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1.  Association of Non-alcoholic Fatty Liver Disease with Chronic Kidney Disease: A Systematic Review and Meta-analysis 
PLoS Medicine  2014;11(7):e1001680.
In a systematic review and meta-analysis, Giovanni Musso and colleagues examine the association between non-alcoholic fatty liver disease and chronic kidney disease.
Please see later in the article for the Editors' Summary
Background
Chronic kidney disease (CKD) is a frequent, under-recognized condition and a risk factor for renal failure and cardiovascular disease. Increasing evidence connects non-alcoholic fatty liver disease (NAFLD) to CKD. We conducted a meta-analysis to determine whether the presence and severity of NAFLD are associated with the presence and severity of CKD.
Methods and Findings
English and non-English articles from international online databases from 1980 through January 31, 2014 were searched. Observational studies assessing NAFLD by histology, imaging, or biochemistry and defining CKD as either estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m2 or proteinuria were included. Two reviewers extracted studies independently and in duplicate. Individual participant data (IPD) were solicited from all selected studies. Studies providing IPD were combined with studies providing only aggregate data with the two-stage method. Main outcomes were pooled using random-effects models. Sensitivity and subgroup analyses were used to explore sources of heterogeneity and the effect of potential confounders. The influences of age, whole-body/abdominal obesity, homeostasis model of insulin resistance (HOMA-IR), and duration of follow-up on effect estimates were assessed by meta-regression. Thirty-three studies (63,902 participants, 16 population-based and 17 hospital-based, 20 cross-sectional, and 13 longitudinal) were included. For 20 studies (61% of included studies, 11 cross-sectional and nine longitudinal, 29,282 participants), we obtained IPD. NAFLD was associated with an increased risk of prevalent (odds ratio [OR] 2.12, 95% CI 1.69–2.66) and incident (hazard ratio [HR] 1.79, 95% CI 1.65–1.95) CKD. Non-alcoholic steatohepatitis (NASH) was associated with a higher prevalence (OR 2.53, 95% CI 1.58–4.05) and incidence (HR 2.12, 95% CI 1.42–3.17) of CKD than simple steatosis. Advanced fibrosis was associated with a higher prevalence (OR 5.20, 95% CI 3.14–8.61) and incidence (HR 3.29, 95% CI 2.30–4.71) of CKD than non-advanced fibrosis. In all analyses, the magnitude and direction of effects remained unaffected by diabetes status, after adjustment for other risk factors, and in other subgroup and meta-regression analyses. In cross-sectional and longitudinal studies, the severity of NAFLD was positively associated with CKD stages. Limitations of analysis are the relatively small size of studies utilizing liver histology and the suboptimal sensitivity of ultrasound and biochemistry for NAFLD detection in population-based studies.
Conclusion
The presence and severity of NAFLD are associated with an increased risk and severity of CKD.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Chronic kidney disease (CKD)—the gradual loss of kidney function—is becoming increasingly common. In the US, for example, more than 10% of the adult population (about 26 million people) and more than 25% of individuals older than 65 years have CKD. Throughout life, the kidneys perform the essential task of filtering waste products (from the normal breakdown of tissues and from food) and excess water from the blood to make urine. CKD gradually destroys the kidneys' filtration units, the rate of blood filtration decreases, and dangerous amounts of waste products build up in the blood. Symptoms of CKD, which rarely occur until the disease is very advanced, include tiredness, swollen feet, and frequent urination, particularly at night. There is no cure for CKD, but progression of the disease can be slowed by controlling high blood pressure and diabetes (two risk factors for CKD), and by adopting a healthy lifestyle. The same interventions also reduce the chances of CKD developing in the first place.
Why Was This Study Done?
CKD is associated with an increased risk of end-stage renal (kidney) disease and of cardiovascular disease. These life-threatening complications are potentially preventable through early identification and treatment of CKD. Because early recognition of CKD has the potential to reduce its health-related burden, the search is on for new modifiable risk factors for CKD. One possible new risk factor is non-alcoholic fatty liver disease (NAFLD), which, like CKD is becoming increasingly common. Healthy livers contain little or no fat but, in the US, 30% of the general adult population and up to 70% of patients who are obese or have diabetes have some degree of NAFLD, which ranges in severity from simple fatty liver (steatosis), through non-alcoholic steatohepatitis (NASH), to NASH with fibrosis (scarring of the liver) and finally cirrhosis (extensive scarring). In this systematic review and meta-analysis, the researchers investigate whether NAFLD is a risk factor for CKD by looking for an association between the two conditions. A systematic review identifies all the research on a given topic using predefined criteria, meta-analysis uses statistical methods to combine the results of several studies.
