• 1.

    Vivarelli M, et al.. Minimal change disease. Clin Am J Soc Nephrol 2017; 12:332345. doi: 10.2215/CJN.05000516

  • 2.

    Shalhoub RJ. Pathogenesis of lipoid nephrosis: A disorder of T-cell function. Lancet 1974; 2:556560. doi: 10.1016/s0140-6736(74)91880-7

  • 3.

    Maas RJ, et al.. Permeability factors in idiopathic nephrotic syndrome: Historical perspectives and lessons for the future. Nephrol Dial Transplant 2014; 29:22072216. doi: 10.1093/ndt/gfu355

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

    Hogan J, Radhakrishnan J. The treatment of minimal change disease in adults. J Am Soc Nephrol 2013; 24:702711. doi: 10.1681/ASN.2012070734

  • 5.

    Tarshish P, et al.. Prognostic significance of the early course of minimal change nephrotic syndrome: Report of the International Study of Kidney Disease in Children. J Am Soc Nephrol 1997; 8:769776. https://jasn.asnjournals.org/content/jnephrol/8/5/769.full.pdf?with-ds=yes

    • 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.

    Nakayama M, et al.. Steroid responsiveness and frequency of relapse in adult-onset minimal change nephrotic syndrome. Am J Kidney Dis 2002; 39:503512. doi: 10.1053/ajkd.2002.31400

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 8.

    Waldman M, et al.. Adult minimal-change disease: Clinical characteristics, treatment, and outcomes. Clin J Am Soc Nephrol 2007; 2:445453. doi: 10.2215/CJN.03531006

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 9.

    Tse K-C, et al.. Idiopathic minimal change nephrotic syndrome in older adults: Steroid responsiveness and pattern of relapses. Nephrol Dial Transplant 2003; 18:13161320. doi: 10.1093/ndt/gfg134

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

    Chapter 5: Minimal-change disease in adults. Kidney Int Suppl 2012; 2:177180. doi:10.1038/kisup.2012.1

  • 11.

    Boumpas DT, et al.. Glucocorticoid therapy for immune-mediated diseases: Basic and clinical correlates. Ann Intern Med 1993; 119:11981208. doi: 10.7326/0003-4819-119-12-199312150-00007

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

    Huscher D, et al.. Dose-related patterns of glucocorticoid-induced side effects. Ann Rheum Dis 2009; 68:11191124. doi: 10.1136/ard.2008.092163

  • 13.

    Whitworth JA. Mechanisms of glucocorticoid-induced hypertension. Kidney Int 1987; 31:12131224. doi: 10.1038/ki.1987.131

  • 14.

    Gabriel SE, et al.. Risk for serious gastrointestinal complications related to use of nonsteroidal anti-inflammatory drugs. A meta-analysis. Ann Intern Med 1991; 115:787796. doi: 10.7326/0003-4819-115-10-787

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

    van Staa TP, et al.. The epidemiology of corticosteroid-induced osteoporosis: A meta-analysis. Osteoporosis Int 2002; 13:777787. doi: 10.1007/s001980200108

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

    Gurwitz JH, et al.. Glucocorticoids and the risk for initiation of hypoglycemic therapy. Arch Intern Med 1994; 154:97101. doi: 10.1001/archinte.1994.00420010131015

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

    Dixon WG, et al.. Immediate and delayed impact of oral glucocorticoid therapy on risk of serious infection in older patients with rheumatoid arthritis: A nested case-control analysis. Ann Rheum Dis 2012; 71:11281133. doi: 10.1136/annrheumdis-2011-200702

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

    Pepper RJ, et al.. A novel glucocorticoid-free maintenance regimen for anti-neutrophil cytoplasm antibody-associated vasculitis. Rheumatology (Oxford) 2019; 58:260268. doi: 10.1093/rheumatology/key288

    • Search Google Scholar
    • Export Citation
  • 19.

    Fervenza FC, et al.. Rituximab or cyclosporine in the treatment of membranous nephropathy. N Engl J Med 2019; 381:3646. doi: 10.1056/NEJMoa1814427

  • 20.

    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
  • 21.

    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
  • 22.

    Ainley L, et al.. Treatment of concurrent minimal change disease and Epstein Barr virus-driven post-transplant lymphoproliferative disorder with rituximab following hematopoietic stem cell transplantation. Kidney Int Rep 2021; 6:224227. doi: 10.1016/j.ekir.2020.10.012

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 23.

    Fenoglio R, et al.. Rituximab as a front-line therapy for adult-onset minimal change disease with nephrotic syndrome. Oncotarget 2018; 9:2879928804. doi: 10.18632/oncotarget.25612.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 24.

    Kim YC, et al.. Complete remission induced by tacrolimus and low-dose prednisolone in adult minimal change nephrotic syndrome: A pilot study. Kidney Res Clin Pract 2012; 31:112117. doi: 10.1016/j.krcp.2012.04.321

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 25.

    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

Minimization in Minimal Change Disease: Maximal Change in Practice?

