Faculty Bibliography

BACKGROUND: Recipients of incompatible allografts are at increased risk of graft loss. We hypothesized that analysis of sequential biopsies from these grafts could define progression of graft lesions and identify features predictive of progression. METHODS: We studied the time course of histologic injury in 745 kidney graft biopsies from 129 patients transplanted with a positive crossmatch human leukocyte antigen-incompatible kidney between 2000 and 2010 (follow-up of 1-9 years). RESULTS: Graft survival was 98% at 1 year and 80% at 5 years after transplantation. Throughout follow-up, 70% of patients experienced rejection, with 52% showing subclinical rejection in the first year. Cell-mediated rejection was more frequent than antibody-mediated rejection throughout follow-up. Transplant glomerulopathy (TxGN; cg>/=1) developed in 47% of patients over the period of the study, as early as 3 months in a few patients. TxGN was preceded by glomerulitis in more than 90% of cases, with a median time interval of 12 months. Glomerulitis and detectable posttransplantation donor-specific antibodies were risk factors for TxGN (P<0.0001 and P<0.05). C4d-negative antibody-mediated rejection manifesting as capillaritis (g>/=1 and ptc>/=1) with detectable donor-specific antibodies was observed in some recipients (<20%). There was progressively higher average tubulointerstitial scarring (ci+ct) from 3 to 6 to 12 months (P<0.001). CONCLUSIONS: Despite good graft survival, a significant incidence of biopsy-proven rejection occurred in this subset of closely monitored human leukocyte antigen-incompatible recipients throughout follow-up. Microcirculation inflammation, particularly glomerulitis, irrespective of C4d, is associated with a high risk of development of TxGN at 1 year.

Renal transplantation in patients with antiphospholipid antibodies has historically proven challenging due to increased risk for thrombosis and allograft failure. This is especially true for patients with antiphospholipid antibody syndrome (APS) and its rare subtype, the catastrophic antiphospholipid antibody syndrome (CAPS). Since a critical mechanism of thrombosis in APS/CAPS is one mediated by complement activation, we hypothesized that preemptive treatment with the terminal complement inhibitor, eculizumab, would reduce the extent of vascular injury and thrombosis, enabling renal transplantation for patients in whom it would otherwise be contraindicated. Three patients with APS, two with a history of CAPS, were treated with continuous systemic anticoagulation together with eculizumab prior to and following live donor renal transplantation. Two patients were also sensitized to human leukocyte antigens (HLA) and required plasmapheresis for reduction of donor-specific antibodies. After follow-up ranging from 4 months to 4 years, all patients have functioning renal allografts. No systemic thrombotic events or early graft losses were observed. While the appropriate duration of treatment remains to be determined, this case series suggests that complement inhibitors such as eculizumab may prove to be effective in preventing the recurrence of APS after renal transplantation.

BACKGROUND: Human leukocyte antigen (HLA) sensitization presents a major obstacle for patients awaiting renal transplantation. HLA antibody reduction and favorable transplantation rates have been reported after treatment with high-dose intravenous immunoglobulin (IVIg). METHODS: We enrolled 27 patients whose median flow cytometric calculated panel reactive antibody (CPRA) was 100% and mean wait-list time exceeded 4 years in a protocol whereby high-dose IVIg was administered, HLA antibody profiles of sera obtained before and after treatment were characterized, and cross-match tests were performed with all blood group identical kidney offers. RESULTS: Whereas 12.8% of a similarly sensitized historic control cohort underwent transplantation in the course of a year, 41% of the IVIg-treated group underwent transplantation during the study period. Surprisingly, HLA antibody profiles, measured by CPRA, showed no significant change in response to IVIg treatment. In fact, retrospective cross-match testing using pretreatment sera of those receiving deceased-donor allografts showed that all patients would have been eligible for transplantation with their respective donors before IVIg infusions. CONCLUSIONS: This study does not corroborate previous reports of CPRA reduction leading to increased deceased-donor transplantation rates in broadly sensitized patients undergoing desensitization with high-dose IVIg. The increased rate of transplantation relative to historic controls is not related to improved cross-match eligibility and likely resulted from frequent crossmatching using a cytotoxic strength threshold, improved medical readiness for transplantation, and newly recognized options for live-donor transplantation, all of which could have been achieved without IVIg treatment.

