Glucocorticoids for IgA nephropathy—pro

Since IgA nephropathy (IgAN) was first described in 1968 by Jean Berger, supportive lifestyle measures and blood pressure lowering agents, especially renin-angiotensin system inhibitors (RASi), have become first-line treatment. Despite this, a substantial risk of progression remains even when these therapies are optimally employed.1Kidney 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 This is important as these supportive therapies, and more recently sodium-glucose cotransporter-2 inhibitors,2Wheeler D.C. Toto R.D. Stefansson B.V. et al.A pre-specified analysis of the DAPA-CKD trial demonstrates the effects of dapagliflozin on major adverse kidney events in patients with IgA nephropathy.Kidney Int. 2021; 100: 215-224Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar do not address the underlying cause of IgAN. Data from clinical and pathomechanistic studies have demonstrated an immune-mediated basis for IgAN, providing a strong rationale for the use of immunomodulatory therapy. These suggest that the primary abnormality is the production of galactose-deficient IgA1 by B cells, along with production of anti-glycan antibodies. The resulting circulating immune complexes deposit in the kidney and set off local inflammation and progressive sclerosis and fibrosis, potentiated by the resulting hemodynamic changes.3Mestecky J. Raska M. Julian B.A. et al.IgA nephropathy: molecular mechanisms of the disease.Annu Rev Pathol. 2013; 8: 217-240Crossref PubMed Scopus (104) Google Scholar,4Wyatt R.J. Julian B.A. IgA nephropathy.N Engl J Med. 2013; 368: 2402-2414Crossref PubMed Scopus (786) Google Scholar Nonspecific supportive therapies such as RASi and sodium-glucose cotransporter-2 inhibitors act on these very last steps in this process and do not address the underlying disease process. Ongoing studies (NCT03762850 and NCT 04573478) are assessing endothelin antagonists, which are also likely to act via nonspecific, hemodynamic, and perhaps antifibrotic processes. It is unlikely that these nonspecific therapies will provide adequate long-term kidney protection. More specific therapies directly targeted to the underlying disease process are required to address the fundamental disease abnormality and provide long-term kidney protection. Systemic glucocorticoids are the archetypal immunomodulatory therapy with effects across the spectrum of immune function. This is likely to include effects on abnormal IgA1 production, immune complex formation, and the inflammatory reaction stimulated by the deposition of these immune complexes in the glomerulus.5Cain D.W. Cidlowski J.A. Immune regulation by glucocorticoids.Nat Rev Immunol. 2017; 17: 233-247Crossref PubMed Scopus (805) Google Scholar There is thus a good reason to expect that glucocorticoids may protect the kidney in IgAN. Initial data regarding the effects of glucocorticoid therapy came from relatively small, single-center trials conducted in people with high-risk IgAN. These were powered for surrogate outcomes and suggested benefit individually. A meta-analysis found a reduction in major clinical outcomes including kidney failure when the results of the trials were pooled.6Lv J. Xu D. Perkovic V. et al.Corticosteroid therapy in IgA nephropathy.J Am Soc Nephrol. 2012; 23: 1108-1116Crossref PubMed Scopus (141) Google Scholar While suggestive, the lack of benefit in individual studies and the variable use of background therapies such as RASi led to uncertainty about robustness. The only trial specifically designed and powered to assess the effects of glucocorticoids on major kidney outcomes was the Therapeutic Evaluation of Steroids in IgA Nephropathy Global (TESTING) study.7Lv 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,8Lv 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 This was an international, double-blinded, randomized trial initiated in 2012. It evaluated the efficacy and safety of the oral glucocorticoid methylprednisolone on major kidney outcomes in patients with persistent proteinuria above 1 g/d, estimated glomerular filtration rate (eGFR) between 20 and 120 ml/min per 1.73 m2 after at least 3 months of RASi, and optimized blood pressure control. The primary endpoint was a composite of kidney failure, death due to kidney disease, or a 40% decrease in eGFR. Overall, the risk of the primary outcome was reduced by almost half in participants randomized to methylprednisolone (hazard ratio [HR]: 0.53, 95% confidence