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author:("Ojo, akintola")
1.  Race modifies the association between adiposity and inflammation in patients with chronic kidney disease: findings from the CRIC study 
Obesity (Silver Spring, Md.)  2014;22(5):1359-1366.
To examine the race-specific association of inflammation with adiposity and muscle mass in subjects with chronic kidney disease (CKD).
Design and Methods
Plasma concentration of IL-1β, IL-Receptor antagonist (IL-1RA), IL-6, IL-10, TNF-α, TGF-β, hs-CRP, fibrinogen, and serum albumin were measured in 3,939 Chronic Renal Insufficiency Cohort study participants. Bioelectric impedance analysis was used to determine body fat mass (BFM) and fat free mass (FFM).
Plasma levels of hs-CRP, fibrinogen, IL-1RA, IL-6, and TNF-α increased and serum albumin decreased across the quartiles of body mass index. In multivariable analysis, BFM and FFM were positively associated with hs-CRP, fibrinogen, IL-1β, IL-1RA and IL-6. One standard deviation (SD) increase in BFM and FFM was associated with 0.36 (95% CI 0.33, 0.39) and 0.26 (95% CI 0.22, 0.30) SD increase in log transformed hs-CRP, respectively (p<0.001). Race stratified analysis showed that the association between biomarkers and BFM and FFM differed by race, with Caucasians demonstrating a stronger association with markers of inflammation than African Americans.
BFA and FFM are positively associated with markers of inflammation in patients with CKD. Race stratified analysis showed that Caucasians have a stronger association with markers of inflammation compared to African Americans.
PMCID: PMC4327849  PMID: 24415732
Bioelectric impedance analysis; cytokines; acute phase proteins; muscle mass; Body mass index; African Americans
2.  Association of Serum Bicarbonate With Risk of Renal and Cardiovascular Outcomes in CKD: A Report From the Chronic Renal Insufficiency Cohort (CRIC) Study 
The purpose of this study is to evaluate serum bicarbonate as a risk factor for renal outcomes, cardiovascular events and mortality in patients with chronic kidney disease (CKD).
Study Design
Observational cohort study.
Setting & Participants
3939 participants with CKD stages 2-4 who enrolled in the Chronic Renal Insufficiency Cohort (CRIC) between June 2003 - December 2008.
Serum bicarbonate.
Renal outcomes, defined as end-stage renal disease (either initiation of dialysis or kidney transplantation) or 50% reduction in eGFR; atherosclerotic events (myocardial infarction, stroke, peripheral arterial disease); congestive heart failure events; and death.
Time to event.
The mean eGFR was 44.8 ± 16.8 (SD) mL/min/1.73 m2, and the median serum bicarbonate was 24 (IQR, 22-26) mEq/L. During a median follow-up of 3.9 years, 374 participants died, 767 had a renal outcome, and 332 experienced an atherosclerotic event and 391 had a congestive heart failure event. In adjusted analyses, the risk of developing a renal endpoint was 3% lower per mEq/L increase in serum bicarbonate (HR, 0.97; 95% CI, 0.94-0.99; p=0.01). The association was stronger for participants with eGFR> 45ml/min/1.73m2 (HR, 0.91; 95%CI, 0.85-0.97; p=0.004). The risk of heart failure increased by 14% (HR, 1.14; 95%CI, 1.03-1.26; p=0.02) per mEq/L increase in serum bicarbonate over 24 mEq/L. Serum bicarbonate was not independently associated with atherosclerotic events (HR, 0.99; 95%CI, 0.95-1.03; p=0.6) and all-cause mortality (HR, 0.98; 95%CI, 0.95-1.02; p=0.3).
Single measurement of sodium bicarbonate.
In a cohort of participants with CKD, low serum bicarbonate was an independent risk factor for kidney disease progression, particularly for participants with preserved kidney function. The risk of heart failure was higher at the upper extreme of serum bicarbonate. There was no association between serum bicarbonate and all-cause mortality or atherosclerotic events.
PMCID: PMC3701754  PMID: 23489677
metabolic acidosis; serum bicarbonate; chronic kidney disease; cardiovascular morbidity
3.  Candidate Gene Association Study of Coronary Artery Calcification in Chronic Kidney Disease: Findings from the Chronic Renal Insufficiency Cohort Study 
To identify loci for coronary artery calcification (CAC) in patients with chronic kidney disease (CKD).
CKD is associated with increased CAC and subsequent coronary heart disease (CHD) but the mechanisms remain poorly defined. Genetic studies of CAC in CKD may provide a useful strategy for identifying novel pathways in CHD.
We performed a candidate gene study (~2,100 genes; ~50,000 SNPs) of CAC within the Chronic Renal Insufficiency Cohort (CRIC) Study (n=1,509; 57% European, 43% African ancestry). SNPs with preliminary evidence of association with CAC in CRIC were examined for association with CAC in PennCAC (n=2,560) and Amish Family Calcification Study (AFCS; n=784) samples. SNPs with suggestive replication were further analyzed for association with myocardial infarction (MI) in the Pakistan Risk of Myocardial Infarction study (PROMIS) (n=14,885).
Of 268 SNPs reaching P <5×10−4 for CAC in CRIC, 28 SNPs in 23 loci had nominal support (P <0.05 and in same direction) for CAC in PennCAC or AFCS. Besides chr9p21 and COL4A1, known loci for CHD, these included SNPs having reported GWAS association with hypertension (e.g., ATP2B1). In PROMIS, four of the 23 suggestive CAC loci (chr9p21, COL4A1, ATP2B1 and ABCA4) had significant associations with MI consistent with their direction of effect on CAC.
