Outcome predictors in African-American deceased-donor renal allograft recipients.

The relative importance of donor and recipient risk factors in predicting outcomes in African-American (AA) renal allograft recipients receiving contemporary immunosuppression, including early steroid withdrawal, has not been previously examined. We assessed the impact of 21 risk factors on five primary outcomes in 132 deceased-donor AA renal allograft recipients transplanted from July 2001 to August 2006 with follow-up 6-67 (mean 35 +/- 17) months by univariate and multivariate analysis. Thymoglobulin or basiliximab was given for induction, and mycophenolate mofetil with either tacrolimus or sirolimus (SRL) +/- prednisone for maintenance. Non-compliance accounted for 26% of graft loss (GL) and 19% of acute rejection (AR) episodes, and was more prevalent in patients who were HCV+ and those on prednisone. Delayed graft function remained a significant predictor of GL, but not via increased AR, and donor ethnicity emerged as an important predictor of patient death. De novo use of SRL resulted in increased AR, and only increased recipient age significantly predicted new-onset diabetes mellitus. Our preliminary results suggest the need for improvements in patient education, pre-transplant psychosocial assessment, and late post-transplant psychosocial support and can be utilized to help guide donor/recipient selection and tailor immunosuppressive management to optimize outcomes in this challenging group of patients.

Two-dose daclizumab induction in pediatric renal transplantation.

DCZ, an IL-2 receptor antagonist, has been widely used for induction therapy in pediatric and adult solid organ transplantation. Originally, it was recommended as a five-dose regimen; however, fewer doses may be efficacious and less costly for prevention of rejection. There is limited experience with the use of fewer doses in pediatric renal transplantation. We retrospectively reviewed the outcomes of 26 primary pediatric renal transplants performed at a single center between June 2004 and May 2007 receiving induction therapy with two-dose DCZ (1.5 mg/kg preoperatively and day seven post-transplant). Maintenance immunosuppression included tacrolimus, MMF, and prednisone in all patients. Forty-six percent were African American and 92% were deceased-donor transplants. After a mean follow-up of 17.8 +/- 7.5 months, acute rejection was noted in 11.5% and graft survival was 92.3%. CMV infection occurred in 11.5%, but no case of BK nephropathy or post-transplant lymphoproliferative disorder was observed. Our preliminary results suggest that induction therapy with two-dose DCZ was convenient, economical, and effective in preventing rejection episodes without an increase in adverse events or hospital stay. Larger randomized clinical trials with longer duration of follow-up are needed to more fully validate the use of this regimen in pediatric renal transplantation.

Preliminary experience with renal transplantation in HIV+ recipients: low acute rejection and infection rates.

BACKGROUND: Only four centers have reported their results with renal transplantation in human immunodeficiency virus (HIV)+ recipients on highly active antiretroviral therapy, and acute rejection (AR) rates have consistently ranged from 43% to 67%. METHODS: We examined the outcomes of eight adult HIV+ primary renal allograft recipients with median 15 (range 8-47) months follow-up with multiple other high-risk factors, including African American ethnicity, hepatitis C virus (HCV) positivity, long waiting times, prior sensitization, paucity of live donors, and delayed graft function. Our immunosuppressive protocol consisted of an anti-interleukin-2 receptor antibody for induction, and mycophenolate mofetil, cyclosporin A, and prednisone for maintenance. Initial and 3- to 6-month cyclosporin A trough level targets were 250 to 300 and 225 to 275 ng/mL, respectively, and mycophenolate mofetil dose was adjusted according to 2 to 4 week surveillance and subsequent as needed mycophenolic acid predose concentrations during the first 6 months. RESULTS: Patient and graft survival were 100% and 88%, respectively, with an AR rate of 13% and excellent renal function. No patients developed new-onset diabetes, opportunistic or other serious infections, malignancy, or progression of hepatitis C virus-related liver disease. Excellent suppression of HIV replication with maintenance of CD4 counts was noted in all cases. CONCLUSIONS: Our findings suggest that HIV+ patients on highly active antiretroviral therapy can undergo successful renal transplantation with a low incidence of both AR and AIDS-associated and non-AIDS associated infections, despite associated risk factors for poorer outcome. Our encouraging but preliminary results with this protocol will need to be verified in larger numbers of HIV+ renal allograft recipients with longer follow-up.