  • 1 Dearbhla Kelly, MB, BCh, BAO, MSc, MRCPI, is a renal specialist registrar with Beaumont Hospital, Dublin, Ireland.
Full access

Minimal change disease (MCD) is one of the major causes of idiopathic nephrotic syndrome, accounting for up to 70%−90% of cases in children and approximately 15% of cases in adults (1). The characteristic appearance of MCD on a kidney biopsy is normal glomeruli on light microscopy with diffuse effacement of the epithelial foot processes on electron microscopy. The pathogenesis of MCD is not fully elucidated, but systemic T cell dysfunction producing increased levels of a glomerular permeability factor has been implicated (2, 3). Although the pathogenesis remains uncertain, similar to focal segmental glomerulosclerosis, a circulating factor that damages the glomerular capillary wall has been postulated, resulting in proteinuria and foot process fusion (1).

Glucocorticoid therapy has been the mainstay of therapy for MCD for decades. This management strategy in children has been informed by several large prospective randomized clinical trials (RCTs) in addition to observational studies (4). Over 90% of children respond with complete remission to initial steroid therapy (5). The recommendation for glucocorticoid therapy in adults has been informed mostly by observational studies (4), as RCT data are lacking, with the majority of information coming from a single RCT published in 1970. This trial compared low-dose prednisone (<30 mg/day) with no specific therapy among 31 adults. More than 75% of treated patients had remission of proteinuria to less than 1 g/day within 6 months (6). Subsequently, several retrospective observational studies have demonstrated a high but variable response rate (67%−100%) in adult patients treated with higher doses (e.g., 60 mg/day or 1 mg/kg/day) (7−9). Kidney Disease: Improving Global Outcomes (KDIGO) currently recommends glucocorticoid therapy as treatment for the initial episode of adult MCD, while acknowledging that there is only low-quality evidence available and that this recommendation is based largely on extrapolation from trial data in children in addition to small observational studies in adults (10).

Steroids, however, have a significant adverse side effect profile, including Cushingoid features (11), weight gain (12), hypertension (13), gastrointestinal bleeding (14), osteoporosis (15), diabetes (16), and increased infection risk (17). This is particularly concerning because a prolonged course of steroid treatment is often required in MCD, and relapse rates in adults can be high (8). Therefore, there has been increasing interest in steroid-sparing or minimizing regimens. Steroid-sparing regimens have already been investigated for other glomerulonephritides, including antineutrophil cytoplasmic antibody (ANCA) vasculitis (18) and membranous nephropathy (19), with encouraging results to date.

One large investigation into a steroid-sparing regimen for MCD is the Tacrolimus Versus Prednisolone for the Treatment of Minimal Change Disease (MinTac) trial, a multi-center, open-label RCT based in the United Kingdom, in which 52 adult patients with MCD were randomized to treatment with either oral tacrolimus at 0.05 mg/kg twice daily for 12 weeks (then tapered over a further 8 weeks) or prednisolone at 1 mg/kg daily up to 60 mg daily for 16 weeks. The primary objective was to demonstrate the non-inferiority of tacrolimus compared to prednisolone for inducing remission in MCD, in addition to showing that relapse rates were similar, and adverse events were less common. Although there was no statistically significant difference in the primary outcome (complete remission at 8 weeks) between groups (68% for tacrolimus vs. 84% for prednisolone; p = 0.32), the a priori definition of non-inferiority was not met in either the per-protocol or the intention-to-treat analysis. Relapse rates (73% for tacrolimus vs. 74% for prednisolone; p = 0.99) and safety profile were found to be similar between groups (20). This was the first study to investigate the use of tacrolimus monotherapy to treat MCD, and although the sample size was small, and further research is required, the results do suggest that tacrolimus may be an effective alternative treatment to steroids for MCD in adult patients.

More recently, another randomized controlled trial compared combined tacrolimus and low-dose steroid treatment with the standard high-dose steroid protocol in adult patients (21). In this open-label, non-inferiority study, 144 adults with MCD were randomized to receive either 0.05 mg/kg twice-daily tacrolimus plus once-daily 0.5 mg/kg prednisolone or once-daily 1 mg/kg prednisolone alone for up to 8 weeks or until achieving complete remission. The steroid dose was then tapered to a maintenance dose of 5−7.5 mg/day in both groups, 2 weeks after complete remission, until 24 weeks after study-drug initiation. The primary end point, defined as complete remission within 8 weeks (urine protein:creatinine ratio <0.2 g/g), was achieved in 79.1% of those receiving tacrolimus and low-dose steroid compared to 76.8% receiving high-dose steroid, confirming non-inferiority of this treatment protocol. Of note, the relapse rate was also much lower in the combined tacrolimus/low-dose steroid protocol compared to the high-dose steroid-alone group (5.7% vs. 22.6%, respectively; p = 0.01) with no major safety differences observed (21). Studies investigating steroid minimization regimens for MCD are summarized in Table 1. Use of rituximab has already been shown to facilitate such regimens in other glomerulonephritides (18), and there is some emerging evidence from case series to suggest that it also could have a future role in steroid-sparing treatment strategies for MCD (22, 23).

t1

Tacrolimus, with or without low-dose steroids, therefore appears to be an effective alternative to high-dose steroids in MCD, particularly in patients at high risk of adverse effects from steroids, such as those with diabetes, obesity, osteoporosis, or mood disorders. However, further research is needed to establish long-term safety data, as well as the best protocol for its use.

