HDCN Article Review/Hyperlink

Wissmann C, Frey FJ, Ferrari P, Uehlinger DE

Acute cyclosporine-induced nephrotoxicity in renal transplant recipients: The role of the transplanted kidney

J Am Soc Nephrol (Dec) 7:2677-2681 1996

Cyclosporine nephrotoxicity continues to be a major factor in limiting its long term use. Animal studies suggest that nephrotoxicity is related to afferent arteriolar vasoconstriction mediated by a rise in intracellular calcium, a fall in vasodilatory prostaglandins or direct endothelial injury. The investigators in this study were particularly interested in identifying whether this vasoconstrictive response was "extrinsic" and largely determined by the recipient of a renal transplant or was "intrinsic" to the donor kidney itself. They followed 16 patients (nine men and seven women, mean age 47, matched for concomitant meds) who received eight pairs of kidneys over a four week course during which the dose of cyclosporine was increased by 25% every two weeks. Mean serum cyclosporine levels (ng/ml) rose from a baseline of 117 to 160 after a 25% increase in dose and 188 after a 50% dose increase. A rise in serum creatinine by greater than 15% was felt to reflect nephrotoxicity (vasoconstrictive response).

Patients who received kidneys from seven of eight donors showed a similar response in serum creatinine levels to cyclosporine dose increases (either no nephrotoxicity or matched nephrotoxicity). The authors conclude that because the probability of this happening randomly is less than 5%, paired responses suggest the major effect of cyclosporin nephrotoxicity is mediated by the donor kidney rather than by host factors.

Comment: This intriguing study has a number of systematic flaws. While the extent of rise in serum creatinine as a function of cyclosporine was similar in recipients with kidneys from the same donor, no data are presented to establish causality. Cyclosporin levels varied by 50% at baseline so subjects did not start at the same point. It would have been more accurate to study a change in GFR associated with levels of CsA rather than based on a given oral dose, as the absorptive and pharmacokinetic parameters vary significantly between individuals. Finally, no explanation is offered that would link these findings to any established or novel theoretical models of CsA nephrotoxicity. (Sri Narsipur, MD, SUNY-HSC at Syracuse, NY)