TESTING Corticosteroids in IgA Nephropathy

IgA nephropathy (IgAN) is the most common type of GN worldwide, although the prevalence in some countries may be underestimated depending on the local policy for kidney biopsy. Patients with IgAN have a wide range of prognosis, from microscopic hematuria with stable kidney function through to kidney failure. Long-term data show that 20%–40% of patients progress to ESRD within 10–20 years of diagnosis. Recurrence of IgA deposition in the transplanted kidney is common, despite patients being on immunosuppression, and is an important cause of graft failure (1). Clinical features, including hypertension and proteinuria, have been shown to be useful in assessing prognosis. Recently, a combination of histopathologic score with clinical data has improved prediction of the risk of progression to kidney failure (2). However, the main role of histology in recent trials has been to confirm the diagnosis of IgAN and exclude patients with other types of GN or severely scarred kidneys.

Although the pathogenesis of IgAN is only partially understood, several lines of research have led to proposal of a multihit model, which incorporates abnormalities of IgA1 in the development of inflammation and fibrosis: (1) increased production of polymeric galactose-deficient IgA1 (Gd-IgA1); (2) Gd-IgA1 becomes autoantigenic, resulting in formation of autoantibodies and immune complexes; (3) deposition of Gd-IgA1 and immune complexes in the glomeruli; and (4) stimulation of inflammation and sclerosis in the glomeruli. Immunosuppressive therapy for IgAN has been used for many years, but its safety and effectiveness remain controversial. Over the last decade, the key advance in treatment of IgAN has been the use of renin-angiotensin system (RAS) blockade to control hypertension and proteinuria (3). This approach provides an opportunity to design a robust run-in period before the initiation of immunotherapy, so that the benefits of RAS blockade may be distinguished from the effect of immunosuppressive therapy.

Recently, Lv et al. (4) conducted a global double-blind, randomized, controlled clinical trial of oral methylprednisolone in patients with IgAN (the TESTING Randomized Clinical Trial). In this study, patients had a run-in period of 4–12 weeks (at least 3 months with optimized BP control) with a maximum recommended or tolerated dose of RAS blockade. Patients were then randomized to receive 0.6–0.8 mg/kg per day of methylprednisolone (equivalent anti-inflammatory activity to 0.75–1 mg/kg per day of oral prednisolone) or placebo for 2 months, which was tapered by 8 mg/d each month, for a total treatment period of 6–8 months. The original intention was to recruit 750 patients with a follow-up of at least 5 years. Because of early termination of the study, 262 patients were randomized with a median follow-up of 2.1 years. Fewer patients in the methylprednisolone group (5.9%), compared with the placebo group (15.9%), reached the primary end point (40% reduction in eGFR or development of ESRD). The mean rate of decline in eGFR was slower in the methylprednisolone group at −1.79 ml/min per 1.73 m², compared with −6.95 ml/min per 1.73 m² in the placebo group. Mean proteinuria was significantly reduced in the methylprednisolone group (1.37 g/d), compared with the placebo group (2.37 g/d).

The use of oral corticosteroids is a realistic approach to deliver immunotherapy to a large number of patients at an affordable price. Further, corticosteroids are known to have immunosuppressive effects on multiple mechanisms, which may be relevant to the multihit model of IgAN. However, in The Therapeutic Evaluation of Steroids in IgA Nephropathy Global (TESTING Randomized Clinical Trial), there were serious adverse events in 14.7% of patients treated with methylprednisolone, compared with 3.2% in the placebo group. There was an increased frequency of severe infection (8.1%) in the methylprednisolone group, including two fatalities, but none in the placebo group. Other serious adverse events included pulmonary embolism, deep vein thrombosis, avascular necrosis, and fracture in the treated group, even during the short follow-up period. Appropriately, the researchers terminated this study early, in view of the major adverse events in the treatment group.

Despite stopping early, the TESTING Randomized Clinical Trial is a valuable study that suggests some benefit from oral corticosteroid therapy in IgAN, but clearly demonstrates the high risk of adverse events. The side effects of corticosteroids have been reported to be more frequent in patients with a lower GFR (5). High-dose corticosteroids were used in this study, which included patients with a low GFR (inclusion criterion 20–120 ml/min per 1.73 m²). It remains to be tested whether a lower dose of corticosteroids will have a better benefit-to-risk ratio in such patients. It is also unclear whether patients from different ethnic groups will have a similar frequency of severe adverse effects. This high risk of adverse events is supported by the results of the Supportive Versus Immunosuppressive Therapy for the Treatment of Progressive IgA Nephropathy (STOP-IgAN) study in Germany (3), in which immunosuppressive treatment consisted of corticosteroid monotherapy for patients with eGFR≥60 ml/min per 1.73 m², or a combination of oral cyclophosphamide for 3 months followed by azathioprine for 33 months, plus oral prednisolone, for those with an eGFR of 30–59 ml/min per 1.73 m². There was an increased number of patients with severe infection (including one death with sepsis) in the treated group, compared with the supportive care group. In the STOP-IgAN trial, there was transient improvement in proteinuria at 1 year (but not at 3 years), and the number of patients achieving clinical remission (resolution of proteinuria and stabilization of eGFR) was greater in the treated group, but there was no difference in the rate of decline in eGFR between the two groups over 3 years follow-up.

