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Written by: Oscar R. Durón Vargas, MD; Francisco Santamaría, MD
AcademicCME (www.academiccme.com) is accrediting this educational activity for CE and CME for clinician learners. Please go to https://academiccme.com/kicr_blogposts/ to claim credit for participation.
Introduction
Podocytopathies represent a group of glomerular diseases characterized by damage to podocytes, the specialized cells crucial for maintaining the kidney's filtration barrier. Among these, Minimal Change Disease (MCD) and Focal Segmental Glomerulosclerosis (FSGS) stand out as significant causes of nephrotic syndrome, in both adult and pediatric populations. While MCD is traditionally considered a non-inflammatory disease with unclear etiology, recent research has shed light on the role of anti-nephrin antibodies, opening new avenues for understanding and managing this condition.
Overview of Podocytopathies
Podocytopathies are kidney diseases in which direct or indirect podocyte injury drives proteinuria and/or nephrotic syndrome. Research into the pathophysiology of podocytopathies is ongoing, but it has been determined that multiple factors are related to this kind of kidney disease including genetic variants, environmental triggers, infection/immune-related factors, toxic exposures, hemodynamic factors, and obesity.
Figure 1. Mechanisms of injury in podocytopathies. Mediators released by T or B cells have a suggested role in the development of proteinuria. The podocyte suffers morphological and molecular changes in key proteins including nephrin. Original source of the image here.
Immunological and soluble factors have proven to play a role in the pathophysiology. The effectiveness of glucocorticoids and other immunosuppressive drugs in many podocytopathies suggests a central role of the immune system in the pathogenesis of these disorders. There is evidence of persistent remission of proteinuria after treatment with rituximab or ofatumumab, both of which deplete B cells. Some trials have evaluated the use of that selective extracorporeal immunoadsorption, which may induce remission of nephrotic syndrome relapses, suggesting a soluble factor may be at least partially responsible for inducing proteinuria.
In general, the degree of podocyte damage correlates with signs and symptoms related to typical nephrotic syndrome.
Diagnosis and Treatment
Pathological diagnosis of nephrotic syndrome is often based on kidney biopsy, however, children and individuals in low-resource settings may defer renal biopsy. Typical manifestations are minimal change lesions and focal segmental glomerulosclerosis lesions.
PATH PICTURE
Figure 2. Images taken from Pathology Kidney.
Standard treatment for primary podocytopathies manifesting with minimal change disease or focal segmental glomerulosclerosis lesions includes glucocorticoids and other immunosuppressive drugs.
What is Nephrin and what is its role in the Glomerulus?
Nephrin is a key protein located in the slit diaphragm of podocytes, which are vital for the kidney's filtration function. Acting like a molecular zipper, nephrin forms a barrier that prevents the leakage of large proteins like albumin into the urine. Disruption in nephrin’s function, whether through genetic mutations or immune-mediated damage, can lead to proteinuria—a hallmark of nephrotic syndrome.
Figure 3. Podocyte and Nephrin, from Vivarelli et al, CJASN, 2021.
Anti-Nephrin Antibodies: Discovery and Mechanism
The discovery of anti-nephrin antibodies marked a significant breakthrough in nephrology.
For a long time, experts postulated that there were circulating factors involved in MCD given the efficacy of B-cell targeted therapy and a minority of biopsies having IgG staining in the immunofluorescence. These later found autoantibodies, target nephrin, leading to podocyte injury and increased permeability of the glomerular filtration barrier. Check-out the Freely Filtered podcast featuring Dr. Astrid Weins discussing this article and the discovery of anti-nephrin antibodies here. Measurement of autoantibodies is not commercially available yet and is only used for research purposes. Although the role of anti-nephrin antibodies in MCD is still under investigation, they are increasingly recognized as potential contributors to the disease's pathogenesis.
While anti-nephrin antibodies have been primarily studied in MCD, their role extends to other podocytopathies like FSGS. MCD typically presents with normal appearing glomeruli with diffuse effacement of podocyte foot processes observed on electron microscopy. In addition to diffuse podocyte effacement, FSGS is also defined by focal segmental scarring within the glomeruli. The presence of anti-nephrin antibodies in both of these conditions suggests a shared underlying mechanism involving immune-mediated podocyte injury.
The Evidence
The NEJM recently published a study about antibodies targeting nephrin in podocytopathies.
