Optimizing Risk Assessment In Simultaneous Liver and Kidney Transplant: Donor and Recipient Factors Associated With Improved Outcome.

Standardization in allocation of kidneys for transplant simultaneous with livers and the creation of a "safety net" for kidney transplant after liver transplant alone (LTA) was designed to encourage clinicians to list patients for LTA when the likelihood of renal recovery and the necessity of simultaneous liver and kidney (SLK) transplant were unclear. We analyzed the United Network for Organ Sharing database of SLK recipients starting January 1, 2015. Organs from one deceased donor were used in each individual case. Univariate analysis was used to analyze recipient and donor characteristics against patient and graft survival of at least 1 year. Cox regression was employed for multivariable analysis controlling for donor risk index variables. SLK recipients who failed to achieve 1 year of post-transplant survival were more likely to be older, have higher model for end-stage liver disease scores, have diabetes, have received dialysis within one week of transplant, and required intensive care unit admission at transplantation. Patients who failed to survive for at least 1 year after SLK were more likely to have received organs from donors who were older with a higher kidney donor profile index. Using national data we identified SLK donor and recipient characteristics associated with poor post-transplant outcome. Clinicians involved in the decision to list patients with liver failure for LTA or SLK may use these associations to help guide decision making.

Preformed Angiotensin II Type-1 Receptor Antibodies Are Associated With Rejection After Kidney Transplantation: A Single-Center, Cohort Study.

Antibodies against angiotensin II type-1 receptors (AT1R) have been increasingly recognized in association with rejection and poor allograft outcomes. Our goal was to define the prevalence of preformed antibodies against AT1R and evaluate the association with renal allograft outcomes in a consecutive cohort of 150 transplant recipients. IgG antibodies against AT1R were measured by enzyme-linked immunosorbent assay using cryopreserved serum samples obtained for HLA testing at the time of transplantation. Results were categorized as negative if <10 U/mL (44%), intermediate from 10 to 17 U/mL (38%), or strongly positive if >17 U/mL (18%). The presence of AT1R antibodies was inversely associated with age, dialysis status, and diabetes. We found a strong association between the presence of AT1R antibodies and acute cellular rejection using multivariate analyses, odds ratio 3.86 (95% CI, 1.03-14.47) for intermediate titers and 9.99 (95% CI, 2.6-38.4) for strongly positive titers. There was no association with HLA sensitization or C4d-positive antibody-mediated rejection. We did not observe a significant association with graft failure, allograft function, or proteinuria. Preformed AT1R antibodies are prevalent and highly associated with acute cellular rejection early after transplant, independent of anti-HLA antibodies. The presence of AT1R antibodies correlates with recipient characteristics that may denote stronger immune responses. Future studies are needed to evaluate the mechanism and causative effect of AT1R antibodies.

Are we underestimating the quality of aviremic hepatitis C-positive kidneys? Time to reconsider.

Kidney Donor Risk Index (KDRI) introduced in 2009 included hepatitis C serologic but not viremic status of the donors. With nucleic acid amplification testing (NAT) now being mandatory, further evaluation of these donors is possible. We conducted a retrospective matched case-control analysis of adult deceased donor kidney transplants performed between December 5, 2014 to December 31, 2016 with the KDRI score and hepatitis C virus antibody (HCV Ab) and NAT testing status obtained from the United Network for Organ Sharing database. The 205 aviremic HCV Ab+ NAT - kidney transplants were compared to KDRI matched control kidneys that were HCV Ab-NAT-. The aviremic HCV kidneys were recovered from donors who were significantly younger, more likely to be white, and less likely to have hypertension and diabetes. The majority of the recipients of the aviremic HCV kidneys when compared to matched controls were HCV positive: 90.2% vs 4.3%. The recipients were significantly older, were on dialysis for a shorter time, and were transplanted sooner. The graft survival of aviremic HCV kidneys was similar (P < .08). If the HCV status of the aviremic kidneys was assumed to be negative, 122 more kidneys could have been allocated to patients with estimated posttransplant survival <20. Seven kidneys would no longer have Kidney Donor Profile Index >85%. Further policies might consider these findings to appropriately allocate these kidneys.

