- Email: [email protected]
Kidney Transplantation in Hepatitis C-Positive Recipients: Does Type of Induction Influence Outcomes?
Kidney Transplantation in Hepatitis C-Positive Recipients: Does Type of Induction Influence Outcomes? K.K. Sureshkumar, N.L. Thai, and R.J. Marcus ABSTRACT Background. Kidney transplantation in hepatitis C virus-seropositive (HCV⫹) recipients improves survival compared to staying on the waiting list. A concern for using depleting (versus nondepleting) induction agent during kidney transplantation in HCV⫹ recipients is the possibility that the associated enhanced immunosuppression might favor the progression of hepatitis C infection, leading to adverse outcomes. Methods. Utilizing data from the Organ Procurement and Transplant Network, we identified HCV⫹ patients ⱖ 18 years of age who underwent deceased donor kidney (DDK) transplants from either HCV⫹ or HCV⫺ donors between 1998 and 2008. Patients were divided into two groups based on the induction type they received during the transplant: depleting agent (rabbit-antithymocyte globulin or alemtuzumab) or nondepleting agent (basiliximab or daclizumab) groups. Unadjusted and adjusted graft and patient survivals (Cox regression) between the groups were compared. Results. A total of 3490 HCV⫹ DDK recipients were identified (1859 in the depleting and 1631 in the nondepleting groups). When compared to nondepleting agent, adjusted graft (hazard ratio [HR] 1.11, 95% confidence interval [CI] 0.96 –1.28, P ⫽ .16) and patient (HR 1.15, 95% CI 0.93–1.42, P ⫽ .2) survivals were similar with depleting agent induction. HCV donor seropositivity did not adversely impact either graft (HR 1.11, 95% CI 0.96 – 1.29, P ⫽ .17) or patient (HR 1.15, 95% CI 0.93–1.42, P ⫽ .2) outcomes. Conclusions. Our analysis supports the practice of transplanting HCV⫹ donor kidneys into HCV⫹ recipients to alleviate waiting list burden. Recipient HCV positivity should not influence selection of induction agent. IDNEY TRANSPLANTATION in hepatitis C virusseropositive (HCV⫹) recipients without advanced liver disease is associated with improved survival compared to staying on the waiting list.1– 4 A concern for using depleting (versus nondepleting) induction agent during kidney transplantation in HCV⫹ recipients is the possibility that the associated enhanced immunosuppression might favor the progression of hepatitis C infection, leading to adverse outcomes. We aimed to compare the graft and patient survival in HVC⫹ patients who received induction with depleting versus nondepleting agent during deceased donor kidney (DDK) transplantation. We also evaluated the influence of donor heaptits C seropositivity status on graft and patient outcomes in such patients.
K
PATIENTS AND METHODS HCV⫹ recipients ⱖ 18 years of age, who underwent DDK transplantation from either HCV⫹ or HCV⫺ donors from January
1998 to December 2008 were identified using Organ Procurement and Transplant Network/United Network of Organ Sharing standard transplant analysis and research files. Recipients of multiorgan transplants were excluded from the analysis. Patients were divided into two groups based on the induction type they received From the Department of Medicine, Division of Nephrology and Hypertension (K.K.S., R.J.M.), and Department of Surgery, Division of Abdominal Transplantation (N.L.T.), Allegheny General Hospital, Pittsburgh, Pennsylvania, USA. This work was supported in part by Health Resources and Services Administration contract 231-00-0115. The content is the responsibility of the authors alone and does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. Address reprint requests to K.K. Sureshkumar, MD, FRCP (Glasg), FASN, Division of Nephrology, Allegheny General Hospital, pittsburgh, PA 15212. E-mail: [email protected]
0041-1345/12/$–see front matter http://dx.doi.org/10.1016/j.transproceed.2011.12.076
© 2012 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
