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      Chronic Graft Loss and Death in Patients With Post-Transplant Malignancy in Living Kidney Transplantation: A Competing Risk Analysis

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          Abstract

          Background:

          Malignancy is a common complication after renal transplantation. Death with functioning graft and chronic graft loss are two competing outcomes in patients with post-transplant malignancies.

          Objectives:

          The purpose of our study was to evaluate the risk factors associated with cumulative incidence of these two outcomes.

          Patients and Methods:

          Fine-Gray model was used for 266 cases with post-transplant malignancy in Iran. These patients were followed-up from the diagnosis until the date of last visit, chronic graft loss, or death, subsequently.

          Results:

          At the end of the study, as competing events, chronic graft loss and death with functioning graft were seen in 27 (10.2%) and 53 cases (19.9%), respectively, while 186 cases (69.9%) were accounted as censored. The incidence rate of death was approximately two-time of the incidence rate of chronic graft loss (8.6 vs. 4.4 per 100 person-years). In multivariate analysis, significant risk factors associated with cumulative incidence of death included age (P < 0.007, subhazard ratio (SHR) = 1.03), type of cancer (P < 0.0001), and response to treatment (P < 0.0001, SHR = 0.027). The significant risk factors associated with cumulative incidence of chronic graft loss were gender (P = 0.05, SHR = 0.37), treatment modality (P < 0.0001), and response to treatment (P = 0.048, SHR = 0.47).

          Conclusions:

          Using these factors, nephrologists may predict the occurrence of graft loss or death. If the probability of graft loss was higher, physicians can decrease the immunosuppressive medications dosage to decrease the incidence of graft loss.

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          Most cited references40

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          The analysis of failure times in the presence of competing risks.

          Distinct problems in the analysis of failure times with competing causes of failure include the estimation of treatment or exposure effects on specific failure types, the study of interrelations among failure types, and the estimation of failure rates for some causes given the removal of certain other failure types. The usual formation of these problems is in terms of conceptual or latent failure times for each failure type. This approach is criticized on the basis of unwarranted assumptions, lack of physical interpretation and identifiability problems. An alternative approach utilizing cause-specific hazard functions for observable quantities, including time-dependent covariates, is proposed. Cause-specific hazard functions are shown to be the basic estimable quantities in the competing risks framework. A method, involving the estimation of parameters that relate time-dependent risk indicators for some causes to cause-specific hazard functions for other causes, is proposed for the study of interrelations among failure types. Further, it is argued that the problem of estimation of failure rates under the removal of certain causes is not well posed until a mechanism for cause removal is specified. Following such a specification, one will sometimes be in a position to make sensible extrapolations from available data to situations involving cause removal. A clinical program in bone marrow transplantation for leukemia provides a setting for discussion and illustration of each of these ideas. Failure due to censoring in a survivorship study leads to further discussion.
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            Immunosuppressive drugs in kidney transplantation: impact on patient survival, and incidence of cardiovascular disease, malignancy and infection.