Unintended Consequences in Use of Increased Risk Donor Kidneys in the New Kidney Allocation Era.

BACKGROUND: The new kidney allocation system (KAS) intends to allocate the top 20% of kidneys to younger recipients with longer life expectancy. We hypothesized that the new KAS would lead to greater allocation of Public Health Service (PHS) increased-risk donor organs to younger recipients. METHODS: Analyses of the Organ Procurement and Transplantation Network data of patients who underwent primary deceased kidney transplantation were performed in pre- and post-KAS periods. RESULTS: The allocation of PHS increased-risk kidney allografts in various age groups changed significantly after implementation of the new KAS, with an increased proportion of younger individuals receiving increased-risk kidneys (7% vs 10% in age group 20-29 y and 13% vs 18% in age group 30-39 y before and after KAS, respectively; P < .0001). This trend was reversed in recipients 50-59 years old, with 31% in the pre-KAS period compared with 26% after KAS (P < .0001). CONCLUSIONS: The new KAS resulted in a substantial increase in allocation of PHS increased-risk kidneys to candidates in younger age groups. Because increased-risk kidneys are generally underutilized, future efforts to optimize the utilization of these organs should target younger recipients and their providers.

Landscape of Kidney Transplantation in Patients With Compensated Liver Disease: Results of a Survey of Transplant Surgeons in the United States.

BACKGROUND: The therapeutic options that provide the best long-term outcome for patients who have a combination of end-stage renal disease and compensated cirrhosis are unknown. METHODS: Given the paucity of data and the lack of clinical guidance in this area, a national survey was conducted in the form of an e-mail-based questionnaire addressed to the transplantation surgeons registered with the American Society of Transplant Surgeons. RESULTS: Of the 818 surgeons invited to participate in the survey, 167 (20%) responded. Twenty-one (12.6%) respondents indicated that their program performed <50 kidney transplantations per year, 49 (29.3%) reported performing 50 to 100 kidney transplantations per year, and the majority, 97 (58.1%) of respondents, performed >100 kidney transplantations per year. The majority, 116 (69.5%), believed that compensated cirrhotic patients with end-stage renal disease could be considered for renal transplantation alone, 45 (26.9%) respondents believed that compensated cirrhotic patients on dialysis could only be considered for simultaneous liver-kidney transplantation, and 6 (3.6%) believed that this population of patients was not suitable for kidney transplantation alone. CONCLUSIONS: Our findings suggest that there is a substantial heterogeneity of opinion among transplantation surgeons towards transplantation options for compensated cirrhotic patients. Further data is needed to define best practices and clinical guidelines.

Immunosuppressive Medications and Squamous Cell Skin Carcinoma: Nested Case-Control Study Within the Skin Cancer after Organ Transplant (SCOT) Cohort.

Organ transplant recipients (OTRs) have a substantially elevated risk of squamous cell skin carcinoma (SCSC), largely attributed to immunosuppressive medications used to prevent graft rejection, although data to support the role of newer drugs in SCSC risk are sparse. We investigated the association between immunosuppressive medications and SCSC risk among cardiac and renal transplant recipients in the SCOT cohort study. Incident cases were ascertained through medical record review after self-report of skin biopsy (n = 170). Controls without SCSC (n = 324) were matched to cases on sex, age, race, transplant year, hospital, donor type, organ transplanted, and time between transplantation and interview. Conditional logistic regression was used to evaluate the association between specific medications and SCSC. Users of the antimetabolite azathioprine were more than twice as likely to develop SCSC (odds ratio [OR] = 2.67, 95% confidence interval [CI] 1.23-5.76). In contrast, the newer antimetabolite preparations (i.e., mycophenolic acid [MPA]) were associated with lower SCSC risk (OR = 0.45, 95% CI 0.29-0.69). This inverse association between MPA and SCSC persisted among OTRs with no history of azathioprine use, even after adjustment for simultaneous use of the calcineurin inhibitor tacrolimus (OR = 0.52, 95% CI 0.32-0.84). Our data suggest that the increased risk of SCSC historically associated with azathioprine is not seen in OTRs prescribed newer regimens, including MPA and tacrolimus.