What Did the Researchers Do and Find?
The researchers identified 33 studies that assessed NAFLD and CKD in nearly 64,000 participants, including 20 cross-sectional studies in which participants were assessed for NAFLD and CKD at a single time point and 13 longitudinal studies in which participants were assessed for NAFLD and then followed up to see whether they subsequently developed CKD. Meta-analysis of the data from the cross-sectional studies indicated that NAFLD was associated with a 2-fold increased risk of prevalent (pre-existing) CKD (an odds ratio [OR]of 2.12; an OR indicates the chance that an outcome will occur given a particular exposure, compared to the chance of the outcome occurring in the absence of that exposure). Meta-analysis of data from the longitudinal studies indicated that NAFLD was associated with a nearly 2-fold increased risk of incident (new) CKD (a hazard ratio [HR] of 1.79; an HR indicates often a particular event happens in one group compared to how often it happens in another group, over time). NASH was associated with a higher prevalence and incidence of CKD than simple steatosis. Similarly, advanced fibrosis was associated with a higher prevalence and incidence of CKD than non-advanced fibrosis.
What Do These Findings Mean?
These findings suggest that NAFLD is associated with an increased prevalence and incidence of CKD and that increased severity of liver disease is associated with an increased risk and severity of CKD. Because these associations persist after allowing for established risk factors for CKD, these findings identify NAFLD as an independent CKD risk factor. Certain aspects of the studies included in this meta-analysis (for example, only a few studies used biopsies to diagnose NAFLD; most used less sensitive tests that may have misclassified some individuals with NAFLD as normal) and the methods used in the meta-analysis may limit the accuracy of these findings. Nevertheless, these findings suggest that individuals with NAFLD should be screened for CKD even in the absence of other risk factors for the disease, and that better treatment of NAFLD may help to prevent CKD.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001680.
The US National Kidney and Urologic Diseases Information Clearinghouse provides information about all aspects of kidney disease; the US National Digestive Diseases Information Clearinghouse provides information about non-alcoholic liver disease
The US National Kidney Disease Education Program provides resources to help improve the understanding, detection, and management of kidney disease (in English and Spanish)
The UK National Health Service Choices website provides information for patients on chronic kidney disease, including some personal stories, and information on non-alcoholic fatty liver disease
The US National Kidney Foundation, a not-for-profit organization, provides information about chronic kidney disease (in English and Spanish)
The not-for-profit UK National Kidney Federation provides support and information for patients with kidney disease and for their carers
The British Liver Trust, a not-for-profit organization, provides information about non-alcoholic fatty liver disease, including a patient story
doi:10.1371/journal.pmed.1001680
PMCID: PMC4106719  PMID: 25050550
2.  Prevalence of low glomerular filtration rate, proteinuria and associated risk factors in North India using Cockcroft-Gault and Modification of Diet in Renal Disease equation: an observational, cross-sectional study 
BMC Nephrology  2009;10:4.
Background
Chronic kidney disease (CKD) is increasingly being recognized as an emerging public health problem in India. However, community based estimates of low glomerular filtration rate (GFR) and proteinuria are few. Validity of traditional serum creatinine based GFR estimating equations in South Asian subjects is also debatable. We intended to estimate and compare the prevalence of low GFR, proteinuria and associated risk factors in North India using Cockcroft-Gault (CG) and Modification of Diet In Renal Disease (MDRD) equation.
Methods
A community based, cross-sectional study involving multistage random cluster sampling was done in Delhi and its surrounding regions. Adults ≥ 20 years were surveyed. CG and MDRD equations were used to estimate GFR (eGFR). Low GFR was defined as eGFR < 60 ml/min/1.73 m2. Proteinuria (≥ 1+) was assessed using visually read dipsticks. Odds ratios, crude and adjusted, were calculated to ascertain associations between renal impairment, proteinuria and risk factors.
Results
The study population had 3,155 males and 2,097 females. The mean age for low eGFR subjects was 54 years. The unstandardized prevalence of low eGFR was 13.3% by CG equation and 4.2% by MDRD equation. The prevalence estimates of MDRD equation were lower across gender and age groups when compared with CG equation estimates. There was a strong correlation but poor agreement between GFR estimates of two equations. The survey population had a 2.25% prevalence of proteinuria. In a multivariate logistic regression analysis; age above 60 years, female gender, low educational status, increased waist circumference, hypertension and diabetes were associated with low eGFR. Similar factors were also associated with proteinuria. Only 3.3% of subjects with renal impairment were aware of their disease.
