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author:("Ojo, akintola")
1.  Blood pressure and risk of all-cause mortality in advanced chronic kidney disease and hemodialysis: the CRIC study 
Hypertension  2014;65(1):93-100.
Studies of hemodialysis patients have shown a U-shaped association between systolic blood pressure (SBP) and mortality. These studies have largely relied on dialysis-unit SBP measures and have not evaluated whether this U-shape also exists in advanced chronic kidney disease (CKD), prior to starting hemodialysis. We determined the association between SBP and mortality at advanced CKD and again after initiation of hemodialysis. This was a prospective study of Chronic Renal Insufficiency Cohort (CRIC) participants with advanced CKD followed through initiation of hemodialysis. We studied the association between SBP and mortality when participants: 1) had an estimated glomerular filtration rate <30 ml/min/1.73m2 (N=1,705); 2) initiated hemodialysis and had dialysis-unit SBP measures (N=403) and; 3) initiated hemodialysis and had out-of-dialysis-unit SBP measured at a CRIC study visit (N=326). Cox models adjusted for demographics, cardiovascular risk factors and dialysis parameters. A quadratic term for SBP was included to test for a U-shaped association. At advanced CKD, there was no association between SBP and mortality (HR 1.02 [95% CI: 0.98–1.07] per every 10 mm Hg increase). Among participants who started hemodialysis, a U-shaped association between dialysis-unit SBP and mortality was observed. In contrast, there was a linear association between out-of-dialysis-unit SBP and mortality (HR 1.26 [95% CI: 1.14–1.40] per every 10 mm Hg increase). In conclusion, more efforts should be made to obtain out-of-dialysis-unit SBP which may merit more consideration as a target for clinical management and in interventional trials.
doi:10.1161/HYPERTENSIONAHA.114.04334
PMCID: PMC4268143  PMID: 25287404
CKD; hypertension; dialysis; mortality; ESRD
2.  Factors affecting willingness to receive a kidney transplant among minority patients at an urban safety-net hospital: a cross-sectional survey 
BMC Nephrology  2015;16:191.
Background
In the US, African Americans (AAs) are four times more likely to develop end stage renal disease (ESRD) but half as likely to receive a kidney transplant as whites. Patient interest in kidney transplantation is a fundamental step in the kidney transplant referral process. Our aim was to determine the factors associated with the willingness to receive a kidney transplant among chronic kidney disease (CKD) patients in a predominantly minority population.
Methods
CKD patients from an outpatient nephrology clinic at a safety-net hospital (n = 213) participated in a cross-sectional survey from April to June, 2013 to examine the factors associated with willingness to receive a kidney transplant among a predominantly minority population. The study questionnaire was developed from previously published literature. Multivariable logistic regression analysis was used to determine factors associated with willingness to undergo a kidney transplant.
Results
Respondents were primarily AAs (91.0 %), mostly female (57.6 %) and middle aged (51.6 %). Overall, 53.9 % of participants were willing to undergo a kidney transplant. Willingness to undergo a kidney transplant was associated with a positive perception towards living kidney donation (OR 7.31, 95 % CI: 1.31–40.88), willingness to attend a class about kidney transplant (OR = 7.15, CI: 1.76–29.05), perception that a kidney transplant will improve quality of life compared to dialysis (OR = 5.40, 95 % CI: 1.97–14.81), and obtaining information on kidney transplant from other sources vs. participant’s physician (OR =3.30, 95 % CI: 1.13–9.67), when compared with their reference groups.
Conclusion
It is essential that the quality of life benefits of kidney transplantation be known to individuals with CKD to increase their willingness to undergo kidney transplantation. Availability of multiple sources of information and classes on kidney transplantation may also contribute to willingness to undergo kidney transplantation, especially among AAs.
