Faculty Bibliography

BACKGROUND: Kidney paired donation (KPD) offers the best transplant option for patients with incompatible live kidney donors. Although studies suggest substantial expansion of the donor pool if fully used, few patients in the United States have undergone KPD. METHODS: We analyzed the 209 KPD and 89 list paired donation (LPD) transplants reported to United Network for Organ Sharing to better understand access to these modalities, clinical outcomes, and areas of potential expansion. RESULTS: Although many centers offer KPD/LPD, most centers have performed no more than a handful of transplants. As expected, outcomes with KPD/LPD were equivalent to direct donation matched controls. In analyzing current practice, we identified two limitations to KPD in its current use. First, KPD is likely limited now by benefiting mostly patients who are easy to identify and match (such as A donors with B recipients or B donors with A recipients). Second, although some expansion of local KPD availability has reduced travel requirements for patients in those areas, significant room for growth remains. CONCLUSIONS: Our results suggest that full utilization of KPD would encourage registration of and improve matching for patients who are more difficult to identify and match (such as highly sensitized recipients). Furthermore, expansion of KPD would likely reduce travel requirements and thereby improve access to this treatment modality.

Use of live non-directed donors (LNDDs), or altruistic donors, has increased significantly over the past decade and has fueled debate regarding the ethics and allocation of this new source of live donor kidneys. Three allocation philosophies are currently in use, including donor-centric, recipient-centric and socio-centric models, and our group has also advocated the use of LNDDs in paired donation. However, no universally accepted allocation policy exists, nor does national oversight. To determine allocation patterns resulting from current practice models, we analyzed the 372 LNDD kidney transplants performed in the United States since 1998. Most LNDD transplants occurred at a minority of centers, with only five centers performing over 10, and over 28% of LNDDs traveled out-of-state to donate. Furthermore, a center's use of LNDD kidneys did not correlate with that center's organ shortage. Finally, African Americans were significantly under-represented among recipients who were allocated LNDD kidneys, even after accounting for differences in the racial makeup of the waiting list representing centers using LNDD kidneys. These disparities suggest the need for continued monitoring and discussion of LNDD at a national level. If non-directed donation continues to rise at its current rate, a national allocation policy may be reasonable.

Renal ischemia was induced in the rat by constriction of the renal artery for 45 min, and the ability of the ATP-sensitive K(+) (K(ATP)) channel opener diazoxide (DZ) to ameliorate renal ischemia-reperfusion (I/R) injury was evaluated. In this model, blood urea nitrogen and creatinine were elevated 2 days after I/R injury but returned closer to normal levels by 7 days after reperfusion. Histological staining for reactive oxygen species (ROS) was clearly positive and oxidized DNA, detected by the presence of the stable adduct 8-hydroxy-2'-deoxyguanosine, was clearly present in the cytoplasm of tubular cells after 1 h of reperfusion and declined 7 days after reperfusion. This finding was confirmed by ELISA, which detected 8-hydroxy-2'-deoxyguanosine in the mitochondrial fraction of kidney homogenates. Despite evidence of improved function measured by blood urea nitrogen and creatinine 7 days after reperfusion, the early changes in tubules were alarming. Mitochondrial DNA showed the common deletion, and the number of TdT-mediated dUTP nick-end label-positive tubular cells increased. Activation of caspase-3 continued, and abnormal levels of ROS were found in the mitochondrial fraction of cellular homogenates. Treatment with DZ before ischemia reduced or prevented the acute and subacute deleterious effects associated with renal I/R injury. We conclude that excess production of ROS by mitochondria on reperfusion is a major upstream event in renal reperfusion injury and that DZ functioned by preventing ROS accumulation in the mitochondria after I/R injury, thereby reducing oxidative stress as measured by the presence of oxidized mitochondrial DNA and features of apoptosis.

Current billing practices and mandates to report surgical outcomes are disincentives to surgical treatment of obese patients, who are at increased risk for longer hospital stays and higher complication rates. The objective of this study was to quantify the independent association between body mass index (BMI) and waiting time for kidney transplantation to identify potential provider bias against surgical treatment of the obese. A secondary data analysis was performed of a prospective cohort of 132,353 patients who were registered for kidney transplantation in the United States between 1995 and 2006. Among all patients awaiting kidney transplantation, the likelihood of receiving a transplant decreased with increasing degree of obesity, categorized by ranges of BMI (adjusted hazard ratios 0.96 for overweight, 0.93 for obese, 0.72 for severely obese, and 0.56 for morbidly obese, compared with a reference group of patients with normal BMI). Similarly, the likelihood of being bypassed when an organ became available increased in a graded manner with category of obesity (adjusted incidence rate ratio 1.02 for overweight, 1.05 for obese, 1.11 for severely obese, and 1.22 for morbidly obese). Although matching an available organ with an appropriate recipient requires clinical judgment, which could not be fully captured in this study, the observed differences are dramatic and warrant further studies to understand this effect better and to design a system that is less susceptible to unintended bias.

