A Randomized Trial to Reduce Disparities in Referral for Transplant Evaluation.

Georgia has the lowest kidney transplant rates in the United States and substantial racial disparities in transplantation. We determined the effectiveness of a multicomponent intervention to increase referral of patients on dialysis for transplant evaluation in the Reducing Disparities in Access to kidNey Transplantation Community Study (RaDIANT), a randomized, dialysis facility-based, controlled trial involving >9000 patients receiving dialysis from 134 dialysis facilities in Georgia. In December of 2013, we selected dialysis facilities with either low transplant referral or racial disparity in referral. The intervention consisted of transplant education and engagement activities targeting dialysis facility leadership, staff, and patients conducted from January to December of 2014. We examined the proportion of patients with prevalent ESRD in each facility referred for transplant within 1 year as the primary outcome, and disparity in the referral of black and white patients as a secondary outcome. Compared with control facilities, intervention facilities referred a higher proportion of patients for transplant at 12 months (adjusted mean difference [aMD], 7.3%; 95% confidence interval [95% CI], 5.5% to 9.2%; odds ratio, 1.75; 95% CI, 1.36 to 2.26). The difference between intervention and control facilities in the proportion of patients referred for transplant was higher among black patients (aMD, 6.4%; 95% CI, 4.3% to 8.6%) than white patients (aMD, 3.7%; 95% CI, 1.6% to 5.9%; P<0.05). In conclusion, this intervention increased referral and improved equity in kidney transplant referral for patients on dialysis in Georgia; long-term follow-up is needed to determine whether these effects led to more transplants.

Referral for Kidney Transplantation and Indicators of Quality of Dialysis Care: A Cross-sectional Study.

BACKGROUND: Dialysis facility performance measures to improve access to kidney transplantation are being considered. Referral of patients for kidney transplantation evaluation by the dialysis facility is one potential indicator, but limited data exist to evaluate whether referral is associated with existing dialysis facility quality indicators. STUDY DESIGN: Cross-sectional study. SETTING & PARTICIPANTS: 12,926 incident (July 2005 to September 2011) adult (aged 18-69 years) patients treated at 241 dialysis facilities with complete quality indicator information from US national registry data linked to transplantation referral data from all 3 Georgia kidney transplantation centers. FACTORS: Facility performance on dialysis quality indicators (high, intermediate, and low tertiles). OUTCOME: Percentages of patients referred within 1 year of dialysis therapy initiation at dialysis facility. RESULTS: Overall, a median of 25.4% of patients were referred for kidney transplantation within 1 year of dialysis therapy initiation. Higher facility-level referral was associated with better performance with respect to standardized transplantation ratio (high, 28.6%; intermediate, 25.1%; and low, 22.9%; P=0.001) and percentage waitlisted (high, 30.7%; intermediate, 26.8%; and low, 19.2%; P<0.001). Facility-level referral was not associated with indicators of quality of care associated with dialysis therapy initiation, including percentage of incident patients being informed of transplantation options. For most non-transplantation-related indicators of high-quality care, including those capturing mortality, morbidity, and anemia management, better performance was not associated with higher facility-level transplantation referral. LIMITATIONS: Potential ecologic fallacy and residual confounding. CONCLUSIONS: Transplantation referral among patients at dialysis facilities does not appear to be associated with overall quality of dialysis care at the facility. Quality indicators related to kidney transplantation were positively associated with, but not entirely correspondent with, higher percentages of patients referred for kidney transplantation evaluation from dialysis facilities. These results suggest that facility-level referral, which is within the control of the dialysis facility, may provide information about the quality of dialysis care beyond current indicators.

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 D(3) deficiency. The prevalence rates of 25(OH) Vitamin D(3) deficiency and its association with parathyroid hormone (PTH) levels in African American kidney transplant recipients have not been examined. We measured 25(OH) Vitamin D(3) 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 D(3) 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 D(3) 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 D(3) deficiency and insufficiency is present in most of the African American kidney transplant patients.

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 (alpha=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 (alpha=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.

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.

Living kidney donors requiring transplantation: focus on African Americans.

Risks of kidney donation include a poorly characterized risk of late kidney failure. We hypothesized that African Americans (AA) kidney donors were at greater risk for kidney failure. The United Network for Organ Sharing/Organ Procurement Transplantation Network database was searched for patients who previously donated a kidney and were subsequently placed on the kidney transplant waiting list. We then compared the race of donors listed for kidney transplant to the race of all living donors during the same time period. Between 1993 and 2005, 8889 donors (14.3%) were AA and 42,419 (68.1%) were Caucasian. During this same time period, 102 previous kidney donors developed kidney failure and were listed for kidney transplantation. Although AAs comprised 14.3% of all living kidney donors, they constituted 44% of donors reaching the waiting list (P<0.001). These data provide indirect evidence that the risk of kidney failure may be exaggerated in AA donors.

