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    Randomized clinical therapies of tacrolimus as steroid sparing/minimization therapies

  • 1.

    Barisoni L, et al.. A proposed taxonomy for the podocytopathies: A reassessment of the primary nephrotic diseases. Clin J Am Soc Nephrol 2007; 2:529542. doi: 10.2215/CJN.04121206

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 2.

    Garin EH, et al.. Urinary CD80 is elevated in minimal change disease but not in focal segmental glomerulosclerosis. Kidney Int 2010; 78:296302. doi: 10.1038/ki.2010.143

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 3.

    Clement LC, et al.. Podocyte-secreted angiopoietin-like-4 mediates proteinuria in glucocorticoid-sensitive nephrotic syndrome. Nat Med 2011; 17:117122. doi: 10.1038/nm.2261

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 4.

    Kopp JB, et al.. Clinical features and histology of apolipoprotein L1-associated nephropathy in the FSGS Clinical Trial. J Am Soc Nephrol 2015; 26:14431448. doi: 10.1681/ASN.2013111242

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 5.

    Landini S, et al.. Reverse phenotyping after whole-exome sequencing in steroid-resistant nephrotic syndrome. Clin J Am Soc Nephrol 2020; 15:89100. doi: 10.2215/CJN.06060519

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 6.

    Black DA, et al.. Controlled trial of prednisone in adult patients with the nephrotic syndrome. Br Med J 1970; 3:421426. doi: 10.1136/bmj.3.5720.421

  • 7.

    Coggins CH. Adult minimal change nephropathy: Experience of the collaborative study of glomerular disease. Trans Am Clin Climatol Assoc 1986; 97:1826. PMID: 3915841

    • Search Google Scholar
    • Export Citation
  • 8.

    Kidney Disease: Improving Global Outcomes (KDIGO) Glomerulonephritis Work Group. KDIGO clinical practice guideline for glomerulonephritis. Kidney Int Suppl 2012; 2:139274. https://www.sciencedirect.com/journal/kidney-international-supplements/vol/2/issue/2

    • Search Google Scholar
    • Export Citation
  • 9.

    Li X, et al.. Tacrolimus monotherapy after intravenous methylprednisolone in adults with minimal change nephrotic syndrome. J Am Soc Nephrol 2017; 28:12861295. doi: 10.1681/ASN.2016030342

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 10.

    Patil MR, et al.. Tacrolimus as the first-line agent in adult-onset minimal change disease: A randomized controlled study. Saudi J Kidney Dis Transpl 2019; 30:129137. https://www.sjkdt.org/article.asp?issn=1319-2442;year=2019;volume=30;issue=1;spage=129;epage=137;aulast=Patil

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 11.

    Medjeral-Thomas NR, 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; 15:209218. doi: 10.2215/CJN.06180519

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 12.

    Chin HJ, et al.. Comparison of the efficacy and safety of tacrolimus and low-dose corticosteroid with high-dose corticosteroid for minimal change nephrotic syndrome in adults. J Am Soc Nephrol 2021; 32:199210. doi: 10.1681/ASN.2019050546

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 13.

    Rémy P, et al.. An open-label randomized controlled trial of low-dose corticosteroid plus enteric-coated mycophenolate sodium versus standard corticosteroid treatment for minimal change nephrotic syndrome in adults (MSN Study). Kidney Int 2018; 94:12171226. doi: 10.1016/j.kint.2018.07.021

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 14.

    Trachtman H, et al.. DUET: A phase 2 study evaluating the efficacy and safety of sparsentan in patients with FSGS. J Am Soc Nephrol 2018; 29:27452754. doi: 10.1681/ASN.2018010091

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 15.

    Basu B, et al.. Efficacy of rituximab vs tacrolimus in pediatric corticosteroid-dependent nephrotic syndrome: A randomized clinical trial. JAMA Pediatr 2018; 172:757764. doi: 10.1001/jamapediatrics.2018.1323

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 16.