Electronic supplementary material
The online version of this article (doi:10.1186/s12882-015-0186-2) contains supplementary material, which is available to authorized users.
doi:10.1186/s12882-015-0186-2
PMCID: PMC4654893  PMID: 26588895
African Americans; Willingness; Kidney transplant; CKD; Perceptions; Attitudes; Knowledge
3.  Arterial Stiffness, Central Pressures and Incident Hospitalized Heart Failure in the Chronic Renal Insufficiency Cohort (CRIC) Study 
Circulation. Heart failure  2014;7(5):709-716.
Background
Chronic kidney disease (CKD) is associated with an increased risk of heart failure (HF). We aimed to evaluate the role of large artery stiffness, brachial and central blood pressure as predictors of incident hospitalized HF in the Chronic Renal Insufficiency Cohort (CRIC), a multi-ethnic multi-center prospective observational study of patients with CKD.
Methods and Results
We studied 2602 participants who were free of HF at baseline. Carotid-femoral pulse wave velocity (CF-PWV, the gold-standard index of large artery stiffness), brachial and central pressures (estimated via radial tonometry and a generalized transfer function) were assessed at baseline. Participants were prospectively followed to assess the development of new-onset hospitalized HF. During 3.5 years of follow-up, 154 participants had a first hospital admission for HF. CF-PWV was a significant independent predictor of incident hospitalized HF. Compared to the lowest tertile, the HR among subjects in the middle and top CF-PWV tertiles were 2.33 (95%CI=1.37-3.97; P=0.002) and 5.24 (95%CI=3.22-8.53; P<0.0001), respectively. After adjustment for multiple confounders, the HR for the middle and top CF-PWV tertiles were 1.95 (95%CI=0.92-4.13; P=0.079) and 3.01 (95%CI=1.45-6.26; P=0.003), respectively. Brachial systolic and pulse pressure were also independently associated with incident hospitalized HF, whereas central pressures were less consistently associated with this endpoint. The association between CF-PWV and incident HF persisted after adjustment for systolic blood pressure.
Conclusions
Large artery stiffness is an independent predictor of incident HF in CKD, an association with strong biologic plausibility given the known effects of large artery stiffening of left ventricular pulsatile load.
doi:10.1161/CIRCHEARTFAILURE.113.001041
PMCID: PMC4167968  PMID: 25059422
chronic kidney disease; heart failure; pulse wave velocity; arterial stiffness; central pressures
4.  Higher Levels of Cystatin C are Associated with Worse Cognitive Function Among Older Adults with Chronic Kidney Disease: The CRIC COG Study 
OBJECTIVES
Cystatin C, a measure of kidney function, has been linked to cognitive impairment, but the association between cognition and levels of cystatin C in persons with chronic kidney disease (CKD) is unknown.
DESIGN/SETTING/PARTICPANTS
We studied 821 participants from the Chronic Renal Insufficiency Cohort Cognitive Study with a baseline cognitive assessment completed at the same visit as serum cystatin C measurement.
MEASUREMENTS
Levels of serum cystatin C were categorized into tertiles; cognitive function was assessed with six neuropsychological tests. We compared scores on these tests across tertiles of cystatin C using linear regression and logistic regression to examine the association between cystatin C level and poor cognitive performance (1 SD difference from the mean).
RESULTS
The mean participant age was 64.9 years, 50.6% were male, and 48.6% were white. After multivariable adjustment for age, race, education, and medical comorbidities in linear models, higher levels of cystatin C were associated with worse cognition on the 3MS, Buschke Delayed Recall, Trails A, Trails B, and Boston Naming (p<0.05 for all). This association remained statistically significant for Buschke Delayed Recall (p=0.01) and Trails A (p=0.03) after additional adjustment for eGFR. Compared to the lowest tertile of cystatin C, the highest tertile was associated with increased likelihood of poor cognitive performance on Trails A (OR=2.17; 95% CI: 1.16-4.06), Trails B (OR=1.89; 95% CI: 1.09-3.27), and Boston Naming (OR=1.85; 95% CI: 1.07-3.19) after multivariate adjustment in logistic models.