Conclusion
The prevalence of low eGFR in North India is probably higher than previous estimates. There is a significant difference between GFR estimates derived from CG and MDRD equations. These equations may not be useful in epidemiological research. GFR estimating equations validated for South Asian populations are needed before reliable estimates of CKD prevalence can be obtained. Till then, primary prevention and management targeted at CKD risk factors must play a critical role in controlling rising CKD magnitude. Cost-benefit analysis of targeted screening programs is needed.
doi:10.1186/1471-2369-10-4
PMCID: PMC2663556  PMID: 19220921
3.  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
4.  Renal Function and Risk of Coronary Heart Disease in General Populations: New Prospective Study and Systematic Review 
PLoS Medicine  2007;4(9):e270.
Background
End-stage chronic kidney disease is associated with striking excesses of cardiovascular mortality, but it is uncertain to what extent renal function is related to risk of subsequent coronary heart disease (CHD) in apparently healthy adults. This study aims to quantify the association of markers of renal function with CHD risk in essentially general populations.
Methods and Findings
Estimated glomerular filtration rate (eGFR) was calculated using standard prediction equations based on serum creatinine measurements made in 2,007 patients diagnosed with nonfatal myocardial infarction or coronary death during follow-up and in 3,869 people without CHD in the Reykjavik population-based cohort of 18,569 individuals. There were small and nonsignificant odds ratios (ORs) for CHD risk over most of the range in eGFR, except in the lowest category of the lowest fifth (corresponding to values of <60 ml/min/1.73m2), in which the OR was 1.33 (95% confidence interval 1.01–1.75) after adjustment for several established cardiovascular risk factors. Findings from the Reykjavik study were reinforced by a meta-analysis of six previous reports (identified in electronic and other databases) involving a total of 4,720 incident CHD cases (including Reykjavik), which yielded a combined risk ratio of 1.41 (95% confidence interval 1.19–1.68) in individuals with baseline eGFR less than 60 ml/min/1.73m2 compared with those with higher values.
Conclusions
Although there are no strong associations between lower-than-average eGFR and CHD risk in apparently healthy adults over most of the range in renal function, there may be a moderate increase in CHD risk associated with very low eGFR (i.e., renal dysfunction) in the general population. These findings could have implications for the further understanding of CHD and targeting cardioprotective interventions.
John Danesh and colleagues conclude there may be a moderate increase in risk of coronary heart disease associated with very low estimated glomerular filtration rate.
Editors' Summary
Background.
Coronary heart disease (CHD), the leading cause of death in most Western countries, is a “cardiovascular” disease—literally a disorder affecting the heart and/or blood vessels. In CHD, the blood vessels that supply the heart become increasingly narrow. Eventually, the flow of blood to the heart slows or stops, causing chest pains (angina), breathlessness, and heart attacks. Many factors increase the risk of developing CHD and other cardiovascular diseases, including high blood pressure, high blood levels of cholesterol (a type of fat), or being overweight. Individuals can reduce their chances of developing cardiovascular disease by taking drugs to reduce their blood pressure or cholesterol levels or by making lifestyle changes (so-called cardioprotective interventions). Another important risk factor for cardiovascular disease is end-stage chronic kidney disease (CKD), a condition in which the kidneys stop working. (In healthy people, the kidneys remove waste products and excess fluid from the body.) People with end-stage CKD (which is treated by dialysis) have about a five times higher risk of dying from cardiovascular disease compared with healthy people.
Why Was This Study Done?
End-stage CKD is preceded by a gradual loss of kidney function. There is a clear association between non-dialysis–dependent CKD and the incidence of cardiovascular events (such as heart attacks) in people who already have signs of cardiovascular disease. But are people with slightly dysfunctional kidneys (often because of increasing age) but without any obvious cardiovascular disease at greater risk of developing cardiovascular diseases than people with fully functional kidneys? If the answer is yes, it might be possible to reduce CHD deaths by minimizing the exposure of people with CKD to other risk factors for cardiovascular disease. In this study, the researchers have taken two approaches to answer this question. In a population-based study, they have examined whether there is any association in healthy adults between kidney function measured at the start of the study and incident CHD (the first occurrence of CHD) over subsequent years. In addition, they have systematically searched the published literature for similar studies and combined the results of these studies using statistical methods, a so-called “meta-analysis.”
What Did the Researchers Do and Find?
