Cyclosporin nephrotoxicity following cardiac transplantation

Abstract

The greatest change in GFR in response to treatment with cyclosporin occurs in the first 3-6 months and the magnitude of the decrement in the first year (or perhaps the first few months) appears to be a vital indicator of future problems. However, the apparent stabilization of renal function, particularly when monitored only by plasma creatinine, can conceal progressive tubulointerstitial injury, and increasing proteinuria is an ominous sign. Although lower doses of cyclosporin and careful monitoring of renal function may be helpful, there is at present no pharmacological intervention to protect or reverse the reduction in GFR that occurs. We believe that the vascular lesion induced by cyclosporin is fundamental, with early and initially reversible cyclosporin-induced vasospasm leading to progressive vascular damage with activation of endothelial cells and increased platelet interactions. Amongst other determinants, the renal response to this vasculopathy will depend on the balance between the presence of vasoactive factors with the vasoconstrictors promoting interstitial fibrosis and the vasodilators inhibiting proliferation. It is likely that the kidneys of heart-transplant recipients are chronically ischaemic and as a consequence their renin-angiotensin systems massively activated, which may further sensitize their kidneys to cyclosporin. Overproduction of angiotensin II, associated with the DD ACE genotype, has already been associated with poor prognosis in diabetic and IgA nephropathy. It is interesting to speculate that this ACE genotype, which is associated with a poor outcome in non-ischaemic heart disease can influence renal sensitivity to cyclosporin and predict the development of morphological injury. Extension of these experimental findings into the clinical arena with a placebo-controlled trial of early introduction of ACE inhibitor therapy in recipients of cardiac transplants would be timely.

Anti–Transforming Growth Factor Antibody at Low but Not High Doses Limits Cyclosporine-Mediated Nephrotoxicity Without Altering Rat Cardiac Allograft Survival

“…[2][3][4][5][6][7][8][9] Van Gelder et al 11 noted that endstage renal disease occurred in 8% of heart transplant recipients treated with cyclosporine. Goldstein et al 12 observed that 6.5% of patients developed end-stage renal failure.…”

“…1 A number of clinical studies [2][3][4][5][6][7][8][9] suggest that one of the common clinical complications after heart transplantation is chronic cyclosporine-induced nephrotoxicity, which generally leads to progressive renal failure. 10 Van Gelder et al 11 demonstrated that a significant rise in serum creatinine was found in cases compared with controls as early as 3 months after transplantation.…”

A Randomized Controlled Trial of Late Conversion from CNI‐Based to Sirolimus‐Based Immunosuppression Following Renal Transplantation

“…In the short-term, CNIs produce renal arteriolar vasoconstriction and a decrease in glomerular filtration rate (GFR) that is dose related and reversible (2)(3)(4). Long-term exposure to CNIs causes chronic nonreversible changes that are characterized by interstitial fibrosis and obliterative arteriolar changes due to fibrous intimal thickening (5). A recent study of renal transplants undergoing annual protocol biopsies showed histological evidence of CNI toxicity in all grafts by 10 years (6).…”

Sirolimus-based, calcineurin inhibitor- free regimen in kidney transplant patients: An open-label, randomized, controlled trial

“…A total of 124 patients were recruited, of whom 38 proceeded beyond randomization. Forty-one patients refused to participate, and 16 were excluded for reasons other than those specified in the inclusion criteria, including relocation (4), undergoing investigation for co-morbidity (8), delayed decision until after study closure (4). Baseline demographic, transplant-related and clinical data of the randomized patients are presented in Table 1 and 2.…”

“…Notably, 68% of the biopsy specimens with CAN were obtained from patients who developed CNI nephrotoxicity during the first year post-transplantation. In the short-term, CNI produce renal arteriolar vasoconstriction and a decrease in glomerular filtration rate (GFR) that is dose related and reversible (1)(2)(3)(4)(5). Long-term exposure to CNI causes chronic non-reversible changes that are characterized by interstitial fibrosis and obliterative arteriolar changes due to fibrous intimal thickening (6).…”