We identified several loci associated with CAC in CKD that also relate to MI in a general population sample. CKD imparts a high risk of CHD and may provide a useful setting for discovery of novel CHD genes and pathways.
PMCID: PMC3953823  PMID: 23727086
Coronary artery calcification (CAC); chronic kidney disease (CKD); Chronic Renal Insufficiency Cohort Study (CRIC); myocardial infarction (MI); risk factors; candidate genes; single nucleotide polymorphisms (SNPs)
4.  APOL1 Risk Variants, Race, and Progression of Chronic Kidney Disease 
The New England journal of medicine  2013;369(23):2183-2196.
Among patients in the United States with chronic kidney disease, black patients are at increased risk for end-stage renal disease, as compared with white patients.
In two studies, we examined the effects of variants in the gene encoding apolipoprotein L1 (APOL1) on the progression of chronic kidney disease. In the African American Study of Kidney Disease and Hypertension (AASK), we evaluated 693 black patients with chronic kidney disease attributed to hypertension. In the Chronic Renal Insufficiency Cohort (CRIC) study, we evaluated 2955 white patients and black patients with chronic kidney disease (46% of whom had diabetes) according to whether they had 2 copies of high-risk APOL1 variants (APOL1 high-risk group) or 0 or 1 copy (APOL1 low-risk group). In the AASK study, the primary outcome was a composite of end-stage renal disease or a doubling of the serum creatinine level. In the CRIC study, the primary outcomes were the slope in the estimated glomerular filtration rate (eGFR) and the composite of end-stage renal disease or a reduction of 50% in the eGFR from baseline.
In the AASK study, the primary outcome occurred in 58.1% of the patients in the APOL1 high-risk group and in 36.6% of those in the APOL1 low-risk group (hazard ratio in the high-risk group, 1.88; P<0.001). There was no interaction between APOL1 status and trial interventions or the presence of baseline proteinuria. In the CRIC study, black patients in the APOL1 high-risk group had a more rapid decline in the eGFR and a higher risk of the composite renal outcome than did white patients, among those with diabetes and those without diabetes (P<0.001 for all comparisons).
Renal risk variants in APOL1 were associated with the higher rates of end-stage renal disease and progression of chronic kidney disease that were observed in black patients as compared with white patients, regardless of diabetes status. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others.)
PMCID: PMC3969022  PMID: 24206458
5.  Retinopathy and Cognitive Impairment in Adults With CKD 
Retinal microvascular abnormalities have been associated with cognitive impairment, possibly serving as a marker of cerebral small vessel disease. This relationship has not been evaluated among persons with chronic kidney disease (CKD), a condition associated with increased risk of both retinal pathology and cognitive impairment.
Study Design
Cross-sectional study
Setting & Participants
588 participants ≥ 52 years old with CKD in the Chronic Renal Insufficiency Cohort (CRIC) Study
Retinopathy graded using the Early Treatment Diabetic Retinopathy Study severity scale and diameters of retinal vessels.
Neuropsychological battery of six cognitive tests
Logistic regression models were used to evaluate the association of retinopathy, individual retinopathy features, and retinal vessel diameters with cognitive impairment (≤1 SD from the mean), and linear regression models were used to compare cognitive test scores across levels of retinopathy adjusting for age, race, sex, education, and medical comorbidities.
The mean age of the cohort was 65.3 +/− 5.6 (SD) years; 51.9% were non-White, and 52.6% were male. The prevalence of retinopathy was 30.1% and 14.3% for cognitive impairment. Compared to those without retinopathy, participants with retinopathy had increased likelihood of cognitive impairment on executive function (35.1% vs. 11.5%; OR, 3.4; 95% CI, 2.0-6.0), attention (26.7% vs. 7.3%; OR, 3.0; 95% CI, 1.8-4.9), and naming (26.0% vs. 10.0%; OR, 2.1; 95% CI, 1.2-3.4) after multivariable adjustment. Increased level of retinopathy was also associated with lower cognitive performance on executive function and attention. Microaneurysms were associated with cognitive impairment on some domains, but there were no significant associations with other retinal measures after multivariable adjustment.
Unknown temporal relationship between retinopathy and impairment.
In adults with CKD, retinopathy is associated with poor performance on several cognitive domains including executive function and attention. Evaluation of retinal microvascular abnormalities may be a promising tool for identifying patients with CKD who are at increased risk of cognitive impairment.
PMCID: PMC4030670  PMID: 23206534
6.  Immunological Aspect on Late Allograft Dysfunction 
Journal of Immunology Research  2014;2014:625031.
PMCID: PMC4009131  PMID: 24834436
7.  Metabolic Syndrome, Vitamin D Deficiency and Hypoadiponectinemia among Non-Diabetic Patients Early after Kidney Transplantation 
American journal of nephrology  2013;37(5):10.1159/000349930.
Background and Aims
Metabolic syndrome (MetS) is common among kidney transplant patients. We studied the relationship between MetS, vitamin D deficiency/insufficiency and hypoadiponectinemia early post-transplantation and their impact on clinical outcomes.
Seventy-four previously non-diabetic kidney transplant patients were enrolled in a prospective cohort study between February and November 2008. Participants underwent a 2-hours oral glucose tolerance test (OGTT) and had their plasma levels of 25-hydroxyvitamin D (25[OH]D), adiponectin, insulin, intact parathyroid hormone and lipids measured at 11 weeks after transplantation. Clinical events including cardiovascular events, new onset diabetes after transplantation, acute rejection, graft loss and death were recorded during the follow-up to December 2012.
