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Nephrotic syndrome is a prevalent kidney disorder characterized by dysfunction of the glomerular filtration barrier. Numerous genetic mutations have been identified, mainly affecting podocytes. In adults, nephrotic syndrome due to focal segmental glomerulosclerosis (FSGS) is generally related to primary FSGS.
We present a 32-year-old female patient with nephrotic syndrome (GFR 118 mL/min, serum albumin 3 g/dL, proteinuria 4,59 g/day) due to FSGS diagnosed at age 27 resistant to many previous immunosuppressive regimens. She was referred to our site.
A genetic study was performed wich revealed a podocyte mutation in KANK-2 gene: c.2068G>T, p.(Gly690Cys), reported as “of uncertain significance”. Subsequently, immunosuppression was stopped and continued with losartan 100mg daily, enalapril 10mg bid plus dapaglifozin 10mg/day, with a partial decrease in proteinuria. She later became pregnant, and nephroprotective withheld. She restarted previous treatment after a normal pregnancy (she had received enoxaparin 40 mg daily). Latest laboratory results: GFR 169 mL/min, serum albumin 2.3 g/dL, proteinuria 6.89 g/day.
The Kidney ankyrin repeat-containing protein (KANK1-4) regulates podocyte actin polymerization, microtubule targeting and cell adhesion. In both rats and cultured human podocytes, KANK1-4 was found to localize in podocytes. Knockdown of KANK2 reproduces a nephrotic syndrome phenotype, resulting in proteinuria and podocyte foot process effacement.
In conclusion, genetic podocyte studies in adults with proteinuria who do not respond to immunosuppression are mandatory, even in those with nephrotic syndrome. It also determines the avoidance of immunosuppression and heralds non-recurrency in renal transplantation. The publication of case reports/series with identified podocyte mutations will change the classification of certain mutations from “of uncertain significance” to “pathogenic”. Podocyte KANK-2 mutation appears to be an ultrarare cause of FSGS and nephrotic syndrome.