40 mg every other week.24 Although, during a 6-month period, none of the 7 patients met the endpoint of reduced proteinuria by ≥ 50%, and the authors suggested that careful patient selection may improve the treatment response in future trials.24

A recent study involving transcriptomics on renal tissue samples combined with available pathology (fibrosis), urinary markers, and clinical characteristics on 285 patients with MCD or FSGS from 3 different continents identified 3 distinct clusters. Patients with evidence of activated kidney TNF pathway (n = 72, aged > 18 years) were found to have poor clinical outcomes.25 The study identified 2 urine markers associated with the TNF pathway (ie, tissue inhibitor of metalloproteinases-1 and monocyte chemoattractant protein-1), which aligns with the preclinical findings previously mentioned.25

 

Conclusions

The patient’s condition in this case illustrates the complex nature of biologically predetermined cascading events in the emergence of glomerular disease upon environmental triggers under the influence of genetic factors. Observations on this child’s treatment response suggest that downregulation of somatic tissue-driven proinflammatory milieu originating from the constituents of glomerular microenvironment can help in recovery from emerging podocytopathy. The prolonged time span and stepwise resolution of proteinuria, followed by microalbuminuria (data not shown), and finally microscopic hematuria, supports the delicate balance and presence of reciprocal feedback loops between the podocytes and mesangial cells. Within this framework, blocking TNF-α, even temporarily, may allow time for the de novo regenerative process to prevail.

Chronic kidney disease affects 7.7% of veterans annually, illustrating the need for new therapeutics.26 Based on our experience and literature review, upregulation of TNF-α is a root cause of glomerulopathy; further studies are warranted to evaluate the efficacy of anti-TNF biologic response modifiers for the treatment of these patients. Long-term postmarketing safety profile and steroid-sparing properties of adalimumab should allow inclusion of pediatric cases in future trials. Results may also contribute to identifying new predictive biomarkers related to the basement membrane when combined with precision nephrology to further advance patient selection and targeted treatment.25,27

Acknowledgments

The authors thank the patient’s mother for providing consent to allow publication of this case report.

References

1. Arif E, Nihalani D. Glomerular filtration barrier assembly: an insight. Postdoc J. 2013;1(4):33-45.

2. Garg PA. Review of podocyte biology. Am J Nephrol. 2018;47(suppl 1):3-13. doi:10.1159/000481633SUPPL

3. Warady BA, Agarwal R, Bangalore S, et al. Alport syndrome classification and management. Kidney Med. 2020;2(5):639-649. doi:10.1016/j.xkme.2020.05.014

4. Angioi A, Pani A. FSGS: from pathogenesis to the histological lesion. J Nephrol. 2016;29(4):517-523. doi:10.1007/s40620-016-0333-2

5. Roca N, Martinez C, Jatem E, Madrid A, Lopez M, Segarra A. Activation of the acute inflammatory phase response in idiopathic nephrotic syndrome: association with clinicopathological phenotypes and with response to corticosteroids. Clin Kidney J. 2021;14(4):1207-1215. doi:10.1093/ckj/sfaa247

6. Vivarelli M, Massella L, Ruggiero B, Emma F. Minimal change disease. Clin J Am Soc Nephrol. 2017;12(2):332-345.

7. Medjeral-Thomas NR, Lawrence C, Condon M, et al. Randomized, controlled trial of tacrolimus and prednisolone monotherapy for adults with De Novo minimal change disease: a multicenter, randomized, controlled trial. Clin J Am Soc Nephrol. 2020;15(2):209-218. doi:10.2215/CJN.06290420

8. Ye Q, Lan B, Liu H, Persson PB, Lai EY, Mao J. A critical role of the podocyte cytoskeleton in the pathogenesis of glomerular proteinuria and autoimmune podocytopathies. Acta Physiol (Oxf). 2022;235(4):e13850. doi:10.1111/apha.13850

9. Trautmann A, Schnaidt S, Lipska-Ziμtkiewicz BS, et al. Long-term outcome of steroid-resistant nephrotic syndrome in children. J Am Soc Nephrol. 2017;28:3055-3065. doi:10.1681/ASN.2016101121

10. Kashtan CE, Gross O. Clinical practice recommendations for the diagnosis and management of Alport syndrome in children, adolescents, and young adults-an update for 2020. Pediatr Nephrol. 2021;36(3):711-719. doi:10.1007/s00467-020-04819-6

11. Savige J, Rana K, Tonna S, Buzza M, Dagher H, Wang YY. Thin basement membrane nephropathy. Kidney Int. 2003;64(4):1169-78. doi:10.1046/j.1523-1755.2003.00234.x

12. Rosenberg AZ, Kopp JB. Focal segmental glomerulosclerosis. Clin J Am Soc Nephrol. 2017; 12(3):502-517. doi:10.2215/CJN.05960616

13. Savige J. Should we diagnose autosomal dominant Alport syndrome when there is a pathogenic heterozygous COL4A3 or COL4A4 variant? Kidney Int Rep. 2018;3(6):1239-1241. doi:10.1016/j.ekir.2018.08.002

14. Gigante M, Caridi G, Montemurno E, et al. TRPC6 mutations in children with steroid-resistant nephrotic syndrome and atypical phenotype. Clin J Am Soc Nephrol. 2011;6(7):1626-1634. doi:10.2215/CJN.07830910

15. Saurus P, Kuusela S, Lehtonen E, et al. Podocyte apoptosis is prevented by blocking the toll-like receptor pathway. Cell Death Dis. 2015;6(5):e1752. doi:10.1038/cddis.2015.125

16. Baud L, Oudinet JP, Bens M, et al. Production of tumor necrosis factor by rat mesangial cells in response to bacterial lipopolysaccharide. Kidney Int. 1989;35(5):1111-1118. doi:10.1038/ki.1989.98

17. White S, Lin L, Hu K. NF-κB and tPA signaling in kidney and other diseases. Cells. 2020;9(6):1348. doi:10.3390/cells9061348

18. Tesch GH, Lan HY, Atkins RC, Nikolic-Paterson DJ. Role of interleukin-1 in mesangial cell proliferation and matrix deposition in experimental mesangioproliferative nephritis. Am J Pathol. 1997;151(1):141-150.

19. Lai KN, Leung JCK, Chan LYY, et al. Podocyte injury induced by mesangial-derived cytokines in IgA Nephropathy. Nephrol Dial Transplant. 2009;24(1):62-72. doi:10.1093/ndt/gfn441

20. Saleem MA, Kobayashi Y. Cell biology and genetics of minimal change disease. F1000 Res. 2016;5: F1000 Faculty Rev-412. doi:10.12688/f1000research.7300.1

21. Kim KP, Williams CE, Lemmon CA. Cell-matrix interactions in renal fibrosis. Kidney Dial. 2022;2(4):607-624. doi:10.3390/kidneydial2040055

22. Zvaifler NJ. Relevance of the stroma and epithelial-mesenchymal transition (EMT) for the rheumatic diseases. Arthritis Res Ther. 2006;8(3):210. doi:10.1186/ar1963

23. Angeletti A, Magnasco A, Trivelli A, et al. Refractory minimal change disease and focal segmental glomerular sclerosis treated with Anakinra. Kidney Int Rep. 2021;7(1):121-124. doi:10.1016/j.ekir.2021.10.018

24. Trachtman H, Vento S, Herreshoff E, et al. Efficacy of galactose and adalimumab in patients with resistant focal segmental glomerulosclerosis: report of the font clinical trial group. BMC Nephrol. 2015;16:111. doi:10.1186/s12882-015-0094-5

25. Mariani LH, Eddy S, AlAkwaa FM, et al. Precision nephrology identified tumor necrosis factor activation variability in minimal change disease and focal segmental glomerulosclerosis. Kidney Int. 2023;103(3):565-579. doi:10.1016/j.kint.2022.10.023

26. Korshak L, Washington DL, Powell J, Nylen E, Kokkinos P. Kidney Disease in Veterans. US Dept of Veterans Affairs, Office of Health Equity. Updated May 13, 2020. Accessed June 28, 2024. https://www.va.gov/HEALTHEQUITY/Kidney_Disease_In_Veterans.asp

27. Malone AF, Phelan PJ, Hall G, et al. Rare hereditary COL4A3/COL4A4 variants may be mistaken for familial focal segmental glomerulosclerosis. Kidney Int. 2014;86(6):1253-1259. doi:10.1038/ki.2014.305

References

1. Arif E, Nihalani D. Glomerular filtration barrier assembly: an insight. Postdoc J. 2013;1(4):33-45.

2. Garg PA. Review of podocyte biology. Am J Nephrol. 2018;47(suppl 1):3-13. doi:10.1159/000481633SUPPL

3. Warady BA, Agarwal R, Bangalore S, et al. Alport syndrome classification and management. Kidney Med. 2020;2(5):639-649. doi:10.1016/j.xkme.2020.05.014

4. Angioi A, Pani A. FSGS: from pathogenesis to the histological lesion. J Nephrol. 2016;29(4):517-523. doi:10.1007/s40620-016-0333-2

5. Roca N, Martinez C, Jatem E, Madrid A, Lopez M, Segarra A. Activation of the acute inflammatory phase response in idiopathic nephrotic syndrome: association with clinicopathological phenotypes and with response to corticosteroids. Clin Kidney J. 2021;14(4):1207-1215. doi:10.1093/ckj/sfaa247

6. Vivarelli M, Massella L, Ruggiero B, Emma F. Minimal change disease. Clin J Am Soc Nephrol. 2017;12(2):332-345.

7. Medjeral-Thomas NR, Lawrence C, Condon M, et al. Randomized, controlled trial of tacrolimus and prednisolone monotherapy for adults with De Novo minimal change disease: a multicenter, randomized, controlled trial. Clin J Am Soc Nephrol. 2020;15(2):209-218. doi:10.2215/CJN.06290420

8. Ye Q, Lan B, Liu H, Persson PB, Lai EY, Mao J. A critical role of the podocyte cytoskeleton in the pathogenesis of glomerular proteinuria and autoimmune podocytopathies. Acta Physiol (Oxf). 2022;235(4):e13850. doi:10.1111/apha.13850

9. Trautmann A, Schnaidt S, Lipska-Ziμtkiewicz BS, et al. Long-term outcome of steroid-resistant nephrotic syndrome in children. J Am Soc Nephrol. 2017;28:3055-3065. doi:10.1681/ASN.2016101121

10. Kashtan CE, Gross O. Clinical practice recommendations for the diagnosis and management of Alport syndrome in children, adolescents, and young adults-an update for 2020. Pediatr Nephrol. 2021;36(3):711-719. doi:10.1007/s00467-020-04819-6

11. Savige J, Rana K, Tonna S, Buzza M, Dagher H, Wang YY. Thin basement membrane nephropathy. Kidney Int. 2003;64(4):1169-78. doi:10.1046/j.1523-1755.2003.00234.x

12. Rosenberg AZ, Kopp JB. Focal segmental glomerulosclerosis. Clin J Am Soc Nephrol. 2017; 12(3):502-517. doi:10.2215/CJN.05960616

13. Savige J. Should we diagnose autosomal dominant Alport syndrome when there is a pathogenic heterozygous COL4A3 or COL4A4 variant? Kidney Int Rep. 2018;3(6):1239-1241. doi:10.1016/j.ekir.2018.08.002

14. Gigante M, Caridi G, Montemurno E, et al. TRPC6 mutations in children with steroid-resistant nephrotic syndrome and atypical phenotype. Clin J Am Soc Nephrol. 2011;6(7):1626-1634. doi:10.2215/CJN.07830910

15. Saurus P, Kuusela S, Lehtonen E, et al. Podocyte apoptosis is prevented by blocking the toll-like receptor pathway. Cell Death Dis. 2015;6(5):e1752. doi:10.1038/cddis.2015.125

16. Baud L, Oudinet JP, Bens M, et al. Production of tumor necrosis factor by rat mesangial cells in response to bacterial lipopolysaccharide. Kidney Int. 1989;35(5):1111-1118. doi:10.1038/ki.1989.98

17. White S, Lin L, Hu K. NF-κB and tPA signaling in kidney and other diseases. Cells. 2020;9(6):1348. doi:10.3390/cells9061348

18. Tesch GH, Lan HY, Atkins RC, Nikolic-Paterson DJ. Role of interleukin-1 in mesangial cell proliferation and matrix deposition in experimental mesangioproliferative nephritis. Am J Pathol. 1997;151(1):141-150.

19. Lai KN, Leung JCK, Chan LYY, et al. Podocyte injury induced by mesangial-derived cytokines in IgA Nephropathy. Nephrol Dial Transplant. 2009;24(1):62-72. doi:10.1093/ndt/gfn441

20. Saleem MA, Kobayashi Y. Cell biology and genetics of minimal change disease. F1000 Res. 2016;5: F1000 Faculty Rev-412. doi:10.12688/f1000research.7300.1

21. Kim KP, Williams CE, Lemmon CA. Cell-matrix interactions in renal fibrosis. Kidney Dial. 2022;2(4):607-624. doi:10.3390/kidneydial2040055

22. Zvaifler NJ. Relevance of the stroma and epithelial-mesenchymal transition (EMT) for the rheumatic diseases. Arthritis Res Ther. 2006;8(3):210. doi:10.1186/ar1963

23. Angeletti A, Magnasco A, Trivelli A, et al. Refractory minimal change disease and focal segmental glomerular sclerosis treated with Anakinra. Kidney Int Rep. 2021;7(1):121-124. doi:10.1016/j.ekir.2021.10.018

24. Trachtman H, Vento S, Herreshoff E, et al. Efficacy of galactose and adalimumab in patients with resistant focal segmental glomerulosclerosis: report of the font clinical trial group. BMC Nephrol. 2015;16:111. doi:10.1186/s12882-015-0094-5

25. Mariani LH, Eddy S, AlAkwaa FM, et al. Precision nephrology identified tumor necrosis factor activation variability in minimal change disease and focal segmental glomerulosclerosis. Kidney Int. 2023;103(3):565-579. doi:10.1016/j.kint.2022.10.023

26. Korshak L, Washington DL, Powell J, Nylen E, Kokkinos P. Kidney Disease in Veterans. US Dept of Veterans Affairs, Office of Health Equity. Updated May 13, 2020. Accessed June 28, 2024. https://www.va.gov/HEALTHEQUITY/Kidney_Disease_In_Veterans.asp

27. Malone AF, Phelan PJ, Hall G, et al. Rare hereditary COL4A3/COL4A4 variants may be mistaken for familial focal segmental glomerulosclerosis. Kidney Int. 2014;86(6):1253-1259. doi:10.1038/ki.2014.305

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Intensive BP Control May Benefit CKD Patients in Real World

Article Type
News
Changed
Wed, 01/08/2025 - 15:04
Author(s)
Shrabasti Bhattacharya

TOPLINE:

The cardiovascular benefits observed with intensive blood pressure (BP) control in patients with hypertension and elevated cardiovascular risk from the Systolic Blood Pressure Intervention Trial (SPRINT) can be largely replicated in real-world settings among patients with chronic kidney disease (CKD), highlighting the advantages of adopting intensive BP targets.
 

METHODOLOGY:

  • The SPRINT showed that an intensive systolic BP goal < 120 mm Hg reduced mortality, cardiovascular events, and mild cognitive impairment in patients with hypertension and elevated cardiovascular risk, including in patients with CKD.
  • Researchers conducted a comparative effectiveness study to determine if the beneficial and adverse effects of intensive vs standard BP control observed in SPRINT were replicable in patients with CKD and hypertension in clinical practice.
  • They identified 85,938 patients (mean age, 75.7 years; 95.0% men) and 13,983 patients (mean age, 77.4 years; 38.4% men) from the Veterans Health Administration (VHA) and Kaiser Permanente of Southern California (KPSC) databases, respectively.
  • The treatment effect was estimated by combining baseline covariate, treatment, and outcome data of participants from the SPRINT with covariate data from the VHA and KPSC databases.
  • The primary outcomes included major cardiovascular events, all-cause death, cognitive impairment, CKD progression, and adverse events at 4 years.

TAKEAWAY:

  • Compared with SPRINT participants, those in the VHA and KPSC databases were older, had less prevalent cardiovascular disease, higher albuminuria, and used more statins.
  • The benefits of intensive vs standard BP control on major cardiovascular events, all-cause mortality, and certain adverse events (hypotension, syncope, bradycardia, acute kidney injury, and electrolyte abnormality) were transferable from the trial to the VHA and KPSC populations.
  • The treatment effect of intensive BP management on CKD progression was transportable to the KPSC population but not to the VHA population. However, the trial’s impact on cognitive outcomes, such as dementia, was not transportable to either the VHA or KPSC populations.
  • On the absolute scale, intensive vs standard BP treatment showed greater cardiovascular benefits and fewer safety concerns in the VHA and KPSC populations than in the SPRINT.

IN PRACTICE:

“This example highlights the potential for transportability methods to provide insights that can bridge evidence gaps and inform the application of novel therapies to patients with CKD who are treated in everyday practice,” the authors wrote.
 

SOURCE:

This study was led by Manjula Kurella Tamura, MD, MPH, Division of Nephrology, Department of Medicine, Stanford University School of Medicine, Palo Alto, California. It was published online on January 7, 2025, in JAMA Network Open.
 