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Transplantation Proceedings, 44, 1262–1264 (2012)
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Table 1. Demographic Charecteristics of the HCVⴙ Recipients by Induction
Donor age (ys) Donor gender (M/F), % Donor death from CVA (%) ECD kidney (%) DCD kidney (%) Donor hepatitis C seropositivity (%) Recipient age (ys) Recipient gender (M/F), % Recipient African-American race (%) Recipient diabetes (%) Pretransplant dialysis duration (mon) Peak PRA (%) HLA mismatch Cold ischemia time (ho) Delayed graft function (%) Acute rejection in 1 st year Previous transplant (%)
Depleting (n ⫽ 1859)
Nondepleting (n ⫽ 1631)
P Value
38.9 ⫾ 14.7 62/38 41.0 13.5 7.3 27.0
37.6 ⫾ 14.8 63/37 40.1 10.4 3.2 25.0
.009 .49 .57 .005 ⬍.001 .17
50.8 ⫾ 9.7 74/26 52.0
50.2 ⫾ 10.2 74/26 43.5
.08 .81 ⬍.001
16.2 59.3 ⫾ 57.4
9.7 50.3 ⫾ 44.0
⬍.001 ⬍.001
23.9 ⫾ 14.9 3.9 ⫾ 1.8 18.9 ⫾ 8.4 29.7 10.5 22.4
35.2 ⫾ 28.2 3.9 ⫾ 1.8 18.7 ⫾ 8.4 26.7 11.5 14.2
⬍.001 .47 .65 .05 .36 ⬍.001
incidence when compared to the nondepleting group. Patients in the nondepleting group had higher sensitization compared to the depleting group. Maintenance immunosuppression use among depleting versus nondepleting groups was as follows: calcineurin inhibitor, 93.7% versus 93.2%; mycophenolic acid derivative, 88.4% versus 88.1%, and steroids, 68.6% versus 92.9%. When compared to nondepleting agent, induction with a depleting agent was associated with similar unadjusted graft (hazard ratio [HR] 1.05, 95% confidence interval [CI] 0.94 –1.17, P ⫽ .42) and patient (HR 1.03, 95% CI 0.89 – 1.19, P ⫽ .72) survival rates. After correction for confounding variables, depleting agent induction was associated with similar graft (HR 1.11, 95% CI 0.96 –1.28, P ⫽ .16) and patient (HR 1.15, 95% CI 0.93–1.42, P ⫽ .2) survival when
CVA, cerebrovascular accident; DCD, donation after cardiac death; ECD, expanded criteria donor; HCV⫹, hepatitis C virus positive; HLA, human leukocyte antigen; PRA, panel-reactive antibody.
during the transplant: depleting agent (rabbit-antithymocyte globulin or alemtuzumab) or nondepleting agent (basiliximab or daclizumab) groups. Unadjusted and adjusted graft and patient survivals were compared between the depleting and nondepleting groups. Multivariate analysis using a Cox regression model was utilized to evaluate the independent effects of the type of induction on graft and patient outcomes. Confounding variables included in the model were: donor-related (hepatitis C serology status, age, gender, expanded criteria donor [ECD] kidney, donation after cardiac death [DCD] kidney, death from cerebrovascular accident [CVA]); recipient-related (age, African-American race, diabetes mellitus, dialysis duration, peak panel reactive antibody titer, human leukocyte antigen mismatch); and transplant related (cold ischemia time, delayed graft function [DGF, defined as the need for dialysis within the first posttransplant week], previous transplant, acute rejection in first year, transplant year). Statistical analysis was performed using SPSS software version 14.
RESULTS
The median follow-up was 34.5 months (range 18.0 –53.6) in the depleting group and 47.6 months (range 23.2– 81.7) in the nondepleting group. Demographic characteristics of the HCV⫹ recipients by the induction type are shown in Table 1. A total of 3490 HCV⫹ recipients underwent DDK transplantation from January 1998 to December 2008 and received induction with either a depleting (n ⫽ 1859) or a nondepleting (n ⫽ 1631) agent. Donor hepatitis C seropositivity was similar between the groups (27.0% versus 25.0%, P ⫽ .17). In the depleting group, donor age was higher, with higher prevalence of ECD/DCD kidneys, recipient AfricanAmerican race, diabetes, and previous transplant, along with longer pretransplant dialysis duration and higher DGF
Fig 1. Adjusted graft (A) and patient (B) survival in depleting versus nondepleting agent induction in hepatitis C virus-seropositive recipients.
