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Figure. 
Kidney graft survival by risk factor and human immunodeficiency virus (HIV) status. Death-censored graft survival (DCGS) rates by HIV status among recipients of kidneys from donors 50 years or older (A) and from donors younger than 50 years (B). The DCGS rates by HIV status among transplant recipients who developed delayed graft function (DGF) (C) and those who did not develop DGF (D). Each panel contains a graphic representation of the Kaplan-Meier survival function generated from the matched control data set. HIV-positive recipients (cases) and HIV-negative recipients (controls) were matched on donor type (living or deceased) and age; recipient age, race, history of diabetes, hepatitis C serostatus, and DGF; and cold ischemic time.

Kidney graft survival by risk factor and human immunodeficiency virus (HIV) status. Death-censored graft survival (DCGS) rates by HIV status among recipients of kidneys from donors 50 years or older (A) and from donors younger than 50 years (B). The DCGS rates by HIV status among transplant recipients who developed delayed graft function (DGF) (C) and those who did not develop DGF (D). Each panel contains a graphic representation of the Kaplan-Meier survival function generated from the matched control data set. HIV-positive recipients (cases) and HIV-negative recipients (controls) were matched on donor type (living or deceased) and age; recipient age, race, history of diabetes, hepatitis C serostatus, and DGF; and cold ischemic time.

Table 1. 
Demographic Characteristics Among HIV-Positive and HIV-Negative Kidney Transplant Recipientsa
Demographic Characteristics Among HIV-Positive and HIV-Negative Kidney Transplant Recipientsa
Table 2. 
Risk Factors for Kidney Graft Loss Among HIV-Positive Kidney Transplant Recipients
Risk Factors for Kidney Graft Loss Among HIV-Positive Kidney Transplant Recipients
1.
UNAIDS, AIDS Epidemic Update 2006. Geneva, Switzerland UNAIDS2006;
2.
Centers for Disease Control and Prevention, HIV/AIDS Surveillance Report. Atlanta, GA Centers for Disease Control and Prevention2006;
3.
Wyatt  CMMurphy  B Kidney transplantation in HIV-infected patients.  Semin Dial 2005;18 (6) 495- 498PubMedGoogle ScholarCrossref
4.
Kumar  MSSierka  DRDamask  AM  et al.  Safety and success of kidney transplantation and concomitant immunosuppression in HIV-positive patients.  Kidney Int 2005;67 (4) 1622- 1629PubMedGoogle ScholarCrossref
5.
Selik  RMByers  RH  JrDworkin  MS Trends in diseases reported on U.S. death certificates that mentioned HIV infection, 1987-1999.  J Acquir Immune Defic Syndr 2002;29 (4) 378- 387PubMedGoogle ScholarCrossref
6.
Ahuja  TSGrady  JKhan  S Changing trends in the survival of dialysis patients with human immunodeficiency virus in the United States.  J Am Soc Nephrol 2002;13 (7) 1889- 1893PubMedGoogle ScholarCrossref
7.
Stock  PGRoland  ME Evolving clinical strategies for transplantation in the HIV-positive recipient.  Transplantation 2007;84 (5) 563- 571PubMedGoogle ScholarCrossref
8.
Hossain  MMCoull  JJDrusano  GLMargolis  DM Dose proportional inhibition of HIV-1 replication by mycophenolic acid and synergistic inhibition in combination with abacavir, didanosine, and tenofovir.  Antiviral Res 2002;55 (1) 41- 52PubMedGoogle ScholarCrossref
9.
Karpas  ALowdell  MJacobson  SKHill  F Inhibition of human immunodeficiency virus and growth of infected T cells by the immunosuppressive drugs cyclosporin A and FK 506.  Proc Natl Acad Sci U S A 1992;89 (17) 8351- 8355PubMedGoogle ScholarCrossref
10.
Roy  JPaquette  JSFortin  JFTremblay  MJ The immunosuppressant rapamycin represses human immunodeficiency virus type 1 replication.  Antimicrob Agents Chemother 2002;46 (11) 3447- 3455PubMedGoogle ScholarCrossref
11.
Dummer  JSErb  SBreinig  MK  et al.  Infection with human immunodeficiency virus in the Pittsburgh transplant population: a study of 583 donors and 1043 recipients, 1981-1986.  Transplantation 1989;47 (1) 134- 140PubMedGoogle ScholarCrossref
12.
Qiu  JTerasaki  PIWaki  KCai  JGjertson  DW HIV-positive renal recipients can achieve survival rates similar to those of HIV-negative patients.  Transplantation 2006;81 (12) 1658- 1661PubMedGoogle ScholarCrossref
13.
Granville  DJTashakkor  BTakeuchi  C  et al.  Reduction of ischemia and reperfusion-induced myocardial damage by cytochrome P450 inhibitors.  Proc Natl Acad Sci U S A 2004;101 (5) 1321- 1326PubMedGoogle ScholarCrossref
14.
Bhagani  SSweny  PBrook  G Guidelines for kidney transplantation in patients with HIV disease.  HIV Med 2006;7 (3) 133- 139PubMedGoogle ScholarCrossref
15.
Frassetto  LABrowne  MCheng  A  et al.  Immunosuppressant pharmacokinetics and dosing modifications in HIV-1 infected liver and kidney transplant recipients.  Am J Transplant 2007;7 (12) 2816- 2820PubMedGoogle ScholarCrossref
Resident's Forum
January 19, 2009

