Immunosuppression withdrawal in living-donor renal transplant recipients following induction with antithymocyte globulin and rituximab: Results of a prospective clinical trial.

Durable tolerance in kidney transplant recipients remains an important but elusive goal. We hypothesized that adding B cell depletion to T cell depletion would generate an immune milieu postreconstitution dominated by immature transitional B cells, favoring tolerance. The Immune Tolerance Network ITN039ST Research Study of ATG and Rituximab in Renal Transplantation was a prospective multicenter pilot study of live donor kidney transplant recipients who received induction with rabbit antithymocyte globulin and rituximab and initiated immunosuppression (IS) withdrawal (ISW) at 26 weeks. The primary endpoint was freedom from rejection at 52 weeks post-ISW. Six of the 10 subjects successfully completed ISW. Of these 6 subjects, 4 restarted immunosuppressive medications due to acute rejection or recurrent disease, 1 remains IS-free for over 9 years, and 1 was lost to follow-up after being IS-free for 42 weeks. There were no cases of patient or graft loss. CD19+ B cell frequencies returned to predepletion levels by 26 weeks posttransplant; immunoglobulin D+CD27--naïve B cells predominated. In contrast, memory cells dominated the repopulation of the T cell compartment. A regimen of combined B and T cell depletion did not generate the tolerogenic B cell profile observed in preclinical studies and did not lead to durable tolerance in the majority of kidney transplant recipients.

Validation of a noninvasive prognostic signature for allograft failure following BK virus associated nephropathy.

Identifying kidney transplant recipients at risk for graft failure following BK virus nephropathy (BKVN) may allow personalization of therapy. We have reported that a noninvasive composite signature of urinary cell level of plasminogen activator inhibitor-1(PAI-1) mRNA and serum creatinine level, measured at the time of BKVN diagnosis, is prognostic of graft failure. In this investigation, we determined whether the composite signature is prognostic of graft failure in an independent cohort of 25 patients with BKVN. Of the 25 patients, 8 developed graft failure and 17 did not. We measured urinary cell levels of PAI-1 mRNA, 18S rRNA, and BKV VP1 mRNA at the time of BKVN diagnosis and evaluated clinical parameters including Banff pathology scores, acute rejection, and graft function. The area under the receiver operating characteristic curve for the noninvasive composite signature was 0.95 (P < .001) for prognosticating graft failure. The previously reported threshold of -0.858 predicted graft failure with a sensitivity of 75% and a specificity of 94%. Our current study validates the use of composite signature and the threshold of -0.858 to identify those at risk for graft failure following BKVN diagnosis, and supports future studies utilizing the composite signature score to personalize treatment of BKVN.

Kidney allograft recipients, immunosuppression, and coronavirus disease-2019: a report of consecutive cases from a New York City transplant center.

BACKGROUND: Kidney graft recipients receiving immunosuppressive therapy may be at heightened risk for coronavirus disease 2019 (Covid-19) and adverse outcomes. It is therefore important to characterize the clinical course and outcome of Covid-19 in this population and identify safe therapeutic strategies. METHODS: We performed a retrospective chart review of 73 adult kidney graft recipients evaluated for Covid-19 from 13 March to 20 April 2020. Primary outcomes included recovery from symptoms, acute kidney injury, graft failure and case fatality rate. RESULTS: Of the 73 patients screened, 54 tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-39 with moderate to severe symptoms requiring hospital admission and 15 with mild symptoms managed in the ambulatory setting. Hospitalized patients were more likely to be male, of Hispanic ethnicity and to have cardiovascular disease. In the hospitalized group, tacrolimus dosage was reduced in 46% of patients and mycophenolate mofetil (MMF) therapy was stopped in 61% of patients. None of the ambulatory patients had tacrolimus reduction or discontinuation of MMF. Azithromycin or doxycycline was prescribed at a similar rate among hospitalized and ambulatory patients (38% versus 40%). Hydroxychloroquine was prescribed in 79% of hospitalized patients. Graft failure requiring hemodialysis occurred in 3 of 39 hospitalized patients (8%) and 7 patients died, resulting in a case fatality rate of 13% among Covid-19-positive patients and 18% among hospitalized Covid-19-positive patients. CONCLUSIONS: Data from our study suggest that a strategy of systematic triage to outpatient or inpatient care, early management of concurrent bacterial infections and judicious adjustment of immunosuppressive drugs rather than cessation is feasible in kidney transplant recipients with Covid-19.

