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1.  Impact of Age, Race and Ethnicity on Dialysis Patient Survival and Kidney Transplantation Disparities 
American journal of nephrology  2014;39(3):183-194.
Prior studies show that African-American and Hispanic dialysis patients have lower mortality risk than whites. Recent age-stratified analyses suggest this survival advantage may be limited to younger age groups, but did not concurrently compare Hispanic, African-American, and white patients, nor account for differences in nutritional and inflammatory status as potential confounders. Minorities experience inequities in kidney transplantation access, but it is unknown whether these racial/ethnic disparities differ across age groups.
The associations between race/ethnicity with all-cause mortality and kidney transplantation were separately examined among 130,909 adult dialysis patients from a large national dialysis organization (entry period 2001-2006, follow-up through 2009) within 7 age categories using Cox proportional hazard models adjusted for case-mix and malnutrition and inflammatory surrogates.
African-Americans had similar mortality vs. whites in younger age groups (18-40 years), but decreased mortality in older age groups (>40 years). In contrast, Hispanics had lower mortality vs. whites across all ages. In sensitivity analyses using competing risk regression to account for differential kidney transplantation rates across racial/ethnic groups, the African-American survival advantage was limited to >60 year old age categories. African-Americans and Hispanics were less likely to undergo kidney transplantation from all donor types vs. whites across all ages, and these disparities were even more pronounced for living donor kidney transplantations (LDKT).
Hispanic dialysis patients have greater survival vs. whites across all ages; in African-Americans, this survival advantage is limited to patients >40 years old. Minorities are less likely to undergo kidney transplantation, particularly LDKT, across all ages.
PMCID: PMC4024458  PMID: 24556752
Race; Ethnicity; Disparities; Survival; Transplantation
2.  Using Hemoglobin A1c to Derive Mean Blood Glucose in Peritoneal Dialysis Patients 
American journal of nephrology  2013;37(5):10.1159/000349929.
Although hemoglobin A1c (HbA1c) has been widely used as a clinical assessment tool for outcome analyses related to glycemic control, the relationship between HbA1c and average blood glucose (BG) specific to peritoneal dialysis (PD) patients with diabetes has not been characterized. We sought to develop HbA1c-BG equation models for PD patients.
We examined associations between HbA1c and random serum BG values over time in a contemporary 5-year (2001–2006) cohort of DaVita PD patients with diabetes. We identified 850 patients (mean age 58±13 years old and 56% male) with 4,566 paired measurements of HbA1c and BG. The bootstrapping method was used to estimate average BG and corresponding HbA1c.
Linear regression analyses yielded the following HbA1c-BG equations: (1) BG (mg/dL)=24.1 + 28.6 × HbA1c – 12.2 × Albumin (R2adj=0.454), (2) BG = 55.3+ 28.8 × HbA1c-10.2 × Albumin −3.3 × Hemoglobin (R2adj=0.457), (3) and BG =69.5 +28.7 × HbA1c- 10.1 × Albumin- 3.7 × Hemoglobin- 0.1 × Age+ Race/Ethnicity (−10.1 African-Americans, −5.4 other race/ethnicities; R2adj=0.457). All models showed greater explanatory power of BG variation than previously established HbA1c-BG equation models defined within non-PD cohorts (R2adj=0.446 for both the DCCT and the ADAG equations).
The association between HbA1c and BG in PD patients is different than that of patients with normal kidney function. Our analysis suggests that equations incorporating serum albumin and/or hemoglobin values better estimate the HbA1c-BG relationship in PD patients compared to equations using HbA1c alone.
PMCID: PMC3844668  PMID: 23594745
Hemoglobin A1c; blood glucose; equation model; glycemic control; albumin; hemoglobin; peritoneal dialysis; race
4.  Uremic plasma impairs barrier function and depletes the tight junction protein constituents of intestinal epithelium 
American journal of nephrology  2012;36(5):438-443.
Back ground
CKD causes intestinal barrier dysfunction which by allowing influx of endotoxin and other noxious products contributes to the CKD-associated systemic inflammation and uremic toxicity. We have recently shown that intestinal barrier dysfunction in CKD animals is due to degradation of trans-cellular [claudin-1 and occludin] and intra-cellular [ZO1] constituents of epithelial tight junction (TJ). This study determined whether CKD-associated disruption of TJ is mediated by retained uremic toxins/metabolites and if so whether they are removed by hemodialysis.