Thirty-four study patients (45.9%) had MetS. Patients with MetS had lower plasma concentrations of 25[OH]D (20.5±7.2 vs. 24.8±11.1 ng/ml, p=0.049) and adiponectin (8.2±4.5 vs. 14.6±8.0 μg/ml, p<0.0001) early on, and higher composite clinical event rate (61.8% vs. 27.5%, p=0.003) during the follow-up. Multivariate analysis showed that the presence of MetS early after transplantation was independently associated with 25[OH]D insufficiency/deficiency (OR 14.0, 95% CI 1.8, 107.5, p=0.011), depressed plasma adiponectin levels (β -6.39, r2 0.195, p<0.0001) and increased risk for clinical events (OR 5.6, 95% CI 1.9, 16.5, p=0.002).
Kidney transplants patients with MetS early after transplantation had lower levels of 25[OH]D and adiponectin, and unfavorable clinical outcomes.
PMCID: PMC3816759  PMID: 23751485
adiponectin; clinical outcomes; kidney transplantation; metabolic syndrome; vitamin D deficiency
8.  Comparison of the long-term outcomes of kidney transplantation: USA versus Spain 
On comparing the rates of graft failure and death among United States and Spanish kidney transplant recipients…the 10 year graft and patient survival was significantly better in the Spanish population.”
The long-term outcomes of kidney transplantation are suboptimal because many patients lose their allografts or experience premature death. Cross-country comparisons of long-term outcomes of kidney transplantation may provide insight into factors contributing to premature graft failure and death. We evaluated the rates of late graft failure and death among US and Spanish kidney recipients.
This is a cohort study of US (n = 9609) and Spanish (n = 3808) patients who received a deceased donor kidney transplant in 1990, 1994, 1998 or 2002 and had a functioning allograft 1 year after transplantation with follow-up through September 2006. Ten-year overall and death-censored graft survival and 10-year overall recipient survival and death with graft function (DWGF) were estimated with multivariate Cox models.
Among recipients alive with graft function 1 year after transplant, the 10-year graft survival was 71.3% for Spanish and 53.4% for US recipients (P < 0.001). The 10-year, death-censored graft survival was 75.6 and 76.0% for Spanish and US recipients, respectively (P = 0.73). The 10-year recipient survival was 86.2% for Spanish and 67.4% for US recipients (P < 0.001). In recipients with diabetes as the cause of ESRD, the adjusted DWGF rates at 10 years were 23.9 and 53.8 per 1000 person-years for Spanish and US recipients, respectively (P < 0.001). Among recipients whose cause of ESRD was not diabetes mellitus, the adjusted 10-year DWGF rates were 11.0 and 25.4 per 1000 person-years for Spanish and US recipients, respectively.
US kidney transplant recipients had more than twice the long-term hazard of DWGF compared with Spanish kidney transplant recipients and similar levels of death-censored graft function. Pre-transplant medical care, comorbidities, such as cardiovascular disease, and their management in each country's health system are possible explanations for the differences between the two countries.
PMCID: PMC3616762  PMID: 22759384
death with a functioning allograft; diabetes mellitus; end stage renal disease; graft survival; international comparison
9.  Risk Factors for Coronary Artery Calcium Among Patients with Chronic Kidney Disease (From the Chronic Renal Insufficiency Cohort Study) 
The American journal of cardiology  2012;110(12):1735-1741.
Cardiovascular disease is the leading cause of death in patients with chronic kidney disease (CKD). We examined the cross-sectional association between novel risk factors and coronary artery calcium (CAC) measured by electron-beam computed tomography or multidetector computed tomography among 2,018 patients with CKD. Based on total Agatston scores, participants were classified as no (0), moderate (>0–100) or high (>100) CAC. After adjustment for age, sex, race, study sites, cigarette smoking, prior cardiovascular disease, hypertension, and diabetes, use of lipid-lowering drugs, body-mass index, waist circumference, and cystatin C, several novel risk factors were significantly associated with high CAC. For example, odds ratios (95% confidence interval) of high CAC associated with one standard deviation higher levels of risk factors were 1.20 (1.04, 1.38) for serum calcium, 1.21 (1.04, 1.41) for serum phosphate, 0.83 (0.71, 0.97) for log (total parathyroid hormone), 1.21 (1.03, 1.43) for log (HOMA-insulin resistance), and 1.23 (1.04, 1.45) for hemoglobin A1c. Additionally, the multivariable-adjusted odds ratio for one standard deviation higher level of cystatin C was 1.31 (1.14, 1.50). Serum high-sensitive C-reactive protein, interleukin-6, tumor necrosis factor-α, and homocysteine were not statistically significantly associated with high CAC. In conclusion, these data indicate that abnormal calcium and phosphate metabolism, insulin resistance, and declined kidney function were associated with the prevalence of high CAC independent of traditional risk factors in patients with CKD. Further studies are warranted to examine the causal effect of these risk factors on CAC in CKD patients.
PMCID: PMC3511639  PMID: 22980963
calcium; chronic kidney disease; coronary artery calcium; cystatin C; insulin-resistance; phosphate; total parathyroid hormone
10.  The time interval between kidney and pancreas transplantation and the clinical outcomes of pancreas after kidney transplantation 
Clinical transplantation  2011;26(3):10.1111/j.1399-0012.2011.01519.x.