CONTEXT: Although risks associated with live kidney donation are low, there are few pathologic studies of kidneys from live donors, and possible risk factors for development of hypertension or renal insufficiency remain unknown. There are many studies of histopathologic changes in deceased donor kidneys and how these changes affect subsequent graft function; most are based on wedge rather than needle core biopsies. OBJECTIVE: To examine the frequency and severity of arterial fibrointimal thickening and other pathologic lesions in kidneys from healthy live donors and compare wedge and needle core biopsies as methods for evaluating these changes. DESIGN: For 36 of 332 live donor renal transplantations performed from January 2004 through November 2006, a wedge biopsy of the transplanted kidney was done prior to and/or after implantation, and a needle core biopsy was done postimplantation or during the ensuing 7 days. For these 36 allografts, we compared pathologic features of the wedge and core perioperative biopsies. RESULTS: Findings on core and wedge biopsies were similar, except for arterial fibrointimal thickening. Moderate thickening (Banff cv2) was present on 13 core biopsies, and mild thickening (cv1) was present on another 10; by contrast, no wedge biopsies showed cv2 lesions, and only 8 showed cv1. Arterial thickening on core but not wedge biopsies correlated significantly with increasing patient age. CONCLUSIONS: The findings indicate that needle core biopsies are superior to wedge biopsies for evaluating vascular changes in donor kidneys, and they suggest a need for studies correlating such changes with long-term outcomes of live donors, particularly older donors.

OBJECTIVE: To quantify the independent association between obesity and access to liver transplantation. BACKGROUND: Obesity is associated with higher complication rates, longer hospitalization, and worse survival after liver transplantation. Nevertheless, transplantation provides survival benefit to patients with end-stage liver disease, regardless of body mass index (BMI). We hypothesized that, despite survival benefit, providers were reluctant to transplant obese patients because of the inherent difficulty of these cases and their inferior outcomes. Our goal was to quantify the independent association between BMI and waiting time for orthotopic liver transplantation as a surrogate marker for this reluctance. METHODS: We studied 29,136 wait-list candidates in the model for end-stage liver disease (MELD) era, categorized as severely obese (BMI 35-40), morbidly obese (BMI 40-60), and reference (BMI 18.5-35). All models were adjusted for factors relevant to the allocation system, factors possibly influencing access to healthcare, and factors biologically related to disease progression and outcomes. RESULTS: The odds of receiving a MELD exception were 30% lower in severely obese and 38% lower in morbidly obese patients. Similarly, the likelihoods of being turned down for an organ were 10% and 16% higher, and the rates of being transplanted were 11% and 29% lower in severely obese and morbidly obese patients, respectively. CONCLUSIONS: Current practice seems to indicate a reluctance to transplant obese patients. If indeed as a community we feel that liver allografts should not be distributed to patients with excessive postoperative risk, we should consider expressing this as a formal change to our allocation policy rather than through informal practice patterns.

OBJECTIVE: Animal organs engineered to be chimeric for human cells could contribute significantly to the field of transplantation, including studies of human-specific diseases such as hepatitis-C, as treatment for in-born errors of metabolism, and for development of a renewable source of transplantable organs via modified xenotransplantation. We sought to use human embryoid body-derived stem cells (EBDs) to populate livers in animals for applications in transplant surgery. METHODS: SCID mice and rats underwent liver injury with carbon tetrachloride exposure or partial hepatectomy. Animals received intrasplenic injection of fluorescently labeled human stem cells. Spleen and liver were assessed at 2, 7, 15, and 30 days after transplant for the presence of EBDs and markers of human hepatocyte differentiation. RESULTS: EBDs migrate to and engraft in animal liver after splenic injection under conditions of hepatic injury. EBDs are detectable at 2 days and are in abundance at 1 week after transplant. EBDs persist in rodent liver long term (>1 month), and once engrafted differentiate into functional human hepatocytes as assessed by production of human alpha-feto-protein (AFP) and human albumin. CONCLUSIONS: We developed a novel animal model in which hepatic injury and stem cell transplantation lead to the generation of humanized animal organs. We are currently using our model to study recurrent hepatitis-C after liver transplantation, and as an alternative to whole organ transplantation for treatment of in-born errors of metabolism.

PURPOSE OF REVIEW: Neither the concept nor the formal application of unacceptable antigens is new. However, identification of unacceptable antigens is now sufficiently accurate to be used as a virtual crossmatch, which can both prevent the unnecessary shipment of organs and increase the access for sensitized patients. RECENT FINDINGS: Desensitization protocols and an increasing array of cell-depleting agents can overcome the immunological barriers to transplantation for some patients, reducing the risk of graft rejection to an acceptable level. Increasingly sensitive and specific assays for identifying HLA antigens and antibodies are providing more accurate definition of incompatibilities. Additionally, tests of various biomarkers may permit characterization of responder types. SUMMARY: The definition of unacceptable antigens is determined by the clinical protocols and the physiological and immunological characteristics of the recipient and donor. These data should be integrated to maximize the opportunity for transplantation. The development of additional tests to assess a patient's capacity for recognizing and responding to a transplant will improve the identification of incompatible donor-recipient pairs.

When considering advocacy of split-liver transplantation, it is important to understand whether comparable outcomes can be achieved. The goal of this study was to identify donor and transplant characteristics predictive of comparable outcomes by risk factor analysis. Using the United Network for Organ Sharing/ Organ Procurement and Transplantation Network data base between January 1996 and May 2006, first time adult/child split cases (568 adults, 508 children) were examined. In multivariate analysis, recipient medical condition (hospitalization), status 1 assignment, ABO incompatibility, donor age (>40 years), donor body weight (< or = 40 kg), calculated whole graft volume to recipient body weight ratio (cGRWR < or = 1.5%) and no sharing between centers were significant risk factors in adult recipients. Recipient diagnosis of tumor, dialysis prior to transplant, recipient body weight (< or = 6 kg), donor age (>30 years), donor history of cardiac arrest after declaration of death and cold ischemia time (CIT > 6 h) increased the risk of graft failure in pediatric recipients. The livers from young donors showed comparable outcomes to whole deceased liver transplantation (LT) when other transplant-related risk factors were minimized in adult recipients. Reducing CIT is important to obtain comparable outcomes to living donor LT in pediatric recipients.