First do no harm: systemic glucocorticoids should not be used for the treatment of progressive IgA nephropathy

Over recent years, significant progress has been made in the understanding of the pathogenesis of IgA nephropathy (IgAN). A multihit model is widely accepted; in patients with IgAN, there is an increase in circulating poorly galactosylated IgA1, likely to be of mucosal origin, that drives autoantibody production, immune complex formation, and deposition of these poorly galactosylated IgA1-containing immune complexes within the glomerular mesangium, resulting in inflammation and progressive kidney damage.1Suzuki H. Kiryluk K. Novak J. et al.The pathophysiology of IgA nephropathy.J Am Soc Nephrol. 2011; 22: 1795-1803Crossref PubMed Scopus (482) Google Scholar,2Cheung C.K. Barratt J. Further evidence for the mucosal origin of pathogenic IgA in IgA nephropathy.J Am Soc Nephrol. 2022; 33: 873-875Crossref PubMed Scopus (2) Google Scholar This is driven in large part by alternative and lectin pathway activation of the complement system.1Suzuki H. Kiryluk K. Novak J. et al.The pathophysiology of IgA nephropathy.J Am Soc Nephrol. 2011; 22: 1795-1803Crossref PubMed Scopus (482) Google Scholar Despite these advances, there remains a lack of safe and effective treatments for IgAN. With its autoimmune pathogenesis, many conventional immunosuppressive agents, including mycophenolate mofetil, calcineurin inhibitors, azathioprine, cyclophosphamide, and rituximab, have been studied in IgAN, but no consistent beneficial effects have been observed.3Floege J. Rauen T. Tang S.C.W. Current treatment of IgA nephropathy.Semin Immunopathol. 2021; 43: 717-728Crossref PubMed Scopus (23) Google Scholar The foundation of management of IgAN is goal-directed supportive care, in the form of rigorous blood pressure control, use of renin-angiotensin system (RAS) blockade to the maximally tolerated dose, and a focus on lifestyle modification, that includes smoking cessation, weight management, and restriction of sodium intake. Ongoing clinical trials may also embed the use of sodium-glucose cotransporter-2 inhibitors and/or endothelin receptor antagonists within best supportive care. Apart from in exceptional cases of rapidly progressive glomerulonephritis, the role of systemic glucocorticoids in IgAN, however, remains controversial. Glucocorticoids are used in several glomerular diseases for their potent anti-inflammatory effects but are also associated with a range of familiar treatment-associated toxicities, that include serious infection, diabetes mellitus, hypertension, osteoporosis, sarcopenia, mood disturbance, multiple cosmetic changes, and a cumulative increase in cardiovascular risk and a reduction in quality of life. The significance of these toxicities for patients with IgAN has been clearly articulated in the National Kidney Foundation and IgAN Foundation of America's Voice of the Patient Report (Box 1).4National Kidney Foundation and IgA Nephropathy Foundation of America, IncThe voice of the patient: externally led patient-focused drug development meeting on IgA nephropathy.https://nkf.egnyte.com/dl/aHGCS6tPNMDate accessed: April 19, 2022Google Scholar As a consequence, there has been a significant drive to develop treatment protocols and new therapies to reduce or avoid the use of glucocorticoids in most glomerular diseases.Box 1Selected patient testimonies from the National Kidney Foundation and IgA Nephropathy Foundation of America's Voice of the Patient Report on IgAN"Prednisone is another one I'm taking, which has made me very tired, moody, hungry, and mean. I even yell at everyone. I refuse to do what my parents ask, and I am mean to my little brother.""The prednisone made me gain 40 pounds in three months and gave me really bad acne. As a teenager, that was horrible. Kids made fun of me all the time.""At about five months into treatment, I had 25 pounds of weight gain, my face ballooned, and of course, I got the notorious fat hump at the back of my neck. What I didn't expect was the furry face, tooth sensitivity, missed periods, and sleepless nights." "Prednisone is another one I'm taking, which has made me very tired, moody, hungry, and mean. I even yell at everyone. I refuse to do what my parents ask, and I am mean to my little brother." "The prednisone made me gain 40 pounds in three months and gave me really bad acne. As a teenager, that was horrible. Kids made fun of me all the time." "At about five months into treatment, I had 25 pounds of weight gain, my face ballooned, and of course, I got the notorious fat hump at the back of my neck. What I didn't expect was the furry face, tooth sensitivity, missed periods, and sleepless