Eric M. Gibney

Cardiovascular disease in kidney donors: matched cohort study

Objective To determine whether people who donate a kidney have an increased risk of cardiovascular disease. Design Retrospective population based matched cohort study. Participants All people who were carefully selected to become a living kidney donor in the province of Ontario, Canada, between 1992 and 2009. The information in donor charts was manually reviewed and linked to provincial healthcare databases. Matched non-donors were selected from the healthiest segment of the general population. A total of 2028 donors and 20 280 matched non-donors were followed for a median of 6.5 years (maximum 17.7 years). Median age was 43 at the time of donation (interquartile range 34-50) and 50 at the time of follow-up (42-58). Main outcome measures The primary outcome was a composite of time to death or first major cardiovascular event. The secondary outcome was time to first major cardiovascular event censored for death. Results The risk of the primary outcome of death and major cardiovascular events was lower in donors than in non-donors (2.8 v 4.1 events per 1000 person years; hazard ratio 0.66, 95% confidence interval 0.48 to 0.90). The risk of major cardiovascular events censored for death was no different in donors than in non-donors (1.7 v 2.0 events per 1000 person years; 0.85, 0.57 to 1.27). Results were similar in all sensitivity analyses. Older age and lower income were associated with a higher risk of death and major cardiovascular events in both donors and non-donors when each group was analysed separately. Conclusions The risk of major cardiovascular events in donors is no higher in the first decade after kidney donation compared with a similarly healthy segment of the general population. While we will continue to follow people in this study, these interim results add to the evidence base supporting the safety of the practice among carefully selected donors.

Cardiovascular disease and hypertension risk in living kidney donors: an analysis of health administrative data in Ontario, Canada.

Background. Knowledge of any harm associated with living kidney donation guides informed consent and living donor follow-up. Risk estimates in the literature are variable, and most studies did not use a healthy control group to assess outcomes attributable to donation. Methods. We observed a retrospective cohort using health administrative data for donations which occurred in Ontario, Canada between the years 1993 and 2005. There were a total of 1278 living donors and 6359 healthy adults who acted as a control group. Individuals were followed for a mean of 6.2 years (range, 1-13 years) after donation. The primary outcome was a composite of time to death or first cardiovascular event (myocardial infarction, stroke, angioplasty, and bypass surgery). The secondary outcome was time to a diagnosis of hypertension. Results. There was no significant difference in death or cardiovascular events between donors and controls (1.3% vs. 1.7%; hazard ratio 0.7, 95% confidence interval 0.4-1.2). Donors were more frequently diagnosed with hypertension than controls (16.3% vs. 11.9%, hazard ratio 1.4, 95% confidence interval 1.2-1.7) but were also seen more often by their primary care physicians (median [interquartile range] 3.6 [1.9-6.1] vs. 2.6 [1.4-4.3] visits per person year, P<0.001). Conclusions. Based on administrative data, the risk of cardiovascular disease was unchanged in the first decade after kidney donation. The observed increase in diagnosed hypertension may be due to nephrectomy or more blood pressure measurements received by donors in follow-up and requires prospective study.

Establishing the molecular pathways involved in chronic allograft nephropathy for testing new noninvasive diagnostic markers.