LIMITATIONS:

Transportability analyses could not account for characteristics that were not well-documented in electronic health records, such as limited life expectancy. The study was conducted before the widespread use of sodium-glucose cotransporter 2 inhibitors, glucagon-like peptide 1 receptor agonists, and nonsteroidal mineralocorticoid receptor antagonists, making it unclear whether intensive BP treatment would result in similar benefits with current pharmacotherapy regimens. Eligibility for this study was based on BP measurements in routine practice, which tend to be more variable than those collected in research settings.
 

DISCLOSURES:

This study was supported by grants from the National Institutes of Health. Some authors disclosed serving as a consultant and receiving grants, personal fees, and consulting fees from pharmaceutical companies and other sources.
 

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

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Author(s)
Shrabasti Bhattacharya
Author(s)
Shrabasti Bhattacharya

TOPLINE:

The cardiovascular benefits observed with intensive blood pressure (BP) control in patients with hypertension and elevated cardiovascular risk from the Systolic Blood Pressure Intervention Trial (SPRINT) can be largely replicated in real-world settings among patients with chronic kidney disease (CKD), highlighting the advantages of adopting intensive BP targets.
 

METHODOLOGY:

  • The SPRINT showed that an intensive systolic BP goal < 120 mm Hg reduced mortality, cardiovascular events, and mild cognitive impairment in patients with hypertension and elevated cardiovascular risk, including in patients with CKD.
  • Researchers conducted a comparative effectiveness study to determine if the beneficial and adverse effects of intensive vs standard BP control observed in SPRINT were replicable in patients with CKD and hypertension in clinical practice.
  • They identified 85,938 patients (mean age, 75.7 years; 95.0% men) and 13,983 patients (mean age, 77.4 years; 38.4% men) from the Veterans Health Administration (VHA) and Kaiser Permanente of Southern California (KPSC) databases, respectively.
  • The treatment effect was estimated by combining baseline covariate, treatment, and outcome data of participants from the SPRINT with covariate data from the VHA and KPSC databases.
  • The primary outcomes included major cardiovascular events, all-cause death, cognitive impairment, CKD progression, and adverse events at 4 years.

TAKEAWAY:

  • Compared with SPRINT participants, those in the VHA and KPSC databases were older, had less prevalent cardiovascular disease, higher albuminuria, and used more statins.
  • The benefits of intensive vs standard BP control on major cardiovascular events, all-cause mortality, and certain adverse events (hypotension, syncope, bradycardia, acute kidney injury, and electrolyte abnormality) were transferable from the trial to the VHA and KPSC populations.
  • The treatment effect of intensive BP management on CKD progression was transportable to the KPSC population but not to the VHA population. However, the trial’s impact on cognitive outcomes, such as dementia, was not transportable to either the VHA or KPSC populations.
  • On the absolute scale, intensive vs standard BP treatment showed greater cardiovascular benefits and fewer safety concerns in the VHA and KPSC populations than in the SPRINT.

IN PRACTICE:

“This example highlights the potential for transportability methods to provide insights that can bridge evidence gaps and inform the application of novel therapies to patients with CKD who are treated in everyday practice,” the authors wrote.
 

SOURCE:

This study was led by Manjula Kurella Tamura, MD, MPH, Division of Nephrology, Department of Medicine, Stanford University School of Medicine, Palo Alto, California. It was published online on January 7, 2025, in JAMA Network Open.
 

LIMITATIONS:

Transportability analyses could not account for characteristics that were not well-documented in electronic health records, such as limited life expectancy. The study was conducted before the widespread use of sodium-glucose cotransporter 2 inhibitors, glucagon-like peptide 1 receptor agonists, and nonsteroidal mineralocorticoid receptor antagonists, making it unclear whether intensive BP treatment would result in similar benefits with current pharmacotherapy regimens. Eligibility for this study was based on BP measurements in routine practice, which tend to be more variable than those collected in research settings.
 

DISCLOSURES:

This study was supported by grants from the National Institutes of Health. Some authors disclosed serving as a consultant and receiving grants, personal fees, and consulting fees from pharmaceutical companies and other sources.
 

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

TOPLINE:

The cardiovascular benefits observed with intensive blood pressure (BP) control in patients with hypertension and elevated cardiovascular risk from the Systolic Blood Pressure Intervention Trial (SPRINT) can be largely replicated in real-world settings among patients with chronic kidney disease (CKD), highlighting the advantages of adopting intensive BP targets.
 

METHODOLOGY:

  • The SPRINT showed that an intensive systolic BP goal < 120 mm Hg reduced mortality, cardiovascular events, and mild cognitive impairment in patients with hypertension and elevated cardiovascular risk, including in patients with CKD.
  • Researchers conducted a comparative effectiveness study to determine if the beneficial and adverse effects of intensive vs standard BP control observed in SPRINT were replicable in patients with CKD and hypertension in clinical practice.
  • They identified 85,938 patients (mean age, 75.7 years; 95.0% men) and 13,983 patients (mean age, 77.4 years; 38.4% men) from the Veterans Health Administration (VHA) and Kaiser Permanente of Southern California (KPSC) databases, respectively.
  • The treatment effect was estimated by combining baseline covariate, treatment, and outcome data of participants from the SPRINT with covariate data from the VHA and KPSC databases.
  • The primary outcomes included major cardiovascular events, all-cause death, cognitive impairment, CKD progression, and adverse events at 4 years.

TAKEAWAY:

  • Compared with SPRINT participants, those in the VHA and KPSC databases were older, had less prevalent cardiovascular disease, higher albuminuria, and used more statins.
  • The benefits of intensive vs standard BP control on major cardiovascular events, all-cause mortality, and certain adverse events (hypotension, syncope, bradycardia, acute kidney injury, and electrolyte abnormality) were transferable from the trial to the VHA and KPSC populations.
  • The treatment effect of intensive BP management on CKD progression was transportable to the KPSC population but not to the VHA population. However, the trial’s impact on cognitive outcomes, such as dementia, was not transportable to either the VHA or KPSC populations.
  • On the absolute scale, intensive vs standard BP treatment showed greater cardiovascular benefits and fewer safety concerns in the VHA and KPSC populations than in the SPRINT.

IN PRACTICE:

“This example highlights the potential for transportability methods to provide insights that can bridge evidence gaps and inform the application of novel therapies to patients with CKD who are treated in everyday practice,” the authors wrote.
 

SOURCE:

This study was led by Manjula Kurella Tamura, MD, MPH, Division of Nephrology, Department of Medicine, Stanford University School of Medicine, Palo Alto, California. It was published online on January 7, 2025, in JAMA Network Open.
 

LIMITATIONS:

Transportability analyses could not account for characteristics that were not well-documented in electronic health records, such as limited life expectancy. The study was conducted before the widespread use of sodium-glucose cotransporter 2 inhibitors, glucagon-like peptide 1 receptor agonists, and nonsteroidal mineralocorticoid receptor antagonists, making it unclear whether intensive BP treatment would result in similar benefits with current pharmacotherapy regimens. Eligibility for this study was based on BP measurements in routine practice, which tend to be more variable than those collected in research settings.
 

DISCLOSURES:

This study was supported by grants from the National Institutes of Health. Some authors disclosed serving as a consultant and receiving grants, personal fees, and consulting fees from pharmaceutical companies and other sources.
 

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

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Lowering Urate May Protect Kidneys in Gout Patients With CKD

Article Type
News
Changed
Fri, 12/20/2024 - 13:16
Author(s)
Manasi Talwadekar

TOPLINE:

Achieving serum urate to below 6 mg/dL with urate-lowering therapy (ULT) in patients with gout and chronic kidney disease (CKD) stage III is not linked to an increased risk for severe or end-stage kidney disease.

METHODOLOGY:

  • Researchers emulated analyses of a hypothetical target trial using a cloning, censoring, and weighting approach to evaluate the association between achieving target serum urate level with ULT and the progression of CKD in patients with gout and CKD stage III.
  • They included 14,972 patients (mean age, 73.1 years; 37.7% women) from a general practice database who had a mean baseline serum urate level of 8.9 mg/dL and initiated ULTs such as allopurinol or febuxostat.
  • Participants were divided into two groups: Those who achieved a target serum urate level < 6 mg/dL and those who did not within 1 year after the initiation of ULT; the mean follow-up duration was a little more than 3 years in both groups.
  • The primary outcome was the occurrence of severe or end-stage kidney disease over 5 years of initiating ULT, defined by an estimated glomerular filtration rate below 30 mL/min per 1.73 m2 on two occasions more than 90 days apart within 1 year, or at least one Read code for CKD stages IV or V, dialysis, or kidney transplant.
  • A prespecified noninferiority margin for the hazard ratio was set at 1.2 to compare the outcomes between those who achieved the target serum urate level < 6 mg/dL and those who did not.

TAKEAWAY:

  • Among the patients who initiated ULT, 31.8% achieved a target serum urate level < 6 mg/dL within 1 year.
  • The 5-year risk for severe or end-stage kidney disease was lower (10.32%) in participants with gout and stage III CKD who achieved the target serum urate level than in those who did not (12.73%).
  • The adjusted 5-year risk difference for severe to end-stage kidney disease was not inferior in patients who achieved the target serum urate level vs those who did not (adjusted hazard ratio [aHR], 0.89; 95% CI, 0.80-0.98; P for noninferiority < .001); results were consistent for end-stage kidney disease alone (aHR, 0.67; P for noninferiority = .001).
  • Similarly, in participants with gout and CKD stages II-III, the 5-year risks for severe or end-stage kidney disease (aHR, 0.91) and end-stage kidney disease alone (aHR, 0.73) were noninferior in the group that did vs that did not achieve target serum urate levels, with P for noninferiority being < .001 and .003, respectively.

IN PRACTICE:

“Our findings suggest that lowering serum urate levels to < 6 mg/dL is generally well tolerated and may even slow CKD progression in these individuals. Initiatives to optimize the use and adherence to ULT could benefit clinicians and patients,” the authors wrote.

SOURCE:

This study was led by Yilun Wang, MD, PhD, Xiangya Hospital, Central South University, Changsha, China. It was published online in JAMA Internal Medicine.

LIMITATIONS:

Residual confounding may still have been present despite rigorous methods to control it, as is common in observational studies. Participants who achieved target serum urate levels may have received better healthcare, adhered to other treatments more consistently, and used ULT for a longer duration. The findings may have limited generalizability, as participants who did not achieve target serum urate levels prior to initiation were excluded.

DISCLOSURES:

This study was supported by the China National Key Research and Development Plan, the National Natural Science Foundation of China, the Project Program of the National Clinical Research Center for Geriatric Disorders, and other sources. Two authors reported receiving personal fees and/or grants from multiple pharmaceutical companies.

This article was created using several editorial tools, including artificial intelligence, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

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Author(s)
Manasi Talwadekar
Author(s)
Manasi Talwadekar

TOPLINE:

Achieving serum urate to below 6 mg/dL with urate-lowering therapy (ULT) in patients with gout and chronic kidney disease (CKD) stage III is not linked to an increased risk for severe or end-stage kidney disease.

METHODOLOGY:

  • Researchers emulated analyses of a hypothetical target trial using a cloning, censoring, and weighting approach to evaluate the association between achieving target serum urate level with ULT and the progression of CKD in patients with gout and CKD stage III.
  • They included 14,972 patients (mean age, 73.1 years; 37.7% women) from a general practice database who had a mean baseline serum urate level of 8.9 mg/dL and initiated ULTs such as allopurinol or febuxostat.
  • Participants were divided into two groups: Those who achieved a target serum urate level < 6 mg/dL and those who did not within 1 year after the initiation of ULT; the mean follow-up duration was a little more than 3 years in both groups.
  • The primary outcome was the occurrence of severe or end-stage kidney disease over 5 years of initiating ULT, defined by an estimated glomerular filtration rate below 30 mL/min per 1.73 m2 on two occasions more than 90 days apart within 1 year, or at least one Read code for CKD stages IV or V, dialysis, or kidney transplant.
  • A prespecified noninferiority margin for the hazard ratio was set at 1.2 to compare the outcomes between those who achieved the target serum urate level < 6 mg/dL and those who did not.

TAKEAWAY:

  • Among the patients who initiated ULT, 31.8% achieved a target serum urate level < 6 mg/dL within 1 year.
  • The 5-year risk for severe or end-stage kidney disease was lower (10.32%) in participants with gout and stage III CKD who achieved the target serum urate level than in those who did not (12.73%).
  • The adjusted 5-year risk difference for severe to end-stage kidney disease was not inferior in patients who achieved the target serum urate level vs those who did not (adjusted hazard ratio [aHR], 0.89; 95% CI, 0.80-0.98; P for noninferiority < .001); results were consistent for end-stage kidney disease alone (aHR, 0.67; P for noninferiority = .001).
  • Similarly, in participants with gout and CKD stages II-III, the 5-year risks for severe or end-stage kidney disease (aHR, 0.91) and end-stage kidney disease alone (aHR, 0.73) were noninferior in the group that did vs that did not achieve target serum urate levels, with P for noninferiority being < .001 and .003, respectively.

IN PRACTICE:

“Our findings suggest that lowering serum urate levels to < 6 mg/dL is generally well tolerated and may even slow CKD progression in these individuals. Initiatives to optimize the use and adherence to ULT could benefit clinicians and patients,” the authors wrote.

SOURCE:

This study was led by Yilun Wang, MD, PhD, Xiangya Hospital, Central South University, Changsha, China. It was published online in JAMA Internal Medicine.

LIMITATIONS:

Residual confounding may still have been present despite rigorous methods to control it, as is common in observational studies. Participants who achieved target serum urate levels may have received better healthcare, adhered to other treatments more consistently, and used ULT for a longer duration. The findings may have limited generalizability, as participants who did not achieve target serum urate levels prior to initiation were excluded.

DISCLOSURES:

This study was supported by the China National Key Research and Development Plan, the National Natural Science Foundation of China, the Project Program of the National Clinical Research Center for Geriatric Disorders, and other sources. Two authors reported receiving personal fees and/or grants from multiple pharmaceutical companies.

This article was created using several editorial tools, including artificial intelligence, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

TOPLINE:

Achieving serum urate to below 6 mg/dL with urate-lowering therapy (ULT) in patients with gout and chronic kidney disease (CKD) stage III is not linked to an increased risk for severe or end-stage kidney disease.

METHODOLOGY:

  • Researchers emulated analyses of a hypothetical target trial using a cloning, censoring, and weighting approach to evaluate the association between achieving target serum urate level with ULT and the progression of CKD in patients with gout and CKD stage III.
  • They included 14,972 patients (mean age, 73.1 years; 37.7% women) from a general practice database who had a mean baseline serum urate level of 8.9 mg/dL and initiated ULTs such as allopurinol or febuxostat.
  • Participants were divided into two groups: Those who achieved a target serum urate level < 6 mg/dL and those who did not within 1 year after the initiation of ULT; the mean follow-up duration was a little more than 3 years in both groups.
  • The primary outcome was the occurrence of severe or end-stage kidney disease over 5 years of initiating ULT, defined by an estimated glomerular filtration rate below 30 mL/min per 1.73 m2 on two occasions more than 90 days apart within 1 year, or at least one Read code for CKD stages IV or V, dialysis, or kidney transplant.
  • A prespecified noninferiority margin for the hazard ratio was set at 1.2 to compare the outcomes between those who achieved the target serum urate level < 6 mg/dL and those who did not.

TAKEAWAY:

  • Among the patients who initiated ULT, 31.8% achieved a target serum urate level < 6 mg/dL within 1 year.
  • The 5-year risk for severe or end-stage kidney disease was lower (10.32%) in participants with gout and stage III CKD who achieved the target serum urate level than in those who did not (12.73%).
  • The adjusted 5-year risk difference for severe to end-stage kidney disease was not inferior in patients who achieved the target serum urate level vs those who did not (adjusted hazard ratio [aHR], 0.89; 95% CI, 0.80-0.98; P for noninferiority < .001); results were consistent for end-stage kidney disease alone (aHR, 0.67; P for noninferiority = .001).
  • Similarly, in participants with gout and CKD stages II-III, the 5-year risks for severe or end-stage kidney disease (aHR, 0.91) and end-stage kidney disease alone (aHR, 0.73) were noninferior in the group that did vs that did not achieve target serum urate levels, with P for noninferiority being < .001 and .003, respectively.

IN PRACTICE:

“Our findings suggest that lowering serum urate levels to < 6 mg/dL is generally well tolerated and may even slow CKD progression in these individuals. Initiatives to optimize the use and adherence to ULT could benefit clinicians and patients,” the authors wrote.

SOURCE:

This study was led by Yilun Wang, MD, PhD, Xiangya Hospital, Central South University, Changsha, China. It was published online in JAMA Internal Medicine.

LIMITATIONS:

Residual confounding may still have been present despite rigorous methods to control it, as is common in observational studies. Participants who achieved target serum urate levels may have received better healthcare, adhered to other treatments more consistently, and used ULT for a longer duration. The findings may have limited generalizability, as participants who did not achieve target serum urate levels prior to initiation were excluded.

DISCLOSURES:

This study was supported by the China National Key Research and Development Plan, the National Natural Science Foundation of China, the Project Program of the National Clinical Research Center for Geriatric Disorders, and other sources. Two authors reported receiving personal fees and/or grants from multiple pharmaceutical companies.

This article was created using several editorial tools, including artificial intelligence, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

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How to Avoid Freaking Out About Kidney Function

Article Type
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Changed
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Author(s)
Matthew F. Watto, MD
Paul N. Williams, MD

This transcript has been edited for clarity. 

