Global kidney chains.

Kidney failure is a worldwide scourge, made more lethal by the shortage of transplants. We propose a way to organize kidney exchange chains internationally between middle-income countries with financial barriers to transplantation and high-income countries with many hard to match patients and patient-donor pairs facing lengthy dialysis. The proposal involves chains of exchange that begin in the middle-income country and end in the high-income country. We also propose a way of financing such chains using savings to US health care payers.

Characterizing the risk of human leukocyte antigen-incompatible living donor kidney transplantation in older recipients.

Older compatible living donor kidney transplant (CLDKT) recipients have higher mortality and death-censored graft failure (DCGF) compared to younger recipients. These risks may be amplified in older incompatible living donor kidney transplant (ILDKT) recipients who undergo desensitization and intense immunosuppression. In a 25-center cohort of ILDKT recipients transplanted between September 24, 1997, and December 15, 2016, we compared mortality, DCGF, delayed graft function (DGF), acute rejection (AR), and length of stay (LOS) between 234 older (age ≥60 years) and 1172 younger (age 18-59 years) recipients. To investigate whether the impact of age was different for ILDKT recipients compared to 17 542 CLDKT recipients, we used an interaction term to determine whether the relationship between posttransplant outcomes and transplant type (ILDKT vs CLDKT) was modified by age. Overall, older recipients had higher mortality (hazard ratio: 1.632.072.65, P < .001), lower DCGF (hazard ratio: 0.360.530.77, P = .001), and AR (odds ratio: 0.390.540.74, P < .001), and similar DGF (odds ratio: 0.461.032.33, P = .9) and LOS (incidence rate ratio: 0.880.981.10, P = 0.8) compared to younger recipients. The impact of age on mortality (interaction P = .052), DCGF (interaction P = .7), AR interaction P = .2), DGF (interaction P = .9), and LOS (interaction P = .5) were similar in ILDKT and CLDKT recipients. Age alone should not preclude eligibility for ILDKT.

Deceased donors as nondirected donors in kidney paired donation.

As proof of concept, we simulate a revised kidney allocation system that includes deceased donor (DD) kidneys as chain-initiating kidneys (DD-CIK) in a kidney paired donation pool (KPDP), and estimate potential increases in number of transplants. We consider chains of length 2 in which the DD-CIK gives to a candidate in the KPDP, and that candidate's incompatible donor donates to theDD waitlist. In simulations, we vary initial pool size, arrival rates of candidate/donor pairs and (living) nondirected donors (NDDs), and delay time from entry to the KPDP until a candidate is eligible to receive a DD-CIK. Using data on candidate/donor pairs and NDDs from the Alliance for Paired Kidney Donation, and the actual DDs from the Scientific Registry of Transplant Recipients (SRTR) data, simulations extend over 2 years. With an initial pool of 400, respective candidate and NDD arrival rates of 2 per day and 3 per month, and delay times for access to DD-CIK of 6 months or less, including DD-CIKs increases the number of transplants by at least 447 over 2 years, and greatly reduces waiting times of KPDP candidates. Potential effects on waitlist candidates are discussed as are policy and ethical issues.

Delayed graft function and acute rejection following HLA-incompatible living donor kidney transplantation.

Incompatible living donor kidney transplant recipients (ILDKTr) have pre-existing donor-specific antibody (DSA) that, despite desensitization, may persist or reappear with resulting consequences, including delayed graft function (DGF) and acute rejection (AR). To quantify the risk of DGF and AR in ILDKT and downstream effects, we compared 1406 ILDKTr to 17 542 compatible LDKT recipients (CLDKTr) using a 25-center cohort with novel SRTR linkage. We characterized DSA strength as positive Luminex, negative flow crossmatch (PLNF); positive flow, negative cytotoxic crossmatch (PFNC); or positive cytotoxic crossmatch (PCC). DGF occurred in 3.1% of CLDKT, 3.5% of PLNF, 5.7% of PFNC, and 7.6% of PCC recipients, which translated to higher DGF for PCC recipients (aOR = 1.03 1.682.72 ). However, the impact of DGF on mortality and DCGF risk was no higher for ILDKT than CLDKT (p interaction > .1). AR developed in 8.4% of CLDKT, 18.2% of PLNF, 21.3% of PFNC, and 21.7% of PCC recipients, which translated to higher AR (aOR PLNF = 1.45 2.093.02 ; PFNC = 1.67 2.403.46 ; PCC = 1.48 2.243.37 ). Although the impact of AR on mortality was no higher for ILDKT than CLDKT (p interaction = .1), its impact on DCGF risk was less consequential for ILDKT (aHR = 1.34 1.621.95 ) than CLDKT (aHR = 1.96 2.292.67 ) (p interaction = .004). Providers should consider these risks during preoperative counseling, and strategies to mitigate them should be considered.