Background. Chronic allograft nephropathy (CAN) is a cause of graft loss. The multistage processes that result in CAN are poorly understood. Noninvasive assays for detecting allograft dysfunction and predicting long-term outcomes are a priority in transplantation (Tx). Methods. Renal tissue from kidney transplant patients (KTP) with CAN (n=11) and normal kidneys (NK; n=7) were studied using microarrays. Markers resulting from the microarray analysis (transforming growth factor [TGF]-β, epidermal growth factor receptor [EGFR], angiotensinogen [AGT]) were tested in urine (Ur) and peripheral blood (PB) samples from the CAN patients (collected at the biopsy time) using reverse-transcriptase real-time polymerase chain reaction. Ur and PB samples from long-term KTP with stable renal function (SRF; n=20) were used as control. Results. Assuming unequal variances between CAN and NK, using a false discovery rate of 0.005, and running 1,000 of all possible permutations, 728 probe sets were differentially expressed. Genes related to fibrosis and extracellular matrix deposition (i.e., TGF-β, laminin, gamma 2, metalloproteinases-9, and collagen type IX alpha 3) were up-regulated. Genes related to immunoglobulins, B cells, T-cell receptor, nuclear factor of activated T cells, and cytokine and chemokines receptors were also upregulated. EGFR and growth factor receptor activity (FGFR)2 were downregulated in CAN samples. AGT, EGFR, and TGF-β levels were statistical different in urine but not in blood samples of CAN patients when compared to KTP with SRF (P<0.001, P=0.04, and P<0.001, respectively). Conclusions. Genes related to fibrosis, extracellular matrix deposition, and immune response were found up-regulated in CAN. Markers resulting from the microarray analysis were differentially expressed in Ur samples of the CAN patients and in concordance with the microarray profiles.

Hepatitis C virus infection and kidney transplantation : Predictors of patient and graft survival

Background. The effect of hepatitis C virus (HCV) infection on patients undergoing kidney transplantation (KTx) is uncertain. This study aimed to evaluate the outcomes of our HCV+/end-stage renal disease (ESRD) patient population based on the therapeutic option including KTx or continuation in dialysis. Methods. KTx performed at Virginia Commonwealth University Hospital between January 2000 and December 2004 were tracked prospectively. Forty-three out of a total of 394 KTx patients included in the analysis were HCV+. A group of 52 contemporaneous HCV+/ESRD patients listed, but never transplanted, was also analyzed. HCV-negative transplanted patients were used as the control group. Results. Patient survival posttransplantation was 81.4% and 68.5% at 1 and 3 years in the HCV+ group, and 97.1% and 92.9% at 1 and 3 years in the HCV- group, respectively (P=0.001). Graft survival was 81.2% and 64.1% at 1 and 3 years in the HCV+ group, and 93.2% and 84.1% at 1 and 3 years posttransplantation in the HCV- group (P=0.01). Univariate analysis identified Knodell score as a predictor of mortality in HCV+ patients (P=0.04). Cox proportional hazards multivariate analysis identified deceased donor (P=0.02), previous kidney transplant (P=0.007), pretransplant diabetes (P=0.05), and Knodell Score (P=0.012) as predictors of patient mortality. Patient survival was superior in HCV+ patients undergoing KTx versus remaining on dialysis. Conclusions. Patients with ESRD/HCV+ benefit from KTx without achieving the excellent survival of HCV-/ESRD patients. Liver biopsy is a useful tool to identify advanced liver disease at pretransplantation time.

Kidney Transplantation for Systemic Sclerosis Improves Survival and may Modulate Disease Activity

Systemic sclerosis (SS) may lead to sclerodema renal crisis, an unusual cause of end‐stage renal disease (ESRD) with historically poor hemodialysis outcomes. Little information is available on outcomes after kidney transplantation. Information from the UNOS registry was obtained on SS patients in the United States, listed for kidney transplants between 1985–2002. We compared survival at 1 and 3 years in patients who received cadaveric transplants with patients who remained on the waiting list. Graft survival, cause of graft loss, frequency of early graft loss and pre‐ and post‐transplant skin scores were analyzed. Two hundred and fifty‐eight patients with SS were listed for transplantation. Survival was significantly prolonged in patients receiving transplants (p = 0.005). Graft survival at 1 and 3 years was 68% and 60%. Early graft loss was common. Skin scores improved in all four subjects at our center, with an average decline of 60.7% (p = 0.024). Kidney transplantation confers a survival benefit in ESRD due to SS. Transplantation may be associated with an improvement in systemic manifestations of disease. Despite suboptimal graft survival, kidney transplant should be considered the treatment of choice in ESRD due to SS.

Molecular pathways involved in loss of kidney graft function with tubular atrophy and interstitial fibrosis.

