Avaliação da nefrina e podocina como biomarcadores precoces de proteinúria associada ao uso de inibidores do mTOR em pacientes transplantados renais

Abstract

Albuminuria is the main clinical manifestation of glomerular damage (GD) following renal transplantation (KTx). It can be induced by the use of mammalian target of rapamycin inhibitors (mTORi). Since GD starts from podocyte injury, proteins of these cells found in urinary extracellular vesicles (uEVs), such as nephrin and podocin, are potential biomarkers for early GD evaluation. Therefore, the objectives of this study were: to evaluate the expression of nephrin and podocin in uEVs of KTx patients with or without mTORi treatment for immunosuppression, for a period of 12-months, and to evaluate the use of these proteins as specific biomarkers of GD. Thus, 47 KTx patients were recruited and distributed in two groups according to mTORi use (non-mTORi and mTORi groups). The expression of nephrin and podocin was measured at 3, 6, 9 and 12-months post-KTx. Increased values of urinary nephrin/creatinine and podocin/creatinine ratios were found in the mTORi group [3 (p = 0.004), 6 (p = 0.009) and 9-months (p = 0.001); and 3 (p = 0.002), 6 (p = 0.030) and 9-months (p <0.001) post-KTx, respectively] when compared to the corresponding values in the non-mTORi group. Patients of the mTORi group, who presented with nephrinuria and podocinuria 3-months post-KTx had a glomerular filtration rate (GFR) lower than 42 mL/min/1.73 m2 in all follow-up periods. In the ROC (receiver operating characteristic curve) analysis, it was observed that the nephrin/creatinine and podocin/creatinine ratios presented high AUROC (area under the ROC) values for prediction of proteinuria development and GFR <60 mL/min/1.73 m2 . In summary, this study is the first to show increased expression of nephrin and podocin released in uEVs in patients using mTORi 3-months post-KTx, while albumin/creatinine ratio was only increased after 9- months of KTx. Thus, nephrin and podocin, obtained from uEVs, can become an important diagnostic tool for the early detection of GD in KTx patients.