Methods
A multicenter study was conducted to analyze anti-nephrin antibodies in adults with glomerular diseases including MCD, FSGS, Membranous Nephropathy (MN), and other glomerulopathies and in children with Idiopathic Nephrotic Syndrome (INS). Other glomerulopathies include disease processes that typically do not present with nephrotic syndrome such as IgA nephropathy, antineutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis (GMN), and lupus nephritis (LN).
Plasma samples from adults with biopsy-proven glomerular disease were analyzed. Samples from children with INS were obtained as well. Healthy adult and children samples were used as controls. anti-nephrin autoantibody status was determined by immunoprecipitation-ELISA hybrid assay.
Results
Among adults, anti-nephrin autoantibodies were found in 44% with MCD, 9% with primary FSGS, 2% with non-primary FSGS, and 2% with MN. Patients with IgA nephropathy, ANCA associated GMN, LN, and healthy controls were negative for anti-nephrin autoantibodies.
In children with INS, 52% had detectable anti-nephrin antibodies.
In a subgroup of patients with active MCD or INS who were not receiving treatment with immunosuppressive agents, the prevalence of anti-nephrin autoantibodies was as high as 69% and 90%, respectively.
Figure 4, from Hengel et al, NEJM, 2024
Longitudinal measurement of anti-nephrin autoantibodies was performed in patients with anti-nephrin associated podocytopathies. Follow-up samples of 38 adult patients with MCD or primary FSGS were examined and it was found that the presence and absence of anti-nephrin autoantibodies were associated with active disease and remission, respectively. Follow-up samples were also available in 13 children with anti-nephrin-associated INS and all that were anti-nephrin positive at onset were anti-nephrin negative in remission.
Figure 5, from Hengel et al, NEJM, 2024. Correlation of anti-nephrin autoantibodies with longitudinal disease course of remission and relapse.
Treatment with immunosuppressive agents also seems to have a relation with the presence of anti-nephrin autoantibodies as it was observed prospectively in two patients treated with rituximab, as seen in figure 6.
Figure 6, from Hengel et al, NEJM, 2024. B-celll depletion with rituximab appeared to induce the reduction of anti-nephrin autoantibodies and lead to clinical remission.
These results were also observed in a KI Reports single center case series with 7 patients of adult-onset MCD, which after therapeutic interventions, those with anti-nephrin antibodies had a reduction in anti-nephrin antibody titer concordant with clinical response.
Could the detection of anti-nephrin antibodies guide therapeutic decisions in MCD and FSGS?
More studies have to be made to answer this question, but evidence so far would suggest that B cell targeted therapies have an impact in this kind of kidney disease. Research about how the effects of anti-nephrin autoantibodies might best be mitigated not only include B-cell depleting based drugs but also plasmapheresis (PLEX), as seen in a KI Reports case report of a patient with FSGS resistant to glucocorticoid treatment that after 7 sessions of PLEX achieved complete clinical and immunological remission with disappearance of anti-nephrin antibodies.
In a Japanese pediatric population with genetic and non-genetic FSGS that underwent kidney transplants, an association between the recurrence of FSGS and high-level anti-nephrin antibodies was observed. However, the study was focused on a small sample of Japanese patients and lacked pretransplant antibody assessment. A recently published cohort including a larger population from North America and Europe demonstrated pre-transplant anti-nephrin antibodies are predictors of recurrent podocytopathies in the kidney allograft, which may be a method for pre-transplant screening to identify patients at risk.
Conclusion
Research into anti-nephrin antibodies is evolving rapidly, with studies exploring their potential as biomarkers for disease activity and targets for novel therapies. Recent publications dive into the clinicopathologic characteristics of anti-nephrin positive primary podocytopathies in adult patients. The development of treatments that specifically neutralize these antibodies holds promise for more effective management of MCD and other podocytopathies. As our understanding deepens, personalized approaches to treatment may become a reality, offering hope for better outcomes in patients with these challenging diseases.
Understanding the role of anti-nephrin antibodies in MCD and other podocytopathies represents a significant step forward in nephrology. As research continues to uncover the complexities of these immune mechanisms, new therapeutic strategies are likely to emerge, offering hope for improved patient care and outcomes.
AcademicCME (www.academiccme.com) is accrediting this educational activity for CE and CME for clinician learners. Please go to https://academiccme.com/kicr_blogposts/ to claim credit for participation.
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