The Combined Roles of Race/Ethnicity and Substance Use in Predicting Likelihood of Kidney Transplantation.

BACKGROUND: Racial/ethnic minorities face known disparities in likelihood of kidney transplantation. These disparities may be exacerbated when coupled with ongoing substance use, a factor also reducing likelihood of transplantation. We examined whether race/ethnicity in combination with ongoing substance use predicted incidence of transplantation. METHODS: Patients were enrolled between March 2010 and October 2012 at the time of transplant evaluation. Substance use data were retrieved from transplant evaluations. Following descriptive analyses, the primary multivariable analyses evaluated whether, relative to the referent group (White patients with no substance use), racial/ethnic minority patients using any substances at the time of evaluation were less likely to receive transplants by the end of study follow-up (August 2020). RESULTS: Among 1152 patients, 69% were non-Hispanic White, 23% non-Hispanic Black, and 8% Other racial/ethnic minorities. White, Black, and Other patients differed in percentages of current tobacco smoking (15%, 26%, and 18%, respectively; P = 0.002) and illicit substance use (3%, 8%, and 9%; P < 0.001) but not heavy alcohol consumption (2%, 4%, and 1%; P = 0.346). Black and Other minority patients using substances were each less likely to receive transplants than the referent group (hazard ratios ≤0.45, P ≤ 0.021). Neither White patients using substances nor racial/ethnic minority nonusers differed from the referent group in transplant rates. Additional analyses indicated that these effects reflected differences in waitlisting rates; once waitlisted, study groups did not differ in transplant rates. CONCLUSIONS: The combination of minority race/ethnicity and substance use may lead to unique disparities in likelihood of transplantation. To facilitate equity, strategies should be considered to remove any barriers to referral for and receipt of substance use care in racial/ethnic minorities.

The kSORT assay to detect renal transplant patients at high risk for acute rejection: results of the multicenter AART study.

BACKGROUND: Development of noninvasive molecular assays to improve disease diagnosis and patient monitoring is a critical need. In renal transplantation, acute rejection (AR) increases the risk for chronic graft injury and failure. Noninvasive diagnostic assays to improve current late and nonspecific diagnosis of rejection are needed. We sought to develop a test using a simple blood gene expression assay to detect patients at high risk for AR. METHODS AND FINDINGS: We developed a novel correlation-based algorithm by step-wise analysis of gene expression data in 558 blood samples from 436 renal transplant patients collected across eight transplant centers in the US, Mexico, and Spain between 5 February 2005 and 15 December 2012 in the Assessment of Acute Rejection in Renal Transplantation (AART) study. Gene expression was assessed by quantitative real-time PCR (QPCR) in one center. A 17-gene set--the Kidney Solid Organ Response Test (kSORT)--was selected in 143 samples for AR classification using discriminant analysis (area under the receiver operating characteristic curve [AUC] = 0.94; 95% CI 0.91-0.98), validated in 124 independent samples (AUC = 0.95; 95% CI 0.88-1.0) and evaluated for AR prediction in 191 serial samples, where it predicted AR up to 3 mo prior to detection by the current gold standard (biopsy). A novel reference-based algorithm (using 13 12-gene models) was developed in 100 independent samples to provide a numerical AR risk score, to classify patients as high risk versus low risk for AR. kSORT was able to detect AR in blood independent of age, time post-transplantation, and sample source without additional data normalization; AUC = 0.93 (95% CI 0.86-0.99). Further validation of kSORT is planned in prospective clinical observational and interventional trials. CONCLUSIONS: The kSORT blood QPCR assay is a noninvasive tool to detect high risk of AR of renal transplants. Please see later in the article for the Editors' Summary.

New immunosuppressive agents in pediatric transplantation.

Immunosuppressive therapy in pediatrics continues to evolve. Over the past decade, newer immunosuppressive agents have been introduced into adult and pediatric transplant patients with the goal of improving patient and allograft survival. Unfortunately, large-scale randomized clinical trials are not commonly performed in children. The purpose of this review is to discuss the newer immunosuppressive agents available for induction therapy, maintenance immunosuppression, and the treatment of rejection.

New immunosuppressive agents in pediatric transplantation

Immunosuppressive therapy in pediatrics continues to evolve. Over the past decade, newer immunosuppressive agents have been introduced into adult and pediatric transplant patients with the goal of improving patient and allograft survival. Unfortunately, large-scale randomized clinical trials are not commonly performed in children. The purpose of this review is to discuss the newer immunosuppressive agents available for induction therapy, maintenance immunosuppression, and the treatment of rejection.

Long-term patient and allograft outcomes of renal transplant recipients undergoing cardiac surgery.

OBJECTIVES: Cardiovascular complications are a major cause of morbidity and mortality among renal transplant recipients. This study assessed perioperative risk factors for mortality and long-term outcomes in renal transplant recipients who underwent cardiac surgery. METHODS: From 1999 to 2010, 92 renal transplant recipients with a functioning allograft underwent cardiac surgery at our institution. Cardiac procedures included coronary artery bypass grafting (43 patients, 46%), isolated valve surgery (17 patients, 18%), combined coronary artery bypass grafting and valve surgery (18 patients, 19%), and aortic procedures (7 patients, 7%). RESULTS: Transient renal failure requiring dialysis occurred in 20 of 92 patients (21%), with 3 not recovering renal function and returning to a permanent dialysis regimen while in the hospital. After cardiac surgery 30-day, 1-year, 5-year, and 8-year survival rates were 89%, 72%, 47%, and 30%, respectively. Freedom from dialysis was 90% after 1 year, 66% after 5 years, and 49% after 8 years. Risk factors for 30-day mortality were age > 65 years, left ventricle ejection fraction < 35%, and a combined cardiac procedure. Pulmonary hypertension and diabetes were risk factors for death from a cardiac cause after discharge. Diabetes, dyslipidemia, preoperative use of an intra-aortic balloon pump, postoperative creatinine > 2 mg/dL, and transient renal failure requiring dialysis were associated with a permanent dialysis requirement after cardiac surgery. CONCLUSIONS: Cardiac surgery in patients receiving renal transplant who have functioning allograft has acceptable outcomes. If combined procedures are required, patients should be carefully considered. Transient postoperative renal impairment, even if resolved at discharge, increases the risk for allograft failure during long-term follow-up.

