Nephrotoxicity of cyclosporin A in humans: effects on glomerular filtration and tubular reabsorption rates

Abstract

The contention that cyclosporin A (CyA) nephrotoxicity may be due to renal afferent arteriolar constriction was inferred from rat studies showing CyA to increase renal vascular resistance, to reduce glomerular filtration rate (GFR) and delivery of tubular fluid from the end of the proximal tubule to the loop of Henle (Vprox), and to increase proximal fractional reabsorption. In order to test whether the mechanism of human CyA nephrotoxicity is similar to its rat analogue, and whether CyA treatment causes prolonged renal malfunction after drug withdrawal, renal function was investigated with clearance techniques including lithium clearance (CLi) as a measure of Vprox. The subjects were patients (n = 11) with previously normal renal function, given CyA in the treatment of ocular manifestation of extrarenal disease, or bone-marrow transplant recipients. Nine out of these eleven patients were investigated before and during CyA treatment: GFR (P less than 0.05) and Vprox (P less than 0.005) decreased while proximal fractional reabsorption increased (P less than 0.01). In six patients investigated before CyA was given, and re-examined a mean of 273 days (range 84-384 days) after CyA withdrawal, CLi was reduced (P less than 0.05) while mean GFR was not significantly lowered (0.5 greater than P greater than 0.2). In one of these six patients GFR was reduced to a subnormal value of 26 ml min-1 (1.73 m2 body surface)-1. In conclusion, human and rat CyA nephrotoxicity have the same pattern of renal functional deterioration. Cyclosporin A nephrotoxicity was evident in patients investigated a mean of 9 months after CyA withdrawal.

Comparative Study on the Effects of Cyclosporin A in Renal Cells in Culture

“…Due to the contrast between the efficacy of CSA as an immunosuppressant and its high nephrotoxicity, many studies have been conducted to understand the mechanisms of CSA-induced nephrotoxicity. It has been shown that renal arteriolar constriction [4], direct fibrogenic effect on human tubulointerstitial cells [5], amplification of Ca 2+ signaling pathway [36], inhibition of COX-2 expression in response to low salt intake [37], inhibition of the adaptive responses to hypertonicity occurring during the urinary concentrating mechanism [38]and apoptosis involving mitochondrial injury [39]may contribute to CSA-induced nephrotoxicity.…”

“…Nonetheless, treatment with CSA is limited due to its nephrotoxicity and, despite the many studies, the mechanisms underlying this harmful effect are still not understood. It has been suggested that it is due to renal arteriolar constriction, which reduces renal blood flow and glomerular filtration rate [4]. However, other studies suggested that CSA toxicity might be independent of hemodynamic alterations [5].…”

Enalaprilat Directly Ameliorates in vitro Cyclosporin Nephrotoxicity in Human Tubulo-Interstitial Cells

“…Chronic cyclosporin A (CyA) nephropathy is a major dose-limiting side effect of CyA therapy and is characterized by early structural and functional derangements of the proximal tubule [1, 2], extracellular matrix accumulation [3], and increased cortical expression of fibrogenic growth factors, such as transforming growth factor beta 1 (TGFβ 1 ) [4, 5], insulin-like growth factor I (IGF-I) [6, 7], and platelet-derived growth factor (PDGF) [8]. The pathogenesis of such nephrotoxicity is not fully explained.…”

Long-term maintenance of therapeutic cyclosporine levels leads to optimal graft survival without evidence of chronic nephrotoxicity

“…While there is little doubt that CyA can result in acute nephrotoxicity [4,7], its ability to cause a chronic progressive loss of renal function remains questionable [5,8,10,14,171. The classic studies of Myers et al [12, 131 resulted in the widely accepted view that CyA causes a chronic and progressive loss of renal function with heart transplant patients.…”