Faculty Bibliography

Despite the success of desensitization protocols, antibody-mediated rejection (AMR) remains a significant contributor to renal allograft failure in patients with donor-specific antibodies. Plasmapheresis and high-dose intravenous immunoglobulin have proved to be effective treatments to prevent and treat AMR, but irreversible injury in the form of transplant glomerulopathy can commonly manifest months to years later. There is an unmet need to improve the outcomes for patients at risk for AMR. Updated Banff criteria now take into account the increasing understanding of the complex and heterogeneous nature of AMR phenotypes, including the timing of rejection, subclinical and chronic AMR, C4d-negative AMR, and antibody-mediated vascular rejection. Treatment for AMR is not standardized, and there is little in the way of evidence-based treatment guidelines. Refining more precisely the mechanisms of injury responsible for different AMR phenotypes and establishing relevant surrogate endpoints to facilitate more informative studies will likely allow for more accurate determination of prognosis and efficacious intervention using new therapeutic approaches. In addition to plasma exchange and intravenous immunoglobulin, a number of other add-on therapies have been tried in small studies without consistent benefit, including anti-CD20, proteasome inhibitors, complement inhibitors, anti-interleukin-6 receptor blockers, and immunoglobulin G-degrading enzyme of Streptococcus pyogenes (called IdeS).

Background/UNASSIGNED:Kidney transplantation is the first-line therapy for patients with end-stage renal disease since it offers greater long-term survival and improved quality of life when compared to dialysis. The advent of calcineurin inhibitor (CNI)-based maintenance immunosuppression has led to a clinically significant decline in the rate of acute rejection and better short-term graft survival rates. However, these gains have not translated into improvement in long-term graft survival. CNI-related nephrotoxicity and metabolic side effects are thought to be partly responsible for this. Case Presentation/UNASSIGNED:Here, we report the conversion of a highly sensitized renal transplant recipient with pretransplant donor-specific antibodies from tacrolimus to belatacept within 1 week of transplantation. This substitution was necessitated by the diagnosis of CNI-induced de novo post-transplant hemolytic uremic syndrome. Conclusion/UNASSIGNED:Belatacept is a novel costimulation blocker that is devoid of the nephrotoxic properties of CNIs and has been shown to positively impact long-term graft survival and preserve renal allograft function in low-immunologic-risk kidney transplant recipients. Data regarding its use in patients who are broadly sensitized to human leukocyte antigens are scarce, and the increased risk of rejection associated with belatacept has been a deterrent to more widespread use of this immunosuppressive agent. This case serves as an example of a highly sensitized patient that has been successfully converted to a belatacept-based CNI-free regimen.

Background: Inheritance of two APOL1 risk variants accounts for the excess risk of non-diabetic ESRD in African Americans when compared to Caucasian, Hispanic and Asian Americans. African American living donors have a higher risk of ESRD than matched non-black donors. APOL1 genotyping in potential kidney donors of African descent may identify individuals at risk for progressive CKD following donation.
Method(s): We report the retrospective analysis of APOL1 genotyping in a cohort of African American potential kidney donors. In July 2016, we initiated targeted genotyping of all African American kidney donor candidates. African American candidates with two APOL1 risk variants were excluded from kidney donation.
Result(s): A total of 28 African American kidney donor candidates were evaluated between July 2016 and April 2018. 2 (7%) were found to have two APOL1 risk variants (high risk genotype). Low risk genotype was identified in 10 (36%) candidates who had one risk variant and 16 (57%) candidates who had none. To date, 15 candidates have completed their donor work-up. Of these, 7 (47%) have already undergone donor nephrectomy, and 4 (27%) were cleared for surgery and are awaiting operation. 4 (27%) of the candidates did not meet our center specific criteria for donation. 2 out these 4 candidates who were excluded from donation were ruled out expressly for having been found to have two APOL1 risk variants.
Conclusion(s): APOL1 genotyping led to the exclusion of two donors who might have previously been allowed to donate, possibly mitigating their risk of CKD/ESRD and suboptimal graft outcomes in recipients. (Table Presented)

