David W. Gjertson

High Survival Rates of Kidney Transplants from Spousal and Living Unrelated Donors

BACKGROUND In the United States, increasing numbers of persons are donating kidneys to their spouses. Despite greater histoincompatibility, the survival rates of these kidneys are higher than those of cadaveric kidneys. We examined the factors influencing the high survival rates of spousal-donor kidneys. METHODS Kidney-transplant data from the United Network for Organ Sharing Renal Transplant Registry were used to calculate graft-survival rates with Kaplan-Meier analysis. RESULTS The three-year survival rates were 85 percent for kidneys from 368 spouses, 81 percent for kidneys from 129 living unrelated donors who were not married to the recipients, 82 percent for kidneys from 3368 parents, and 70 percent for 43,341 cadaveric kidneys. The three-year survival rate for wife-to-husband grafts was 87 percent, which was the same as for husband-to-wife grafts if the wife had never been pregnant. If the wife had previously been pregnant, the three-year graft-survival rate was 76 percent (P = 0.40). The three-year graft-survival rate among recipients of spousal grafts who did not receive transfusions preoperatively was 81 percent, as compared with 90 percent for recipients who received 1 to 10 transfusions preoperatively (P = 0.008). The superior survival rate of grafts from unrelated donors could not be attributed to better HLA matching, white race, younger donor age, or shorter cold-ischemia times, but might be explained by damage due to shock before removal in 10 percent of the cadaveric kidneys. CONCLUSIONS Spouses are an important source of living-donor kidney grafts because, despite poor HLA matching, the graft-survival rate is similar to that of parental-donor kidneys. This high rate of survival is attributed to the fact that the kidneys were uniformly healthy.

Transplantation of kidneys from donors whose hearts have stopped beating.

Background Attempts have recently been made to expand the number of cadaveric kidneys available for transplantation by using kidneys from donors without heartbeats in addition to those from brain-dead donors with beating hearts. We studied the efficacy of transplanting kidneys from donors without heartbeats on the basis of aggregate results from the Kidney Transplant Registry of the United Network for Organ Sharing. Methods We compared the early function and survival rates of 229 kidney grafts from donors without heartbeats with those of 8718 grafts from cadaveric donors with heartbeats. All transplantations were performed at 64 U.S. transplantation centers. Cox proportional-hazards analysis was used to evaluate 10 major risk factors for graft failure. Results The survival rate at one year was 83 percent for kidney grafts from donors without heartbeats, as compared with 86 percent for grafts from donors with heartbeats (P=0.26). Among the kidneys from donors without heartbeats, the survival rate at one year was 89 percent for grafts from donors who had died of trauma, as compared with 78 percent for grafts from donors who had died of other causes (P=0.04). The survival rates were high for grafts from donors without heartbeats despite the poorer early function of these grafts; 48 percent of the recipients required dialysis within the first week after transplantation, as compared with 22 percent of the recipients of grafts from donors with heartbeats. The primary-failure rate for kidneys from donors without heartbeats was 4 percent, as compared with 1 percent for kidneys from donors with heartbeats. Conclusions Transplantation of kidneys from donors whose hearts have stopped beating, especially those who have died of trauma, is often successful, and the use of kidneys from such donors could increase the overall supply of cadaveric kidney transplants.

Recurrent Glioblastoma Multiforme: ADC Histogram Analysis Predicts Response to Bevacizumab Treatment