interval [CI]: 0.39–0.72; P < 0.001),8Lv 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 along with a separately statistically significant 41% reduction in kidney failure (HR: 0.59, 95% CI: 0.40–0.87; P = 0.008), with a slower eGFR decline and reduced proteinuria. It clearly and conclusively demonstrated that oral methylprednisolone protects against kidney failure in IgAN. An updated meta-analysis (Figure 1a8Lv 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, 9Rauen 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,S1–S7) incorporating this trial estimates that a 53% reduction in the risk of major kidney outcomes is achieved with glucocorticoid (HR: 0.47, 95% CI: 0.32–0.70), with consistent results between trials (P-heterogeneity 0.12), reinforcing these results. An outlier in these results is the Supportive versus Immunosuppressive Therapy for the Treatment of Progressive IgA Nephropathy (STOP-IgAN) trial,9Rauen 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,10Rauen 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 multicenter trial from Germany assessing additional immunosuppressive treatment (glucocorticoid when eGFR >60 ml/min per 1.73 m2 or a prednisolone, cyclophosphamide, and azathioprine regimen for eGFR 30–59 ml/min per 1.73 m2). Although remission of proteinuria was improved, additional immunosuppressive therapy did not improve eGFR or prevent major kidney outcomes, despite more adverse effects including severe infections. A likely reason for the lack of effect is the low-risk participants in STOP-IgAN. The rate of eGFR decline in the control group was 2.68 ml/min per 1.73 m2 per year, so it is unlikely that any intervention could have realistically been shown to slow this rate further in a trial of its size (Figure 1b). Ethnicity has been suggested to impact both prognosis and treatment effects in IgAN. Specifically, Asian people may have more aggressive disease that has been proposed to be more amenable to immunomodulatory therapy. The data demonstrate similar benefits overall in pooled analyses in both Asian and Caucasian participants. Examination of other subgroup analyses in TESTING also suggested similar benefits across subgroups, as have meta-analyses broken down by several of these factors (Figure 1). Taken together, the data clearly demonstrate a kidney-protective effect of glucocorticoids in high-risk IgAN that is consistent across trials overall and across subgroups. Glucocorticoid therapy has long been known to increase the risk of a range of adverse effects, including effects on weight, mood, skin, muscle, bone, glucose metabolism, lipids, and the risk of infection. Although data were collected inconsistently in earlier studies, TESTING and STOP-IgAN carefully collected all serious adverse events (SAEs) and found a significantly increased risk. TESTING was interrupted after randomizing 262 patients due to 28 SAEs in 20 participants (14.7%) randomized to methylprednisolone (mainly serious infections including 2 deaths), versus 4 SAEs in 4 placebo participants (3.2%, P = 0.001). The subsequent 241 randomized participants had the dose reduced (0.4 mg/kg/d of methylprednisolone, maximum 32 mg/d) from the original regimen (0.6–0.8 mg/kg/d, maximum 48 mg/d), tapering for a total of 6 to 8 months. Antibiotic prevention for Pneumocystis jirovecii was added for 12 weeks, and the lower eGFR threshold increased from 20 to 30 ml/min per 1.73 m2. Among participants randomized to reduced dose methylprednisolone, a modest imbalance in SAEs was observed (6 patients compared with 3 patients, P = 0.50), compared with the final results in the full dose regimen (22 vs. 4 participants, P = 0.0004). Along with better safety, the reduced dose efficacy results (HR: 0.27, 95% CI: 0.11–0.65) were consistent with full dose treatment (HR: 0.58, 95% CI: 0.41–0.81; P-heterogeneity 0.11).8Lv 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 An updated meta-analysis according to dose showed similar results (Figure 1a). Collectively, these results show that the reduced dose regimen had a favorable risk-benefit profile. For every 100 participants treated, and followed for 2.5 years, reduced dose methylprednisolone is estimated to prevent 16.7 primary outcomes, including 5.8 kidney failure outcomes, at a cost of 2.4 SAEs, with 1 likely fatal. The risk-benefit ratio for full dose therapy is more evenly balanced (11.8 primary outcomes prevented including 5.8 kidney failure events, vs. 11.7 