CONCLUSION
Among patients with CKD, higher levels of serum cystatin C were associated with worse cognition and increased likelihood of poor cognitive performance on attention, executive function, and naming. Cystatin C is a marker of cognitive impairment and may be associated with cognition independent of eGFR levels.
doi:10.1111/jgs.12986
PMCID: PMC4201363  PMID: 25125225
cystatin C; cognition; chronic kidney disease
5.  Higher plasma CXCL12 levels predict incident myocardial infarction and death in chronic kidney disease: findings from the Chronic Renal Insufficiency Cohort study 
European Heart Journal  2013;35(31):2115-2122.
Aims
Genome-wide association studies revealed an association between a locus at 10q11, downstream from CXCL12, and myocardial infarction (MI). However, the relationship among plasma CXCL12, cardiovascular disease (CVD) risk factors, incident MI, and death is unknown.
Methods and results
We analysed study-entry plasma CXCL12 levels in 3687 participants of the Chronic Renal Insufficiency Cohort (CRIC) Study, a prospective study of cardiovascular and kidney outcomes in chronic kidney disease (CKD) patients. Mean follow-up was 6 years for incident MI or death. Plasma CXCL12 levels were positively associated with several cardiovascular risk factors (age, hypertension, diabetes, hypercholesterolaemia), lower estimated glomerular filtration rate (eGFR), and higher inflammatory cytokine levels (P < 0.05). In fully adjusted models, higher study-entry CXCL12 was associated with increased odds of prevalent CVD (OR 1.23; 95% confidence interval 1.14, 1.33, P < 0.001) for one standard deviation (SD) increase in CXCL12. Similarly, one SD higher CXCL12 increased the hazard of incident MI (1.26; 1.09,1.45, P < 0.001), death (1.20; 1.09,1.33, P < 0.001), and combined MI/death (1.23; 1.13–1.34, P < 0.001) adjusting for demographic factors, known CVD risk factors, and inflammatory markers and remained significant for MI (1.19; 1.03,1.39, P = 0.01) and the combined MI/death (1.13; 1.03,1.24, P = 0.01) after further controlling for eGFR and urinary albumin:creatinine ratio.
Conclusions
In CKD, higher plasma CXCL12 was associated with CVD risk factors and prevalent CVD as well as the hazard of incident MI and death. Further studies are required to establish if plasma CXCL12 reflect causal actions at the vessel wall and is a tool for genomic and therapeutic trials.
doi:10.1093/eurheartj/eht481
PMCID: PMC4132636  PMID: 24306482
Atherosclerosis; Chemokines; Myocardial infarction; CXCL12
6.  Urinary sodium is a potent correlate of proteinuria: Lessons from the CRIC Study 
American journal of nephrology  2012;36(5):397-404.
Background
While higher blood pressure is known to increase proteinuria, whether increased dietary sodium as estimated from 24-hour urinary excretion correlates with increased proteinuria in patients with chronic kidney disease (CKD) is not well studied.
Methods
We measured 24-hour urine sodium, potassium, and protein excretion in 3,680 participants in the Chronic Renal Insufficiency Cohort (CRIC) study, to determine the relationship between urinary sodium and potassium and urinary protein excretion in patients with CKD. We stratified our data based on the presence or absence of diabetes given the absence of any data on this relationship, and evidence that diabetics had greater urinary protein excretion at nearly every level of urinary sodium excretion. Multiple linear regressions were used with a stepwise inclusion of covariates such as systolic blood pressure (SBP), demographics, hemoglobin A1C, and type of antihypertensive medications to evaluate the relationship between urinary electrolyte excretion and proteinuria.
