Therapy of IgA nephropathy: time for a paradigm change

Abstract

Immunoglobulin A nephropathy (IgAN) often has a poor outcome, with many patients reaching kidney failure within their lifetime. Therefore, the primary goal for the treatment of IgAN should be to reduce nephron loss from the moment of diagnosis. To achieve this, IgAN must be recognized and treated as both a chronic kidney disease and an immunological disease. Agents that have received US Food and Drug Administration and European Medicines Agency approval for the treatment of IgAN include modified-release/targeted-release formulation budesonide (Nefecon) and sparsentan, a selective dual endothelin-A and angiotensin II receptor type 1 antagonist. Other agents, including selective endothelin receptor antagonists, selective or combined APRIL and BAFF antagonists, and a vast array of complement inhibitors are being investigated for the treatment of IgAN. Furthermore, treatment combinations are also being studied, including sodium-glucose cotransporter-2 inhibitors with endothelin receptor antagonists. Due to the complexity of IgAN, combination treatment, rather than a single-agent approach, may provide maximum benefit. With the number of treatments for IgAN likely to increase, combinations allowing safe and effective treatment to halt progression to kidney failure seem within grasp. While trials evaluating combinations are ongoing, more are needed to pave the way for a comprehensive IgAN treatment strategy. Furthermore, an approach to IgAN treatment in which agents are combined early to achieve rapid induction of remission and prevent unnecessary and irreversible nephron loss is required. Following remission, treatments may be adjusted and stripped back as necessary in the maintenance phase with close monitoring. This review discusses the current status of IgAN treatment and explores future strategies to improve outcomes for patients with IgAN.

Keywords: IgA nephropathy; SGLT2 inhibitor; budesonide; eGFR; glucocorticoids; nephron; proteinuria; sparsentan.

Figure 1

A stylized representation of the unmet need in a typical adult patient with IgAN. At the time a patient is typically diagnosed with IgAN, both disease-specific, immune-mediated nephron loss and universal CKD causes of nephron loss are at play. During the earlier stages of IgAN, often prior to diagnosis, the immunological aspects are the greatest contributor to disease progression. However, the adverse response to nephron loss through fundamental CKD responses, including systemic hypertension, glomerular hyperfiltration, and tubulointerstitial damage in response to proteinuria, which initially contribute little, become a greater factor as nephron loss increases. It is important to note that treatment approaches and aspirations will differ in some IgAN populations; for example, in pediatric patients, IgAN is often diagnosed earlier in the natural history, while in transplant patients there is the opportunity to detect recurrent disease early and therefore intervene before significant nephron loss has occurred. CKD, chronic kidney disease; IgAN, IgA nephropathy.

Figure 2

The pillars of IgAN treatment. To gain control of disease progression, the foundational basis of optimized kidney care should be initiated in combination with B/plasma cell-directed agents to switch off pathogenic IgA production and anti-inflammatory agents immediately after diagnosis. It should be noted that FIND-CKD investigating finerenone in IgAN is ongoing, and therefore MRA inclusion as a pillar of IgAN treatment remains to be confirmed. The inclusion of anti-fibrotic agents (dashed box) in this multilevel treatment strategy is aspirational as none are currently in clinical trials for IgAN. Once remission is achieved, therapies not required for maintenance may be removed with ongoing monitoring of eGFR and proteinuria. APRIL, a proliferation-inducing ligand; BAFF, B-cell activating factor; CD38, cluster of differentiation 38; DEARA, dual endothelin angiotensin receptor antagonist; eGFR, estimated glomerular filtration rate; ERA, endothelin receptor antagonist; IgAN, IgA nephropathy; MRA, mineralocorticoid receptor antagonist; RASi, renin–angiotensin system inhibitors; SGLT2i, sodium–glucose cotransporter-2 inhibitors.