The long-term course of cyclosporine-associated chronic nephropathy

Abstract

We evaluated a chronic renal injury in 37 cardiac transplant recipients treated for 12 to 24 months with cyclosporine (CsA). Twenty-four cardiac transplant recipients treated with azathioprine for more than 24 months served as controls. Despite equivalent cardiac performance, GFR in those treated with CsA was depressed, 47 +/- 3 versus 94 +/- 4 ml/min/1.73 m2 (P less than 0.001). CsA therapy was also associated with significant elevation of renal vascular resistance (RVR), proteinuria, arterial hypertension, and impaired intrarenal conversion of inactive prorenin to active renin. Histopathological changes associated with CsA included an obliterative arteriolopathy with deposition of proteinaceous material in necrotic arteriolar walls, and associated tubulointerstitial damage. A minority of glomeruli exhibited either ischemic collapse or sclerosis. Area perimeter analysis revealed enlargement of the remaining glomeruli with significant expansion of the mesangium. Longitudinal examination over a 48 month period (N = 15) during which CsA was reduced in dosage or withdrawn revealed persistent hypofiltration, increasingly elevated RVR and heavier proteinuria. Further histopathological deterioration was observed when renal tissue was sampled a second time in six patients, and three members of the experimental group developed end-stage renal disease. We conclude that continuous CsA therapy for more than 12 months causes a chronic injury to renal microvessels that is rarely reversible and potentially progressive.

Effects of transplantation on the renin angiotensin system (RAS)

“…In addition, we found a weak but significant negative correlation between urinary sodium excretion and active renin in CTR and LTR. Our results agreed with early work from Myers 31 during the long-term course of chronic nephropathy in cardiac transplant recipients, when he had shown a striking increase in inactive renin and lower PRA values under high doses of cyclosporin compared to azathioprine. Increase in prorenin is an early marker of vascular complications among insulin-dependent diabetics.…”

“…As shown by Bantle, 29 among 10 renal transplant recipients under cyclosporin compared to 10 others under azathioprine and seven patients with renal insufficiency, cyclosporin induces a significant fall in GFR and in effective renal plasma flow, which is related to direct vasoconstriction of glomerular afferent arterioles and increase in renal vascular resistances. In the long term, Cy nephrotoxicity 30,31 is responsible for chronic renal disease and progressive decline in renal function, as demonstrated by Myers since 1988 31 in cardiac transplant recipients under high doses of cyclosporin (up to 17 mg/kg daily) compared to those receiving azathioprine. Therefore, acute and chronic renal ischaemia due to direct Cy nephrotoxicity increase renin release and ANG II production, which in turn favours sodium retention with enhanced vascular sensitivity to ANG II and increased peripheral resistances.…”

“…34 However, Na + retention can also be due to altered Na + excretion at a tubular level, a specific abnormality probably related to Cy nephrotoxicity. 32 Second, the effects of cyclosporin per se on renin production have long been controversial, but both initial works by Myers 30,31 and recent studies 35 suggest that de novo hypertension after transplantation could be a direct renin dependent hypertension. Using primary cell cultures from rat renal cortex, Kurtz 36 found that cyclosporin A (CsA) stimulated renin secretion three-fold and this stimulation was paralleled by a dose dependent two-fold increase in inactive renin within the cells, whereas intracellular active renin remained the same.…”

“…Cyclosporin induces direct vasoconstriction within the kidney 30,31,33 and the peripheral vessels, 44 with consequent renal ischaemia, increased vascular resistances and RAS stimulation with an increase in ANG II production. Cyclosporin also indirectly modifies the local RASs, within the kidney, the vessels and the heart, 45 since its peripheral effects combine both enhancement of the vasoconstriction induced by ANG II, catecholamines and TXA2 and inhibition of the vasodilation due to prostacycline release.…”

Cyclosporin A: Drug discontinuation for the management of long-term toxicity after liver transplantation

“…studies are needed to determine whether this approach cardiac, renal, and liver transplants. [1][2][3] In renal transplantLiver biopsies were performed when follow-up liver chemistry recipients, CsA nephrotoxicity has usually been managed by tests showed graft dysfunction, manifested by a ¢50% increase in discontinuing or markedly reducing the dose of CsA, while the total serum bilirubin, alkaline phosphatase, and/or alanine amiprescribing larger doses of azathioprine and continuing treat-notransferase levels. A diagnosis of rejection was considered to be ment with prednisone.…”