    Gauckler P, et al.. Rituximab in adult minimal change disease and focal segmental glomerulosclerosis—what is known and what is still unknown? Autoimmun Rev 2020; 19:102671. doi: 10.1016/j.autrev.2020.102671

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 17.

    Büscher AK, et al.. Rapid response to cyclosporin A and favorable renal outcome in nongenetic versus genetic steroid-resistant nephrotic syndrome. Clin J Am Soc Nephrol 2016; 11:245253. doi: 10.2215/CJN.07370715

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 18.

    De Vriese AS, et al.. Differentiating primary, genetic, and secondary FSGS in adults: A clinicopathologic approach. J Am Soc Nephrol 2018; 29:759774. doi: 10.1681/ASN.2017090958

    • Crossref
    • Search Google Scholar
    • Export Citation

Treatment of Adult Podocytopathy: Uncharted Territory

  • 1 Raja Ramachandran is Assistant Professor with the Department of Nephrology, Post-Graduate Institute of Medical Education and Research, Chandigarh, India. Mayuri Trivedi is Assistant Professor with the Department of Nephrology, Lokmanya Tilak Medical General Hospital, Mumbai, India.
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Podocytopathies are a group of kidney diseases caused by direct or indirect injury to the glomerular podocytes, resulting in proteinuria. Examples of podocytopathies are minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS), and collapsing glomerulopathy (CG) (1). T-regulatory cell dysfunction and the podocyte proteins CD80 (2)/angiopoietin-like protein 4 (Angptl4) (3) have been shown to participate in the pathogenesis of MCD. An insult to the network of the visceral and parietal epithelial cells of the glomerulus by the immune system or a genetic defect is thought to be responsible for the development of primary FSGS and CG (4, 5).

The last several decades have seen major advances in unraveling the pathogenesis of many podocytopathies. However, the use of steroids continues to be a cornerstone of therapy in adults and children, and the basis for recommending steroids in adult podocytopathy hinges on a shred of low-grade evidence. The management of adult podocytopathy encompasses at least three discrete entities: achievement of remission in patients with nephrotic syndrome, maintenance of steroid-free remission in cases with a frequently relapsing (FR) or steroid-dependent (SD) course, and therapies for the steroid-resistant disease.

Based on randomized studies described four to five decades ago (6, 7) and extrapolating evidence from the pediatric nephrotic syndrome, steroid therapy compared to no specific treatment induces a rapid decline in proteinuria and achievement of remission. The Kidney Disease: Improving Global Outcomes (KDIGO) guidelines recommend up to a 16-week course of oral prednisolone (8). However, the current evidence suggests 8 weeks to be reasonably successful in inducing remission in the vast majority.

The quest for a safer therapeutic option culminates in a steroid-free/steroid-minimized protocol in the adult-onset podocytopathies (9−13). At least four randomized studies evaluated the role of the steroid-free/steroid-minimized protocol with adjunct immunosuppression versus oral prednisolone in adult MCD. To put it in a nutshell, at least three-fourths of the patients treated with tacrolimus, with/without low-dose steroids, achieved clinical remission, with a reasonable side-effect profile and acceptable relapse rates (9−12). At least two randomized trials evaluate the role of mycophenolate sodium with low-dose steroids in adult-onset MCD. Rémy et al. (13) reported a remission rate of 80% each at week 24 with low-dose steroid/mycophenolate sodium and high-dose steroids. The relapse rates were numerically better in the low-dose steroids/mycophenolate sodium group than in the patients receiving high-dose steroids (19% versus 27%) (13). To conclude, the last 5 years have been a step in the right direction, with the reinvigoration of a steroid-free/steroid-minimization strategy as the first-line therapy to manage adult MCD (Figure 1). However, there is no controlled trial of tacrolimus or cyclosporine as a front-line therapy in FSGS, although experts prescribe low-dose steroids in combination with calcineurin inhibitors (CNIs). Also, there is an emerging role of dual endothelin (ETA) and angiotensin receptor blocker sparsentan in reducing proteinuria in patients of FSGS and subnephrotic proteinuria (14).

