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Pacheco LS, Ventura PE, Kist R, Garcia VD, Meinerz G, Tovo CV, Cantisani GPC, Zanotelli ML, Mucenic M, Keitel E. Real-world effectiveness and safety of direct-acting antivirals for the treatment of hepatitis C virus in kidney and liver transplant recipients: experience of a large transplant center in Brazil. Rev Inst Med Trop Sao Paulo 2023; 65:e59. [PMID: 38055377 PMCID: PMC10703500 DOI: 10.1590/s1678-9946202365059] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2023] [Accepted: 10/26/2023] [Indexed: 12/08/2023] Open
Abstract
Direct-acting antivirals are the gold-standard treatment for chronic HCV infections, but few studies have investigated their use on kidney and liver transplant recipients. We conducted a real-world study to evaluate the rates of sustained virological response with direct-acting antivirals in kidney and liver transplant recipients. Moreover, it also aimed to evaluate direct-acting antivirals (DAAs) interference with immunosuppressant levels and to describe the frequency of adverse events. As part of this retrospective observational cohort, we included adult patients that had undergone a kidney transplant (KT) or liver transplant (LT) at our center, had a chronic HCV infection, and were treated with DAAs from June 2016 to December 2021. A total of 165 patients were included in the analysis, divided in 108 KT and 57 LT recipients. HCV genotype 1 was more frequent in KT (58.4%), and genotype 3 was more prevalent in LT (57.9%) patients. Sustained virological response was achieved in 89.6% of patients. Adverse effects were reported by 36% of patients. There were significant interactions with immunosuppressants requiring dose adjustments. A total of three episodes of rejection were reported in KT recipients. In conclusion, DAA treatment resulted in high rates of SVR and was well tolerated in both kidney and liver transplant patients. Adverse events were frequent but not severe in most patients, with low treatment drop-out rates. Interactions with immunosuppressants need monitoring since dose adjustments may be required. Reporting real-life experiences is important to help build evidence for patient management in non-controlled environments.
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Affiliation(s)
- Larissa Sgaria Pacheco
- Universidade Federal de Ciências da Saúde de Porto Alegre,
Programa de Pós-Graduação em Patologia, Porto Alegre, Rio Grande do Sul,
Brazil
- Irmandade da Santa Casa de Misericórdia de Porto Alegre,
Departamento de Nefrologia e Transplante de Rim e Pâncreas, Porto Alegre, Rio
Grande do Sul, Brazil
| | - Pedro Enrico Ventura
- Irmandade da Santa Casa de Misericórdia de Porto Alegre,
Departamento de Nefrologia e Transplante de Rim e Pâncreas, Porto Alegre, Rio
Grande do Sul, Brazil
| | - Roger Kist
- Irmandade da Santa Casa de Misericórdia de Porto Alegre,
Departamento de Nefrologia e Transplante de Rim e Pâncreas, Porto Alegre, Rio
Grande do Sul, Brazil
| | - Valter Duro Garcia
- Irmandade da Santa Casa de Misericórdia de Porto Alegre,
Departamento de Nefrologia e Transplante de Rim e Pâncreas, Porto Alegre, Rio
Grande do Sul, Brazil
| | - Gisele Meinerz
- Irmandade da Santa Casa de Misericórdia de Porto Alegre,
Departamento de Nefrologia e Transplante de Rim e Pâncreas, Porto Alegre, Rio
Grande do Sul, Brazil
| | - Cristiane Valle Tovo
- Universidade Federal de Ciências da Saúde de Porto Alegre,
Departamento de Medicina Interna, Porto Alegre, Rio Grande do Sul, Brazil
| | - Guido Pio Cracco Cantisani
- Irmandade da Santa Casa de Misericórdia de Porto Alegre, Grupo
de Transplante Hepático, Porto Alegre, Rio Grande do Sul, Brazil
| | - Maria Lucia Zanotelli
- Irmandade da Santa Casa de Misericórdia de Porto Alegre, Grupo
de Transplante Hepático, Porto Alegre, Rio Grande do Sul, Brazil
| | - Marcos Mucenic
- Universidade Federal de Ciências da Saúde de Porto Alegre,