Matthew F. Watto, MD: I’m Dr Matthew Frank Watto, here with my great friend and America’s primary care physician, Dr Paul Nelson Williams. 

We had a great discussion with Kidney Boy, Dr Joel Topf, everyone’s favorite nephrologist, and he taught us how to manage blood pressure in chronic kidney disease (CKD).

When should I start freaking out about a patient’s kidney function? 

Paul N. Williams, MD: Dr Topf focuses more on albuminuria than we are used to doing. It’s probably one of the most important prognostic indicators of how a patient is going to do from a renal standpoint.

Historically, I’ve tended to focus on the estimated glomerular filtration rate (eGFR), and the lower that number gets, the more I sweat, but albuminuria is probably equally, if not more, important as a way of prognosticating whether a patient is going to progress to dialysis or transplant. He directed us towards this nifty little calculator, kidneyfailurerisk.com, where you plug in the patient’s age, eGFR, and degree of albuminuria, and it spits out their risk of progressing to hemodialysis or renal transplantation over the next 5 years. It’s a nice way to concretely explain to patients their risk for progression.

Instead of telling the patient, “You are high risk,” Dr Topf will say, “Your risk is 6% of needing dialysis in the next 5 years.” You can even use these thresholds to gauge when to refer a patient. If someone has a 5-year risk between 3% and 5% or higher, that patient should probably be seeing a nephrologist.

If their 2-year risk is greater than 20%, that patient probably should be evaluated for transplantation. This gives us have more concrete numbers to work with rather than just saying, “Your kidneys aren’t working as well as we would like and you should see a kidney doctor.” Patients have a better sense of how serious things might be. 

Watto: It’s just easier for them to understand. Dr Topf made the point that we used to have a heat map based on the stage of CKD that would tell you how high a patient’s risk was compared with other people. But patients don’t really understand relative risk, so Dr Topf tells them their absolute risk for ending up on dialysis over the next 2-5 years. 

Patients come in and they are worried because they looked at their lab results and see that their creatinine level is red, or their eGFR is low. They think, It says I have stage 3a CKD. 

We should probably have the stages of CKD start at stage 3, which should be called stage 1 so it doesn’t sound as bad. Patients think they are halfway to dialysis; they are already at stage 3 and didn’t even know their kidneys were a problem. 

Dr Topf said that cystatin C (something I only recently started ordering) can be obtained, and sometimes you can recategorize the patient, especially those with an eGFR between 45 and 60. The cystatin C can predict their renal function better than the creatinine-based equations. If you are using the creatinine equation, he recommends using the 2021 equations.

Another nice thing about cystatin C is that it isn’t tripped up in younger patients with a lot of muscle mass. You just have to watch out for inflammation, which can throw the test off. For example, when a patient is in the intensive care unit, it’s probably not that helpful, but for your outpatients, cystatin C works well. 

Williams: I’ve been using it a fair amount in my patients with more muscle mass. And some patients have been taking creatine as a supplement, and that can alter the numbers as well. This is a nice way to get them out of CKD stage 2 or 3 and back where they belong, with normal healthy functioning kidneys.

Watto: Now, Paul, if we find a patient with more advanced CKD — let’s say stage 4, whether by cystatin C or serum creatinine, and their eGFR is less than 30 — should we start peeling off the angiotensin-converting enzyme ACE inhibitor or the angiotensin receptor blocker (ARB)? Those drugs can raise potassium. What should we do here? 

Williams: That’s the temptation, Matt, and I feel like that was the old orthodoxy, back in residency. It didn’t take much for us to start taking off ACE inhibitors or ARBs once the kidney function started to drop, but it turns out you may be doing more harm than good.

Some data have shown that if you peel off those medications, you actually increase mortality and cardiovascular risk. So, in general, if you can keep them going, the patient will be better off. Hang onto the ACE inhibitors or ARBs as long as you are able to, because they confer a fair amount of benefit.

Watto: As long as the potassium isn’t in red on your lab’s range. It might go up to 5.2 or 5.4, but as long as it’s stable, that should be OK. You probably wouldn’t initiate an ACE inhibitor or ARB or spironolactone with a potassium level above 5, but if it’s below 5 when you start and it goes up slightly after you start the drug, that could be acceptable. 

Another thing we talked about was when a patient progresses to CKD and ends up on dialysis, how helpful are those intradialysis blood pressures in predicting cardiovascular outcomes? 

Williams: For someone who’s performing the dialysis, probably really helpful. In the outpatient setting to predict cardiovascular risk, probably less so. Dr Topf makes the point that the readings are done either shortly after or right when the patient is about to have a large-bore catheter inserted into their arm. And then they have liters of fluid drained out of them. So those numbers are going to have huge amounts of variability. You would not base the patient’s blood pressure treatment solely on those numbers. But regardless of what the numbers are, or even regardless of your office numbers, hopefully you’re working with a nephrologist to make sure that you’re actually in concert and not fighting each other with the blood pressure medications.

Watto: Dr Topf said that a lot of the hypertension in dialysis is because of too much volume. If you can get the volume down, you might be able to peel off blood pressure medications instead of adding more. But some patients have issues with cramping; it’s uncomfortable and not everyone tolerates it. 

I was really surprised to learn that beta blockers, specifically atenolol, have some evidence of improving cardiovascular outcomes in patients on dialysis. Dr Topf speculated that this was because they are largely dying of cardiovascular disease, so maybe that’s why, but that’s one of the places, the only places I can think of aside from thyroid disease, where atenolol really shines. 

If you want to hear this fantastic episode and all the great pearls, then click on this link. 

Matthew F. Watto, MD, Clinical Assistant Professor, Department of Medicine, Perelman School of Medicine at University of Pennsylvania; Internist, Department of Medicine, Hospital Medicine Section, Pennsylvania Hospital, Philadelphia, Pennsylvania, disclosed no relevant financial relationships. Paul N. Williams, MD, has disclosed ties with The Curbsiders.

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This transcript has been edited for clarity. 

Matthew F. Watto, MD: I’m Dr Matthew Frank Watto, here with my great friend and America’s primary care physician, Dr Paul Nelson Williams. 

We had a great discussion with Kidney Boy, Dr Joel Topf, everyone’s favorite nephrologist, and he taught us how to manage blood pressure in chronic kidney disease (CKD).

When should I start freaking out about a patient’s kidney function? 

Paul N. Williams, MD: Dr Topf focuses more on albuminuria than we are used to doing. It’s probably one of the most important prognostic indicators of how a patient is going to do from a renal standpoint.

Historically, I’ve tended to focus on the estimated glomerular filtration rate (eGFR), and the lower that number gets, the more I sweat, but albuminuria is probably equally, if not more, important as a way of prognosticating whether a patient is going to progress to dialysis or transplant. He directed us towards this nifty little calculator, kidneyfailurerisk.com, where you plug in the patient’s age, eGFR, and degree of albuminuria, and it spits out their risk of progressing to hemodialysis or renal transplantation over the next 5 years. It’s a nice way to concretely explain to patients their risk for progression.

Instead of telling the patient, “You are high risk,” Dr Topf will say, “Your risk is 6% of needing dialysis in the next 5 years.” You can even use these thresholds to gauge when to refer a patient. If someone has a 5-year risk between 3% and 5% or higher, that patient should probably be seeing a nephrologist.

If their 2-year risk is greater than 20%, that patient probably should be evaluated for transplantation. This gives us have more concrete numbers to work with rather than just saying, “Your kidneys aren’t working as well as we would like and you should see a kidney doctor.” Patients have a better sense of how serious things might be. 

Watto: It’s just easier for them to understand. Dr Topf made the point that we used to have a heat map based on the stage of CKD that would tell you how high a patient’s risk was compared with other people. But patients don’t really understand relative risk, so Dr Topf tells them their absolute risk for ending up on dialysis over the next 2-5 years. 

Patients come in and they are worried because they looked at their lab results and see that their creatinine level is red, or their eGFR is low. They think, It says I have stage 3a CKD. 

We should probably have the stages of CKD start at stage 3, which should be called stage 1 so it doesn’t sound as bad. Patients think they are halfway to dialysis; they are already at stage 3 and didn’t even know their kidneys were a problem. 

Dr Topf said that cystatin C (something I only recently started ordering) can be obtained, and sometimes you can recategorize the patient, especially those with an eGFR between 45 and 60. The cystatin C can predict their renal function better than the creatinine-based equations. If you are using the creatinine equation, he recommends using the 2021 equations.

Another nice thing about cystatin C is that it isn’t tripped up in younger patients with a lot of muscle mass. You just have to watch out for inflammation, which can throw the test off. For example, when a patient is in the intensive care unit, it’s probably not that helpful, but for your outpatients, cystatin C works well. 

Williams: I’ve been using it a fair amount in my patients with more muscle mass. And some patients have been taking creatine as a supplement, and that can alter the numbers as well. This is a nice way to get them out of CKD stage 2 or 3 and back where they belong, with normal healthy functioning kidneys.

Watto: Now, Paul, if we find a patient with more advanced CKD — let’s say stage 4, whether by cystatin C or serum creatinine, and their eGFR is less than 30 — should we start peeling off the angiotensin-converting enzyme ACE inhibitor or the angiotensin receptor blocker (ARB)? Those drugs can raise potassium. What should we do here? 

Williams: That’s the temptation, Matt, and I feel like that was the old orthodoxy, back in residency. It didn’t take much for us to start taking off ACE inhibitors or ARBs once the kidney function started to drop, but it turns out you may be doing more harm than good.

Some data have shown that if you peel off those medications, you actually increase mortality and cardiovascular risk. So, in general, if you can keep them going, the patient will be better off. Hang onto the ACE inhibitors or ARBs as long as you are able to, because they confer a fair amount of benefit.

Watto: As long as the potassium isn’t in red on your lab’s range. It might go up to 5.2 or 5.4, but as long as it’s stable, that should be OK. You probably wouldn’t initiate an ACE inhibitor or ARB or spironolactone with a potassium level above 5, but if it’s below 5 when you start and it goes up slightly after you start the drug, that could be acceptable. 

Another thing we talked about was when a patient progresses to CKD and ends up on dialysis, how helpful are those intradialysis blood pressures in predicting cardiovascular outcomes? 

Williams: For someone who’s performing the dialysis, probably really helpful. In the outpatient setting to predict cardiovascular risk, probably less so. Dr Topf makes the point that the readings are done either shortly after or right when the patient is about to have a large-bore catheter inserted into their arm. And then they have liters of fluid drained out of them. So those numbers are going to have huge amounts of variability. You would not base the patient’s blood pressure treatment solely on those numbers. But regardless of what the numbers are, or even regardless of your office numbers, hopefully you’re working with a nephrologist to make sure that you’re actually in concert and not fighting each other with the blood pressure medications.

Watto: Dr Topf said that a lot of the hypertension in dialysis is because of too much volume. If you can get the volume down, you might be able to peel off blood pressure medications instead of adding more. But some patients have issues with cramping; it’s uncomfortable and not everyone tolerates it. 

I was really surprised to learn that beta blockers, specifically atenolol, have some evidence of improving cardiovascular outcomes in patients on dialysis. Dr Topf speculated that this was because they are largely dying of cardiovascular disease, so maybe that’s why, but that’s one of the places, the only places I can think of aside from thyroid disease, where atenolol really shines. 

If you want to hear this fantastic episode and all the great pearls, then click on this link. 

Matthew F. Watto, MD, Clinical Assistant Professor, Department of Medicine, Perelman School of Medicine at University of Pennsylvania; Internist, Department of Medicine, Hospital Medicine Section, Pennsylvania Hospital, Philadelphia, Pennsylvania, disclosed no relevant financial relationships. Paul N. Williams, MD, has disclosed ties with The Curbsiders.

This transcript has been edited for clarity. 

Matthew F. Watto, MD: I’m Dr Matthew Frank Watto, here with my great friend and America’s primary care physician, Dr Paul Nelson Williams. 

We had a great discussion with Kidney Boy, Dr Joel Topf, everyone’s favorite nephrologist, and he taught us how to manage blood pressure in chronic kidney disease (CKD).

When should I start freaking out about a patient’s kidney function? 

Paul N. Williams, MD: Dr Topf focuses more on albuminuria than we are used to doing. It’s probably one of the most important prognostic indicators of how a patient is going to do from a renal standpoint.

Historically, I’ve tended to focus on the estimated glomerular filtration rate (eGFR), and the lower that number gets, the more I sweat, but albuminuria is probably equally, if not more, important as a way of prognosticating whether a patient is going to progress to dialysis or transplant. He directed us towards this nifty little calculator, kidneyfailurerisk.com, where you plug in the patient’s age, eGFR, and degree of albuminuria, and it spits out their risk of progressing to hemodialysis or renal transplantation over the next 5 years. It’s a nice way to concretely explain to patients their risk for progression.

Instead of telling the patient, “You are high risk,” Dr Topf will say, “Your risk is 6% of needing dialysis in the next 5 years.” You can even use these thresholds to gauge when to refer a patient. If someone has a 5-year risk between 3% and 5% or higher, that patient should probably be seeing a nephrologist.

If their 2-year risk is greater than 20%, that patient probably should be evaluated for transplantation. This gives us have more concrete numbers to work with rather than just saying, “Your kidneys aren’t working as well as we would like and you should see a kidney doctor.” Patients have a better sense of how serious things might be. 

Watto: It’s just easier for them to understand. Dr Topf made the point that we used to have a heat map based on the stage of CKD that would tell you how high a patient’s risk was compared with other people. But patients don’t really understand relative risk, so Dr Topf tells them their absolute risk for ending up on dialysis over the next 2-5 years. 

Patients come in and they are worried because they looked at their lab results and see that their creatinine level is red, or their eGFR is low. They think, It says I have stage 3a CKD. 

We should probably have the stages of CKD start at stage 3, which should be called stage 1 so it doesn’t sound as bad. Patients think they are halfway to dialysis; they are already at stage 3 and didn’t even know their kidneys were a problem. 

Dr Topf said that cystatin C (something I only recently started ordering) can be obtained, and sometimes you can recategorize the patient, especially those with an eGFR between 45 and 60. The cystatin C can predict their renal function better than the creatinine-based equations. If you are using the creatinine equation, he recommends using the 2021 equations.

Another nice thing about cystatin C is that it isn’t tripped up in younger patients with a lot of muscle mass. You just have to watch out for inflammation, which can throw the test off. For example, when a patient is in the intensive care unit, it’s probably not that helpful, but for your outpatients, cystatin C works well. 

Williams: I’ve been using it a fair amount in my patients with more muscle mass. And some patients have been taking creatine as a supplement, and that can alter the numbers as well. This is a nice way to get them out of CKD stage 2 or 3 and back where they belong, with normal healthy functioning kidneys.

Watto: Now, Paul, if we find a patient with more advanced CKD — let’s say stage 4, whether by cystatin C or serum creatinine, and their eGFR is less than 30 — should we start peeling off the angiotensin-converting enzyme ACE inhibitor or the angiotensin receptor blocker (ARB)? Those drugs can raise potassium. What should we do here? 

Williams: That’s the temptation, Matt, and I feel like that was the old orthodoxy, back in residency. It didn’t take much for us to start taking off ACE inhibitors or ARBs once the kidney function started to drop, but it turns out you may be doing more harm than good.

Some data have shown that if you peel off those medications, you actually increase mortality and cardiovascular risk. So, in general, if you can keep them going, the patient will be better off. Hang onto the ACE inhibitors or ARBs as long as you are able to, because they confer a fair amount of benefit.

Watto: As long as the potassium isn’t in red on your lab’s range. It might go up to 5.2 or 5.4, but as long as it’s stable, that should be OK. You probably wouldn’t initiate an ACE inhibitor or ARB or spironolactone with a potassium level above 5, but if it’s below 5 when you start and it goes up slightly after you start the drug, that could be acceptable. 

Another thing we talked about was when a patient progresses to CKD and ends up on dialysis, how helpful are those intradialysis blood pressures in predicting cardiovascular outcomes? 

Williams: For someone who’s performing the dialysis, probably really helpful. In the outpatient setting to predict cardiovascular risk, probably less so. Dr Topf makes the point that the readings are done either shortly after or right when the patient is about to have a large-bore catheter inserted into their arm. And then they have liters of fluid drained out of them. So those numbers are going to have huge amounts of variability. You would not base the patient’s blood pressure treatment solely on those numbers. But regardless of what the numbers are, or even regardless of your office numbers, hopefully you’re working with a nephrologist to make sure that you’re actually in concert and not fighting each other with the blood pressure medications.

Watto: Dr Topf said that a lot of the hypertension in dialysis is because of too much volume. If you can get the volume down, you might be able to peel off blood pressure medications instead of adding more. But some patients have issues with cramping; it’s uncomfortable and not everyone tolerates it. 

I was really surprised to learn that beta blockers, specifically atenolol, have some evidence of improving cardiovascular outcomes in patients on dialysis. Dr Topf speculated that this was because they are largely dying of cardiovascular disease, so maybe that’s why, but that’s one of the places, the only places I can think of aside from thyroid disease, where atenolol really shines. 

If you want to hear this fantastic episode and all the great pearls, then click on this link. 

Matthew F. Watto, MD, Clinical Assistant Professor, Department of Medicine, Perelman School of Medicine at University of Pennsylvania; Internist, Department of Medicine, Hospital Medicine Section, Pennsylvania Hospital, Philadelphia, Pennsylvania, disclosed no relevant financial relationships. Paul N. Williams, MD, has disclosed ties with The Curbsiders.

