Comparison of Three Immunosuppressive Regimens in Cadaver Renal Transplantation: Long-Term Cyclosporine, Short-Term Cyclosporine Followed by Azathioprine and Prednisolone, and Azathioprine and Prednisolone without Cyclosporine

Hall, Bruce M.; Tiller, David J.; Hardie, Ian R.; Mahony, J. F.; Mathew, Timothy H.; Thatcher, G.N.; Miach, P. J.; Thomson, Napier M.; Sheil, A. G. R.

doi:10.1056/nejm198806093182304

Cited by 118 publications

(30 citation statements)

References 24 publications

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“…The primary and secondary outcomes of the study-death-censored graft survival, patient survival, and the combined end point of death or graft loss 4,5,18 -have previously been reported. Cancer outcomes were prespecified in the original trial and were briefly reported at 15 and 20 years 4,5 but were not previously analyzed and reported in detail.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Long-Term Cancer Risk of Immunosuppressive Regimens after Kidney Transplantation

Gallagher¹,

Kelly²,

Jardine³

et al. 2010

Journal of the American Society of Nephrology

184

121

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Cancer is a widely recognized complication of transplantation, and the effects of various immunosuppressive drugs on cancer risk remains controversial. This randomized trial allocated 489 recipients of first cadaveric renal transplants to one of three groups: Azathioprine and prednisolone, cyclosporine monotherapy, or cyclosporine monotherapy followed by a switch to azathioprine and prednisolone after 3 months. Here, we report cancer outcomes by non-skin cancer (including melanoma) and skin cancer (excluding melanoma) for 481 patients during a median follow-up of 20.6 years. A total of 226 patients developed at least one cancer: 95 with non-skin cancer and 171 with skin cancer. In the intention-to-treat analysis, mean times to first non-skin cancer (16.0, 15.3, and 15.7 years for groups 1 through 3, respectively) and first skin cancer (13.6, 14.3, and 15.2 years, respectively) were not different among the three groups or between any subgroup. In multivariate analyses, non-skin cancer associated with increasing age and previous smoking history, whereas skin cancer associated with increasing age, nonbrown eye color, fairer skin, and a functioning transplant. Treatment allocation did not associate with development of either form of cancer in multivariate analyses. In conclusion, these immunosuppressive regimens, widely used in recent decades, carry similar risks for carcinogenicity after kidney transplantation.

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Section: Discussionmentioning

confidence: 99%

“…Details of the trial, including the extent of deviations from protocol therapy, have been previously reported 4,5,18 but will be summarized in brief here.…”

Section: Concise Methodsmentioning

confidence: 99%

Long-Term Cancer Risk of Immunosuppressive Regimens after Kidney Transplantation

Gallagher¹,

Kelly²,

Jardine³

et al. 2010

Journal of the American Society of Nephrology

184

121

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“…As minimizing immunosuppression is presumed to be beneficial, clinical trials were performed using conversion studies from CsA to AZA or MMF, avoiding or tapering one of the immunosuppressive drugs [6][7][8][9][10]12,13,30].…”

Section: Discussionmentioning

confidence: 99%

“…nephrotoxicity and hypertension [2,4,5]. To minimize these side effects, and in an attempt to preserve benefits on graft survival, administration of CsA for one year and thereafter, conversion to the less nephrotoxic drugs AZA [6][7][8][9][10] or mycophenolate mofetil (MMF) [10], would be an option. To reduce the long-term side effects (cancer) [11] of immunosuppressive agents, and to improve the quality of life after transplantation, the AZA, MMF or prednison (Pred) dose can be tapered [10,12,13], provided this is not accompanied by rejection.…”

Section: Introductionmentioning

confidence: 99%

Down-regulated donor-specific T-cell reactivity during successful tapering of immunosuppression after kidney transplantation