PURPOSE To determine if apparent diffusion coefficient (ADC) histogram analysis can stratify progression-free survival in patients with recurrent glioblastoma multiforme (GBM) prior to bevacizumab treatment. MATERIALS AND METHODS The study was approved by the institutional review board and was HIPAA compliant; informed consent was obtained. Bevacizumab-treated and control patients (41 per cohort) diagnosed with recurrent GBM were analyzed by using whole enhancing tumor ADC histograms with a two normal distribution mixture fitting curve on baseline (pretreatment) magnetic resonance (MR) images to generate ADC classifiers, including the overall mean ADC as well as the mean ADC from the lower curve (ADC(L)). Overall and 6-month progression-free survival (as defined by the Macdonald criteria) was determined by using Cox proportional hazard ratios and the Kaplan-Meier method with log-rank test. RESULTS For bevacizumab-treated patients, the hazard ratio for progression by 6 months in patients with less than versus greater than mean ADC(L) was 4.1 (95% confidence interval: 1.6, 10.4), and there was a 2.75-fold reduction in the median time to progression. For the control patients, there was no significant difference in median time to progression for the patients with low versus high ADC(L) (hazard ratio, 1.8; 95% confidence interval: 0.9, 3.7). For bevacizumab-treated patients, pretreatment ADC more accurately stratified 6-month progression-free survival than did change in enhancing tumor volume at first follow-up (73% vs 58% accuracy, P = .034). CONCLUSION Pretreatment ADC histogram analysis can stratify progression-free survival in bevacizumab-treated patients with recurrent GBM.

Twelve Years' Experience with National Sharing of HLA-Matched Cadaveric Kidneys for Transplantation

BACKGROUND In October 1987, the United Network for Organ Sharing (UNOS) established a national kidney-sharing program to increase the number of HLA-matched transplantations. Since then, over 7500 cadaveric kidneys have been shipped to centers in 48 states for transplantation to HLA-matched patients. We evaluated the efficacy of the program during its first 12 years of operation. METHODS We compared the rates of rejection and actuarial graft survival for 7614 HLA-matched and 81,364 HLA-mismatched cadaveric kidney transplantations reported to the UNOS Scientific Registry between October 1987 and September 1999. To assess the effects of the extended period of ischemia associated with shipping HLA-matched kidneys, we identified 3562 pairs of cadaveric kidneys in which one kidney went to an HLA-matched recipient and the other went to an HLA-mismatched recipient. RESULTS The estimated 10-year rate of graft survival was 52 percent for HLA-matched transplants, as compared with 37 percent for HLA-mismatched transplants. The estimated half-lives of the transplants were 12.5 years and 8.6 years, respectively, and the mean duration of cold ischemia was 23 hours and 22 hours, respectively. After adjustment for the effects of demographic characteristics, at 10 years the overall rates of graft survival and the rates of functional-graft survival (with data censored on patients who died with a functioning graft) were 10 percent and 11 percent higher, respectively, for HLA-matched transplants than for HLA-mismatched transplants. Among 3562 pairs of kidneys, HLA-matched transplants had higher rates of survival, a lower incidence of episodes of rejection, and a lower risk of loss as a result of rejection. CONCLUSIONS A superior graft outcome with little increase in the duration of cold ischemia justifies national sharing of HLA-matched kidney transplants.

ISFG: Recommendations on biostatistics in paternity testing

The Paternity Testing Commission (PTC) of the International Society for Forensic Genetics has taken up the task of establishing the biostatistical recommendations in accordance with the ISO 17025 standards and a previous set of ISFG recommendations specific to the genetic investigations in paternity cases. In the initial set, the PTC recommended that biostatistical evaluations of paternity are based on a likelihood ratio principle - yielding the paternity index, PI. Here, we have made five supplementary biostatistical recommendations. The first recommendation clarifies and defines basic concepts of genetic hypotheses and calculation concerns needed to produce valid PIs. The second and third recommendations address issues associated with population genetics (allele probabilities, Y-chromosome markers, mtDNA, and population substructuring) and special circumstances (deficiency/reconstruction and immigration cases), respectively. The fourth recommendation considers strategies regarding genetic evidence against paternity. The fifth recommendation covers necessary documentation, reporting details and assumptions underlying calculations. The PTC strongly suggests that these recommendations should be adopted by all laboratories involved in paternity testing as the basis for their biostatistical analysis.