Figure 1.
Figure 1.

Randomized clinical therapies of tacrolimus as steroid sparing/minimization therapies

Citation: Kidney News 13, 4

Summary: Remission rates of adult MCD- Tacrolimus with or without steroids is 79-96%. Relapse 6-45%Figure edits courtesy Edgar V. Lerma

The management of FR and SD adult podocytopathy is also an extrapolation of pediatric literature. CNIs (tacrolimus/cyclosporine), cyclophosphamide, and mycophenolate mofetil are the conventionally used agents to manage FR or SD MCD/FSGS. However, execrable long-term safety profiles dampen the enthusiasm for using cyclophosphamide and CNIs to manage SD/FR-MCD/FSGS. The pediatric datasets portend rituximab as a superior agent to tacrolimus in maintaining remission in SD-nephrotic syndrome (15). Despite the lack of data from large, randomized controlled trials, rituximab has changed the therapeutic landscape and propounds promise to manage adult FR/SD podocytopathy (16). Hypogammaglobulinemia and neutropenia are potential long-term adverse events that underscore the monitoring of immunoglobulin levels in rituximab-treated patients. Currently, there are at least two large, ongoing randomized trials evaluating the role of rituximab with and without steroids in achieving (The Use of Rituximab in the Treatment of Nephrotic Glomerulonephritis [TURING] trial; European Union Drug Regulating Authorities Clinical Trials Database [EudraCT]: 2018-004611-50) and maintaining (Rituximab from the First Episode of Idiopathic Nephrotic Syndrome [RIFIREINS] trial; ClinicalTrials.gov: NCT03970577) remission in adult podocytopathy.

The management of steroid-resistant FSGS is controversial. Traditionally, tacrolimus or cyclosporine are the first-line therapy to manage adult steroid-resistant FSGS. With the sustained evolution of genetic testing, up to 60% of the patients with steroid-resistant FSGS have genetic mutations in podocyte and non-podocyte genes (5). Data from the pediatric population suggest that over three-fourths of the patients with non-genetic-associated, steroid-resistant FSGS respond favorably to cyclosporine therapy (17). With the unceasing expansion of the library of genes incriminated in the development of steroid-resistant FSGS, experts recommend genetic testing in all steroid-resistant FSGS, hence procrastinating ineffective treatment (18). As per the current consensus, all steroid-resistant FSGS patients need to be started on an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker and lipid lowering with statin therapy. Both the disease and its treatment affect the bone and cardiovascular system adversely. Hence, future research needs to solicit safeguards for bone and cardiovascular health in patients with steroid-resistant FSGS.

To conclude, the management of adult podocytopathy graduates from steroids (only) to steroid-minimized or steroid-free therapies, primarily involving tacrolimus/mycophenolate sodium and rituximab, thus offering a new perspective to the management of SD or FR podocytopathy. Genetic testing is the key to manage steroid-resistant FSGS, at least before subjecting it to toxic second-line agents. Admittedly, adult nephrologists worldwide with renewed interest in glomerular diseases need to collaborate and examine a steroid-free or steroid-minimized protocol for managing MCD/FSGS. Understandably, the TURING and RIFIREINS trials are steps in the right direction.

References

  • 1.

    Barisoni L, et al.. A proposed taxonomy for the podocytopathies: A reassessment of the primary nephrotic diseases. Clin J Am Soc Nephrol 2007; 2:529542. doi: 10.2215/CJN.04121206

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 2.

    Garin EH, et al.. Urinary CD80 is elevated in minimal change disease but not in focal segmental glomerulosclerosis. Kidney Int 2010; 78:296302. doi: 10.1038/ki.2010.143

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 3.

    Clement LC, et al.. Podocyte-secreted angiopoietin-like-4 mediates proteinuria in glucocorticoid-sensitive nephrotic syndrome. Nat Med 2011; 17:117122. doi: 10.1038/nm.2261

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 4.

