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1.  Comparison of CKD Awareness in a Screening Population Using the Modification of Diet in Renal Disease (MDRD) Study and CKD Epidemiology Collaboration (CKD-EPI) Equations 
Background
Low awareness of chronic kidney disease (CKD) may reflect uncertainty about the accuracy or significance of a CKD diagnosis in individuals otherwise perceived to be low-risk. Whether reclassification of CKD severity using the CKD Epidemiology Collaboration (CKD-EPI) equation to estimate glomerular filtration rate (GFR) modifies estimates of CKD awareness is unknown.
Methods
In this cross-sectional study, we used data collected from 2000 to 2009 for 26,213 participants in the Kidney Early Evaluation Program (KEEP), a community-based screening program, with CKD based on GFR estimated using the 4-variable Modification of Diet in Renal Disease (MDRD) Study equation and measurement of albuminuria. We assessed CKD awareness after CKD stage was reclassified using the CKD-EPI equation.
Results
Of 26,213 participants with CKD based on eGFRMDRD, 23,572 (90%) were also classified with CKD based on eGFRCKD-EPI. Based on eGFRMDRD, 9.5% of participants overall were aware of CKD, as were 4.9%, 6.3%, 9.2%, 41.9%, and 59.2% with Stages 1-5, respectively. Based on eGFRCKD-EPI, 10.0% of participants overall were aware of CKD, as were 5.1%, 6.6%, 10.0%, 39.3%, and 59.4% with Stages 1-5, respectively. Reclassification to a less advanced CKD stage with eGFRCKD-EPI was associated with lower odds for awareness (OR, 0.58; 95% CI, 0.50-0.67); reclassification to a more advanced stage was associated with higher odds for awareness (OR, 1.50; 95% CI, 1.05-2.13) after adjustment for confounding factors. Of participants unaware of CKD, 10.6% were reclassified as not having CKD using eGFRCKD-EPI.
Conclusions
Using eGFRCKD-EPI led to a modest increase in overall awareness rates, primarily due to reclassification of low-risk unaware participants.
doi:10.1053/j.ajkd.2010.11.008
PMCID: PMC3075598  PMID: 21338846
awareness; chronic kidney disease; CKD-EPI; estimated glomerular filtration rate
2.  The Impact of Kidney Function at HAART Initiation on Mortality in HIV-infected Women 
Background
In the early highly active antiretroviral therapy (HAART) era, kidney dysfunction was strongly associated with death among HIV-infected individuals. We re-examined this association in the later HAART period to determine whether chronic kidney disease (CKD) remains a predictor of death after HAART-initiation.
Methods
To evaluate the effect of kidney function at the time of HAART initiation on time to all-cause mortality, we evaluated 1415 HIV-infected women initiating HAART in the Women’s Interagency HIV Study (WIHS). Multivariable proportional hazards models with survival times calculated from HAART initiation to death were constructed; participants were censored at the time of the last available visit or December 31, 2006.
Results
CKD (eGFR <60 ml/min/1.73 m2) at HAART initiation was associated with higher mortality risk adjusting for age, race, hepatitis C serostatus, AIDS history and CD4+ cell count (hazard ratio [HR]=2.23, 95% confidence interval [CI]: 1.45–3.43). Adjustment for hypertension and diabetes history attenuated this association (HR=1.89, CI: 0.94–3.80). Lower kidney function at HAART initiation was weakly associated with increased mortality risk in women with prior AIDS (HR=1.09, CI: 1.00–1.19, per 20% decrease in eGFR).
Conclusions
Kidney function at HAART initiation remains an independent predictor of death in HIV-infected individuals, especially in those with a history of AIDS. Our study emphasizes the necessity of monitoring kidney function in this population. Additional studies are needed to determine mechanisms underlying the increased mortality risk associated with CKD in HIV-infected persons.
doi:10.1097/QAI.0b013e3181e674f4
PMCID: PMC3243740  PMID: 20581688
kidney disease; mortality; HIV; WIHS; antiretroviral therapy
3.  Hepatitis B and C Co-Infection Are Independent Predictors of Progressive Kidney Disease in HIV-Positive, Antiretroviral-Treated Adults 
PLoS ONE  2012;7(7):e40245.
Chronic kidney disease (CKD) is an important cause of morbidity and mortality in HIV-positive individuals. Hepatitis C (HCV) co-infection has been associated with increased risk of CKD, but prior studies lack information on potential mechanisms. We evaluated the association between HCV or hepatitis B (HBV) co-infection and progressive CKD among 3,441 antiretroviral-treated clinical trial participants. Progressive CKD was defined as the composite of end-stage renal disease, renal death, or significant glomerular filtration rate (eGFR) decline (25% decline to eGFR <60 mL/min/1.73 m2 or 25% decline with a baseline <60). Generalized Estimating Equations were used to model the odds of progressive CKD. At baseline, 13.8% and 3.3% of participants were co-infected with HCV and HBV, respectively. Median eGFR was 111, and 3.7% developed progressive CKD. After adjustment, the odds of progressive CKD were increased in participants with HCV (OR 1.72, 95% CI 1.07–2.76) or HBV (OR 2.26, 95% CI 1.15–4.44). Participants with undetectable or low HCV-RNA had similar odds of progressive CKD as HCV seronegative participants, while participants with HCV-RNA >800,000 IU/ml had increased odds (OR 3.07; 95% CI 1.60–5.90). Interleukin-6, hyaluronic acid, and the FIB-4 hepatic fibrosis index were higher among participants who developed progressive CKD, but were no longer associated with progressive CKD after adjustment. Future studies should validate the relationship between HCV viremia and CKD.
Trial Registration
ClinicalTrials.gov NCT00027352; NCT00004978
doi:10.1371/journal.pone.0040245
PMCID: PMC3401192  PMID: 22911697
4.  Association between Kidney Function and Framingham Global Cardiovascular Disease Risk Score: A Chinese Longitudinal Study 
PLoS ONE  2014;9(1):e86082.