Survival of Nationally Shared, HLA-Matched Kidney Transplants from Cadaveric Donors

BACKGROUND The importance of HLA histocompatibility typing to the outcome of transplantation of cadaveric kidneys has been controversial. Four years ago, a prospective trial began in all U.S. transplantation centers to determine whether the results of transplantation would improve with the nationwide shipment of kidneys from cadaveric donors to waiting patients undergoing dialysis when there was a match at the HLA-A, B, and DR loci. METHODS A total of 1386 cadaveric kidneys were shipped from 108 organ centers to 198 transplantation centers and distributed among HLA-matched recipients, 1004 of whom were receiving a first transplant and 382 of whom were receiving a subsequent transplant. Graft survival in these recipients was compared with that in 22,188 recipients of first transplants and 3950 recipients of subsequent transplants whose HLA antigens differed from those of the donor. RESULTS The rate of graft survival at one year in recipients of HLA-matched first transplants was 88 percent, as compared with 79 percent in the recipients of mismatched grafts (P less than 0.001). The estimated half-life of the kidney after the first year was 17.3 years for matched grafts, as compared with 7.8 years for mismatched grafts (P = 0.003). Among paired kidneys from 470 donors, one-year graft survival was 87 percent in the recipients of matched first grafts, as compared with 80 percent in the recipients of the contralateral kidneys, who did not have HLA matches with the donors. In donors and recipients matched for the more highly defined split Class I and Class II HLA antigens, the rate of graft survival after one year was as high as 90 percent. CONCLUSIONS The collaborative renal-transplantation program for HLA matching of donors and recipients yielded an increased rate of one-year graft survival and an estimated half-life for matched grafts twice that for mismatched grafts. An increased role for HLA matching in kidney allocation is therefore indicated.

The relative effects of FK506 and cyclosporine on short- and long-term kidney graft survival.

As reported to the UNOS Kidney Transplant Registry from 1988 through 1994, 544 first cadaveric kidney graft recipients have been discharged with maintenance tacrolimus (FK506) therapy. Total follow-up data was available on 38,057 first cadaveric kidney transplants from 224 centers reporting at least 10 grafts each to the Registry. We examined the effects of FK506 on short- and long-term renal graft outcomes and compared its effect with that of cyclosporine (CsA). Three drug categories (FK506, CsA, and Other) were defined using therapies through discharge (i.e., grafts surviving more than 15 days). The 1-year graft survival rate of 2366 recipients receiving Other therapies was 69.2 +/- 1.0%. By comparison, both FK506 and CsA recipients demonstrated significantly improved early graft function (1-yr survival rates of 91.1 +/- 1.3% and 86.6 +/- 0.2%, respectively). The long-term graft survival, as measured by half-lives, varied little (8-9 yr) between Other and CsA groups, but was significantly (P = 0.04) increased for FK506 patients (to approximately 14 yrs). CsA usage was reported by all 224 transplant centers, whereas FK506 was administered at only 24 (11%) centers. Using multivariate methods, a drug regimens graft survival rate was adjusted for center effects and 19 covariates. The adjusted FK506 and CsA cadaveric graft survival rates at 1 and 3 years mirrored their unadjusted rates, indicating that demographic differences did not confound our results. Based on this study, FK506 appears to be the first therapeutic agent to significantly improve long-term kidney graft survival rates.

Outcomes of Kidney Transplantation From Older Living Donors to Older Recipients

BACKGROUND More than half the newly wait-listed patients for kidney transplantation in 2005 were older than 50 years, and 13% were older than 65 years. As waiting times for a deceased donor kidney increase, these older candidates are disadvantaged by rapidly deteriorating health, often resulting in death or removal from the wait list before transplantation. STUDY DESIGN An observational cohort study was conducted using data from the Organ Procurement Transplant Network/United Network for Organ Sharing. SETTING & PARTICIPANTS All adult kidney-only transplantations performed in recipients 60 years and older from 1996 to 2005 were included. PREDICTOR The recipient cohort was stratified into 4 groups based on donor source: older living donor (OLD: living donor age > 55 years), younger living donor (YLD: living donor age </= 55 years), standard criteria deceased donor (SCD), and expanded criteria deceased donor (ECD). OUTCOMES & MEASUREMENTS Early posttransplantation outcomes, graft survival, patient survival, renal function 1 year posttransplantation, and relative risk of graft loss and patient death were compared. RESULTS Of 23,754 kidney transplantations performed in recipients 60 years and older, 7,006 were living donor transplantations (1,133 were > 55 years [OLD] and 5,873 were <or= 55 years [YLD]), 12,197 from SCDs, and 4,551 from ECDs. Early posttransplantation outcomes were best in YLD transplantations, followed by SCD and OLD transplantations. OLD transplantations were associated with inferior 3-year graft survival rates (85.7%), but similar 3-year patient survival rates (88.4%) compared with YLD (3-year graft survival, 83.4%; patient survival, 87.4%) and had superior graft survival compared with all deceased donor options. Compared with OLD transplantations, ECD transplantations were associated with a greater risk of graft loss (hazard ratio, 2.36; 95% confidence interval, 1.18 to 4.74). LIMITATIONS Observational retrospective studies using registry data are subject to inherent limitations, including the possibility of selection bias. CONCLUSIONS With superior graft and patient survival in recipients of transplants from OLDs compared with SCDs and ECDs, OLDs may be an important option for elderly transplantation candidates and should be considered for older patients with a willing and suitable older donor.