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An 81-Year-Old White Woman Presented With a 2-Week History of a Painful Lesion on Her Left Calf

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Fri, 12/13/2024 - 15:14
Author(s)
Lucas Shapiro, BS
Donna Bilu Martin, MD

Calciphylaxis, also known as calcific uremic arteriolopathy, is a rare condition most commonly observed in patients with end-stage renal disease (ESRD). Patients with calciphylaxis present with necrotic, painful skin lesions secondary to arteriolar calcification, which leads to tissue ischemia and infarction. Because of the non-healing nature of the wounds and need for frequent hospitalizations, there is a significant risk of sepsis with a 1-year mortality rate greater than 50%.

Beyond ESRD, calciphylaxis is also associated with obesity, diabetes, hypoalbuminemia, autoimmune conditions, hepatic disease, malignancies, and dialysis. Rates in patients on dialysis have been increasing, ranging from 1% to 4%. Certain medications have also been implicated in the development of calciphylaxis, including warfarin, steroids, calcium-based phosphate binders, vitamin D, and iron. There is also an association with White individuals and more cases have been reported in females. 

Pathophysiology of this condition includes calcification of the medial layer of arterioles and small arteries near the skin. Damage to vessel endothelium and formation of microthrombi contribute to the ischemia, which results in necrosis and ulceration of the skin. Elevated calcium and phosphate have been associated with these findings; however, these lab abnormalities alone are typically not enough to cause calciphylaxis. Vascular calcification inhibitors such as fetuin-A, osteoprotegerin, and matrix G1a protein may play a role in pathogenesis, with individuals lacking these factors potentially being at a greater risk. Specifically, matrix G1a protein is dependent on vitamin K dependent carboxylation, which may elucidate why warfarin has been implicated in the development of calciphylaxis because of interference with this pathway. 

Upon presentation, patients will have painful ischemic plaques on the skin or painful subcutaneous nodules. Long-standing lesions may have a necrotic eschar or secondary infection, or may be associated with livedo reticularis. Areas with a greater concentration of adipose tissue such as the abdomen, thighs, and buttocks are most commonly affected, but lesions may appear anywhere. A biopsy may be done, but a clinical diagnosis is often sufficient as biopsies carry risks of prolonged healing and infection. 

Dr. Donna Bilu Martin

The differential diagnosis includes warfarin skin necrosis, cholesterol embolization, vasculitis, antiphospholipid syndrome, and cellulitis. Although this is a cutaneous manifestation, calciphylaxis is indicative of a systemic problem and requires multidisciplinary intervention. 

Patients who present with calciphylaxis require a complete metabolic panel, liver function tests, coagulation studies, and albumin tests. Depending on the presentation, imaging studies such as nuclear medicine scans may be used if extensive soft tissue involvement is suspected.

Clinical management includes carefully avoiding electrolyte imbalances, initiating dialysis if necessary, discontinuing potentially offending supplements and medications, and administering proper wound care and pain management. Debridement of necrotic tissue may be necessary and should be initiated early as this has been associated with a 6-month increase in survival. Physicians should have a low threshold for starting antibiotics if secondary infection is suspected, but prophylaxis is not recommended. Sodium thiosulfate has been used off-label, but the mechanism of action is unknown and some meta-analyses indicate this treatment is not significantly associated with improvement of skin lesions. Interventions such as hyperbaric oxygen have also been used, but there is still more research to be done on these modalities. 

The case and photo were submitted by Lucas Shapiro, BS, Nova Southeastern University College of Osteopathic Medicine, and Dr. Bilu Martin.

 

Dr. Bilu Martin is a board-certified dermatologist in private practice at Premier Dermatology, MD, Fort Lauderdale, Fla. More diagnostic cases are available at mdedge.com/dermatology. To submit a case for possible publication, send an email to dermnews@mdedge.com. 

References

Kodumudi V et al. Adv Ther. 2020 Dec;37(12):4797-4807. doi: 10.1007/s12325-020-01504-w.

Seethapathy H et al. Adv Chronic Kidney Dis. 2019 Nov;26(6):484-490. doi: 10.1053/j.ackd.2019.09.005.

Turek M et al. Am J Case Rep. 2021 Jun 7:22:e930026. doi: 10.12659/AJCR.930026.

Wen W at al. JAMA Netw Open. 2023;6(4):e2310068. doi:10.1001/jamanetworkopen.2023.10068.

Westphal SG, Plumb T. Calciphylaxis. [Updated 2023 Aug 8]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. Available from: www.ncbi.nlm.nih.gov/books/NBK519020/.

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Author(s)
Lucas Shapiro, BS
Donna Bilu Martin, MD
Author(s)
Lucas Shapiro, BS
Donna Bilu Martin, MD

Calciphylaxis, also known as calcific uremic arteriolopathy, is a rare condition most commonly observed in patients with end-stage renal disease (ESRD). Patients with calciphylaxis present with necrotic, painful skin lesions secondary to arteriolar calcification, which leads to tissue ischemia and infarction. Because of the non-healing nature of the wounds and need for frequent hospitalizations, there is a significant risk of sepsis with a 1-year mortality rate greater than 50%.

Beyond ESRD, calciphylaxis is also associated with obesity, diabetes, hypoalbuminemia, autoimmune conditions, hepatic disease, malignancies, and dialysis. Rates in patients on dialysis have been increasing, ranging from 1% to 4%. Certain medications have also been implicated in the development of calciphylaxis, including warfarin, steroids, calcium-based phosphate binders, vitamin D, and iron. There is also an association with White individuals and more cases have been reported in females. 

Pathophysiology of this condition includes calcification of the medial layer of arterioles and small arteries near the skin. Damage to vessel endothelium and formation of microthrombi contribute to the ischemia, which results in necrosis and ulceration of the skin. Elevated calcium and phosphate have been associated with these findings; however, these lab abnormalities alone are typically not enough to cause calciphylaxis. Vascular calcification inhibitors such as fetuin-A, osteoprotegerin, and matrix G1a protein may play a role in pathogenesis, with individuals lacking these factors potentially being at a greater risk. Specifically, matrix G1a protein is dependent on vitamin K dependent carboxylation, which may elucidate why warfarin has been implicated in the development of calciphylaxis because of interference with this pathway. 

Upon presentation, patients will have painful ischemic plaques on the skin or painful subcutaneous nodules. Long-standing lesions may have a necrotic eschar or secondary infection, or may be associated with livedo reticularis. Areas with a greater concentration of adipose tissue such as the abdomen, thighs, and buttocks are most commonly affected, but lesions may appear anywhere. A biopsy may be done, but a clinical diagnosis is often sufficient as biopsies carry risks of prolonged healing and infection. 

Dr. Donna Bilu Martin

The differential diagnosis includes warfarin skin necrosis, cholesterol embolization, vasculitis, antiphospholipid syndrome, and cellulitis. Although this is a cutaneous manifestation, calciphylaxis is indicative of a systemic problem and requires multidisciplinary intervention. 

Patients who present with calciphylaxis require a complete metabolic panel, liver function tests, coagulation studies, and albumin tests. Depending on the presentation, imaging studies such as nuclear medicine scans may be used if extensive soft tissue involvement is suspected.

Clinical management includes carefully avoiding electrolyte imbalances, initiating dialysis if necessary, discontinuing potentially offending supplements and medications, and administering proper wound care and pain management. Debridement of necrotic tissue may be necessary and should be initiated early as this has been associated with a 6-month increase in survival. Physicians should have a low threshold for starting antibiotics if secondary infection is suspected, but prophylaxis is not recommended. Sodium thiosulfate has been used off-label, but the mechanism of action is unknown and some meta-analyses indicate this treatment is not significantly associated with improvement of skin lesions. Interventions such as hyperbaric oxygen have also been used, but there is still more research to be done on these modalities. 

The case and photo were submitted by Lucas Shapiro, BS, Nova Southeastern University College of Osteopathic Medicine, and Dr. Bilu Martin.

 

Dr. Bilu Martin is a board-certified dermatologist in private practice at Premier Dermatology, MD, Fort Lauderdale, Fla. More diagnostic cases are available at mdedge.com/dermatology. To submit a case for possible publication, send an email to dermnews@mdedge.com. 

References

Kodumudi V et al. Adv Ther. 2020 Dec;37(12):4797-4807. doi: 10.1007/s12325-020-01504-w.

Seethapathy H et al. Adv Chronic Kidney Dis. 2019 Nov;26(6):484-490. doi: 10.1053/j.ackd.2019.09.005.

Turek M et al. Am J Case Rep. 2021 Jun 7:22:e930026. doi: 10.12659/AJCR.930026.

Wen W at al. JAMA Netw Open. 2023;6(4):e2310068. doi:10.1001/jamanetworkopen.2023.10068.

Westphal SG, Plumb T. Calciphylaxis. [Updated 2023 Aug 8]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. Available from: www.ncbi.nlm.nih.gov/books/NBK519020/.

Calciphylaxis, also known as calcific uremic arteriolopathy, is a rare condition most commonly observed in patients with end-stage renal disease (ESRD). Patients with calciphylaxis present with necrotic, painful skin lesions secondary to arteriolar calcification, which leads to tissue ischemia and infarction. Because of the non-healing nature of the wounds and need for frequent hospitalizations, there is a significant risk of sepsis with a 1-year mortality rate greater than 50%.

Beyond ESRD, calciphylaxis is also associated with obesity, diabetes, hypoalbuminemia, autoimmune conditions, hepatic disease, malignancies, and dialysis. Rates in patients on dialysis have been increasing, ranging from 1% to 4%. Certain medications have also been implicated in the development of calciphylaxis, including warfarin, steroids, calcium-based phosphate binders, vitamin D, and iron. There is also an association with White individuals and more cases have been reported in females. 

Pathophysiology of this condition includes calcification of the medial layer of arterioles and small arteries near the skin. Damage to vessel endothelium and formation of microthrombi contribute to the ischemia, which results in necrosis and ulceration of the skin. Elevated calcium and phosphate have been associated with these findings; however, these lab abnormalities alone are typically not enough to cause calciphylaxis. Vascular calcification inhibitors such as fetuin-A, osteoprotegerin, and matrix G1a protein may play a role in pathogenesis, with individuals lacking these factors potentially being at a greater risk. Specifically, matrix G1a protein is dependent on vitamin K dependent carboxylation, which may elucidate why warfarin has been implicated in the development of calciphylaxis because of interference with this pathway. 

Upon presentation, patients will have painful ischemic plaques on the skin or painful subcutaneous nodules. Long-standing lesions may have a necrotic eschar or secondary infection, or may be associated with livedo reticularis. Areas with a greater concentration of adipose tissue such as the abdomen, thighs, and buttocks are most commonly affected, but lesions may appear anywhere. A biopsy may be done, but a clinical diagnosis is often sufficient as biopsies carry risks of prolonged healing and infection. 

Dr. Donna Bilu Martin

The differential diagnosis includes warfarin skin necrosis, cholesterol embolization, vasculitis, antiphospholipid syndrome, and cellulitis. Although this is a cutaneous manifestation, calciphylaxis is indicative of a systemic problem and requires multidisciplinary intervention. 

Patients who present with calciphylaxis require a complete metabolic panel, liver function tests, coagulation studies, and albumin tests. Depending on the presentation, imaging studies such as nuclear medicine scans may be used if extensive soft tissue involvement is suspected.

Clinical management includes carefully avoiding electrolyte imbalances, initiating dialysis if necessary, discontinuing potentially offending supplements and medications, and administering proper wound care and pain management. Debridement of necrotic tissue may be necessary and should be initiated early as this has been associated with a 6-month increase in survival. Physicians should have a low threshold for starting antibiotics if secondary infection is suspected, but prophylaxis is not recommended. Sodium thiosulfate has been used off-label, but the mechanism of action is unknown and some meta-analyses indicate this treatment is not significantly associated with improvement of skin lesions. Interventions such as hyperbaric oxygen have also been used, but there is still more research to be done on these modalities. 

The case and photo were submitted by Lucas Shapiro, BS, Nova Southeastern University College of Osteopathic Medicine, and Dr. Bilu Martin.

 

Dr. Bilu Martin is a board-certified dermatologist in private practice at Premier Dermatology, MD, Fort Lauderdale, Fla. More diagnostic cases are available at mdedge.com/dermatology. To submit a case for possible publication, send an email to dermnews@mdedge.com. 

References

Kodumudi V et al. Adv Ther. 2020 Dec;37(12):4797-4807. doi: 10.1007/s12325-020-01504-w.

Seethapathy H et al. Adv Chronic Kidney Dis. 2019 Nov;26(6):484-490. doi: 10.1053/j.ackd.2019.09.005.

Turek M et al. Am J Case Rep. 2021 Jun 7:22:e930026. doi: 10.12659/AJCR.930026.

Wen W at al. JAMA Netw Open. 2023;6(4):e2310068. doi:10.1001/jamanetworkopen.2023.10068.

Westphal SG, Plumb T. Calciphylaxis. [Updated 2023 Aug 8]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. Available from: www.ncbi.nlm.nih.gov/books/NBK519020/.

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Special Considerations Needed in Applying Lupus Nephritis Guideline to Children

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WASHINGTON — When the American College of Rheumatology (ACR) released its updated guideline for management of lupus nephritis (LN) at its 2024 Annual Meeting, they included recommendations for managing pediatric LN for the first time. 

The pediatric recommendations use the same classification criteria, outcome measures, and treatments as in adults — including the first-line triple therapy recommendation — but there remain important differences between pediatric and adult LN, Mary Beth Son, MD, clinical chief of immunology and section chief of rheumatology at Boston Children’s Hospital in Massachusetts, and an associate professor of pediatrics at Harvard Medical School, also in Boston, told attendees. 

“In general, kids and adolescents with lupus are sicker,” Son said. They are more likely to have renal manifestations and neuropsychiatric lupus at diagnosis, compared with adults. Further, “although the disease is the same, it’s happening to kids and adolescents who are undergoing critical periods of growth and development.” 

Medication risk profiles also shift for younger patients, Son noted. 

“Importantly, they’re at risk for higher cumulative dosing of both glucocorticoids and cyclophosphamide,” Son said. “When we give an adolescent a course of cyclophosphamide, we have to be aware that this might be the first of a few courses over the course of the lifetime disease, and with increasing numbers of cyclophosphamide courses, you have increased risk for infertility and malignancy.” 

Son also acknowledged challenges of pediatric literature, including differences in definitions of pediatric lupus, very few randomized controlled trials, and fewer pediatric studies in general, with fewer participants. Given these research gaps, the guideline panels included pediatric rheumatologists and nephrologists, and the patient panel included several patients with childhood-onset disease.

Son also addressed differences in pediatric drug development. Dosing studies also do not always directly translate from adults to children because children have larger drug volume distribution and differences in drug clearance, and they may need different formulations, she said. Children tend to tolerate medications better than adults because they usually have fewer comorbidities, but the assessment of a drug’s safety must take its impact on growth and development into consideration.

During a press conference after the session where the guideline was presented, Linda Hiraki, MD, ScD, a clinician-scientist in rheumatology at the Hospital for Sick Children, Toronto, Ontario, Canada, said the panel took into consideration that pediatric patients receive their diagnosis during a critical time of development, so considerations of medication risks include the fact that children “have much more life to live.”

 

Triple Therapy Recommended

As with adults, the pediatric LN guideline recommends a triple therapy approach: glucocorticoids plus mycophenolate mofetil and belimumab, in addition to the usual renin-angiotensin-aldosterone system inhibitors and hydroxychloroquine. But Son acknowledged limitations of applying the new guideline to children. For one, voclosporin has not been studied in or approved for pediatric patients, although there exists modest evidence for other calcineurin inhibitors, mainly tacrolimus, in children.

“The other important consideration is that the lower dose of prednisone that’s being offered by the guidelines of 40 mg per day as a starting dose has not been studied in pediatric lupus nephritis patients,” Son said. “However, I would offer that, given that we know that kids get higher doses and longer courses, it’s even more important to consider a lower dose to begin with in the setting of other immunosuppressants.”

 

Good Practice Statements for Pediatric LN

Son also reviewed three good practice statements for pediatric LN. First, “glucocorticoid regimens should use pediatric-appropriate doses for children, as reduction of human glucocorticoid dosing is critically important given the early age of pediatric lupus onset and attendant comorbidities,” she said.

That statement is based on both common sense and some literature, including awareness that children are more likely to receive higher doses of steroids and that children’s higher damage scores are driven in part by steroid-related toxicity, such as avascular necrosis and cataracts. In addition, glucocorticoids can have profound effects on body mass index, mood, and height attainment.

“This is during a period of emerging self-identity and struggles with appearance; steroids exacerbate that” as well as mood issues already associated with puberty, Son said.

The second good practice statement recommends that clinicians monitor patients “for delayed pubertal onset and decreased growth velocity that can result from disease activity and glucocorticoid treatment and consider referral to pediatric endocrinology if indicated.” The third states that “a structured, intentional transition from pediatric to adult rheumatology care is indicated to avoid poor outcomes during this vulnerable period.” 

During the press conference, Hiraki said that pediatric rheumatologists already recognize the need for discussions about transfer to adult care to begin very early, even years before patients are ready to transfer.

