Tarek Alhamad

Checkpoint Inhibitors in Kidney Transplant Recipients and the Potential Risk of Rejection.

Enhancing anti-tumor T cell immunity with checkpoint inhibitor antibodies such as anticytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and antiprogram death 1 (PD-1) has shown significant clinical benefits in tumor regression and prolonged stabilization of non–small cell lung cancer, melanoma, and renal cell cancer (1,2). Clinical trials of CTLA-4 and PD-1 antibodies excluded patients receiving immunosuppression medications for organ transplantation (3). Therefore, the adverse events related to CTLA-4 and PD-1 antibody treatment in kidney transplant recipients with metastatic cutaneous melanoma have not been examined.

The outcomes of simultaneous liver and kidney transplantation using donation after cardiac death organs.

Background There has been a remarkable increase in simultaneous liver and kidney transplantations (SLK). As organ demand has increased, so has the use of donation after cardiac death (DCD). However, little is known about the outcomes of DCD in SLK. Methods We performed a retrospective analysis using the United Network for Organ Sharing database to compare the outcomes of DCD SLK to donation after brain death (DBD) and determine the impact of donor and recipient factors on allograft and patient survival. Results Between 2002 and 2011, a total of 3,026 subjects received SLK from DBD and 98 from DCD. Kidney, liver, and patient survival from DCD donors were inferior to DBD at 1, 3, and 5 years (P=0.0056, P=0.0035, and P=0.0205, respectively). With the use of the Cox model, DCD was a significant risk factor for kidney and liver allograft failure and patient mortality. Recipient factors that were associated with worse allograft and patient outcomes included black race, diabetes, being on a ventilator, hospitalization, delayed graft function, hepatocellular carcinoma, and intensive care unit stay. Older age of the donor was also associated with worse outcomes. Conclusion Despite the decreased allograft and patient survival compared with DBD, DCD SLK provides an acceptable option for SLK, with a survival probability of more than 50% at 5 years.

Survival Implications of Opioid Use Before and After Liver Transplantation

Implications of prescription opioid use for outcomes after liver transplantation (LT) have not been described. We integrated national transplant registry data with records from a large pharmaceutical claims clearinghouse (2008‐2014; n = 29,673). Opioid fills on the waiting list were normalized to morphine equivalents (MEs), and exposure was categorized as follows: > 0‐2 ME/day (level 1), > 2‐10 ME/day (level 2), > 10‐70 ME/day (level 3), and >70 ME/day (level 4). Associations (adjusted hazard ratio [aHR], 95% LCL aHR 95% UCL) of pretransplant ME level with patient and graft survival over 5 years after transplant were quantified by multivariate Cox regression including adjustment for recipient, donor, and transplant factors, as well as propensity adjustment for opioid use. Overall, 9.3% of recipients filled opioids on the waiting list. Compared with no use, level 3 (aHR 1.061.281.55) and 4 (aHR 1.161.521.98) opioid use during listing were associated with increased mortality over 5 years after transplant. These associations were driven by risk after the first transplant anniversary, such that mortality >1‐5 years increased in a graded manner with higher use on the waiting list (level 2, aHR, 1.001.271.62; level 3, aHR, 1.081.381.77; level 4, aHR, 1.492.012.72). Similar patterns occurred for graft failure. Of recipients with the highest level of opioids on the waiting list, 65% had level 3 or 4 use in the first year after transplant, including 55% with use at these levels from day 90‐365 after transplant. Opioid use in the first year after transplant also bore graded associations with subsequent death and graft loss >1‐5 years after transplant. Opioid use history may be relevant in assessing and providing care to LT candidates. Liver Transplantation 23 305–314 2017 AASLD.

Transplant Center Volume and the Risk of Pancreas Allograft Failure.

Background Successful pancreas transplantation requires surgical expertise and multidisciplinary medical management. The impact of transplant center volume on pancreas allograft survival remains unclear. Methods We examined Organ Procurement and Transplantation Network data on 11 568 simultaneous pancreas-kidney (SPK) and 4308 solitary pancreas (pancreas transplant alone and pancreas after kidney) transplants between 2000 and 2013. Results Average annual transplant center volume was categorized by tertiles into low, medium, and high volume, respectively, as follows: 1 to 6 (n = 3861), 7 to 13 (n = 3891), and 14 to 34 (n = 3888) for SPK, and 1 to 3 (n = 1417), 4 to 10 (n = 1518), and 11 to 33 (n = 1377) for solitary pancreas transplants. Favorable donor characteristics were seen in low-volume centers. For SPK transplantation, low (adjusted hazard ration [aHR], 1.55, 95% confidence interval [CI], 1.34-1.8) and medium (aHR, 1.24; 95% CI, 1.07-1.44) center volumes were associated with a higher risk of early pancreas graft failure at 3 months. The increased risk associated with low center volume extended to 1, 5, and 10 years. For solitary pancreas transplants, low, but not medium, center volume was associated with a higher risk of early pancreas graft failure at 3 months (aHR, 1.56; 95% CI, 1.232-1.976), and this risk persisted over 10 years. Patients transplanted at high-volume centers had better pancreas survival rates across all categories of the Pancreas Donor Risk Index. Conclusion On average, low center volume were associated with higher risk for pancreas failure. Future studies should seek to identify care processes that support optimal outcomes after pancreas transplantation irrespective of center volume.