Background
Chronic kidney disease (CKD) is generally considered an independent risk factor for cardiovascular disease (CVD) development, but rates in individuals with estimated glomerular filtration rate (eGFR) >60 ml/min/1.73 m2 are uncertain. The Framingham global CVD risk score (FRS) equation is a widely accepted tool used to predict CVD risk in the general population. The purpose of the present study was to examine whether an association exists between eGFR and FRS in a Chinese population with no CKD or CVD.
Methods
A total of 333 participants were divided into three groups based on FRS. The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation and CKD-EPI equation for Asians (CKD-EPI-ASIA) were used to measure eGFR.
Results
A significant inverse association between eGFR and FRS was confirmed with Pearson correlation coefficients of –0.669, –0.698 (eGFRCKD-EPI, P<0.01) and –0.658, –0.690 (eGFRCKD-EPI-ASIA, P<0.01). This association gradually diminished with progression from the low- to high-risk groups (eGFRCKD-EPI, r = –0.615, –0.282, –0.197, P<0.01, P<0.01, P>0.05; similar results according to the CKD-EPI-ASIA equation). In the low- or moderate-risk new-groups, this association became stronger with increased FRS (eGFRCKD-EPI-ASIA, r = –0557, –0.622 or –0.326, –0.329, P<0.01). In contrast to the results from 2008, eGFR was independently associated with FRS following adjustment for traditional cardiovascular risk factors (P<0.05).
Conclusion
Renal function has multiple influences on predicting CVD risk in various populations. With increasing FRS and decreasing eGFR, it is also independently associated with CVD, even in individuals with eGFR >60 ml/min/1.73 m2.
doi:10.1371/journal.pone.0086082
PMCID: PMC3896450  PMID: 24465883
5.  Prevalence of chronic kidney disease and its association with metabolic diseases: a cross-sectional survey in Zhejiang province, Eastern China 
BMC Nephrology  2014;15:36.
Background
The prevalence of chronic kidney disease (CKD) and metabolic diseases has increased at different rates in different regions in China. The aim of our study was to estimate the prevalence of CKD and to analyze associated risk factors of CKD in Zhejiang province, Eastern China.
Methods
A cross-sectional survey of 11,013 adults was conducted from September 2009 to June 2012 in Zhejiang Province, located in Eastern China. CKD was defined as having an estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2 or the presence of albuminuria. Medical history, physical examination and laboratory data were used to diagnose metabolic diseases. Age- and sex-standardized prevalence was calculated using the data on the population distribution in China in 2010. We examined risk factors associated with decreased renal function and albuminuria using multivariate logistic regression.
Results
A total of 10,384 adults (94.3%) completed the screening. The standardized prevalence of reduced renal function (eGFR < 60 mL/min/1.73 m2) was 1.83% (95% CI 1.52–2.13) and that of albuminuria was 8.65% (95% CI 7.98–9.31). The overall prevalence of CKD was 9.88% (95% CI 9.18–10.59). The prevalence of reduced renal function was greater in the eastern rural areas in Zhejiang province. Multivariate logistic regression revealed that metabolic diseases such as diabetes, obesity, hypertension, and hyperuricemia were independent risk factors of CKD. Patients with metabolic diseases had a significantly (P < 0.001) higher prevalence of CKD than those without such diseases.
Conclusions
CKD has become a severe public health problem in Zhejiang Province, and metabolic diseases may increase the risk of CKD in Zhejiang population.
doi:10.1186/1471-2369-15-36
PMCID: PMC3936864  PMID: 24559433
Cross-sectional survey; Chronic kidney disease; Metabolic diseases; Prevalence; Risk factors; Eastern China
6.  Clinical Utility of Creatinine- and Cystatin C–Based Definition of Renal Function for Risk Prediction of Primary Cardiovascular Events in Patients With Diabetes 
Diabetes Care  2012;35(4):879-886.
OBJECTIVE
To assess the cardiovascular risk of diabetic subjects with chronic kidney disease (CKD) based on different estimated glomerular filtration rate (eGFR) equations and to evaluate which definition of CKD best improves cardiovascular risk prediction of the Framingham Cardiovascular Risk Score (Framingham-CV-RS).
RESEARCH DESIGN AND METHODS
CKD was defined as eGFR <60 mL/min/1.73 m2, estimated by the creatinine-based Modification of Diet in Renal Disease (MDRD) and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations and a cystatin C–based equation (CKD-CysC). Cox regression was used to estimate hazard ratios (HRs) of subjects with CKD for incident cardiovascular events in a cohort of 1,153 individuals with diabetes (baseline age 50–74 years). Furthermore, the CKD definitions were added individually to a reference model comprising the Framingham-CV-RS variables and HbA1c, and measures of model discrimination and reclassification were assessed.
RESULTS
During 5 years of follow-up, 95 individuals had a primary cardiovascular event. Crude HRs were increased for all CKD definitions. However, after adjusting for established cardiovascular risk factors, HRs for both creatinine-based CKD definitions were attenuated to point estimates of 1.03, whereas the HRs for the cystatin C–based CKD definition remained significantly increased (HR 1.75 [95% CI 1.07–2.87]). Extension of the reference model by the different CKD definitions resulted in an increase in the c statistic only when adding CKD-CysC (from 0.638 to 0.644) along with a net reclassification improvement of 8.9%.
CONCLUSIONS
Only the cystatin C–based CKD definition was an independent risk predictor for cardiovascular events in our diabetic study cohort and indicated a potentially better clinical utility for cardiovascular risk prediction than creatinine-based equations.
doi:10.2337/dc11-1998
PMCID: PMC3308288  PMID: 22338108
7.  Chronic kidney disease: a large-scale population-based study of the effects of introducing the CKD-EPI formula for eGFR reporting 
BMJ Open  2011;1(2):e000308.
Objective
To evaluate the effects of introducing the Chronic Kidney Disease-Epidemiology Collaboration (CKD-EPI) formula for estimated glomerular filtration rate (eGFR) reporting in the adult population in routine clinical practice with clinician-directed testing.
Design
Retrospective study of all creatinine measurements and calculation of eGFRs using Modification of Diet in Renal Disease (MDRD) and CKD-EPI formulae.
Setting
General population, Oxfordshire, UK.