“The transition from being a pediatric patient to being an adult patient is very challenging for a number of reasons,” starting with loss of insurance coverage, added Bonnie Bermas, MD, a professor of internal medicine at UT Southwestern Medical Center in Dallas, Texas. When adult rheumatologists take on these patients, they may not have had care for 2 or 3 years, she said. 

Rebecca Sadun, MD, PhD, an associate professor of pediatrics in rheumatology at Duke University School of Medicine, Durham, North Carolina, and vice-chair of the Systemic Lupus Erythematosus Committee for the Childhood Arthritis and Rheumatology Research Alliance, was not involved in the guideline development process but reviewed the new guideline. 

“We appreciate that the ACR took care to involve pediatric rheumatologists, pediatric nephrologists, and patients with childhood-onset lupus in the development of the newest lupus nephritis treatment guidelines,” she said in an interview. She also noted, however, that “the dearth of pediatric-specific clinical trial data means that we continue to wonder when it is appropriate to extrapolate from adult data regarding the efficacy, safety, and dosing of certain medications, including steroids and voclosporin.” She also noted that voclosporin use can increase pill burden and therefore be difficult to use in pediatrics.

“Children, adolescents, and young adults are a unique population with unique challenges, including significant struggles with adherence to complex medication regimens,” she said. Sadun drew attention to two themes from the guideline that she found particularly applicable to management of pediatric LN.

“First, we must remain wary of the serious consequences of long-term, high-dose glucocorticoids, and we should continue to look towards steroid-sparing strategies that will reduce reliance on glucocorticoids,” Sadun said. “Second, we are likely to see better outcomes, including better renal response, when we take advantage of combination immunosuppression earlier in the disease course.”

Son, Bermas, and Sadun had no disclosures. Hiraki has consulted for Janssen. The guideline development did not involve outside funding.

A version of this article first appeared on Medscape.com.

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WASHINGTON — When the American College of Rheumatology (ACR) released its updated guideline for management of lupus nephritis (LN) at its 2024 Annual Meeting, they included recommendations for managing pediatric LN for the first time. 

The pediatric recommendations use the same classification criteria, outcome measures, and treatments as in adults — including the first-line triple therapy recommendation — but there remain important differences between pediatric and adult LN, Mary Beth Son, MD, clinical chief of immunology and section chief of rheumatology at Boston Children’s Hospital in Massachusetts, and an associate professor of pediatrics at Harvard Medical School, also in Boston, told attendees. 

“In general, kids and adolescents with lupus are sicker,” Son said. They are more likely to have renal manifestations and neuropsychiatric lupus at diagnosis, compared with adults. Further, “although the disease is the same, it’s happening to kids and adolescents who are undergoing critical periods of growth and development.” 

Medication risk profiles also shift for younger patients, Son noted. 

“Importantly, they’re at risk for higher cumulative dosing of both glucocorticoids and cyclophosphamide,” Son said. “When we give an adolescent a course of cyclophosphamide, we have to be aware that this might be the first of a few courses over the course of the lifetime disease, and with increasing numbers of cyclophosphamide courses, you have increased risk for infertility and malignancy.” 

Son also acknowledged challenges of pediatric literature, including differences in definitions of pediatric lupus, very few randomized controlled trials, and fewer pediatric studies in general, with fewer participants. Given these research gaps, the guideline panels included pediatric rheumatologists and nephrologists, and the patient panel included several patients with childhood-onset disease.

Son also addressed differences in pediatric drug development. Dosing studies also do not always directly translate from adults to children because children have larger drug volume distribution and differences in drug clearance, and they may need different formulations, she said. Children tend to tolerate medications better than adults because they usually have fewer comorbidities, but the assessment of a drug’s safety must take its impact on growth and development into consideration.

During a press conference after the session where the guideline was presented, Linda Hiraki, MD, ScD, a clinician-scientist in rheumatology at the Hospital for Sick Children, Toronto, Ontario, Canada, said the panel took into consideration that pediatric patients receive their diagnosis during a critical time of development, so considerations of medication risks include the fact that children “have much more life to live.”

 

Triple Therapy Recommended

As with adults, the pediatric LN guideline recommends a triple therapy approach: glucocorticoids plus mycophenolate mofetil and belimumab, in addition to the usual renin-angiotensin-aldosterone system inhibitors and hydroxychloroquine. But Son acknowledged limitations of applying the new guideline to children. For one, voclosporin has not been studied in or approved for pediatric patients, although there exists modest evidence for other calcineurin inhibitors, mainly tacrolimus, in children.

“The other important consideration is that the lower dose of prednisone that’s being offered by the guidelines of 40 mg per day as a starting dose has not been studied in pediatric lupus nephritis patients,” Son said. “However, I would offer that, given that we know that kids get higher doses and longer courses, it’s even more important to consider a lower dose to begin with in the setting of other immunosuppressants.”

 

Good Practice Statements for Pediatric LN

Son also reviewed three good practice statements for pediatric LN. First, “glucocorticoid regimens should use pediatric-appropriate doses for children, as reduction of human glucocorticoid dosing is critically important given the early age of pediatric lupus onset and attendant comorbidities,” she said.

That statement is based on both common sense and some literature, including awareness that children are more likely to receive higher doses of steroids and that children’s higher damage scores are driven in part by steroid-related toxicity, such as avascular necrosis and cataracts. In addition, glucocorticoids can have profound effects on body mass index, mood, and height attainment.

“This is during a period of emerging self-identity and struggles with appearance; steroids exacerbate that” as well as mood issues already associated with puberty, Son said.

The second good practice statement recommends that clinicians monitor patients “for delayed pubertal onset and decreased growth velocity that can result from disease activity and glucocorticoid treatment and consider referral to pediatric endocrinology if indicated.” The third states that “a structured, intentional transition from pediatric to adult rheumatology care is indicated to avoid poor outcomes during this vulnerable period.” 

During the press conference, Hiraki said that pediatric rheumatologists already recognize the need for discussions about transfer to adult care to begin very early, even years before patients are ready to transfer.

“The transition from being a pediatric patient to being an adult patient is very challenging for a number of reasons,” starting with loss of insurance coverage, added Bonnie Bermas, MD, a professor of internal medicine at UT Southwestern Medical Center in Dallas, Texas. When adult rheumatologists take on these patients, they may not have had care for 2 or 3 years, she said. 

Rebecca Sadun, MD, PhD, an associate professor of pediatrics in rheumatology at Duke University School of Medicine, Durham, North Carolina, and vice-chair of the Systemic Lupus Erythematosus Committee for the Childhood Arthritis and Rheumatology Research Alliance, was not involved in the guideline development process but reviewed the new guideline. 

“We appreciate that the ACR took care to involve pediatric rheumatologists, pediatric nephrologists, and patients with childhood-onset lupus in the development of the newest lupus nephritis treatment guidelines,” she said in an interview. She also noted, however, that “the dearth of pediatric-specific clinical trial data means that we continue to wonder when it is appropriate to extrapolate from adult data regarding the efficacy, safety, and dosing of certain medications, including steroids and voclosporin.” She also noted that voclosporin use can increase pill burden and therefore be difficult to use in pediatrics.

“Children, adolescents, and young adults are a unique population with unique challenges, including significant struggles with adherence to complex medication regimens,” she said. Sadun drew attention to two themes from the guideline that she found particularly applicable to management of pediatric LN.

“First, we must remain wary of the serious consequences of long-term, high-dose glucocorticoids, and we should continue to look towards steroid-sparing strategies that will reduce reliance on glucocorticoids,” Sadun said. “Second, we are likely to see better outcomes, including better renal response, when we take advantage of combination immunosuppression earlier in the disease course.”

Son, Bermas, and Sadun had no disclosures. Hiraki has consulted for Janssen. The guideline development did not involve outside funding.

A version of this article first appeared on Medscape.com.

WASHINGTON — When the American College of Rheumatology (ACR) released its updated guideline for management of lupus nephritis (LN) at its 2024 Annual Meeting, they included recommendations for managing pediatric LN for the first time. 

The pediatric recommendations use the same classification criteria, outcome measures, and treatments as in adults — including the first-line triple therapy recommendation — but there remain important differences between pediatric and adult LN, Mary Beth Son, MD, clinical chief of immunology and section chief of rheumatology at Boston Children’s Hospital in Massachusetts, and an associate professor of pediatrics at Harvard Medical School, also in Boston, told attendees. 

“In general, kids and adolescents with lupus are sicker,” Son said. They are more likely to have renal manifestations and neuropsychiatric lupus at diagnosis, compared with adults. Further, “although the disease is the same, it’s happening to kids and adolescents who are undergoing critical periods of growth and development.” 

Medication risk profiles also shift for younger patients, Son noted. 

“Importantly, they’re at risk for higher cumulative dosing of both glucocorticoids and cyclophosphamide,” Son said. “When we give an adolescent a course of cyclophosphamide, we have to be aware that this might be the first of a few courses over the course of the lifetime disease, and with increasing numbers of cyclophosphamide courses, you have increased risk for infertility and malignancy.” 

Son also acknowledged challenges of pediatric literature, including differences in definitions of pediatric lupus, very few randomized controlled trials, and fewer pediatric studies in general, with fewer participants. Given these research gaps, the guideline panels included pediatric rheumatologists and nephrologists, and the patient panel included several patients with childhood-onset disease.

Son also addressed differences in pediatric drug development. Dosing studies also do not always directly translate from adults to children because children have larger drug volume distribution and differences in drug clearance, and they may need different formulations, she said. Children tend to tolerate medications better than adults because they usually have fewer comorbidities, but the assessment of a drug’s safety must take its impact on growth and development into consideration.

During a press conference after the session where the guideline was presented, Linda Hiraki, MD, ScD, a clinician-scientist in rheumatology at the Hospital for Sick Children, Toronto, Ontario, Canada, said the panel took into consideration that pediatric patients receive their diagnosis during a critical time of development, so considerations of medication risks include the fact that children “have much more life to live.”

 

Triple Therapy Recommended

As with adults, the pediatric LN guideline recommends a triple therapy approach: glucocorticoids plus mycophenolate mofetil and belimumab, in addition to the usual renin-angiotensin-aldosterone system inhibitors and hydroxychloroquine. But Son acknowledged limitations of applying the new guideline to children. For one, voclosporin has not been studied in or approved for pediatric patients, although there exists modest evidence for other calcineurin inhibitors, mainly tacrolimus, in children.

“The other important consideration is that the lower dose of prednisone that’s being offered by the guidelines of 40 mg per day as a starting dose has not been studied in pediatric lupus nephritis patients,” Son said. “However, I would offer that, given that we know that kids get higher doses and longer courses, it’s even more important to consider a lower dose to begin with in the setting of other immunosuppressants.”

 

Good Practice Statements for Pediatric LN

Son also reviewed three good practice statements for pediatric LN. First, “glucocorticoid regimens should use pediatric-appropriate doses for children, as reduction of human glucocorticoid dosing is critically important given the early age of pediatric lupus onset and attendant comorbidities,” she said.

That statement is based on both common sense and some literature, including awareness that children are more likely to receive higher doses of steroids and that children’s higher damage scores are driven in part by steroid-related toxicity, such as avascular necrosis and cataracts. In addition, glucocorticoids can have profound effects on body mass index, mood, and height attainment.

“This is during a period of emerging self-identity and struggles with appearance; steroids exacerbate that” as well as mood issues already associated with puberty, Son said.

The second good practice statement recommends that clinicians monitor patients “for delayed pubertal onset and decreased growth velocity that can result from disease activity and glucocorticoid treatment and consider referral to pediatric endocrinology if indicated.” The third states that “a structured, intentional transition from pediatric to adult rheumatology care is indicated to avoid poor outcomes during this vulnerable period.” 

During the press conference, Hiraki said that pediatric rheumatologists already recognize the need for discussions about transfer to adult care to begin very early, even years before patients are ready to transfer.

“The transition from being a pediatric patient to being an adult patient is very challenging for a number of reasons,” starting with loss of insurance coverage, added Bonnie Bermas, MD, a professor of internal medicine at UT Southwestern Medical Center in Dallas, Texas. When adult rheumatologists take on these patients, they may not have had care for 2 or 3 years, she said. 

Rebecca Sadun, MD, PhD, an associate professor of pediatrics in rheumatology at Duke University School of Medicine, Durham, North Carolina, and vice-chair of the Systemic Lupus Erythematosus Committee for the Childhood Arthritis and Rheumatology Research Alliance, was not involved in the guideline development process but reviewed the new guideline. 

“We appreciate that the ACR took care to involve pediatric rheumatologists, pediatric nephrologists, and patients with childhood-onset lupus in the development of the newest lupus nephritis treatment guidelines,” she said in an interview. She also noted, however, that “the dearth of pediatric-specific clinical trial data means that we continue to wonder when it is appropriate to extrapolate from adult data regarding the efficacy, safety, and dosing of certain medications, including steroids and voclosporin.” She also noted that voclosporin use can increase pill burden and therefore be difficult to use in pediatrics.

“Children, adolescents, and young adults are a unique population with unique challenges, including significant struggles with adherence to complex medication regimens,” she said. Sadun drew attention to two themes from the guideline that she found particularly applicable to management of pediatric LN.

“First, we must remain wary of the serious consequences of long-term, high-dose glucocorticoids, and we should continue to look towards steroid-sparing strategies that will reduce reliance on glucocorticoids,” Sadun said. “Second, we are likely to see better outcomes, including better renal response, when we take advantage of combination immunosuppression earlier in the disease course.”

Son, Bermas, and Sadun had no disclosures. Hiraki has consulted for Janssen. The guideline development did not involve outside funding.

A version of this article first appeared on Medscape.com.

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Could a Urinary Biomarker Panel Be a ‘Game Changer’ for Lupus Nephritis Management?

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WASHINGTON — An investigational 12-protein panel of urinary biomarkers predicted histologically active lupus nephritis (LN) with 86% accuracy, according to research presented at the American College of Rheumatology (ACR) 2024 Annual Meeting.

The noninvasive biomarker panel “robustly predicts meaningful and actionable histological findings” in patients with active proliferative LN, Andrea Fava, MD, assistant professor of medicine in the Division of Rheumatology at Johns Hopkins Medicine in Baltimore, told attendees.

“In contrast to proteinuria, which can’t differentiate inflammation from damage, this panel for histological activity includes a set of 12 proteins linked to intrarenal inflammation,” said Fava, director of Lupus Translational Research at Johns Hopkins. A decline in the biomarker score at 3 months predicted a clinical response at 1 year, and persistent elevation of the score at 1 year predicted permanent loss of kidney function, “which makes it tempting as a treatment endpoint,” Fava said. “Upon further validation, this biomarker panel could aid in the diagnosis of lupus nephritis and guide treatment decisions.” 

Alfred Kim, MD, PhD, an associate professor of medicine at Washington University in St. Louis, was not involved in the research but noted the potential value of a reliable biomarker panel.

“If we have urinary biomarkers that strongly associate with histologic activity, this would be a game changer in the management of LN,” Kim told Medscape Medical News. “Right now, the gold standard is to perform another kidney biopsy to determine if therapy is working. But this is invasive, and many patients do not want to do another kidney biopsy. Conversely, the easiest way to assess lupus nephritis activity is through a urinalysis, focusing on urinary protein levels,” but relying on proteinuria has limitations as well.

“The most important [limitation] is that proteinuria cannot distinguish treatable inflammation from chronic damage,” Fava said. Persistent histologic activity in patients without proteinuria predicts flares, but tracking histologic activity, as Kim noted, requires repeat biopsies.

“So we need better biomarkers because biomarkers that can reflect tissue biology in real time can guide personalized treatment, and that’s one of the main goals of the Accelerating Medicines Partnership [AMP],” he said. The AMP is a public-private partnership between the National Institutes of Health (NIH), the US Food and Drug Administration (FDA), multiple biopharmaceutical and life science companies, and nonprofit and other organizations. Lupus is one of the AMP’s funded projects.

Kim agreed that “effective biomarkers are a huge unmet need in LN.” Further, he said, “imagine a world where the diagnosis of LN can be made just through urinary biomarkers and obviate the need for biopsy. Both patients and providers will be ecstatic at this possibility.” 

Fava described the background for how his research team determined what biomarkers to test. They had previously enrolled 225 patients with LN undergoing a clinically indicated kidney biopsy and collected urine samples from them at baseline and at 12, 24, and 52 weeks after their biopsy.

Of the 225 patients included, 9% with only mesangial LN (class I-II), 25% with pure membranous LN (class V), 24% with mixed LN (class III or IV with or without V), 38% with proliferative LN (class III or IV), and 4% with advanced sclerosis LN (class VI). From these samples, they quantified 1200 proteins and looked at how they correlated with histologic activity.

“What was interesting was that in patients who were classified as responders after 1 year, there were many of these proteins that declined as early as 3 months, suggesting that effective immunosuppression is reducing intrarenal inflammation, and we can capture it in real time,” Fava said.

 

Biomarker Panel Predicts Histologically Active LN

So they set to determining whether they could develop a urinary biomarker for histologically active LN that could be useful in clinical decision-making. They focused on one that could detect active proliferative LN with an NIH activity index score > 2. Their 179 participants included 47.5% Black, 27.9% White, and 14.5% Asian participants, with 10.1% of other races. The predominantly female (86.6%) cohort had an average age of 37 years. Among the LN classes, about one third (34.6%) had pure proliferative disease, 17.9% had mixed proliferative, 27.9% had pure membranous, 11.7% had class I or II, and 5% had class VI. Just over half the participants (55.7%) had not responded to treatment at 12 months, whereas 25% had a complete response, and 19.3% had a partial response.