Results
Our data demonstrated that urinary sodium (+1SD above the mean), as a univariate variable, explained 12% of the variation in proteinuria (β=0.29, p<.0001) with rising urinary sodium excretion associated with increasing proteinuria. The significance of that relationship was only partially attenuated with adjustment for demographic and clinical factors and the addition of 24-hour urinary potassium to the model (β=0.13, R2=0.35, p<.0001).
Conclusions
An understanding of the relationship between these clinical factors and dietary sodium may allow a more tailored approach for dietary salt restriction in patients with CKD.
doi:10.1159/000342966
PMCID: PMC4448958  PMID: 23076013
proteinuria; sodium; potassium; blood pressure
7.  Association between Inflammation and Cardiac Geometry in Chronic Kidney Disease: Findings from the CRIC Study 
PLoS ONE  2015;10(4):e0124772.
Background
Left ventricular hypertrophy (LVH) and myocardial contractile dysfunction are independent predictors of mortality in patients with chronic kidney disease (CKD). The association between inflammatory biomarkers and cardiac geometry has not yet been studied in a large cohort of CKD patients with a wide range of kidney function.
Methods
Plasma levels of interleukin (IL)-1β, IL-1 receptor antagonist (IL-1RA), IL-6, tumor necrosis factor (TNF)-α, transforming growth factor (TGF)-β, high-sensitivity C-Reactive protein (hs-CRP), fibrinogen and serum albumin were measured in 3,939 Chronic Renal Insufficiency Cohort study participants. Echocardiography was performed according to the recommendations of the American Society of Echocardiography and interpreted at a centralized core laboratory.
Results
LVH, systolic dysfunction and diastolic dysfunction were present in 52.3%, 11.8% and 76.3% of the study subjects, respectively. In logistic regression analysis adjusted for age, sex, race/ethnicity, diabetic status, current smoking status, systolic blood pressure, urinary albumin- creatinine ratio and estimated glomerular filtration rate, hs-CRP (OR 1.26 [95% CI 1.16, 1.37], p<0.001), IL-1RA (1.23 [1.13, 1.34], p<0.0001), IL-6 (1.25 [1.14, 1.36], p<0.001) and TNF-α (1.14 [1.04, 1.25], p = 0.004) were associated with LVH. The odds for systolic dysfunction were greater for subjects with elevated levels of hs-CRP (1.32 [1.18, 1.48], p<0.001) and IL-6 (1.34 [1.21, 1.49], p<0.001). Only hs-CRP was associated with diastolic dysfunction (1.14 [1.04, 1.26], p = 0.005).
Conclusion
In patients with CKD, elevated plasma levels of hs-CRP and IL-6 are associated with LVH and systolic dysfunction.
doi:10.1371/journal.pone.0124772
PMCID: PMC4409366  PMID: 25909952
8.  Development of the National Living Donor Assistance Center: reducing financial disincentives to living organ donation 
Over the years, the transplant community has worked to advance the care of living organ donors; however, barriers remain, including the nonmedical expenses incurred by living donors. A new center, funded by a grant from the Health Resources and Services Administration (HRSA), was established to operate a nationwide system to remove these financial disincentives. The HRSA grant was awarded to an academic institution and the daily operations are managed by a transplant professional society. Expenses are reimbursed prospectively for financially needy living donors. Combining the legislative authority and economic resources of the federal government, the research experience of an academic institution, and the management know-how of a professional society has proven to be successful. To date, the center has received 3918 applications submitted by 199 different transplant centers and receives about 80 applications per month. On average, a donor spends $2767 for their travel expenses to the transplant center. Of the 3918 applications that have been submitted, 1941 of those applicants (50%) have completed their donor surgery.
doi:10.7182/pit2014593
PMCID: PMC4374738  PMID: 24598569
9.  Abnormal Glucose Metabolism and Metabolic Syndrome in Non-Diabetic Kidney Transplant Recipients Early After Transplantation 
Transplantation  2010;89(8):1034-1039.