Renal Transplant in HIV-Positive Patients: Long-term Outcomes and Risk Factors for Graft Loss

Author Affiliations

Author Affiliations:Division of Transplantation, Department of Surgery (Drs Locke, Montgomery, Warren, and Segev), and Division of Infectious Diseases, Department of Medicine (Dr Subramanian), Johns Hopkins Medical Institutions, Baltimore, Maryland.

 

RICHARD D.SCHULICKMD

Arch Surg. 2009;144(1):83-86. doi:10.1001/archsurg.2008.508
Abstract

In the highly active antiretroviral therapy era of improved survival for patients living with human immunodeficiency virus (HIV), chronic kidney disease now accounts for more than 10% of HIV-related deaths. The role of kidney transplant among HIV-positive patients with end-stage renal disease is under consideration, but concerns remain regarding allocation of kidneys to these patients when long-term benefit has not been firmly established. We evaluated 39 501 patients undergoing a renal transplant between January 1, 2004, and June 30, 2006, identified through the United Network for Organ Sharing national registry and found that, although long-term allograft survival is lower among HIV-positive recipients, controllable risk factors may explain this disparity. With proper donor selection and transplant recipient management, including the avoidance of prolonged cold ischemic time, use of living donors, and determination of optimal immunosuppression dosing before transplant, long-term graft survival comparable to that in HIV-negative patients can be achieved.

During the past decade, the human immunodeficiency virus (HIV) epidemic in the United States has changed markedly. Introduction of highly active antiretroviral therapy (HAART) has resulted in an 80% decrease in HIV death rates,1,2and chronic diseases resulting from HIV have replaced opportunistic infections as the leading cause of death among HIV-infected patients.3In fact, HIV-associated nephropathy is now the third leading cause of end-stage renal disease (ESRD) among African Americans,4and chronic kidney disease accounts for more than 10% of HIV-related deaths.5Traditionally, HIV infection has been considered an absolute contraindication to solid organ transplant. However, in the context of improved survival,6the role of renal transplant (RT) among HIV-positive patients is currently being revisited.7

Concerns have been raised about the potential additive effect of immunosuppression agents and HIV on the risk for opportunistic infections and malignant neoplasms and the potential for acceleration of HIV infection in the setting of decreased immune surveillance. However, several studies8-10have demonstrated the ability of calcineurin inhibitors, mycophenolate mofetil, and sirolimus to inhibit the replication of HIV in vitro, and other studies11have suggested that progression to AIDS is unaffected or even delayed in patients receiving cyclosporine-based immunosuppression. Although these data are encouraging, concerns also remain regarding allocation of kidneys to HIV-positive patients when long-term benefit has not been firmly established, particularly in the context of an ongoing organ shortage.3

The goal of the study reported herein was to critically evaluate long-term outcomes among HIV-positive patients undergoing RT using the United Network for Organ Sharing (UNOS) national registry.

Methods

We analyzed adult patients undergoing primary RT reported in the UNOS Standard Transplant Analysis and Research Files. We evaluated 39 501 patients undergoing RT between January 1, 2004, and June 30, 2006, and excluded (1) pediatric patients (<18 years old) (n = 2036) and (2) adult patients who underwent a multiorgan transplant (n = 873). One-year death-censored graft survival (DCGS) was the primary outcome, and 1-year patient survival was the secondary outcome.

Both DCGS and patient survival were estimated using the Kaplan-Meier method, and survival curves were compared using the log-rank test. Exploratory data analysis was used to identify differences in the demographic backgrounds among HIV-positive and HIV-negative patients undergoing RT. Covariates associated with graft loss among HIV-positive patients were included in a matched control analysis (5 HIV-negative matched controls for each HIV-positive patient), matching on donor type (living or deceased) and age; recipient age, race, history of diabetes mellitus, hepatitis C virus, and development of delayed graft function (DGF); and cold ischemic time (CIT).