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compared to nondepleting agent induction (Fig 1). HCV donor seropositivity did not adversely impact either graft (HR 1.11, 95% CI 0.96 –1.29, P ⫽ .17) or patient (HR 1.15, 95% CI 0.93–1.42, P ⫽ .2) outcomes. Factors that emerged as significant predictors of adverse graft outcomes were: DGF (HR 1.48, 95% CI 1.30 –1.70, P ⬍ .001), donor death from CVA (HR 1.28, 95% CI 1.11–1.48, P ⫽ .001), recipient African-American race (HR 1.23, 95% CI 1.07–1.41, P ⫽ .003), dialysis duration per year (HR 1.02, 95% CI 1.01–1.04, P ⫽ .002), donor age per year (HR 1.01, 95% CI 1.004 –1.015, P ⫽ .001) and recipient age per year (HR 1.009, 95% CI 1.002–1.016, P ⫽ .014). Adverse patient outcomes were predicted by the following factors: DGF (HR 1.38, 95% CI 1.15–1.67, P ⫽ .001), donor death from CVA (HR 1.33, 95% CI 1.09 –1.63, P ⫽ .005), recipient age per year (HR 1.04, 95% CI 1.03–1.05, P ⬍ .001), and dialysis duration per year (HR 1.04, 95% CI 1.02–1.06, P ⬍ .001). DISCUSSION
Our study showed similar graft and patient outcomes with depleting versus nondepleting antibody induction in HCV ⫹ recipients undergoing DDK transplantation. Donor HCV seropositivity was not an independent predictor of graft or patient outcomes. Previous meta-analyses have shown significant independent impact of hepatits C infection on mortality in both dialysis and transplant patients.5,6 As mentioned, kidney transplantation conferred survival advantage in HCV⫹ recipients when compared to staying on the waiting list.1–3 In the recently published study by Roth et al looking at kidney transplant outcomes in HCV⫹ patients, liver histology remained stable in the majority of rebiopsied kidney transplant recipients despite many years of immunosup-
SURESHKUMAR, THAI, AND MARCUS
pression, whereas liver injury progressed more commonly in patients who remained on the waiting list.1 Interestingly, a subset analysis of patients who received daclizumab induction revealed a significantly worse liver fibrosis progression rate compared to patients who received lymphocyte-depleting therapy in this study. In summary, our analysis supports the practice of transplanting HCV⫹ donor kidneys into HCV⫹ recipients without advanced liver disease in order to alleviate waiting list burden in DDK transplantation. Recipient hepatitis C seropositivity should not influence the selection of induction agent used during kidney transplantation in these patients. Retrospective study design, lack of more specific hepatitis C serum polymerase chain reactions as well as liver histology as markers of disease activity were study limitations. REFERENCES 1. Roth D, Gaynor JJ, Reddy KR, et al: Effect of kidney transplantation on outcomes among patients with hepatits C. J Am Soc Nephrol 22:1152, 2011 2. Abbott KC, Lentine KL, Bucci JR, et al: The impact of transplantation with deceased donor hepatitis C-positive kidneys on survival in wait-listed long-term dialysis patients. Am J Transplant 4:2032, 2004 3. Pereira BJ, Natov SN, Bouthot BA, et al: Effects of hepatits C infection and renal transplantation on survival in end-stage renal disease. The New England Organ Bank Hepatitis C Study Group. Kidney Int 53:1374, 1998 4. Maluf DG, Fisher RA, King AL, et al: Hepatits C virus infection and kidney transplantation: predictors of patient and graft survival. Transplantation 83:853, 2007 5. Fabrizi F, Martin P, Dixit V, et al: Meta-analysis: Effect of hepatits C virus infection on mortality in dialysis. Aliment Pharmacol Ther 20:1271, 2004 6. Fabrizi F, Martin P, Dixit V, et al: Hepatits C virus antibody status and survival after renal transplantation: meta-analysis of observational studies. Am J Transplant 5:1452, 2005
K
PATIENTS AND METHODS HCV⫹ recipients ⱖ 18 years of age, who underwent DDK transplantation from either HCV⫹ or HCV⫺ donors from January
1998 to December 2008 were identified using Organ Procurement and Transplant Network/United Network of Organ Sharing standard transplant analysis and research files. Recipients of multiorgan transplants were excluded from the analysis. Patients were divided into two groups based on the induction type they received From the Department of Medicine, Division of Nephrology and Hypertension (K.K.S., R.J.M.), and Department of Surgery, Division of Abdominal Transplantation (N.L.T.), Allegheny General Hospital, Pittsburgh, Pennsylvania, USA. This work was supported in part by Health Resources and Services Administration contract 231-00-0115. The content is the responsibility of the authors alone and does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. Address reprint requests to K.K. Sureshkumar, MD, FRCP (Glasg), FASN, Division of Nephrology, Allegheny General Hospital, pittsburgh, PA 15212. E-mail: [email protected]