Pancreas after kidney (PAK) transplantation is one of the accepted pancreas transplant modalities. We studied the impact of time interval between kidney and pancreas transplantation on the outcomes of PAK transplantation. Using OPTN/SRTR data, we included 1853 PAK transplants performed between 1996 and 2005 with follow-up until November 1, 2008. Kaplan–Meier survival and multivariate Cox regression analyses were performed using the time interval between kidney and pancreas transplantation either as a categorical (less than one yr, between one and less than three yr, and greater than or equal to three yr) or as a continuous variable (months) to assess kidney graft and patient survival. Patients who received a pancreas transplant three yr or later after kidney transplantation had higher risk of death-censored kidney graft loss (HR 1.56, 95% CI 1.04, 2.32, p = 0.03). Each month beyond three yr between kidney and pancreas transplantation incurred 1% higher risk of subsequent death-censored kidney graft loss (HR 1.01, 95% CI 1.001, 1.02, p = 0.03). In conclusion, time interval between pancreas and kidney transplantation is an independent risk factor of kidney graft loss following pancreas transplantation. Shortening the time interval between pancreas and kidney transplantation to less than three yr may reduce the risk of kidney graft loss in qualified PAK transplant candidates.
PMCID: PMC3856569  PMID: 22003873
death-censored kidney graft failure; pancreas after kidney transplantation; time interval
11.  Metabolic syndrome and new onset diabetes after transplantation in kidney transplant recipients 
Clinical transplantation  2010;24(6):10.1111/j.1399-0012.2009.01194.x.
Metabolic syndrome (MS) and new onset diabetes after transplant (NODAT) are common in kidney transplant patients. We studied the relationship between the two conditions and their impact on metabolic and cardiovascular risk profiles.
All non-diabetic patients transplanted between 1999 and 2005 who were followed up to 2006 were included. MS and NODAT were determined. Kaplan–Meier survival and various regression analyses were performed to determine the clinical correlates for both conditions and their association with various cardiovascular risk factors.
Among 591 patients, 314 (53.1%) had MS and 90 (15.2%) developed NODAT. The two conditions were highly associated with each other as 84 patients with NODAT also had MS (14.2%). Elevated body mass index and fasting glucose levels at transplant were risk factors for both conditions, whereas weight gain after transplant was associated only with MS. African American, old age, and hypertension-related ESRD were risk factors for NODAT. Finally, the presence of MS was associated with reduced kidney function and elevated uric acid levels, whereas the presence of NODAT with elevated pulse pressure.
MS and NODAT are highly prevalent and significantly associated with impaired metabolic and cardiovascular risk profiles. Early identification of such conditions may facilitate targeted therapeutic intervention.
PMCID: PMC3831507  PMID: 20047609
kidney transplant; metabolic syndrome; new onset diabetes
12.  Steroid-free maintenance immunosuppression in kidney transplantation: is it time to consider it as a standard therapy? 
Kidney international  2009;76(8):10.1038/ki.2009.248.
Steroid-free immunosuppression in kidney transplantation has been gaining popularity over the past decade, as documented by a continuous and steady rise in the number of kidney transplant patients discharged on steroid-free regimens. This increased interest in steroid-free immunosuppression is fueled by the recognition that half of transplant loss is related to patient death due to cardiovascular disease and/or infectious complications and that the long-term use of steroids contributes to such elevated cardiovascular morbidity and mortality. The availability of newer and more potent immunosuppressive agents has furthered such interest. Many clinical trials over the past two decades have demonstrated the feasibility of steroid-free regimens, at the expense of a slight increase in the rate of acute rejection, which is an important end point in any clinical trial of relatively short duration. The largest epidemiological study to date has reassured the transplant community that the selective use of steroid-free immunosuppression in kidney transplant patients provides no inferior outcome in patient and graft survival at intermediate term. Steroid-free regimens have the potential to improve cardiovascular risk profile. The challenges that remain are to identify the subset of kidney transplant patients who may not benefit from steroid-free immunosuppression and to demonstrate the survival advantage of steroid-free immunosuppresion in suitable kidney transplant candidates.
PMCID: PMC3831511  PMID: 19625995
cardiovascular risk; graft survival; kidney transplant; new-onset diabetes; patient survival; steroid-free immunosuppression
13.  Transition from Donor Candidates to Live Kidney Donors: The Impact of Race and Undiagnosed Medical Disease States 
Clinical transplantation  2011;25(1):10.1111/j.1399-0012.2009.01188.x.
Living kidney donors (LKD) allow for increased access to lifesaving organs for transplantation. There is a relative paucity of African American (AA) live kidney donors. The prevalence of medical disease in LKD candidates has not been well studied. We examined the medical limitations to living kidney donation in a large Mid-Western transplant center.
A total of 2,519 adults (age ≥ 18 years) evaluated as potential LKD between January 1, 1996 and June 30, 2006 were prospectively followed until evaluation outcome (completed live donation, medical exclusion from live donation, non-medical exclusion from live donation). Logistic regression was used to examine the effect of age on donor exclusion and Chi square tests were used to compare the likelihood of donor exclusions between racial and gender groups.
Sixty percent of PD were female (n=1300) and 86% were Caucasian (CA) (n=1862). Overall, 48.7% of PD who underwent evaluation became LKD. The odds of donation were 52% lower in AA compared to CA (OR 0.48 p< 0.001). Among PD excluded from donation, the most common medical diagnoses were HTN (24.7%), inadequate creatinine clearance, (10.6%) and a positive final crossmatch (10.5%). The rate of PD exclusion for obesity was two-fold higher in AA compared to CA (12.8% vs. 5.8%, p < 0.001).
Hypertension in PD is equally significant barrier to living kidney donation in AA and CA whereas obesity is a greater barrier in AA.
PMCID: PMC3807634  PMID: 20047616
Donation; access; contraindications; hypertension; obesity
14.  Design of the Nephrotic Syndrome Study Network (NEPTUNE) to evaluate primary glomerular nephropathy by a multi-disciplinary approach 
Kidney international  2013;83(4):749-756.