Results

A total of 36 492 HIV-negative and 100 HIV-positive patients undergoing RT met the inclusion criteria. The HIV-positive patients were more likely to be African American, to be hepatitis C virus positive, to receive a deceased-donor kidney, and to develop DGF (Table 1). The HIV-negative patients undergoing RT were more likely to have a history of diabetes.

No difference was found in patient survival among HIV-positive compared with HIV-negative patients (95.4% vs 96.2%; P = .32). In contrast, DCGS was significantly lower among HIV-positive patients (87.9% vs 94.6%; P = .03). Among HIV-positive patients, donor age and hypertension history, CIT of 16 hours or longer, and development of DGF were associated with more than a 4-fold increase in allograft loss (Table 2). However, even after performing a matched control analysis in which cases (HIV positive) and controls (HIV negative) were matched on multiple factors associated with graft loss, HIV-positive patients continued to have lower DCGS (85.2% vs 94.1%; P = .05).

Detailed subgroup analyses within the matched control data set showed several trends that may explain the lower DCGS rates in HIV-positive patients. The HIV-positive patients had lower DCGS rates when undergoing transplants with grafts from donors 50 years or older (59.9% vs 89.9%; P = .05) but no difference when undergoing transplants with grafts from younger donors (93.2% vs 95.4%; P = .42) (Figure, A and B). Furthermore, among those patients who developed DGF, HIV-positive patients had worse DCGS rates than did HIV-negative patients (61.1% vs 84.2%; P = .11) (Figure, C), whereas among patients who did not develop DGF, the DCGS rates were similar between HIV-positive and HIV-negative patients (95.9% vs 96.6%; P = .51) (Figure, D). Not surprisingly, among HIV-positive patients, prolonged CIT (18.2% with CIT <16 hours vs 29% with CIT ≥16 hours) and deceased-donor kidneys (29.2% deceased vs 8.8% living) were associated with higher incidences of DGF.

Comment

With the advent of HAART, HIV-positive patients are living longer and are developing more chronic diseases; as a result, kidney disease is now a major cause of mortality among these patients. In the context of improved survival, RT has reemerged as a potential treatment option for HIV-positive patients with ESRD.12Our results suggest that HIV-positive serostatus has a negative long-term effect on kidney graft survival. However, the disparity in outcomes between HIV-positive and HIV-negative recipients appears to be explained by several risk factors, in particular, donor age and DGF. In fact, HIV-positive patients who receive a kidney from a donor younger than 50 years have DCGS rates equivalent to their HIV-negative counterparts. Furthermore, HIV-positive patients do not tolerate DGF as well as their HIV-negative counterparts, as demonstrated by a 20% lower DCGS rate at 1 year.

This increased susceptibility to the adverse effects of DGF among HIV-positive patients undergoing RT may be in part explained by their increased risk for calcineurin inhibitor nephrotoxic effects.4,13In particular, calcineurin inhibitors are metabolized via the cytochrome P450 system, and protease inhibitors interfere with the cytochrome P450 system. The interaction of a common immunosuppressant medication and a common component of HAART increases the risk among HIV-positive patients for the development of nephrotoxic effects and ultimately DGF. A 4-week trial of immunosuppression before transplant with therapeutic drug monitoring has been recommended in HIV-positive patients.14When such a trial is not possible, careful dosing of immunosuppressant medications based on anticipated pharmacokinetic interactions with HAART is indicated.15

We must emphasize that these results are preliminary and limited by the data available for analysis. Currently, our center is a part of a prospective multicenter trial to evaluate the safety and efficacy of RT in HIV-positive individuals. The goal of this trial is to collect more detailed information about HIV-positive patients so that the impact of transplant immunosuppression and HAART on long-term outcomes, including patient and graft survival and infectious complications, can be better understood.

Although preliminary, these results were generated from the largest available RT data set and provide new insight into the evolving role of RT in the treatment of HIV-positive patients with ESRD. Our results suggest that, with proper donor selection and transplant recipient management, including the avoidance of prolonged CIT, use of living donors, and determination of optimal immunosuppression dosing before transplant, HIV-positive patients undergoing RT can achieve long-term graft survival comparable to that in HIV-negative patients.

Correspondence:Dorry L. Segev, MD, Division of Transplantation, Department of Surgery, Johns Hopkins Medical Institutions, 600 N Wolfe St, Harvey 611, Baltimore, MD 21287 (dorry@jhmi.edu).