Besouw¹,

Mast²,

Kuiper³

et al. 2002

Clinical and Experimental Immunology

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SUMMARY Stable cadaveric renal transplant patients were routinely converted from cyclosporin A (CsA) to either azathioprine (AZA) or mycophenolate mofetil (MMF) 1 year after transplantation to reduce the side effects of long-term immunosuppressive therapy. Thereafter, the AZA and MMF dose was gradually tapered to 50% at 2 years after transplantation. We questioned whether a reduction of immunosuppressive treatment results in a rise of donor-specific T-cell reactivity. Before transplantation (no immunosuppression), 1 year (high dose immunosuppression) and 2 years (low dose immunosuppression) after transplantation, the T-cell reactivity of peripheral blood mononuclear cells (PBMC) against donor and third-party spleen cells was tested in mixed lymphocyte cultures (MLC) and against tetanus toxoid (TET) to test the general immune response. We also measured the frequency of donor and third-party reactive helper (HTLpf) and cytotoxic (CTLpf) T-lymphocyte precursors in a limiting dilution assay. Donor-specific responses, calculated by relative responses (RR = donor/third-party reactivity), were determined. Comparing responses after transplantation during high dose immunosuppression with responses before transplantation (no immmunosuppression), the donor-specific MLC-RR (P = 0·04), HTLp-RR (P = 0·04) and CTLp-RR (P = 0·09) decreased, while the TET-reactivity did not change. Comparing the responses during low dose with high dose immunosuppression, no donor- specific differences were found in the MLC-RR, HTLp-RR and CTLp-RR, although TET-reactivity increased considerably (P = 0·0005). We observed a reduction in donor-specific T-cell reactivity in stable patients after renal transplantation during in vivo high dose immunosuppression. Tapering of the immunosuppressive load had no rebound effect on the donor-specific reactivity, while it allowed recovery of the response to nominal antigens.

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“…The major advantage was a reduction in the number of acute rejections and improvement in 1-year graft survival [8,12,481. Its impact on medium-and long-term graft survival has not been firmly established [ll].…”

Section: Introductionmentioning

confidence: 99%

Single-center experience with tacrolimus versus cyclosporine-Neoral in renal transplant recipients

Boots¹,

Duijnhoven²,

Christiaans³

et al. 2001

Transplant Int

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Tacrolimus has proven to be superior to cyclosporine-Sandimmune with regard to the prevention of acute rejections, but data comparing tacrolimus with Neoral are scarce. A total of 128 consecutive renal transplant recipients was studied. The patients were treated with Neoral-based (n = 74) or tacrolimus-based (n = 54) immunosuppressive regimens. Survival analyses (Cox regression analysis) were performed on an intention-to-treat basis. Renal function and cardiovascular risk profile were analyzed by means of a repeated-measures analysis of variance (ANOVA) up to 12 months after transplantation. Immunological features were less favorable in the tacrolimus group. Two-year patient and graft survival were comparable. Acute-rejectionfree survival was 82 Yo in the tacrolimus group versus 40 Yo in the Neoral group ( P < 0.0001). The severity of the rejections (1997 Banff classification) was comparable ( P = 0.43). Immunological graft loss (3.7 Yo vs 12.2 YO, P = 0.02) and conversion because of rejection (0 % vs 28.4 YO, P < 0.001) were less in the tacrolimus group. A higher proportion (68.5 YO vs 14.9 YO, P < 0.001) was successfully put on monotherapy. Creatinine clearance, proteinuria, and fractional uric acid clearance were similar. In the tacrolimus group mean blood pressure was comparable, but patients needed less antihypertensive drugs ( P < 0.001) and, even with fewer patients on lipidlowering drugs, total cholesterol was lower (5.2 vs 6.0 mmol/l, P = 0.003). Treatment for post-transplant diabetes mellitus was 18.5 % versus 10.8 % ( P = 0.22). In both groups, antidiabetic medication could be withdrawn for most patients. This study indicates that tacrolimus is superior to cyclosporine-Neoral in preventing acute rejection with comparable patient and graft survival rates. Because of a lower need for treatment of hypertension and hypercholesterolemia, the cardiovascular risk profile is more favorable. A considerable proportion of patients can be successfully weaned off co-medication and treated with tacrolimus monotherapy.

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Comparison of Three Immunosuppressive Regimens in Cadaver Renal Transplantation: Long-Term Cyclosporine, Short-Term Cyclosporine Followed by Azathioprine and Prednisolone, and Azathioprine and Prednisolone without Cyclosporine

Cited by 118 publications

References 24 publications

Long-Term Cancer Risk of Immunosuppressive Regimens after Kidney Transplantation

Long-Term Cancer Risk of Immunosuppressive Regimens after Kidney Transplantation

Down-regulated donor-specific T-cell reactivity during successful tapering of immunosuppression after kidney transplantation

Single-center experience with tacrolimus versus cyclosporine-Neoral in renal transplant recipients

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