Antibiotic prophylaxis for ureteral stent removal after kidney transplantation.

There are no guidelines for antibiotic prophylaxis for ureteral stent removal after kidney transplantation. We reviewed the charts of 277 adult kidney transplant recipients with ureteral stents transplanted at our center between September 2014 and December 2015 and investigated whether antibiotic prophylaxis for stent removal was associated with reduced incidence of urinary tract infections (UTI). We defined UTI as a urine culture ≥104  CFU/mL of bacterial isolates irrespective of symptoms. Primary outcome was the incidence of UTI within four weeks of stent removal. Among the 277 recipients, 199 (72%) were on sulfamethoxazole/trimethoprim (SMZ/TMP) as Pneumocystis jirovecii prophylaxis. At the time of ureteral stent removal, 56 recipients (20%) received additional antibiotic prophylaxis (ABX+) and 221 (80%) did not (ABX-). The difference in the incidence of UTI in the ABX(+) group (16%) and ABX(-) group (19%) was not statistically significant (P = 0.85). Variables independently associated with the development of UTI were recipient age (odds ratio [OR] 1.04, [95% confidence interval 1.01-1.07]) and UTI while stents were in situ (OR 3.9 [2.00-7.62]). Use of SMZ/TMP was protective (OR 0.35 [0.18-0.7]). Our study does not show a statistically significant benefit for additional antibiotic prophylaxis for ureteral stent removal. Antibiotic prophylaxis may be beneficial for recipients not on SMZ/TMP at the time of stent removal.

Differences in Attitudes Toward Immunosuppressant Therapy in a Multi-ethnic Sample of Kidney Transplant Recipients.

Barriers for renal transplant patients to immunosuppressant medication adherence are poorly understood, despite the high rate and toll of non-adherence. We sought to assess factors that contribute to barriers to immunosuppressive medication adherence in an ethnically diverse sample of 312 renal transplant patients recruited from three transplant centers across New York City. Transplant patients who were at least 6 months post-transplant completed questionnaires while waiting for their medical appointment. Ethnic differences were observed on barriers to immunosuppressant adherence. Black and Hispanic participants reported significantly more barriers to adherence compared to Caucasian participants. Differences in perception about the potential harm and necessity of immunosuppressant medications also were present. Using hierarchical multiple regression, age and income were significant predictors of reported barriers to adherence, even while controlling for ethnicity. The most robust predictor of reported barriers was the perception of the medication cost-benefit differential, i.e., the balance between concerns about immunosuppressant medications and their perceived helpfulness (B = - 0.5, p < .001), indicating that varying beliefs about the medication's necessity and utility rather than ethnicity explain the differences in barriers to medication adherence. Future interventions targeting non-adherence should aim to reduce the barriers to adherence by addressing perceived risks and benefits of taking immunosuppressant medication.

Kidney allograft failure in the steroid-free immunosuppression era: A matched case-control study.