Non-simultaneous kidney exchange cycles in resource-restricted countries without non-directed donation - a prospective single-center cohort study.

Recent reports suggest that bridge-donor reneging is rare (1.5%) in non-simultaneous kidney exchange chains. However, in developing countries, the non-directed donors who would be needed to initiate chains are unavailable, and furthermore, limited surgical space and resources restrain the feasibility of simultaneous kidney exchange cycles. Therefore, the aim of this study was to evaluate the bridge-donor reneging rate during non-simultaneous kidney exchange cycles (NSKEC) in a prospective single-center cohort study (n = 67). We describe the protocol used to prepare co-registered donor-recipient pairs for non-simultaneous surgeries, in an effort to minimize the reneging rate. In addition, in order to protect any recipients who might be left vulnerable by this arrangement, we proposed the use of standard criteria deceased-donor kidneys to rectify the injustice in the event of any bridge-donor reneging. We report 17 successful NSKEC resulting in 67 living-donor kidney transplants (LDKT) using 23 bridge-donors without donor renege and no intervening pairs became unavailable. We propose that NSKEC could increase LDKT, especially for difficult-to-match sensitized pairs (25 of our 67 pairs) in countries with limited transplantation resources. Our study confirms that NSKEC can be safely performed with careful patient-donor selection and non-anonymous kidney exchanges.

Survival Benefit with Kidney Transplants from HLA-Incompatible Live Donors.

BACKGROUND: A report from a high-volume single center indicated a survival benefit of receiving a kidney transplant from an HLA-incompatible live donor as compared with remaining on the waiting list, whether or not a kidney from a deceased donor was received. The generalizability of that finding is unclear. METHODS: In a 22-center study, we estimated the survival benefit for 1025 recipients of kidney transplants from HLA-incompatible live donors who were matched with controls who remained on the waiting list or received a transplant from a deceased donor (waiting-list-or-transplant control group) and controls who remained on the waiting list but did not receive a transplant (waiting-list-only control group). We analyzed the data with and without patients from the highest-volume center in the study. RESULTS: Recipients of kidney transplants from incompatible live donors had a higher survival rate than either control group at 1 year (95.0%, vs. 94.0% for the waiting-list-or-transplant control group and 89.6% for the waiting-list-only control group), 3 years (91.7% vs. 83.6% and 72.7%, respectively), 5 years (86.0% vs. 74.4% and 59.2%), and 8 years (76.5% vs. 62.9% and 43.9%) (P<0.001 for all comparisons with the two control groups). The survival benefit was significant at 8 years across all levels of donor-specific antibody: 89.2% for recipients of kidney transplants from incompatible live donors who had a positive Luminex assay for anti-HLA antibody but a negative flow-cytometric cross-match versus 65.0% for the waiting-list-or-transplant control group and 47.1% for the waiting-list-only control group; 76.3% for recipients with a positive flow-cytometric cross-match but a negative cytotoxic cross-match versus 63.3% and 43.0% in the two control groups, respectively; and 71.0% for recipients with a positive cytotoxic cross-match versus 61.5% and 43.7%, respectively. The findings did not change when patients from the highest-volume center were excluded. CONCLUSIONS: This multicenter study validated single-center evidence that patients who received kidney transplants from HLA-incompatible live donors had a substantial survival benefit as compared with patients who did not undergo transplantation and those who waited for transplants from deceased donors. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases.).

The 6-year clinical outcomes for patients registered in a multiregional United States Kidney Paired Donation program - a retrospective study.

