Faculty Bibliography

Incompatible live donor kidney transplantation (ILDKT) offers a survival advantage over dialysis to patients with anti-HLA donor-specific antibody (DSA). Program-specific reports (PSRs) fail to account for ILDKT, placing this practice at regulatory risk. We collected DSA data, categorized as positive Luminex, negative flow crossmatch (PLNF) (n = 185), positive flow, negative cytotoxic crossmatch (PFNC) (n = 536) or positive cytotoxic crossmatch (PCC) (n = 304), from 22 centers. We tested associations between DSA, graft loss and mortality after adjusting for PSR model factors, using 9669 compatible patients as a comparison. PLNF patients had similar graft loss; however, PFNC (adjusted hazard ratio [aHR] = 1.64, 95% confidence interval [CI]: 1.15-2.23, p = 0.007) and PCC (aHR = 5.01, 95% CI: 3.71-6.77, p < 0.001) were associated with increased graft loss in the first year. PLNF patients had similar mortality; however, PFNC (aHR = 2.04; 95% CI: 1.28-3.26; p = 0.003) and PCC (aHR = 4.59; 95% CI: 2.98-7.07; p < 0.001) were associated with increased mortality. We simulated Centers for Medicare & Medicaid Services flagging to examine ILDKT's effect on the risk of being flagged. Compared to equal-quality centers performing no ILDKT, centers performing 5%, 10% or 20% PFNC had a 1.19-, 1.33- and 1.73-fold higher odds of being flagged. Centers performing 5%, 10% or 20% PCC had a 2.22-, 4.09- and 10.72-fold higher odds. Failure to account for ILDKT's increased risk places centers providing this life-saving treatment in jeopardy of regulatory intervention.

BACKGROUND: Although several strategies for treating early antibody-mediated rejection (AMR) in kidney transplants have been investigated, evidence on treatment of late AMR manifesting after 6 months is sparse. In this single-center series, we present data on 23 consecutive patients treated for late AMR. METHODS: Late AMR was diagnosed using Banff 2007 criteria along with presence of donor-specific antibodies (DSA) and acute rise in serum creatinine (SCr). Response to therapy was assessed by improvement in SCr, histologic improvement, and decline in DSA strength. RESULTS: Overall, 17% (4/23) had documented nonadherence while 69% (16/23) had physician-recommended reduction in immunosuppression before AMR. Eighteen patients (78%) were treated with plasmapheresis or low-dose IVIg+rituximab; 11 (49%) with refractory AMR also received one to three cycles of bortezomib. While there was an improvement (P=0.02) in mean SCr (2.4 mg/dL) at the end of therapy compared with SCr at the time of diagnosis (2.9 mg/dL), this improvement was not sustained at most recent follow-up. Eleven (48%) patients had no histologic resolution on follow-up biopsy. Lack of histologic response was associated with older patients (odds ratio [OR]=3.17; P=0.04), presence of cytotoxic DSA at time of diagnosis (OR=200; P=0.04), and severe chronic vasculopathy (cv>/=2) on index biopsy (OR=50; P=0.06). CONCLUSIONS: A major setting in which late AMR occurred in our cohort was reduction or change in immunosuppression. Our data demonstrate an inadequate response of late AMR to current and novel (bortezomib) therapies. The benefits of therapy need to be counterweighed with potential adverse effects especially in older patients, large antibody loads, and chronic allograft vasculopathy.

BACKGROUND: The correlation between histopathologic phenotypes and allograft outcomes among patients desensitized for donor-specific antibody (HLA-incompatible) is unknown. METHODS: We analyzed 1-year biopsies from desensitized recipients transplanted between 1999 and 2010 and estimated graft survival for each histologic phenotype identified. Median time posttransplant for the 1-year biopsy was 367 days (interquartile range 357-388 days) and median follow-up of all patients post-1-year biopsy was 42 months (interquartile range 19.5-65 months). RESULTS: Transplant glomerulopathy was present in 25.0% of biopsies and resulted in worse graft survival (66.7% vs. 96.7%, P<0.001). C4d positivity and transplant glomerulopathy together portended exceptionally poor graft survival (33.3% vs. 97.2%, P<0.001). Microcirculation inflammation was prevalent, with glomerulitis and peritubular capillaritis found in 60.0% and 47.6% of 1-year biopsies, respectively. Glomerulitis was associated with worse graft survival (82.1% vs. 98.1%, P=0.004), whereas capillaritis was not (88.1% vs. 97.7% respectively, P=0.091). Among C4d-negative HLA-incompatible recipients (82.6% of biopsies), no difference in graft survival was observed between patients with or without microcirculation inflammation in contrast to previous reports by other investigators. Patients who had no C4d deposition, transplant glomerulopathy, or microcirculation inflammation had a 100.0% graft survival. On Cox regression analysis, no independent histopathological parameter was associated with graft survival. CONCLUSIONS: We have identified several histopathologic phenotypes in HLA-incompatible kidney recipients that correlate with allograft outcomes. Characterization of these phenotypes is the first step towards better understanding the pathophysiologic basis of chronic antibody-mediated allograft injury and individualizing therapeutic intervention.