Participants
An unselected population of around 660 000.
Interventions
Reporting of eGFRs using MDRD or CKD-EPI formulae.
Primary and secondary outcome measures
Evaluation of the effects of the CKD-EPI formula on the prevalence of different stages of chronic kidney disease (CKD).
Results
The CKD-EPI formula reduced the prevalence of CKD (stages 2–5) by 16.4% in patients tested in primary care. At the important stage 2–stage 3 cut-off, there was a relative reduction of 7.5% in the prevalence of CKD stages 3–5 from 15.7% to 14.5%. The CKD-EPI formula reduced the prevalence of CKD stages 3–5 in those aged <70 but increased it at ages >70. Above 70 years, the prevalence of stages 3–5 was similar with both equations for women (around 41.2%) but rose in men from 33.3% to 35.5%. CKD stages 4–5 rose by 15% due exclusively to increases in the over 70s, which could increase specialist referral rates. The CKD classification of 18.3% of all individuals who had a creatinine measurement was altered by a change from the MDRD to the CKD-EPI formula. In the UK population, the classification of up to 3 million patients could be altered, the prevalence of CKD could be reduced by up to 1.9 million and the prevalence of CKD stages 3–5 could fall by around 200 000.
Conclusions
Introduction of the CKD-EPI formula for eGFR reporting will reduce the prevalence of CKD in a primary care setting with current testing practice but will raise the prevalence in the over 70s age group. This has implications for clinical practice, healthcare policy and current prevalence-based funding arrangements.
Article summary
Article focus
Estimated glomerular filtration rates form the basis for clinical and health policy decisions in chronic kidney disease.
The new CKD-EPI formula for estimated glomerular filtration rates estimates renal function better than the Modification of Diet in Renal Disease formula in current use.
We have studied the effects of using the CKD-EPI formula in a UK population of over half a million.
Key messages
Overall, the CKD-EPI formula produces higher better estimated glomerular filtration rates, which reduces the diagnosis of chronic kidney disease. However, in men older than 70 years, it produces lower worse estimated glomerular filtration rates and increases the number with chronic kidney disease stages 3–5.
Our results predict a net reduction of around 200 000 in the numbers with chronic kidney disease stages 3–5 in the UK. This would reduce the primary care chronic kidney disease registers, inappropriate disease labelling and patient monitoring.
The chronic kidney disease classification of up to 3 million patients could be altered by the use of the CKD-EPI formula in the UK.
Strengths and limitations of this study
The study is large and unbiased. All primary care samples taken during the study period were analysed, so the results represent current clinical testing practice.
Estimated glomerular filtration rates are sufficient to diagnose chronic kidney disease stages 3–5, but stages 1–2 also require proteinuria or a structural abnormality, which cannot be assessed in this study. However, a change in estimated glomerular filtration rate can still alter the classification of stage 1 or 2.
doi:10.1136/bmjopen-2011-000308
PMCID: PMC3244664  PMID: 22184586
8.  Chronic kidney disease, creatinine and cognitive functioning 
Nephrology Dialysis Transplantation  2009;24(8):2446-2452.
Background. Non-dialysis-dependent chronic kidney disease (CKD) is related to cognitive impairment. Previous studies have not explored the extent of impairment across multiple cognitive domains. We examined the range of specific cognitive abilities affected by CKD and whether the associations of CKD with cognition were eliminated by statistical control for cardiovascular disease correlates of CKD.
Methods. We performed a community-based cross-sectional study with 923 individuals free from dementia and end-stage renal disease. Two groups were defined based on estimated glomerular filtration rate (eGFR): eGFR<60 mL/min/1.73 m2 versus eGFR ≥ 60 mL/min/1.73 m2. Outcome measures were scores from multiple clinical tests of specific cognitive abilities. The GFR classifications and serum creatinine levels were related to measures of cognitive performance using logistic and linear regression analyses with three sets of covariates: (1) basic (age, education, gender and race); (2) basic+risk factors for cardiovascular disease (CVD) and (3) basic+risk factors for CVD+stroke.
Results. An eGFR <60 mL/min/1.73 m2 was present in 142 (15.4%) individuals; the mean (SD) eGFR in this subgroup was 49.7 (10.7). CKD was related to lower cognitive performance despite adjustment for CVD risk factors (CVD-RF). Adjusting for CVD-RF and stroke, odds ratios and 95% confidence intervals associated with performing in the lowest quartile of the distribution of the Global, Visual–Spatial Organization/Memory and Scanning and Tracking scores for the eGFR < 60 group were 1.97 (1.25, 3.10); 1.88 (1.21, 2.93) and 1.83 (1.56, 2.87), P < 0.01 with eGFR ≥ 60 group as the reference group.
Conclusions. Global performance and specific cognitive functions are negatively affected early in CKD. Targeted screening for cognitive deficits in kidney disease patients early in their disease course may be warranted.
doi:10.1093/ndt/gfp107
PMCID: PMC2727297  PMID: 19297357
cardiovascular disease; chronic kidney disease; cognitive performance; serum creatinine
9.  Risk Factors for Chronic Kidney Disease among American Indians and Alaska Natives – Findings from the Kidney Early Evaluation Program 
American Journal of Nephrology  2008;29(5):440-446.
Background
American Indians and Alaska Natives (AIAN) have a high incidence of end-stage renal disease. Less is known about chronic kidney disease (CKD) among AIAN and whether risk factors differ for low estimated glomerular filtration rate (eGFR) versus albuminuria with a normal eGFR.
Methods
Cross-sectional study examining the associations of age, sex, smoking, obesity, diabetes, hypertension, family history, and geographic region with CKD among a screened population of AIAN participants in the Kidney Early Evaluation Program from 2000 to 2006. CKD was defined by the presence of either a low eGFR, <60 ml/min/1.73 m2, or albuminuria, a urine albumin/creatinine ratio ≥30 mg/g.
