Plasma-Derived C1 Esterase Inhibitor for Acute Antibody-Mediated Rejection Following Kidney Transplantation: Results of a Randomized Double-Blind Placebo-Controlled Pilot Study.

Antibody-mediated rejection (AMR) is typically treated with plasmapheresis (PP) and intravenous immunoglobulin (standard of care; SOC); however, there is an unmet need for more effective therapy. We report a phase 2b, multicenter double-blind randomized placebo-controlled pilot study to evaluate the use of human plasma-derived C1 esterase inhibitor (C1 INH) as add-on therapy to SOC for AMR. Eighteen patients received 20 000 units of C1 INH or placebo (C1 INH n = 9, placebo n = 9) in divided doses every other day for 2 weeks. No discontinuations, graft losses, deaths, or study drug-related serious adverse events occurred. While the study's primary end point, a difference between groups in day 20 pathology or graft survival, was not achieved, the C1 INH group demonstrated a trend toward sustained improvement in renal function. Six-month biopsies performed in 14 subjects (C1 INH = 7, placebo = 7) showed no transplant glomerulopathy (TG) (PTC+cg≥1b) in the C1 INH group, whereas 3 of 7 placebo subjects had TG. Endogenous C1 INH measured before and after PP demonstrated decreased functional C1 INH serum concentration by 43.3% (p < 0.05) for both cohorts (C1 INH and placebo) associated with PP, although exogenous C1 INH-treated patients achieved supraphysiological levels throughout. This new finding suggests that C1 INH replacement may be useful in the treatment of AMR.

Quantifying renal allograft loss following early antibody-mediated rejection.

Unlike antibody-mediated rejection (AMR) with clinical features, it remains unclear whether subclinical AMR should be treated, as its effect on allograft loss is unknown. It is also uncertain if AMR's effect is homogeneous across donor (deceased/live) and (HLA/ABO) antibody types. We compared 219 patients with AMR (77 subclinical, 142 clinical) to controls matched on HLA/ABO-compatibility, donor type, prior transplant, panel reactive antibody (PRA), age and year. One and 5-year graft survival in subclinical AMR was 95.9% and 75.7%, compared to 96.8% and 88.4% in matched controls (p = 0.0097). Subclinical AMR was independently associated with a 2.15-fold increased risk of graft loss (95% CI: 1.19-3.91; p = 0.012) compared to matched controls, but not different from clinical AMR (p = 0.13). Fifty three point two percent of subclinical AMR patients were treated with plasmapheresis within 3 days of their AMR-defining biopsy. Treated subclinical AMR patients had no difference in graft loss compared to matched controls (HR 1.73; 95% CI: 0.73-4.05; p = 0.21), but untreated subclinical AMR patients did (HR 3.34; 95% CI: 1.37-8.11; p = 0.008). AMR's effect on graft loss was heterogeneous when stratified by compatible deceased donor (HR = 4.73; 95% CI: 1.57-14.26; p = 0.006), HLA-incompatible deceased donor (HR = 2.39; 95% CI: 1.10-5.19; p = 0.028), compatible live donor (no AMR patients experienced graft loss), ABO-incompatible live donor (HR = 6.13; 95% CI: 0.55-67.70; p = 0.14) and HLA-incompatible live donor (HR = 6.29; 95% CI: 3.81-10.39; p < 0.001) transplant. Subclinical AMR substantially increases graft loss, and treatment seems warranted.

Experiences obtaining insurance after live kidney donation.

The impact of kidney donation on the ability to change or initiate health or life insurance following donation is unknown. To quantify this risk, we surveyed 1046 individuals who donated a kidney at our center between 1970 and 2011. Participants were asked whether they changed or initiated health or life insurance after donation, and if they had any difficulty doing so. Among 395 donors who changed or initiated health insurance after donation, 27 (7%) reported difficulty; among those who reported difficulty, 15 were denied altogether, 12 were charged a higher premium and 8 were told they had a preexisting condition because they were kidney donors. Among 186 donors who changed or initiated life insurance after donation, 46 (25%) reported difficulty; among those who reported difficulty, 23 were denied altogether, 27 were charged a higher premium and 17 were told they had a preexisting condition because they were kidney donors. In this single-center study, a high proportion of kidney donors reported difficulty changing or initiating insurance, particularly life insurance. These practices by insurers create unnecessary burden and stress for those choosing to donate and could negatively impact the likelihood of live kidney donation among those considering donation.