Programa de Pós-Graduação em Patologia, Porto Alegre, Rio Grande do Sul,
Brazil
- Irmandade da Santa Casa de Misericórdia de Porto Alegre, Grupo
de Transplante Hepático, Porto Alegre, Rio Grande do Sul, Brazil
| | - Elizete Keitel
- Universidade Federal de Ciências da Saúde de Porto Alegre,
Programa de Pós-Graduação em Patologia, Porto Alegre, Rio Grande do Sul,
Brazil
- Irmandade da Santa Casa de Misericórdia de Porto Alegre,
Departamento de Nefrologia e Transplante de Rim e Pâncreas, Porto Alegre, Rio
Grande do Sul, Brazil
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Al-Imam A, Abdulrahman Al-Tabbakh A. Predictors of New-onset Diabetes After Kidney Transplantation During 2019-nCoV Pandemic: A Unison of Frequentist Inference and Narrow AI. Open Access Maced J Med Sci 2022. [DOI: 10.3889/oamjms.2022.7521] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022] Open
Abstract
BACKGROUND: New-onset diabetes after kidney transplant (NODAT) is a severe metabolic complication that frequently occurs in recipients following transplantation.
AIM: The study aims to verify NODAT, compare cases and non-cases of this entity, and explore potential predictors in recipients within 1 year following kidney transplantation.
METHODS: The research is a retrospective study of 90 renal transplant recipients (n = 90). Demographic factors and clinical aspects were analyzed using non-Bayesian statistics and machine learning (ML). The clinical aspects included the glycated hemoglobin (HbA1c) level, associated viral infections (hepatitis B virus [HBV], hepatitis C virus [HCV], and cytomegalovirus [CMV]), prior kidney transplant, hemodialysis status, body mass index (BMI) at transplant time, and 3 months later, primary causes of renal failure, and post-transplant therapeutics. All individuals were on cyclosporine and prednisolone treatment.
RESULTS: The mean age was 39 (±1.5) years; recipients included 27 females (30%) and 63 males (70%). Donor type was live related (16, 17.8%) or live unrelated (74, 82.2%); 27 recipients (30%) had O+ blood group, while 70% belonged to other groups. Thirteen recipients (14.4%) were not on dialysis. Only 32 individuals (35.6%) developed NODAT. Concerning virology, confirmed by real-time polymerase chain reaction before transplantation, 19 recipients (21.1%) were CMV positive, 9 (10%) were HCV positive, and 2 (2.2%) had HBV.
CONCLUSIONS: In reconciliation with frequentist statistics, the dual ML model validated several predictors that either negatively (protective) or positively (harmful) influenced HbA1c level, the majority of which were significant at 95% confidence interval. Individuals who are HCV and CMV positive are predicted to develop NODAT. Further, older individuals, with blood group O+ve, prior history of hemodialysis, a relatively high BMI before the transplant, and receiving higher doses of prednisolone following the transplant are more likely to develop NODAT. The current study represents the first research from Iraq to explore NODAT predictors among kidney transplant recipients using frequentist statistics and artificial intelligence models.
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Kotha S, Lawendy B, Asim S, Gomes C, Yu J, Orchanian-Cheff A, Tomlinson G, Bhat M. Impact of immunosuppression on incidence of post-transplant diabetes mellitus in solid organ transplant recipients: Systematic review and meta-analysis. World J Transplant 2021; 11:432-442. [PMID: 34722172 PMCID: PMC8529944 DOI: 10.5500/wjt.v11.i10.432] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2021] [Revised: 08/27/2021] [Accepted: 09/19/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Solid organ transplantation is a life-saving intervention for end-stage organ disease. Post-transplant diabetes mellitus (PTDM) is a common complication in solid organ transplant recipients, and significantly compromises long-term survival beyond a year.