            Renal transplant recipients have increased mortality rates when compared with the general population. The new immunosuppressive drugs have improved short-term patient survival up to 95% at 1-2 years, but these data have to be confirmed in long-term follow-up. Furthermore, no particular regimen has proved to be superior over others with regard to patient survival. Cardiovascular diseases are the most common cause of mortality in renal transplant recipients and while no immunosuppressive drug has been directly associated with cardiovascular events, immunosuppressive drugs have different impacts on traditional risk factors. Corticosteroids and ciclosporin are the agents with the most negative impact on weight gain, blood pressure and lipids. Tacrolimus increases the risk of new-onset diabetes mellitus. Sirolimus and everolimus have the most impact on risk factors for post-transplant hyperlipidaemia. Modifications in immunosuppression could improve the cardiovascular profile but there is little evidence regarding the beneficial effects of these changes on patient outcomes. Malignancies are also an increasing cause of mortality, overtaking cardiovascular disease in some series. Induction therapy, azathioprine and calcineurin inhibitors (CNIs) are probably the immunosuppressive agents most linked with post-transplant malignancies. Mycophenolate mofetil (MMF) has no negative impact on the incidence of malignancies. Target of rapamycin (mTOR) inhibitors have antioncogenic properties and they are associated with a lower incidence of malignancies. In addition, these agents have been recommended for use to decrease the dose or withdrawal of CNIs in patients with malignancies. Infections are still an important cause of morbidity and mortality in renal transplant recipients. Some immunosuppressive agents such as MMF increase the incidence of cytomegalovirus infection and the need for prophylactic measures in risk recipients. The use of potent immunosuppressive therapy has resulted in the appearance of BK virus nephropathy, which progresses to graft failure in a high percentage of patients. Although first associated with tacrolimus and MMF immunosuppression, recent data suggest that BK nephropathy appears with any kind of triple therapy. In conclusion, reducing risk factors for patient death should be a major target to improve outcomes after renal transplantation. Effort should be made to control cardiovascular diseases, malignancies and infections with improved use of immunosuppressive drugs. Preliminary results with belatacept suggest its safety and efficacy, and open new perspectives in the immunosuppression of de novo renal transplant recipients.
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              Iranian model of paid and regulated living-unrelated kidney donation.

              Since the 1980s, many countries have passed legislation prohibiting monetary compensation for organ donation. Organ donation for transplantation has become altruistic worldwide. During the past two decades, advances in immunosuppressive therapy has led to greater success in transplantation and to increased numbers of patients on transplant waiting lists. Unfortunately, the altruistic supply of organs has been less than adequate, and severe organ shortage has resulted in many patient deaths. A number of transplant experts have been convinced that providing financial incentives to organ sources as an alternative to altruistic organ donation needs careful reconsideration. In 1988, a compensated and regulated living-unrelated donor renal transplant program was adopted in Iran. As a result, the number of renal transplants performed substantially increased such that in 1999, the renal transplant waiting list was completely eliminated. By the end of 2005, a total of 19,609 renal transplants were performed (3421 from living related, 15,356 from living-unrelated and 823 from deceased donors). In this program, many ethical problems that are associated with paid kidney donation also were prevented. Currently, Iran has no renal transplant waiting lists, and >50% of patients with ESRD in the country are living with a functioning graft. In developed countries, the severe shortage of transplantable kidneys has forced the transplant community to adopt new strategies to expand the kidney donor pool. However, compared with the Iranian model, none of these approaches has the potential to eliminate or even alleviate steadily worsening renal transplant waiting lists.
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                Author and article information

                Journal
                Nephrourol Mon
                Nephrourol Mon
                10.5812/numonthly
                Kowsar
                Nephro-urology Monthly
                Kowsar
                2251-7006
                2251-7014
                10 March 2014
                March 2014
                : 6
                : 2
                : e14302
                Affiliations
                [1 ]Department of Epidemiology and Biostatistics, School of Public Health, Tehran University of Medical Sciences, Tehran, IR Iran
                [2 ]Nephrology and Urology Research Center, Baqiyatallah University of Medical Sciences, Tehran, IR Iran
                [3 ]Department of Psychology, Faculty of Humanities, Tarbiat Modares University, Tehran, IR Iran
                [4 ]Salamat Hospital, Ahvaz University of Medical Sciences, Ahvaz, IR Iran
                Author notes
                [* ]Corresponding author: Mohammad Reza Eshraghian, Department of Epidemiology and Biostatistics, School of Public Health, Tehran University of Medical Sciences, P.O. Box: 14155-6446, Tehran, IR Iran. Tel/Fax: +98-2188989127, E-mail: eshraghianm@ 123456tums.ac.ir
                Article
                10.5812/numonthly.14302
                4090583
                9eb03813-0381-4834-badb-104a9b3b8bd6
                Copyright © 2014, Nephrology and Urology Research Center; Published by Kowsar Corp.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 19 August 2013
                : 12 September 2013
                : 22 September 2013
                Categories
                Research Article

                neoplasms,kidney transplantation,cumulative trauma disorders,risk

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