Monogenic focal segmental glomerulosclerosis: A conceptual framework for identification and management of a heterogeneous disease

Abstract

Focal segmental glomerulosclerosis (FSGS) is not a disease, rather a pattern of histological injury occurring from a variety of causes. The exact pathogenesis has yet to be fully elucidated but is likely varied based on the type of injury and the primary target of that injury. However, the approach to treatment is often based on the degree of podocyte foot process effacement and clinical presentation without sufficient attention paid to etiology. In this regard, there are many monogenic causes of FSGS with variable presentation from nephrotic syndrome with histological features of primary podocytopathy to more modest degrees of proteinuria with limited evidence of podocyte foot process injury. It is likely that genetic causes are largely underdiagnosed, as the role and the timing of genetic testing in FSGS is not established and genetic counseling, testing options, and interpretation of genotype in the context of phenotype may be outside the scope of practice for both nephrologists and geneticists. Yet most clinicians believe that a genetic diagnosis can lead to targeted therapy, limit the use of high-dose corticosteroids as a therapeutic trial, and allow the prediction of the natural history and risk for recurrence in the transplanted kidney. In this manuscript, we emphasize that genetic FSGS is not monolithic in its presentation, opine on the importance of genetic testing and provide an algorithmic approach to deployment of genetic testing in a timely fashion when faced with a patient with FSGS.

The Clinical Utility of Genetic Testing in the Diagnosis and Management of Adults with Chronic Kidney Disease

“…In addition, accurate diagnosis can prevent the use of ineffective or nephrotoxic treatments, as can occur in individuals with steroid-resistant nephrotic syndrome or FSGS, which often have a genetic etiology. 28…”

“…In addition, accurate diagnosis can prevent the use of ineffective or nephrotoxic treatments, as can occur in individuals with steroid-resistant nephrotic syndrome or FSGS, which often have a genetic etiology. 28 Numerous practice guidelines have been issued recommending genetic testing as a first-line diagnostic tool for CKD. 14,22,[29][30][31][32] For example, guidelines for the management of Alport syndrome recommend genetic testing as the gold standard for diagnosis given the improved sensitivity and specificity over kidney biopsy.…”

Genetic Counseling in Kidney Disease: A Perspective

“…Genetic testing has been recommended for use as an early diagnostic tool for patient evaluation in CKD by multiple expert bodies. 13 , 14 , 15 Recent studies have demonstrated that monogenic causes can be identified in up to 10% of adults and 20%-50% of children with CKD. 13 , 16 , 17 , 18 Furthermore, diagnostic genetic findings have management implications for 26%-95% of patients.…”

The role of HLA antigens in recurrent primary focal segmental glomerulosclerosis

“…Diagnosing genetic FSGS is also challenging. While the most common monogenic causes of FSGS can now be efficiently identified using targeted gene panels, the list of genetic causes is continually expanding (7). Furthermore, it is increasingly apparent that common inherited variants, such as HLA polymorphisms, may also contribute to the risk of primary FSGS (8), which complicates the current definition of genetic FSGS.…”