We studied the causes and predictors of death-censored kidney allograft failure among 1670 kidney recipients transplanted at our center in the corticosteroid-free maintenance immunosuppression era. As of January 1, 2012, we identified 137 recipients with allograft failure; 130 of them (cases) were matched 1-1 for recipient age, calendar year of transplant, and donor type with 130 recipients with functioning grafts (controls). Median time to allograft failure was 29 months (interquartile range: 18-51). Physician-validated and biopsy-confirmed categories of allograft failure were as follows: acute rejection (21%), glomerular disease (19%), transplant glomerulopathy (13%), interstitial fibrosis tubular atrophy (10%), and polyomavirus-associated nephropathy (7%). Graft failures were attributed to medical conditions in 21% and remained unresolved in 9%. Donor race, donor age, human leukocyte antigen mismatches, serum creatinine, urinary protein, acute cellular rejection, acute antibody-mediated rejection, BK viremia, and CMV viremia were associated with allograft failure. Independent predictors of allograft failure were acute cellular rejection (odds ratio: 18.31, 95% confidence interval: 5.28-63.45) and urine protein ≥1 g/d within the first year post-transplantation (5.85, 2.37-14.45). Serum creatinine ≤1.5 mg/dL within the first year post-transplantation reduced the odds (0.29, 0.13-0.64) of allograft failure. Our study has identified modifiable risk factors to reduce the burden of allograft failure.

Long term follow up of kidney donors with asymptomatic renal stones.

Patients with asymptomatic kidney stones have a high rate of progression to becoming symptomatic kidney stones when followed for several years. Small kidney stones are often found incidentally on imaging when evaluating patients for kidney donation, and there is a concern that after nephrectomy, the donor may become symptomatic and incur damage to the remaining kidney. We reviewed kidney donors at our institution with asymptomatic stones and surveyed them several years after donation to see if the stones became clinically active.

Development and validation of a prognostic index for allograft outcome in kidney recipients with transplant glomerulopathy.

We studied 92 patients with transplant glomerulopathy to develop a prognostic index based on the risk factors for allograft failure within five years of diagnosis (Development cohort). During 60 months (median) follow-up, 64 patients developed allograft failure. A chronic-inflammation score generated by combining Banff ci, ct and ti scores, serum creatinine and proteinuria at biopsy, were independent risk factors for allograft failure. Based on the Cox model, we developed a prognostic index and classified patients into risk groups. Compared to the low-risk group (median allograft survival over 60 months from diagnosis), patients in the medium risk group had a hazard ratio of 2.83 (median survival 25 months), while those in the high-risk group had a hazard ratio of 5.96 (median survival 3.7 months). We next evaluated the performance of the prognostic index in an independent external cohort of 47 patients with transplant glomerulopathy (Validation cohort). The hazard ratios were 2.18 (median survival 19 months) and 16.27 (median survival 1.6 months), respectively, for patients in the medium and high-risk groups, compared to the low-risk group (median survival 47 months). Our prognostic index model did well in measures of discrimination and calibration. Thus, risk stratification of transplant glomerulopathy based on our prognostic index may provide informative insight for both the patient and physician regarding prognosis and treatment.

Semiautomated CT-Based Quantification of Donor Kidney Volume Applied to a Predictive Model of Outcomes in Renal Transplantation.

OBJECTIVE: The purpose of this study was to assess the use of semiautomated CT-based quantification of renal graft volume as a preoperative predictor of graft function. MATERIALS AND METHODS: All transplants over a 3-year period in which donors underwent CT and for which recipient outcomes were available were included. Two blinded readers used a commercially available reconstruction tool to independently measure donated kidney cortical volume and total parenchymal kidney volume. Transplant characteristics obtained by chart review included subject demographics, recipient pretransplant weight, immunologic matching, and recipient creatinine values at multiple time points. Intraclass correlation of measurements by the two readers was calculated. The ratios between donated kidney cortical volume and recipient pretransplant weight were correlated with graft function over 24 months and used in logistic regression models to calculate the odds of development of diminished renal function. RESULTS: After application of the inclusion and exclusion criteria, 153 transplants were included in the study. Donated kidney cortical and total parenchymal volume measurements had high correlation (R > 0.9) and high reproducibility (intraclass correlation coefficient, 0.93-0.94). Unadjusted correlations existed between estimated glomerular filtration rate (eGFR) and the ratio between donated kidney cortical volume and recipient pretransplant weight 12 months (R = 0.8489) and 24 months (R = 0.6839) after transplant. After adjustment for transplant parameters, recipients in the highest tertile for ratio between donated kidney cortical volume and recipient pretransplant weight (2.7 mL/kg) had higher mean eGFR values at all time points in the 24 months than did recipients in the lower tertiles (1.2 and 1.6 mL/kg). Recipients in the highest tertile had a significantly lower risk of development of diminished renal function 12 and 24 months after transplant (adjusted odds ratios, 0.25 at 12 months [95% CI, 0.09-0.66]; 0.27 at 24 months [95% CI, 0.10-0.71]). CONCLUSION: The CT-derived ratio between donated kidney cortical volume and recipient pretransplant weight is a noninvasively and readily obtained reproducible biomarker that is predictive of 12- and 24-month renal transplant outcomes.