However, both the 78 participants with an NIH activity index score > 2 and the 101 with a score ≤ 2 had a median score of 3 on the NIH chronicity index. And the urine protein-to-creatinine ratio — 2.8 in the group with an NIH activity index score > 2 and 2.4 in the other group — was nearly indistinguishable between the two groups, Fava said.

They then trained multiple algorithms on 80% of the data to find the best performing set of proteins (with an area under the curve [AUC] of 90%) for predicting an NIH activity index score > 2. They reduced the number of proteins to maximize practicality and performance of the panel, Fava said, and ultimately identified a 12-protein panel that was highly predictive of an NIH activity index score > 2. Then, they validated that panel using the other 20% of the data. The training set had an AUC of 90%, and the test set was validated with an AUC of 93%.

The 12-protein panel score outperformed anti-dsDNA, C3 complement, and proteinuria, with a sensitivity of 81%, a specificity of 90%, a positive predictive value of 87%, a negative predictive value of 86%, and an accuracy of 86%. The proteins with the greatest relative importance were CD163, cathepsin S, FOLR2, and CEACAM-1.

“In contrast to proteinuria, these proteins were related to inflammatory processes found in the kidneys in patients with lupus nephritis, such as activation of macrophages, neutrophils and monocytes, lymphocytes, and complement,” Fava said.

When they looked at the trajectories of the probabilities from the biomarker panel at 3, 6, and 12 months, the probability of the NIH activity index score remaining > 2 stayed high in the nonresponders over 1 year, but the trajectory declined at 3 months in the responders, indicating a decrease in kidney inflammation (P < .001).

 

Can the Biomarker Panel Serve as a Treatment Endpoint?

Then, to determine whether the panel could act as a reliable treatment endpoint, the researchers followed the patients for up to 7 years. One third of the patients lost more than 40% of their kidney function during the follow-up. They found that a high urinary biomarker score at 12 months predicted future glomerular filtration rate loss, independent of proteinuria.

This panel was tested specifically for proliferative LN, so “we may need distinct panels for each [LN type] to capture most of these patients,” Kim said. “I think that’s where the gold mine is: A personalized medicine approach where a large biomarker panel identifies which smaller panel that patient best fits, then use that for monitoring.”

Kim did note an important potential limitation in the study regarding how samples are used in biomarker discovery and validation vs in clinical practice. “Most samples in research studies are frozen, then thawed, while urine is assayed within a couple hours after collection in the clinical setting,” he said. “Do sample processing differences create a situation where a biomarker works in a research project but not in the clinical setting?” But more likely, he said, the opposite may be the case, where frozen samples allow for more degradation of proteins and potentially useful LN biomarker candidates are never detected.

Another challenge, Kim added, albeit unrelated to the study findings, is that diagnostic companies are finding it difficult to get payers to cover new tests, so that could become a challenge if the panel undergoes further validation and then FDA qualification.

The research was funded by Exagen. Fava reported disclosures with Arctiva, AstraZeneca, Exagen, Novartis, UCB, Bristol Myers Squibb, Annexon Bio, and Bain Capital. His coauthors reported financial relationships with numerous pharmaceutical and life science companies, including Exagen, and some are employees of Exagen.

Kim reported research agreements with AstraZeneca, Bristol Myers Squibb, Novartis, and CRISPR Therapeutics; receiving royalties from Kypha; and receiving consulting/speaking fees from AbbVie, Amgen, Atara Bio, Aurinia, Cargo Tx, Exagen, GlaxoSmithKline, Hinge Bio, Kypha, and UpToDate.

 

A version of this article appeared on Medscape.com.

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WASHINGTON — An investigational 12-protein panel of urinary biomarkers predicted histologically active lupus nephritis (LN) with 86% accuracy, according to research presented at the American College of Rheumatology (ACR) 2024 Annual Meeting.

The noninvasive biomarker panel “robustly predicts meaningful and actionable histological findings” in patients with active proliferative LN, Andrea Fava, MD, assistant professor of medicine in the Division of Rheumatology at Johns Hopkins Medicine in Baltimore, told attendees.

“In contrast to proteinuria, which can’t differentiate inflammation from damage, this panel for histological activity includes a set of 12 proteins linked to intrarenal inflammation,” said Fava, director of Lupus Translational Research at Johns Hopkins. A decline in the biomarker score at 3 months predicted a clinical response at 1 year, and persistent elevation of the score at 1 year predicted permanent loss of kidney function, “which makes it tempting as a treatment endpoint,” Fava said. “Upon further validation, this biomarker panel could aid in the diagnosis of lupus nephritis and guide treatment decisions.” 

Alfred Kim, MD, PhD, an associate professor of medicine at Washington University in St. Louis, was not involved in the research but noted the potential value of a reliable biomarker panel.

“If we have urinary biomarkers that strongly associate with histologic activity, this would be a game changer in the management of LN,” Kim told Medscape Medical News. “Right now, the gold standard is to perform another kidney biopsy to determine if therapy is working. But this is invasive, and many patients do not want to do another kidney biopsy. Conversely, the easiest way to assess lupus nephritis activity is through a urinalysis, focusing on urinary protein levels,” but relying on proteinuria has limitations as well.

“The most important [limitation] is that proteinuria cannot distinguish treatable inflammation from chronic damage,” Fava said. Persistent histologic activity in patients without proteinuria predicts flares, but tracking histologic activity, as Kim noted, requires repeat biopsies.

“So we need better biomarkers because biomarkers that can reflect tissue biology in real time can guide personalized treatment, and that’s one of the main goals of the Accelerating Medicines Partnership [AMP],” he said. The AMP is a public-private partnership between the National Institutes of Health (NIH), the US Food and Drug Administration (FDA), multiple biopharmaceutical and life science companies, and nonprofit and other organizations. Lupus is one of the AMP’s funded projects.

Kim agreed that “effective biomarkers are a huge unmet need in LN.” Further, he said, “imagine a world where the diagnosis of LN can be made just through urinary biomarkers and obviate the need for biopsy. Both patients and providers will be ecstatic at this possibility.” 

Fava described the background for how his research team determined what biomarkers to test. They had previously enrolled 225 patients with LN undergoing a clinically indicated kidney biopsy and collected urine samples from them at baseline and at 12, 24, and 52 weeks after their biopsy.

Of the 225 patients included, 9% with only mesangial LN (class I-II), 25% with pure membranous LN (class V), 24% with mixed LN (class III or IV with or without V), 38% with proliferative LN (class III or IV), and 4% with advanced sclerosis LN (class VI). From these samples, they quantified 1200 proteins and looked at how they correlated with histologic activity.

“What was interesting was that in patients who were classified as responders after 1 year, there were many of these proteins that declined as early as 3 months, suggesting that effective immunosuppression is reducing intrarenal inflammation, and we can capture it in real time,” Fava said.

 

Biomarker Panel Predicts Histologically Active LN

So they set to determining whether they could develop a urinary biomarker for histologically active LN that could be useful in clinical decision-making. They focused on one that could detect active proliferative LN with an NIH activity index score > 2. Their 179 participants included 47.5% Black, 27.9% White, and 14.5% Asian participants, with 10.1% of other races. The predominantly female (86.6%) cohort had an average age of 37 years. Among the LN classes, about one third (34.6%) had pure proliferative disease, 17.9% had mixed proliferative, 27.9% had pure membranous, 11.7% had class I or II, and 5% had class VI. Just over half the participants (55.7%) had not responded to treatment at 12 months, whereas 25% had a complete response, and 19.3% had a partial response.

However, both the 78 participants with an NIH activity index score > 2 and the 101 with a score ≤ 2 had a median score of 3 on the NIH chronicity index. And the urine protein-to-creatinine ratio — 2.8 in the group with an NIH activity index score > 2 and 2.4 in the other group — was nearly indistinguishable between the two groups, Fava said.

They then trained multiple algorithms on 80% of the data to find the best performing set of proteins (with an area under the curve [AUC] of 90%) for predicting an NIH activity index score > 2. They reduced the number of proteins to maximize practicality and performance of the panel, Fava said, and ultimately identified a 12-protein panel that was highly predictive of an NIH activity index score > 2. Then, they validated that panel using the other 20% of the data. The training set had an AUC of 90%, and the test set was validated with an AUC of 93%.

The 12-protein panel score outperformed anti-dsDNA, C3 complement, and proteinuria, with a sensitivity of 81%, a specificity of 90%, a positive predictive value of 87%, a negative predictive value of 86%, and an accuracy of 86%. The proteins with the greatest relative importance were CD163, cathepsin S, FOLR2, and CEACAM-1.

“In contrast to proteinuria, these proteins were related to inflammatory processes found in the kidneys in patients with lupus nephritis, such as activation of macrophages, neutrophils and monocytes, lymphocytes, and complement,” Fava said.

When they looked at the trajectories of the probabilities from the biomarker panel at 3, 6, and 12 months, the probability of the NIH activity index score remaining > 2 stayed high in the nonresponders over 1 year, but the trajectory declined at 3 months in the responders, indicating a decrease in kidney inflammation (P < .001).

 

Can the Biomarker Panel Serve as a Treatment Endpoint?

Then, to determine whether the panel could act as a reliable treatment endpoint, the researchers followed the patients for up to 7 years. One third of the patients lost more than 40% of their kidney function during the follow-up. They found that a high urinary biomarker score at 12 months predicted future glomerular filtration rate loss, independent of proteinuria.

This panel was tested specifically for proliferative LN, so “we may need distinct panels for each [LN type] to capture most of these patients,” Kim said. “I think that’s where the gold mine is: A personalized medicine approach where a large biomarker panel identifies which smaller panel that patient best fits, then use that for monitoring.”

Kim did note an important potential limitation in the study regarding how samples are used in biomarker discovery and validation vs in clinical practice. “Most samples in research studies are frozen, then thawed, while urine is assayed within a couple hours after collection in the clinical setting,” he said. “Do sample processing differences create a situation where a biomarker works in a research project but not in the clinical setting?” But more likely, he said, the opposite may be the case, where frozen samples allow for more degradation of proteins and potentially useful LN biomarker candidates are never detected.

Another challenge, Kim added, albeit unrelated to the study findings, is that diagnostic companies are finding it difficult to get payers to cover new tests, so that could become a challenge if the panel undergoes further validation and then FDA qualification.

The research was funded by Exagen. Fava reported disclosures with Arctiva, AstraZeneca, Exagen, Novartis, UCB, Bristol Myers Squibb, Annexon Bio, and Bain Capital. His coauthors reported financial relationships with numerous pharmaceutical and life science companies, including Exagen, and some are employees of Exagen.

Kim reported research agreements with AstraZeneca, Bristol Myers Squibb, Novartis, and CRISPR Therapeutics; receiving royalties from Kypha; and receiving consulting/speaking fees from AbbVie, Amgen, Atara Bio, Aurinia, Cargo Tx, Exagen, GlaxoSmithKline, Hinge Bio, Kypha, and UpToDate.

 

A version of this article appeared on Medscape.com.

WASHINGTON — An investigational 12-protein panel of urinary biomarkers predicted histologically active lupus nephritis (LN) with 86% accuracy, according to research presented at the American College of Rheumatology (ACR) 2024 Annual Meeting.

The noninvasive biomarker panel “robustly predicts meaningful and actionable histological findings” in patients with active proliferative LN, Andrea Fava, MD, assistant professor of medicine in the Division of Rheumatology at Johns Hopkins Medicine in Baltimore, told attendees.

“In contrast to proteinuria, which can’t differentiate inflammation from damage, this panel for histological activity includes a set of 12 proteins linked to intrarenal inflammation,” said Fava, director of Lupus Translational Research at Johns Hopkins. A decline in the biomarker score at 3 months predicted a clinical response at 1 year, and persistent elevation of the score at 1 year predicted permanent loss of kidney function, “which makes it tempting as a treatment endpoint,” Fava said. “Upon further validation, this biomarker panel could aid in the diagnosis of lupus nephritis and guide treatment decisions.” 

Alfred Kim, MD, PhD, an associate professor of medicine at Washington University in St. Louis, was not involved in the research but noted the potential value of a reliable biomarker panel.

“If we have urinary biomarkers that strongly associate with histologic activity, this would be a game changer in the management of LN,” Kim told Medscape Medical News. “Right now, the gold standard is to perform another kidney biopsy to determine if therapy is working. But this is invasive, and many patients do not want to do another kidney biopsy. Conversely, the easiest way to assess lupus nephritis activity is through a urinalysis, focusing on urinary protein levels,” but relying on proteinuria has limitations as well.

“The most important [limitation] is that proteinuria cannot distinguish treatable inflammation from chronic damage,” Fava said. Persistent histologic activity in patients without proteinuria predicts flares, but tracking histologic activity, as Kim noted, requires repeat biopsies.

“So we need better biomarkers because biomarkers that can reflect tissue biology in real time can guide personalized treatment, and that’s one of the main goals of the Accelerating Medicines Partnership [AMP],” he said. The AMP is a public-private partnership between the National Institutes of Health (NIH), the US Food and Drug Administration (FDA), multiple biopharmaceutical and life science companies, and nonprofit and other organizations. Lupus is one of the AMP’s funded projects.

Kim agreed that “effective biomarkers are a huge unmet need in LN.” Further, he said, “imagine a world where the diagnosis of LN can be made just through urinary biomarkers and obviate the need for biopsy. Both patients and providers will be ecstatic at this possibility.” 

Fava described the background for how his research team determined what biomarkers to test. They had previously enrolled 225 patients with LN undergoing a clinically indicated kidney biopsy and collected urine samples from them at baseline and at 12, 24, and 52 weeks after their biopsy.

Of the 225 patients included, 9% with only mesangial LN (class I-II), 25% with pure membranous LN (class V), 24% with mixed LN (class III or IV with or without V), 38% with proliferative LN (class III or IV), and 4% with advanced sclerosis LN (class VI). From these samples, they quantified 1200 proteins and looked at how they correlated with histologic activity.

“What was interesting was that in patients who were classified as responders after 1 year, there were many of these proteins that declined as early as 3 months, suggesting that effective immunosuppression is reducing intrarenal inflammation, and we can capture it in real time,” Fava said.

 

Biomarker Panel Predicts Histologically Active LN

So they set to determining whether they could develop a urinary biomarker for histologically active LN that could be useful in clinical decision-making. They focused on one that could detect active proliferative LN with an NIH activity index score > 2. Their 179 participants included 47.5% Black, 27.9% White, and 14.5% Asian participants, with 10.1% of other races. The predominantly female (86.6%) cohort had an average age of 37 years. Among the LN classes, about one third (34.6%) had pure proliferative disease, 17.9% had mixed proliferative, 27.9% had pure membranous, 11.7% had class I or II, and 5% had class VI. Just over half the participants (55.7%) had not responded to treatment at 12 months, whereas 25% had a complete response, and 19.3% had a partial response.

However, both the 78 participants with an NIH activity index score > 2 and the 101 with a score ≤ 2 had a median score of 3 on the NIH chronicity index. And the urine protein-to-creatinine ratio — 2.8 in the group with an NIH activity index score > 2 and 2.4 in the other group — was nearly indistinguishable between the two groups, Fava said.

They then trained multiple algorithms on 80% of the data to find the best performing set of proteins (with an area under the curve [AUC] of 90%) for predicting an NIH activity index score > 2. They reduced the number of proteins to maximize practicality and performance of the panel, Fava said, and ultimately identified a 12-protein panel that was highly predictive of an NIH activity index score > 2. Then, they validated that panel using the other 20% of the data. The training set had an AUC of 90%, and the test set was validated with an AUC of 93%.

The 12-protein panel score outperformed anti-dsDNA, C3 complement, and proteinuria, with a sensitivity of 81%, a specificity of 90%, a positive predictive value of 87%, a negative predictive value of 86%, and an accuracy of 86%. The proteins with the greatest relative importance were CD163, cathepsin S, FOLR2, and CEACAM-1.

“In contrast to proteinuria, these proteins were related to inflammatory processes found in the kidneys in patients with lupus nephritis, such as activation of macrophages, neutrophils and monocytes, lymphocytes, and complement,” Fava said.

When they looked at the trajectories of the probabilities from the biomarker panel at 3, 6, and 12 months, the probability of the NIH activity index score remaining > 2 stayed high in the nonresponders over 1 year, but the trajectory declined at 3 months in the responders, indicating a decrease in kidney inflammation (P < .001).

 

Can the Biomarker Panel Serve as a Treatment Endpoint?

Then, to determine whether the panel could act as a reliable treatment endpoint, the researchers followed the patients for up to 7 years. One third of the patients lost more than 40% of their kidney function during the follow-up. They found that a high urinary biomarker score at 12 months predicted future glomerular filtration rate loss, independent of proteinuria.

This panel was tested specifically for proliferative LN, so “we may need distinct panels for each [LN type] to capture most of these patients,” Kim said. “I think that’s where the gold mine is: A personalized medicine approach where a large biomarker panel identifies which smaller panel that patient best fits, then use that for monitoring.”

Kim did note an important potential limitation in the study regarding how samples are used in biomarker discovery and validation vs in clinical practice. “Most samples in research studies are frozen, then thawed, while urine is assayed within a couple hours after collection in the clinical setting,” he said. “Do sample processing differences create a situation where a biomarker works in a research project but not in the clinical setting?” But more likely, he said, the opposite may be the case, where frozen samples allow for more degradation of proteins and potentially useful LN biomarker candidates are never detected.