0041-1345/12/$–see front matter http://dx.doi.org/10.1016/j.transproceed.2011.12.076
© 2012 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
1262
Transplantation Proceedings, 44, 1262–1264 (2012)
INDUCTION FOR HCV-POSITIVE PATIENTS
1263
Table 1. Demographic Charecteristics of the HCVⴙ Recipients by Induction
Donor age (ys) Donor gender (M/F), % Donor death from CVA (%) ECD kidney (%) DCD kidney (%) Donor hepatitis C seropositivity (%) Recipient age (ys) Recipient gender (M/F), % Recipient African-American race (%) Recipient diabetes (%) Pretransplant dialysis duration (mon) Peak PRA (%) HLA mismatch Cold ischemia time (ho) Delayed graft function (%) Acute rejection in 1 st year Previous transplant (%)
Depleting (n ⫽ 1859)
Nondepleting (n ⫽ 1631)
P Value
38.9 ⫾ 14.7 62/38 41.0 13.5 7.3 27.0
37.6 ⫾ 14.8 63/37 40.1 10.4 3.2 25.0
.009 .49 .57 .005 ⬍.001 .17
50.8 ⫾ 9.7 74/26 52.0
50.2 ⫾ 10.2 74/26 43.5
.08 .81 ⬍.001
16.2 59.3 ⫾ 57.4
9.7 50.3 ⫾ 44.0
⬍.001 ⬍.001
23.9 ⫾ 14.9 3.9 ⫾ 1.8 18.9 ⫾ 8.4 29.7 10.5 22.4
35.2 ⫾ 28.2 3.9 ⫾ 1.8 18.7 ⫾ 8.4 26.7 11.5 14.2
⬍.001 .47 .65 .05 .36 ⬍.001
incidence when compared to the nondepleting group. Patients in the nondepleting group had higher sensitization compared to the depleting group. Maintenance immunosuppression use among depleting versus nondepleting groups was as follows: calcineurin inhibitor, 93.7% versus 93.2%; mycophenolic acid derivative, 88.4% versus 88.1%, and steroids, 68.6% versus 92.9%. When compared to nondepleting agent, induction with a depleting agent was associated with similar unadjusted graft (hazard ratio [HR] 1.05, 95% confidence interval [CI] 0.94 –1.17, P ⫽ .42) and patient (HR 1.03, 95% CI 0.89 – 1.19, P ⫽ .72) survival rates. After correction for confounding variables, depleting agent induction was associated with similar graft (HR 1.11, 95% CI 0.96 –1.28, P ⫽ .16) and patient (HR 1.15, 95% CI 0.93–1.42, P ⫽ .2) survival when
CVA, cerebrovascular accident; DCD, donation after cardiac death; ECD, expanded criteria donor; HCV⫹, hepatitis C virus positive; HLA, human leukocyte antigen; PRA, panel-reactive antibody.
during the transplant: depleting agent (rabbit-antithymocyte globulin or alemtuzumab) or nondepleting agent (basiliximab or daclizumab) groups. Unadjusted and adjusted graft and patient survivals were compared between the depleting and nondepleting groups. Multivariate analysis using a Cox regression model was utilized to evaluate the independent effects of the type of induction on graft and patient outcomes. Confounding variables included in the model were: donor-related (hepatitis C serology status, age, gender, expanded criteria donor [ECD] kidney, donation after cardiac death [DCD] kidney, death from cerebrovascular accident [CVA]); recipient-related (age, African-American race, diabetes mellitus, dialysis duration, peak panel reactive antibody titer, human leukocyte antigen mismatch); and transplant related (cold ischemia time, delayed graft function [DGF, defined as the need for dialysis within the first posttransplant week], previous transplant, acute rejection in first year, transplant year). Statistical analysis was performed using SPSS software version 14.
RESULTS
The median follow-up was 34.5 months (range 18.0 –53.6) in the depleting group and 47.6 months (range 23.2– 81.7) in the nondepleting group. Demographic characteristics of the HCV⫹ recipients by the induction type are shown in Table 1. A total of 3490 HCV⫹ recipients underwent DDK transplantation from January 1998 to December 2008 and received induction with either a depleting (n ⫽ 1859) or a nondepleting (n ⫽ 1631) agent. Donor hepatitis C seropositivity was similar between the groups (27.0% versus 25.0%, P ⫽ .17). In the depleting group, donor age was higher, with higher prevalence of ECD/DCD kidneys, recipient AfricanAmerican race, diabetes, and previous transplant, along with longer pretransplant dialysis duration and higher DGF
Fig 1. Adjusted graft (A) and patient (B) survival in depleting versus nondepleting agent induction in hepatitis C virus-seropositive recipients.