The TJ-forming human enterocytes (T84 cells) were seeded on the Transwell plates and utilized when trans-epithelial electrical resistance (TER) exceeded 1000 mΩ/cm2 to ensure full polarization and TJ formation. The cells were then incubated for 24 hr in media containing 10% pre- or post-hemodialysis plasma from ESRD patients or healthy individuals. TER was then measured and cells were processed for Western blot and immunohistological analyses.
Compared with the control plasma, incubation in media containing pre-dialysis plasma from ESRD patients resulted in a marked drop in TER pointing to increased epithelial permeability. This was accompanied by significant reductions in cluadin-1 (85%), occludin (15%), and ZO1 (70%) abundance. The severity of TJ damage and dysfunction was significantly less in cells exposed to the post-dialysis than per-dialysis plasma. These findings point to the presence of as-yet unidentified product(s) in the uremic plasma capable of depleting epithelial TJ.
Exposure to uremic milieu damages the intestinal epithelial TJ and impairs its barrier function, events which are mediated by agents which are partially removed by hemodialysis.
PMCID: PMC3725306  PMID: 23128155
Tight junction; inflammation; hemodialysis; ESRD; CKD
5.  Mortality Associated with Dose Response of Erythropoiesis-Stimulating Agents in Hemodialysis versus Peritoneal Dialysis Patients 
American Journal of Nephrology  2012;35(2):198-208.
Several studies have shown an association between erythropoietin-stimulating agent (ESA) responsiveness and mortality in chronic kidney disease (CKD) patients. In our present study, we examined the association between prescribed ESA dose and mortality in peritoneal dialysis (PD) and hemodialysis (HD) patients. We hypothesized that PD patients received lower ESA dose for the same achieved hemoglobin compared to HD patients and that ESA dose-mortality associations were different between PD and HD patients.
We compared the prescribed doses of ESA between 139,103 HD and 10,527 PD patients treated in DaVita dialysis clinics from 7/2001 through 6/2006 using adjusted Poisson regression and examined mortality-predictability of prescribed ESA dose and ESA responsiveness index (ESA/hemoglobin) in PD and HD with follow-up through 6/2007 using Cox regression models.
Poisson adjusted ratio of ESA dose of HD to PD was 3.6 (95% CI 3.5–3.7). In PD patients, adjusted all-cause death hazard ratios (HR) for ESA doses of 3,000–5,999, 6,000–8,999 and ≥9,000 U/week (reference <3,000 U/week) were 0.97 (0.87–1.07), 0.85 (0.76–0.95) and 1.08 (0.98–1.18), respectively; whereas in HD patients across commensurate ESA dose increments of 10,000–19,999, 20,000–29,999 and ≥30,000 U/week (reference <10,000 U/week) were 1.14 (1.11–1.17), 1.54 (1.50–1.58) and 2.15 (2.10–2.21), respectively. In PD and HD patients, the adjusted death HR of the 4th to 1st quartile of ESA responsiveness index were 1.14 (1.04–1.26) and 2.37 (2.31–2.43), respectively.
Between 2001 and 2006, most PD patients received substantially lower ESA dose for same achieved hemoglobin levels, and low ESA responsiveness was associated with higher mortality in both HD and PD patients.
PMCID: PMC3326284  PMID: 22286821
Anemia; Hemoglobin; Erythropoietin-stimulating agent therapy; Peritoneal dialysis; Hemodialysis; Mortality; Cardiovascular mortality
6.  Association of Cumulatively Low or High Serum Calcium Levels with Mortality in Long-Term Hemodialysis Patients 
American Journal of Nephrology  2010;32(5):403-413.
The outcome-predictability of baseline and instantaneously changing serum calcium in hemodialysis patients has been examined. We investigated the mortality-predictability of time-averaged calcium values to reflect the ‘cumulative’ effect of calcium burden over time.
