Ross B. Isaacs

Racial disparities in renal transplant outcomes

The purpose of our study was to evaluate the association of race and ethnicity with outcomes in the living related donor (LRD) renal transplant population, using multivariable adjustment for potential confounding variables. We prospectively analyzed 14,617 patients from the UNOS Renal Transplant Registry who underwent LRD renal transplantations in the United States between January 1, 1988 and December 31, 1996 using the Cox proportional hazards model. This model adjusts for the effects of potential genetic, social, and demographic confounding variables that may be associated with race or ethnicity long-term graft survival. Blacks were 1.8 times as likely as whites (P < 0.01, RR = 1.77) to suffer graft failure during the 9-year study period, which decreased minimally to 1.7 (P < 0.01, RR = 1.65) after controlling for potential confounding variables. Neither genotypic nor phenotypic HLA matching improved outcomes in blacks. Black renal transplant recipients had lower graft survival even after adjustment for matching and rejection, suggesting that non-HLA or socioeconomic mechanisms may contribute to racial differences in transplantation outcomes.

Role of Socioeconomic Status in Kidney Transplant Outcome

There is controversy regarding the influence of genetic versus environmental factors on kidney transplant outcome in minority groups. The goal of this project was to evaluate the role of certain socioeconomic factors in allograft and recipient survival. Graft and recipient survival data from the United States Renal Data System were analyzed using Cox modeling with primary variables of interest, including recipient education level, citizenship, and primary source of pay for medical service. College (hazard ratio [HR] 0.93, P < 0.005) and postcollege education (HR 0.85, P < 0.005) improved graft outcome in the whole group and in patients of white race. Similar trends were observed for recipient survival (HR 0.9, P < 0.005 for college; HR 0.88, P = 0.09 for postcollege education) in the whole population and in white patients. Resident aliens had a significantly better graft outcome in the entire patient population (HR 0.81, P < 0.001) and in white patients in subgroup analysis (HR 0.823, P < 0.001) compared with US citizens. A similar effect was observed for recipient survival. Using Medicare as a reference group, there is a statistically significant benefit to graft survival from having private insurance in the whole group (HR 0.87, P < 0.001) and in the black (HR 0.8, P < 0.001) and the white (HR 0.89, P < 0.001) subgroups; a similar effect of private insurance is observed on recipient survival in the entire group of patients and across racial groups. Recipients with higher education level, resident aliens, and patients with private insurance have an advantage in the graft and recipient outcomes independent of racial differences.

Predictors of graft survival in pediatric living-related kidney transplant recipients.

BACKGROUND A successful kidney transplant from a living-related donor (LRD) remains the most effective renal replacement therapy for children with end-stage renal failure. The use of LRD kidneys results in decreased time on dialysis, increased graft survival, and better function compared with kidneys transplanted from cadaver donors. We retrospectively analyzed data from the United Network of Organ Sharing (UNOS) Scientific Renal Transplant Registry to determine risk factors for graft loss in children who received an LRD kidney. METHODS Data was obtained from the UNOS Scientific Renal Transplant Registry on 2418 children ranging in age from 0 to 18 years who underwent an LRD kidney transplantation between January 1988 and December 1994. Multivariate analysis of graft survival was performed using Kaplan-Meier and Cox regression models. RESULTS The effects of age, pretransplantation dialysis, early rejection, and race were found to significantly affect graft survival. Gender, peak panel-reactive antibody, and ABO blood type were not found to be significant risk factors. Infants <2 years of age initially had the worst graft survival; however, over time their results stabilized, and at 7 years estimated graft survival was good (71%). Adolescents ranging in age from 13-18 years had the best initial graft survival, but as time went on graft survival worsened (55%). Patients who underwent pretransplantation dialysis had a relative risk for graft loss of 1.77 (P<0.001), whereas those who had an early rejection had a relative risk for graft loss of 1.41 (P<0.002). African-Americans had a significantly higher relative risk for graft loss than either Caucasians (1.57, P<0.0005) or Hispanics (2.01, P<0.0003). CONCLUSIONS Predictors of graft survival for children who receive LRD kidney transplants include age at transplantation, pretransplantation dialysis, early rejection, and race. Over time, adolescents and African-Americans seem to have the lowest graft survival.

