Geoffrey Dube

Donor-Specific Antibodies Adversely Affect Kidney Allograft Outcomes

The effect of low titers of donor-specific antibodies (DSAs) detected only by sensitive solid-phase assays (SPAs) on renal transplant outcomes is unclear. We report the results of a systematic review and meta-analysis of rejection rates and graft outcomes for renal transplant recipients with such preformed DSAs, defined by positive results on SPA but negative complement-dependent cytotoxicity and flow cytometry crossmatch results. Our search identified seven retrospective cohort studies comprising a total of 1119 patients, including 145 with isolated DSA-SPA. Together, these studies suggest that the presence of DSA-SPA, despite a negative flow cytometry crossmatch result, nearly doubles the risk for antibody-mediated rejection (relative risk [RR], 1.98; 95% confidence interval [CI], 1.36-2.89; P<0.001) and increases the risk for graft failure by 76% (RR, 1.76; 95% CI, 1.13-2.74; P=0.01). These results suggest that donor selection should consider the presence of antibodies in the recipient, identified by the SPA, even in the presence of a negative flow cytometry crossmatch result.

Reduced fracture risk with early corticosteroid withdrawal after kidney transplant

Corticosteroid use after kidney transplantation results in severe bone loss and high fracture risk. Although corticosteroid withdrawal in the early posttransplant period has been associated with bone mass preservation, there are no published data regarding corticosteroid withdrawal and risk of fracture. We hypothesized lower fracture incidence in patients discharged from the hospital without than with corticosteroids after transplantation. From the United States Renal Data System (USRDS), 77 430 patients were identified who received their first kidney transplant from 2000 to 2006. Fracture incidence leading to hospitalization was determined from 2000 to 2007; discharge immunosuppression was determined from United Networks for Organ Sharing forms. Time‐to‐event analyses were used to evaluate fracture risk. Median (interquartile range) follow‐up was 1448 (808–2061) days. There were 2395 fractures during follow‐up; fracture incidence rates were 0.008 and 0.0058 per patient‐year for recipients discharged with and without corticosteroid, respectively. Corticosteroid withdrawal was associated with a 31% fracture risk reduction (HR 0.69; 95% CI 0.59–0.81). Fractures associated with hospitalization are significantly lower with regimens that withdraw corticosteroid. As this study likely underestimates overall fracture incidence, prospective studies are needed to determine differences in overall fracture risk in patients managed with and without corticosteroids after kidney transplantation.

Kidneys at Higher Risk of Discard: Expanding the Role of Dual Kidney Transplantation

Half of the recovered expanded criteria donor (ECD) kidneys are discarded in the United States. A new kidney allocation system offers kidneys at higher risk of discard, Kidney Donor Profile Index (KDPI) > 85%, to a wider geographic area to promote broader sharing and expedite utilization. Dual kidney transplantation (DKT) based on the KDPI is a potential option to streamline allocation of kidneys which otherwise would have been discarded. To assess the clinical utility of the KDPI in kidneys at higher risk of discard, we analyzed the OPTN/UNOS Registry that included the deceased donor kidneys recovered between 2002 and 2012. The primary outcomes were allograft survival, patient survival and discard rate based on different KDPI categories (<80%, 80–90% and >90%). Kidneys with KDPI > 90% were associated with increased odds of discard (OR = 1.99, 95% CI 1.74–2.29) compared to ones with KDPI < 80%. DKTs of KDPI > 90% were associated with lower overall allograft failure (HR = 0.74, 95% CI 0.62–0.89) and better patient survival (HR = 0.79, 95% CI 0.64–0.98) compared to single ECD kidneys with KDPI > 90%. Kidneys at higher risk of discard may be offered in the up‐front allocation system as a DKT. Further modeling and simulation studies are required to determine a reasonable KDPI cutoff percentile.

