Correspondence
Efficacy and Safety of Cyclosporine in Renal-Transplant Recipients
N Engl J Med 1994; 331:1777-1778December 29, 1994
- Article
To the Editor:
Burke et al. (Aug. 11 issue)1 concluded from their retrospective study that cyclosporine does not cause progressive toxic nephropathy in renal-transplant recipients. Their analysis of 1663 recipients revealed remarkable stability in serum creatinine concentrations during a follow-up of 54 months. However, cyclosporine was discontinued in 149 of the 1663 patients for a variety of reasons, including nephrotoxicity, chronic graft dysfunction, and the physician's preference. When did these patients stop taking cyclosporine, and what happened to their renal function thereafter? Did the mean serum creatinine concentration during follow-up change when the results in the 149 patients who stopped taking cyclosporine were omitted from the analysis? In evaluating the long-term effects of cyclosporine on renal function, the authors' inclusion of patients who were not actually taking the drug could distort the results, particularly if renal function in these patients had improved over time.
1 ReferencesAjay K. Singh, M.B.
New England Medical Center, Boston, MA 021111
Burke JF Jr ,Pirsch JD ,Ramos EL , et al. Long-term efficacy and safety of cyclosporine in renal-transplant recipients. N Engl J Med 1994;331:358-363
Full Text | Web of Science | Medline
To the Editor:
In their article on the efficacy and safety of cyclosporine, Burke et al. conclude that graft failure is usually due to chronic rejection and not to cyclosporine-induced nephropathy. This distinction requires morphologic confirmation. In the absence of biopsy specimens showing involvement of blood vessels within the kidney, it is impossible to discern whether graft failure is due to cyclosporine-induced nephrotoxicity, chronic rejection, or both. The only information given to support the elimination of cyclosporine as a factor in graft failure is the fact that there was no decrease in the serum creatinine concentration after the dose of cyclosporine was reduced. However, the effects of cyclosporine on glomerular filtration and tubulointerstitial processes may be dissociable. In rats given cyclosporine, glomerular filtration improves but tubulointerstitial injury persists after the drug is discontinued.1
The real question is why kidney-transplant recipients should be different and not have progressive chronic nephropathy when other patients treated with low-dose cyclosporine do. One possibility is that cyclosporine is less toxic if the kidney is denervated, although chronic cyclosporine-induced nephropathy can be produced experimentally regardless of whether the kidney is innervated.2
If cyclosporine and drugs like it are to be given to patients for reasons other than preventing rejection after organ transplantation, we must know more about their actions in the kidney.
2 ReferencesWilliam M. Bennett, M.D.
Oregon Health Sciences University, Portland, OR 97201-29401
Elzinga LW ,Rosen S ,Bennett WM . Dissociation of glomerular filtration rate from tubulointerstitial fibrosis in experimental chronic cyclosporine nephropathy: role of sodium intake. J Am Soc Nephrol 1993;4:214-221
Web of Science | Medline2
Elzinga LW ,Rosen S ,Lindsley J ,Burdmann E ,Bennett WM . The role of the sympathetic nervous system in a model of chronic cyclosporine nephropathy. J Am Soc Nephrol 1992;3:722-722
Author/Editor Response
The authors reply:
To the Editor: Dr. Singh raises an important question about the outcome of the 149 transplant recipients who stopped taking cyclosporine. Graft failure occurred in 72 of these patients (48 percent). Renal function did not improve after cyclosporine was withdrawn. Despite the high rate of graft loss, the median three-year serum creatinine concentration in this group of 149 patients was 5.0 mg per deciliter (442 μmol per liter), as compared with a concentration of 1.9 mg per deciliter (168 μmol per liter) in the remaining cyclosporine-treated patients. Cyclosporine was discontinued in the majority because of chronic allograft dysfunction, the course of which was not affected by stopping the drug.
We do not think that the lack of kidney-biopsy specimens diminishes our conclusions about the safety of cyclosporine. It is difficult to separate chronic rejection from cyclosporine-induced nephrotoxicity on the basis of strict pathological criteria, and the presence of evidence of both rejection and toxicity in the same biopsy specimen can further confuse interpretation. Data from the UCLA transplantation registry suggest that the incidence of chronic rejection has not changed with the advent of cyclosporine use.1 If cyclosporine contributes to long-term graft loss, one would reasonably expect an increase in late graft failure. Similarly, the Cooperative Transplant Study reported that five-year graft survival was better in patients receiving higher doses of cyclosporine either alone or with azathioprine.2 The long-term administration of higher doses of cyclosporine can reduce the risk of chronic rejection.3 The balance of data supports our conclusion that cyclosporine-induced toxicity is not an important cause of late graft dysfunction and loss.
Finally, follow-up studies of recipients of other solid-organ transplants who were receiving cyclosporine do not suggest a difference in response to long-term cyclosporine therapy, as suggested by Dr. Bennett. Although some cyclosporine-treated recipients of heart or liver transplants have had progression to end-stage renal failure, most have impaired but stable renal function.4,5
5 ReferencesJames F. Burke, Jr., M.D.
Thomas Jefferson University Hospital, Philadelphia, PA 19107-5098John D. Pirsch, M.D.
University of Wisconsin Hospital, Madison, WI 53792-7375Daniel R. Salomon, M.D.
Scripps Clinic and Research Foundation, La Jolla, CA 920371
Cho YW, Terasaki PI. Long-term survival. In: Terasaki PI, ed. Clinical transplants, 1988. Los Angeles: UCLA Tissue Typing Laboratory, 1988:277-82.
2
Opelz G . Effect of the maintenance immunosuppressive drug regimen on kidney transplant outcome. Transplantation 1994;58:443-446
CrossRef | Web of Science | Medline3
Almond PS ,Matas A ,Gillingham K , et al. Risk factors for chronic rejection in renal allograft recipients. Transplantation 1993;55:752-757
CrossRef | Web of Science | Medline4
Gonwa TA ,Mai ML ,Pilcher J , et al. Stability of long-term renal function in heart transplant patients treated with induction therapy and low-dose cyclosporine. J Heart Lung Transplant 1992;11:926-928
Web of Science | Medline5
Weisner RH ,Porayko MK ,Lake JR ,Batts KP ,Krom RAF . Long-term management of liver transplant recipients. Semin Gastrointest Dis 1993;4:151-164