Between 1967 and 1991, nearly 19,000 middle-aged men and women without a history of heart attacks living in Reykjavik, Iceland, enrolled in a prospective study of cardiovascular disease. Baseline blood samples were taken at enrollment and the participants' health monitored for 20 years on average. The researchers identified 2,007 participants who suffered a nonfatal heart attack or died of CHD during follow-up and 3,869 who remained disease free. They then calculated the estimated glomerular filtration rate (eGFR; a measure of kidney function) for each participant from baseline creatinine measurements (creatinine is a muscle waste product). There was no association between lower-than-average eGFRs and the risk of developing CHD over most of the range of eGFR values. However, people whose eGFR was below approximately 60 units had about a 40% higher risk of developing CHD after allowing for established cardiovascular risk factors than individuals with higher eGFRs. This finding was confirmed by the meta-analysis of six previous studies, which included a further 2,700 incident CHD cases.
What Do These Findings Mean?
These findings indicate that people with an eGFR below about 60 units (the cut-off used to define CKD) may have an increased risk of developing CHD. They also indicate a nonliner association between kidney function and CHD risk. That is, any association with CHD became evident only when the eGFR dropped below about 60 units. These findings need confirming in different ethnic groups and by using more accurate methods to measure eGFRs. Nevertheless, they suggest that improving kidney function across the board is unlikely to have much effect on the overall incidence of CHD. Instead, they suggest that targeting cardioprotective interventions at the one in ten adults in Western countries whose eGFR is below 60 units might be a good way to reduce the burden of CHD.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040270.
MedlinePlus encyclopedia pages on coronary heart disease, chronic kidney failure, and end-stage kidney disease (in English and Spanish).
Information for patients and carers from the American Heart Association on all aspects of heart disease, including prevention of CHD
Information from the British Heart Foundation on heart disease and on keeping the heart healthy
Information on chronic kidney disease from the US National Kidney Foundation, and the US National Kidney and Urologic Diseases Information Clearing House (in English and Spanish)
Information on chronic kidney disease from the UK National Kidney Foundation
doi:10.1371/journal.pmed.0040270
PMCID: PMC1961630  PMID: 17803353
5.  Epidemiology and prognostic significance of chronic kidney disease in the elderly--the Three-City prospective cohort study 
Nephrology Dialysis Transplantation  2011;26(10):3286-3295.
Background
Little is known about normal kidney function level and the prognosis significance of low estimated glomerular filtration rate(eGFR) in the elderly.
Methods
We determined age and sex distribution of eGFR with both the Modification of Diet in Renal Disease (MDRD) study and the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations in 8705 community-dwelling elderly aged ≥ 65 years and studied its relation to 6-year mortality. In a subsample of 1298 examined at 4 yrs, we assessed annual eGFR decline and clinically relevant markers including microalbuminuria (3–30 mg/mmol creatinine) with diabetes, proteinuria ≥ 50 mg/mmol, haemoglobin<11 g/L, or resistant hypertension despite 3 drugs.
Results
Median (interquartile range) MDRD eGFR was 78 (68–89)mL/min/1.73m2 in men and 74 (65–83)in women; there were 79 (68–87) and 77 (67–85) for CKD-EPI eGFR, respectively. Prevalence of MDRD eGFR< 60mL/min/1.73m2 was13.7%, and of CKD-EPI eGFR, 12.9%. After adjustment for several confounders, only those with an eGFR<45 mL/min/1.73 m2 had significantly higher all-cause and cardiovascular mortality than those with an eGFR of 75 to 89 mL/min/1.73 m2 whatever the equation. In subsample men and women with MDRD eGFR of 45–59 mL/min/1.73m2, 15% and 13% had at least one clinical marker, and 15% and 3% had microalbuminuria without diabetes, respectively; these percentages were 41% and 21%, and 23% and 10%, in men and women with eGFR<45, respectively. Mean MDRD eGFR decline rate was steeper in men than women, 1.75 vs 1.41 mL/min/1.73m2 per year.