Preliminary experience with cinacalcet use in persistent secondary hyperparathyroidism after kidney transplantation.

BACKGROUND: There is limited experience with the use of cinacalcet in the treatment of persistent secondary hyperparathyroidism after kidney transplantation. METHODS: We retrospectively analyzed our experience in 18 renal allograft recipients who initiated cinacalcet therapy from 1 month to 23 years (median 3 years) posttransplantation and were maintained on the drug for 6 months. The daily dose was titrated from 30 mg up to a maximum of 180 mg to achieve a reduction in serum intact parathyroid hormone (PTH) levels. RESULTS: Sustainable, significant decreases in mean calcium and alkaline phosphatase were noted at 1 month and intact PTH by 3 months, with 50% of patients achieving at least a 30% drop in PTH levels at 6 months. Serum phosphorous increased at 6 months, whereas urine N-telopeptides decreased. There were no significant changes in serum osteocalcin, albumin, and hemoglobin levels. We did not observe a tachyphylaxis phenomenon. Two patients reported occasional nausea, but did not require medication discontinuation. Estimated glomerular filtration rate did decrease progressively over the 6-month period. CONCLUSION: Cinacalcet appears to be an effective drug for the treatment of posttransplant hypercalcemia due to persistent secondary hyperparathyroidism. Further studies with more patients and longer follow-up will be needed to better elucidate the efficacy/safety profile for this agent, particularly with regard to long-term bone histology and renal outcomes.

Intermediate-term outcomes with early steroid withdrawal in African-American renal transplant recipients undergoing surveillance biopsy.

BACKGROUND: There is a paucity of data regarding the use of early corticosteroid withdrawal (ESW) in African-American renal allograft recipients, and very few reports with >or=1 year follow-up in all patients. METHODS: We examined the outcomes of 57 African-American renal allograft recipients with minimum follow-up 12 months who did not receive maintenance steroids after day 4 posttransplant. All patients received thymoglobulin induction, mycophenolate mofetil, and initial tacrolimus (n = 48) or sirolimus (n = 9). RESULTS: Patient and graft survival were 98% and 96% at 1 year, and 95% and 89% over the entire follow-up period (mean, 23 +/- 8 months). Incidence of acute rejection and cytomegalovirus infection were 18% and 7%, respectively, with mean serum creatinine 1.6 +/- 0.5 and 1.7 +/- 0.9 mg/dL at 6 and 12 months. Of patients with functioning grafts, 84% remained steroid free at 1 year, of which 11 (24%) were also calcineurin inhibitor free. Twenty-seven patients underwent surveillance biopsy at 1 month and 28 at 12 months, with 15 surveyed at both time points. There were significant increases in only 2 of the 6 1997 Banff chronic allograft nephropathy (CAN) category scores in this subgroup, with all mean values remaining <1 (mild in severity) at 1 year. Overall, from 82% to 96% of the 12-month scores were

Induction therapy with basiliximab versus Thymoglobulin in African-American kidney transplant recipients.

BACKGROUND: It has been suggested that the use of antilymphocyte induction therapy in African-American (AA) renal transplant recipients reduces the risk of acute rejection (AR) and improves graft survival. It is not clear whether the efficacy of basiliximab (BSX) is different from that of Thymoglobulin (ATG) in this regard. METHODS: We retrospectively assessed the effect of induction therapy with BSX versus ATG in 88 AA renal allograft recipients receiving transplants at our center between July 2001 and June 2003 and followed for 19+/-7 months. All patients were maintained on mycophenolate mofetil, prednisone, and either tacrolimus or sirolimus. Study endpoints included patient and graft survival, graft function, and incidence of AR and cytomegalovirus infection. Regression models were used to evaluate the independent effect of each induction agent on these endpoints. RESULTS: Thirty-six patients received ATG, and 52 received BSX. The groups were comparable with regard to donor race and age, and recipient sex, body mass index, human leukocyte antigen (HLA) matching, and hepatitis C virus serostatus. The ATG group was younger, more likely to receive retransplant, had longer duration of end-stage renal disease and higher panel reactive antibody, and was less likely to receive live-donor organs. However, after adjusting for all these variables, graft outcomes, as well as renal function, were comparable between the two induction groups. We found that the degree of HLA mismatch, delayed graft function, and AR were the only significant predictors of graft loss. CONCLUSION: The results of our study suggest that the choice of induction agent may not have a major impact on graft outcomes in AA renal-allograft recipients.