Background
Abnormal glucose metabolism (AGM) and metabolic syndrome (MS) are individually associated with a poor cardiovascular outcome in kidney transplant recipients. We prospectively studied the relationship between AGM and MS in non-diabetic kidney transplant recipients early after transplantation.
Methods
A total of 203 de novo kidney transplant recipients underwent standard 2-hr glucose tolerance test 10 weeks after transplantation. Demographic and clinical characteristics were collected. AGM was defined as impaired fasting glucose, impaired glucose tolerance, and new onset diabetes after transplant according to the WHO criteria, and MS was defined according to the National Cholesterol Education Expert Panel criteria.
Results
Overall, 97 patients (47.8%) met the diagnosis of AGM and 98 patients (48.3%) met the criteria of MS. AGM and MS are highly associated (χ2, P<0.001). Fasting plasma glucose levels before the transplant are independent predictors common for AGM and MS. Age predicts AGM with and without MS, whereas body mass index before transplant predicts MS. Patients with impaired glucose tolerance and new-onset diabetes after transplant displayed significant worsening of their fasting plasma glucose levels during the 10-week observational period. MS and the components of MS, but not AGM, were associated with reduced transplant renal function (P=0.002).
Conclusion
The early screening of AGM and MS should be emphasized, and the role of early therapeutic interventions aimed at both conditions explored. The long-term follow-up of these patients will yield more insight on the significance of such findings.
doi:10.1097/TP.0b013e3181d05a90
PMCID: PMC4372660  PMID: 20130496
Kidney transplant; Abnormal glucose metabolism; Metabolic syndrome
10.  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.
Objective
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).
Results
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.
Conclusion
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.
doi:10.1002/oby.20692
PMCID: PMC4327849  PMID: 24415732
Bioelectric impedance analysis; cytokines; acute phase proteins; muscle mass; Body mass index; African Americans
11.  Association of Serum Bicarbonate With Risk of Renal and Cardiovascular Outcomes in CKD: A Report From the Chronic Renal Insufficiency Cohort (CRIC) Study 
Background
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.
Predictor
Serum bicarbonate.
Outcomes
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.
Measurements
Time to event.
Results
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).
Limitations
Single measurement of sodium bicarbonate.
Conclusions
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.
doi:10.1053/j.ajkd.2013.01.017
PMCID: PMC3701754  PMID: 23489677
metabolic acidosis; serum bicarbonate; chronic kidney disease; cardiovascular morbidity
12.  Candidate Gene Association Study of Coronary Artery Calcification in Chronic Kidney Disease: Findings from the Chronic Renal Insufficiency Cohort Study 
Objectives
To identify loci for coronary artery calcification (CAC) in patients with chronic kidney disease (CKD).
Background
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.
Methods
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).
Results
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.
Conclusions
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.
doi:10.1016/j.jacc.2013.01.103
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)
13.  APOL1 Risk Variants, Race, and Progression of Chronic Kidney Disease 
The New England journal of medicine  2013;369(23):2183-2196.
BACKGROUND
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.
METHODS
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.
RESULTS
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).
CONCLUSIONS
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.)
doi:10.1056/NEJMoa1310345
PMCID: PMC3969022  PMID: 24206458
14.  Retinopathy and Cognitive Impairment in Adults With CKD 
Background
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
Predictor
Retinopathy graded using the Early Treatment Diabetic Retinopathy Study severity scale and diameters of retinal vessels.
Outcomes
Neuropsychological battery of six cognitive tests
Measurements
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.
Results
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.
Limitations
Unknown temporal relationship between retinopathy and impairment.
Conclusions
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.
doi:10.1053/j.ajkd.2012.10.006
PMCID: PMC4030670  PMID: 23206534
15.  Immunological Aspect on Late Allograft Dysfunction 
Journal of Immunology Research  2014;2014:625031.
doi:10.1155/2014/625031
PMCID: PMC4009131  PMID: 24834436
16.  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.
Methods
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.
Results
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).