The weekend effect alters the procurement and discard rates of deceased donor kidneys in the United States

Factors contributing to the high rate of discard among deceased donor kidneys remain poorly understood and the influence of resource limitations of weekends on kidney transplantation is unknown. To quantify this we used data from the Scientific Registry of Transplant Recipients and assembled a retrospective cohort of 181,799 deceased donor kidneys recovered for transplantation from 2000-2013. We identified the impact of the day of the week on the procurement and subsequent utilization or discard of deceased donor kidneys in the United States, as well as report the geographic variation of the impact of weekends on transplantation. Compared with weekday kidneys, organs procured on weekends were significantly more likely to be discarded than transplanted (odds ratio: 1.16; 95% confidence interval: 1.13-1.19), even after adjusting for organ quality (adjusted odds ratio: 1.13; 95% confidence interval: 1.10-1.17). Weekend discards were of a significantly higher quality than weekday discards (Kidney Donor Profile Index: 76.5% vs. 77.3%). Considerable geographic variation was noted in the proportion of transplants that occurred over the weekend. Kidneys available for transplant over the weekend were significantly more likely to be used at larger transplant centers, be shared without payback, and experienced shorter cold ischemia times. Thus, factors other than kidney quality are contributing to the discard of deceased donor kidneys, particularly during weekends. Policy prescriptions, administrative or organizational solutions within transplant programs may potentially mitigate against the recent increase in kidney discards.

Simultaneous liver and kidney transplantation.

Purpose of reviewThe Model for End-Stage Liver Disease (MELD) scoring system for prioritizing patients for liver transplantation heavily weights serum creatinine, leading to increased numbers of liver transplant patients with renal insufficiency receiving both liver-alone transplants and liver-kidney transplants. With available organs being scarce, review of recent outcomes and guidelines for their use is timely. Recent findingsDespite lower average renal function in liver transplant recipients in the era of Model for End-Stage Liver Disease scoring, and poor renal function predicting inferior outcomes, overall outcomes are unchanged. Combined liver-kidney transplants have increased three-fold. Despite inferior short-term kidney and liver-graft survival rates, long-term success rates are equivalent to single-organ transplantation. Only patients requiring dialysis at the time of transplantation clearly benefit from combined liver-kidney transplants. Waitlisted patients with nonresolving severe acute kidney injury for 6–8 weeks or substantial irreversible renal parenchymal damage are also deemed appropriate candidates. Many combined liver-kidney recipients have lesser degrees of renal dysfunction, however. Accurate determination of renal function in patients with cirrhosis remains problematic. SummaryAppropriate patients with irreversible end-stage renal and liver disease clearly deserve combined liver-kidney transplants. More data on the reliable assessment of renal function, renal pathology, and outcomes are needed, however.

Availability, Utilization and Outcomes of Deceased Diabetic Donor Kidneys; Analysis Based on the UNOS Registry

The number of kidneys obtained from deceased diabetic donors available for transplantation has increased >eightfold increase in the past 15 years. We assessed allograft outcomes associated with deceased diabetic donors and compared them with that of standard and extended criteria donors (ECD) in the UNOS data registry. We identified 1982 recipients of diabetic standard criteria donors over a 10‐year period from 1995 through 2004. Both overall and death‐censored survival of organs from diabetic standard criteria donors was significantly better than that of organs obtained from nondiabetic ECD while inferior to that from nondiabetic standard criteria donors. Compared with ECD donors, diabetic donors had lower serum creatinine, less cold ischemia and these kidneys were less likely to be pump‐perfused. Recipients of diabetic kidneys were younger and less likely to experience delayed graft function compared with recipient of ECD kidneys. More recently, many diabetic donor kidneys have been given to diabetic recipients with early graft survival being similar to that among nondiabetic recipients. These findings demonstrate the potential to expand and to improve utilization of this resource without compromising outcomes for recipients. Improved, evidence‐based evaluation and allocation of deceased diabetic donor kidneys is needed to optimize their use.

