The Broad Spectrum of Quality in Deceased Donor Kidneys

The quality of the deceased donor organ clearly is one of the most crucial factors in determining graft survival and function in recipients of a kidney transplant. There has been considerable effort made towards evaluating these organs culminating in an amendment to allocation policy with the introduction of the expanded criteria donor (ECD) policy.
Our study, from first solitary adult deceased donor transplant recipients from 1996 to 2002 in the National Scientific Transplant Registry database, presents a donor kidney risk grade based on significant donor characteristics, donor–recipient matches and cold ischemia time, generated directly from their risk for graft loss. We investigated the impact of our donor risk grade in a naïve cohort on short- and long-term graft survival, as well as in subgroups of the population.
The projected half-lives for overall graft survival in recipients by donor risk grade were I (10.7 years), II (10.0 years), III (7.9 years), IV (5.7 years) and V (4.5 years). This study indicates that there is great variability in the quality of deceased donor kidneys and that the assessment of risk might be enhanced by this scoring system as compared to the simple two-tiered system of the current ECD classification.     

Disparities in the Utilization of Live Donor Renal Transplantation

Despite universal payer coverage with Medicare, sociodemographic disparities confound the care of patients with renal failure. We sought to determine whether adults who realize access to kidney transplantation suffer inequities in the utilization of live donor renal transplantation (LDRT). We identified adults undergoing primary renal transplantation in 2004–2006 from the United Network for Organ Sharing (UNOS). We modeled receipt of live versus deceased donor renal transplant on multilevel multivariate models that examined recipient, center and UNOS region-specific covariates. Among 41 090 adult recipients identified, 39% underwent LDRT. On multivariate analysis, older recipients (OR 0.62, 95% CI 0.56–0.68 for 50–59 year-olds vs. 18–39 year-old recipients), those of African American ethnicity (OR 0.54, 95% CI 0.50–0.59 vs. whites) and of lower socioeconomic status (OR 0.72, 95% CI 0.67–0.79 for high school-educated vs. college-educated recipients; OR 0.78, 95% CI 0.71–0.87 for lowest vs. highest income quartile) had lower odds of LDRT. These characteristics accounted for 14.2% of the variation in LDRT, more than recipient clinical variables, transplant center characteristics and UNOS region level variation. We identified significant racial and socioeconomic disparities in the utilization of LDRT. Educational initiatives and dissemination of processes that enable increased utilization of LDRT may address these disparities.     

Laparoscopic (vs. Open) Live Donor Nephrectomy: A UNOS Database Analysis of Early Graft Function and Survival

The impact of laparoscopic (lap) live donor nephrectomy on early graft function and survival remains controversial. We compared 2734 kidney transplants (tx) from lap donors and 2576 tx from open donors reported to the U.S. United Network for Organ Sharing from 11/1999 to 12/2000. Early function quality (>40 mL urine and/or serum creatinine [creat] decline >25% during the first 24 h post-tx) and delayed function incidence were similar for both groups. Significantly more lap (vs. open) txs, however, had discharge creats greater than 1.4 mg/dL (49.2% vs. 44.9%, p = 0.002) and 2.0 mg/dL (21.8% vs. 19.5%, p = 0.04). But all later creats, early and late rejection, as well as graft survival at 1 year (94.4%, lap tx vs. 94.1%, open tx) were similar for lap and open recipients. Our data suggests that lap nephrectomy is associated with slower early graft function. Rejection rates and short-term graft survival, however, were similar for lap and open graft recipients. Further prospective studies with longer follow up are necessary to assess the potential impact of the laparoscopic procurement mode on early graft function and long-term outcome.     

Gene Expression Profiling of Acute Liver Stress During Living Donor Liver Transplantation

During liver transplantation, the donor graft is subjected to a number of acute stresses whose molecular basis is not well-understood. The effects of surgical stress, preservation and reperfusion injury were studied in 24 consecutive living donor liver transplant (LDLT) operations. Liver biopsies were taken early in the donor operation (OPENING), after transection of the donor liver (PRECLAMP) and following implantation of the graft (post hepatic artery, [PHA]); these were evaluated for histology, tissue glutathione content and gene expression using a 19K-human cDNA microarray. LDLT was associated with an ischemia/reperfusion injury, with accumulation of small numbers of neutrophils and decreased glutathione in the PHA biopsies. Following reperfusion, the expression of 129 genes increased and 106 genes decreased when compared to OPENING levels (> or <2-fold, p < 0.01). By real-time PCR a subset of 25 genes was verified (15 increased, 10 decreased). These genes were similarly altered in another condition of acute liver stress (the response to brain-death), but not in three chronic liver disease states (HCV, HBV and PBC). This study has identified a set of genes whose expression is altered in acute, but not chronic, liver stress, likely to play a central role in the pathogenesis of acute liver injury of liver transplantation.     