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.

The association of nephrolithiasis with cystic fibrosis.

BACKGROUND: There is a growing body of evidence regarding the association between cystic fibrosis (CF) and nephrolithiasis and the role that Oxalobacter formigenes may have in that association. METHODS: We performed a MEDLINE search of "cystic fibrosis and nephrolithiasis" and "Oxalobacter formigenes." Epidemiological and experimental evidence and possible mechanisms explaining the association were critically reviewed. RESULTS: Of patients with CF, 3.0% to 6.3% are affected with nephrolithiasis, a percentage greater than that of age-matched controls without CF, in whom the rate is 1% to 2%. Studies have suggested possible mechanisms for the association, including hyperuricosuria, hyperoxaluria, primary defects in calcium handling caused by mutation of the CF transmembrane regulator (CFTR), hypocitraturia, and lack of colonization with O formigenes, an enteric oxalate-degrading bacterium. The absence of colonization could be related to frequent courses of antibiotics. CONCLUSION: Although the incidence of stones in patients with CF may be increased compared with controls without CF, many possible mechanisms are implicated. The relative contributions of these mechanisms remain uncertain. Future directions may include specific identification of lithogenic risks and therapy aimed at stone prevention in this population.

Health insurance status of US living kidney donors.

BACKGROUND AND OBJECTIVES: Ensuring follow-up of living kidney donors (LKDs) is essential to long-term preventive care. We sought information on health insurance status of US LKDs, with particular attention to age, gender, and ethnicity. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The United Network for Organ Sharing/Organ Procurement Transplantation Network database was queried for associations among age at donation, race, gender, and health insurance status. We studied all US LKDs between July 2004 and September 2006. RESULTS: A total of 10,021 LKDs with known health insurance status were studied, 1765 (18%) of whom lacked health insurance at donation. There were 4852 donors without health insurance information. Younger kidney donors had higher rates of being uninsured (age 18 to 34: 26.2%; age 35 to 49: 15.2%; age 50 to 64: 11.2%; age >65: 3.8%; P < 0.0001), as did men (19.5 versus 16.3% for women; P < 0.0001), and ethnic minorities (white 13.4%, black 21%, Hispanic 35.6%, Asian 26.7%; P < 0.0001). CONCLUSIONS: This study confirms that younger patients, ethnic minorities, and men are less likely to have health insurance when donating a kidney, which could negatively affect adherence to long-term follow-up.

Discovering misattributed paternity in living kidney donation: prevalence, preference, and practice.

When evaluating a living kidney donor and recipient with a father-child relationship, it may be discovered that the two are not biologically related. We analyzed data from the United Network for Organ Sharing and the Canadian Organ Replacement Registry to determine how frequently this occurs. We surveyed 102 potential donors, recipients, and transplant professionals for their opinion on whether such information should be disclosed to the donor-recipient pair. We communicated with transplant professionals from 13 Canadian centers on current practices for handling this information. In the United States and Canada, the prevalence of father-child living kidney donor-recipient pairs with less than a one-haplotype human leukocyte antigen match (i.e., misattributed paternity) is between 1% and 3%, or approximately 0.25% to 0.5% of all living kidney donations. Opinions about revealing this information were variable: 23% strongly favored disclosure; whereas, 24% were strongly opposed to it. Current practices are variable; some centers disclose this information, whereas others do not. Discovering misattributed paternity in living donation is uncommon but can occur. Opinions on how to deal with this sensitive information are variable. Discussion among transplant professionals will facilitate best practices and policies. Strategies adopted by some centers can be considered.

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.

Evaluation of gene panel mRNAs in urine samples of kidney transplant recipients as a non-invasive tool of graft function.