We examined what happened during a 6-year period to 1121 end-stage renal disease patients who registered with their willing/incompatible living donors for kidney exchanges with the Alliance for Paired Donation (APD). Of all patients, 65% were transplanted: 37% in kidney paired donation (APD-KPD, APD-other-KPD); 10% with compatible live donors (APD-LD); and 18% with deceased donors (APD-DD). The remaining patients were withdrawn (sick/died/others; 15%), or were still waiting (20%). For those patients with a cPRA 0-94%, 72% received a transplant. In contrast, only 49% of very highly sensitized (VHS; cPRA 95-100%) were transplanted. Of the VHS patients, 50% were transplanted by KPD/APD-LD while 50% benefited through prioritization of deceased donors in the modified kidney allocation system (KAS introduced in 2014). All APD transplanted groups had similar death-censored 4-year graft survivals as their relevant Organ Procurement and Transplantation Network (OPTN) groups. It is noteworthy that VHS graft and patient survival results were comparable to less sensitized and nonsensitized patients. All patients should be encouraged to search for compatible donors through different options. Expanding the donor pool through KPD and the new KAS of the OPTN increases the likelihood of transplantation for VHS patients.

Effect of match-run frequencies on the number of transplants and waiting times in kidney exchange.

Numerous kidney exchange (kidney paired donation [KPD]) registries in the United States have gradually shifted to high-frequency match-runs, raising the question of whether this harms the number of transplants. We conducted simulations using clinical data from 2 KPD registries-the Alliance for Paired Donation, which runs multihospital exchanges, and Methodist San Antonio, which runs single-center exchanges-to study how the frequency of match-runs impacts the number of transplants and the average waiting times. We simulate the options facing each of the 2 registries by repeated resampling from their historical pools of patient-donor pairs and nondirected donors, with arrival and departure rates corresponding to the historical data. We find that longer intervals between match-runs do not increase the total number of transplants, and that prioritizing highly sensitized patients is more effective than waiting longer between match-runs for transplanting highly sensitized patients. While we do not find that frequent match-runs result in fewer transplanted pairs, we do find that increasing arrival rates of new pairs improves both the fraction of transplanted pairs and waiting times.

Hospital readmissions following HLA-incompatible live donor kidney transplantation: A multi-center study.

Thirty percent of kidney transplant recipients are readmitted in the first month posttransplantation. Those with donor-specific antibody requiring desensitization and incompatible live donor kidney transplantation (ILDKT) constitute a unique subpopulation that might be at higher readmission risk. Drawing on a 22-center cohort, 379 ILDKTs with Medicare primary insurance were matched to compatible transplant-matched controls and to waitlist-only matched controls on panel reactive antibody, age, blood group, renal replacement time, prior kidney transplantation, race, gender, diabetes, and transplant date/waitlisting date. Readmission risk was determined using multilevel, mixed-effects Poisson regression. In the first month, ILDKTs had a 1.28-fold higher readmission risk than compatible controls (95% confidence interval [CI] 1.13-1.46; P < .001). Risk peaked at 6-12 months (relative risk [RR] 1.67, 95% CI 1.49-1.87; P < .001), attenuating by 24-36 months (RR 1.24, 95% CI 1.10-1.40; P < .001). ILDKTs had a 5.86-fold higher readmission risk (95% CI 4.96-6.92; P < .001) in the first month compared to waitlist-only controls. At 12-24 (RR 0.85, 95% CI 0.77-0.95; P = .002) and 24-36 months (RR 0.74, 95% CI 0.66-0.84; P < .001), ILDKTs had a lower risk than waitlist-only controls. These findings of ILDKTs having a higher readmission risk than compatible controls, but a lower readmission risk after the first year than waitlist-only controls should be considered in regulatory/payment schemas and planning clinical care.

Office-Based Point of Care Testing (IgA/IgG-Deamidated Gliadin Peptide) for Celiac Disease.