Accepted for Publication:May 12, 2008.

Author Contributions:Study concept and design: Locke, Montgomery, and Segev. Acquisition of data: Locke and Segev. Analysis and interpretation of data: Locke, Warren, Subramanian, and Segev. Drafting of the manuscript: Locke. Critical revision of the manuscript for important intellectual content: Locke, Montgomery, Warren, Subramanian, and Segev. Statistical analysis: Locke and Segev. Administrative, technical, and material support: Locke. Study supervision: Montgomery, Warren, Subramanian, and Segev.

Financial Disclosure:None reported.

Funding/Support:The UNOS National Data Registry is supported by Health Resources and Services Administration contract 231-00-0115.

Disclaimer:The analyses described are the responsibility of the authors alone and do not necessarily reflect the views or policies of the US Department of Health and Human Services. Mention of trade names, commercial products, or organizations do not imply endorsement by the US government.

References
1.
UNAIDS, AIDS Epidemic Update 2006. Geneva, Switzerland UNAIDS2006;
2.
Centers for Disease Control and Prevention, HIV/AIDS Surveillance Report. Atlanta, GA Centers for Disease Control and Prevention2006;
3.
Wyatt  CMMurphy  B Kidney transplantation in HIV-infected patients.  Semin Dial 2005;18 (6) 495- 498PubMedGoogle ScholarCrossref
4.
Kumar  MSSierka  DRDamask  AM  et al.  Safety and success of kidney transplantation and concomitant immunosuppression in HIV-positive patients.  Kidney Int 2005;67 (4) 1622- 1629PubMedGoogle ScholarCrossref
5.
Selik  RMByers  RH  JrDworkin  MS Trends in diseases reported on U.S. death certificates that mentioned HIV infection, 1987-1999.  J Acquir Immune Defic Syndr 2002;29 (4) 378- 387PubMedGoogle ScholarCrossref
6.
Ahuja  TSGrady  JKhan  S Changing trends in the survival of dialysis patients with human immunodeficiency virus in the United States.  J Am Soc Nephrol 2002;13 (7) 1889- 1893PubMedGoogle ScholarCrossref
7.
Stock  PGRoland  ME Evolving clinical strategies for transplantation in the HIV-positive recipient.  Transplantation 2007;84 (5) 563- 571PubMedGoogle ScholarCrossref
8.
Hossain  MMCoull  JJDrusano  GLMargolis  DM Dose proportional inhibition of HIV-1 replication by mycophenolic acid and synergistic inhibition in combination with abacavir, didanosine, and tenofovir.  Antiviral Res 2002;55 (1) 41- 52PubMedGoogle ScholarCrossref
9.
Karpas  ALowdell  MJacobson  SKHill  F Inhibition of human immunodeficiency virus and growth of infected T cells by the immunosuppressive drugs cyclosporin A and FK 506.  Proc Natl Acad Sci U S A 1992;89 (17) 8351- 8355PubMedGoogle ScholarCrossref
10.
Roy  JPaquette  JSFortin  JFTremblay  MJ The immunosuppressant rapamycin represses human immunodeficiency virus type 1 replication.  Antimicrob Agents Chemother 2002;46 (11) 3447- 3455PubMedGoogle ScholarCrossref
11.
Dummer  JSErb  SBreinig  MK  et al.  Infection with human immunodeficiency virus in the Pittsburgh transplant population: a study of 583 donors and 1043 recipients, 1981-1986.  Transplantation 1989;47 (1) 134- 140PubMedGoogle ScholarCrossref
12.
Qiu  JTerasaki  PIWaki  KCai  JGjertson  DW HIV-positive renal recipients can achieve survival rates similar to those of HIV-negative patients.  Transplantation 2006;81 (12) 1658- 1661PubMedGoogle ScholarCrossref
13.
Granville  DJTashakkor  BTakeuchi  C  et al.  Reduction of ischemia and reperfusion-induced myocardial damage by cytochrome P450 inhibitors.  Proc Natl Acad Sci U S A 2004;101 (5) 1321- 1326PubMedGoogle ScholarCrossref
14.
Bhagani  SSweny  PBrook  G Guidelines for kidney transplantation in patients with HIV disease.  HIV Med 2006;7 (3) 133- 139PubMedGoogle ScholarCrossref
15.
Frassetto  LABrowne  MCheng  A  et al.  Immunosuppressant pharmacokinetics and dosing modifications in HIV-1 infected liver and kidney transplant recipients.  Am J Transplant 2007;7 (12) 2816- 2820PubMedGoogle ScholarCrossref
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