additional SAEs, with 3 likely fatal). These results raise the question of whether even lower doses of glucocorticoids might achieve similar benefits, with further safety improvements. This may be partly answered by the ongoing trial of oral budesonide (NCT03643965), with promising interim findings,11Barratt J. Lafayette R. Kristensen J. et al.Results from part A of the multi-center, double-blind, randomized, placebo-controlled NefIgArd trial, which evaluated targeted-release formulation of budesonide for the treatment of primary immunoglobulin A nephropathy.Kidney Int. 2023; 103: 391-402Abstract Full Text Full Text PDF Scopus (20) Google Scholar and phase 2 trial results12Fellstrom B.C. Barratt J. Cook H. et al.Targeted-release budesonide versus placebo in patients with IgA nephropathy (NEFIGAN): a double-blind, randomised, placebo-controlled phase 2b trial.Lancet. 2017; 389: 2117-2127Abstract Full Text Full Text PDF PubMed Scopus (195) Google Scholar demonstrating proteinuria reduction and stabilized kidney function over 12 months. Although this agent may achieve its effects via the intestinal mucosa rather than systemic absorption (due to first pass metabolism by the liver), the demonstrated systemic effects (Cushingoid features, new onset diabetes, acne, etc.) and an early increase in the eGFR characteristic of glucocorticoid studies suggest at least some systemic absorption and therefore systemic effects. It is not possible to compare the efficacy of this agent with prior glucocorticoid regimens, but the full results will be important. The completed trials of glucocorticoids clearly demonstrate that these agents protect kidney function and reduce the risk of kidney failure and are thus an important tool for people at high renal risk. It is equally clear now that this protection comes at a cost with an increased risk of serious infections in particular. The TESTING study has demonstrated that reduced dose glucocorticoid therapy as used in that study was at least as effective as full dose treatment, with a much lower risk of SAEs. Further dose reductions may be possible, and the budesonide data will be important in this regard. The optimal duration of therapy remains an important unanswered question with most of the benefits of the 6- to 12-month treatment regimens studied to date appearing early, and it is not clear whether longer treatment regimens might provide better long-term outcomes. Similar questions exist about the potential for more specifically targeted immunomodulatory therapy to achieve long-term kidney protection. Studies of treatments targeting B cells or the complement cascade more specifically are currently underway, and early data appear promising.13Selvaskandan H. Cheung C.K. Muto M. et al.New strategies and perspectives on managing IgA nephropathy.Clin Exp Nephrol. 2019; 23: 577-588Crossref PubMed Scopus (41) Google Scholar Whether these agents can produce similar benefits at reduced risk of adverse events remains to be defined. We are in the middle of a golden age of evidence generation in IgAN. We have supportive treatment options that clearly protect the kidney (blood pressure control, RASi, and sodium-glucose cotransporter-2 inhibitors), and others being studied (endothelin antagonists). In glucocorticoids, we also have a proven kidney-protective therapy that specifically targets the underlying pathological processes and which therefore can and should be offered to people with IgAN at high risk of progression. The promise of more specific and therefore potentially safer kidney-protective immunomodulatory therapies is strong, but remains to be proven, and results from several ongoing trials are awaited with great interest. HZ and VP are the co-chairs and JC-L and MGW are members of the steering committee of the Therapeutic Evaluation of Steroids in IgA Nephropathy Global (TESTING) study. The TESTING trial was funded by the Australian National Health and Medical Research Council, Chinese Academy of Medical Sciences Innovation Fund for Medical Science (2019-I2M-5-046), China National Funds for Distinguished Young Scientists (81925006), National Key Research and Development Program of China (2018YFC1314004), and the Canadian Institutes for Health Research (MOP126078) and had study drug and initial funding ($75,000) provided by Pfizer. Y-MZ declared no competing interests. Download .docx (.01 MB) Help with docx files Supplementary File (Word) 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