Immunoglobulin A Nephropathy: Challenges and Emerging Treatments
Researchers and clinicians seek to improve upon the existing approach to immunoglobulin A nephropathy (IgAN). As the understanding of the pathogenesis of IgAN grows, many new treatment strategies are being explored, some of which were highlighted at the NKF 2023 Spring Clinical Meetings (SCM23).
Following these presentations, featured expert Andrew S. Bomback, MD, MPH, was interviewed by Conference Reporter Editor-in-Chief Tom Iarocci, MD. Dr Bomback's clinical perspectives on these findings are presented here.
Andrew S. Bomback, MD, MPH
Associate Professor of Medicine
“In terms of emerging treatments for IgAN, we are blessed in that so many studies are being conducted with a variety of different agents. These studies are all coming along at the same time, as we are gaining a better understanding of the pathogenesis of the disease.”
The challenge with IgAN has always been trying to tailor our therapies toward the right patients. There are different versions of the disease, ranging from a very mild course that would not be expected to progress and should be managed with conservative therapy only to a very aggressive course that would be expected to progress to end-stage kidney disease (ESKD) if not treated early and thoroughly. Then there is a substantial middle group that includes untreated or undertreated patients who would be expected to have a slower, more chronic progression to ESKD compared with those with more aggressive disease. We believe that with the right treatment, we should be able to modify the projected course of IgAN and prevent progression to ESKD.
The International IgA Nephropathy Prediction Tool can help clinicians make treatment-related decisions. Further, I think that the standardization of the kidney biopsy reading, in terms of the Oxford classification of IgAN, has really provided us with a good set of guidelines on how to help predict outcomes in IgAN, and that pathology classification (ie, the Oxford MEST histologic score) is included in the risk score. We have gotten more comfortable as more and more data have emerged to help us prognosticate risk, evaluating the risks vs benefits of using appropriately dosed immunosuppression in select patients with IgAN.
One of the biggest unmet needs in IgAN is a good biomarker of disease activity. We still rely on proteinuria, microscopic hematuria, and a conventional assessment of kidney function as markers of disease activity, unless repeat biopsies are being performed (which some centers do and some centers do not do). However, those parameters are not specific to IgAN the way that a true biomarker would be.
In terms of emerging treatments for IgAN, we are blessed in that so many studies are being conducted with a variety of different agents. These studies are all coming along at the same time, as we are gaining a better understanding of the pathogenesis of the disease. I think that it is very helpful to break up the emerging therapies or novel therapies into those that are immune mediated vs those that are non–immune mediated. Within the immune-mediated category, it is helpful to divide the treatments up further into complement-targeting therapies vs non–complement-targeting therapies. The non–immune-modulating therapies include recently US Food and Drug Administration–approved sparsentan, which is a dual endothelin and angiotensin receptor antagonist.
There was a poster on sparsentan at SCM23 in which Radhakrishnan et al reported the interim results of the phase 3 PROTECT study in 404 adults with IgAN with proteinuria 1 g per day or higher despite maximized treatment (poster 333). Patients treated with sparsentan (n=202) had a significantly greater mean reduction in urine protein/creatinine ratio from baseline at week 36 compared with patients treated with active control irbesartan (n=202; -49.8% vs -15.1%, respectively). It is important to highlight that this reduction at 36 weeks relative to the active control agent is a pretty significant drop in proteinuria.
The other non–immune modulator, which sometimes gets forgotten because it was not examined in a direct study, is the sodium-glucose cotransporter 2 (SGLT2) inhibitor dapagliflozin. A prespecified subanalysis of the DAPA-CKD study involved 270 patients with IgAN; at the time, this was the largest IgAN study. Patients admittedly had a chronic form of IgAN. Now, this is not the type of patient with IgAN who would typically be enrolled in a study of a new IgAN agent, but these individuals are followed in the clinic by so many of us. The benefits of dapagliflozin that were reported in these patients were astounding. In fact, the SGLT2 inhibitor reduced the risk of the primary composite outcome by 71% and the secondary kidney-specific outcome by 75%.
So, for every patient with IgAN, I think that it will be important to at least be asking the question: Should we be thinking about going beyond an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker? Might a dual endothelin and angiotensin receptor antagonist be appropriate? Would the patient benefit from an SGLT2 inhibitor? These are important questions that we are able to ask now with the emergence of new treatments for IgAN, as they provide our patients with the potential for even better conservative therapy. Not every patient will need these additional strategies, but it is important to ask the questions.
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