Results
The prevalence of any CKD was 29%, of low eGFR was 17%, and of albuminuria with a normal eGFR was 12%. Older age was the strongest predictor of low eGFR (61+ years OR 8.42, 95% CI 5.92–11.98), followed by hypertension (OR 2.38, 95% CI 1.74–3.26). In contrast, diabetes (OR 2.04, 95% CI 1.57–2.64) and hypertension (OR 2.63, 95% CI 1.93–3.59) were the only predictors of albuminuria among persons with a normal eGFR.
Conclusion
The burden of CKD was high among this screened population of AIAN, and different risk factor patterns were associated with low eGFR and albuminuria. Innovative programs and longitudinal research are needed to address CKD among AIAN.
doi:10.1159/000174857
PMCID: PMC2821946  PMID: 19011277
Chronic kidney disease; Risk factors; American Indians; Alaska Natives
10.  Performance of Creatinine and Cystatin C GFR Estimating Equations in an HIV-positive population on Antiretrovirals 
Objective
To evaluate the performance of CKD-EPI creatinine, cystatin C and creatinine-cystatin C estimating equations in HIV-positive patients.
Methods
We evaluated the performance of the MDRD Study and CKD-EPI creatinine 2009, CKD-EPI cystatin C 2012 and CKD-EPI creatinine-cystatin C 2012 glomerular filtration rate (GFR) estimating equations compared to GFR measured using plasma clearance of iohexol in 200 HIV-positive patients on stable antiretroviral therapy. Creatinine and cystatin C assays were standardized to certified reference materials.
Results
Of the 200 participants, median (IQR) CD4 count was 536 (421) and 61% had an undetectable HIV-viral load. Mean (SD) measured GFR (mGFR) was 87 (26) ml/min/1.73m2. All CKD-EPI equations performed better than the MDRD Study equation. All three CKD-EPI equations had similar bias and precision. The cystatin C equation was not more accurate than the creatinine equation. The creatinine-cystatin C equation was significantly more accurate than the cystatin C equation and there was a trend toward greater accuracy than the creatinine equation. Accuracy was equal or better in most subgroups with the combined equation compared to either alone.
Conclusions
The CKD-EPI cystatin C equation does not appear to be more accurate than the CKD-EPI creatinine equation in patients who are HIV-positive, supporting the use of the CKD-EPI creatinine equation for routine clinical care for use in North American populations with HIV. The use of both filtration markers together as a confirmatory test for decreased estimated GFR based on creatinine in individuals who are HIV-positive requires further study.
doi:10.1097/QAI.0b013e31826a6c4f
PMCID: PMC3598619  PMID: 22842844
measured glomerular filtration rate; estimated glomerular filtration rate; Chronic Kidney Disease Epidemiology collaboration equation (CKD-EPI); Modification of Diet in Renal Disease Study equation (MDRD); creatinine; cystatin C
11.  Validation of The Health Improvement Network (THIN) Database for Epidemiologic Studies of Chronic Kidney Disease 
Pharmacoepidemiology and drug safety  2011;20(11):1138-1149.
Purpose
Chronic kidney disease (CKD) is a prevalent and important outcome and covariate in pharmacoepidemiology. The Health Improvement Network (THIN) in the U.K. represents a unique resource for population-based studies of CKD. We compiled a valid list of Read codes to identify subjects with moderate to advanced CKD.
Methods
A cross-sectional validation study was performed to identify codes that best define CKD stages 3–5. All subjects with at least one non-zero measure of serum creatinine after 1-Jan-2002 were included. Estimated glomerular filtration rate (eGFR) was calculated according to the Schwartz formula for subjects <18 years and the Modification of Diet in Renal Disease formula for subjects ≥18 years of age. CKD was defined as an eGFR <60 ml/min/1.73m2 on at least two occasions, more than 90 days apart.
Results
The laboratory definition identified 230,426 subjects with CKD, for a period prevalence in 2008 of 4.56% (95% CI: 4.54, 4.58). A list of 45 Read codes was compiled which yielded a positive predictive value of 88.9% (95% CI: 88.7, 89.1), sensitivity of 48.8%, negative predictive value of 86.5%, and specificity of 98.2%. Of the 11.1% of subjects with a code who did not meet the laboratory definition, 83.6% had at least one eGFR <60. The most commonly used code was for CKD stage 3.
Conclusions
The proposed list of codes can be used to accurately identify CKD when serum creatinine data are limited. The most sensitive approach for the detection of CKD is to use this list to supplement creatinine measures.
doi:10.1002/pds.2203
PMCID: PMC3245984  PMID: 22020900
Chronic kidney disease (CKD); validity; database; epidemiology
12.  Hepatitis C and the Risk of Kidney Disease and Mortality in Veterans With HIV 
Objectives
To examine the effect of hepatitis C virus (HCV) on the prevalence of chronic kidney disease (CKD) among veterans with HIV and to evaluate independent associations of HCV and CKD with mortality.
Methods
We studied a national cohort of HIV-infected patients receiving care through the Veterans Healthcare Administration from 1998 to 2004. CKD was defined as an estimated glomerular filtration rate [eGFR (mL/min/1.73 m2)] < 60. Poisson regression was used to assess relationships between CKD, HCV, and mortality.
Results
Among 23,155 HIV-infected veterans, 12% had CKD. Forty percent of the cohort was coinfected with HCV, and a higher proportion of coinfected subjects had CKD compared with monoinfected subjects (14% vs 11%, P < 0.001). During the median follow-up of 7.6 years, 37% of subjects died and a graduated increase in adjusted mortality rates occurred with lower levels of eGFR (P < 0.001). Adjusted mortality rates were consistently higher in HCV-coinfected subjects across all levels of eGFR (P < 0.001). HCV was independently associated with increased mortality (incidence rate ratio 1.23, 95% confidence interval 1.17–1.29).
Conclusions
CKD is prevalent in HIV-infected veterans and associated with substantially higher mortality. Compared with their monoinfected counterparts, veterans coinfected with HCV have significantly higher rates of CKD and mortality.
doi:10.1097/QAI.0b013e3181b980d4
PMCID: PMC3032564  PMID: 20104121
death; HIV; hepatitis C; kidney failure; veterans
13.  Relationship between Stage of Kidney Disease and Incident Heart Failure in Older Adults 
American Journal of Nephrology  2011;34(2):135-141.
