Highly active antiretroviral therapy (HAART) has had a dramatic positive impact on the survival of HIV-infected individuals (1). However, the prevalence of kidney disease among individuals infected with HIV is increasing (2, 3), and the survival of HIV-infected individuals with end-stage renal disease and managed with dialysis therapy is lower than that of matched HIV-negative individuals (4). With respect to renal transplantation, the understandable reluctance to use immunosuppressive therapy in patients with HIV and the striking disparity between organ supply and demand have functioned to restrain organ transplantation in this patient population. Fortunately, thoughtful reconsiderations of the risks involved (reviewed in 5) have resulted in a welcome foray into providing kidney or liver allografts to HIV-infected patients (6–9). Indeed, the evolving literature supports the strategy of renal transplantation in carefully selected HIV-infected recipients (Table 1).
Major challenges exist in the management of HIV-infected organ graft recipients. A consistent finding across studies, perhaps counterintuitive, is the high incidence of acute rejection (AR) in the HIV-infected recipients (6, 9–11). Whether HIV-related perturbations to the immune system, the difficulties in maintaining therapeutic concentrations of calcineurin inhibitors in the context of drugs administered to control HIV replication, and/or the general reluctance to use lymphocyte-depleting induction agents contribute to the high rates of AR compared with the 12% reported in the U.S. Scientific Registry of Transplant Recipients (12) remain unresolved.
We examined the efficacy of a novel corticosteroid sparing regimen (novel for HIV-infected recipients) composed of antithymocyte globulin as the primary induction agent, intravenous methylprednisolone during postoperative days 0 to 4 only, and maintenance therapy with tacrolimus, mycophenolate mofetil, and no prednisone. This regimen initiated at our center in November 2001 originally for low-risk living-related donor renal allografts has been found to be associated with a low AR rate (13). Because of this low incidence of AR and because induction with antithymocyte globulin is associated with a lower AR rate compared with induction with monoclonal antibodies directed at CD25 (14, 15), we considered it reasonable to investigate the safety and efficacy of antithymocyte globulin induction and early steroid withdrawal protocol in HIV-infected recipients of kidney allografts. Our approach was also informed by considerations that steroid sparing regimens may help reduce adverse cardiovascular outcomes (16). The salutatory impact on cardiovascular outcomes is significant because cardiovascular diseases have emerged as a major cause of mortality and morbidity in HIV-infected patients (17) and HAART increases risk of myocardial infarction (18).
Generalized immune activation is a key feature of HIV infection that continues despite sustained antiretroviral therapy (19, 20). To begin to resolve the immune consequences of an antithymocyte induction and early corticosteroid withdrawal protocol in HIV-infected recipients, we performed urinary cell mRNA profiling and measured levels of mRNA encoding proteins implicated in innate immunity and adaptive immunity. We and others have shown that renal allograft rejection can be defined noninvasively by measurement of urinary cell mRNA levels of a panel of mechanistically related genes (21–30). Importantly, in a prospective multicenter trial composed of 485 renal allograft recipients, we also found that urinary cell mRNA profiles of allograft recipients distinguish those who develop AR from those with stable allograft function and whose clinical status does not require clinically indicated (for-cause) biopsies during the first 12 months of transplantation (31).
Herein, we report the excellent clinical outcomes, albeit short-term, observed with an early corticosteroids withdrawal protocol, and demonstrate that urinary cell mRNA profiles of HIV-infected recipients are indistinguishable from the profiles found in HIV-negative recipients with stable graft function and normal biopsy results.
Kidney Allograft Recipients
Between May 2006 and May 2010, 11 consecutive HIV-infected patients received kidney allografts at our institution (Table 2). All patients were being managed with hemodialysis therapy before transplantation and were continued on their HAART after transplantation with HAART resumed on the same day of transplantation in six recipients, on posttransplantation day 1 in three recipients, and on posttransplantation day 2 in two recipients. Survivors (10 of 11 patients) were followed for a median (range) duration of 44.5 (26–73) months. At the time of data analysis, all 10 patients had completed 2 years and 7 patients had completed 3 years of follow-up.