Hepatitis C virus and death risk in hemodialysis patients.

In maintenance hemodialysis (MHD) patients, hepatitis C virus (HCV) infection is common and may be associated with poor clinical outcomes. It was hypothesized that HCV infection would be associated with high all-cause and cardiovascular mortality in these patients after controlling for demographic and clinical characteristics, including surrogates of malnutrition-inflammation complex syndrome. A national database of 13,664 MHD patients who underwent HCV antibody serology testing at least once during a 3-yr interval (July 2001 through June 2004) was analyzed. Measurements included third-generation HCV enzyme immunoassay and routine laboratory measurements. The HCV enzyme immunoassay was reported positive in 1590 (12%) patients. In logistic regression models that included case mix and available surrogates of malnutrition-inflammation complex syndrome, HCV infection was associated with younger age, male gender, black race, Hispanic ethnicity, Medicaid insurance, longer dialysis vintage (duration), unmarried status, HIV infection, and smoking history. In proportional-hazards regressions, the mortality hazard ratio that was associated with HCV infection was 1.25 (95% confidence interval 1.12 to 1.39; P < 0.001). Mortality hazards were higher among incident (dialysis duration <6 mo) than prevalent HD patients. Subgroup analyses indicated that HCV was associated with higher all-cause and cardiovascular mortality across almost all clinical, demographic, and laboratory groups of patients. Hence, in MHD patients, HCV infection exhibits distinct demographic, clinical, and laboratory patterns, including associations with higher dialysis treatment vintage, and is associated with higher mortality. More diligent efforts to prevent and treat HCV infection may improve outcomes in MHD patients.

Receptor-ligand analyses define minimal killer cell Ig-like receptor (KIR) in humans

Interactions between inhibitory killer cell immunoglobulin-like receptors (iKIR) and human leukocyte antigen (HLA) class I molecules regulate natural killer (NK) cell responses to eliminate infected and transformed cells while maintaining tolerance to healthy cells. Unlinked polymorphic gene families encode KIR receptors and HLA class I ligands and their independent segregation results in a variable number and type of iKIR + HLA pairs inherited in individuals. The diversity in the co-inheritance of iKIR + HLA pairs and activating KIR (aKIR) genes in 759 unrelated individuals from four ethnic populations was analyzed. Every individual studied inherited a minimum of one iKIR + HLA pair; suggesting that major histocompatibility complex class I-dependent inhibitory KIR signaling is essential for human NK cell function. In contrast, 13.4% of the study group lacked all aKIR genes. Twenty percent of the study group carried only one of the four iKIR + HLA pairs. Interestingly, 3% of the study group carrying only KIR2DL3 + HLA-C1 as an iKIR + HLA pair lacked aKIR genes. These data suggest that a single iKIR can constitute the minimal KIR repertoire for human NK cells. Genotypes carrying an equal number of iKIR + HLA pairs and aKIR genes represented 20% of the study group. The remaining individuals had either a dominant inhibitory KIR genotype (iKIR + HLA > aKIR) or a dominant activating KIR genotype (iKIR + HLA < aKIR). Genotypes encoding these imbalanced inhibitory and activating interactions may contribute to susceptibility or resistance to human diseases.