Background
The relationship between stage of chronic kidney disease (CKD) and incident heart failure (HF) remains unclear.
Methods
Of the 5,795 community-dwelling adults ≥65 years in the Cardiovascular Health Study, 5,450 were free of prevalent HF and had baseline estimated glomerular filtration rate (eGFR: ml/min/1.73 m2) data. Of these, 898 (16%) had CKD 3A (eGFR 45–59 ml/min/1.73 m2) and 242 (4%) had CKD stage ≥3B (eGFR <45 ml/min/1.73 m2). Data on baseline proteinuria were not available and 4,310 (79%) individuals with eGFR ≥60 ml/min/1.73 m2 were considered to have no CKD. Propensity scores estimated separately for CKD 3A and ≥3B were used to assemble two cohorts of 1,714 (857 pairs with CKD 3A and no CKD) and 557 participants (148 CKD ≥3B and 409 no CKD), respectively, balanced on 50 baseline characteristics.
Results
During 13 years of follow-up, centrally-adjudicated incident HF occurred in 19, 24 and 38% of pre-match participants without CKD (reference), with CKD 3A [unadjusted hazard ratio (HR) 1.40; 95% confidence interval (CI) 1.20–1.63; p < 0.001] and with CKD ≥3B (HR 3.37; 95% CI 2.71–4.18; p < 0.001), respectively. In contrast, among matched participants, incident HF occurred in 23 and 23% of those with CKD 3A and no CKD, respectively (HR 1.03; 95% CI 0.85–1.26; p = 0.746), and 36 and 28% of those with CKD ≥3B and no CKD, respectively (HR 1.44; 95% CI 1.04–2.00; p = 0.027).
Conclusions
Among community-dwelling older adults, CKD is a marker of incident HF regardless of stage; however, CKD ≥3B, not CKD 3A, has a modest independent association with incident HF.
doi:10.1159/000328905
PMCID: PMC3136373  PMID: 21734366
Chronic kidney disease; Heart failure
14.  Chronic kidney disease at presentation is not an independent risk factor for AIDS-defining events or death in HIV-infected persons 
Clinical nephrology  2013;79(2):93-100.
Studies have documented an association between chronic kidney disease (CKD) and increased risk of end-stage renal disease (ESRD), death and comorbidities, including cardiovascular disease and metabolic syndrome, in the general population. However, there is little data on the relationship between CKD and ADE (AIDS defining event), and to our knowledge, no studies have analyzed death as a competing risk for ADE among HIV-infected persons. An observational cohort study was performed to determine the incidence and risks for developing an ADE or death among HIV-infected persons with and without CKD from 1998 – 2005. CKD was defined as an estimated glomerular filtration rate (eGFR) less than 60 ml/min/1.73 m2 using the CKD-Epidemiology Collaboration (CKD-EPI) equation. Log rank test and Cox regression which determined time to development of ADE and/or death as combined and separate outcomes, and competing risk models for ADE versus mortality, were performed. Among the 2,127 persons that contributed to the 5,824 person years of follow-up: 22% were female, 34% African-American, 38% on HAART, and 3% had CKD at baseline. ADE occurred in 227 (11%) persons and there were 80 (4%) deaths. CKD was not significantly associated with ADE/death (HR 1.3, 95% CIs: 0.5, 3.2), ADE (HR 1.0, 95% CIs: 0.4, 3.1), or death (HR 1.6, 95% CIs: 0.4, 3.1). Competing risk analyses confirmed no statistically significant associations between CKD and these outcomes. CKD was uncommon in HIV-infected persons presenting for care in this racially diverse cohort, and was not independently associated with risk of developing an ADE or dying during follow-up.
doi:10.5414/CN107390
PMCID: PMC3726221  PMID: 23270930
HIV; CKD; AIDS defining event (ADE); mortality
15.  High Prevalence of Stage 3 Chronic Kidney Disease in Older Adults Despite Normal Serum Creatinine 
BACKGROUND
Serum creatinine is commonly used to diagnose chronic kidney disease (CKD), but may underestimate CKD in older adults when compared with using glomerular filtration rates (eGFR). The magnitude of this underestimation is not clearly defined.
OBJECTIVE
Using the Modification of Diet in Renal Disease (MDRD) equation, to describe both the prevalence and the magnitude of underestimation of stage 3 CKD (GFR 30–59 ml/min/1.73 m2), as well as ideal serum creatinine cutoff values to diagnose stage 3 CKD among Americans ≥65 years of age.
DESIGN
Cross-sectional.
PARTICIPANTS
A total of 3,406 participants ≥65 years of age from the 1999–2004 National Health and Nutrition Examination Surveys (NHANES).
MEASUREMENTS
Serum creatinine levels were used to determine eGFR from the MDRD equation. Information on clinical conditions was self-reported.
RESULTS
Overall, 36.1% of older adults in the US have stage 3 or greater CKD as defined by eGFR values. Among older adults with stage 3 CKD, 80.6% had creatinine values ≤1.5 mg/dl, and 38.6% had creatinine values ≤1.2 mg/dl. Optimal cutoff values for serum creatinine in the diagnosis of stage 3 CKD in older adults were ≥1.3 mg/dl for men and ≥1.0 mg/dl for women, regardless of the presence or absence of hypertension, diabetes, or congestive heart failure.
CONCLUSION
Use of serum creatinine underestimates the presence of advanced (stage 3 or greater) CKD among older adults in the US. Automated eGFR reporting may improve the accuracy of risk stratification for older adults with CKD.
doi:10.1007/s11606-008-0850-3
PMCID: PMC2607515  PMID: 18987917
chronic kidney disease; serum creatinine; older adults; glomerular filtration rate
16.  Chronic kidney disease and estimates of kidney function in HIV infection: a cross-sectional study in the Multicenter AIDS Cohort Study 
Background
Cystatin C has been proposed as an alternative marker of kidney function among HIV-infected persons in whom serum creatinine is affected by extra-renal factors.