We employed a Cox model using up-to-5-year (7/2001–6/2006) time-averaged values to examine the mortality-predictability of cumulative serum calcium levels in 107,200 hemodialysis patients prior to the use of calcimimetics, but during the time where other calcium-lowering interventions, including lower dialysate calcium, were employed.
Both low (<9.0 mg/dl) and high (>10.0 mg/dl) calcium levels were associated with increased mortality (reference: 9.0 to <9.5 mg/dl). Whereas mortality of hypercalcemia was consistent, hypocalcemia mortality was most prominent with higher serum phosphorus (>3.5 mg/dl) and PTH levels (>150 pg/ml). Higher paricalcitol doses shifted the calcium range associated with the greatest survival to the right, i.e. from 9.0 to <9.5 to 9.5 to <10.0 mg/dl. African-Americans exhibited the highest death hazard ratio of hypocalcemia <8.5 mg/dl, being 1.35 (95% CI: 1.22–1.49). Both a rise and drop in serum calcium over 6 months were associated with increased mortality compared to the stable group.
Whereas in hemodialysis patients cumulatively high or low calcium levels are associated with higher death risk, subtle but meaningful interactions with phosphorus, PTH, paricalcitol dose and race exist.
PMCID: PMC2941140  PMID: 20814200
Hypocalcemia; Hypercalcemia; Phosphorus; Hyperparathyroidism; Racial disparities; Mineral and bone disorder; Chronic kidney disease; Paricalcitol
7.  Racial and Ethnic Differences in Mortality of Hemodialysis Patients: Role of Dietary and Nutritional Status and Inflammation 
American Journal of Nephrology  2011;33(2):157-167.
Racial/ethnic disparities prevail among hemodialysis patients. We hypothesized that significant differences exist between Black and non-Hispanic and Hispanic White hemodialysis patients in nutritional status, dietary intake and inflammation, and that they account for racial survival disparities.
In a 6-year (2001–2007) cohort of 799 hemodialysis patients, we compared diet and surrogates of nutritional-inflammatory status and their mortality-predictabilities between 279 Blacks and 520 Whites using matched and regression analyses and Cox with cubic splines.
In age-, gender- and diabetes-matched analyses, Blacks had higher lean body mass and serum prealbumin, creatinine and homocysteine levels than Whites. In case-mix-adjusted analyses, dietary intakes in Blacks versus Whites were higher in energy (+293 ± 119 cal/day) and fat (+18 ± 5 g/day), but lower in fiber (−2.9 ± 1.3 g/day) than Whites. In both races, higher serum albumin, prealbumin and creatinine were associated with greater survival, whereas CRP and IL-6, but not TNF-α, were associated with increased mortality. The highest (vs. lowest) quartile of IL-6 was associated with a 2.4-fold (95% CI: 1.3–3.8) and 4.1-fold (2.2–7.2) higher death risk in Blacks and Whites, respectively.
Significant racial disparities exist in dietary, nutritional and inflammatory measures, which may contribute to hemodialysis outcome disparities. Testing race-specific dietary and/or anti-inflammatory interventions is indicated.
PMCID: PMC3202917  PMID: 21293117
Black race; Hispanic ethnicity; African Americans; Non-Hispanic White; Nutritional status; Inflammatory markers; Dietary intake; Survival
8.  Total and Individual Coronary Artery Calcium Scores as Independent Predictors of Mortality in Hemodialysis Patients 
American Journal of Nephrology  2010;31(5):419-425.
Many traditional and nontraditional risk factors contribute to vascular calcification among maintenance hemodialysis (MHD) patients. It is not clear whether coronary artery calcification (CAC) delineates a higher mortality risk independent of known risk factors. We examined 6-year (10/2001–9/2007) survival of 166 MHD patients, aged 53 ± 13 years, with baseline CAC scores. Patients were grouped into four CAC groups: 0, 1–100, 101–400, and 400+. The 101–400 and 400+ groups were associated with a significantly higher adjusted risk of death than CAC 0 with hazard ratios (HR) 8.5 (95% CI: 1.1–48.1, p = 0.02) and 13.3 (95% CI: 1.3–65.1, p = 0.01), respectively, independent of demographics, comorbidity, lipids and other cardiovascular risks, surrogates of bone disease, nutritional and inflammatory markers and dialysis dose. Total CAC [HR 6.7 (1.1–21.5, p = 0.03)] followed by the presence of CAC in the left main [4.6 (2.2–9.8, p = 0.001)] and left anterior descending artery [4.3 (2.1–14.2, p = 0.001)] were strong independent predictors of mortality even after adjusting for above covariates. Total and vessel-specific CAC predict mortality in MHD patients independent of traditional and nontraditional risk factors.
