Nephrotoxicity of cyclosporin A. A lithium clearance and micropuncture study in rats

Abstract

Renal function was studied in rats treated with cyclosporin A (CyA). Peroral CyA 25 mg kg-1 day-1 depressed glomerular filtration rate (GFR) from 1284 +/- 429 to 500 +/- 228 microliters min-1 g-1 kidney weight (KW) (P less than 0.01). Absolute rate of proximal tubular reabsorption (APR) decreased from 1075 +/- 437 to 468 +/- 203 microliters min g KW-1 (P less than 0.01). Proximal tubular fractional reabsorption (PFR) was 67.7 and 68.5% measured with the TT/OT and fractional lithium-clearance methods, respectively. Amiloride had no effect on lithium-clearance in CyA treated rats. Acute isotonic volume expansion increased GFR and APR towards normal, while PFR remained increased. Increased sodium clearance did not normalize renal function. CyA intravenously (12.5 mg kg-1) depressed GFR and APR acutely, while PFR increased. Proximal intratubular pressures were low normal (mean 11.6 mmHg). Proximal transit times were prolonged (mean 25.2 s, P less than 0.01). Renal morphology was normal. The data are evidence against a primary tubular damage of CyA, and makes it less likely that the major lesion is located to the glomerular membrane. The results suggest that CyA nephrotoxicity mainly is due to a haemodynamic effect.

Glomerular and Tubular Function in Renal Transplant Patients Treated with and without Ciclosporin A

“…It has been proposed that an increase in proximal tubular reabsortion rate should be a mechanism in CsA-induced hypertension [18], but, as demonstrated in the present study, no elevation in APR occurs in CsA-treated patients. This is in accordance with previous studies performed in animals, RTx, non-transplanted patients, and healthy volunteers [2, 3, 4, 16, 17]. …”

“…These changes in renal function have been found to occur within a few hours after the CsA peak blood concentration [2, 3, 4]. Chronic treatment with higher CsA doses in transplanted and nontransplanted humans and in rats is also accompanied by increased FPR [16, 17, 19]. This increase in FPR seems to be secondary to the CsA-induced preglomerular vasoconstriction and subsequent hypoperfusion and decline in GFR.…”

“…The hyperuricaemia in CsA-treated patients has also been attributed to an effect of CsA on renal tubular function [12, 13, 14]. Using the lithium clearance method, some studies have tried to evaluate whether CsA affects proximal and distal tubular reabsorption rates of sodium and water [2, 3, 4, 15, 16, 17, 18, 19, 20, 21], but the results are conflicting. We have previously shown that a few hours after the CsA peak blood concentration, a transient decrease in renal clearance of lithium (C Li ) and an increase in fractional proximal tubular reabsorption (FPR) of sodium and water occurs in parallel with the decrease in GFR in both healthy volunteers and RTx chronically receiving CsA [2, 3, 4].…”

Evolution of Ciclosporin Nephrotoxicity in Patients Treated for Autoimmune Uveitis

“…Acute renal dysfunction may occur within the first few weeks or months of initiating therapy and is usually reversible fol lowing ciclosporin dosage adjustment [10][11][12], However, the impact of protracted pathophysiologic factors could lead to irreversible kidney injury [9,13,20], Drug-induced tubular injury [36,37] and increased renal vascular resistance [38,39] have been suggested as possible primary pathogenetic mechanisms. Recently, there has been considerable interest in ciclosporin-induced renal hemodynamic changes as probable factors contributing to the observed alterations in renal function and morphology [13,[40][41][42][43]. Several mechanisms have been proposed to explain the decreased renal blood flow associated with ciclosporin administration including in creased sympathetic nervous activity [38,44], activation of the renin-angiotensin system [45][46][47], increased renal thromboxane A2 production [48][49][50], and altered produc tion of prostacyclin-stimulating factor [51].…”

Hypertensive Exercise Responses in Ciclosporin-Treated Normotensive Renal Transplant Recipients

“…This pressor effect may be inhibited by sympathetic ct-blockade with pra zosin or by denervation [38]. CS can reduce renal blood flow by up to 50% when given acutely [39,40], and flow to heart, lungs and liver may also be reduced [41], A further effect of CS might be the retention of so dium. Certainly CS may be responsible for sodium reten tion in the maintenance phase of CS therapy [42], but suggestions that this in turn determines the hypertensive tendency remain speculative [43].…”