Methods
In this cross-sectional study, we compared estimated glomerular filtration rates (eGFR) using serum creatinine versus cystatin C between 150 HIV-uninfected and 783 HIV-infected men. We evaluated the prevalence of chronic kidney disease (CKD; eGFR<60 mL/min/1.73 m2) and examined the influence of extra-renal factors on GFR-estimates among HIV-infected men.
Results
Estimated GFRSCR was similar by HIV serostatus, but eGFRCYSC was lower in HIV-infected men. A higher proportion of HIV-infected men were classified as having CKD when using eGFRCYSC versus eGFRSCR (7% vs. 5%, P<0.01). In HIV-infected individuals without CKD, eGFRSCR was higher than eGFRCYSC while it was lower than eGFRCYSC in persons with CKD. In HIV-infected men, older age, proteinuria, and prior clinical AIDS were inversely associated with both GFR-estimates. Higher serum albumin levels and ACE-inhibitor/ARB use were associated with lower eGFRSCR. HIV viral load, hepatitis C co-infection, and serum alkaline phosphatase were inversely associated with eGFRCYSC.
Conclusion
Among HIV-uninfected and HIV-infected men of similar social risk behaviors, GFR estimates differed by biomarker and kidney function level. Estimated GFRCYSC classified a larger proportion of HIV-infected men with CKD compared to eGFRSCR. Differences between these GFR-estimating methods may be due to the effects of extra-renal factors on serum creatinine and cystatin C. Until GFR-estimating equations are validated among HIV-infected individuals, current GFR estimates based on these biomarkers should be interpreted with care in this patient population.
doi:10.1097/QAI.0b013e318222f461
PMCID: PMC3159728  PMID: 21646913
HIV; kidney disease; serum creatinine; cystatin C; glomerular filtration rate; Multicenter AIDS Cohort Study
17.  Delayed Progression to Dialysis with Early and Intensive Management of Predialysis Chronic Kidney Disease: A Case-Based Approach 
In addition to hypertension and diabetes, disorders in mineral metabolism and bone disease (e.g. affecting phosphorus, calcium, parathyroid hormone, and vitamin D) are common complications of chronic kidney disease (CKD) and contribute to morbidity and mortality. Consequently, CKD requires multifactorial treatment to slow CKD progression and avoid end-stage renal disease. CKD progression and treatment outcomes are monitored by measuring the estimated glomerular filtration rate (eGFR), which decreases by 2–12 ml/min/1.73 m2 per year depending on the stage of CKD and comorbidities, such as diabetes. This paper presents representative case studies illustrating the delay and reversal of CKD progression with comprehensive, individualized treatment regimens, including non-calcium phosphate binders, antihypertensives, lipid-lowering drugs, calcimimetics, and other drugs as required, to treat each component of CKD including CKD-mineral and bone disorder. Four patients are included, with an average age of 70–81 years and CKD stage 3 or 4 accompanied by various comorbidities, most notably diabetes and hypertension. The range of treatment and follow-up durations was 6–7 years. In each case, there was evidence of slowing or prevention of CKD progression, according to eGFR and serum creatinine, regardless of the patient's age or CKD stage. Despite a baseline eGFR of <20 ml/min/1.73 m2 in 1 female patient, after 6 years of follow-up, her eGFR had stabilized and was maintained at >15 ml/min/1.73 m2. These observations reinforce the value of early nephrology referral and comprehensive management of CKD and underlying conditions (hypertension and diabetes) beginning at eGFR <60 ml/min/1.73 m2.
doi:10.1159/000353265
PMCID: PMC3808807  PMID: 24167516
Chronic kidney disease; Estimated GFR; Comorbidities; Multifactorial treatment regimen
18.  Relationship of Estimated GFR and Coronary Artery Calcification in the (CRIC) Chronic Renal Insufficiency Cohort Study 
Background
Coronary artery calcification (CAC) is associated with increased mortality risk in the general population. Although individuals with chronic kidney disease (CKD) are at markedly increased mortality risk, the incidence, prevalence, and prognosis of CAC in CKD is not well-understood.
Study Design
Cross-sectional observational study.
Setting and Participants
Analysis of 1,908 participants who underwent coronary calcium scanning as part of the multi-ethnic CRIC (Chronic Renal Insufficiency Cohort) Study.
Predictor
Estimated glomerular filtration rate (eGFR) computed using the Modification of Diet in Renal Disease (MDRD) Study equation, stratified by race, sex and diabetic status. eGFR was treated as a continous variable and a categorical variable compared to the reference range of >60 ml/min/1.73 m2
Measurements
CAC detected using CT scans using either an Imatron C-300 electron beam computed tomography scanner or multi-detector CT scanner. CAC was computed using the Agatston score, as a categorical variable. Analyses were performed using ordinal logistic regression.
Results
We found a strong and graded relationship between lower eGFR and increasing CAC. In unadjusted models, ORs increased from 1.68 (95% CI, 1.23–2.31) for eGFR from 50–59 to 2.82 (95% CI, 2.06–3.85) for eGFR of <30. Multivariable adjustment only partially attenuated the results (OR, 1.53; 95% CI, 1.07–2.20) for eGFR<30.
Limitations
Use of eGFR rather than measured GFR.
Conclusions
We demonstrated a graded relationship between severity of CKD and CAC, independent of traditional risk factors. These findings supports recent guidelines that state that if vascular calcification is present, it should be considered as a complementary component to be included in the decision making required for individualizing treatment of CKD.
doi:10.1053/j.ajkd.2011.04.024
PMCID: PMC3183168  PMID: 21783289
19.  Renal Function Following Curative Surgery for Renal Cell Carcinoma: Who Is at Risk for Renal Insufficiency? 
Korean Journal of Urology  2013;54(12):830-833.
Purpose
To investigate the incidence and predictive factors associated with the development of chronic kidney disease (CKD) in patients undergoing curative surgery for renal cell carcinoma.
Materials and Methods
From 2003 to 2010, we retrospectively investigated 108 patients undergoing partial nephrectomy or radical nephrectomy (RN) for renal tumors with a preoperative glomerular filtration rate (GFR)≥60. The GFR was calculated by use of the four-variable modification of diet in renal disease (MDRD) formula. CKD was defined as an estimated GFR (eGFR) less than 60 mL/min per 1.73 m2. Demographic and clinicopathologic parameters were evaluated by using the chi-square and Student t-tests and multivariate regression analysis to determine the variables independently associated with the development of postoperative CKD.