The worldwide focus on work hour regulations and patient safety has led to the re-examination of the merits of night-time surgery, including kidney transplantation. The risks of operating during nontraditional work hours with potentially fatigued surgeons and staff must be weighed against the negative effects of prolonged cold ischemic time with resultant graft compromise. The aim of this study was to evaluate the impact of performing renal transplantation procedures during evening versus day time hours. The main outcome measures assessed between the day and night cohorts included comparisons of the postoperative complication rates and survival outcomes for both the renal allograft and the patient. A retrospective review of 633 deceased donor renal transplants performed at a single institution was analyzed. Three statistically significant results were noted, namely, a decrease in vascular complications in the nighttime cohort, an increase in urologic complications on subgroup analysis in the 3 AM to 6 AM cohort, and the 12 AM to 3 AM subgroup had the greatest odds of any complication. There was no statistical difference in either patient or graft survival over a twelve month period following transplantation. We conclude that although the complication rate varied among cohorts this was clinically insignificant and there was no overall clinically relevant impact on patient or graft survival.

Recurrent hepatitis C virus (HCV) infection is the most common cause of graft loss and patient death after transplantation for HCV cirrhosis. Transplant surgeons have access to uninfected explanted livers before transplantation and an opportunity to deliver RNA interference-based protective gene therapy to uninfected grafts. Conserved HCV sequences were used to design short interfering RNAs and test their ability to knockdown HCV transcript expression in an in vitro model, both by transfection and when delivered via an adeno-associated viral vector. In a rodent model of liver transplantation, portal venous perfusion of explanted grafts with an adeno-associated viral vector before transplantation produced detectable short hairpin RNA transcript expression after transplantation. The ability to deliver anti-HCV short hairpin RNAs to uninfected livers before transplantation and subsequent exposure to HCV offers hope for the possibility of preventing the currently inevitable subsequent infection of liver grafts with HCV.

HYPOTHESIS: The use of kidneys from deceased donors considered at increased infectious risk represents a strategy to increase the donor pool. DESIGN: Single-institution longitudinal observational study. SETTING: Tertiary care center. PATIENTS: Fifty patients who gave special informed consent to receive Centers for Disease Control and Prevention high-risk (CDCHR) donor kidneys were followed up by serial testing for viral transmission after transplantation. Nucleic acid testing for human immunodeficiency virus, hepatitis B virus, and hepatitis C virus was performed on all high-risk donors before transplantation. Outcomes of CDCHR kidney recipients were compared with outcomes of non-high-risk (non-HR) kidney recipients. MAIN OUTCOME MEASURES: New viral transmission, graft function, and waiting list time. RESULTS: No recipient seroconversion was detected during a median follow-up period of 11.3 months. Compared with non-HR donors, CDCHR donors were younger (mean [SD] age, 35 [11] vs 43 [18] years, P = .01), fewer were expanded criteria donors (2.0% vs 24.8%, P < .001), and fewer had a terminal creatinine level exceeding 2.5 mg/dL (4.0% vs 8.8%, P = .002). The median creatinine levels at 1 year after transplantation were 1.4 (interquartile range, 1.2-1.7) mg/dL for CDCHR recipients and 1.4 (interquartile range, 1.1-1.9) mg/dL for non-HR recipients (P = .4). Willingness to accept a CDCHR kidney significantly shortened the median waiting list time (274 vs 736 days, P < .001). CONCLUSIONS: We show safe use of CDCHR donor kidneys and good 1-year graft function. With continued use of these organs and careful follow-up care, we will be better able to gauge donor risk and match it to recipient need to expand the donor pool and optimize patient benefit.