Non-immunologic mechanisms of calcineurin inhibitors explain its antiproteinuric effects in genetic glomerulopathies

Abstract

It has been reported (this issue Pediatric Nephrology) that cyclosporine A (CyA) therapy in combination with corticosteroids, angiotensin-converting enzyme inhibitor, and an angiotensin receptor blocker decreased proteinuria in three patients with nephrotic syndrome (NS) due to WT1 mutations. Treatment with calcineurin inhibitors were found to induce a partial remission of proteinuria in several other children with genetic forms of NS, such as mutation in the podocine and in the phospholipase C epsilon gene. CyA therapy has also been reported to be beneficial to patients with Alport syndrome. Recent data have shown that the antiproteinuric effect of CyA in these cases may be due to a non-immunologic mechanism. CyA exerts an antiproteinuria effect by preventing the degradation of the actin organizing protein synaptodpodin and by a downregulation of TRPC6. This mechanism leads to the stabilization of the actin cytoskeleton in the kidney podocytes. This beneficial effect of CyA is interesting, but long-term results regarding function and nephrotoxicity are still missing.

Podocyte directed therapy of nephrotic syndrome—can we bring the inside out?

“…Additional evidence derives from studies in children with genetic podocytopathies. Here cyclosporine A was demonstrated to have an anti-proteinuric effect in cases with mutations in the WT-1, podocin and phospholipase C epsilon genes [45][46][47].…”

Regulation of TRPC6 ion channels in podocytes — Implications for focal segmental glomerulosclerosis and acquired forms of proteinuric diseases

“…In fact, a non-T-cell inhibitory dose of CsA is presumably sufficient to affect podocytes, sparing many of the side effects of regular dose, is of interest. CsA has been reported to decrease proteinuria even in genetically inherited forms of FSGS, where the beneficial effect of specific T-cell mediated immunosuppression can hardly be expected (4,76). In a model, where proteinuria arises from dysfunctions in a multilevel signaling cascade (bringing together upstream receptor pathways, TRPCs, synaptopodin, NFAT, Rho GTPases, and downstream targets such as the actin cytoskeleton or the mineralocorticoid receptor), multiple therapeutic targets may be identified.…”

Consenso de tratamiento del síndrome nefrótico en la infancia

“…[38][39][40] Además de su efecto inmunosupresor, la ciclosporina tiene una acción hemodinámica (vasoconstrictora de la arteriola aferente), que, al reducir la presión intraglomerular, disminuye la proteinuria. 38 Su efecto antiproteinúrico se debería también a la acción no inmunológica directa que ejerce sobre los podocitos al evitar la degradación de la actina.…”

“…38 Su efecto antiproteinúrico se debería también a la acción no inmunológica directa que ejerce sobre los podocitos al evitar la degradación de la actina. [38][39][40][41] La dosis indicada es 5 mg/kg/d o 150 mg/m 2 en dos dosis diarias para lograr niveles séricos de 50 a 150 ng/ml (medido por inmunoensayo). Puede incrementarse la dosis, pero, si bien tiene un mejor efecto en la reducción de la proteinuria, pueden aumentar los efectos adversos.…”

“…42 Datos recientes muestran que también los síndromes nefróticos de etiología genética pueden beneficiarse con su uso. 39 La toxicidad renal es el efecto adverso más grave e importante de esta droga.…”