Incompatible living donor kidney transplant (ILDKT) has been established as an effective option for end stage renal disease (ESRD) patients with willing but HLA incompatible live donors, reducing mortality and improving quality of life. Depending upon antibody titer, ILDKT can require highly resource intensive procedure including intravenous immunoglobulin, plasma exchange and/or cell depleting antibody treatment as well as protocol biopsies and DSA testing. This study sought to compare the cost and Medicare reimbursement, exclusive of organ acquisition payment, for ILDKT recipients (N=926) with varying antibody titers to matched compatible transplants (N=2762) performed between 2002-2011. Data were assembled from a national cohort study of ILDKT and a unique dataset linking hospital cost accounting data, and Medicare claims. Overall, ILDKT transplants were 41% more expensive than their compatible counterparts ($151,024 vs. $106,636, p<.0001). The incremental cost varied by antibody titers: positive on Luminex assay but negative flow cytometric crossmatch 20% increase, positive flow cytometric crossmatch but negative cytotoxic crossmatch 26% increase, and positive cytotoxic crossmatch 39% increase (p<.0001 for all). ILDKT was associated with higher Medicare payments ($91,330 vs. $63,782 p<.0001), longer median length of stay (12.9 vs. 7.8 days), and greater outlier payments. In conclusion, ILDKT increases the cost of and payments for kidney transplant

Successful renal transplantation requires low-pressure venous drainage to permit adequate outflow from the allograft. We report here a series of three patients in whom the inferior vena cava as well as bilateral iliac veins were thrombosed, making it necessary to explore less traditional vessels for venous drainage of the renal allograft. We utilized the splanchnic vasculature in two cases, and the native left renal vein in another. The resulting atypical intra-abdominal locations of these allografts also presented difficulties for arterial anastomoses and for urinary drainage. Arterial conduits were utilized in two cases to facilitate anastomosis to the common iliac artery or the aorta and in the third case, the splenic artery was used for arterial inflow. A traditional ureterocystostomy was technically feasible for only one patient. In another, ureteroureterostomy to the native ureter was performed, and in the third case the creation of an ileal conduit was necessary. All three patients had antibodies to human leukocyte antigens and two required desensitization. All three kidneys had immediate graft function and continued to function at one year post-transplant. With a combination of planning, creativity, and persistence, patients with IVC thrombosis can enjoy the benefits of renal transplantation.

OBJECTIVE:To test whether frailty, a novel measure of physiologic reserve, is associated with longer kidney transplant (KT) length of stay (LOS), and modifies the association between LOS and mortality. BACKGROUND:Better understanding of LOS is necessary for informed consent and discharge planning. Mortality resulting from longer LOS has important regulatory implications for hospital and transplant programs. Which recipients are at risk of prolonged LOS and its effect on mortality are unclear. Frailty is a novel preoperative predictor of poor KT outcomes including delayed graft function, early hospital readmission, immunosuppression intolerance, and mortality. METHODS:We used registry-augmented hybrid methods, a novel approach to risk adjustment, to adjust for LOS risk factors from the Scientific Registry of Transplant Recipients (n = 74,859) and tested whether (1) frailty, measured immediately before KT in a novel cohort (n = 589), was associated with LOS (LOS: negative binomial regression; LOS ≥2 weeks: logistic regression) and (2) whether frailty modified the association between LOS and mortality (interaction term analysis). RESULTS:Frailty was independently associated with longer LOS [relative risk = 1.15, 95% confidence interval (CI): 1.03-1.29; P = 0.01] and LOS ≥2 weeks (odds ratio = 1.57, 95% CI: 1.06-2.33; P = 0.03) after accounting for registry-based risk factors, including delayed graft function. Frailty also attenuated the association between LOS and mortality (nonfrail hazard rate = 1.55 95% CI: 1.30-1.86; P < 0.001; frail hazard rate = 0.97, 95% CI: 0.79-1.19, P = 0.80; P for interaction = 0.001). CONCLUSIONS:Frail KT recipients are more likely to experience a longer LOS. Longer LOS among nonfrail recipients may be a marker of increased mortality risk. Frailty is a measure of physiologic reserve that may be an important clinical marker of longer surgical LOS.