    Kopp JB, et al.. Clinical features and histology of apolipoprotein L1-associated nephropathy in the FSGS Clinical Trial. J Am Soc Nephrol 2015; 26:14431448. doi: 10.1681/ASN.2013111242

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 5.

    Landini S, et al.. Reverse phenotyping after whole-exome sequencing in steroid-resistant nephrotic syndrome. Clin J Am Soc Nephrol 2020; 15:89100. doi: 10.2215/CJN.06060519

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 6.

    Black DA, et al.. Controlled trial of prednisone in adult patients with the nephrotic syndrome. Br Med J 1970; 3:421426. doi: 10.1136/bmj.3.5720.421

  • 7.

    Coggins CH. Adult minimal change nephropathy: Experience of the collaborative study of glomerular disease. Trans Am Clin Climatol Assoc 1986; 97:1826. PMID: 3915841

    • Search Google Scholar
    • Export Citation
  • 8.

    Kidney Disease: Improving Global Outcomes (KDIGO) Glomerulonephritis Work Group. KDIGO clinical practice guideline for glomerulonephritis. Kidney Int Suppl 2012; 2:139274. https://www.sciencedirect.com/journal/kidney-international-supplements/vol/2/issue/2

    • Search Google Scholar
    • Export Citation
  • 9.

    Li X, et al.. Tacrolimus monotherapy after intravenous methylprednisolone in adults with minimal change nephrotic syndrome. J Am Soc Nephrol 2017; 28:12861295. doi: 10.1681/ASN.2016030342

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 10.

    Patil MR, et al.. Tacrolimus as the first-line agent in adult-onset minimal change disease: A randomized controlled study. Saudi J Kidney Dis Transpl 2019; 30:129137. https://www.sjkdt.org/article.asp?issn=1319-2442;year=2019;volume=30;issue=1;spage=129;epage=137;aulast=Patil

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 11.

    Medjeral-Thomas NR, 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; 15:209218. doi: 10.2215/CJN.06180519

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 12.

    Chin HJ, et al.. Comparison of the efficacy and safety of tacrolimus and low-dose corticosteroid with high-dose corticosteroid for minimal change nephrotic syndrome in adults. J Am Soc Nephrol 2021; 32:199210. doi: 10.1681/ASN.2019050546

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 13.

    Rémy P, et al.. An open-label randomized controlled trial of low-dose corticosteroid plus enteric-coated mycophenolate sodium versus standard corticosteroid treatment for minimal change nephrotic syndrome in adults (MSN Study). Kidney Int 2018; 94:12171226. doi: 10.1016/j.kint.2018.07.021

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 14.

    Trachtman H, et al.. DUET: A phase 2 study evaluating the efficacy and safety of sparsentan in patients with FSGS. J Am Soc Nephrol 2018; 29:27452754. doi: 10.1681/ASN.2018010091

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 15.

    Basu B, et al.. Efficacy of rituximab vs tacrolimus in pediatric corticosteroid-dependent nephrotic syndrome: A randomized clinical trial. JAMA Pediatr 2018; 172:757764. doi: 10.1001/jamapediatrics.2018.1323

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 16.

    Gauckler P, et al.. Rituximab in adult minimal change disease and focal segmental glomerulosclerosis—what is known and what is still unknown? Autoimmun Rev 2020; 19:102671. doi: 10.1016/j.autrev.2020.102671

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 17.

    Büscher AK, et al.. Rapid response to cyclosporin A and favorable renal outcome in nongenetic versus genetic steroid-resistant nephrotic syndrome. Clin J Am Soc Nephrol 2016; 11:245253. doi: 10.2215/CJN.07370715

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 18.

    De Vriese AS, et al.. Differentiating primary, genetic, and secondary FSGS in adults: A clinicopathologic approach. J Am Soc Nephrol 2018; 29:759774. doi: 10.1681/ASN.2017090958

    • Crossref
    • Search Google Scholar
    • Export Citation
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