Preformed donor-specific antibodies and risk of antibody-mediated rejection in repeat renal transplantation

Background Allograft outcomes in patients undergoing repeat renal transplantation are inferior compared to first-time transplant recipient outcomes. Donor-specific antibodies detected by solid-phase assays (DSA-SPA) may contribute to the worse prognosis. The influence of DSA-SPA on repeat renal transplantation outcomes has not been previously studied in detail. Design This study reports the findings in 174 patients who underwent repeat renal transplantation between years 2007 and 2012. These included 62 patients with preformed DSA-SPA detected by Luminex at the time of transplantation. Patients received standard and consistent immunosuppression and were monitored closely for evidence of rejection. Recipients who underwent desensitization were excluded from this analysis. Endpoints included development of biopsy-proven acute rejection and analysis of graft survival and function. Results Patients in the DSA-SPA-positive and DSA-SPA-negative groups received similar immunosuppression, and a similar proportion of recipients had a peak panel reactive antibody greater than 20%; the two groups differed with respect to human leukocyte antigen mismatches (4.7±1.1 vs. 4.1±1.7, P=0.024). Recipients with preformed DSA-SPA had higher rejection rates (54.8% vs. 34.8%, P=0.01), including higher rates of antibody-mediated rejection (AMR) (32.3% vs. 7.1%, P<0.001). Recipients who were DSA-SPA-positive and flow cytometry crossmatch (FCXM)-positive had a higher incidence of both AMR (OR 4.6, P=0.009) and of acute rejection (OR 3.57, P=0.02) as compared to those who were DSA-SPA-positive and FCXM-negative. Overall allograft survival was similar in the DSA-SPA-positive and DSA-SPA-negative groups (log-rank test=0.63, P=0.428). Differences in allograft function were detectable after 2 years (32.8±13.1 vs. 47±20.2 mL/min/1.73 m2, P=0.023) and may be reflective of more AMR among DSA-SPA-positive patients. Conclusions This analysis suggests that DSA-SPA increases the overall risk of acute rejection but does not appear to adversely impact allograft survival during the early follow-up period. Close monitoring of renal function and early biopsy for AMR detection appear to allow for satisfactory short-term allograft outcomes in repeat transplant recipients.BACKGROUND Allograft outcomes in patients undergoing repeat renal transplantation are inferior compared to first-time transplant recipient outcomes. Donor-specific antibodies detected by solid-phase assays (DSA-SPA) may contribute to the worse prognosis. The influence of DSA-SPA on repeat renal transplantation outcomes has not been previously studied in detail. DESIGN This study reports the findings in 174 patients who underwent repeat renal transplantation between years 2007 and 2012. These included 62 patients with preformed DSA-SPA detected by Luminex at the time of transplantation. Patients received standard and consistent immunosuppression and were monitored closely for evidence of rejection. Recipients who underwent desensitization were excluded from this analysis. Endpoints included development of biopsy-proven acute rejection and analysis of graft survival and function. RESULTS Patients in the DSA-SPA-positive and DSA-SPA-negative groups received similar immunosuppression, and a similar proportion of recipients had a peak panel reactive antibody greater than 20%; the two groups differed with respect to human leukocyte antigen mismatches (4.7 ± 1.1 vs. 4.1 ± 1.7, P=0.024). Recipients with preformed DSA-SPA had higher rejection rates (54.8% vs. 34.8%, P=0.01), including higher rates of antibody-mediated rejection (AMR) (32.3% vs. 7.1%, P<0.001). Recipients who were DSA-SPA-positive and flow cytometry crossmatch (FCXM)-positive had a higher incidence of both AMR (OR 4.6, P=0.009) and of acute rejection (OR 3.57, P=0.02) as compared to those who were DSA-SPA-positive and FCXM-negative. Overall allograft survival was similar in the DSA-SPA-positive and DSA-SPA-negative groups (log-rank test=0.63, P=0.428). Differences in allograft function were detectable after 2 years (32.8 ± 13.1 vs. 47 ± 20.2 mL/min/1.73 m(2), P=0.023) and may be reflective of more AMR among DSA-SPA-positive patients. CONCLUSIONS This analysis suggests that DSA-SPA increases the overall risk of acute rejection but does not appear to adversely impact allograft survival during the early follow-up period. Close monitoring of renal function and early biopsy for AMR detection appear to allow for satisfactory short-term allograft outcomes in repeat transplant recipients.