Quantifying the risk of incompatible kidney transplantation: a multicenter study.

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.

The aggressive phenotype revisited: utilization of higher-risk liver allografts.

Organ shortage has led to increased utilization of higher risk liver allografts. In kidneys, aggressive center-level use of one type of higher risk graft clustered with aggressive use of other types. In this study, we explored center-level behavior in liver utilization. We aggregated national liver transplant recipient data between 2005 and 2009 to the center-level, assigning each center an aggressiveness score based on relative utilization of higher risk livers. Aggressive centers had significantly more patients reaching high MELDs (RR 2.19, 2.33 and 2.28 for number of patients reaching MELD>20, MELD>25 and MELD>30, p<0.001), a higher organ shortage ratio (RR 1.51, 1.60 and 1.51 for number of patients reaching MELD>20, MELD>25 and MELD>30 divided by number of organs recovered at the OPO, p<0.04), and were clustered within various geographic regions, particularly regions 2, 3 and 9. Median MELD at transplant was similar between aggressive and nonaggressive centers, but average annual transplant volume was significantly higher at aggressive centers (RR 2.27, 95% CI 1.47-3.51, p<0.001). In cluster analysis, there were no obvious phenotypic patterns among centers with intermediate levels of aggressiveness. In conclusion, highwaitlist disease severity, geographic differences in organ availability, and transplant volume are the main factors associated with the aggressive utilization of higher risk livers.

The aggressive phenotype: center-level patterns in the utilization of suboptimal kidneys.

Despite the fact that suboptimal kidneys have worse outcomes, differences in waiting times and wait-list mortality have led to variations in the use of these kidneys. It is unknown whether aggressive center-level use of one type of suboptimal graft clusters with aggressive use of other types of suboptimal grafts, and what center characteristics are associated with an overall aggressive phenotype. United Network for Organ Sharing (UNOS) data from 2005 to 2009 for adult kidney transplant recipients was aggregated to the center level. An aggressiveness score was assigned to each center based on usage of suboptimal grafts. Deceased-donor transplant volume correlated with aggressiveness in lower volume, but not higher volume centers. Aggressive centers were mostly found in regions 2 and 9. Aggressiveness was associated with wait-list size (RR 1.69, 95% CI 1.20-2.34, p = 0.002), organ shortage (RR 2.30, 95% CI 1.57-3.37, p < 0.001) and waiting times (RR 1.75, 95% CI 1.20-2.57, p = 0.004). No centers in single-center OPOs were classified as aggressive. In cluster analysis, the most aggressive centers were aggressive in all metrics and vice versa; however, centers with intermediate aggressiveness had phenotypic patterns in their usage of suboptimal kidneys. In conclusion, wait-list size, waiting times, geographic region and OPO competition seem to be driving factors in center-level aggressiveness.

Pregnancy outcomes in kidney transplant recipients: a systematic review and meta-analysis.

Approximately 50,000 women of reproductive age in the United States are currently living after kidney transplantation (KT), and another 2800 undergo KT each year. Although KT improves reproductive function in women with ESRD, studies of post-KT pregnancies are limited to a few voluntary registry analyses and numerous single-center reports. To obtain more generalizable inferences, we performed a systematic review and meta-analysis of articles published between 2000 and 2010 that reported pregnancy-related outcomes among KT recipients. Of 1343 unique studies, 50 met inclusion criteria, representing 4706 pregnancies in 3570 KT recipients. The overall post-KT live birth rate of 73.5% (95%CI 72.1-74.9) was higher than the general US population (66.7%); similarly, the overall post-KT miscarriage rate of 14.0% (95%CI 12.9-15.1) was lower (17.1%). However, complications of preeclampsia (27.0%, 95%CI 25.2-28.9), gestational diabetes (8.0%, 95%CI 6.7-9.4), Cesarean section (56.9%, 95%CI 54.9-58.9) and preterm delivery (45.6%, 95%CI 43.7-47.5) were higher than the general US population (3.8%, 3.9%, 31.9% and 12.5%, respectively). Pregnancy outcomes were more favorable in studies with lower mean maternal ages; obstetrical complications were higher in studies with shorter mean interval between KT and pregnancy. Although post-KT pregnancy is feasible, complications are relatively high and should be considered in patient counseling and clinical decision making.