Conclusion
Moderately decreased eGFR is more often associated with clinical markers in men than women. In both sexes, eGFR< 45 mL/min/1.73m2 is related to poor outcomes. The CKD-EPI and the MDRD equations provide very similar prevalence and long-term risk estimates in this elderly population.
doi:10.1093/ndt/gfr323
PMCID: PMC3925095  PMID: 21677301
Aged; Cardiovascular Diseases; epidemiology; etiology; mortality; Creatinine; blood; urine; Female; Follow-Up Studies; Glomerular Filtration Rate; Humans; Kidney Failure, Chronic; complications; epidemiology; mortality; Male; Prevalence; Prognosis; Prospective Studies; Proteinuria; diagnosis; etiology; mortality; Risk Factors; Survival Rate; chronic kidney disease; elderly; glomerular filtration rate; mortality; proteinuriaanaemia
6.  Joint relationship between renal function and proteinuria on mortality of patients with type 2 diabetes: The Taichung Diabetes Study 
Background
Estimated glomerular filtration rate (eGFR) is a powerful predictor of mortality in diabetic patients with limited proteinuria data. In this study, we tested whether concomitant proteinuria increases the risk of mortality among patients with type 2 diabetes.
Methods
Participants included 6523 patients > 30 years with type 2 diabetes who were enrolled in a management program of a medical center before 2007. Renal function was assessed by eGFR according to the Modification of Diet in Renal Disease Study equation for Chinese. Proteinuria was assessed by urine dipstick.
Results
A total of 573 patients (8.8%) died over a median follow-up time of 4.91 years (ranging from 0.01 year to 6.42 years). The adjusted expanded cardiovascular disease (CVD)-related mortality rates among patients with proteinuria were more than three folds higher for those with an eGFR of 60 mL/min/1.73 m2 or less compared with those with an eGFR of 90 mL/min/1.73 m2 or greater [hazard ratio, HR, 3.15 (95% confidence interval, CI, 2.0–5.1)]. The magnitude of adjusted HR was smaller in patients without proteinuria [1.98 (95% CI, 1.1–3.7)]. An eGFR of 60 mL/min/1.73 m2 to 89 mL/min/1.73 m2 significantly affected all-cause mortality and mortality from expanded CVD-related causes only in patients with proteinuria. Similarly, proteinuria affected all outcomes only in patients with an eGFR of <60 mL/min/1.73 m2.
Conclusion
The risks of all-cause mortality, as well as expanded and non-expanded mortality from CVD-related causes associated with proteinuria or an eGFR of 90 mL/min/1.73 m2 or greater are independently increased. Therefore, the use of proteinuria measurements with eGFR increases the precision of risk stratification for mortality.
doi:10.1186/1475-2840-11-131
PMCID: PMC3515506  PMID: 23083001
Renal function; Mortality; Type 2 diabetes
7.  Reduced Glomerular Filtration Rate and Its Association with Clinical Outcome in Older Patients at Risk of Vascular Events: Secondary Analysis 
PLoS Medicine  2009;6(1):e1000016.
Background
Reduced glomerular filtration rate (GFR) is associated with increased cardiovascular risk in young and middle aged individuals. Associations with cardiovascular disease and mortality in older people are less clearly established. We aimed to determine the predictive value of the GFR for mortality and morbidity using data from the 5,804 participants randomized in the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER).
Methods and Findings
Glomerular filtration rate was estimated (eGFR) using the Modification of Diet in Renal Disease equation and was categorized in the ranges ([20–40], [40–50], [50–60]) ≥ 60 ml/min/1.73 m2. Baseline risk factors were analysed by category of eGFR, with and without adjustment for other risk factors. The associations between baseline eGFR and morbidity and mortality outcomes, accrued after an average of 3.2 y, were investigated using Cox proportional hazard models adjusting for traditional risk factors. We tested for evidence of an interaction between the benefit of statin treatment and baseline eGFR status. Age, low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol, C-reactive protein (CRP), body mass index, fasting glucose, female sex, histories of hypertension and vascular disease were associated with eGFR (p = 0.001 or less) after adjustment for other risk factors. Low eGFR was independently associated with risk of all cause mortality, vascular mortality, and other noncancer mortality and with fatal and nonfatal coronary and heart failure events (hazard ratios adjusted for CRP and other risk factors (95% confidence intervals [CIs]) for eGFR < 40 ml/min/1.73m2 relative to eGFR ≥ 60 ml/min/1.73m2 respectively 2.04 (1.48–2.80), 2.37 (1.53–3.67), 3.52 (1.78–6.96), 1.64 (1.18–2.27), 3.31 (2.03–5.41). There were no nominally statistically significant interactions (p < 0.05) between randomized treatment allocation and eGFR for clinical outcomes, with the exception of the outcome of coronary heart disease death or nonfatal myocardial infarction (p = 0.021), with the interaction suggesting increased benefit of statin treatment in subjects with impaired GFRs.