AIM To perform a systematic review and meta-analysis to estimate incidence of PTDM and compare the effects of the 3 major immunosuppressants on incidence of PTDM.
METHODS Two hundred and six eligible studies identified 75595 patients on Tacrolimus, 51242 on Cyclosporine and 3020 on Sirolimus. Random effects meta-analyses was used to calculate incidence.
RESULTS Network meta-analysis estimated the overall risk of developing PTDM was higher with tacrolimus (OR = 1.4 95%CI: 1.0–2.0) and sirolimus (OR = 1.8; 95%CI: 1.5–2.2) than with Cyclosporine. The overall incidence of PTDM at years 2-3 was 17% for kidney, 19% for liver and 22% for heart. The risk factors for PTDM most frequently identified in the primary studies were age, body mass index, hepatitis C, and African American descent.
CONCLUSION Tacrolimus tends to exhibit higher diabetogenicity in the short-term (2-3 years post-transplant), whereas sirolimus exhibits higher diabetogenicity in the long-term (5-10 years post-transplant). This study will aid clinicians in recognition of risk factors for PTDM and encourage careful evaluation of the risk/benefit of different immunosuppressant regimens in transplant recipients.
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Affiliation(s)
- Sreelakshmi Kotha
- Department of Gastroenterology, Guy's and St Thomas' Hospital, London SE1 7JD, United Kingdom
| | - Bishoy Lawendy
- Department of Multi-Organ Transplantation, Toronto General Hospital, Toronto M5G 2C4, Canada
| | - Saira Asim
- Multi Organ Transplant Program, Toronto General Hospital, Toronto M5G 2C4, Canada
| | - Charlene Gomes
- Department of Multi-Organ Transplantation, Toronto General Hospital, Toronto M5G 2C4, Canada
| | - Jeffrey Yu
- Department of Multi-Organ Transplantation, Toronto General Hospital, Toronto M5G 2C4, Canada
| | - Ani Orchanian-Cheff
- Department of Multi-Organ Transplantation, Toronto General Hospital, Toronto M5G 2C4, Canada
| | - George Tomlinson
- Dalla Lana School of Public Health, Department of Medicine, University Health Network - Toronto General Hospital, University of Toronto, Toronto M5G 2C4, Canada
| | - Mamatha Bhat
- Multi-organ Transplant, Toronto General Hospital, Toronto M5G 2C4, Canada
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Emori CT, Uehara SNO, Amaral AC, Carvalho-Filho RJ, Moreira SR, Sandra de Souza E Silva I, Lanzoni VP, Silva-Souza AL, Gama RA, Soares Nunes EJ, Serra Leopércio AP, Appel F, Regina de Almeida Carvalho S, Benedito Silva AE, Medina-Pestana JO, Gomes Ferraz ML. Observational Study Evaluating the Outcome of Cirrhotic Hepatitis C Patients Submitted to Renal Transplantation. Transplant Proc 2020; 52:89-96. [PMID: 32000943 DOI: 10.1016/j.transproceed.2019.10.022] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2019] [Accepted: 10/06/2019] [Indexed: 12/12/2022]
Abstract
BACKGROUND After renal transplantation (RTx) hepatitis C virus (HCV) is associated with higher morbidity and mortality resulting in lower patient and graft survival. Few studies have investigated the evolution of renal transplant patients with cirrhosis owing to HCV. The objectives were to evaluate the post-transplant evolution of cirrhotic patients and to compare them with noncirrhotic patients considering the outcomes, including hepatic decompensation, graft loss, and death. METHODS The retrospective-cohort study analyzed the data of patients undergoing RTx between 1993 and 2014, positive anti-HCV, HCV-RNA before RTx, and availability of data for assessment of