Racial Differences in Determinants of Live Donor Kidney Transplantation in the United States

Few studies have compared determinants of live donor kidney transplantation (LDKT) across all major US racial‐ethnic groups. We compared determinants of racial‐ethnic differences in LDKT among 208 736 patients who initiated treatment for end‐stage kidney disease during 2005–2008. We performed proportional hazards and bootstrap analyses to estimate differences in LDKT attributable to sociodemographic and clinical factors. Mean LDKT rates were lowest among blacks (1.19 per 100 person‐years [95% CI: 1.12–1.26]), American Indians/Alaska Natives‐AI/ANs (1.40 [1.06–1.84]) and Pacific Islanders (1.10 [0.78–1.84]), intermediate among Hispanics (2.53 [2.39–2.67]) and Asians (3.89 [3.51–4.32]), and highest among whites (6.46 [6.31–6.61]). Compared with whites, the largest proportion of the disparity among blacks (20%) and AI/ANs (29%) was attributed to measures of predialysis care, while the largest proportion among Hispanics (14%) was attributed to health insurance coverage. Contextual poverty accounted for 16%, 4%, 18%, and 6% of the disparity among blacks, Hispanics, AI/ANs and Pacific Islanders but none of the disparity among Asians. In the United States, significant disparities in rates of LDKT persist, but determinants of these disparities vary by race‐ethnicity. Efforts to expand preESKD insurance coverage, to improve access to high‐quality predialysis care and to overcome socioeconomic barriers are important targets for addressing disparities in LDKT.     

Unique Early Gene Expression Patterns in Human Adult-to-Adult Living Donor Liver Grafts Compared to Deceased Donor Grafts

Because of inherent differences between deceased donor (DD) and living donor (LD) liver grafts, we hypothesize that the molecular signatures will be unique, correlating with specific biologic pathways and clinical patterns. Microarray profiles of 63 biopsies in 13 DD and 8 LD liver grafts done at serial time points (procurement, backbench and postreperfusion) were compared between groups using class comparisons, network and biological function analyses. Specific genes were validated by quantitative PCR and immunopathology. Clinical findings were also compared. Following reperfusion, 579 genes in DD grafts and 1324 genes in LDs were differentially expressed (p < 0.005). Many upregulated LD genes were related to regeneration, biosynthesis and cell cycle, and a large number of downregulated genes were linked to hepatic metabolism and energy pathways correlating with posttransplant clinical laboratory findings. There was significant upregulation of inflammatory/immune genes in both DD and LD, each with a distinct pattern. Gene expression patterns of select genes associated with inflammation and regeneration in LD and DD grafts correlated with protein expression. Unique patterns of early gene expression are seen in LD and DD liver grafts, correlating with protein expression and clinical results, demonstrating distinct inflammatory profiles and significant downregulation of metabolic pathways in LD grafts.     

Accommodation in ABO-Incompatible Kidney Allografts, a Novel Mechanism of Self-Protection Against Antibody-Mediated Injury

To elucidate the mechanism of self-protection against anti-donor blood-group antibody known as accommodation, we studied 16 human ABO-incompatible living-donor kidney transplant recipients at 3 and 12 months post transplantation. Both circulating anti-blood-group antibody and the target blood-group antigen in the graft were demonstrable in all patients after transplantation. Thirteen of 16 grafts had normal renal function and histology, while three grafts with prior humoral rejection demonstrated significant glomerulopathy and thus did not meet the criterion for accommodation. Using microarrays, we compared five 1-year protocol ABO-compatible renal graft biopsies to four accommodated ABO-incompatible graft biopsies. Significant alterations in gene expression in 440 probe sets, including SMADs, protein tyrosine kinases, TNF-alpha and Mucin 1 were identified. We verified these changes in gene expression using RT-PCR and immunohistochemistry. Heme oxygenase-1, Bcl-2 and Bcl-xl were not increased in ABO-incompatible grafts at any time-point. We conclude that accommodation is always present in well-functioning, long-surviving ABO-incompatible kidney transplants. This self-protection against antibody-mediated damage may involve several novel mechanisms including the disruption of normal signal transduction, attenuation of cellular adhesion and the prevention of apoptosis.