Patient and Kidney Allograft Survival
All patients were alive at 1 year after transplantation. One male patient died 17 months after the kidney transplant procedure. He was 60 years old with a history of diabetes mellitus type II and hypertension and was found dead at his home. The patient was seen at our posttransplantation clinic 1 month before his death and had no specific complaints. His kidney graft function was stable with serum creatinine level of 1.09 mg/dL. The cause of death was thought to be due to cardiovascular event. The 3-year Kaplan-Meier patient survival estimate was 90% (95% confidence interval [CI], 72%–100%; Fig. 1A). One-year allograft survival was 91% (95% CI, 74%–100%) with 1 of the 11 patients not recovering renal function after transplantation (primary nonfunction) and returning to dialysis. Another patient had allograft failure 24 months after transplantation following an episode of AR at 16 months after transplantation. The 3-year death-censored allograft survival was 81% (95% CI, 58%–100%; Fig. 1B).
One of 11 patients experienced a mixed AR (Banff acute antibody-mediated rejection, grade II and acute T-cell–mediated rejection, grade IB) at 3 weeks after transplantation and another patient developed a mixed AR (Banff acute antibody-mediated rejection, grade II and acute T-cell–mediated rejection grade IA) at 16 months after transplantation. The incidence of AR at 1 year after transplantation was 9% (95% CI, 0%–26%). The 3-year Kaplan-Meier estimate of AR was 18% (95% CI, 0%–41%; Fig. 1C).
The two AR episodes were treated with pulse methylprednisolone, intravenous immunoglobulin, and plasmapheresis and both grafts failed despite antirejection therapy. The first patient with mixed AR at 3 weeks after transplantation never recovered allograft function and the second patient with mixed AR at 16 months after transplantation responded to treatment initially but his allograft failed eventually and was returned to dialysis 8 months after the incident rejection episode.
All patients received tacrolimus and all were receiving protease inhibitors (PI; n=7) or nonnucleoside reverse transcriptase inhibitors (NNRTI; n=10). At 1 year following transplantation, only 4 of 10 HIV-positive kidney recipients were on the standard twice-daily tacrolimus regimen to maintain therapeutic tacrolimus trough levels. One patient required a daily dose, one needed alternate day dosing, and in the remaining four patients, tacrolimus dosing needed to be spaced once every 5 to 7 days to maintain tacrolimus trough levels. The mean±SD tacrolimus drug trough levels were 9.3±3.7, 9.0±3.5, 7.8±1.9, 6.9±2.9, and 5.8±1.9 ng/mL, respectively, at 1, 3, 6, 9, and 12 months after transplantation (Fig. 1D).
Tacrolimus Pharmacokinetic Studies
We performed pharmacokinetic profiling of tacrolimus on two kidney transplant recipients who were on PI-based HAART regimen. Patient 1 was on atazanavir and patient 2 was on tipranavir and ritonavir. The first patient required 1.5 mg tacrolimus every 12 hr, whereas the second patient required 0.5 mg every 72 hr to achieve therapeutic level (see Figure S1, SDC,http://links.lww.com/TP/A758). Although both patients were on PI-based HAART regimen, they differed in tacrolimus dose requirement and dosing frequency to maintain tacrolimus therapeutic levels, suggesting that tacrolimus-HAART interactions are difficult to predict even within the same category of HAART medicines.
The mean±SD glomerular filtration rate, estimated using the four-parameter Modification of Diet in Renal Disease formula, was 31±13, 57±22, 56±21, 57±20, and 66±23 mL/min/1.73 m2, respectively, at 1, 3, 6, 9, and 12 months after transplantation (Fig. 1E).
