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      Renal Dysfunction in Liver Transplantation: The Problem and Preventive Strategies

      Canadian Journal of Gastroenterology
      Hindawi Limited

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          Abstract

          Ongoing improvements in survival following liver transplantation have necessitated a re-evaluation of immunosuppression protocols. Corticosteroids and calcineurin inhibitors (CNIs) are the most frequently used immunosuppressive drugs for liver transplantation but are associated with a wide range of adverse effects, such as hypertension, hyperlipidemia and nephrotoxicity. The need for hemodialysis after liver transplantation is associated with poor outcomes. Renal dysfunction in this setting may be caused by pre-existing renal disease, hepatorenal syndrome and/or post-transplant factors, including the use of nephrotoxic drugs, most notably CNIs such as cyclosporine and tacrolimus. The methods that address this problem include the diligent control of metabolic factors (eg, hypertension and hyperlipidemia), therapeutic monitoring of CNIs and withdrawal or reduction of the dosage of CNIs, combined with the use of newer non-nephrotoxic agents. Although there is no clear consensus about the most effective strategy, the optimal long-term immunosuppressive regimen would prevent rejection without causing nephrotoxicity or other significant adverse effects. Recent evidence suggests that the liver is a tolerogenic organ and that some patients may need little, if any, long-term immunosuppression.

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          Transforming growth factor beta in tissue fibrosis.

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            Effect of lipid reduction on the progression of renal disease: a meta-analysis.

            It has been proposed that hyperlipidemia contributes to the progression of renal disease. A large trial has not been performed; however, a number of small, controlled trials have been reported. We examined the effects of antilipemic agents on glomerular filtration rate and proteinuria or albuminuria in patients with renal disease. We used Medline, abstracts from scientific meetings, and bibliographies from recent reviews and scientific reports to locate pertinent studies. Thirteen prospective controlled trials examining the effects of antilipemic agents on renal function, proteinuria, or albuminuria were included. Studies were published as full reports or abstracts and were at least three months in duration. For five of the studies, individual patient data were obtained. Other summary data were independently extracted from the published reports by two investigators and included study quality, subject characteristics, cause of renal disease, change in serum cholesterol, blood pressure, glomerular filtration rate, proteinuria, and albuminuria. There was a lower rate of decline in glomerular filtration rate with treatment compared with controls (treated controls, 0.156 mL/min/month; 95% CI, 0.026 to 0. 285 mL/min/month, P = 0.008). The study results were statistically homogeneous, and in a regression analysis, the effect of treatment on glomerular filtration rate did not correlate with study quality, the percentage change in cholesterol, the type of lipid-lowering agent, or the cause of renal disease. However, longer follow-up correlated with the amount of improvement in glomerular filtration rate from treatment (P = 0.007). There was a tendency for a favorable effect of treatment on protein or albumin excretion [Ln (treatment) - Ln (control) = -0.248, 95% CI, -0.562 to 0.064, P = 0. 077]. However, these results were statistically heterogeneous between studies (P < 0.001). No obvious explanation for this heterogeneity was apparent in a regression analysis examining potential reasons for differences in study results. Lipid reduction may preserve glomerular filtration rate and may decrease proteinuria in patients with renal disease.
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              A worldwide, phase III, randomized, controlled, safety and efficacy study of a sirolimus/cyclosporine regimen for prevention of acute rejection in recipients of primary mismatched renal allografts.

              Despite the various immunosuppressive regimens presently in use, acute rejection in the early postoperative period continues to occur in 20 to 40% of renal transplant patients. In a double-blind, multicentred study, we investigated the ability of two different doses of sirolimus (rapamycin, RAPAMUNE), a new class of immunosuppressant that blocks cell cycle progression, to prevent acute rejection in recipients of primary mismatched renal allografts when added to a regimen of cyclosporine (cyclosporin A, CsA) and corticosteroids. Between October 1996 and September 1997, 576 recipients of primary mismatched cadaveric or living donor renal allografts were randomly assigned in a 2:2:1 ratio (before the transplant operation) to receive an initial loading dose of either 6 or 15 mg of orally administered sirolimus, followed by a daily dose of either 2 or 5 mg/day, or to receive a matched placebo. All groups received cyclosporine (microemulsion formula, CsA) and corticosteroids. The primary endpoint was a composite of first occurrence of biopsy-confirmed acute rejection, graft loss, or death during the first 6 months after transplantation. Safety data were monitored by an independent drug safety monitoring board. Based on an intention-to-treat analysis of 576 patients, there were no significant differences in patient demographic or baseline characteristics among treatment groups. The overall rate of the primary composite endpoint for the 6-month period after transplantation was 30.0% (68/227) in the 2 mg/day sirolimus group and 25.6% (56/219) in the 5 mg/day sirolimus group, significantly lower than the 47.7% (62/130) in the placebo group (P=0.002, P<0.001, respectively). During this period, the incidence of biopsy-confirmed acute rejection was 24.7% (56/227) in the 2 mg/day sirolimus group and 19.2% (42/219) in the 5 mg/day sirolimus group, compared with 41.5% (54/130) in the placebo group (P=0.003, P<0.001, respectively), representing a significant reduction in acute rejection of 40.5 and 53.7%, respectively. The need for antibody therapy to treat the first episode of biopsy-confirmed acute rejection was significantly reduced in the 5 mg/ day sirolimus group (3.2%) compared to the placebo group (8.5%; P=0.044). The results 1 year after transplantation were similar for the efficacy parameters studied. Adverse events and infections occurred in all groups. The addition of either 2 mg/day sirolimus or 5 mg/day sirolimus to CsA/corticosteroid therapy significantly reduces the incidence of acute rejection episodes in primary mismatched renal allograft recipients, without an increase in immunosuppressant-related side effects, including infections and malignancy, at 6 months and at 1 year after transplantation.
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                Author and article information

                Journal
                Canadian Journal of Gastroenterology
                Canadian Journal of Gastroenterology
                Hindawi Limited
                0835-7900
                2004
                2004
                : 18
                : suppl c
                : 27C-40C
                Article
                10.1155/2004/402743
                10412bca-e9e9-4a77-a2bd-41e43fbd1cf0
                © 2004

                http://creativecommons.org/licenses/by-nc/4.0/

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