Impact of small variations in the delivered dose of rabbit antithymocyte induction therapy in kidney transplantation with early corticosteroid withdrawal.

Background Optimal dosing of rabbit antithymocyte globulin (rATG) induction therapy in kidney transplantation is not well defined. The impact of dosing from variations in dose rounding or single dose limits has not been studied. Methods This retrospective study of 242 adult renal transplant recipients receiving rATG induction and steroid-sparing maintenance therapy evaluates the effect of small changes in rATG induction dosing. The local protocol calls for four doses of rATG 1.5 mg/kg, approximated to the nearest 25 mg and limited to a max of 150 mg. Patients were stratified by total rATG dose received 5 to 6 mg/kg (n=151) and 6 mg/kg (n=91) or more. Incidence of biopsy-proven acute rejection, patient and graft survival, and allograft function were examined. Results Baseline and transplantation characteristics were similar between groups except for differences in mean weight (SD) (81 [17.3] vs. 76.3 [15.6]) and cumulative rATG dose received (451.8 [96.2] vs. 481.1 [93]) for patients in the 5- to 6-mg/kg group and 6-mg/kg or more group, respectively. Patients who received more rATG showed a significantly lower incidence of biopsy-proven acute rejection at last follow-up 11% (32/151) vs. 21.2% (10/91) among those who received only 5 to 6 mg/kg (P<0.042). Renal function (mean serum creatinine level) was similar at both 90 days and time of last follow-up. Safety review of leukopenia or thrombocytopenia did not differ. Conclusion Small changes in total rATG induction administered seem to significantly impact the incidence of rejection. Adequate rATG dosing is associated with improved rejection-free graft survival and should be achieved for all patients; doses should be rounded up when appropriate or additional doses should be administered if necessary.

Association between Reperfusion Renal Allograft Biopsy Findings and Transplant Outcomes

Biopsy findings at the time of procurement of deceased donor kidneys remain the most common reason cited for kidney discard. To determine the value of renal allograft histology in predicting outcomes, we evaluated the significance of histologic findings, read by experienced renal pathologists, in 975 postreperfusion biopsy specimens collected from 2005 to 2009 after living donor (n=427) or deceased donor (n=548) renal transplant. We evaluated specimens for the degree of glomerulosclerosis, interstitial fibrosis and tubular atrophy, and vascular disease; specimens with a score of 0 or 1 (scale, 0-3) for each parameter were considered optimal. Overall, 66.3% of living donor kidneys and 50.7% of deceased donor kidneys received an optimal histology score (P<0.001). Irrespective of donor status, suboptimal kidneys came from older donors with a higher incidence of diabetes mellitus, hypertension, and obesity and a higher mean kidney donor risk index (all P<0.001). Death-censored outcomes after transplant differed significantly between optimal and suboptimal kidneys only in the deceased donor transplants (P=0.02). Regardless of histologic classification, outcomes with deceased donor kidneys were inferior to outcomes with living donor kidneys. However, 73.2% of deceased donor kidneys with suboptimal histology remained functional at 5 years. Our findings suggest that histologic findings on postreperfusion biopsy associate with outcomes after deceased donor but not living donor renal transplants, thus donor death and organ preservation-related factors may be of greater prognostic importance. Discarding donated kidneys on the basis of histologic factors may be inappropriate and merits further study.

Pathology of Calcineurin and Mammalian Target of Rapamycin Inhibitors in Kidney Transplantation

The recent evolution in immunosuppression therapy has led to significant improvement in short-term kidney allograft outcomes; however, this progress did not translate into similar improvement in long-term graft survival. The latter, at least in part, is likely to be attributed to immunosuppressant side effects. In this review, we focus on the histologic manifestations of calcineurin inhibitor and mammalian target of rapamycin inhibitor toxicity. We discuss the pathologic features attributed to such toxicity and allude to the lack of highly specific pathognomonic lesions. Finally, we highlight the importance of clinicopathologic correlation to achieve a meaningful pathologic interpretation.