PMCID: PMC2883846  PMID: 20389057
Chronic kidney disease; Coronary artery calcium; Dialysis; Inflammation; Phosphorus binder; Sevelamer; Death risk
9.  Association of Serum Total Iron-Binding Capacity and Its Changes Over Time with Nutritional and Clinical Outcomes in Hemodialysis Patients 
American Journal of Nephrology  2009;29(6):571-581.
Serum transferrin, estimated by total iron-binding capacity (TIBC), may be a marker of protein-energy wasting (PEW) in maintenance hemodialysis (MHD) patients. We hypothesized that low TIBC or its fall over time is associated with poor clinical outcomes. In 807 MHD patients in a prospective 5-year cohort, associations of TIBC and its changes over time with outcomes were examined after adjustment for case-mix and markers of iron stores and malnutrition-inflammation including serum interleukin-6, iron and ferritin. Patients with serum TIBC ≥250 mg/dl had higher body mass index, triceps and biceps skinfolds and mid-arm muscle circumference and higher serum levels of iron but lower ferritin and inflammatory markers. Some SF-36 quality of life (QoL) components were worse in the lowest and/or highest TIBC groups. Mortality was incrementally higher in lower TIBC levels (p-trend <0.001). Adjusted death hazard ratio was 1.75 (95% CI: 1.00–3.05, p = 0.05) for TIBC <150 compared to TIBC of 200–250 mg/dl. A fall in TIBC >20 mg/dl over 6 months was associated with a death hazard ratio of 1.57 (95% CI: 1.04–2.36, p = 0.03) compared to the stable TIBC group. Hence, low baseline serum TIBC is associated with iron deficiency, PEW, inflammation, poor QoL and mortality, and its decline over time is independently associated with increased death risk.
PMCID: PMC2818472  PMID: 19136818
Transferrin; Total iron-binding capacity; Chronic kidney disease; Hemodialysis; Protein-energy wasting
10.  Effects of Sevelamer and Calcium-Based Phosphate Binders on Lipid and Inflammatory Markers in Hemodialysis Patients 
American Journal of Nephrology  2007;28(2):275-279.
Cardiovascular disease accounts for almost half of all deaths in individuals with chronic kidney disease stage 5 despite advances in both dialysis treatment and cardiology. A combination of lipid-lowering and anti-inflammatory effects along with avoidance of hypercalcemia should be taken into account when choosing phosphorus binders for maintenance hemodialysis (MHD) patients.
We examined the association of sevelamer versus calcium-based phosphorus binders with lipid profile, inflammatory markers including C-reactive protein (CRP), and mineral metabolism in MHD patients who participated in the Nutritional and Inflammatory Evaluation of Dialysis Patients (NIED) study from October 2001 to July 2005.
Of the 787 MHD patients in the NIED study, 697 were on either sevelamer, a calcium-based binder, or both and eligible for this study. We compared the groups based on taking sevelamer monotherapy (n = 283) or calcium binder monotherapy (n = 266) for serum phosphate control. There were no differences between the groups on dialysis vintage. There were significant differences in age, serum calcium and phosphorus levels, as well as intact parathyroid hormone levels. Using a logistic regression models, the sevelamer group had a higher odds of serum CRP <10 mg/l [odds ratio (OR): 1.06, 95% CI: 1.02–1.11] and LDL cholesterol <70 mg/dl (OR: 1.33, 95% CI: 1.19–1.47) when compared to the calcium binder group independent of age, vintage, body mass index, statin use or other variables.
The improvements in multiple surrogate markers of inflammation and lipids in the NIED study make sevelamer a promising therapy for treatment in MHD patients with high risk of cardiovascular disease and mortality.
PMCID: PMC2785908  PMID: 17992011
End-stage renal disease; Cardiac computed tomography; Coronary calcium; Phosphate binders

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