Racial differences in determinants of live donor kidney transplantation in the United States.

Few studies have compared determinants of live donor kidney transplantation (LDKT) across all major US racial-ethnic groups. We compared determinants of racial-ethnic differences in LDKT among 208 736 patients who initiated treatment for end-stage kidney disease during 2005-2008. We performed proportional hazards and bootstrap analyses to estimate differences in LDKT attributable to sociodemographic and clinical factors. Mean LDKT rates were lowest among blacks (1.19 per 100 person-years [95% CI: 1.12-1.26]), American Indians/Alaska Natives-AI/ANs (1.40 [1.06-1.84]) and Pacific Islanders (1.10 [0.78-1.84]), intermediate among Hispanics (2.53 [2.39-2.67]) and Asians (3.89 [3.51-4.32]), and highest among whites (6.46 [6.31-6.61]). Compared with whites, the largest proportion of the disparity among blacks (20%) and AI/ANs (29%) was attributed to measures of predialysis care, while the largest proportion among Hispanics (14%) was attributed to health insurance coverage. Contextual poverty accounted for 16%, 4%, 18%, and 6% of the disparity among blacks, Hispanics, AI/ANs and Pacific Islanders but none of the disparity among Asians. In the United States, significant disparities in rates of LDKT persist, but determinants of these disparities vary by race-ethnicity. Efforts to expand preESKD insurance coverage, to improve access to high-quality predialysis care and to overcome socioeconomic barriers are important targets for addressing disparities in LDKT.

Low-dose rabbit antithymocyte globulin induction therapy results in prolonged selective lymphocyte depletion irrespective of maintenance immunosuppression.

Rabbit antithymocyte globulin therapy (rATG) is a potent lymphocyte-depleting agent commonly used following renal transplantation to reduce the risk of acute rejection. Standard doses (7-10 mg/kg) of rATG result in profound lymphopenia and predispose patients to infection and malignancy. The effects of lower doses of rATG (LoD-rATG, 3-5 mg/kg) on peripheral blood lymphocytes (PBL) are as yet unknown. In this prospective clinical trial, PBL subsets were characterized by flow cytometry over 12 months following LoD-rATG therapy. All patients were initially treated with standard doses of tacrolimus, mycophenolic acid, and prednisone. At 3 months, patients were randomized to either lower doses of tacrolimus or sirolimus to examine the effects of maintenance immunosuppression on PBL reemergence. LoD-rATG therapy resulted in prolonged suppression of CD19+ B cells, total CD3+ T cells, as well as naïve and memory CD4+ T cell and CD4/CD25/Foxp3+ T-regulatory subsets irrespective of chronic immunosuppressive therapy. Selective depletion was only noted in the CD4CD45RA+ naïve T-cell subset resulting in an altered memory/naïve CD4+ ratio. LoD-rATG failed to deplete CD8+ T cells, which increased their relative contribution to the total CD3+ pool. All other lymphocyte subsets maintained near normal proportions. Thus, LoD-rATG therapy may lessen the adverse effects of full dose rATG while maintaining overall efficacy.

Conversion to low-dose tacrolimus or rapamycin 3 months after kidney transplantation: a prospective, protocol biopsy-guided study.