All 11 HIV-positive recipients had undetectable HIV mRNA in their plasma 20 (5–73) months (median [range]) before transplantation. Two recipients had detectable viral copies after transplantation: 13,394 and 297 copies at 14 and 15 months, respectively, after transplantation. Both of them had undetectable HIV mRNA at their last follow-up. All 10 survivors had undetectable HIV mRNA in their plasma at a median (range) follow-up of 43 (26–73) months after transplantation.
Six of the 11 kidney recipients with a functioning allograft (55%) had eight episodes of infection requiring hospitalization. The six patients were diagnosed with bacterial pyelonephritis (n=2 patients), Clostridium difficile diarrhea (n=1), pneumonia (n=1), lung abscess (n=1), and cervical spine osteomyelitis (n=1). Five of the six patients had their infections within the first year of transplantation. The patient who developed the lung abscess was also diagnosed with pulmonary tuberculosis 5 months later, and the patient with C. difficile diarrhea developed gram-negative bacteremia 12 months later. An additional patient developed pneumonia 26 months after the transplant procedure and while on dialysis. All patients who developed infections requiring hospitalization were successfully treated.
Two kidney recipients had three cancers (one patient with anal cancer and Kaposi’s sarcoma and another patient with prostate cancer) before the kidney transplant procedure and were cleared by their oncologists for kidney transplantation. The patient with anal cancer and Kaposi’s sarcoma developed a new squamous cell carcinoma of the scalp at 3 months after transplantation. Another patient with no prior cancer history developed penile squamous intraepithelial cancer 28 months after transplantation. Both patients were treated successfully and are alive 23 and 10 months, respectively, following therapy.
Cardiovascular Risk Factors
We examined whether factors that have been associated with cardiovascular disease changed significantly following transplantation. Longitudinal measurement of cardiovascular risk factors showed no significant changes compared with pretransplantation values. Table S1 (see SDC,http://links.lww.com/TP/A758) provides longitudinal data of the parameters analyzed and show that there were no changes in the weight of the recipients (P=0.97, repeated-measures ANOVA), systolic (P=0.24) or diastolic (P=0.82) blood pressure, lipid profile, or the number of blood pressure or lipid-lowering medications. Importantly, there were no cases of new-onset diabetes mellitus after transplantation (NODAT); in fact, a marginal improvement in blood glucose levels, compared with pretransplantation levels, was observed (113 vs. 97 mg/dL; P=0.09).
Levels of mRNA in Urinary Cells
We obtained about 50 mL urine from 9 HIV-infected kidney graft recipients and from 22 HIV-negative kidney graft transplant recipients for urinary cell mRNA profiling. We designed oligonucleotide primers and fluorogenic probes (see Table S2, SDC,http://links.lww.com/TP/A758) for the absolute quantification of levels of mRNA and measured urinary cell levels of 17 mRNAs encoding proteins implicated in innate and/or adaptive immunity.
Unsupervised hierarchical clustering analysis of the absolute levels of 17 mRNAs quantified in the HIV-infected recipients and HIV-negative recipients showed no clustering of kidney graft recipients into those who were infected with HIV or not (Fig. 2).
Urinary cell levels of mRNA for Toll-like receptor-4 (CD284; P=0.12), complement component 3 (P=0.20), C5 (P=0.37), properdin (P=0.06), and complement regulatory proteins CD46 (P=0.40) or CD55 (P=0.06) were not significantly different between the HIV-infected and the HIV-negative kidney graft recipients (Fig. 3). Urinary cell levels of mRNA for the cell surface proteins CD4 (P=0.35), CD8 (P=0.31), and CD3 (P=0.84), T-cell coinhibitory receptor CTLA4 (P=0.62), CD25 (P=0.12), regulatory T-cell specification factor Foxp3 (P=0.81), B-cell CD20 (P=0.11), chemokine IP-10 (P=0.37), and the cytotoxic attack molecules perforin (P=0.53) or granzyme B (P=0.17) were also not significantly different between the two groups (Fig. 3).