The required intensity of monitoring for antibody-mediated rejection (AMR) after of ABO-incompatible (ABOi) kidney transplantation is not clearly formulized. We retrospectively evaluated a single-center cohort of 115 ABO-incompatible (ABOi) kidney transplant recipients, of which 32% were also HLA-incompatible (ABOi/HLAi) with their donors. We used an adjusted negative binomial model to evaluate risk factors for late AMR. Using this model, we risk-stratified patients into high- and low-risk groups for the development of late AMR. 26% of patients had at least one AMR episode. 49% of AMR episodes occurred within 30-days after transplant and were considered early AMR. Patients with an early AMR episode had a 5.5-fold greater incidence of developing late AMR (IRR=5.5,[95%CI:1.5-19.3],p=0.01). ABOi/HLAi recipients trended towards increased late AMR risk (IRR=1.9,[95%CI:0.5-6.6],p=0.3). High-risk recipients (those with an early AMR or those who were ABOi/HLAi) had a 6-fold increased incidence of late AMR (IRR=6.3,[95%CI:1.6-24.6],p=0.008) versus low-risk recipients. The overall incidence of late AMR was 20.8% versus 1.5% in low-risk recipients. Changes in anti-A/B titer did not correlate with late AMR (IRR=0.9 per log titer increase, p=0.7). This risk-stratification scheme uses information available within 30-days of ABOi transplantation to determine risk for late AMR and can help direct longitudinal follow-up for individual patients

BACKGROUND:Frailty increases early hospital readmission and mortality risk among kidney transplantation (KT) recipients. Although frailty represents a high-risk state for this population, the correlates of frailty, the patterns of the 5 frailty components, and the risk associated with these patterns are unclear. METHODS:Six hundred sixty-three KT recipients were enrolled in a cohort study of frailty in transplantation (12/2008-8/2015). Frailty, activities of daily living (ADL)/instrumental ADL (IADL) disability, Centers for Epidemiologic Studies Depression Scale depression, education, and health-related quality of life (HRQOL) were measured. We used multinomial regression to identify frailty correlates. We identified which patterns of the 5 components were associated with mortality using adjusted Cox proportional hazards models. RESULTS:Frailty prevalence was 19.5%. Older recipients (adjusted prevalence ratio [PR], 2.22; 95% confidence interval [CI], 1.21-4.07) were more likely to be frail. The only other factors that were independently associated with frailty were IADL disability (PR, 3.22; 95% CI, 1.72-6.06), depressive symptoms (PR, 11.31; 95% CI, 4.02-31.82), less than a high school education (PR, 3.10; 95% CI, 1.30-7.36), and low HRQOL (fair/poor: PR, 3.71; 95% CI, 1.48-9.31). The most common pattern was poor grip strength, low physical activity, and slowed walk speed (19.4%). Only 2 patterns of the 5 components emerged as having an association with post-KT mortality. KT recipients with exhaustion and slowed walking speed (hazards ratio = 2.43; 95% CI, 1.17-5.03) and poor grip strength, exhaustion, and slowed walking speed (hazard ratio, 2.61; 95% CI, 1.14-5.97) were at increased mortality risk. CONCLUSIONS:Age was the only conventional factor associated with frailty among KT recipients; however, factors rarely measured as part of clinical practice, namely, HRQOL, IADL disability, and depressive symptoms, were significant correlates of frailty. Redefining the frailty phenotype may be needed to improve risk stratification for KT recipients.

BACKGROUND: Disseminated intravascular coagulation (DIC)-positive kidneys have historically been turned down for fear of poor outcomes. Higher severity injuries, which are prone to DIC, are typically seen in younger, otherwise healthy potential donors. The continued kidney allograft shortage has generated interest in the use of these DIC-positive grafts. There have been some reports of acceptable outcomes of renal transplantation using kidneys from donors with DIC. There are multiple clinical series demonstrating good outcomes from DIC-positive kidneys when the extent of glomeruli containing fibrin thrombi is less than 50% and donor renal function is preserved. These grafts are frequently associated with a period of delayed graft function. METHODS: We report 2 transplants with kidneys from brain dead donors with known DIC. RESULTS: Both donors had renal failure and pretransplant renal biopsies showing 100% of the glomeruli containing fibrin thrombi. The recipients experienced delayed graft function requiring hemodialysis which was discontinued on postoperative days 18 and 39 for cases 1 and 2, respectively. Both patients are now over 14 months posttransplant with stable allograft function. CONCLUSIONS: Until clearer organ selection criteria are established, caution should be exercised when considering the use of kidneys with a similar phenotype and allocation decisions made by a multidisciplinary transplant team on a case-by-case basis.