Another challenge, Kim added, albeit unrelated to the study findings, is that diagnostic companies are finding it difficult to get payers to cover new tests, so that could become a challenge if the panel undergoes further validation and then FDA qualification.

The research was funded by Exagen. Fava reported disclosures with Arctiva, AstraZeneca, Exagen, Novartis, UCB, Bristol Myers Squibb, Annexon Bio, and Bain Capital. His coauthors reported financial relationships with numerous pharmaceutical and life science companies, including Exagen, and some are employees of Exagen.

Kim reported research agreements with AstraZeneca, Bristol Myers Squibb, Novartis, and CRISPR Therapeutics; receiving royalties from Kypha; and receiving consulting/speaking fees from AbbVie, Amgen, Atara Bio, Aurinia, Cargo Tx, Exagen, GlaxoSmithKline, Hinge Bio, Kypha, and UpToDate.

 

A version of this article appeared on Medscape.com.

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Real-World Data Question Low-Dose Steroid Use in ANCA Vasculitis

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Changed
Mon, 12/09/2024 - 12:03
Author(s)
Shrabasti Bhattacharya

TOPLINE:

Compared with a standard dosing regimen, a reduced-dose glucocorticoid regimen is associated with an increased risk for disease progression, relapse, death, or kidney failure in antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis, particularly affecting patients receiving rituximab or those with elevated creatinine levels.

METHODOLOGY:

  • The PEXIVAS trial demonstrated that a reduced-dose glucocorticoid regimen was noninferior to standard dosing in terms of death or end-stage kidney disease in ANCA-associated vasculitis. However, the trial did not include disease progression or relapse as a primary endpoint, and cyclophosphamide was the primary induction therapy.
  • Researchers conducted this retrospective study across 19 hospitals (18 in France and one in Luxembourg) between January 2018 and November 2022 to compare the effectiveness of a reduced-dose glucocorticoid regimen, as used in the PEXIVAS trial, with a standard-dose regimen in patients with ANCA-associated vasculitis in the real-world setting.
  • They included 234 patients aged > 15 years (51% men) with severe granulomatosis with polyangiitis (n = 141) or microscopic polyangiitis (n = 93) who received induction therapy with rituximab or cyclophosphamide; 126 and 108 patients received reduced-dose and standard-dose glucocorticoid regimens, respectively.
  • Most patients (70%) had severe renal involvement.
  • The primary composite outcome encompassed minor relapse, major relapse, disease progression before remission, end-stage kidney disease requiring dialysis for > 12 weeks or transplantation, and death within 12 months post-induction.

TAKEAWAY:

  • The primary composite outcome occurred in a higher proportion of patients receiving reduced-dose glucocorticoid therapy than in those receiving standard-dose therapy (33.3% vs 18.5%; hazard ratio [HR], 2.20; 95% CI, 1.23-3.94).
  • However, no significant association was found between reduced-dose glucocorticoids and the risk for death or end-stage kidney disease or the occurrence of serious infections.
  • Among patients receiving reduced-dose glucocorticoids, serum creatinine levels > 300 μmol/L were associated with an increased risk for the primary composite outcome (adjusted HR, 3.02; 95% CI, 1.28-7.11).
  • In the rituximab induction subgroup, reduced-dose glucocorticoid was associated with an increased risk for the primary composite outcome (adjusted HR, 2.36; 95% CI, 1.18-4.71), compared with standard-dose glucocorticoids.

IN PRACTICE:

“Our data suggest increased vigilance when using the [reduced-dose glucocorticoid] regimen, especially in the two subgroups of patients at higher risk of failure, that is, those receiving [rituximab] as induction therapy and those with a baseline serum creatinine greater than 300 μmol/L,” the authors wrote.

SOURCE:

The study was led by Sophie Nagle, MD, National Referral Centre for Rare Autoimmune and Systemic Diseases, Department of Internal Medicine, Hôpital Cochin, Paris, France. It was published online on November 20, 2024, in Annals of the Rheumatic Diseases.

LIMITATIONS:

The retrospective nature of this study may have introduced inherent limitations and potential selection bias. The study lacked data on patient comorbidities, which could have influenced treatment choice and outcomes. Additionally, about a quarter of patients did not receive methylprednisolone pulses prior to oral glucocorticoids, unlike the PEXIVAS trial protocol. The group receiving standard-dose glucocorticoids showed heterogeneity in glucocorticoid regimens, and the minimum follow-up was only 6 months.

DISCLOSURES:

This study did not report any source of funding. The authors reported no relevant conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

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Author(s)
Shrabasti Bhattacharya

TOPLINE:

Compared with a standard dosing regimen, a reduced-dose glucocorticoid regimen is associated with an increased risk for disease progression, relapse, death, or kidney failure in antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis, particularly affecting patients receiving rituximab or those with elevated creatinine levels.

METHODOLOGY:

  • The PEXIVAS trial demonstrated that a reduced-dose glucocorticoid regimen was noninferior to standard dosing in terms of death or end-stage kidney disease in ANCA-associated vasculitis. However, the trial did not include disease progression or relapse as a primary endpoint, and cyclophosphamide was the primary induction therapy.
  • Researchers conducted this retrospective study across 19 hospitals (18 in France and one in Luxembourg) between January 2018 and November 2022 to compare the effectiveness of a reduced-dose glucocorticoid regimen, as used in the PEXIVAS trial, with a standard-dose regimen in patients with ANCA-associated vasculitis in the real-world setting.
  • They included 234 patients aged > 15 years (51% men) with severe granulomatosis with polyangiitis (n = 141) or microscopic polyangiitis (n = 93) who received induction therapy with rituximab or cyclophosphamide; 126 and 108 patients received reduced-dose and standard-dose glucocorticoid regimens, respectively.
  • Most patients (70%) had severe renal involvement.
  • The primary composite outcome encompassed minor relapse, major relapse, disease progression before remission, end-stage kidney disease requiring dialysis for > 12 weeks or transplantation, and death within 12 months post-induction.

TAKEAWAY:

  • The primary composite outcome occurred in a higher proportion of patients receiving reduced-dose glucocorticoid therapy than in those receiving standard-dose therapy (33.3% vs 18.5%; hazard ratio [HR], 2.20; 95% CI, 1.23-3.94).
  • However, no significant association was found between reduced-dose glucocorticoids and the risk for death or end-stage kidney disease or the occurrence of serious infections.
  • Among patients receiving reduced-dose glucocorticoids, serum creatinine levels > 300 μmol/L were associated with an increased risk for the primary composite outcome (adjusted HR, 3.02; 95% CI, 1.28-7.11).
  • In the rituximab induction subgroup, reduced-dose glucocorticoid was associated with an increased risk for the primary composite outcome (adjusted HR, 2.36; 95% CI, 1.18-4.71), compared with standard-dose glucocorticoids.

IN PRACTICE:

“Our data suggest increased vigilance when using the [reduced-dose glucocorticoid] regimen, especially in the two subgroups of patients at higher risk of failure, that is, those receiving [rituximab] as induction therapy and those with a baseline serum creatinine greater than 300 μmol/L,” the authors wrote.

SOURCE:

The study was led by Sophie Nagle, MD, National Referral Centre for Rare Autoimmune and Systemic Diseases, Department of Internal Medicine, Hôpital Cochin, Paris, France. It was published online on November 20, 2024, in Annals of the Rheumatic Diseases.

LIMITATIONS:

The retrospective nature of this study may have introduced inherent limitations and potential selection bias. The study lacked data on patient comorbidities, which could have influenced treatment choice and outcomes. Additionally, about a quarter of patients did not receive methylprednisolone pulses prior to oral glucocorticoids, unlike the PEXIVAS trial protocol. The group receiving standard-dose glucocorticoids showed heterogeneity in glucocorticoid regimens, and the minimum follow-up was only 6 months.

DISCLOSURES:

This study did not report any source of funding. The authors reported no relevant conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

TOPLINE:

Compared with a standard dosing regimen, a reduced-dose glucocorticoid regimen is associated with an increased risk for disease progression, relapse, death, or kidney failure in antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis, particularly affecting patients receiving rituximab or those with elevated creatinine levels.

METHODOLOGY:

  • The PEXIVAS trial demonstrated that a reduced-dose glucocorticoid regimen was noninferior to standard dosing in terms of death or end-stage kidney disease in ANCA-associated vasculitis. However, the trial did not include disease progression or relapse as a primary endpoint, and cyclophosphamide was the primary induction therapy.
  • Researchers conducted this retrospective study across 19 hospitals (18 in France and one in Luxembourg) between January 2018 and November 2022 to compare the effectiveness of a reduced-dose glucocorticoid regimen, as used in the PEXIVAS trial, with a standard-dose regimen in patients with ANCA-associated vasculitis in the real-world setting.
  • They included 234 patients aged > 15 years (51% men) with severe granulomatosis with polyangiitis (n = 141) or microscopic polyangiitis (n = 93) who received induction therapy with rituximab or cyclophosphamide; 126 and 108 patients received reduced-dose and standard-dose glucocorticoid regimens, respectively.
  • Most patients (70%) had severe renal involvement.
  • The primary composite outcome encompassed minor relapse, major relapse, disease progression before remission, end-stage kidney disease requiring dialysis for > 12 weeks or transplantation, and death within 12 months post-induction.

TAKEAWAY:

  • The primary composite outcome occurred in a higher proportion of patients receiving reduced-dose glucocorticoid therapy than in those receiving standard-dose therapy (33.3% vs 18.5%; hazard ratio [HR], 2.20; 95% CI, 1.23-3.94).
  • However, no significant association was found between reduced-dose glucocorticoids and the risk for death or end-stage kidney disease or the occurrence of serious infections.
  • Among patients receiving reduced-dose glucocorticoids, serum creatinine levels > 300 μmol/L were associated with an increased risk for the primary composite outcome (adjusted HR, 3.02; 95% CI, 1.28-7.11).
  • In the rituximab induction subgroup, reduced-dose glucocorticoid was associated with an increased risk for the primary composite outcome (adjusted HR, 2.36; 95% CI, 1.18-4.71), compared with standard-dose glucocorticoids.

IN PRACTICE:

“Our data suggest increased vigilance when using the [reduced-dose glucocorticoid] regimen, especially in the two subgroups of patients at higher risk of failure, that is, those receiving [rituximab] as induction therapy and those with a baseline serum creatinine greater than 300 μmol/L,” the authors wrote.

SOURCE:

The study was led by Sophie Nagle, MD, National Referral Centre for Rare Autoimmune and Systemic Diseases, Department of Internal Medicine, Hôpital Cochin, Paris, France. It was published online on November 20, 2024, in Annals of the Rheumatic Diseases.

LIMITATIONS:

The retrospective nature of this study may have introduced inherent limitations and potential selection bias. The study lacked data on patient comorbidities, which could have influenced treatment choice and outcomes. Additionally, about a quarter of patients did not receive methylprednisolone pulses prior to oral glucocorticoids, unlike the PEXIVAS trial protocol. The group receiving standard-dose glucocorticoids showed heterogeneity in glucocorticoid regimens, and the minimum follow-up was only 6 months.

DISCLOSURES:

This study did not report any source of funding. The authors reported no relevant conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

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REALIZE-K: A New Potassium Binder to Help Keep Spiro on Board

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Thu, 12/05/2024 - 11:17
Author(s)
Ileana L. Piña, MD, MPH

This transcript has been edited for clarity. 

We have talked often in the past about potassium. Why is potassium so important in heart failure? It’s because many doctors are afraid to give some of the drugs that will raise the potassium, because then you need to deal with it —and everybody is afraid of hyperkalemia causing arrhythmias. 

Calm those nerves. Just remember that arrhythmias only occur when the potassium suddenly goes up. This chronic hyperkalemia, which occurs with many of our drugs, usually — I can’t say every time — does not result in arrhythmias.

 

Patiromer and Zirconium Cyclosilicate

Now, we’ve got potassium binders. You’ve heard me talk about the potassium binders in several of my other chats with you, and they work. We have primarily two of them. The first one that came out was patiromer, and now I’m going to talk to you a little bit about zirconium cyclosilicate, which uses sodium as its exchange ion. Whenever you take out one ion, you have to put another one in, and in this case it’s sodium. Maybe if you use it in the higher doses, you can give the patient more edema or you can make the patient congested with more fluid. 

Years ago we did the DIAMOND study; it was a patiromer study, but in essence we found that you could continue to give the drug, particularly the mineralocorticoid receptor antagonists (MRAs) such as spironolactone or eplerenone, as long as you have the patiromer as your safety net, and that the drugs were well tolerated and the adverse events were significantly less.

 

The REALIZE-K Trial

Now, let’s talk about the REALIZE-K trial. The researchers wanted to prove basically the same thing: that the patients could be started or kept on their spironolactone as long as you had that backup of the zirconium cyclosilicate binder.

They picked patients who had HFrEF — so, low ejection fractions, defined as less than 40% — and they were already on guideline-directed medical therapy, but not an MRA. They divided up the patients right from the beginning between those who were already hyperkalemic — in other words, they had potassiums of 5.1-5.9 mEq/L, which is when doctors start getting worried. GFRs had to be better than 30 mL/min per 1.73 m2, and if the potassium was not yet okay, they were given the zirconium cyclosilicate to normalize the potassium and then they entered the study. 

The second group had some history of or were at risk for hyperkalemia. Maybe their GFRs were lower, but their potassiums were somewhere between 3.5 and 5 mEq/L.

They started with about 366 patients. These trials have not been huge, certainly not what we normally see in heart failure trials. About 95 patients had hyperkalemia initially and 271 patients were normokalemic. 

Then they were randomized; about 102 patients went on the potassium binder and the other group went on the placebo. They continued the study and they continued to check whether the patient had to come off the drug or had to reduce or remove the spironolactone. 

These were older patients, mostly in their early seventies. This was an international trial. There were not that many patients from North America, but they had quite a few patients from Europe and some patients from Latin America. There were many with diabetes, atrial fibrillation, and all the usual comorbidities that we typically see. 

The proportions of patients classified as New York Heart Association Class III and IV were about 16% to 17% and the rest were Class II, so this is really the ambulatory population. NT-proBNP levels were elevated, at approximately 1000-1200 pg/mL, and the GFRs were either in the high 40s or about 60 mL/min per 1.73 m2. The patients were pretty well medicated, including with RAAS inhibition, beta-blockers, and even SGLT2 inhibitors. 

This is a very typical population and they wanted to see what happened. Did the patients remain on the binder and were they able to tolerate the spironolactone? In fact, that was the case.

At the end of the study, more patients had been able to stay on their spironolactone, which is that one drug that we’re not doing so well on when you look at large databases. If they were on the zirconium drug, they were more likely to stay on the spironolactone. They even did a sensitivity analysis, which really showed that it was consistent across the board. 

 

Edema and Hyperkalemia

Now we have two binders that have shown to us that patients can stay on their drugs. There were some interesting findings here, though.

There was more edema — again, everything is based on small numbers — and there seemed to be more heart failure events in the group that received the zirconium cyclosilicate. The first episode of hyperkalemia was delayed or didn’t happen at all. Again, the hyperkalemia was controlled. 

What does that tell you? Well, the exchange is sodium. There had been reports before that if you gave this binder at the higher doses, you would have more retention of sodium. I think we see that in this trial, even though the numbers are very small. 

According to the investigators, these were issues that could be resolved through an increase in diuretics or having the patient remember to be careful with their sodium intake so they don’t retain more fluid. 

My message to you is to use these binders, whichever one of the two you want or whichever your hospital has available for you on their formulary, because it may give you that sense of comfort and self-efficacy so that you can actually start your patients on an MRA and keep them on it.

The MRAs are lifesaving drugs and the patients with HFrEF need to be on them. This is a way to do it without having to sacrifice your true guideline-directed medical therapy.

Dr. Piña, Professor of Medicine/Cardiology/Heart Failure/Transplant; Quality Officer, Cardiovascular Line, Sidney Kimmel College of Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania; Clinical Professor of Medicine, Central Michigan University College of Medicine, Mount Pleasant, Michigan; Adjunct Professor of Epidemiology and Biostatistics, Population & Quantitative Health Sciences, Case Western University, Cleveland, Ohio, disclosed ties with the Food and Drug Administration’s Center for Devices and Radiological Health.

A version of this article appeared on Medscape.com

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This transcript has been edited for clarity. 

We have talked often in the past about potassium. Why is potassium so important in heart failure? It’s because many doctors are afraid to give some of the drugs that will raise the potassium, because then you need to deal with it —and everybody is afraid of hyperkalemia causing arrhythmias. 

Calm those nerves. Just remember that arrhythmias only occur when the potassium suddenly goes up. This chronic hyperkalemia, which occurs with many of our drugs, usually — I can’t say every time — does not result in arrhythmias.

 

Patiromer and Zirconium Cyclosilicate

Now, we’ve got potassium binders. You’ve heard me talk about the potassium binders in several of my other chats with you, and they work. We have primarily two of them. The first one that came out was patiromer, and now I’m going to talk to you a little bit about zirconium cyclosilicate, which uses sodium as its exchange ion. Whenever you take out one ion, you have to put another one in, and in this case it’s sodium. Maybe if you use it in the higher doses, you can give the patient more edema or you can make the patient congested with more fluid. 