Functional assessment of a novel COL4A5 splice region variant and immunostaining of plucked hair follicles as an alternative method of diagnosis in X-linked Alport syndrome

BackgroundMany COL4A5 splice region variants have been described in patients with X-linked Alport syndrome, but few have been confirmed by functional analysis to actually cause defective splicing. We sought to demonstrate that a novel COL4A5 splice region variant in a family with Alport syndrome is pathogenic using functional studies. We also describe an alternative method of diagnosis.MethodsTargeted next-generation sequencing results of an individual with Alport syndrome were analyzed and the results confirmed by Sanger sequencing in family members. A splicing reporter minigene assay was used to examine the variant’s effect on splicing in transfected cells. Plucked hair follicles from patients and controls were examined for collagen IV proteins using immunofluorescence microscopy.ResultsA novel splice region mutation in COL4A5, c.1780-6T>G, was identified and segregated with disease in this family. This variant caused frequent skipping of exon 25, resulting in a frameshift and truncation of collagen α5(IV) protein. We also developed and validated a new approach to characterize the expression of collagen α5(IV) protein in the basement membranes of plucked hair follicles. Using this approach we demonstrated reduced collagen α5(IV) protein in affected male and female individuals in this family, supporting frequent failure of normal splicing.ConclusionsDiffering normal to abnormal transcript ratios in affected individuals carrying splice region variants may contribute to variable disease severity observed in Alport families. Examination of plucked hair follicles in suspected X-linked Alport syndrome patients may offer a less invasive alternative method of diagnosis and serve as a pathogenicity test for COL4A5 variants of uncertain significance.

Pretransplant Midodrine Use: A Newly Identified Risk Marker for Complications after Kidney Transplantation

Background Midodrine is prescribed to prevent symptomatic hypotension and decrease complications associated with hypotension during dialysis. We hypothesized that midodrine use before kidney transplantation may be a novel marker for posttransplant risk. Methods We analyzed integrated national US transplant registry, pharmacy records, and Medicare claims data for 16 308 kidney transplant recipients transplanted 2006 to 2008, of whom 308 (1.9%) had filled midodrine prescriptions in the year before transplantation. Delayed graft function (DGF), graft failure, and patient death were ascertained from the registry. Posttransplant cardiovascular complications were identified using diagnosis codes on Medicare billing claims. Adjusted associations of pretransplant midodrine use with complications at 3 and 12 months posttransplant were quantified by multivariate Cox or logistic regression, including propensity for midodrine exposure. Results At 3 months, patients who used midodrine pretransplant had significantly (P < 0.05) higher rates of DGF, 32% versus 19%; hypotension, 14% versus 4%; acute myocardial infarction, 4% versus 2%; cardiac arrest, 2% versus 0.9%, graft failure, 5% versus 2%; and death, 4% versus 1% than nonusers. After multivariate adjustment including recipient and donor factors, as well as for the propensity of midodrine exposure, pretransplant midodrine use was independently associated with risks of DGF (adjusted odds ratio, 1.78; 95% confidence interval [CI], 1.36-2.32), and 3 month death-censored graft failure (adjusted hazard ratio, 2.0; 95% CI, 1.18-3.39), and death (adjusted hazard ratio, 3.49; 95% CI, 1.95-6.24). Patterns were similar at 12 months. Conclusions Although associations may in part reflect underlying conditions, the need for midodrine before kidney transplantation is a risk marker for complications including DGF, graft failure, and death.

An economic assessment of contemporary kidney transplant practice

Kidney transplantation is the optimal therapy for end‐stage renal disease, prolonging survival and reducing spending. Prior economic analyses of kidney transplantation, using Markov models, have generally assumed compatible, low‐risk donors. The economic implications of transplantation with high Kidney Donor Profile Index (KDPI) deceased donors, ABO incompatible living donors, and HLA incompatible living donors have not been assessed. The costs of transplantation and dialysis were compared with the use of discrete event simulation over a 10‐year period, with data from the United States Renal Data System, University HealthSystem Consortium, and literature review. Graft failure rates and expenditures were adjusted for donor characteristics. All transplantation options were associated with improved survival compared with dialysis (transplantation: 5.20‐6.34 quality‐adjusted life‐years [QALYs] vs dialysis: 4.03 QALYs). Living donor and low‐KDPI deceased donor transplantations were cost‐saving compared with dialysis, while transplantations using high‐KDPI deceased donor, ABO‐incompatible or HLA‐incompatible living donors were cost‐effective (<

Center practice drives variation in choice of US kidney transplant induction therapy: a retrospective analysis of contemporary practice

100 000 per QALY). Predicted costs per QALY range from

The impact of direct-acting antiviral agents on liver and kidney transplant costs and outcomes

39 939 for HLA‐compatible living donor transplantation to

Utilization of Kidneys With Acute Kidney Injury in the Extended Criteria Donor Setting

80 486 for HLA‐incompatible donors compared with