OBJECTIVES: Celiac disease (CD) is common yet under-detected. A point of care test (POCT) may improve CD detection. We aimed to assess the diagnostic performance of an IgA/IgG-deamidated gliadin peptide (DGP)-based POCT for CD detection, patient acceptability, and inter-observer variability of the POCT results. METHODS: From 2013-2017, we prospectively recruited patients referred to secondary care with gastrointestinal symptoms, anemia and/or weight loss (group 1); and patients with self-reported gluten sensitivity with unknown CD status (group 2). All patients had concurrent POCT, IgA-tissue transglutaminase (IgA-TTG), IgA-endomysial antibodies (IgA-EMA), total IgA levels, and duodenal biopsies. Five hundred patients completed acceptability questionnaires, and inter-observer variability of the POCT results was compared among five clinical staff for 400 cases. RESULTS: Group 1: 1000 patients, 58.5% female, age 16-91, median age 57. Forty-one patients (4.1%) were diagnosed with CD. The sensitivities of the POCT, IgA-TTG, and IgA-EMA were 82.9, 78.1, and 70.7%; the specificities were 85.4, 96.3, and 99.8%. Group 2: 61 patients, 83% female; age 17-73, median age 35. The POCT had 100% sensitivity and negative predictive value in detecting CD in group 2. Most patients preferred the POCT to venepuncture (90.4% vs. 2.8%). There was good inter-observer agreement on the POCT results with a Fleiss Kappa coefficient of 0.895. CONCLUSIONS: The POCT had comparable sensitivities to serology, and correctly identified all CD cases in a gluten sensitive cohort. However, its low specificity may increase unnecessary investigations. Despite its advantage of convenience and rapid results, it may not add significant value to case finding in an office-based setting.

The Role of an IgA/IgG-Deamidated Gliadin Peptide Point-of-Care Test in Predicting Persistent Villous Atrophy in Patients With Celiac Disease on a Gluten-Free Diet.

OBJECTIVES: Mucosal healing is important in celiac disease (CD) for the prevention of complications. However, obtaining duodenal biopsies is invasive, and there is currently no reliable surrogate marker for histological remission in clinical practice. We aimed to assess the role of a point-of-care test (POCT) based on IgA/IgG-deamidated gliadin peptide, in detecting persistent villous atrophy (VA) in CD. METHODS: We prospectively recruited patients with CD attending endoscopy for the assessment of histological remission. All patients had IgA-endomysial (EMA) antibodies, IgA-tissue transglutaminase (TTG) antibodies, and the POCT performed, and completed a validated dietary adherence questionnaire. A gastroscopy was performed in all patients, with four biopsies taken from the second part of the duodenum and one from the duodenal bulb. We compared the diagnostic performance of the surrogate markers against duodenal histology as the reference standard. RESULTS: A total of 217 patients with CD (70% female, age range 16-83 years, median age 53 years) on a gluten-free diet (median duration 6 years) were recruited from 2013 to 2017. Eighty-five (39.2%) patients had persistent VA. The sensitivities of the POCT, TTG, EMA, and the adherence score in detecting VA were 67.1%, 44.7%, 37.7%, and 24.7% respectively (P=0.0005). The combination of the POCT and adherence score only marginally increased the sensitivity to 70.6% (59.7-80.0%). CONCLUSIONS: The sensitivity of the POCT was higher than the other surrogate markers in predicting VA. A POCT may provide the additional advantage of an immediate objective assessment of mucosal healing at the time of an office-based follow-up consultation.

Decision Making in Kidney Paired Donation Programs with Altruistic Donors.

In recent years, kidney paired donation (KPD) has been extended to include living non-directed or altruistic donors, in which an altruistic donor donates to the candidate of an incompatible donor-candidate pair with the understanding that the donor in that pair will further donate to the candidate of a second pair, and so on; such a process continues and thus forms an altruistic donor-initiated chain. In this paper, we propose a novel strategy to sequentially allocate the altruistic donor (or bridge donor) so as to maximize the expected utility; analogous to the way a computer plays chess, the idea is to evaluate different allocations for each altruistic donor (or bridge donor) by looking several moves ahead in a derived look-ahead search tree. Simulation studies are provided to illustrate and evaluate our proposed method.

Blocking porcine sialoadhesin improves extracorporeal porcine liver xenoperfusion with human blood.