Urinary cell mRNA profiles and differential diagnosis of acute kidney graft dysfunction.

Noninvasive tests to differentiate the basis for acute dysfunction of the kidney allograft are preferable to invasive allograft biopsies. We measured absolute levels of 26 prespecified mRNAs in urine samples collected from kidney graft recipients at the time of for-cause biopsy for acute allograft dysfunction and investigated whether differential diagnosis of acute graft dysfunction is feasible using urinary cell mRNA profiles. We profiled 52 urine samples from 52 patients with biopsy specimens indicating acute rejection (26 acute T cell-mediated rejection and 26 acute antibody-mediated rejection) and 32 urine samples from 32 patients with acute tubular injury without acute rejection. A stepwise quadratic discriminant analysis of mRNA measures identified a linear combination of mRNAs for CD3ε, CD105, TLR4, CD14, complement factor B, and vimentin that distinguishes acute rejection from acute tubular injury; 10-fold cross-validation of the six-gene signature yielded an estimate of the area under the curve of 0.92 (95% confidence interval, 0.86 to 0.98). In a decision analysis, the six-gene signature yielded the highest net benefit across a range of reasonable threshold probabilities for biopsy. Next, among patients diagnosed with acute rejection, a similar statistical approach identified a linear combination of mRNAs for CD3ε, CD105, CD14, CD46, and 18S rRNA that distinguishes T cell-mediated rejection from antibody-mediated rejection, with a cross-validated estimate of the area under the curve of 0.81 (95% confidence interval, 0.68 to 0.93). Incorporation of these urinary cell mRNA signatures in clinical decisions may reduce the number of biopsies in patients with acute dysfunction of the kidney allograft.

Living donor kidney paired donation transplantation: experience as a founding member center of the National Kidney Registry.

Kidney paired donation (KPD) is a safe and effective means of transplantation for transplant candidates with willing but incompatible donors. We report our single-center experience with KPD through participation in the National Kidney Registry. Patient demographics, transplant rates, and clinical outcomes including delayed graft function (DGF), rejection, and survival were analyzed. We also review strategies employed by our center to maximize living donor transplantation through KPD. We entered 44 incompatible donor/recipient pairs into KPD from 9/2007 to 1/2011, enabling 50 transplants. Incompatibility was attributable to blood type (54.4%) and donor-specific sensitization (43.2%). Thirty-six candidates (81.8%) were transplanted after 157 d (median), enabling pre-emptive transplantation in eight patients. Fourteen candidates on the deceased donor waiting list also received transplants. More than 50% of kidneys were received from other transplant centers. DGF occurred in 6%; one-yr rejection rate was 9.1%. One-yr patient and graft survival was 98.0% and 94.8%. KPD involving participation of multiple transplant centers can provide opportunities for transplantation, with potential to expand the donor pool, minimize waiting times, and enable pre-emptive transplantation. Our experience demonstrates promising short-term outcomes; however, longer follow-up is needed to assess the impact of KPD on the shortage of organs available for transplantation.

Complications of rabbit anti-thymocyte globulin induction immunosuppression in HIV-infected kidney transplant recipients.