Long-term survival of kidney allografts is primarily limited by a progressive decline in function characterized by the presence of interstitial fibrosis (IF) and tubular atrophy (TA) on biopsy. Since chronic calcineurin-inhibitor (CNI) drug toxicity has been implicated as a significant cause of IF/TA, a major effort in transplantation has been to decrease or eliminate CNI therapy. We now report the clinical and histological consequences of converting renal transplant recipients at 3 months to either very low levels of tacrolimus (TAC; 4-6 ng/mL) or sirolimus (SRL; 6-10 ng/mL) therapy. Fifty-eight enrollees in this prospective randomized trial received low-dose (2.9±0.6 mg/kg) rabbit antithymocyte globulin induction followed by standard doses of TAC (10-15 ng/mL), mycophenolic acid, and low-dose steroids for 3 months. Protocol biopsies were performed at implantation and 3 and 12 months. Six patients had evidence of either borderline changes (n=5) or grade 1A rejection (n=1) on the 3-month protocol biopsy and were not randomized. Only one patient had clinically evident rejection that occurred after randomization to SRL. One patient in each group had borderline changes at 12 months. Renal function (estimated glomerular filtration rate) was equivalent in both groups at 12 months (TAC 74±15 vs SRL 66±18 mL/min, P=.22). Chronic allograft damage index scores at 1 year were similar in both groups (TAC 2.8±2.4 vs SRL 2.0±2.7, P=.71). The percentage of patients with IF/TA scores greater than 2 at 1 year was low in both groups (TAC 12% vs SRL 9%, P=.78). Therefore, in a low-risk population defined as having a normal 3-month protocol biopsy, TAC levels can be successfully decreased to very low concentrations. One-year graft function and histology were equally well maintained with either low-dose TAC or SRL immunosuppression.

Tubular basement membrane immune deposits in association with BK polyomavirus nephropathy.

Tubular basement membrane immune deposits (TBMID) are rare in renal allografts and usually have been found in association with immune complex mediated glomerular injury. We report an association between TBMID and BK polyomavirus nephropathy (BKN). We reviewed clinical data and results of allograft biopsies of 30 patients with BKN (16 with and 14 without TBMID). TBMID were detected by immunofluorescence or electron microscopy. Initial and follow-up biopsies were assessed for degree of interstitial inflammation and fibrosis and severity of viral infection, and were correlated with patients' clinical data. Biopsies initially diagnostic for BKN with TBMID, compared to BKN biopsies without deposits, demonstrated more severe interstitial inflammation and fibrosis, and greater numbers of virally infected cells. Similar findings were present in follow-up biopsies. Utilizing three different antibodies directed against viral epitopes, viral antigens could not be detected within TBMID. Thirty percent of patients with TBMID and 70% without deposits had follow-up biopsies, in which virus could not be detected immunohistochemically. Treatment for all included decreasing immunosuppression, cidofovir and/or leflunomide. Clinical data correlated well with histological findings. We conclude that a significant proportion of patients with BKN show TBMID on kidney biopsy. The prognostic significance of this finding remains to be elucidated.

Early and severe hyperparathyroidism associated with hypercalcemia after renal transplant treated with cinacalcet.

Bone disease is a common clinical problem following renal transplantation. In renal transplant recipients, multiple underlying factors determine the extent of bone loss and the subsequent risk of fractures. In addition to the well-recognized risk to bone disease posed by steroids, calcineurin inhibitors and pre-existing bone disease, persistent hyperparathyroidism (HPT) contributes to post-transplant bone loss. HPT is usually treated with vitamin D supplements combined with calcium. Patients whose HPT is associated with hypercalcemia pose a difficult therapeutic dilemma which often requires parathyroidectomy. Cinacalcet, a calcium mimetic agent, offers a unique pharmacologic approach to the treatment of patients with post-transplant hypercalcemia and HPT. In this paper, we describe the clinical course and biochemical changes in 10 renal transplant recipients with hypercalcemia and severe HPT early after renal transplantation treated with cinacalcet. Cinacalcet therapy corrected hypercalcemia and decreased parathyroid hormone (PTH) levels in all cases. A transient rise in the level of alkaline phosphatase was noted following initiation of cinacalcet therapy. In this patient population, correction of HPT was not permanent as discontinuing cinacalcet therapy led to a rapid rise in PTH level.