BACKGROUND: Patients in fulminant hepatic failure currently do not have a temporary means of support while awaiting liver transplantation. A potential therapeutic approach for such patients is the use of extracorporeal perfusion with porcine livers as a form of "liver dialysis". During a 72-h extracorporeal perfusion of porcine livers with human blood, porcine Kupffer cells bind to and phagocytose human red blood cells (hRBC) causing the hematocrit to decrease to 2.5% of the original value. Our laboratory has identified porcine sialoadhesin expressed on Kupffer cells as the lectin responsible for binding N-acetylneuraminic acid on the surface of the hRBC. We evaluated whether blocking porcine sialoadhesin prevents the recognition and subsequent destruction of hRBCs seen during extracorporeal porcine liver xenoperfusion. METHODS: Ex vivo studies were performed using wild type pig livers perfused with isolated hRBCs for 72-h in the presence of an anti-porcine sialoadhesin antibody or isotype control. RESULTS: The addition of an anti-porcine sialoadhesin antibody to an extracorporeal porcine liver xenoperfusion model reduces the loss of hRBC over a 72-h period. Sustained liver function was demonstrated throughout the perfusion. CONCLUSIONS: This study illustrates the role of sialoadhesin in mediating the destruction of hRBCs in an extracorporeal porcine liver xenoperfusion model.

Concomitant Polyoma BK Virus and West Nile Virus in Renal Allografts.

Surveillance of the renal allograft recipient is essential when monitoring renal function to detect the early onset of rejection and alter therapeutic treatments to treat acute rejection or other causes and improve long-term graft function. If renal function begins to deteriorate, a renal biopsy is often indicated to assess the Banff grade of potential rejection or other causes, especially in the setting of polyoma BK viral load elevation. Although BK infection in the allograft is asymptomatic, reactivation of the virus is known to be associated with the acceleration of pathologic change and a poor outcome in the allograft. BK reactivation in a transplant kidney is not uncommon, and determining inflammation related to the virus versus acute rejection is paramount for appropriate immunosuppressive therapy management. We identified a concomitant polyoma BK virus and West Nile Virus (WNV) infection in two renal transplant patients which, to our knowledge, has not previously been reported. However, other concomitant infections have been reported in renal allografts including BK virus and cytomegalovirus (CMV), CMV and hepatitis C (HCV), and HCV and human immunodeficiency virus (HIV). As WNV has become endemic in many regions of the United States, and since the transmission of the virus via transplanted organs is associated with significant morbidity and mortality, it may be prudent to consider serologic screening for WNV in living donors prior to organ procurement. Regardless, the observation we made and report here should underscore the potential for concomitant viral infections that may be masked when a renal allograft has a significant inflammatory response to BK virus.

A nonsimultaneous, extended, altruistic-donor chain.

We report a chain of 10 kidney transplantations, initiated in July 2007 by a single altruistic donor (i.e., a donor without a designated recipient) and coordinated over a period of 8 months by two large paired-donation registries. These transplantations involved six transplantation centers in five states. In the case of five of the transplantations, the donors and their coregistered recipients underwent surgery simultaneously. In the other five cases, "bridge donors" continued the chain as many as 5 months after the coregistered recipients in their own pairs had received transplants. This report of a chain of paired kidney donations, in which the transplantations were not necessarily performed simultaneously, illustrates the potential of this strategy.

Voronoff to virion: 1920s testis transplantation and AIDS.

BACKGROUND: We address accusations linking AIDS with testis transplantation performed by a French surgeon, Serge Voronoff (1866-1951), and their implications in the future of animal-to-human organ transplantation. METHODS: Biographical literature on Voronoff and scientific literature on xenotransplantation and the origin of HIV were reviewed. RESULTS: IN the 1920s, Serge Voronoff transplanted testes from primates into humans to revitalize them sexually and physically, making him one of the first surgeons to perform xenotransplantation-transplanting live tissues between species. In recent years, some have postulated that Voronoff's transplants may have caused or contributed to the AIDS epidemic. However, consensus among virologists holds that HIV most likely originated from a chimpanzee virus known as simian immunodeficiency viruses (SIV) which many agree was transmitted to humans during the hunting of primates in the early 1900s. As these accusations have never been addressed, evidence is reviewed which refutes the claims. HIV isolate studies are summarized, which show that SIV was most likely transferred to humans from a chimpanzee species different from those used by Voronoff. Furthermore, literature suggests that Voronoff's experiments were performed in Europe and the United States, not central Africa. CONCLUSIONS: Over 100,000 people await organ transplants, making the prospect of using animal organs to meet demand increasingly favorable. The accusations against Voronoff and others have led to increased concern over cross-species disease transfer. The evidence presented refutes those claims and is used to explain the need for further research into xenotransplantation.