nights." The 2021 Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guideline for the Management of Glomerular Diseases includes the recommendation that patients with IgAN who remain at high risk of progression (i.e., with proteinuria >1 g/d) despite maximal supportive care be considered for a 6-month course of systemic glucocorticoid therapy, but only after the risk of treatment-emergent toxicity has been discussed with patients, and also states that the clinical benefit of systemic glucocorticoids in IgAN is not established.5Kidney Disease: Improving Global Outcomes (KDIGO) Glomerular Diseases Work GroupKDIGO 2021 clinical practice guideline for the management of glomerular diseases.Kidney Int. 2021; 100: S1-S276PubMed Scopus (357) Google Scholar Systemic glucocorticoid use in IgAN was graded at the lowest evidence level and was based on studies that have significant limitations when compared with current standard of care. Pozzi et al.6Pozzi C. Bolasco P.G. Fogazzi G.B. et al.Corticosteroids in IgA nephropathy: a randomised controlled trial.Lancet. 1999; 353: 883-887Abstract Full Text Full Text PDF PubMed Scopus (417) Google Scholar randomized 86 patients to receive a 6-month course of systemic glucocorticoids or placebo and reported improved kidney survival in the glucocorticoid-treated group. However, in keeping with standard of care at the time, less than 15% of patients received RAS blockade at baseline, and blood pressure control was suboptimal. Subsequent studies by Manno et al7Manno C. Torres D.D. Rossini M. et al.Randomized controlled clinical trial of corticosteroids plus ACE-inhibitors with long-term follow-up in proteinuric IgA nephropathy.Nephrol Dial Transplant. 2009; 24 ([published correction appears in Nephrol Dial Transplant. 2010;25:1363–1364]): 3694-3701Crossref PubMed Scopus (207) Google Scholar. and Lv et al8Lv J. Zhang H. Chen Y. et al.Combination therapy of prednisone and ACE inhibitor versus ACE-inhibitor therapy alone in patients with IgA nephropathy: a randomized controlled trial.Am J Kidney Dis. 2009; 53: 26-32Abstract Full Text Full Text PDF PubMed Scopus (158) Google Scholar. again supported systemic glucocorticoid use for 6 months in the treatment of high-risk IgAN. At the start of these studies, RAS blockade was mandated to be withdrawn before being reintroduced, and then during the treatment phase, the dosage of RAS blockade achieved was significantly below the maximally recommended dose. Therefore, blood pressure and RAS blockade were not fully optimized in these studies. Two more recent and larger trials have been completed, where patients received what could be regarded as current standard of care as background therapy. The Supportive Versus Immunosuppressive Therapy for the Treatment of Progressive IgA Nephropathy (STOP-IgAN) trial differed from earlier studies by including a 6-month run-in period, where an intensive program of goal-directed supportive care was instituted, including maximization of RAS blockade.9Rauen T. Eitner F. Fitzner C. et al.Intensive supportive care plus immunosuppression in IgA nephropathy.N Engl J Med. 2015; 373: 2225-2236Crossref PubMed Scopus (378) Google Scholar A key finding was that after this run-in period, approximately one-third of patients, who were previously considered by their treating nephrologists to be suitable for inclusion into a clinical trial of immunosuppression for IgAN, did not proceed in the study as their levels of proteinuria no longer met the continuation threshold of >0.75 g/d, emphasizing the importance of supportive care in the treatment of IgAN. The remaining 162 patients were randomized to receive continued supportive care alone, or supportive care plus immunosuppression in the form of systemic glucocorticoid monotherapy if the estimated glomerular filtration rate (eGFR) was ≥60 ml/min per 1.73 m2, or a combination of systemic glucocorticoids and cyclophosphamide followed by azathioprine in those with eGFR 30–59 ml/min per 1.73 m2. No difference was found between the supportive care and immunosuppression groups, in terms of annual decline in eGFR at 3 years, or the adapted primary endpoint of time to first occurrence of death, kidney failure, or decline in eGFR by 40% compared with baseline over a median follow-up of 7.4 years.9Rauen T. Eitner F. Fitzner C. et al.Intensive supportive care plus immunosuppression in IgA nephropathy.N Engl J Med. 2015; 373: 2225-2236Crossref PubMed Scopus (378) Google Scholar, 10Rauen T. Wied S. Fitzner C. et al.After ten years of follow-up, no difference between supportive care plus immunosuppression and supportive care alone in IgA nephropathy.Kidney Int. 2020; 98: 1044-1052Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar, 