Years ago we did the DIAMOND study; it was a patiromer study, but in essence we found that you could continue to give the drug, particularly the mineralocorticoid receptor antagonists (MRAs) such as spironolactone or eplerenone, as long as you have the patiromer as your safety net, and that the drugs were well tolerated and the adverse events were significantly less.

 

The REALIZE-K Trial

Now, let’s talk about the REALIZE-K trial. The researchers wanted to prove basically the same thing: that the patients could be started or kept on their spironolactone as long as you had that backup of the zirconium cyclosilicate binder.

They picked patients who had HFrEF — so, low ejection fractions, defined as less than 40% — and they were already on guideline-directed medical therapy, but not an MRA. They divided up the patients right from the beginning between those who were already hyperkalemic — in other words, they had potassiums of 5.1-5.9 mEq/L, which is when doctors start getting worried. GFRs had to be better than 30 mL/min per 1.73 m2, and if the potassium was not yet okay, they were given the zirconium cyclosilicate to normalize the potassium and then they entered the study. 

The second group had some history of or were at risk for hyperkalemia. Maybe their GFRs were lower, but their potassiums were somewhere between 3.5 and 5 mEq/L.

They started with about 366 patients. These trials have not been huge, certainly not what we normally see in heart failure trials. About 95 patients had hyperkalemia initially and 271 patients were normokalemic. 

Then they were randomized; about 102 patients went on the potassium binder and the other group went on the placebo. They continued the study and they continued to check whether the patient had to come off the drug or had to reduce or remove the spironolactone. 

These were older patients, mostly in their early seventies. This was an international trial. There were not that many patients from North America, but they had quite a few patients from Europe and some patients from Latin America. There were many with diabetes, atrial fibrillation, and all the usual comorbidities that we typically see. 

The proportions of patients classified as New York Heart Association Class III and IV were about 16% to 17% and the rest were Class II, so this is really the ambulatory population. NT-proBNP levels were elevated, at approximately 1000-1200 pg/mL, and the GFRs were either in the high 40s or about 60 mL/min per 1.73 m2. The patients were pretty well medicated, including with RAAS inhibition, beta-blockers, and even SGLT2 inhibitors. 

This is a very typical population and they wanted to see what happened. Did the patients remain on the binder and were they able to tolerate the spironolactone? In fact, that was the case.

At the end of the study, more patients had been able to stay on their spironolactone, which is that one drug that we’re not doing so well on when you look at large databases. If they were on the zirconium drug, they were more likely to stay on the spironolactone. They even did a sensitivity analysis, which really showed that it was consistent across the board. 

 

Edema and Hyperkalemia

Now we have two binders that have shown to us that patients can stay on their drugs. There were some interesting findings here, though.

There was more edema — again, everything is based on small numbers — and there seemed to be more heart failure events in the group that received the zirconium cyclosilicate. The first episode of hyperkalemia was delayed or didn’t happen at all. Again, the hyperkalemia was controlled. 

What does that tell you? Well, the exchange is sodium. There had been reports before that if you gave this binder at the higher doses, you would have more retention of sodium. I think we see that in this trial, even though the numbers are very small. 

According to the investigators, these were issues that could be resolved through an increase in diuretics or having the patient remember to be careful with their sodium intake so they don’t retain more fluid. 

My message to you is to use these binders, whichever one of the two you want or whichever your hospital has available for you on their formulary, because it may give you that sense of comfort and self-efficacy so that you can actually start your patients on an MRA and keep them on it.

The MRAs are lifesaving drugs and the patients with HFrEF need to be on them. This is a way to do it without having to sacrifice your true guideline-directed medical therapy.

Dr. Piña, Professor of Medicine/Cardiology/Heart Failure/Transplant; Quality Officer, Cardiovascular Line, Sidney Kimmel College of Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania; Clinical Professor of Medicine, Central Michigan University College of Medicine, Mount Pleasant, Michigan; Adjunct Professor of Epidemiology and Biostatistics, Population & Quantitative Health Sciences, Case Western University, Cleveland, Ohio, disclosed ties with the Food and Drug Administration’s Center for Devices and Radiological Health.

A version of this article appeared on Medscape.com

This transcript has been edited for clarity. 

We have talked often in the past about potassium. Why is potassium so important in heart failure? It’s because many doctors are afraid to give some of the drugs that will raise the potassium, because then you need to deal with it —and everybody is afraid of hyperkalemia causing arrhythmias. 

Calm those nerves. Just remember that arrhythmias only occur when the potassium suddenly goes up. This chronic hyperkalemia, which occurs with many of our drugs, usually — I can’t say every time — does not result in arrhythmias.

 

Patiromer and Zirconium Cyclosilicate

Now, we’ve got potassium binders. You’ve heard me talk about the potassium binders in several of my other chats with you, and they work. We have primarily two of them. The first one that came out was patiromer, and now I’m going to talk to you a little bit about zirconium cyclosilicate, which uses sodium as its exchange ion. Whenever you take out one ion, you have to put another one in, and in this case it’s sodium. Maybe if you use it in the higher doses, you can give the patient more edema or you can make the patient congested with more fluid. 

Years ago we did the DIAMOND study; it was a patiromer study, but in essence we found that you could continue to give the drug, particularly the mineralocorticoid receptor antagonists (MRAs) such as spironolactone or eplerenone, as long as you have the patiromer as your safety net, and that the drugs were well tolerated and the adverse events were significantly less.

 

The REALIZE-K Trial

Now, let’s talk about the REALIZE-K trial. The researchers wanted to prove basically the same thing: that the patients could be started or kept on their spironolactone as long as you had that backup of the zirconium cyclosilicate binder.

They picked patients who had HFrEF — so, low ejection fractions, defined as less than 40% — and they were already on guideline-directed medical therapy, but not an MRA. They divided up the patients right from the beginning between those who were already hyperkalemic — in other words, they had potassiums of 5.1-5.9 mEq/L, which is when doctors start getting worried. GFRs had to be better than 30 mL/min per 1.73 m2, and if the potassium was not yet okay, they were given the zirconium cyclosilicate to normalize the potassium and then they entered the study. 

The second group had some history of or were at risk for hyperkalemia. Maybe their GFRs were lower, but their potassiums were somewhere between 3.5 and 5 mEq/L.

They started with about 366 patients. These trials have not been huge, certainly not what we normally see in heart failure trials. About 95 patients had hyperkalemia initially and 271 patients were normokalemic. 

Then they were randomized; about 102 patients went on the potassium binder and the other group went on the placebo. They continued the study and they continued to check whether the patient had to come off the drug or had to reduce or remove the spironolactone. 

These were older patients, mostly in their early seventies. This was an international trial. There were not that many patients from North America, but they had quite a few patients from Europe and some patients from Latin America. There were many with diabetes, atrial fibrillation, and all the usual comorbidities that we typically see. 

The proportions of patients classified as New York Heart Association Class III and IV were about 16% to 17% and the rest were Class II, so this is really the ambulatory population. NT-proBNP levels were elevated, at approximately 1000-1200 pg/mL, and the GFRs were either in the high 40s or about 60 mL/min per 1.73 m2. The patients were pretty well medicated, including with RAAS inhibition, beta-blockers, and even SGLT2 inhibitors. 

This is a very typical population and they wanted to see what happened. Did the patients remain on the binder and were they able to tolerate the spironolactone? In fact, that was the case.

At the end of the study, more patients had been able to stay on their spironolactone, which is that one drug that we’re not doing so well on when you look at large databases. If they were on the zirconium drug, they were more likely to stay on the spironolactone. They even did a sensitivity analysis, which really showed that it was consistent across the board. 

 

Edema and Hyperkalemia

Now we have two binders that have shown to us that patients can stay on their drugs. There were some interesting findings here, though.

There was more edema — again, everything is based on small numbers — and there seemed to be more heart failure events in the group that received the zirconium cyclosilicate. The first episode of hyperkalemia was delayed or didn’t happen at all. Again, the hyperkalemia was controlled. 

What does that tell you? Well, the exchange is sodium. There had been reports before that if you gave this binder at the higher doses, you would have more retention of sodium. I think we see that in this trial, even though the numbers are very small. 

According to the investigators, these were issues that could be resolved through an increase in diuretics or having the patient remember to be careful with their sodium intake so they don’t retain more fluid. 

My message to you is to use these binders, whichever one of the two you want or whichever your hospital has available for you on their formulary, because it may give you that sense of comfort and self-efficacy so that you can actually start your patients on an MRA and keep them on it.

The MRAs are lifesaving drugs and the patients with HFrEF need to be on them. This is a way to do it without having to sacrifice your true guideline-directed medical therapy.

Dr. Piña, Professor of Medicine/Cardiology/Heart Failure/Transplant; Quality Officer, Cardiovascular Line, Sidney Kimmel College of Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania; Clinical Professor of Medicine, Central Michigan University College of Medicine, Mount Pleasant, Michigan; Adjunct Professor of Epidemiology and Biostatistics, Population & Quantitative Health Sciences, Case Western University, Cleveland, Ohio, disclosed ties with the Food and Drug Administration’s Center for Devices and Radiological Health.

A version of this article appeared on Medscape.com

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As-Needed Blood Pressure Medication Linked to Higher Risk for Acute Kidney Injury

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Changed
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Author(s)
Mia Sims

TOPLINE:

Veterans receiving blood pressure (BP) medication as needed while hospitalized were at a 23% higher risk for acute kidney injury (AKI) and a 1.5-fold greater risk for potentially dangerous rapid reductions in BP.

METHODOLOGY:

  • Researchers analyzed the records of 133,760 veterans (90% men; mean age, 71.2 years) hospitalized in Veterans Affairs hospitals between 2015 and 2020.
  • The study analyzed as-needed administration of BP drugs to patients who had an elevated BP but were asymptomatic.
  • Patients who had at least one systolic BP reading above 140 mm Hg and received scheduled BP medication in the first 24 hours of hospitalization were included; those admitted to intensive care units or those who required surgery were excluded.
  • The analysis compared outcomes between 28,526 patients who received as-needed drugs and 105,234 who did not; the primary outcome was time to the first AKI occurrence while hospitalized.
  • Secondary outcomes included a reduction of more than 25% in systolic BP within 3 hours of as-needed BP medication, as well as a composite outcome of myocardial infarction, stroke, or death during hospitalization.

TAKEAWAY:

  • Researchers found that an AKI was 23% more likely to occur in veterans who received at least one as-needed BP medication (hazard ratio [HR], 1.23; 95% CI, 1.18-1.29).
  • Veterans who received BP medication as needed were 50% more likely to experience a rapid drop in BP within 3 hours (HR, 1.50; 95% CI, 1.39-1.62) and more than twice as likely after 1 hour (HR, 2.11; 95% CI, 1.81-2.46) than those who did not receive medication.
  • The risk of experiencing the composite outcome was 69% times higher in the as-needed group (rate ratio [RR], 1.69; 95% CI, 1.49-1.92), with individual increased risks for myocardial infarction (RR, 2.92; 95% CI, 2.09-4.07), stroke (RR, 1.99; 95% CI, 1.30-3.03), and death (RR, 1.52; 95% CI, 1.32-1.75).

IN PRACTICE:

“The practical implication of our findings is that there is at least equipoise regarding the utility of as-needed BP medication use for asymptomatic BP elevations in hospitals ... future prospective trials should evaluate the risks and benefits of this common practice,” the study authors wrote.

SOURCE:

The study was led by Muna Thalji Canales, MD, MS, of the North Florida/South Georgia Veterans Health System in Gainesville, Florida. It was published online on November 25 in JAMA Internal Medicine.

LIMITATIONS:

The analysis may have included confounding factors that could have influenced results. The focus on veterans who had not undergone surgery limits generalizability to women, surgical patients, and nonveteran populations. The researchers noted limited data on factors that might influence BP readings in the hospital such as pain, stress, and faulty machinery.

DISCLOSURES:

Study authors reported grants and consulting fees from Merck Sharp & Dohme and BMS, and Teva Pharmaceuticals, among others.

 

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

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Mia Sims

TOPLINE:

Veterans receiving blood pressure (BP) medication as needed while hospitalized were at a 23% higher risk for acute kidney injury (AKI) and a 1.5-fold greater risk for potentially dangerous rapid reductions in BP.

METHODOLOGY:

  • Researchers analyzed the records of 133,760 veterans (90% men; mean age, 71.2 years) hospitalized in Veterans Affairs hospitals between 2015 and 2020.
  • The study analyzed as-needed administration of BP drugs to patients who had an elevated BP but were asymptomatic.
  • Patients who had at least one systolic BP reading above 140 mm Hg and received scheduled BP medication in the first 24 hours of hospitalization were included; those admitted to intensive care units or those who required surgery were excluded.
  • The analysis compared outcomes between 28,526 patients who received as-needed drugs and 105,234 who did not; the primary outcome was time to the first AKI occurrence while hospitalized.
  • Secondary outcomes included a reduction of more than 25% in systolic BP within 3 hours of as-needed BP medication, as well as a composite outcome of myocardial infarction, stroke, or death during hospitalization.

TAKEAWAY:

  • Researchers found that an AKI was 23% more likely to occur in veterans who received at least one as-needed BP medication (hazard ratio [HR], 1.23; 95% CI, 1.18-1.29).
  • Veterans who received BP medication as needed were 50% more likely to experience a rapid drop in BP within 3 hours (HR, 1.50; 95% CI, 1.39-1.62) and more than twice as likely after 1 hour (HR, 2.11; 95% CI, 1.81-2.46) than those who did not receive medication.
  • The risk of experiencing the composite outcome was 69% times higher in the as-needed group (rate ratio [RR], 1.69; 95% CI, 1.49-1.92), with individual increased risks for myocardial infarction (RR, 2.92; 95% CI, 2.09-4.07), stroke (RR, 1.99; 95% CI, 1.30-3.03), and death (RR, 1.52; 95% CI, 1.32-1.75).

IN PRACTICE:

“The practical implication of our findings is that there is at least equipoise regarding the utility of as-needed BP medication use for asymptomatic BP elevations in hospitals ... future prospective trials should evaluate the risks and benefits of this common practice,” the study authors wrote.

SOURCE:

The study was led by Muna Thalji Canales, MD, MS, of the North Florida/South Georgia Veterans Health System in Gainesville, Florida. It was published online on November 25 in JAMA Internal Medicine.

LIMITATIONS:

The analysis may have included confounding factors that could have influenced results. The focus on veterans who had not undergone surgery limits generalizability to women, surgical patients, and nonveteran populations. The researchers noted limited data on factors that might influence BP readings in the hospital such as pain, stress, and faulty machinery.

DISCLOSURES:

Study authors reported grants and consulting fees from Merck Sharp & Dohme and BMS, and Teva Pharmaceuticals, among others.

 

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

TOPLINE:

Veterans receiving blood pressure (BP) medication as needed while hospitalized were at a 23% higher risk for acute kidney injury (AKI) and a 1.5-fold greater risk for potentially dangerous rapid reductions in BP.

METHODOLOGY:

  • Researchers analyzed the records of 133,760 veterans (90% men; mean age, 71.2 years) hospitalized in Veterans Affairs hospitals between 2015 and 2020.
  • The study analyzed as-needed administration of BP drugs to patients who had an elevated BP but were asymptomatic.
  • Patients who had at least one systolic BP reading above 140 mm Hg and received scheduled BP medication in the first 24 hours of hospitalization were included; those admitted to intensive care units or those who required surgery were excluded.
  • The analysis compared outcomes between 28,526 patients who received as-needed drugs and 105,234 who did not; the primary outcome was time to the first AKI occurrence while hospitalized.
  • Secondary outcomes included a reduction of more than 25% in systolic BP within 3 hours of as-needed BP medication, as well as a composite outcome of myocardial infarction, stroke, or death during hospitalization.

TAKEAWAY:

  • Researchers found that an AKI was 23% more likely to occur in veterans who received at least one as-needed BP medication (hazard ratio [HR], 1.23; 95% CI, 1.18-1.29).
  • Veterans who received BP medication as needed were 50% more likely to experience a rapid drop in BP within 3 hours (HR, 1.50; 95% CI, 1.39-1.62) and more than twice as likely after 1 hour (HR, 2.11; 95% CI, 1.81-2.46) than those who did not receive medication.
  • The risk of experiencing the composite outcome was 69% times higher in the as-needed group (rate ratio [RR], 1.69; 95% CI, 1.49-1.92), with individual increased risks for myocardial infarction (RR, 2.92; 95% CI, 2.09-4.07), stroke (RR, 1.99; 95% CI, 1.30-3.03), and death (RR, 1.52; 95% CI, 1.32-1.75).

IN PRACTICE:

“The practical implication of our findings is that there is at least equipoise regarding the utility of as-needed BP medication use for asymptomatic BP elevations in hospitals ... future prospective trials should evaluate the risks and benefits of this common practice,” the study authors wrote.

SOURCE:

The study was led by Muna Thalji Canales, MD, MS, of the North Florida/South Georgia Veterans Health System in Gainesville, Florida. It was published online on November 25 in JAMA Internal Medicine.

LIMITATIONS:

The analysis may have included confounding factors that could have influenced results. The focus on veterans who had not undergone surgery limits generalizability to women, surgical patients, and nonveteran populations. The researchers noted limited data on factors that might influence BP readings in the hospital such as pain, stress, and faulty machinery.

DISCLOSURES:

Study authors reported grants and consulting fees from Merck Sharp & Dohme and BMS, and Teva Pharmaceuticals, among others.

 

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

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