Results
Of the 108 patients without preoperative CKD, CKD developed in 43 patients (39.8%). In the analysis of clinical factors between patients with and those without CKD development, gender, body mass index, diabetes mellitus, hypertension, and tumor size were not significant clinical factors. Statistical significance for CKD development was found for age of 60 years or greater (p=0.013), decreased preoperative eGFR (p<0.001), and RN group (p<0.001). In the multivariate analysis, decreased preoperative eGFR (p=0.001) and RN group (p=0.002) were significant independent predictors.
Conclusions
The results of our study show that decreased preoperative renal function and RN were significant independent predictors of postoperative CKD. In patients who had a relatively decreased preoperative eGFR, especially when estimated by use of the MDRD formula, nephron-sparing surgery should be considered for the treatment of small renal tumors.
doi:10.4111/kju.2013.54.12.830
PMCID: PMC3866285  PMID: 24363863
Chronic kidney disease; Glomerular filtration rate; Renal cell carcinoma
20.  Chronic Kidney Disease as a Predictor of Cardiovascular Disease (From the Framingham Heart Study) 
Chronic kidney disease (CKD) is a risk factor for cardiovascular disease (CVD), although shared risk factors may mediate much of the association. We related CKD and CVD in the setting of specific CVD risk factors and determined whether more advanced CKD was a CVD risk equivalent. The Framingham Heart Study original cohort (n=2471, mean age 68 years, 58.9% women) was studied. Glomerular filtration rate (eGFR) was estimated using the simplified Modification of Diet in Renal Disease Study equation. CKD was defined as eGFR < 59 mL/min per 1.73 m2 (women) and < 64 (men) and Stage 3b CKD defined as eGFR 30-44 (women) and 30-50 (men). Cox Proportional Hazard models adjusting for CVD risk factors were used to relate CKD to CVD. We tested for effect modification by CVD risk factors. Overall, 23.2% of the study sample had CKD (n=574; mean eGFR 50 mL/min per 1.73 m2) and 5.3% had Stage 3b CKD (n=131; mean eGFR 42 mL/min per 1.73 m2). In multivariable models (mean follow-up time 16 years), Stage 3 CKD was marginally associated with CVD (HR=1.17, 95% CI 0.99-1.38, p=0.06), whereas Stage 3b CKD was associated with CVD [HR=1.41, 95% CI 1.05-1.91, p=0.02]. Upon testing CVD risk equivalency, the risk of CVD for Stage 3b CKD among participants with prior CVD was significantly lower as compared to participants with prior CVD and no Stage 3b CKD (age- and sex-adjusted HR for CVD = 0.66 [95% CI 0.47 to 0.91], p=0.01). Low HDL modified the association between CKD and CVD (p-value=0.004 for interaction). Stage 3b CKD is associated with CVD but is not a CVD risk equivalent. In conclusion, CVD risk in the setting of CKD is higher in the setting of low HDL cholesterol.
doi:10.1016/j.amjcard.2008.02.095
PMCID: PMC2517213  PMID: 18572034
21.  Association of Chronic Kidney Disease with Atrial Fibrillation Among Adults in the United States: Reasons for Geographic and Racial Differences in Stroke (REGARDS) Study 
Background
Atrial fibrillation (AF) is common among patients with end-stage renal disease, but few data are available on its prevalence among adults with chronic kidney disease (CKD) of lesser severity.
Methods and Results
We evaluated the association of CKD with electrocardiogram-detected AF among 26,917 participants in the REasons for Geographic and Racial Differences in Stroke (REGARDS) study, a population-based cohort of African-American and white US adults ≥45 years of age. Estimated glomerular filtration rate (eGFR) was calculated using the abbreviated Modification of Diet in Renal Disease study equation and albuminuria was defined as a urinary albumin to creatinine ratio ≥30 mg/g. Participants were categorized by renal function: no CKD (eGFR ≥60 ml/min/1.73m2 without albuminuria, n=21,081), stage 1–2 CKD (eGFR ≥60 ml/min/1.73m2 with albuminuria n=2,938), stage 3 CKD (eGFR 30 to 59 ml/min/1.73m2, n=2,683) and stage 4–5 CKD (eGFR <30 ml/min/1.73m2, n=215). The prevalence of AF among participants without CKD, and with stage 1–2, stage 3, and stage 4–5 CKD was 1.0%, 2.8%, 2.7% and 4.2%, respectively. Compared to participants without CKD, the age, race, sex adjusted odds ratios for prevalent AF were 2.67 (95% CI 2.04 – 3.48), 1.68 (95% CI 1.26 – 2.24) and 3.52 (95% CI 1.73–7.15) among those with stage 1–2, stage 3 and stage 4–5 CKD. The association between CKD and prevalent AF remained statistically significant after further multivariable adjustment and was consistent across numerous subgroups.
Conclusions
- Regardless of severity, CKD is associated with an increased prevalence of AF among US adults.
doi:10.1161/CIRCEP.110.957100
PMCID: PMC3049935  PMID: 21076159
chronic kidney disease; atrial fibrillation; electrocardiography
22.  Association of Dyslipidemia with Renal Outcomes in Chronic Kidney Disease 
PLoS ONE  2013;8(2):e55643.