The Nephrotic Syndrome Study Network (NEPTUNE) is a North American multi-center collaborative consortium established to develop a translational research infrastructure for Nephrotic Syndrome. This includes a longitudinal observational cohort study, a pilot and ancillary studies program, a training program, and a patient contact registry. NEPTUNE will enroll 450 adults and children with minimal change disease, focal segmental glomerulosclerosis and membranous nephropathy for detailed clinical, histopathologic, and molecular phenotyping at the time of clinically-indicated renal biopsy. Initial visits will include an extensive clinical history, physical examination, collection of urine, blood and renal tissue samples, and assessments of quality of life and patient-reported outcomes. Follow-up history, physical measures, urine and blood samples, and questionnaires will be obtained every 4 months in the first year and bi-annually, thereafter. Molecular profiles and gene expression data will be linked to phenotypic, genetic, and digitalized histologic data for comprehensive analyses using systems biology approaches. Analytical strategies were designed to transform descriptive information to mechanistic disease classification for Nephrotic Syndrome and to identify clinical, histological, and genomic disease predictors. Thus, understanding the complexity of the disease pathogenesis will guide further investigation for targeted therapeutic strategies.
PMCID: PMC3612359  PMID: 23325076
15.  Donor Morbidity After Living Donation for Liver Transplantation 
Gastroenterology  2008;135(2):468-476.
Background & Aims
Reports of complications among adult right hepatic lobe donors have been limited to single centers. The rate and severity of complications in living donors were investigated in the 9-center Adult-to-Adult Living Donor Liver Transplantation Cohort Study (A2ALL).
A retrospective observational study design was used. Participants included all potential living donors evaluated between 1998 and 2003. Complication severity was graded using the Clavien scoring system.
Of 405 donors accepted for donation, 393 underwent donation, and 12 procedures were aborted. There were 245 donors (62%) who did not experience complications; 82 (21%) had 1 complication, and 66 (17%) had 2 or more. Complications were scored as grade 1 (minor; n = 106, 27%), grade 2 (potentially life threatening; n = 103, 26%), grade 3 (life threatening; n = 8, 2%), and grade 4 (leading to death; n = 3, 0.8%). Common complications included biliary leaks beyond postoperative day 7 (n = 36, 9%), bacterial infections (n = 49, 12%), incisional hernia (n = 22, 6%), pleural effusion requiring intervention (n = 21, 5%), neuropraxia (n = 16, 4%), reexploration (n = 12, 3%), wound infections (n = 12, 3%), and intraabdominal abscess (n = 9, 2%). Two donors developed portal vein thrombosis, and 1 had inferior vena caval thrombosis. Fifty-one (13%) donors required hospital readmission, and 14 (4%) required 2 to 5 readmissions.
Adult living liver donation was associated with significant donor complications. Although most complications were of low-grade severity, a significant proportion were severe or life threatening. Quantification of complication risk may improve the informed consent process, perioperative planning, and donor care.
PMCID: PMC3731061  PMID: 18505689
16.  Estimated glomerular filtration rate at reinitiation of dialysis and mortality in failed kidney transplant recipients 
Nephrology Dialysis Transplantation  2012;27(7):2913-2921.
Recent observational studies and a controlled trial suggest more favorable outcomes upon later dialysis initiation in chronic kidney disease. The role of estimated glomerular filtration rate (eGFR) in predicting outcome at reinitiation of dialysis in failed kidney transplant recipients is unclear.
Five-year data in a large dialysis organization was linked to the ‘Scientific Registry of Transplant Recipients’ to identify 747 failed kidney transplant patients with CKD Stage 5, who had restarted dialysis therapy. A propensity score for early (eGFR >10.5 mL/min/1.73m2) versus late reinitiation of dialysis was fit by logistic regression. The mortality hazard ratio (HR) was estimated across tertiles of the fitted score.
Patients were 44 ± 14 years old and included 42% women. Male gender {odds ratio (OR), [95% confidence interval (CI)]: 1.82 (1.22–2.73)}, diabetes mellitus [OR: 1.75 (1.14–2.68)] and peripheral vascular disease [OR: 3.55 (1.17–10.77)] were associated with higher odds of early dialysis reinitiation. Each mL/min/1.73m2 higher eGFR was associated with 6% higher death risk in unadjusted model [HR: 1.06 (1.01–1.11)], and although not significant in fully adjusted models [HR: 1.02 (0.96–1.07)], it was significant in some subgroups including women and younger patients. The death HR of higher eGFR across lowest to highest tertiles of propensity score of early dialysis initiation (corresponding healthiest to sickest patients) were 1.10 (0.98–1.24), 1.00 (0.91–1.10) and 0.99 (0.92–1.07), respectively (P for trend <0.05), indicating a trend toward higher mortality risk with earlier dialysis initiation in the healthiest patients.
Earlier return to dialysis therapy in failed kidney transplant patients tends to correlate with worse dialysis survival especially among healthiest and younger patients and women. Additional studies need to verify these findings.
PMCID: PMC3398063  PMID: 22523118
eGFR; failed kidney; initiation of dialysis; kidney transplantation; mortality
17.  Risk Factors for Peripheral Arterial Disease among Patients with Chronic Kidney Disease 
The American journal of cardiology  2012;110(1):136-141.