Conclusion
Kidney transplants patients with MetS early after transplantation had lower levels of 25[OH]D and adiponectin, and unfavorable clinical outcomes.
doi:10.1159/000349930
PMCID: PMC3816759  PMID: 23751485
adiponectin; clinical outcomes; kidney transplantation; metabolic syndrome; vitamin D deficiency
17.  Novel views on new-onset diabetes after transplantation: development, prevention and treatment 
New-onset diabetes after transplantation (NODAT) is associated with increased risk of allograft failure, cardiovascular disease and mortality, and therefore, jeopardizes the success of renal transplantation. Increased awareness of NODAT and the prediabetic states (impaired fasting glucose and impaired glucose tolerance, IGT) has fostered previous and present recommendations, based on the management of type 2 diabetes mellitus (T2DM). Unfortunately, the idea that NODAT merely resembles T2DM is potentially misleading, because the opportunity to initiate adequate anti-hyperglycaemic treatment early after transplantation might be given away for ‘tailored’ immunosuppression in patients who have developed NODAT or carry personal risk factors. Risk factor-independent mechanisms, however, seem to render postoperative hyperglycaemia with subsequent development of overt or ‘full-blown’ NODAT, the unavoidable consequence of the transplant and immunosuppressive process itself, at least in many cases. A proof of the concept that timely preventive intervention with exogenous insulin against post-transplant hyperglycaemia may decrease NODAT was recently provided by a small clinical trial, which is awaiting confirmation from a multicentre study. However, because early insulin therapy aimed at beta-cell protection seems to contrast the currently recommended, stepwise approach of ‘watchful waiting’ prior to pancreatic decompensation, we here aim at reviewing recent concepts regarding the development, prevention and treatment of NODAT, some of which seem to challenge the traditional view on T2DM and NODAT. In summary, we suggest a novel, risk factor-independent management approach to NODAT, which includes glycaemic monitoring and anti-hyperglycaemic treatment in virtually everybody after transplantation. This approach has widespread implications for future research and is intended to tackle NODAT and also ultimately cardiovascular disease.
doi:10.1093/ndt/gfs583
PMCID: PMC4375396  PMID: 23328712
18.  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.”
Background
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1093/ndt/gfs287
PMCID: PMC3616762  PMID: 22759384
death with a functioning allograft; diabetes mellitus; end stage renal disease; graft survival; international comparison
19.  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.
doi:10.1016/j.amjcard.2012.07.044
PMCID: PMC3511639  PMID: 22980963
calcium; chronic kidney disease; coronary artery calcium; cystatin C; insulin-resistance; phosphate; total parathyroid hormone
20.  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.
doi:10.1111/j.1399-0012.2011.01519.x
PMCID: PMC3856569  PMID: 22003873
death-censored kidney graft failure; pancreas after kidney transplantation; time interval
21.  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.
Background
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1111/j.1399-0012.2009.01194.x
PMCID: PMC3831507  PMID: 20047609
kidney transplant; metabolic syndrome; new onset diabetes
22.  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.
doi:10.1038/ki.2009.248
PMCID: PMC3831511  PMID: 19625995
cardiovascular risk; graft survival; kidney transplant; new-onset diabetes; patient survival; steroid-free immunosuppression
23.  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.
Background
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.
Methods
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.
Results
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).
Conclusions
Hypertension in PD is equally significant barrier to living kidney donation in AA and CA whereas obesity is a greater barrier in AA.
doi:10.1111/j.1399-0012.2009.01188.x
PMCID: PMC3807634  PMID: 20047616
Donation; access; contraindications; hypertension; obesity
24.  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.
doi:10.1038/ki.2012.428
PMCID: PMC3612359  PMID: 23325076
25.  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).
Methods
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.
Results
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.
Conclusions
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.
doi:10.1053/j.gastro.2008.04.018
PMCID: PMC3731061  PMID: 18505689

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