Gadolinium-based Contrast and Carbon Dioxide Angiography to Evaluate Renal Transplants for Vascular Causes of Renal Insufficiency and Accelerated Hypertension

PURPOSE To evaluate the utility and potential nephrotoxicity of gadolinium-based contrast angiography when used with carbon dioxide angiography in renal transplant patients with suspected vascular causes of renal insufficiency and/or accelerated hypertension. MATERIALS AND METHODS Thirteen consecutive renal transplant patients with suspected vascular causes of renal insufficiency and/or accelerated hypertension were evaluated with gadolinium-based contrast and CO2 angiography with use of digital subtraction techniques. Stenotic lesions were treated with angioplasty with/or without stent placement. No iodinated contrast agents were used. Serum creatinine levels were obtained before and at 24 and 48 hours after the procedure. An increase in creatinine levels greater than 0.5 mg/dL (44 micromol/L) was considered significant. RESULTS Nine patients were studied for renal insufficiency, two for accelerated hypertension, and two for both. All 13 studies were considered diagnostic. Significant stenoses were treated in four patients with angioplasty with or without stent placement. Two patients had progression of their renal insufficiency. One of these patients underwent biopsy and was found to have both acute and chronic rejection. The other patient underwent cardiac catheterization 2 days after a transplant renal artery angioplasty. In the remaining nine patients with renal insufficiency (creatinine range, 1.8-3.9 mg/dL [159-345 micromol/L]; mean, 2.7 mg/dL [239 micromol/L]), renal function improved or did not worsen. CONCLUSION Based on this limited study, gadolinium-based contrast angiography appears to be a promising supplement to CO2 angiography for the diagnosis and treatment of vascular lesions in patients with renal transplant insufficiency and/or accelerated hypertension. Further study is necessary to determine safety, optimal gadolinium dosage, and imaging parameters.

Role of pre‐transplant marital status in renal transplant outcome

Abstract:  Background:  End‐stage renal disease is associated with illness‐induced disruptions that challenge patients and their families to accommodate and adapt. However, the impact of patients’ marital status on kidney transplant outcome has never been studied. This project, based on data from United States Renal Data System (USRDS), helps to answer how marriage affects renal transplant outcome.

Improved specificity and sensitivity when using pronase-digested lymphocytes to perform flow-cytometric crossmatch prior to renal transplantation

Abstract Several laboratories have resorted to flow‐cytometric crossmatch (FCXM) in an effort to prevent hyperacute and accelerated renal allograft rejections. The currently employed FCXM has problems with both false‐positive and ‐negative reactions, largely as a result of irrelevant IgG binding to Fc IgG receptors. In 1980, we circumvented this problem by digesting Fc IgG receptors with pronase, and demonstrated that, with immunofluorescnce microscopy (IF), detection of IgG anti‐HLA antibodies was highly sensitive and specific. In 1995, we introduced the pronase technique to FCXM and showed that this enzyme did not decrease HLA expression. We present herein a prospective study at our institution to determine whether FCXM using pronase‐digested (PD) lymphocytes is as sensitive and more specific than FCXM with undigested (UD) lymphocytes when compared with the highly sensitive and specific IF assay. In analyzing the 186 donor‐specific prerenal‐transplant crossmatches, we found that PD FCXM was as sensitive and specific as IF and was able to detect weak IgG anti‐HLA antibodies that bound to B cells. Fourteen of these patients would have been denied transplants if one were to have relied on UD FCXM. The data clearly indicate that PD FCXM can reliably be used to detect weak IgG anti‐HLA antibodies before renal transplantation.

Hyperacute renal allograft rejection from anti‐HLA class 1 antibody to B cells ‐antibody detection by two color FCXM was possible only after using pronase‐digested donor lymphocytes

Abstract We present a report of a transplant recipient who lost her renal allograft from hyperacute rejection. This was secondary to a weak IgG anti‐HLA class I antibody that was only reactive to donor B lymphocytes. This antibody was not detected in her pretransplant serum by the conventional complement‐dependent cytotoxicity assays using donor blood lymphocytes. Pretransplant sera were analyzed retrospectively by two‐color flow cytometric crossmatching (FCXM). It was difficult to determine if the recipients serum contained an IgG antibody specific for HLA on donor B cells since IgG from control AB sera and pretransplant sera bound equally well to CD19 B cells. However, when donor lymphocytes were pretreated with pronase to digest the membrane receptor for Fc domain of IgG (FcyR) on non‐T‐cells, control IgG in AB serum did not bind to B cells and, hence, it was easy to detect binding of IgG (in pretransplant sera) to HLA on B cells. This case underscores the importance of identifying weak anti‐HLA class I antibodies reactive only to B cells. Moreover, it shows that the currently used two‐color FCXM lacks the specificity to detect such antibodies.