Patients with chronic kidney disease (CKD) have an increased risk of developing peripheral arterial disease (PAD). We examined the cross-sectional association between novel risk factors and prevalent PAD among patients with CKD. A total of 3,758 patients with an estimated glomerular filtration rate (eGFR) of 20-70 mL/min/1.73 m2 who participated in the chronic renal insufficiency cohort (CRIC) study were included in the current analysis. PAD was defined as an ankle-brachial index <0.9 or a history of arm or leg revascularization. After adjustment for age, sex, race, cigarette smoking, physical activity, history of hypertension and diabetes, pulse pressure, high-density lipoprotein cholesterol, eGFR, and CRIC clinical sites, several novel risk factors were significantly associated with PAD. For example, odds ratios (95% confidence intervals) for a one standard deviation higher level of risk factors were 1.18 (1.08–1.29) for log-transformed high sensitivity-C reactive protein, 1.18 (1.08–1.29) for white blood cell count, 1.15 (1.05–1.25) for fibrinogen, 1.13 (1.03–1.24) for uric acid, 1.14 (1.02–1.26) for hemoglobin A1c, 1.11 (1.00–1.23) for log-transformed homeostasis model assessment-insulin resistance, and 1.35 (1.18–1.55) for cystatin C. In conclusion, these data indicate that inflammation, prothrombotic state, oxidative stress, insulin resistance, and cystatin C were associated with an increased prevalence of PAD in patients with CKD. Further studies are warranted to examine the causal effect of these risk factors on PAD in CKD patients.
PMCID: PMC3586781  PMID: 22465315
peripheral arterial disease; novel risk factors; chronic kidney disease
18.  Validation of the Kidney Disease Quality of Life Short Form 36 (KDQOL-36™) US Spanish and English Versions in a Cohort of Hispanics with Chronic Kidney Disease 
Ethnicity & disease  2013;23(2):202-209.
Evaluate the reliability and validity of the Kidney Disease Quality of Life Short Form 36 (KDQOL-36™) in Hispanics with mild-to-moderate chronic kidney disease (CKD).
Chronic Renal Insufficiency Cohort Study
420 Hispanic (150 English- and 270 Spanish-speakers), and 409 non-Hispanic White individuals, matched by age (mean 57 years), sex (60% male), kidney function (mean estimated glomerular filtration rate 36ml/min/1.73m2), and diabetes (70%).
To measure construct validity, we selected instruments, comorbidities, and laboratory tests related to at least one KDQOL-36™ subscale. Reliability was determined by calculating Cronbach’s alpha.
Reliability of each KDQOL-36™ subscale [SF-12 Physical Component Summary (PCS) and Mental Component Summary (MCS), Symptoms/Problems, Burden of Kidney Disease and Effects of Kidney Disease] was very good (Cronbach’s alpha >0.8). Construct validity was supported by expected negative correlation between MCS scores and the Beck Depression Inventory in all three subgroups (r= −0.56 to −0.61, P<.0001). There was inverse correlation between the Symptoms/Problems subscale and the Patient Symptom Form (r= −0.70 to −0.77, P<.0001). We also found significant, positive correlation between the PCS score and a physical activity survey (r= +0.29 to +0.38, P≤.003); and between the PCS and MCS scores and the Kansas City Questionnaire (r= +0.31 to +0.64, P<.0001). Reliability and validity were similar across all racial/ethnic groups analyzed separately.
Our findings support the use of the KDQOL-36™ as a measure of HRQOL in this cohort of US Hispanics with CKD.
PMCID: PMC3651651  PMID: 23530302
Validation; Quality of Life; Hispanics
19.  Fluid overload at initiation of renal replacement therapy is associated with lack of renal recovery in patients with acute kidney injury 
Patients with acute kidney injury (AKI) requiring initiation of renal replacement therapy (RRT) have poor short- and long-term outcomes, including the development of dialysis dependence. Currently, little is known about what factors may predict renal recovery in this population.
We conducted a single-center, retrospective analysis of 170 hospitalized adult patients with AKI attributed to acute tubular necrosis who required inpatient initiation of RRT. Data collection included patient characteristics, laboratory data, details of hospital course and degree of fluid overload at RRT initiation. The primary outcome was recovery of renal function to dialysis independence.
Within 1 year of RRT initiation, 35.9% (61/170) of patients reached the primary end point of renal recovery. The median (interquartile range) duration of RRT was 11 (3–33) days and 83.6% (51/61) recovered prior to hospital discharge. Recovering patients had significantly less fluid overload at the time of RRT initiation compared to non-recovering patients (3.5 versus 9.3%, P = 0.004). In multivariate Cox proportional hazard regression analysis, a rise in percent fluid overload at dialysis initiation remained a significant negative predictor of renal recovery (hazard ratio 0.97, 95% confidence interval 0.95–1.00, P = 0.024).
In patients with AKI, a higher degree of fluid overload at RRT initiation predicts worse renal recovery at 1 year. Clinical trials are needed to determine whether interventions targeting fluid overload may improve patient and renal outcomes.
PMCID: PMC3471547  PMID: 21856761
acute kidney injury; dialysis; fluid overload; renal recovery
20.  CKD in Hispanics: Baseline Characteristics From the CRIC (Chronic Renal Insufficiency Cohort) and Hispanic-CRIC Studies 
Little is known regarding chronic kidney disease (CKD) in Hispanics. We compared baseline characteristics of Hispanic participants in the Chronic Renal Insufficiency Cohort (CRIC) and Hispanic-CRIC (H-CRIC) Studies with non-Hispanic CRIC participants.
Study Design
Cross-sectional analysis
Setting and Participants
Participants were aged 21–74 years with CKD using age-based glomerular filtration rate (eGFR) at enrollment into the CRIC/H-CRIC Studies. H-CRIC included Hispanics recruited at the University of Illinois from 2005–2008 while CRIC included Hispanics and non-Hispanics recruited at seven clinical centers from 2003–2007.
