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mTOR inhibitor versus mycophenolic acid as the primary immunosuppression regime combined with calcineurin inhibitor for kidney transplant recipients: a meta-analysis

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      Abstract

      Background

      A number of studies have provided information regarding the risks and benefits of mammalian target of rapamycin inhibitors (mTOR-I) combined with calcineurin inhibitors (CNI) versus mycophenolic acid (MPA).

      Methods

      Medline, Embase and the Cochrane Central Register of Controlled Trials were searched. Randomized controlled trials comparing mTOR-I to MPA as the primary immunosuppressive regimen in combination with CNI were selected and meta-analyzed.

      Results

      Eleven randomized controlled trials consisting of 4930 patients in total were included. No significant difference was observed in the risk of biopsy-proven acute rejection and patient death between the two groups. However, an increased risk of graft loss (relative risk (RR) = 1.20) and inferior graft function (creatinine clearance, weighted mean difference (WMD) = −2.41 μmol/L) were demonstrated in mTOR-I-treated patients. Patients treated with mTOR-I had a higher risk of new-onset diabetes mellitus (RR = 1.32), dyslipidemia, proteinuria (RR = 1.79), peripheral edema (RR = 1.34), thrombocytopenia (RR = 1.97) and lymphocoele (RR = 1.80), but a lower risk of cytomegalovirus infection (RR = 0.40), malignancy (RR = 0.64) and leucopenia (RR = 0.43). There was no difference in diarrhea, anemia, urinary tract infection, polyoma virus infection and impaired wound healing when mTOR-I was compared with MPA.

      Conclusions

      mTOR-I showed no particular superiority to MPA. Notably, mTOR-I had an increased risk of graft loss when combined with CNI, even when combined with a reduced dose of CNI. Therefore, the optimal dosage strategies for mTOR-I and CNI need to be further explored.

      Electronic supplementary material

      The online version of this article (doi:10.1186/s12882-015-0078-5) contains supplementary material, which is available to authorized users.

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      Most cited references 37

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      A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group.

      Serum creatinine concentration is widely used as an index of renal function, but this concentration is affected by factors other than glomerular filtration rate (GFR). To develop an equation to predict GFR from serum creatinine concentration and other factors. Cross-sectional study of GFR, creatinine clearance, serum creatinine concentration, and demographic and clinical characteristics in patients with chronic renal disease. 1628 patients enrolled in the baseline period of the Modification of Diet in Renal Disease (MDRD) Study, of whom 1070 were randomly selected as the training sample; the remaining 558 patients constituted the validation sample. The prediction equation was developed by stepwise regression applied to the training sample. The equation was then tested and compared with other prediction equations in the validation sample. To simplify prediction of GFR, the equation included only demographic and serum variables. Independent factors associated with a lower GFR included a higher serum creatinine concentration, older age, female sex, nonblack ethnicity, higher serum urea nitrogen levels, and lower serum albumin levels (P < 0.001 for all factors). The multiple regression model explained 90.3% of the variance in the logarithm of GFR in the validation sample. Measured creatinine clearance overestimated GFR by 19%, and creatinine clearance predicted by the Cockcroft-Gault formula overestimated GFR by 16%. After adjustment for this overestimation, the percentage of variance of the logarithm of GFR predicted by measured creatinine clearance or the Cockcroft-Gault formula was 86.6% and 84.2%, respectively. The equation developed from the MDRD Study provided a more accurate estimate of GFR in our study group than measured creatinine clearance or other commonly used equations.
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        Understanding the causes of kidney transplant failure: the dominant role of antibody-mediated rejection and nonadherence.

        We prospectively studied kidney transplants that progressed to failure after a biopsy for clinical indications, aiming to assign a cause to every failure. We followed 315 allograft recipients who underwent indication biopsies at 6 days to 32 years posttransplant. Sixty kidneys progressed to failure in the follow-up period (median 31.4 months). Failure was rare after T-cell-mediated rejection and acute kidney injury and common after antibody-mediated rejection or glomerulonephritis. We developed rules for using biopsy diagnoses, HLA antibody and clinical data to explain each failure. Excluding four with missing information, 56 failures were attributed to four causes: rejection 36 (64%), glomerulonephritis 10 (18%), polyoma virus nephropathy 4 (7%) and intercurrent events 6 (11%). Every rejection loss had evidence of antibody-mediated rejection by the time of failure. Among rejection losses, 17 of 36 (47%) had been independently identified as nonadherent by attending clinicians. Nonadherence was more frequent in patients who progressed to failure (32%) versus those who survived (3%). Pure T-cell-mediated rejection, acute kidney injury, drug toxicity and unexplained progressive fibrosis were not causes of loss. This prospective cohort indicates that many actual failures after indication biopsies manifest phenotypic features of antibody-mediated or mixed rejection and also underscores the major role of nonadherence. © 2011 The American Society of Transplantation and the American Society of Transplant Surgeons.
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          Maintenance immunosuppression with target-of-rapamycin inhibitors is associated with a reduced incidence of de novo malignancies.

          Immunosuppressive drug therapy has been identified as one etiological factor in the increased incidence of and deaths from malignancies in renal transplant recipients. In animal models, calcineurin inhibitors have a positive growth effect, whereas target-of-rapamycin (TOR) inhibitors have a negative growth effect on malignant cells. A multivariate analysis of posttransplant malignancies in 33,249 deceased donor primary solitary renal recipients reported by 264 kidney transplant programs to the Organ Procurement and Transplantation Network database from July 1, 1996 to December 31, 2001 was performed. Data were censored at 963 days to allow comparable follow-up time among drug treatment groups. The incidence and relative risks of any de novo malignancy (skin and solid) and for non-skin solid malignancies in patients receiving TOR inhibitors compared to patients receiving calcineurin inhibitors were the primary endpoints. The incidence rates of patients with any de novo posttransplant malignancy were 0.60% with sirolimus/everolimus alone, 0.60% with sirolimus/everolimus + cyclosporine/tacrolimus, and 1.81% with cyclosporine/tacrolimus (P<0.0001); the rates with a de novo solid tumor were 0%, 0.47%, and 1.00%, respectively. In the Cox regression model the relative risk associated with sirolimus/everolimus immunosuppression for any de novo cancer was 0.39 (95% CI: 0.24-0.64; P=0.0002) and for de novo solid cancer was 0.44 (0.24-0.82; P=0.0092). Other significant risk factors were male sex, adult age group, white race, and history of a malignancy. Maintenance immunosuppression with the TOR inhibitor drugs, sirolimus and everolimus, is associated with a significantly reduced risk of developing any posttransplant de novo malignancy and non-skin solid malignancy.
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            Author and article information

            Affiliations
            Kidney Disease Center, The First Affiliated Hospital, Medical School of Zhejiang University, Qingchun Rd, Hangzhou, Zhejiang China
            Contributors
            xiexishao@126.com
            amandakimi@zju.edu.cn
            lxx1989lxx@163.com
            xiaoxiangno2@sina.com
            zfshou@zju.edu.cn
            chenjhzju@sina.com
            Journal
            BMC Nephrol
            BMC Nephrol
            BMC Nephrology
            BioMed Central (London )
            1471-2369
            1 July 2015
            1 July 2015
            2015
            : 16
            26126806 4486141 78 10.1186/s12882-015-0078-5
            © Xie et al. 2015

            This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

            Categories
            Research Article
            Custom metadata
            © The Author(s) 2015

            Nephrology

            mtor inhibitor, mycophenolic acid, kidney transplantation, meta-analysis

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