HLA matching for simultaneous pancreas-kidney transplantation in the United States: a multivariable analysis of the UNOS data.

BACKGROUND As the incidence of diabetic nephropathy increases, especially in minority populations, more simultaneous pancreas-kidney (SPK) transplants are being performed both in the United States and worldwide. The role of matching on SPK outcomes and organ allocation remains controversial. The purpose of this analysis was to determine the influence of HLA matching using currently employed criteria on 5-year SPK graft survival. METHODS We performed an analysis of all 3,316 SPK transplants performed in the United States reported to the United Network for Organ Sharing (UNOS) between December 31, 1988 and December 31, 1994. Kaplan-Meier unadjusted 1- and 5-year graft survival with log rank comparisons and Cox multivariable regression models that adjusted for 12 confounding variables were used to analyze the influence of HLA matching on outcomes. RESULTS Despite low-grade HLA or DR matching or high levels of common reactive groups (CREG) mismatching, 1- and 5-year allograft survival rates were 90% and 78% for kidney, and 85% and 75% for pancreas transplantation. CONCLUSIONS SPK transplantation is associated with excellent outcomes independent of the level of HLA matching. These data support the hypothesis that SPK transplants need not be allocated based on matching criteria, thus minimizing organ ischemia time and promoting a more racially equitable allocation for SPKs in the US today.

New social adaptability index predicts overall mortality.

Introduction Definitions of underprivileged status based on race, gender and geographic location are neither sensitive nor specific; instead we proposed and validated a composite index of social adaptability (SAI). Material and methods Index of social adaptability was calculated based on employment, education, income, marital status, and substance abuse, each factor contributing from 0 to 3 points. Index of social adaptability was validated in NHANES-3 by association with all-cause and cause-specific mortality. Results Weighted analysis of 19,593 subjects demonstrated mean SAI of 8.29 (95% CI 8.17-8.40). Index of social adaptability was higher in Whites, followed by Mexican-Americans and then the African-American population (ANOVA, p < 0.001). The SAI was higher in subjects living in metropolitan compared to rural areas (T-test, p < 0.001), and was greater in men than in women (T-test, p < 0.001). In Cox models adjusted for age, comorbidity index, BMI, race, sex, geographic location, hemoglobin, serum creatinine, albumin, cholesterol, and glycated hemoglobin levels, SAI was inversely associated with mortality (HR 0.87 per point, 95% CI 0.84-0.90, p < 0.001). This association was confirmed in subgroups. Conclusions We proposed and validated an indicator of social adaptability with a strong association with mortality, which can be used to identify underprivileged populations at risk of death.

Ethnic disparities in outcome from posttransplant infections.

Black transplant recipients have decreased graft survival and increased rejection rates compared with whites. Because increased rejection rates may lead to more immunosuppression in black recipients, ethnic differences may exist for outcomes of posttransplant infectious complications. All episodes of infection between December 1996 and October 1998 on the transplant services at the University of Virginia Health Sciences Center were prospectively evaluated. Parameters recorded included self-designated ethnicity, demographics, APACHE II scores, laboratory and microbiologic data, immunosuppression, episodes of rejection, and outcome measures. Evaluation of 303 episodes of infection demonstrated an increased mortality rate for white compared with black recipients (19% vs. 3%, P = 0.0006) despite having a similar severity of illness (APACHE II score). Among renal transplant recipients, episodes of infection occurring in black recipients (n = 46) were also associated with a decreased mortality rate versus whites (n = 89) (0% vs. 15%, P = 0.006) and shorter mean length of stay (12 ± 2 vs. 25 ± 4 days, P = 0.002) despite similar severity of illness and rejection rates. For posttransplant infections in liver transplant recipients, blacks (n = 23) demonstrated a trend toward decreased mortality (9% vs. 26%, P = 0.07) but equal lengths of stay despite similar APACHE II scores, rejection rates, and age. White liver transplant recipients had an increased incidence of viral infections (15% vs. 0%, P = 0.03). All other infecting organisms were similar. The unexpected finding of a significantly decreased rate of mortality associated with posttransplant infections in black recipients remains largely unexplained but may be related to subtle differences in immune response between racial or ethnic groups.