In a large, retrospective analysis of patients from the European Validation Study of Oxford Classification of IgAN cohort, immunosuppression (mainly with corticosteroids) was associated with a significant reduction of proteinuria and slower rate of decline in kidney function, but it was not possible to assess the adverse events (6). An open-label pilot study of Adrenocorticotropic Hormone gel in the treatment of IgAN is ongoing (Clinicaltrials.gov identifier: NCT02282930). There are conflicting results from clinical trials of myophenolate mofetil (MMF) in IgAN. In a recent, randomized, controlled trial, the combination of MMF with a moderate dose of prednisolone was shown to have a lower incidence of Cushing syndrome and newly diagnosed diabetes mellitus, compared with a higher dose prednisolone-only group over 12 months of follow-up. The MMF group and prednisolone-only group had comparable remission rates of 48% and 53%, respectively, but not all patients were treated with RAS blockade (7). Oral tacrolimus has been shown to reduce proteinuria in a single-center, randomized, controlled trial of patients with IgAN and normal BP over 16 weeks, but not in the subgroup of patients also taking angiotensin receptor blockers (8).

Taken together, these studies suggest that immunosuppressive therapy may be effective in IgAN, but with appreciable adverse effects. In the absence of clear evidence, it is not easy to recommend an optimum treatment protocol. The way forward may be to deliver more specific therapy by (1) targeting the relevant lymphoid tissue, or (2) inhibiting selective immune mechanisms. Recently, targeted release of budesonide was tested in the Targeted-Release Budesonide Versus Placebo in Patients with IgA Nephropathy (NEFIGAN), a phase 2b trial (9). The aim was to suppress gastrointestinal mucosal production of IgA1, without exposing patients to systemic side effects of corticosteroids. Dose-dependent reduction of proteinuria and stabilization of eGFR were demonstrated in patients treated with budesonide. However, most patients who discontinued active therapy experienced corticosteroid-related adverse events.

An alternative approach is to give mechanistic specific therapy, such as targeting the production of IgA. In a recent trial of rituximab (anti-CD20 mAb) in patients with IgAN, treatment was successful in depleting peripheral B cells, but had no effect on the circulating concentration of underglycosylated IgA1 or immune complexes, or on severity of disease (10). In the recently completed Blisibimod Response in IgA Nephropathy Following At-Home Treatment by Subcutaneous Administration (BRIGHT-SC) trial, patients with IgAN were treated with blisibimod, a fusion protein blocking B-lymphocyte stimulator (Clinicaltrials.gov identifier: NCT02062684). In another ongoing trial, patients were treated with atacicept, a fusion protein blocking two B cell survival/maturation factors, B-lymphocyte stimulator, and a proliferation-inducing ligand (Clinicaltrials.gov identifier: NCT02808429).

Complement is a potential effector pathway in IgA mediated kidney injury. In a phase 2 trial of IgAN, treatment with OMS721, an mAb inhibiting mannan-binding lectin-associated serine protease-2, the effector enzyme of the lectin pathway of the complement system, was reported to show reduction in proteinuria (Clinicaltrials.gov identifier: NCT02682407). There is an ongoing randomized, controlled trial of fostamatinib, a spleen tyrosine kinase inhibitor, in treatment of IgAN (Clinicaltrials.gov identifier: NCT02112838). Spleen tyrosine kinase is important in downstream signaling from B cell receptors and Fc receptors, so may modulate different aspects of the multihit model.

In conclusion, the recent report of the TESTING Randomized Clinical Trial in IgAN demonstrates that development of safe and effective therapy is still a major challenge. This study provides encouraging evidence that large-scale clinical trials for IgAN are achievable. It is important that future trials should aim at recruiting patients from multiple ethnic groups globally, so that results are broadly applicable. Inclusion criteria should include histopathologic findings, to recruit patients who are most likely to benefit from immunotherapy. With increased understanding of the immune mechanisms of IgAN, it is hoped that more selective and effective immunotherapy will be developed in the near future.

Disclosures

F.W.K.T. is the chief investigator of an international clinical trial of spleen tyrosine kinase inhibitor in IgAN (funded by Rigel Pharmaceuticals, San Francisco, CA); has received research project grants from AstraZeneca Limited, Baxter Biosciences, Boehringer Ingelheim, and MedImmune; and has consultancy agreements with Rigel Pharmaceuticals, Novartis, and Baxter Biosciences. C.D.P. has received a research project grant from GlaxoSmithKline.