Antilymphoid antibody preconditioning and tacrolimus monotherapy for pediatric kidney transplantation.

OBJECTIVE: Heavy post-transplant immunosuppression may contribute to long-term immunosuppression dependence by subverting tolerogenic mechanisms; thus, we sought to determine if this undesirable consequence could be mitigated by pretransplant lymphoid depletion and minimalistic post-transplant monotherapy. STUDY DESIGN: Lymphoid depletion in 17 unselected pediatric recipients of live (n = 14) or deceased donor kidneys (n = 3) was accomplished with antithymocyte globulin (ATG) (n = 8) or alemtuzumab (n = 9). Tacrolimus was begun post-transplantation with subsequent lengthening of intervals between doses (spaced weaning). Maintenance immunosuppression, morbidity, graft function, and patient/graft survival were collated. RESULTS: Steroids were added temporarily to treat rejection in two patients (both ATG subgroup) or to treat hemolytic anemia in two others. After 16 to 31 months (mean 22), patient and graft survival was 100% and 94%, respectively. The only graft loss was in a nonweaned noncompliant recipient. In the other 16, serum creatinine was 0.85 +/- 0.35 mg/dL and creatinine clearance was 90.8 +/- 22.1 mL/1.73 m2. All 16 patients are on monotherapy (15 tacrolimus, one sirolimus), and 14 receive every other day or 3 times per week doses. There were no wound or other infections. Two patients developed insulin-dependent diabetes. CONCLUSION: The strategy of lymphoid depletion and minimum post-transplant immunosuppression appears safe and effective for pediatric kidney recipients.

Occurrence of urinary tract infection in patients with renal allograft biopsies showing neutrophilic tubulitis.

Lymphocytic tubulitis is a well-accepted criterion for acute cellular rejection in renal allograft biopsies. Neutrophilic tubulitis has been used as a surrogate marker for urinary tract infection, but it is not clear how reliably this lesion can be used to make this diagnosis. Biopsy findings were correlated with clinical features in 26 renal allograft biopsies with interstitial polymorphonuclear infiltrates associated with neutrophilic tubulitis. The grade of neutrophilic tubulitis exceeded the grade of lymphocytic tubulitis in 7 (44%) of 16 patients with, but in only 0 patients without, a positive urine culture. Culture confirmed urinary tract infection in 16 (62%) of 26 patients. It is possible that prior antibiotic therapy led to a false-negative culture and masked the diagnosis in two additional patients. Lymphocytic tubulitis made it difficult to exclude concurrent acute cellular rejection in all biopsies studied. In 6 (23%) of 26 patients, negative cultures and response to steroid treatment confirmed that neutrophilic tubulitis can occur in biopsies without urinary tract infection. The relative contributions of infection and rejection could not be determined in patients treated with both steroids and antibiotics. Neutrophilic tubulitis in a renal allograft biopsy should alert the clinician to the possibility of urinary tract infection, even if concurrent lymphocytic tubulitis is present. Confirmation by urine culture is needed because biopsies with ischemic injury and acute cellular or antibody-mediated rejection can show overlapping histology.

Cadaveric renal transplantation using kidneys from donors greater than 60 years old.

Transplantation of kidneys from donors over the age of 60 yr is controversial. However, as the demand for cadaveric kidneys far exceeds the supply, exploration of the usefulness of kidneys outside the currently accepted donor pool is necessary. Between January 1987 and July 1989, 31 (5.5%) of the 558 cadaveric renal transplants performed at the University of Pittsburgh utilized organs from donors older than 60 yr. Median recipient age was 41 yr (range 24-71 yr); 4 recipients were diabetic and 6 had panel-reactive antibody levels greater than 20% at the time of transplant. All recipients were treated with cyclosporine, prednisone and azathioprine. The 1-yr allograft survival was 65% which was less than but not statistically different from the graft survival of 80% in a retrospective selected control group who received grafts from younger donors aged 11 to 50 yr. However, the 1-yr graft survival of older donor kidneys with cold ischemia time greater than 48 hours was 38%, which was significantly poorer than the 78% 1-yr graft survival seen with cold ischemia times less than 48 h (p=0.04 Breslow). The mean serum creatinine was significantly higher in the older donor kidneys at 1, 3, and 12 months post-transplant than in the control kidneys even when kidneys with greater than 48 h of cold ischemia time were excluded. In summary, transplantation of cadaver kidneys from donors older than 60 yr results in acceptable graft survival rates. These kidneys are more susceptible to cold ischemic injury and function with a higher serum creatinine than kidneys from younger donors. Expansion of the donor pool by the use of older donor kidneys in selected recipients could have an impact on alleviating the chronic national cadaver kidney shortage.