Preliminary results with early corticosteroid withdrawal in African American renal allograft recipients.

BACKGROUND: There is a paucity of data regarding the use of steroid-avoidance immunosuppression (SAI) in African American (AA) renal allograft recipients, traditionally considered a high-risk subgroup of patients with higher reported rates of acute rejection and graft loss. METHODS: We compared the outcomes of 27 AA renal allograft recipients receiving SAI (SA group; mean follow-up period, 12 +/- 3 mo) with those of 20 patients receiving a steroid taper (ST group; 24 +/- 11 mo). In both groups, thymoglobulin was used for induction, and mycophenolate mofetil and tacrolimus were used for maintenance. Four doses of methylprednisolone were given on days 0 to 3. In the SA group no further steroids were given, whereas in the ST group a prednisone taper was continued thereafter. RESULTS: ST patients were more likely to have current panel reactive antibody titers greater than 10%, undergo retransplantation, and receive more doses of thymoglobulin. There were no significant differences between the SA and ST groups with regard to patient survival (96% vs 95%), graft survival (96% vs 90%), acute rejection (11% vs 14%), cytomegalovirus infection (7% vs 10%), posttransplant diabetes mellitus (11% vs 24%), or mean serum creatinine concentration at 6 months (1.6 vs 1.5 mg/dL), respectively, with a trend toward less percent weight gain in SA patients at 6 months (5% vs 11%, P = .06). CONCLUSIONS: SAI can produce excellent short-term results in AA kidney transplant patients when compared with a conventional ST protocol. Our results will need to be verified in larger numbers of patients with longer follow-up evaluation.

Does donor race still make a difference in deceased-donor African-American renal allograft recipients?

BACKGROUND: Prior studies have demonstrated that African-American (AA) donor kidneys are independently associated with an increased risk for graft loss. METHODS: We examined outcomes in comparable groups of AA deceased-donor (DD) kidney transplant patients receiving an AA donor (n=35) versus a Caucasian donor (C group; n=150) organ. RESULTS: There were no differences between AA and C groups in patient survival, new-onset diabetes, or BK nephropathy. The AA group demonstrated a significantly higher 6-month and overall incidence of acute rejection (AR), increased cytomegalovirus (CMV) infection, and decreased graft survival. Recurrent or de novo focal segmental glomerulosclerosis (FSGS) accounted for a significantly higher fraction of graft losses in the AA versus C group. CONCLUSIONS: AA DD renal allograft recipients have equivalent patient but decreased graft survival when transplanted with an AA versus C kidney using current immunosuppression. This may be the result of increased AR, CMV infection, and recurrence/development of FSGS.

Different patterns of cancer incidence among African American and Caucasian renal allograft recipients.

BACKGROUND: Little data are available regarding cancer incidence in separately analyzed African American renal allograft recipients, with no study examining in detail the incidence and relative distribution of individual post-transplant malignancies versus those occurring in Caucasians. METHODS: We compared the incidence of nonskin cancer occurring in 495 African Americans transplanted at our center from 1984 to 2007 and followed through June 2009 with that occurring in 11,155 patients in the Canadian Organ Replacement Registry transplanted from 1981 to 1998 and followed through December 1999, of which 97% were Caucasian. RESULTS: Despite a shorter follow-up, the overall incidence of nonskin cancer, as well as that of prostate, renal cell, pancreatic, and esophageal cancer, was significantly higher in the African American group. Cancers of the prostate and pancreas comprised a significantly higher fraction of neoplasms occurring in the African American group, whereas lip cancer did so in the Canadian Organ Replacement Registry group. CONCLUSION: In our pilot study, the overall incidence of nonskin cancers was higher in African American versus Caucasian renal allograft recipients, reflecting a significantly different relative distribution of cancer types that follows cancer incidence trends by race in the general population in several but not all cases. If verified in subsequent studies, these findings have important implications with regard to the need for transplant programs to tailor cancer education and pretransplant and post-transplant surveillance appropriately to the African American patient.

