REFRACTORY NEPHROTIC SYNDROME IN FOCAL AND SEGMENTAL GLOMERULOSCLEROSIS BY PMM2 GENETIC VARIANT

Introduction:

Nephrotic syndrome (NS) is a clinical condition characterized by massive proteinuria, edema, hypoalbuminemia, and hyperlipidemia. The etiology may be secondary to systemic, metabolic, infectious, neoplastic, and pharmacological diseases. There is a group of primary causes of unknown etiology whose pathophysiological mechanism is immunological whose most frequent histological pattern in adults is focal segmental glomerulosclerosis (FSGS), minimal change disease and membranous nephropathy that represent podocithopathies. Currently, the KDIGO guidelines add that FSGS may have a genetic etiology, which merits a different diagnostic and therapeutic approach due to its refractoriness to immunosuppressive management, determining the causative gene is of great importance to predict its relapse in transplantation. A diversity of genes contributing to podocitopathies (NEPH1, TRPC6, CRB2, FAT1) located in the diaphragm slit has been highlighted, but very few cases have been reported with the PMM2 genetic variant.

Methods:

Clinical case:

This is a patient who is currently 37 years old, whose disease began early at 3 years of age, manifested as a nephrotic syndrome, it was managed as if it were a disease of minimal changes, for which she was managed with steroids, with preserved renal function, but with occasional relapses.  There is no family history. Later, when she reached the age of majority, she was referred to adult nephrology care. However, with the passage of time he had frequent relapse episodes, for this reason an infectious and autoimmune profile was requested in 2015 that were negative, in addition to a renal biopsy showing a FSGS with podocyte effacement of <50%, and diffuse thinning of the glomerular basement membrane (GBM) (see table 1), the treatment was optimized by adding calcineurin inhibitor,  statin and ARB II, in addition to steroid. However, the patient had fluctuations between partial remissions and relapses, so a rebiopsy was requested in 2018 (Table 1), which highlights the progression of the superior podocyte effacement of 60%, with no alterations in the GBM. An ISGLT2 was added to its baseline management, and its clinical response was torpid again, presenting partial remissions and relapses of the NS. Thus, in 2024, the need to perform genetic and autoimmune studies and perform a rebiopsy is raised, see tables 1 and 2 and image 1. In this biopsy, a podocyte effacement of 80-90% and a segmental thinning of the GBM are highlighted, as for the result of the genetic panel, it was negative for the main highlighted variants, but a finding of a variant in the PMM2 gene was reported, which has been reported in very few cases as a cause of NS.

Results:

Table 1. Summary of Main Biopsy Results

Table 2. Autoimmune profile

Discussion

The approach to  (NS) involves a comprehensive evaluation to identify the underlying etiology, ranging from ruling out infectious, autoimmune and systemic pathologies, to considering primary etiologies and genetic factors(1). Focal segmental glomerulosclerosis (FSGS), a histological pattern of injury, can be classified according to its primary etiology, which is suspected when there is refractoriness to treatment and elevated podocyte effacement(2). Secondary FSGS is caused by infections, medications, or adaptive changes with glomerular hyperfiltration(2). FSGS of indeterminate cause is characterized by podocyte segmental effacement, after ruling out secondary causes(2). Genetic FSGS includes familial, syndromic and sporadic forms, with variants in various genes: NEPH1, TRPC6, CRB2, FAT1, NPHS1, NPHS2, CD2AP, which are located in the "diaphragm slit"(3)(4). The classification of FSGS based on etiology is crucial for guiding treatment and predicting prognosis. In secondary FSGS, identifying and managing the underlying cause is essential(2). FSGS of indeterminate cause may respond to immunosuppressive therapy, although the response is often less favorable compared to minimal change disease(2). Genetic FSGS, particularly when presenting in childhood, is less responsive to immunosuppression and has a higher risk of progression to end-stage kidney disease(3). Genetic testing can help identify the specific mutation and guide counseling regarding recurrence risk and potential for kidney transplantation(4). In conclusion, a thorough evaluation for the etiology of FSGS is essential for appropriate management and prognostication, and further research is needed to elucidate the complex interplay between genetic and environmental factors in the pathogenesis of this disease.

A wide variety of genetic mutations have been reported to cause steroid-resistant nephrotic syndrome (SRNS), allowing us to better understand its pathophysiological mechanisms(5). The suspicion of a genetic etiology should be raised when there is resistance to steroids, a positive family history, extensive podocyte effacement on kidney biopsy, and the presence of extrarenal manifestations(5).Very few cases of SRNS have been reported as a result of variants in the PMM2 (phosphomanomutase 2) gene, which is associated with congenital disorders of glycosylation(6). This is a rare metabolic, systemic entity that can lead to steroid resistance in nephrotic syndrome(6).The identification of PMM2 mutations in patients with SRNS is clinically relevant, as it suggests a specific underlying pathogenic mechanism involving abnormal glycosylation. This knowledge can guide further diagnostic testing and management strategies. Patients with PMM2-related SRNS may benefit from a multidisciplinary approach involving nephrologists, metabolic specialists, and geneticists. Early recognition of the genetic etiology can help avoid unnecessary immunosuppressive treatment and inform prognosis and family counseling. In conclusion, while rare, PMM2 gene variants should be considered in the differential diagnosis of SRNS, especially in the setting of multisystem involvement. Continued research is needed to fully elucidate the spectrum of genetic causes of nephrotic syndrome and their associated clinical phenotypes.

Conclusions:

 The importance of performing a genetic panel in patients with (NS) is multifaceted. It provides insights into the underlying pathogenic mechanisms of the disease, which can vary depending on the affected gene. Certain genetic forms of NS are associated with extrarenal features, such as in syndromic forms. Genetic testing can help identify these cases and guide appropriate screening and management of associated conditions. Additionally, it allows for screening of other family members, both to identify asymptomatic carriers and to provide accurate genetic counseling regarding recurrence risks in future pregnancies. Knowing the genetic cause can help avoid unnecessary immunosuppressive therapy in cases of monogenic NS, as these forms are typically resistant to such treatments. In patients with genetic NS, genetic testing is crucial prior to kidney transplantation to assess the risk of disease recurrence in the allograft. This information can guide the choice of donor (living related vs. unrelated) and post-transplant management. In conclusion, genetic testing in NS provides valuable insights that can significantly impact patient management, from diagnosis to treatment and family planning. While not all cases of NS are monogenic, a targeted genetic panel can be a useful tool in selected patients, especially those with early-onset disease, a positive family history, or atypical features.

I have no potential conflict of interest to disclose.

I did not use generative AI and AI-assisted technologies in the writing process.