cirrhosis. Demographic, clinical, and laboratory variables were compared between the groups according to the outcomes. The same were made between cirrhotic patients with and without portal hypertension (PH). Survival curves were constructed by the Kaplan-Meier test and compared by the log-rank test. Variables associated with the outcomes were analyzed using Cox regression. RESULTS This study included noncirrhotic (n = 201) and cirrhotic patients (n = 23). In cirrhotic patients, they were significantly older (49 vs 41.6 years) and mostly male (87% vs 65%), with a greater number of previous RTx (48% vs 18%), less frequent use of azathioprine (26% vs 54%), cyclosporine (13% vs 46.5%), more frequent use of tacrolimus (87% vs 55%), lower count of platelets × 1000 cells/mm3(110 vs 187), and higher pre-RTx international normalized ratio (1.20 vs 1.1).The Kaplan-Meier survival differed in cirrhotic vs noncirrhotic patients only in hepatic decompensation. Cox regression analysis identified pretransplant cirrhosis (hazard ratio 6.64, 95% confidence interval, 2.59-17.06) and tacrolimus (hazard ratio 3.17,95% confidence interval, 1.05-9.58) as variables independently associated with decompensation. CONCLUSIONS Patients with HCV and cirrhosis exhibit higher morbidity when submitted to RTx than noncirrhotic patients, with a higher risk of hepatic decompensation. However, no difference was observed in liver-related mortality, suggesting that RTx is a feasible option in cirrhotic patients without decompensation, even if they have PH.
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Affiliation(s)
| | | | - Ana Cristina Amaral
- Department of Gastroenterology, Federal University of São Paulo, São Paulo, Brazil
| | | | | | | | | | | | - Raimundo Araújo Gama
- Department of Gastroenterology, Federal University of São Paulo, São Paulo, Brazil
| | | | | | - Flávia Appel
- Department of Gastroenterology, Federal University of São Paulo, São Paulo, Brazil
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Abstract
With a worldwide prevalence of 6% to 40% among patients with end-stage renal disease, hepatitis C virus (HCV) infection is a significant cause of comorbidity in kidney transplant candidates and recipients alike. Hepatitis C infection negatively impacts patient and allograft outcomes, predisposes to progressive liver disease and increases the risks of glomerular disease as well as new onset diabetes after transplantation. Treatment options until now have revolved around interferon, limited in efficacy, restricted to pretransplant administration because of concerns related to allograft dysfunction and immune stimulation, and fraught with high rates of intolerance. Direct-acting antivirals therapies are now emerging, providing the opportunity to effectively cure chronic HCV infection and to reduce the burden of hepatic and extrahepatic complications of HCV that are observed in kidney recipients, thereby offering hope of improved patient outcomes. Against a description of the major outcomes and risks that HCV+ kidney candidates and recipients encounter, and a summary of the pertinent studies of interferon-based therapies in this population, this review discusses the potential role for emerging direct-acting antivirals, proposing treatment algorithms that should be considered in the management of these complex patients. Conundrums relating to the new treatment, including the potential impact on the utilization of kidneys from HCV-infected donors, are presented.