Equivalent outcomes with primary and retransplantation in African-American deceased-donor renal allograft recipients.

BACKGROUND: Graft survival following renal retransplantation has been inferior to that following primary allografting, particularly in African Americans (AAs) receiving deceased-donor (DD) kidneys. METHODS: Among 166 AA DD renal allograft recipients transplanted from July 2001 through July 2007, we compared the outcomes of 26 (16%) receiving a second graft with those of 140 primary cases. All patients received either thymoglobulin (ATG) or an IL-2 receptor antagonist for induction, and were maintained on either tacrolimus or sirolimus + mycophenolate mofetil +/- prednisone. RESULTS: When compared with primary transplants, regrafts received kidneys from older donors, were younger, more sensitized, more likely to receive ATG and to be maintained on prednisone, received more doses of ATG, and were less likely diabetic. There was no difference between primary and retransplant groups in overall patient or graft survival; incidence of acute rejection, CMV infection, BK nephropathy, or new-onset diabetes mellitus; and serum creatinine at 1 year. CONCLUSION: AA renal allograft recipients can undergo a second DD transplant with intermediate-term outcomes comparable to that of a primary graft, despite the presence of multiple immunologic and non-immunologic high-risk factors, by extending the course of ATG induction and continuing prednisone therapy in the vast majority of cases.

Intermediate-term outcomes of hepatitis C-positive compared with hepatitis C-negative deceased-donor renal allograft recipients.

BACKGROUND: Prior studies have yielded conflicting results concerning the impact of HCV on renal transplant outcomes. METHODS: We examined outcomes in comparable groups of predominantly African American hepatitis C virus (HCV)-positive (n = 34) and HCV-negative (n = 111) kidney transplant patients receiving contemporary immunosuppression. RESULTS: There was no difference in patient survival or acute rejection, but new-onset diabetes (NODM) was increased and graft survival decreased in the HCV-positive group, with increased graft loss secondary to noncompliance and Type I MPGN. The incidence of NODM among patients undergoing early corticosteroid withdrawal was 11% in both groups, while among those on prednisone, it was 47% in HCV-positive versus 25% in HCV-negative recipients. CONCLUSIONS: Deceased-donor HCV-positive renal allograft recipients have equivalent patient but decreased graft survival. Noncompliance and Type I MPGN play a role in producing this negative effect on graft outcome. Steroids may be required for HCV to exert its diabetogenicity in kidney transplant patients.

Intravenous immunoglobulin, HLA allele typing and HLAMatchmaker facilitate successful transplantation in highly sensitized pediatric renal allograft recipients.

The use of intravenous immunoglobulin (IVIG) in sensitized transplant candidates has resulted in reduced HLA antibody levels and shorter transplant wait times. In addition, the HLAMatchmaker program has been used to identify acceptable mismatches to permit transplantation in highly sensitized patients. We used IVIG desensitization in conjunction with high resolution HLA allele typing and HLAMatchmaker grading of donor offers to facilitate successful transplantation in two highly sensitized children who were awaiting second renal transplants. Both patients lost their initial transplant in <10 days to accelerated acute rejection, and were on dialysis for an average of 50 months with high panel reactive antibody (PRA) levels. They were started on monthly IVIG infusions (2 g/kg/dose). Within one wk following their third and fifth IVIG doses, both patients received a crossmatch compatible, deceased donor renal transplant selected by HLAMatchmaker as a suitable donor offer. Both patients remain rejection free with excellent renal function 19 and 15 months post-transplant, respectively. In conclusion, combining IVIG therapy and donor selection by HLA humoral epitope matching permitted successful transplantation of two highly sensitized children. Further studies in larger numbers of patients with longer follow-up are needed to determine the individual role played by, and relative importance of each component of this combined strategy.

Sirolimus exposure during the early post-transplant period reduces the risk of CMV infection relative to tacrolimus in renal allograft recipients.