Loss of kidney graft function with tubular atrophy (TA) and interstitial fibrosis (IF) causes most kidney allograft losses. We aimed to identify the molecular pathways involved in IF/TA progression. Kidney biopsies from normal kidneys (n = 24), normal allografts (n = 6), and allografts with IF/TA (n = 17) were analyzed using high-density oligonucleotide microarray. Probe set level tests of hypotheses tests were conducted to identify genes with a significant trend in gene expression across the three groups using Jonckheere-Terpstra test for trend. Interaction networks and functional analysis were used. An unsupervised hierarchical clustering analysis showed that all the IF/TA samples were associated with high correlation. Gene ontology classified the differentially expressed genes as related to immune response, inflammation, and matrix deposition. Chemokines (CX), CX receptor (for example, CCL5 and CXCR4), interleukin, and interleukin receptor (for example, IL-8 and IL10RA) genes were overexpressed in IF/TA samples compared with normal allografts and normal kidneys. Genes involved in apoptosis (for example, CASP4 and CASP5) were importantly overexpressed in IF/TA. Genes related to angiogenesis (for example, ANGPTL3, ANGPT2, and VEGF) were downregulated in IF/TA. Genes related to matrix production-deposition were upregulated in IF/TA. A distinctive gene expression pattern was observed in IF/TA samples compared with normal allografts and normal kidneys. We were able to establish a trend in gene expression for genes involved in different pathways among the studied groups. The top-scored networks were related to immune response, inflammation, and cell-to-cell interaction, showing the importance of chronic inflammation in progressive graft deterioration.

Age, Gender, Race, and Associations With Kidney Failure Following Living Kidney Donation

INTRODUCTION Our previous reports suggested that African Americans (AA) are more likely to develop end-stage renal disease (ESRD) following kidney donation when compared with white counterparts. We sought information on age, gender, and race of kidney donors to determine which groups were over-represented on the kidney transplant waiting list. METHODS We queried the United Network for Organ Sharing United Network for Organ Sharing (UNOS) Organ Procurement Transplantation Network (OPTN) database for former donors who were subsequently placed on the kidney transplant waiting list. Information was retrieved on race, gender, age at donation, years between donation and listing, and diagnosis leading to ESRD. Comparisons were made to all kidney donors between 1988 and 2006 using chi-square testing. RESULTS In this study, 126 individual kidney donors entered the kidney transplant waiting list. Fifty of the 126 (40%) were AA (P < .0001 compared with all donors, 13% AA). For both AA and whites, male donors and those who donated before age 35 made up a larger proportion of donors on the waiting list than would be expected by their proportion of overall donors. CONCLUSION AA, males, and young donors may be at higher risk for kidney failure in the years following kidney donation. Mechanisms of increased risk are unclear but deserve further scrutiny. Our data are limited by the small number of patients developing kidney failure, the lack of complete follow-up on all living kidney donors, and the possibility that older donors with kidney failure were not listed because of death or other medical conditions. We believe that discussion of long-term risks may be different for various subgroups, especially for young AA kidney donors.

Gene expression patterns in deceased donor kidneys developing delayed graft function after kidney transplantation.

Background. Delayed graft function (DGF) after kidney transplantation (KTx) ranges between 2% and 50%. The mechanisms leading to DGF deserve special interest because DGF exerts negative influences on long-term outcomes. We studied gene expression profiles in deceased donor kidney (DDK) biopsies with and without DGF. Methods. Gene expression profiling was performed on donor kidney tissues from 33 DDK with the use of microarrays. DDK were classified as grafts with immediate function (non-DGF; n=21) and grafts with DGF (n=12). DGF was defined as a dialysis requirement in the first week after transplantation. Demographic donor and recipient information was collected. The robust-multiarray average method was used to estimate probe set expression summaries. Logistic regression was used to identify genes significantly associated with DGF development. Results. Patients were followed for 3 months after KTx. Thirty-eight probe sets (n=36 genes) were univariably differentially expressed in DDK with DGF when compared with DDK with non-DGF (&agr;=0.001). Sixty-nine probe sets (n=65 genes) were differentially expressed in DDK with DGF when compared with DDK with non-DGF after adjusting for cold ischemia time (&agr;=0.001). Gene ontology terms classified the overexpressed genes in DDK with DGF as principally related to cell cycle/growth (e.g., IGFBP5, CSNK2A2), signal transduction (e.g., RASGRP3), immune response (e.g., CD83, BCL3, MX1), and metabolism (e.g., ENPP4, GBA3). TNFRSF1B was overexpressed in DDK with DGF. Conclusions. Cold ischemia time was a predictor of DGF independently of the preservation method. We identified a set of 36 genes candidates of DGF in DDK, with genes involved in the inflammatory response being the more important.