Background: Kidney transplantation in HIV-infected individuals with end-stage kidney disease is associated with improved survival compared to dialysis. Rabbit anti-thymocyte globulin (rATG) induction in HIV-infected kidney transplant recipients has been associated with a lower risk of acute rejection, but data on the rates of de novo malignancy and BK viremia in these patients is lacking. Methods: We performed a single-center retrospective cohort study of adult HIV-infected individuals who underwent kidney transplantation with rATG induction between January 2006 and December 2016. The primary outcome was the development of de novo malignancy. Secondary outcomes included the development of BK viremia, infections requiring hospitalization, HIV progression, biopsy-proven acute rejection, and patient and allograft survival. Results: Twenty-seven HIV-infected individuals with end-stage kidney disease received deceased (n=23) or living (n=4) donor kidney transplants. The cumulative rate of malignancy at five years was 29%, of whom 29% died because of advanced malignancy. BK viremia was detected in six participants (22%), of whom one had biopsy-proven BK virus-associated nephropathy and all of whom cleared the BK viremia. Five-year acute rejection rates, patient survival and death-censored allograft survival were 17%, 85% and 80% respectively. Conclusion: rATG induction in HIV-infected kidney transplant recipients was associated with a low risk of acute rejection, but a potentially higher risk of de novo malignancies and BK viremia in this cohort. Screening strategies to closely monitor for BK virus infection and malignancy post-transplantation may improve outcomes in HIV-infected kidney transplant recipients receiving rATG induction.

Deceased-donor kidney transplantation: improvement in long-term survival.

BACKGROUND: Despite marked improvement in short-term renal allograft survival rates (GSR) in recent years, improvement in long-term GSR remained elusive. METHODS: We analysed the kidney transplant experience at our centre accrued over four decades to evaluate how short-term and long-term GSR had changed and to identify risk factors affecting graft survival. The study included 1476 adult recipients of a deceased-donor kidney transplant who were transplanted between 1963 and 2006 and who had received one of five distinct immunosuppressive protocols. RESULTS: Five-year actual GSR steadily improved over the years as immunosuppressive therapy evolved (22-86%, P < 0.001) in spite of an increasing trend in the transplantation of higher-risk donor-recipient pairings. For those whose grafts functioned for the first year, subsequent 4-year GSR (5-year conditional GSR) also improved significantly (63-92%, P < 0.001). Acute rejection and delayed graft function (DGF) were the most significant risk factors for actual graft survival, while acute rejection was the only significant risk factor for conditional GSR. Use of kidneys from expanded-criteria donors (ECD) was not a risk factor, compared to the use of standard-criteria donor kidneys for either 5-year actual or conditional GSR. There was an impressive decline in the incidence of acute rejection events (77.4-5.8%, P < 0.001). While the DGF rate had decreased, it still remained high (68.7-38.5%, P < 0.001). CONCLUSIONS: We found a significant improvement in both short-term and long-term GSR of deceased-donor kidney transplants over the last four decades. These improvements are most likely related to the decreased incidence of acute rejection episodes. Minimizing acute rejection events and preventing DGF could result in further improvement in the GSR. Our experience in the judicious use of ECD kidneys suggests that this source of kidneys could be expanded further.

Pancreas transplantation considering the spectrum of body mass indices.