We have reported that BKV replication can be ascertained by measurement of BKV VP1 mRNA in urinary cells (32). We examined whether BKV replication, an index of overimmunosuppression, is more frequent in HIV-infected recipients than the HIV-negative recipients. BKV VP1 mRNA was not detected in the urinary cells from either the HIV-infected recipients or the HIV-negative recipients.
We show in our single-center study of HIV-infected kidney graft recipients that an early corticosteroid withdrawal immunosuppression regimen is associated with excellent patient and kidney graft survival rates and that the AR rate is numerically lower than that reported in studies of HIV-infected recipients managed with immunosuppressive regimens that have included maintenance corticosteroids therapy.
Rationale for and Outcomes with the Early Corticosteroid Withdrawal Protocol
The prolonged use of corticosteroids in kidney graft recipients is associated with a plethora of complications, including hypertension, new-onset diabetes, and hypercholesterolemia (33, 34). On the other hand, early corticosteroid withdrawal has been found beneficial over the long term in HIV-negative recipients (35, 36). As HIV-infected persons are living longer (1, 37), avoidance or minimization of steroids may be beneficial in HIV-infected recipients.
In the multicenter trial of 150 HIV-infected kidney recipients, all treated with a steroid-based triple-drug immunosuppression regimen, Stock et al. (9) observed 90% kidney allograft survival and 95% patient survival at 1 year (Table 1). Touzot et al. (38) reported 98% graft survival and 100% patient survival in 27 patients who received their kidney grafts in five transplant centers in Paris, and Mazuecos et al. (39) reported 85% graft survival and 100% patient survival in 20 patients who received their renal transplants in multiple centers in Spain. Our 1-year allograft graft survival rate of 91% and patient survival rate of 100%, accomplished with an early corticosteroid withdrawal regimen, compares favorably with the earlier reports. Because of the small sample size of the current study (n=11 HIV-infected recipients) and the resultant wide CIs of the outcome measures reported here, the high efficacy observed in this first investigation of early corticosteroid withdrawal regimen must be interpreted with due caution.
Low Incidence of Acute Rejection
The 1-year incidence of AR in our HIV-infected kidney recipients was 9%. In the multicenter trial (9), the incidence of AR at 1 year was 31%. Patient selection and the tacrolimus trough levels at 1 month were similar between the multicenter cohort and our study. However, all our kidney recipients received antibody induction therapy compared with 83% in the multicenter trial. Also, all our patients received tacrolimus; only 66% of the patients in the multicenter trial received tacrolimus and 12% were not on calcineurin inhibitor-based regimen. In the study by Touzot et al. (38), all 27 HIV-infected kidney recipients received induction therapy and the incidence of AR was 15% at 1 year. It is tempting to hypothesize that the universal use of induction therapy and tacrolimus-based immunosuppression contributed to the reduced incidence of AR in our study. In this regard, the early corticosteroid withdrawal regimen used in this study was associated with a 6.7% incidence of AR in 634 HIV-negative kidney recipients treated at our center (13). In a recent study, the 1-year incidence of AR was 13% with antithymocyte globulin and 20% with basiliximab (40).
Drugs belonging to the PI or NNRTI group of HAART are substrates for CYP3A4 enzyme that metabolizes tacrolimus and can induce, inhibit, or have a mixed effect on the enzyme (41). Our tacrolimus pharmacokinetic profiles of the two HIV-infected kidney graft recipients suggest that tacrolimus-HAART interactions are difficult to predict even within the same category of HAART medicines. Close monitoring of drug levels and individualization of drug dosages may be of considerable importance.
Infection and malignancy are dreaded posttransplantation complications. We did not observe progression of HIV in our kidney recipients and the lack of detection of HIV viral copies at 24 months after transplantation in our study mimics the finding from the multicenter trial (9). The incidence of infection in our study was not different from that in the Induction with Tacromilus study of kidney recipients without HIV infection who all received antibody induction and managed with or without an early steroid withdrawal protocol (40).
One of the HIV-infected recipients developed a new squamous cell carcinoma of the scalp at 3 months after transplantation and another developed penile squamous intraepithelial cancer 28 months after transplantation. Malignancy was successfully managed and both patients are alive currently, one 23 months and the other 10 months after therapy.