Variation in Dialysis Facility Referral for Kidney Transplantation Among Patients With End-Stage Renal Disease in Georgia

IMPORTANCE Dialysis facilities in the United States are required to educate patients with end-stage renal disease about all treatment options, including kidney transplantation. Patients receiving dialysis typically require a referral for kidney transplant evaluation at a transplant center from a dialysis facility to start the transplantation process, but the proportion of patients referred for transplantation is unknown. OBJECTIVE To describe variation in dialysis facility-level referral for kidney transplant evaluation and factors associated with referral among patients initiating dialysis in Georgia, the US state with the lowest kidney transplantation rates. DESIGN, SETTING, AND PARTICIPANTS Examination of United States Renal Data System data from a cohort of 15,279 incident, adult (18-69 years) patients with end-stage renal disease from 308 Georgia dialysis facilities from January 2005 to September 2011, followed up through September 2012, linked to kidney transplant referral data collected from adult transplant centers in Georgia in the same period. MAIN OUTCOMES AND MEASURES Referral for kidney transplant evaluation within 1 year of starting dialysis at any of the 3 Georgia transplant centers was the primary outcome; placement on the deceased donor waiting list was also examined. RESULTS The median within-facility percentage of patients referred within 1 year of starting dialysis was 24.4% (interquartile range, 16.7%-33.3%) and varied from 0% to 75.0%. Facilities in the lowest tertile of referral (<19.2%) were more likely to treat patients living in high-poverty neighborhoods (absolute difference, 21.8% [95% CI, 14.1%-29.4%]), had a higher patient to social worker ratio (difference, 22.5 [95% CI, 9.7-35.2]), and were more likely nonprofit (difference, 17.6% [95% CI, 7.7%-27.4%]) compared with facilities in the highest tertile of referral (>31.3%). In multivariable, multilevel analyses, factors associated with lower referral for transplantation, such as older age, white race, and nonprofit facility status, were not always consistent with the factors associated with lower waitlisting. CONCLUSIONS AND RELEVANCE In Georgia overall, a limited proportion of patients treated with dialysis were referred for kidney transplant evaluation between 2005 and 2011, but there was substantial variability in referral among facilities. Variables associated with referral were not always associated with waitlisting, suggesting that different factors may account for disparities in referral.

High prevalence of vitamin D deficiency in African American kidney transplant recipients.

Kidney transplant patients are at high risk for developing Vitamin D3 deficiency. The prevalence rates of 25(OH) Vitamin D3 deficiency and its association with parathyroid hormone (PTH) levels in African American kidney transplant recipients have not been examined. We measured 25(OH) Vitamin D3 and intact PTH concentrations in 38 African American transplant patients at our center in October 2006. We collected various laboratory data including serum creatinine, calcium, phosphate, alkaline phosphatase, and glomerular filtration rate. Vitamin D3 deficiency was present in 57.8% of the patients and 94.7% had insufficiency. Ten of 22 (45%) patients with chronic kidney disease stage 3 had intact PTH more than or equal to 70 pg/mL. On multivariate analysis, 25(OH) Vitamin D3 level was negatively correlated with intact PTH (P<0.01) and alkaline phosphatase level was positively associated with intact PTH levels (P<0.002). Vitamin D3 deficiency and insufficiency is present in most of the African American kidney transplant patients.