BACKGROUND: In kidney, liver, heart, and lung transplantation, extremes of body mass index (BMI) have been reported to influence post-operative outcomes and even survival. Given the limited data in pancreas transplantation, we sought to elucidate the influence of BMI on outcomes. METHODS: We reviewed 139 consecutive pancreas transplants performed at our institution and divided them into four categories based on BMI: underweight (≤18.5 kg/m(2)), normal (18.6-24.9 kg/m(2)), overweight (25-29.9 kg/m(2)), and obese (≥30 kg/m(2)). Parameters analyzed included post-operative complications, early graft loss, one-yr acute rejection rate (AR), non-surgical infections, and survival. RESULTS: Demographic data were similar between the groups. Compared with normal, only obese patients trended toward more post-operative complications (p = 0.06). Underweight and obese patients had significantly more post-operative infectious complications than normal (p = 0.0005 and p = 0.03, respectively). Obese patients had more complications requiring percutaneous drainage compared with normal (p = 0.03). Overweight and obese patients had significantly more complications requiring re-laparotomy (p = 0.03 and p = 0.048, respectively). Early graft loss, AR, non-surgical infections, and patient and graft survival rates were not different between normal and underweight, overweight, or obese patients (p > 0.05). CONCLUSIONS: Extremes of BMI were associated with increased morbidity. Donors and recipients should be carefully selected to maximize potential for successful outcomes.

Noninvasive diagnosis of acute rejection of renal allografts.

PURPOSE OF REVIEW: Acute rejection is an immune process that begins with the recognition of the allograft as nonself and ends in graft destruction. Histological features of the allograft biopsy are currently used for the differential diagnosis of allograft dysfunction. In view of the safety and the opportunity for repetitive sampling, development of noninvasive biomarkers of allograft status is an important objective in transplantation. Herein, we review some of the progress towards the development of noninvasive biomarkers of human allograft status. RECENT FINDINGS: Urinary cell and peripheral blood cell mRNA profiles have been associated with acute rejection of human renal allografts. Emerging data support the idea that development of noninvasive biomarkers predictive of antibody-mediated rejection is feasible. The demonstration that intragraft microRNA expression predicts renal allograft status suggests that noninvasively ascertained microRNA profiles may be of value. SUMMARY: We are pleased with the progress to date, and anticipate clinical trials investigating the hypotheses that noninvasively ascertained mRNA profiles will minimize the need for invasive biopsy procedures, predict the development of acute rejection and chronic allograft nephropathy, facilitate preemptive therapy capable of preserving graft function, and facilitate personalization of immunosuppressive therapy for the allograft recipient.

Messenger RNA for FOXP3 in the urine of renal-allograft recipients.

BACKGROUND: The outcome of renal transplantation after an episode of acute rejection is difficult to predict, even with an allograft biopsy. METHODS: We studied urine specimens from 36 subjects with acute rejection, 18 subjects with chronic allograft nephropathy, and 29 subjects with normal biopsy results. Levels of messenger RNA (mRNA) for FOXP3, a specification and functional factor for regulatory T lymphocytes, and mRNA for CD25, CD3epsilon, perforin, and 18S ribosomal RNA (rRNA) were measured with a kinetic, quantitative polymerase-chain-reaction assay. We examined associations of mRNA levels with acute rejection, rejection reversal, and graft failure. RESULTS: The log-transformed mean (+/-SE) ratio of FOXP3 mRNA copies to 18S ribosomal RNA copies was higher in urine from the group with acute rejection (3.8+/-0.5) than in the group with chronic allograft nephropathy (1.3+/-0.7) or the group with normal biopsy results (1.6+/-0.4) (P<0.001 by the Kruskal-Wallis test). FOXP3 mRNA levels were inversely correlated with serum creatinine levels measured at the time of biopsy in the acute-rejection group (Spearman's correlation coefficient = -0.38, P=0.02) but not in the group with chronic allograft nephropathy or the group with normal biopsy results. Analyses of receiver-operating-characteristic curves demonstrated that reversal of acute rejection can be predicted with 90 percent sensitivity and 73 percent specificity with use of the optimal identified cutoff for FOXP3 mRNA of 3.46 (P=0.001). FOXP3 mRNA levels identified subjects at risk for graft failure within six months after the incident episode of acute rejection (relative risk for the lowest third of FOXP3 mRNA levels, 6; P=0.02). None of the other mRNA levels were predictive of reversal of acute rejection or graft failure. CONCLUSIONS: Measurement of FOXP3 mRNA in urine may offer a noninvasive means of improving the prediction of outcome of acute rejection of renal transplants.