Non-invasive monitoring may be useful after kidney transplantation (KT), particularly for predicting acute rejection (AR). It is less clear whether chronic allograft nephropathy (CAN) is also associated with changes in urine cells. To identify non-invasive markers of allograft function in kidney transplant patients (KTP), mRNA levels of AGT, TGF-beta1, EGFR, IFN-gamma, TSP-1, and IL-10 in urine (Ur) samples were studied using QRT-PCR. Ninety-five KTP and 111 Ur samples were evaluated. Patients (Pts) were divided as, within six months (N = 31), and with more than six months post-KT (N = 64). KTP with more than six months post-KT were classified as KTP with stable kidney function (SKF) (N = 32), KTP with SKF (creatinine < 2 mg/dL) and proteinuria > 500 mg/24 h (N = 18), and KTP with biopsy proven CAN (N = 14). F-test was used to test for equality of variances between groups. IL-10 mRNA was decreased in Ur samples from KTP with less than six months post-KT (P = 0.005). For KTR groups with more than six months post-KT, AGT and EGFR mRNA were statistically different among KTP with SKF, KTP with SKF and proteinuria, and CAN Pts (P = 0.003, and P = 0.01), with KTP with SKF having higher mean expression. TSP-1 mRNA levels also were significantly different among these three groups (P = 0.04), with higher expression observed in CAN Pts. Using the random forest algorithm, AGT, EGFR, and TGF-beta1 were identified as predictors of CAN, SKF, SKF with proteinuria. A characteristic pattern of mRNA levels in the different KTP groups was observed indicating that the mRNA levels in Ur cells might reflect allograft function.

Detection of donor-specific antibodies using HLA-coated microspheres: another tool for kidney transplant risk stratification.

BACKGROUND: Sensitive techniques are able to detect low levels of circulating antibodies. For many newer techniques, the clinical consequences of these antibodies are unknown. We hoped to determine the significance of antibodies detected through the use of Luminex microsphere-based assay. METHODS: Patients who received kidney transplants between March 2003 and May 2004 with negative anti-human globulin-augmented complement-dependent cytotoxicity (AHG-CDC) crossmatches were retested for pre-transplant panel reactive antibodies (PRA) using Luminex microspheres and stored sera. Patients were considered to have circulating antibodies if either class I or class II Luminex PRA was >or=15%. These patients were then analysed for pre-transplant donor-specific antibodies (DSA). Clinical outcomes were compared in patients with and without DSAs. RESULTS: Out of 136 patients who underwent transplantation, 55 had Luminex PRA >or=15%. Of these 55 patients, only 16 had a standard PRA >or=30% and 75% had a history of a sensitizing event. Twenty out of 55 patients were DSA+. Patients with DSA detected by Luminex had higher rates of primary non-function (PNF), delayed graft function, biopsy-proven acute rejection, and lower rates of graft survival at 6 months. A combined endpoint of immunological and clinical events was far more common in patients with DSA. CONCLUSION: The detection of DSAs by Luminex microspheres was associated with significantly higher rates of graft dysfunction and immunological events. Conversely, the presence of antibodies but no DSA by Luminex was associated with excellent outcomes. In patients with negative AHG-CDC crossmatches, the occurrence of low-level DSA by Luminex could assist in identifying patients that require more aggressive immune monitoring or immunosuppressive strategies.

Cardiovascular medication use after coronary bypass surgery in patients with renal dysfunction: a national Veterans Administration study.

BACKGROUND: Chronic kidney disease is now recognized as an independent risk factor for cardiovascular events. We sought to determine if cardiovascular medications were utilized less in patients with renal dysfunction following coronary artery bypass grafting (CABG) and if the association of decreased medication use was independent of comorbid conditions. We also examined associations between cardiovascular medication use and mortality at 6 months. METHODS: Data from the National Veterans Adminstration (VA) Continuous Improvement in Cardiac Surgery Program were merged with the national VA pharmacy database. Prescription rates within 6 months of discharge for CABG were obtained for four classes of medicines: beta blockers, lipid-lowering agents, antiplatelet agents, and angiotensin antagonists. Utilization of medications in patients with estimated glomerular filtration rate (GFR) 60 to 90, 30 to 60, and <30 were compared with the reference group of GFR >90. RESULTS: In a retrospective analysis of 19,411 patients, the frequency of nonprescription increased with declining GFR. Decreased utilization for patients with GFR 30 to 60 and <30 remained highly significant after adjustment for age, race, hypertension, diabetes, and prior myocardial infarction. In patients with more advanced renal dysfunction (GFR <60), cardiovascular medication use for all medication classes was associated with survival at 6 months after adjusting for demographic and clinical variables. Cumulative protection was seen with use of medication from each additional class. CONCLUSION: In a large VA population undergoing CABG, renal disease is associated with highly significant decreases in utilization of cardiovascular medications. Nonprescription of medications was associated with adverse outcomes in those with renal dysfunction.

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.