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compared to nondepleting agent induction (Fig 1). HCV donor seropositivity did not adversely impact either graft (HR 1.11, 95% CI 0.96 –1.29, P ⫽ .17) or patient (HR 1.15, 95% CI 0.93–1.42, P ⫽ .2) outcomes. Factors that emerged as significant predictors of adverse graft outcomes were: DGF (HR 1.48, 95% CI 1.30 –1.70, P ⬍ .001), donor death from CVA (HR 1.28, 95% CI 1.11–1.48, P ⫽ .001), recipient African-American race (HR 1.23, 95% CI 1.07–1.41, P ⫽ .003), dialysis duration per year (HR 1.02, 95% CI 1.01–1.04, P ⫽ .002), donor age per year (HR 1.01, 95% CI 1.004 –1.015, P ⫽ .001) and recipient age per year (HR 1.009, 95% CI 1.002–1.016, P ⫽ .014). Adverse patient outcomes were predicted by the following factors: DGF (HR 1.38, 95% CI 1.15–1.67, P ⫽ .001), donor death from CVA (HR 1.33, 95% CI 1.09 –1.63, P ⫽ .005), recipient age per year (HR 1.04, 95% CI 1.03–1.05, P ⬍ .001), and dialysis duration per year (HR 1.04, 95% CI 1.02–1.06, P ⬍ .001). DISCUSSION
Our study showed similar graft and patient outcomes with depleting versus nondepleting antibody induction in HCV ⫹ recipients undergoing DDK transplantation. Donor HCV seropositivity was not an independent predictor of graft or patient outcomes. Previous meta-analyses have shown significant independent impact of hepatits C infection on mortality in both dialysis and transplant patients.5,6 As mentioned, kidney transplantation conferred survival advantage in HCV⫹ recipients when compared to staying on the waiting list.1–3 In the recently published study by Roth et al looking at kidney transplant outcomes in HCV⫹ patients, liver histology remained stable in the majority of rebiopsied kidney transplant recipients despite many years of immunosup-
SURESHKUMAR, THAI, AND MARCUS
pression, whereas liver injury progressed more commonly in patients who remained on the waiting list.1 Interestingly, a subset analysis of patients who received daclizumab induction revealed a significantly worse liver fibrosis progression rate compared to patients who received lymphocyte-depleting therapy in this study. In summary, our analysis supports the practice of transplanting HCV⫹ donor kidneys into HCV⫹ recipients without advanced liver disease in order to alleviate waiting list burden in DDK transplantation. Recipient hepatitis C seropositivity should not influence the selection of induction agent used during kidney transplantation in these patients. Retrospective study design, lack of more specific hepatitis C serum polymerase chain reactions as well as liver histology as markers of disease activity were study limitations. REFERENCES 1. Roth D, Gaynor JJ, Reddy KR, et al: Effect of kidney transplantation on outcomes among patients with hepatits C. J Am Soc Nephrol 22:1152, 2011 2. Abbott KC, Lentine KL, Bucci JR, et al: The impact of transplantation with deceased donor hepatitis C-positive kidneys on survival in wait-listed long-term dialysis patients. Am J Transplant 4:2032, 2004 3. Pereira BJ, Natov SN, Bouthot BA, et al: Effects of hepatits C infection and renal transplantation on survival in end-stage renal disease. The New England Organ Bank Hepatitis C Study Group. Kidney Int 53:1374, 1998 4. Maluf DG, Fisher RA, King AL, et al: Hepatits C virus infection and kidney transplantation: predictors of patient and graft survival. Transplantation 83:853, 2007 5. Fabrizi F, Martin P, Dixit V, et al: Meta-analysis: Effect of hepatits C virus infection on mortality in dialysis. Aliment Pharmacol Ther 20:1271, 2004 6. Fabrizi F, Martin P, Dixit V, et al: Hepatits C virus antibody status and survival after renal transplantation: meta-analysis of observational studies. Am J Transplant 5:1452, 2005