Dyslipidemia is highly prevalent in patients with chronic kidney disease (CKD) and the relationship between dyslipidemia with renal outcomes in patients with moderate to advanced CKD remains controversial. Hence, our objective is to determine whether dyslipidemia is independently associated with rapid renal progression and progression to renal replacement therapy (RRT) in CKD patients. The study analyzed the association between lipid profile, RRT, and rapid renal progression (estimated glomerular filtration rate [eGFR] slope <−6 ml/min/1.73 m2/yr) in 3303 patients with stages 3 to 5 CKD. During a median 2.8-year follow-up, 1080 (32.3%) participants commenced RRT and 841 (25.5%) had rapid renal progression. In the adjusted models, the lowest quintile (hazard ratios [HR], 1.23; 95% confidence interval [CI], 1.01 to 1.49) and the highest two quintiles of total cholesterol (HR, 1.25; 95% CI, 1.02 to 1.52 and HR, 1.35; 95% CI, 1.11 to 1.65 respectively) increased risks for RRT (vs. quintile 2). Besides, the highest quintile of total cholesterol was independently associated with rapid renal progression (odds ratio, 1.36; 95% CI, 1.01 to 1.83). Our study demonstrated that certain levels of dyslipidemia were independently associated with RRT and rapid renal progression in CKD stage 3–5. Assessment of lipid profile may help identify high risk groups with adverse renal outcomes.
doi:10.1371/journal.pone.0055643
PMCID: PMC3563532  PMID: 23390545
23.  Risk factors for chronic kidney disease in Japan: a community-based study 
BMC Nephrology  2009;10:34.
Background
Chronic kidney disease (CKD) is increasingly being recognized as a predictor for both end-stage renal disease and cardiovascular disease. The present study, conducted on individuals from a community in Arita, Japan, was designed to evaluate biomarkers that can be used to determine the associated factors for CKD.
Methods
This study involved 1554 individuals. Kidney function was evaluated in terms of the creatinine-based estimated glomerular filtration rate (eGFR), which was determined using the Modification of Diet in Renal Disease equation. Low eGFR was defined as eGFR < 60 mL/min per 1.73 m2. The concentration of both urinary albumin and urinary type IV collagen were measured.
Results
In the younger participants (age, <65 years), the odds ratio (95% confidence interval [CI]) of low eGFR was 1.17 (1.02 to 1.34) for each 1 year older age, 6.28 (1.41 to 28.03) for urinary albumin creatinine ratio (ACR) over 17.9 mg/g and 9.43 (2.55 to 34.91) for hyperlipidemia. On the other hand, among the elderly participants (age, ≥ 65 years), the odds ratio (95% CI) of low eGFR was 2.97 (1.33 to 6.62) for gender, 1.62 (1.06 to 2.50) for hypertension and 1.97 (1.19 to 3.28) for hyperlipidemia. Urinary type IV collagen creatinine ratio was not identified as an associated factor for low eGFR.
Conclusion
In this present cross-sectional community-based study, ACR is associated with CKD, which was defined as an eGFR of less than 60 mL/min per 1.73 m2, in the younger participants but not in the older participants.
doi:10.1186/1471-2369-10-34
PMCID: PMC2773767  PMID: 19860890
24.  Recognition and Management of Chronic Kidney Disease in an Elderly Ambulatory Population 
Journal of General Internal Medicine  2008;23(8):1125-1130.
Background
Chronic kidney disease (CKD) is a growing problem among the elderly. Early detection is considered essential to ensure proper treatment and to avoid drug toxicity, but detection is challenging because elderly patients with CKD often have normal serum creatinine levels. We hypothesized that most cases of CKD in the elderly would go undetected, resulting in inappropriate prescribing.
Objective
To determine whether recognition of CKD is associated with more appropriate treatment
Design
Retrospective chart review
Participants
All patients aged ≥65 years with a measured serum creatinine in the past 3 years at 2 inner city academic health centers.
Measurements
Estimated glomerular filtration rate (eGFR) calculated using the Modified Diet in Renal Disease equation, and for patients with eGFR < 60, documentation of CKD by the provider, diagnostic testing, nephrology referral and prescription of appropriate or contraindicated medications.
Results
Of 814 patients with sufficient information to estimate eGFR, 192 (33%) had moderate (eGFR < 60 mL/min) and 5% had severe (eGFR < 30 mL/min) CKD. Providers identified 38% of moderate and 87% of severe CKD. Compared to patients without recognized CKD, recognized patients were more likely to receive an ACE/ARB (80% vs 61%, p = .001), a nephrology referral (58% vs 2%, p < .0001), or urine testing (75% vs 47%, p < .0001), and less likely to receive contraindicated medications (26% vs 40%, p = .013).
Conclusions
Physicians frequently fail to diagnose CKD in the elderly, leading to inappropriate treatment. Efforts should focus on helping physicians better identify patients with low GFR.
doi:10.1007/s11606-008-0607-z
PMCID: PMC2517961  PMID: 18443883
chronic kidney disease; diagnosis; creatinine; ace inhibitors; elderly
25.  Circulating Endoglin Concentration Is Not Elevated in Chronic Kidney Disease 
PLoS ONE  2011;6(8):e23718.
Background
Soluble endoglin, a TGF-β receptor, plays a key role in cardiovascular physiology. Whether circulating concentrations of soluble endoglin are elevated in CKD or underlie the high risk of cardiovascular death associated with chronic kidney disease (CKD) is unknown.
Methods
Individuals with and without CKD were recruited at a single center. Estimated glomerular filtration rate (eGFR) was estimated using the modified MDRD study equation and the serum creatinine at the time of recruitment, and patients were assigned to specific CKD stage according to usual guidelines. Serum endoglin concentration was measured by ELISA and univariate and multivariable regression was used to analyze the association between eGFR or CKD stage and the concentration of soluble endoglin.
Results
Serum endoglin was measured in 216 patients including 118 with stage 3 or higher CKD and 9 individuals with end stage renal disease (ESRD). Serum endoglin concentration did not vary significantly with CKD stage (increase of 0.16 ng/mL per 1 stage increase in CKD, P = 0.09) or eGFR (decrease -0.06 ng/mL per 10 mL/min/1.73 m2 increase in GFR, P = 0.12), and was not higher in individuals with ESRD than in individuals with preserved renal function (4.2±1.1 and 4.3±1.2 ng/mL, respectively). Endoglin concentration was also not significantly associated with urinary albumin excretion.
Conclusions
Renal function is not associated with the circulating concentration of soluble endoglin. Elevations in soluble endoglin concentration are unlikely to contribute to the progression of CKD or the predisposition of individuals with CKD to develop cardiovascular disease.
doi:10.1371/journal.pone.0023718
PMCID: PMC3158786  PMID: 21886815

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