The author has no conflicts of interest.

References

  • 1.

    Vivarelli M, et al.. Minimal change disease. Clin Am J Soc Nephrol 2017; 12:332345. doi: 10.2215/CJN.05000516

  • 2.

    Shalhoub RJ. Pathogenesis of lipoid nephrosis: A disorder of T-cell function. Lancet 1974; 2:556560. doi: 10.1016/s0140-6736(74)91880-7

  • 3.

    Maas RJ, et al.. Permeability factors in idiopathic nephrotic syndrome: Historical perspectives and lessons for the future. Nephrol Dial Transplant 2014; 29:22072216. doi: 10.1093/ndt/gfu355

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

    Hogan J, Radhakrishnan J. The treatment of minimal change disease in adults. J Am Soc Nephrol 2013; 24:702711. doi: 10.1681/ASN.2012070734

  • 5.

    Tarshish P, et al.. Prognostic significance of the early course of minimal change nephrotic syndrome: Report of the International Study of Kidney Disease in Children. J Am Soc Nephrol 1997; 8:769776. https://jasn.asnjournals.org/content/jnephrol/8/5/769.full.pdf?with-ds=yes

    • 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.

    Nakayama M, et al.. Steroid responsiveness and frequency of relapse in adult-onset minimal change nephrotic syndrome. Am J Kidney Dis 2002; 39:503512. doi: 10.1053/ajkd.2002.31400

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 8.

    Waldman M, et al.. Adult minimal-change disease: Clinical characteristics, treatment, and outcomes. Clin J Am Soc Nephrol 2007; 2:445453. doi: 10.2215/CJN.03531006

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 9.

    Tse K-C, et al.. Idiopathic minimal change nephrotic syndrome in older adults: Steroid responsiveness and pattern of relapses. Nephrol Dial Transplant 2003; 18:13161320. doi: 10.1093/ndt/gfg134

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

    Chapter 5: Minimal-change disease in adults. Kidney Int Suppl 2012; 2:177180. doi:10.1038/kisup.2012.1

  • 11.

    Boumpas DT, et al.. Glucocorticoid therapy for immune-mediated diseases: Basic and clinical correlates. Ann Intern Med 1993; 119:11981208. doi: 10.7326/0003-4819-119-12-199312150-00007

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

    Huscher D, et al.. Dose-related patterns of glucocorticoid-induced side effects. Ann Rheum Dis 2009; 68:11191124. doi: 10.1136/ard.2008.092163

  • 13.

    Whitworth JA. Mechanisms of glucocorticoid-induced hypertension. Kidney Int 1987; 31:12131224. doi: 10.1038/ki.1987.131

  • 14.

    Gabriel SE, et al.. Risk for serious gastrointestinal complications related to use of nonsteroidal anti-inflammatory drugs. A meta-analysis. Ann Intern Med 1991; 115:787796. doi: 10.7326/0003-4819-115-10-787

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

    van Staa TP, et al.. The epidemiology of corticosteroid-induced osteoporosis: A meta-analysis. Osteoporosis Int 2002; 13:777787. doi: 10.1007/s001980200108

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

    Gurwitz JH, et al.. Glucocorticoids and the risk for initiation of hypoglycemic therapy. Arch Intern Med 1994; 154:97101. doi: 10.1001/archinte.1994.00420010131015

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

    Dixon WG, et al.. Immediate and delayed impact of oral glucocorticoid therapy on risk of serious infection in older patients with rheumatoid arthritis: A nested case-control analysis. Ann Rheum Dis 2012; 71:11281133. doi: 10.1136/annrheumdis-2011-200702

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

    Pepper RJ, et al.. A novel glucocorticoid-free maintenance regimen for anti-neutrophil cytoplasm antibody-associated vasculitis. Rheumatology (Oxford) 2019; 58:260268. doi: 10.1093/rheumatology/key288

    • Search Google Scholar
    • Export Citation
  • 19.

    Fervenza FC, et al.. Rituximab or cyclosporine in the treatment of membranous nephropathy. N Engl J Med 2019; 381:3646. doi: 10.1056/NEJMoa1814427

  • 20.

    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
  • 21.

    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
  • 22.

    Ainley L, et al.. Treatment of concurrent minimal change disease and Epstein Barr virus-driven post-transplant lymphoproliferative disorder with rituximab following hematopoietic stem cell transplantation. Kidney Int Rep 2021; 6:224227. doi: 10.1016/j.ekir.2020.10.012

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 23.

    Fenoglio R, et al.. Rituximab as a front-line therapy for adult-onset minimal change disease with nephrotic syndrome. Oncotarget 2018; 9:2879928804. doi: 10.18632/oncotarget.25612.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 24.

    Kim YC, et al.. Complete remission induced by tacrolimus and low-dose prednisolone in adult minimal change nephrotic syndrome: A pilot study. Kidney Res Clin Pract 2012; 31:112117. doi: 10.1016/j.krcp.2012.04.321

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 25.

    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
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