INTRODUCTION: There are limited data regarding the role of individual maintenance immunosuppressive agents in the development of cytomegalovirus (CMV) infection. We examined the association between exposure to sirolimus (SRL) and risk of CMV infection after kidney transplantation when compared with tacrolimus (TCL). METHODS: This is a retrospective observational study of adult renal allograft recipients transplanted between 2001 and 2005 at our center. Patients received anti-lymphocyte antibody induction, and mycophenolate mofetil with either SRL or TCL +/- prednisone. D+/R- patients received valganciclovir 900 mg/d and CMV + patients 450 mg/d for three months. CMV infection was diagnosed with pp65 antigenemia testing prompted by clinical suspicion. RESULTS: A total of 14 Cases with CMV infection and 129 Controls were identified for primary analysis, and 11 D+/R- Cases and 19 D+/R- Controls for secondary analysis. The groups were comparable in both analyses, except for D+/R- serostatus in the primary analysis. All 14 Cases were on TCL for at least three months prior to diagnosis of CMV infection. In the primary analysis, zero Cases, but 30.2% and 34.9% of Controls (p = 0.009 and 0.004), and in secondary analysis, zero Cases, but 31.6% and 42.1% of Controls (p = 0.046 and 0.013), were on SRL at one and three months, respectively. In the primary analysis, zero Cases vs. 45 Controls (p = 0.004), and in secondary analysis, zero Cases vs. eight Controls (p = 0.013), were on SRL for at least three months early post-transplantation. CONCLUSION: These findings suggest that SRL as a component of a multidrug immunosuppressive regimen decreases the risk of CMV infection after kidney transplantation when compared with TCL.

Infectious complications after kidney transplantation: current epidemiology and associated risk factors.

BACKGROUND: The impact of newer immunosuppressive and antimicrobial prophylactic agents on the pattern of infectious complications following kidney transplantation has not been well studied. METHODS: This is an observational study in 127 adult recipients transplanted from 2001 to 2004. Patients received thymoglobulin (ATG) (50%) or basiliximab (50%) for induction and were maintained on mycophenolate mofetil, either tacrolimus (73%) or sirolimus (SRL) (27%), and prednisone (79%). Antimicrobial prophylaxis included perioperative cefazolin, trimethoprim/sulfamethaxazole for six months, valganciclovir for three months and nystatin for two months. Regression models were used to examine the association of various factors with infections. RESULTS: We observed 127 infections in 65 patients, consisting of urinary tract infection (UTI) (47%), viral infections (17%), pneumonia (8%) and surgical wound infections (7%). UTI was the most common infection in all post-transplant periods. Enterococcus spp. (33%) and Escherichia coli (21%) were the most prevalent uropathogens. Of six patients with cytomegalovirus infection, none had tissue-invasive disease. There were no cases of pneumocystis pneumonia or BK nephropathy. Six patients developed fungal infections. Two deaths due to disseminated Rhizopus and Candida albicans accounted for a 1.5% infection-related mortality. Retransplantation and ureteral stents were independently associated with UTI (OR=4.5 and 2.9, p=0.06 and 0.03, respectively), as were ATG and SRL with bacterial infections (OR=3.3 and 2.5, p=0.009 and 0.047, respectively). CONCLUSION: This study suggests that the use of newer immunosuppressive agents in recent years is associated with some changes in the epidemiology of post-transplant infections. Enterococci have become the predominant uropathogen. Invasive fungal infections, although rare, are often fatal.

Predictive value of human leucocyte antigen epitope matching using HLAMatchmaker for graft outcomes in a predominantly African-American renal transplant cohort.