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Acute allograft rejection following interferon therapy for hepatitis C in recipients who have returned to dialysis after kidney transplant failure: case study. Int J Artif Organs 2014; 37:803-8. [PMID: 25362901 DOI: 10.5301/ijao.5000359] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/10/2014] [Indexed: 01/19/2023]
Abstract
Interferon-based therapy remains the gold standard for hepatitis C in patients with chronic kidney disease; however, due to the high rate of IFN-induced rejection after transplant, treatment of HCV-infected kidney transplant recipients is recommended only in particular circumstances. We report the case of a 45-year-old Caucasian female with chronic hepatitis C (genotype 1b) who returned to hemodialysis following the complete functional loss of her kidney transplant. She started combination antiviral therapy with peg-IFN-α2a (135 mcg sc weekly) plus ribavirin (200 mg daily) nine months after the re-initiation of hemodialysis. Antiviral therapy was neither effective nor safe; ribavirin was stopped at week 38 due to hemolytic anemia; on-treatment HCV breakthrough was observed at week 48; and acute rejection occurred after four months of IFN-based therapy. Diagnosis of acute allograft rejection was suspected on the grounds of clinical, radiographic, and laboratory data. Allograft nephrectomy was then performed and histology showed acute-on-chronic rejection. This is an uncommon case of IFN-associated kidney rejection in an allograft recipient who had functional loss of her graft and had returned to hemodialysis. In view of the risk of rejection of renal allograft, and the limited efficacy of IFN-based treatment of hepatitis C, physicians should be aware of effective treatment with oral anti-viral agents and avoid the use of IFN in patients on maintenance dialysis with failed renal allograft.
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Baid-Agrawal S, Pascual M, Moradpour D, Somasundaram R, Muche M. Hepatitis C virus infection and kidney transplantation in 2014: what's new? Am J Transplant 2014; 14:2206-20. [PMID: 25091274 DOI: 10.1111/ajt.12835] [Citation(s) in RCA: 59] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2014] [Revised: 05/15/2014] [Accepted: 05/16/2014] [Indexed: 01/25/2023]
Abstract
Chronic hepatitis C virus (HCV) infection remains an important health problem, which is associated with deleterious consequences in kidney transplant recipients. Besides hepatic complications, several extrahepatic complications contribute to reduced patient and allograft survival in HCV-infected kidney recipients. However, HCV infection should not be considered as a contraindication for kidney transplantation because patient survival is better with transplantation than on dialysis. Treatment of HCV infection is currently interferon-alpha (IFN-α) based, which has been associated with higher renal allograft rejection rates. Therefore, antiviral treatment before transplantation is preferable. As in the nontransplant setting, IFN-free treatment regimens, because of their greater efficacy and reduced toxicity, currently represent promising and attractive therapeutic options after kidney transplantation as well. However, clinical trials will be required to closely evaluate these regimens in kidney recipients. There is also a need for prospective controlled studies to determine the optimal immunosuppressive regimens after transplantation in HCV-infected recipients. Combined kidney and liver transplantation is required in patients with advanced liver cirrhosis. However, in patients with cleared HCV infection and early cirrhosis without portal hypertension, kidney transplantation alone may be considered. There is some agreement about the use of HCV-positive donors in HCV-infected recipients, although data regarding posttransplant survival rates are controversial.
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Affiliation(s)
- S Baid-Agrawal
- Department of Nephrology and Medical Intensive Care, Campus Virchow-Klinikum, Charité Universitaetsmedizin Berlin, Berlin, Germany
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Fabrizi F, Martin P, Dixit V, Messa P. Meta-analysis of observational studies: hepatitis C and survival after renal transplant. J Viral Hepat 2014; 21:314-24. [PMID: 24716634 DOI: 10.1111/jvh.12148] [Citation(s) in RCA: 106] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2013] [Accepted: 06/18/2013] [Indexed: 12/11/2022]
Abstract
Recent evidence has shown that anti-HCV-positive serologic status is significantly linked to lower patient and graft survival after renal transplant, but conflicting results have been given on this point. The aim of this study was to conduct a systematic review of the published medical literature concerning the impact of HCV infection on all-cause mortality and graft loss after RT. The relative risk of all-cause mortality and graft loss was regarded as the most reliable outcome end-point. Study-specific relative risks were weighted by the inverse of their variance to obtain fixed- and random-effect pooled estimates for mortality and graft loss with HCV across the published studies. We identified eighteen observational studies involving 133 530 unique renal transplant recipients. The summary estimate for adjusted relative risk (aRR) of all-cause mortality was 1.85 with a 95% confidence interval (CI) of 1.49; 2.31 (P < 0.0001); heterogeneity statistics, Ri = 0.87 (P-value by Q-test = 0.001). The overall estimate for adjusted RR of all-cause graft loss was 1.76 (95% CI, 1.46; 2.11) (P < 0.0001), heterogeneity statistics, Ri = 0.65 (P-value by Q-test = 0.001). Stratified analysis did not change meaningfully these results. Meta-regression showed that living donor rate had a favourable influence on patient (P = 0.031) and graft survival (P = 0.01), whilst diabetes mellitus having a detrimental role on patient survival (P = 0.001). This meta-analysis of observational studies supports the notion that HCV-positive patients after RT have an increased risk of mortality and graft loss. Further studies are in progress to understand better the mechanisms underlying the relationship between HCV and mortality or graft dysfunction after renal transplant.