Blood pressure, angiotensin-converting enzyme (ACE) inhibitor/angiotensin receptor blocker (ARB) use, CKD-associated complications
Demographic characteristics, laboratory data, blood pressure, and medications were assessed using standard techniques and protocols
Among H-CRIC/ CRIC participants, 497 were Hispanic, 1650 non-Hispanic Black, and 1638 non-Hispanic White. Low income and educational attainment were nearly twice as prevalent in Hispanics compared with non-Hispanics (p<0.01). Hispanics had self-reported diabetes (67%) more frequently than non-Hispanic Blacks (51%) and Whites (40%) (p<0.01). Blood pressure > 130/80 mmHg was more common in Hispanics (62%) compared with Blacks (57%) and Whites (35%) (p<0.05), and abnormalities in hematologic, metabolic, and bone metabolism parameters were more prevalent in Hispanics (p<0.05), even after stratifying by entry eGFR. Hispanics had the lowest receipt of ACE inhibitor/ARB among high-risk subgroups, including participants with diabetes, proteinuria, and blood pressure > 130/80 mmHg. Mean eGFR (ml/min/m2) was lower in Hispanics (39.6) than in Blacks (43.7) and Whites (46.2), while median proteinuria was higher in Hispanics (0.72 g/d) than in Blacks (0.24 g/d) and Whites (0.12 g/d) (p<0.01).
Generalizability; observed associations limited by residual bias and confounding
Hispanics with CKD in CRIC/H-CRIC Studies are disproportionately burdened with lower socioeconomic status, more frequent diabetes mellitus, less ACE inhibitor/ARB use, worse blood pressure control, and more severe CKD and associated complications than their non-Hispanic counterparts.
PMCID: PMC3577064  PMID: 21705121
chronic kidney disease; Hispanics; epidemiology
21.  Metabolic Syndrome, Components, and Cardiovascular Disease Prevalence in Chronic Kidney Disease: Findings from the Chronic Renal Insufficiency Cohort (CRIC) Study 
American Journal of Nephrology  2011;33(6):477-484.
Metabolic syndrome may increase the risk for incident cardiovascular disease (CVD) and all-cause mortality in the general population. It is unclear whether, and to what degree, metabolic syndrome is associated with CVD in chronic kidney disease (CKD). We determined metabolic syndrome prevalence among individuals with a broad spectrum of kidney dysfunction, examining the role of the individual elements of metabolic syndrome and their relationship to prevalent CVD.
We evaluated four models to compare metabolic syndrome or its components to predict prevalent CVD using prevalence ratios in the Chronic Renal Insufficiency Cohort (CRIC) Study.
Among 3,939 CKD participants, the prevalence of metabolic syndrome was 65% and there was a significant association with prevalent CVD. Metabolic syndrome was more common in diabetics (87.5%) compared with non-diabetics (44.3%). Hypertension was the most prevalent component, and increased triglycerides the least prevalent. Using the bayesian information criterion, we found that the factors defining metabolic syndrome, considered as a single interval-scaled variable, was the best of four models of metabolic syndrome, both for CKD participants overall and for diabetics and non-diabetics separately.
The predictive value of this model for future CVD outcomes will subsequently be validated in longitudinal analyses.
PMCID: PMC3095834  PMID: 21525746
Cardiovascular disease; Chronic kidney disease; Chronic Renal Insufficiency Cohort (CRIC) Study; Metabolic syndrome
22.  Fibroblast Growth Factor 23 and Risks of Mortality and End-Stage Renal Disease in Patients with Chronic Kidney Disease 
High levels of the phosphate regulating hormone, fibroblast growth factor 23 (FGF23), associate with mortality in patients with end-stage renal disease (ESRD), but little is known about its relationship with adverse outcomes in the much larger population of patients with earlier stages of chronic kidney disease (CKD).
Evaluate FGF23 as a risk factor for adverse outcomes in patients with CKD.
Design, Setting and Participants
A prospective study of 3,879 participants with CKD stages 2 – 4 who enrolled in the Chronic Renal Insufficiency Cohort between June 2003 and September 2008.
Main Outcome Measures
All-cause mortality and ESRD.
At enrollment, mean estimated glomerular filtration rate (eGFR) was 42.8 ± 13.5 ml/min/1.73m2, and median FGF23 was 145 (interquartile range [IQR] 96 – 239) reference units/ml (RU/ml). During a median follow-up of 3.5 (IQR 2.5 – 4.4) years, 266 participants died (20.3/1000 person-years) and 410 reached ESRD (33.0/1000 person-years). Higher FGF23 levels independently associated with a greater risk of death in adjusted analyses of FGF23 on a continuous scale (hazard ratio [HR] per SD of lnFGF23, 1.5; 95%CI 1.3 – 1.7) or in quartiles (quartile 1, reference; quartile 2, HR 1.3; 95%CI 0.8 – 2.2; quartile 3, HR 2.0; 95%CI 1.2 – 3.3; quartile 4, HR 3.0; 95%CI 1.8 – 5.1). FGF23 was not independently associated with ESRD in adjusted analyses of the entire cohort, however, the effect was modified by eGFR (P for interaction = 0.005), which was the strongest predictor for ESRD. FGF23 independently associated with significantly greater risk of ESRD among participants with eGFR 30 – 44 (HR 1.3 per SD of lnFGF23; 95%CI 1.04 – 1.6) and ≥ 45 (HR 1.7; 95%CI 1.1 – 2.4), but not < 30 ml/min/1.73m2.
Elevated FGF23 is an independent risk factor for ESRD in patients with relatively preserved kidney function and for mortality across the spectrum of CKD.