The HLAMatchmaker program is based on the donor/recipient comparison of the polymorphic triplet amino-acid sequences of the antibody-accessible regions on the human leucocyte antigen (HLA) molecule. The previous reports on its predictive value for renal allograft outcomes are conflicting. We conducted a retrospective study in a predominantly African-American (AA) cohort (N = 101, 94% AA). HLA typing was performed by molecular methods and triplet matching using HLAMatchmaker. Study end points included graft survival and incidence of acute rejection. The relationship between the number of triplet mismatches (TMM) and the degree of HLA antigen MM was evaluated using Pearson's correlation coefficient. Logistic regression models were used to examine the association between triplet matching and the study end points. Kaplan-Meier and Cox proportional hazard models were used for graft survival analysis. The strongest relationship between the number of TMM and HLA antigen MM was observed for HLA-DQ (r = 0.88). The association between triplet matching at HLA-A, -B, -DR and -DRw HLA loci and the study end points was not statistically significant. However, after grouping, the unadjusted estimates of graft survival for those with more than 10 Class I TMM were significantly worse than the others (p = 0.03). Adjusting for the effect of donor source, recipient characteristics and the immunosuppressive regimen did not change this association (hazard ratio = 0.2, confidence interval = 0.04-1.1). We conclude that triplet matching using HLAMatchmaker can provide useful prognostic information in kidney transplantation and that more than 10 donor/recipient Class I HLA TMM is predictive of worse graft outcome.

Cytomegalovirus prophylaxis with valganciclovir in African-American renal allograft recipients based on donor/recipient serostatus.

There is a paucity of data examining the efficacy of valganciclovir (VGC) for cytomegalovirus (CMV) prophylaxis in kidney transplant patients, particularly with regard to utilization of a risk-stratified dosing regimen. Eighty adult African-American (AA) renal allograft recipients transplanted from November 3, 2001 to May 28, 2003 and followed for 22 +/- 8 months received VGC once daily for 90 d post-transplant dosed according to donor/recipient (D/R) serostatus: high risk (D+/R-) received 900 mg (n = 12); moderate risk (D+/R+, D-/R+) received 450 mg (n = 60); and low risk (D-/R-) received no prophylaxis (n = 8). Thymoglobulin or basiliximab was used for induction, and mycophenolate mofetil, prednisone, and either tacrolimus or sirolimus for maintenance immunosuppression. Only six patients (7.5%) developed symptomatic CMV infection diagnosed by pp65 antigenemia, three in the high-risk (25%) and three in the moderate-risk (5%) group (p = 0.02). All patients were on tacrolimus for at least 3 months prior to diagnosis. There were no cases of tissue-invasive disease, resistance to treatment, or recurrence. D+/R- serostatus was the only significant independent predictor for CMV infection using multivariate analysis (odds ratio 10.5; p = 0.04). Thymoglobulin induction was not associated with CMV infection. None of 43 patients who were exposed to sirolimus for >30 d developed CMV infection, vs. six of 37 who were not (p = 0.006). We conclude that VGC dosed according to D/R serostatus provides safe and effective CMV prophylaxis in AA renal allograft recipients.

Sirolimus-induced angioedema.

Sirolimus (SRL) is a macrolide immunosuppressant that has gained widespread use in organ transplantation. Its full spectrum of side-effects is yet to be defined. We describe herein three cases of SRL-induced angioedema (AE) in African-American (AA) primary renal allograft recipients who received SRL in combination with mycophenolate mofetil and steroids. In two cases, AE manifested after SRL was restarted after a period of discontinuation. The third case presented upon initial exposure to the drug. None of the patients was receiving any drug that has been previously associated with AE. Complete resolution occurred only after SRL was withdrawn. AE has not recurred in any of the patients during a follow-up period of up to 21 months. We conclude that AE is a previously unrecognized adverse event associated with SRL use. Close monitoring for this side-effect, especially in AA patients, is warranted.

West Nile virus encephalitis: an emerging disease in renal transplant recipients.

West Nile virus (WNV) has emerged as an important cause of several outbreaks of febrile illness and encephalitis in North America over the past few years. The most common manifestation in symptomatic patients is a transient febrile illness. Neuroinvasive disease, that can be fatal, occurs most often in elderly and immunocompromised hosts. The role of this virus as a cause of meninoencephalitis in organ transplant recipients is becoming better recognized. We describe herein the clinical course of two renal allograft recipients who developed WNV encephalitis. One patient developed status epilepticus and eventually died, while the other had a full recovery. In both cases, the diagnosis was confirmed by detection of WNV-specific IgM in CSF or serum, with a delayed antibody response in one patient. This viral infection should be considered in all renal transplant recipients who present with a febrile illness associated with neurological symptoms.