Podocytopathy and Glomerular Basement Membrane Anomalies in Two Patients With Cubilin Gene Mutations

Proteinuria is a frequent finding in pediatric patients and in most cases, it is intermittent or transient. When proteinuria is moderate/severe and persistent, it may require an extensive complementary study, histopathological examination and genetic test, in order to clarify its etiology. Cubilin (CUBN) is a large glycosylated extracellular protein, initially detected in proximal tubular cells, and later in podocytes. Isolated persistent proteinuria caused by cubilin gene mutations is rare, only a few cases have been reported in the literature and even fewer patients underwent renal biopsy and electron microscopy that could help to elucidate the pathogenesis of the disease. The authors describe two pediatric clinical cases referred to pediatric nephrology consultation due to persistent proteinuria. Neither of them had any other complaints, and renal function and immunological and serological studies were normal. Renal histopathology showed podocytes changes and glomerular basal membrane alterations suggestive of Alport Syndrome. The genetic study identified two heterozygous variants in the cubilin gene in both, also later identified in their parents. They were started on ramipril, with improvement in proteinuria, and both patients remain asymptomatic and without changes in renal function. At present, due to the uncertainty of prognosis, it is suggested to keep CUBN gene mutation patients under close surveillance of proteinuria and renal function. The variable ultrastructural patterns of podocytopathy and glomerular basal membrane alterations in kidney biopsies of pediatric patients with proteinuria should lead to the diagnostic possibility of CUBN gene mutation in the differential diagnosis.