11Cheung C.K. Barratt J. Should we STOP immunosuppression for IgA nephropathy? Long-term outcomes from the STOP-IgAN trial.Kidney Int. 2020; 98: 836-838Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar Systemic glucocorticoid use was associated with a nonsignificant increase in infections (174 infection events vs. 111 events in the supportive care–only group), a significant increased risk of weight gain >5 kg, and the development of impaired glucose tolerance or diabetes mellitus. Interestingly, an initial reduction in proteinuria was observed in the immunosuppression arm, which did not translate into longer term beneficial effects on kidney outcomes. If systemic glucocorticoids provide a nontargeted anti-inflammatory effect without a direct action on the underlying disease pathogenesis, which is chronic and progressive, this discrepancy would be expected, as the disease course would simply continue once glucocorticoids were withdrawn. The Therapeutic Evaluation of Steroids in IgA Nephropathy Global (TESTING) study again included a run-in period where RAS blockade was optimized.12Lv J. Zhang H. Wong M.G. et al.Effect of oral methylprednisolone on clinical outcomes in patients with IgA nephropathy: the TESTING randomized clinical trial.JAMA. 2017; 318: 432-442Crossref PubMed Scopus (276) Google Scholar Patients were originally randomized to receive oral methylprednisolone (0.6–0.8 mg/kg, maximum 48 mg/d) or placebo. Enrollment was halted after randomization of 262 participants because of a 5-fold greater risk of serious adverse events in the methylprednisolone group, mostly due to severe infections including 2 deaths, although an interim analysis at this point indicated potential kidney benefit. Compared with STOP-IgAN, which enrolled a European cohort, the study population was recruited mainly from Asia and had higher baseline proteinuria levels and a more rapid rate of kidney function decline. This study was subsequently redesigned to examine a lower dose of methylprednisolone with the addition of antibiotic prophylaxis for pneumocystis pneumonia.13Lv J. Wong M.G. Hladunewich M.A. et al.Effect of oral methylprednisolone on decline in kidney function or kidney failure in patients with IgA nephropathy: the TESTING randomized clinical trial.JAMA. 2022; 327: 1888-1898Crossref PubMed Scopus (27) Google Scholar It should be noted that methylprednisolone was used at 0.4 mg/kg, which still represents a significant dose and equates to 35–40 mg of prednisone for a typical 70 kg patient. With the lower dose, a significant reduction in the risk of the composite outcome of 40% reduction in eGFR, kidney failure, or death due to kidney disease was observed during the follow-up period, compared with those in the placebo group, with no significant heterogeneity of treatment effect compared with the higher dose. There did, however, remain a greater number of serious adverse events including death in those treated with methylprednisolone, although the magnitude of this was smaller than in the full-dose protocol. A summary of serious adverse events was listed, but steroid-related adverse effects were not routinely captured with a standardized and validated questionnaire such as the Glucocorticoid Toxicity Index, and therefore the burden of glucocorticoid toxicity is likely to have been underestimated in this study. The reduction of proteinuria occurred mainly in the initial few months of treatment, and by 36 months after randomization, levels of proteinuria increased again, so that there was no difference between those initially treated with methylprednisolone or placebo. In addition, after an initial period where eGFR increased in the methylprednisolone-treated group, subsequent eGFR decline occurred at the same rate as the placebo arm. In summary, a benefit in terms of potentially delaying renal outcomes was observed after a 6- to 9-month course of systemic glucocorticoids in this study, but this was associated with significant side effects, and the effects on lowering proteinuria and stabilizing kidney function were not sustained in the longer term. Because of both the immediate adverse effects of glucocorticoids and the cumulative effects on bone health and cardiovascular risk, it is unlikely that repeated courses of glucocorticoids would be acceptable to patients or nephrologists to manage IgAN over the lifetime of the patient, which in most cases will be many decades. Although an initial anti-inflammatory treatment is desirable as an induction therapy in IgAN, we also need chronic therapies that impact directly on the fundamental disease pathogenesis and deliver sustained effects on IgA immune complex formation, mesangial