PMCID: PMC3124770  PMID: 21673295
23.  FGF23 induces left ventricular hypertrophy 
The Journal of Clinical Investigation  2011;121(11):4393-4408.
Chronic kidney disease (CKD) is a public health epidemic that increases risk of death due to cardiovascular disease. Left ventricular hypertrophy (LVH) is an important mechanism of cardiovascular disease in individuals with CKD. Elevated levels of FGF23 have been linked to greater risks of LVH and mortality in patients with CKD, but whether these risks represent causal effects of FGF23 is unknown. Here, we report that elevated FGF23 levels are independently associated with LVH in a large, racially diverse CKD cohort. FGF23 caused pathological hypertrophy of isolated rat cardiomyocytes via FGF receptor–dependent activation of the calcineurin-NFAT signaling pathway, but this effect was independent of klotho, the coreceptor for FGF23 in the kidney and parathyroid glands. Intramyocardial or intravenous injection of FGF23 in wild-type mice resulted in LVH, and klotho-deficient mice demonstrated elevated FGF23 levels and LVH. In an established animal model of CKD, treatment with an FGF–receptor blocker attenuated LVH, although no change in blood pressure was observed. These results unveil a klotho-independent, causal role for FGF23 in the pathogenesis of LVH and suggest that chronically elevated FGF23 levels contribute directly to high rates of LVH and mortality in individuals with CKD.
PMCID: PMC3204831  PMID: 21985788
24.  Chronic Kidney Disease and Prevalent Atrial Fibrillation: The Chronic Renal Insufficiency Cohort (CRIC) 
American heart journal  2010;159(6):1102-1107.
The epidemiology of atrial fibrillation (AF) has been mainly investigated in patients with end-stage renal disease (ESRD), with limited data on less advanced chronic kidney disease (CKD) stages.
A total of 3267 adult participants (50% non-Hispanic blacks, 46% females) with CKD from the Chronic Renal Insufficiency Cohort (CRIC) were included in this study. None of the study participants had been on dialysis. Those with self-identified race/ethnicity other than non-Hispanic black or white (N=323) or those without ECG data (N=22) were excluded. AF was ascertained by a 12-lead electrocardiogram (ECG) and self-report. Age- sex- race/ethnicity-specific prevalence rates of AF were estimated and compared between subgroups. Cross sectional associations and correlates with prevalent AF were examined using unadjusted and multivariable adjusted logistic regression analysis.
The mean estimated glomerular filtration rate (GFR) was 43.6 (±13.0) ml/min/1.73 m2. AF was present in 18% of the study population and in more than 25% of those 70 years or older. In multivariable adjusted models, 1-SD increase in age (11 years) [odds ratio (OR) and CI 95%: 1.27 (1.13, 1.43), P<0.0001], female sex [0.80 (0.65, 0.98), P=0.0303], smoking (former vs. never) [1.34 (1.08, 1.66), P= 0.0081], history of heart failure [3.28 (2.47, 4.36), P<0.001], and history of cardiovascular disease [1.94 (1.56, 2.43), P<0.0001] were significantly associated with AF. Race/ethnicity, hypertension, diabetes, body mass index, physical activity, education, high sensitivity C-reactive protein, total cholesterol, and alcohol intake were not significantly associated with AF. An estimated GFR <45 ml/min/1.73 m2 was associated with AF in an unadjusted model [1.35 (1.13–1.62)); P=0.0010)], but not after multivariable adjustment [1.12 (0.92– 1.35), P=0.2710].
Nearly one in five participants in CRIC, a national study of CKD, had evidence for AF at study entry, a prevalence similar to that reported among patients with ESRD and 2–3 times of that reported in the general population. Risk factors for AF in this CKD population do not mirror those reported in the general population.
PMCID: PMC2891979  PMID: 20569726
25.  Chronic Kidney Disease and Cognitive Function in Older Adults: Findings from the Chronic Renal Insufficiency Cohort (CRIC) Cognitive Study 
To investigate cognitive impairment in older, ethnically diverse individuals with a broad range of kidney function, to evaluate a spectrum of cognitive domains and to determine whether the relationship between CKD and cognitive function is independent of demographic and clinical factors.
Cross sectional.
Chronic Renal Insufficiency Cohort Study.
825 adults ≥55 years with CKD.
We estimated glomerular filtration rate (eGFR, ml/min/1.73 m2) using the four-variable Modification of Diet in Renal Disease equation. We compared cognitive scores on six cognitive tests across eGFR strata using linear regression; multivariable logistic regression was used to examine level of CKD and clinically significant cognitive impairment (score ≤1 sd from mean).
Mean age of the participants was 64.9 years, 50% were male and 45% were Black. After multi-variable adjustment, participants with lower eGFR had lower cognitive scores on most cognitive domains (P<0.05). In addition, compared with persons who had mild or moderate CKD (eGFR 45-59), participants with advanced CKD (eGFR <30) were more likely to have clinically significant cognitive impairment on global cognition (adjusted odds ratio [OR] 2.0, 95% CI 1.1-3.9), naming (OR 1.9, 95% CI 1.0-3.3), attention (OR 2.4, 95%CI 1.3-4.5), executive function (OR 2.5, 95%CI 1.9- 4.4) and delayed memory, (OR=1.5, 95%CI 0.9-2.6) but not on category fluency (OR=1.1, 95% CI 0.6-2.0).
Among older adults with CKD, lower level of kidney function was associated with lower cognitive function on most domains. Our results suggest that older patients with advanced CKD should be screened for cognitive impairment.
PMCID: PMC2852884  PMID: 20374407
Chronic kidney disease; cognitive impairment; cognitive function

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