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.

BACKGROUND: Kidney transplantation (KT) is the treatment for end-stage renal disease in appropriate HIV-positive individuals. However, acute rejection (AR) rates are over twice those of HIV-negative recipients. METHODS: To better understand optimal immunosuppression for HIV-positive KT recipients, we studied associations between immunosuppression regimen, AR at 1 year, and survival in 516 HIV-positive and 93,027 HIV-negative adult kidney-only recipients using Scientific Registry of Transplant Recipients data from 2003 to 2011. RESULTS: Consistent with previous reports, HIV-positive patients had twofold higher risk of AR (adjusted relative risk [aRR], 1.77; 95% confidence interval [CI], 1.45-2.2; P<0.001) than their HIV-negative counterparts as well as a higher risk of graft loss (adjusted hazard ratio, 1.51; 95% CI, 1.18-1.94; P=0.001), but these differences were not seen among patients receiving antithymocyte globulin (ATG) induction (aRR for AR, 1.16; 95% CI, 0.41-3.35, P=0.77; adjusted hazard ratio for graft loss, 1.54; 95% CI, 0.73-3.25; P=0.26). Furthermore, HIV-positive patients receiving ATG induction had a 2.6-fold lower risk of AR (aRR, 0.39; 95% CI, 0.18-0.87; P=0.02) than those receiving no antibody induction. Conversely, HIV-positive patients receiving sirolimus-based therapy had a 2.2-fold higher risk of AR (aRR, 2.15; 95% CI, 1.20-3.86; P=0.01) than those receiving calcineurin inhibitor-based regimens. CONCLUSION: These findings support a role for ATG induction, and caution against the use of sirolimus-based maintenance therapy, in HIV-positive individuals undergoing KT.

IMPORTANCE: Risk of end-stage renal disease (ESRD) in kidney donors has been compared with risk faced by the general population, but the general population represents an unscreened, high-risk comparator. A comparison to similarly screened healthy nondonors would more properly estimate the sequelae of kidney donation. OBJECTIVES: To compare the risk of ESRD in kidney donors with that of a healthy cohort of nondonors who are at equally low risk of renal disease and free of contraindications to live donation and to stratify these comparisons by patient demographics. DESIGN, SETTINGS, AND PARTICIPANTS: A cohort of 96,217 kidney donors in the United States between April 1994 and November 2011 and a cohort of 20,024 participants of the Third National Health and Nutrition Examination Survey (NHANES III) were linked to Centers for Medicare & Medicaid Services data to ascertain development of ESRD, which was defined as the initiation of maintenance dialysis, placement on the waiting list, or receipt of a living or deceased donor kidney transplant, whichever was identified first. Maximum follow-up was 15.0 years; median follow-up was 7.6 years (interquartile range [IQR], 3.9-11.5 years) for kidney donors and 15.0 years (IQR, 13.7-15.0 years) for matched healthy nondonors. MAIN OUTCOMES AND MEASURES: Cumulative incidence and lifetime risk of ESRD. RESULTS: Among live donors, with median follow-up of 7.6 years (maximum, 15.0), ESRD developed in 99 individuals in a mean (SD) of 8.6 (3.6) years after donation. Among matched healthy nondonors, with median follow-up of 15.0 years (maximum, 15.0), ESRD developed in 36 nondonors in 10.7 (3.2) years, drawn from 17 ESRD events in the unmatched healthy nondonor pool of 9364. Estimated risk of ESRD at 15 years after donation was 30.8 per 10,000 (95% CI, 24.3-38.5) in kidney donors and 3.9 per 10,000 (95% CI, 0.8-8.9) in their matched healthy nondonor counterparts (P < .001). This difference was observed in both black and white individuals, with an estimated risk of 74.7 per 10,000 black donors (95% CI, 47.8-105.8) vs 23.9 per 10,000 black nondonors (95% CI, 1.6-62.4; P < .001) and an estimated risk of 22.7 per 10,000 white donors (95% CI, 15.6-30.1) vs 0.0 white nondonors (P < .001). Estimated lifetime risk of ESRD was 90 per 10,000 donors, 326 per 10,000 unscreened nondonors (general population), and 14 per 10,000 healthy nondonors. CONCLUSIONS AND RELEVANCE: Compared with matched healthy nondonors, kidney donors had an increased risk of ESRD over a median of 7.6 years; however, the magnitude of the absolute risk increase was small. These findings may help inform discussions with persons considering live kidney donation.

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.