deposition, and consequent kidney damage. Given the known side effect profile, longer or repeated courses of systemic glucocorticoids are not desirable, and indeed we now have data to show that we can achieve a similar acute anti-inflammatory effect by blocking the C5a receptor.14Jayne D.R.W. Merkel P.A. Schall T.J. Bekker P. Avacopan for the treatment of ANCA-associated vasculitis.N Engl J Med. 2021; 384: 599-609Crossref PubMed Scopus (244) Google Scholar Current trials of complement inhibitors will determine their utility specifically in IgAN. There is an emphasis in the latest KDIGO guidelines that all patients who remain at high risk of progressive IgAN despite optimized supportive care should be offered the opportunity to participate in a clinical trial, if one is available, before other therapeutic options are considered. There has been a welcomed resurgence of interest by pharmaceutical companies in performing clinical trials in IgAN, driven by advances in the understanding of the underlying pathogenesis, and from acceptance by regulatory authorities of surrogate endpoints that include proteinuria reduction and rate of change of eGFR for the accelerated and full approval of new therapeutic agents.15Barratt J. Rovin B. Diva U. et al.PROTECT Study Design GroupImplementing the kidney health initiative surrogate efficacy endpoint in patients with IgA nephropathy (the PROTECT trial).Kidney Int Rep. 2019; 4: 1633-1637Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar There are now multiple agents in clinical development that target different steps of the pathogenesis of IgAN, which include modulators or inhibitors of the gut mucosal immune system, endothelin receptor signaling, B-cell survival cytokines, and complement activation.16Cheung C.K. Rajasekaran A. Barratt J. Rizk D.V. An update on the current state of management and clinical trials for IgA nephropathy.J Clin Med. 2021; 10: 2493Crossref PubMed Scopus (11) Google Scholar On December 17, 2021, the US Food and Drug Administration granted accelerated approval for Nefecon (Tarpeyo) delayed-release capsules to reduce proteinuria in adults with IgAN at risk of rapid disease progression, the first drug to be specifically approved for the treatment of IgAN. A number of other drug approvals are likely to follow in the coming years. A New Drug Application to the Food and Drug Administration under subpart H for accelerated approval of sparsentan for the treatment IgAN was submitted in March 2022. In addition, sodium-glucose cotransporter-2 inhibitors are approved in many countries for use in chronic kidney disease, including patients with IgAN. Given the general move away from systemic glucocorticoids for the treatment of glomerular disease in recognition of their significant toxicity profile, a lack of evidence to support a favorable and sustained risk-benefit ratio in IgAN, and the large number of promising new therapies that are being developed, in our opinion, we should now be focusing efforts on the development of new therapeutics that specifically target the underlying pathogenesis in this disease. There has never been a better time for nephrologists and patients to participate in well-designed clinical trials to build a robust evidence base for safe and effective treatments for IgAN. CKC reports having consultancy agreements with Calliditas and George Clinical; reports receiving honoraria from Vifor Pharma; and reports receiving research funding from GlaxoSmithKline and Travere Therapeutics. JB reports having consultancy agreements with Astellas, Alnylam, BioCryst, Calliditas, Chinook, Dimerix, Novartis, Omeros, Travere Therapeutics, Vera Therapeutics, and Visterra; reports receiving research funding from Argenx, Calliditas, Chinook, Galapagos, GlaxoSmithKline, Novartis, Omeros, Travere Therapeutics, and Visterra; and reports being a scientific advisor or member via the Editorial Board of Clinical Journal of the American Society of Nephrology, Glomerular Diseases & Clinical Science, and Kidney International. IgA nephropathy and glucocorticoids—a limbo dance?Kidney InternationalVol. 103Issue 4PreviewIn this issue of Kidney International, arguments are presented for and against the use of systemic glucocorticoids (GCs) in the treatment of IgA nephropathy (IgAN) that is likely to progress. The use of immunomodulation in IgAN makes sense. The immune system, especially the mucosal immune system, appears to be involved in disease pathogenesis. Immune deposits accumulate in the glomerular mesangium and almost certainly activate inflammatory pathways, including complement, resulting in acute kidney damage that heals with scar and often progresses to chronic damage. Full-Text PDF