Lack of Deterioration of Cardiovascular Risk Profile
Longitudinal measurement of cardiovascular risk factors showed no significant changes compared with pretransplantation values and there were no cases of NODAT. These observations are consistent with the recent meta-analysis showing reductions in the risk of hypertension, new-onset diabetes, and hypercholesterolemia with steroid avoidance or withdrawal after kidney transplantation (34). Because we did not have a control group maintained on corticosteroids, we are not able to attribute the lack of deterioration in cardiovascular risk factors and the 0% incidence of NODAT to early steroid withdrawal.
Urinary Cell mRNA Profiles Suggestive of Lack of Intragraft Inflammation
HIV infection, even with suppressive antiretroviral therapy, is characterized by chronic generalized immune activity (19, 20). In this study, we demonstrate that the urinary cell profiles of HIV-infected kidney transplant recipients are indistinguishable from that of HIV-negative kidney graft recipients with stable graft function and normal biopsy results. Our findings that the mRNA levels of proteins implicated in innate and adaptive immunity are not significantly higher in the HIV-infected recipients compared with the HIV-negative recipients suggest that the state of the HIV-infected recipients managed with the early corticosteroid withdrawal regimen is not one of chronic immune activation. It also appears that the use of thymoglobulin induction is not associated with profound depletion of major T-cell subsets and B-cell populations in HIV-infected recipients because the levels of mRNA for CD3, CD4, CD8, CD25, and CD20 were not lower in the HIV-infected recipients compared with HIV-negative recipients. A lack of profound immunosuppression in the study cohort is also suggested by the absence of BKV replication in urine. Our finding that urinary cell Foxp3 mRNA level is not lower in the HIV-infected recipients compared with HIV-negative recipients suggests that posttransplantation immunosuppression did not completely deplete regulatory T cells.
Several limitations to our study must be acknowledged. Our study is composed of 11 patients only and the observed promising outcome measures need confirmation with a larger sample size. Second, the evolution of immune alterations in this study cohort was not analyzable due to the cross-sectional study design. Third, we did not perform surveillance biopsies to validate urinary cell mRNA profiling showing a lack of intragraft inflammation. These shortcomings, however, do not negate the supposition that an early corticosteroid withdrawal regimen for kidney transplantation in HIV-infected individuals is safe, well tolerated, and associated with immunologic profile indistinguishable from the profile observed in HIV-negative recipients with stable graft function and normal biopsy results.
MATERIALS AND METHODS
We reviewed charts to study the clinical course of 11 consecutive kidney transplant recipients infected with HIV who were managed with an early corticosteroid withdrawal immunosuppression protocol at our center. These recipients formed part of our institutional review board–approved early corticosteroid withdrawal immunosuppression protocol after kidney transplantation and urinary mRNA expression studies. Each individual provided a written informed consent for urinary cell mRNA expression profiling. The selection criteria used for transplanting patients infected with HIV, the details of medications, and the data collected for the study are provided in the SDC text (see http://links.lww.com/TP/A758).
Urinary Cell mRNA Expression Studies
We measured absolute levels of mRNAs encoding proteins implicated in innate and adaptive immunity. We isolated total RNA from the urinary cells and measured mRNA levels using preamplification enhanced real-time polymerase chain reaction assays. Additional details are provided in the SDC text and Table S2 (see SDC,http://links.lww.com/TP/A758).
We used Kaplan-Meier analysis to estimate patient survival, death-censored allograft survival, time to development of first episode of AR, and infection requiring hospitalization. The levels of mRNA in the urinary cells for each sample were normalized by the levels of 18S rRNA in the same sample. The overall gene expression pattern was analyzed by unsupervised hierarchical clustering. mRNA levels between groups were compared using Mann-Whitney U test. We used GraphPad Prism version 5.03 (GraphPad Software, La Jolla, CA) for statistical analyses.
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