Unmet Needs and Targeted Treatments for Glomerular Diseases
Researchers are on the cusp of understanding the role of complement and other potential targets in different categories of glomerular diseases. At the NKF 2023 Spring Clinical Meetings (SCM23), data highlighted recent progress and persisting treatment needs.
Following these proceedings, featured expert Carla M. Nester, MD, MSA, FASN, was interviewed by Conference Reporter Editor-in-Chief Tom Iarocci, MD. Dr Nester's clinical perspectives on these findings are presented here.
Carla M. Nester, MD, MSA, FASN
Jean Robillard Professor of Pediatric Nephrology
“ . . . a major unmet need is really knowing how to apply our understanding of the underlying pathology of each glomerular disease to identify the most important treatment target(s).”
Developing effective targeted treatments for patients with glomerular diseases is important, whether you consider lupus nephritis, immunoglobulin A nephropathy (IgAN), or complement 3 glomerulopathy (C3G). There is an unmet need for treatment, but there is also an unmet need with regard to truly having a clear understanding of which target, or targets, can be used in each disease in order to improve outcomes optimally. In lupus nephritis, for example, we know that there are numerous abnormal autoimmune proteins; in IgAN, we understand the multi-hit hypothesis of disease pathology; and, in C3G, we know that complement dysregulation is at the base of that disease.
Applying what we know about the pathophysiology of C3G, the use of anticomplement therapy makes perfect sense because we understand the origin of that disease, and we can target it quite nicely with the newer complement therapeutics. For lupus nephritis, however, nephrologists would likely admit that they are relatively disappointed about how long we have been struggling with the treatment of this disorder. We still cannot say, “For a given patient, I will use drug X because I know that 85% to 90% of patients will respond, and this is what I should expect for the patient in front of me.” And, for IgAN, while we have the 4-hit hypothesis, we do not yet know how best to target these hits; for instance, we do not yet know whether a therapy targeting the lectin pathway of complement activation will have more clinical benefit than a therapy targeting the mesangial proliferation.
In my view, membranous nephropathy is one of the best examples of a glomerular disease for which the rationale for a targeted approach has been relatively well developed; yet, even there, we lack a perfect understanding. Circulating podocyte-targeted autoantibodies (mainly anti-PLA2R) are important, so perhaps targeting B cells makes sense if we can eliminate those autoantibodies. So, again, a major unmet need is really knowing how to apply our understanding of the underlying pathology of each glomerular disease to identify the most important treatment target(s).
As we look ahead to the possibility of targeting complement pathways, another challenge is determining which diseases might be treated solely with complement inhibition and which ones might benefit from a multidrug approach, where complement inhibition may be adjunctive or supportive. In glomerular diseases for which we have another therapy to target a "more primary" mechanism, complement inhibition might be used more supportively, in much the same way that we currently use angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. We are really on the cusp of sorting out which category the various glomerular diseases are in right now.
At SCM23, we saw some posters that highlighted unmet treatment needs in IgAN. For example, Lafayette et al analyzed real-world data among patients with IgAN from June to October 2021, generating a picture of the disease burden and impacts on patient-reported quality of life (poster 324). The top 5 therapies being received at survey were angiotensin-converting enzyme inhibitors (50%), prednisone (41%), statins (39%), angiotensin receptor blockers (39%), and sodium-glucose cotransporter 2 inhibitors (33%). Despite these approaches, the quality-of-life impact and burden to these patients with IgAN were considerable, especially in those with severe proteinuria and decreased kidney function, underscoring the need for new approaches.
In poster 333, also presented at SCM23, Radhakrishnan and colleagues reported interim results from the phase 3 PROTECT study in 404 adults with IgAN and proteinuria 1 g/day or higher despite maximized treatment. Sparsentan treatment significantly reduced the urine protein to creatinine ratio from baseline at week 36 vs active control irbesartan (-49.8% vs -15.1%, respectively), which is a pretty good drop in proteinuria. That said, proteinuria is a surrogate. Reducing proteinuria means that we are making progress, but, ultimately, we want to be able to treat the primary pathophysiology of disease.
The US Food and Drug Administration accepts proteinuria as a surrogate end point based on our current set of tools, but we would all like to have better tools. I might speculate that, in many patients with IgAN, if you could just fix the proteinuria, perhaps their kidney disease would not continue on the same poor trajectory. However, simply fixing the proteinuria is not necessarily the whole story. Based on my experience in C3G, fixing the proteinuria without addressing severe underlying complement dysregulation may not fully address the disease.
Du Y, Cheng T, Liu C, et al. IgA nephropathy: current understanding and perspectives on pathogenesis and targeted treatment. Diagnostics (Basel). 2023;13(2):303. doi:10.3390/diagnostics13020303
Fakhouri F, Schwotzer N, Golshayan D, Frémeaux-Bacchi V. The rational use of complement inhibitors in kidney diseases. Kidney Int Rep. 2022;7(6):1165-1178. doi:10.1016/j.ekir.2022.02.021
Heiderscheit AK, Hauer JJ, Smith RJH. C3 glomerulopathy: understanding an ultra-rare complement-mediated renal disease. Am J Med Genet C Semin Med Genet. 2022;190(3):344-357. doi:10.1002/ajmg.c.31986
Kademani SP, Nelaturi P, Sathyasagar K, Ravikumar S. Noncoding RNAs associated with IgA nephropathy. J Nephrol. 2023;36(3):911-923. doi:10.1007/s40620-022-01498-4
Lafayette R, Aldworth C, George AT, et al. Immunoglobulin A nephropathy patient reported health utility and quality of life: evidence from US real-world data [poster 324]. Poster presented at: National Kidney Foundation 2023 Spring Clinical Meetings; April 11-15, 2023; Austin, TX.
Meuleman M-S, Grunenwald A, Chauvet S. Complement C3-targeted therapy in C3 glomerulopathy, a prototype of complement-mediated kidney diseases. Semin Immunol. 2022;60:101634. doi:10.1016/j.smim.2022.101634
Radhakrishnan J, Wong MG, Heerspink HJL, Komers R, Prasad A, Mercer A. Proteinuria reduction with sparsentan in immunoglobulin A nephropathy (IgAN): PROTECT study interim results [poster 333]. Poster presented at: National Kidney Foundation 2023 Spring Clinical Meetings; April 11-15, 2023; Austin, TX.
Rojas-Rivera JE, Ortiz A, Fervenza FC. Novel treatments paradigms: membranous nephropathy. Kidney Int Rep. 2023;8(3):419-431. doi:10.1016/j.ekir.2022.12.011
Scionti K, Molyneux K, Selvaskandan H, Barratt J, Cheung CK. New insights into the pathogenesis and treatment strategies in IgA nephropathy. Glomerular Dis. 2022;2(1):15-29. doi:10.1159/000519973
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