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Affiliation(s)
- F Fabrizi
- Division of Nephrology and Dialysis, Maggiore Hospital, IRCCS Foundation, Milano, Italy; Division of Hepatology, School of Medicine, University of Miami, Miami, FL, USA
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Chakkera HA, Weil EJ, Pham PT, Pomeroy J, Knowler WC. Can new-onset diabetes after kidney transplant be prevented? Diabetes Care 2013; 36:1406-12. [PMID: 23613600 PMCID: PMC3631828 DOI: 10.2337/dc12-2067] [Citation(s) in RCA: 64] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
Because the negative consequences of new-onset diabetes mellitus after transplantation (NODAT) diminish the significant gains of kidney transplantation, it is imperative to develop clinical interventions to reduce the incidence of NODAT. In this review, we discuss whether intensive lifestyle interventions that delay or prevent type 2 diabetes mellitus may decrease the incidence of NODAT. We examine the literature pertaining to incidence and timing of onset of NODAT, as well as the risk factors and pathophysiology that NODAT shares with type 2 diabetes mellitus, namely pathways related to increased insulin resistance and decreased insulin secretion. Our central hypothesis is that NODAT results from the same metabolic risk factors that underlie type 2 diabetes mellitus. These risk factors are altered and enhanced by transplantation, "tipping" some transplant recipients with seemingly normal glucose homeostasis before transplant toward the development of NODAT. We describe the diabetogenic properties of transplant immunosuppressive drugs. We describe novel methods of prevention that are being explored, including resting the pancreatic β-cells by administration of basal insulin during the period immediately after transplant. On the basis of the current evidence, we propose that intensive lifestyle modification, adapted for individuals with chronic kidney disease or end-stage renal disease, as well as resting pancreatic β-cells during the immediate postoperative period, may lower the incidence of NODAT.
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Abstract
PURPOSE OF REVIEW The purpose of this review is to describe the new insights of hepatitis C virus (HCV) infection and renal transplantation. RECENT FINDINGS HCV is its most frequent cause of liver disease after transplantation. In the long run, HCV infection can lead to cirrhosis, hepatocarcinoma and death in some patients. As interferon is generally contraindicated after transplantation, the best way to treat patients is before transplantation. Long-term patient and graft survival rates are lower in HCV-positive patients than in HCV-negative graft recipients. HCV infection is an independent risk factor for death and graft loss. Mortality is higher, mainly as a result of cardiovascular complications, liver disease and infections but is lower than in HCV-positive patients on the transplant waiting list. New-onset diabetes after transplantation (NODAT), and HCV-related glomerulonephritis, together with chronic rejection and notably transplant glomerulopathy can contribute to graft failure. Despite this factor, transplantation is the best option for the HCV-positive patient on dialysis. Renal transplantation with kidneys from donors with positive anti-HCV antibodies into HCV RNA-positive recipients seems to be safe in the long term. SUMMARY Renal transplantation is the therapy of choice for dialysis patients with HCV infection. To improve the results, a careful follow-up in the outpatient clinic for early detection of HCV-related complications is mandatory.
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