Conclusions
We have established that, in an elderly population over the age of 70 y, impaired GFR is associated with female sex, with presence of vascular disease, and with levels of other risk factors that would be associated with increased risk of vascular disease. Further, impaired GFR is independently associated with significant levels of increased risk of all cause mortality and fatal vascular events and with composite fatal and nonfatal coronary and heart failure outcomes. Our analyses of the benefits of statin treatment in relation to baseline GFR suggest that there is no reason to exclude elderly patients with impaired renal function from treatment with a statin.
Using data from the PROSPER trial, Ian Ford and colleagues investigate whether reduced glomerular filtration rate is associated with cardiovascular and mortality risk among elderly people.
Editors' Summary
Background.
Cardiovascular disease (CVD)—disease that affects the heart and/or the blood vessels—is a common cause of death in developed countries. In the USA, for example, the single leading cause of death is coronary heart disease, a CVD in which narrowing of the heart's blood vessels slows or stops the blood supply to the heart and eventually causes a heart attack. Other types of CVD include stroke (in which narrowing of the blood vessels interrupts the brain's blood supply) and heart failure (a condition in which the heart can no longer pump enough blood to the rest of the body). Many factors increase the risk of developing CVD, including high blood pressure (hypertension), high blood cholesterol, having diabetes, smoking, and being overweight. Tools such as the “Framingham risk calculator” assess an individual's overall CVD risk by taking these and other risk factors into account. CVD risk can be minimized by taking drugs to reduce blood pressure or cholesterol levels (for example, pravastatin) and by making lifestyle changes.
Why Was This Study Done?
Another potential risk factor for CVD is impaired kidney (renal) function. In healthy people, the kidneys filter waste products and excess fluid out of the blood. A reduced “estimated glomerular filtration rate” (eGFR), which indicates impaired renal function, is associated with increased CVD in young and middle-aged people and increased all-cause and cardiovascular death in people who have vascular disease. But is reduced eGFR also associated with CVD and death in older people? If it is, it would be worth encouraging elderly people with reduced eGFR to avoid other CVD risk factors. In this study, the researchers determine the predictive value of eGFR for all-cause and vascular mortality (deaths caused by CVD) and for incident vascular events (a first heart attack, stroke, or heart failure) using data from the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER). This clinical trial examined pravastatin's effects on CVD development among 70–82 year olds with pre-existing vascular disease or an increased risk of CVD because of smoking, hypertension, or diabetes.
What Did the Researchers Do and Find?
The trial participants were divided into four groups based on their eGFR at the start of the study. The researchers then investigated the association between baseline CVD risk factors and baseline eGFR and between baseline eGFR and vascular events and deaths that occurred during the 3-year study. Several established CVD risk factors were associated with a reduced eGFR after allowing for other risk factors. In addition, people with a low eGFR (between 20 and 40 units) were twice as likely to die from any cause as people with an eGFR above 60 units (the normal eGFR for a young person is 100 units; eGFR decreases with age) and more than three times as likely to have nonfatal coronary heart disease or heart failure. A low eGFR also increased the risk of vascular mortality, other noncancer deaths, and fatal coronary heart disease and heart failure. Finally, pravastatin treatment reduced coronary heart disease deaths and nonfatal heart attacks most effectively among participants with the greatest degree of eGFR impairment.
What Do These Findings Mean?
These findings suggest that, in elderly people, impaired renal function is associated with levels of established CVD risk factors that increase the risk of vascular disease. They also suggest that impaired kidney function increases the risk of all-cause mortality, fatal vascular events, and fatal and nonfatal coronary heat disease and heart failure. Because the study participants were carefully chosen for inclusion in PROSPER, these findings may not be generalizable to all elderly people with vascular disease or vascular disease risk factors. Nevertheless, increased efforts should probably be made to encourage elderly people with reduced eGFR and other vascular risk factors to make lifestyle changes to reduce their overall CVD risk. Finally, although the effect of statins in elderly patients with renal dysfunction needs to be examined further, these findings suggest that this group of patients should benefit at least as much from statins as elderly patients with healthy kidneys.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000016.
The MedlinePlus Encyclopedia has pages on coronary heart disease, stroke, and heart failure (in English and Spanish)
MedlinePlus provides links to many other sources of information on heart disease, vascular disease, and stroke (in English and Spanish)
The US National Institute of Diabetes and Digestive and Kidney Diseases provides information on how the kidneys work and what can go wrong with them, including a list of links to further information about kidney disease
The American Heart Association provides information on all aspects of cardiovascular disease for patients, caregivers, and professionals (in several languages)
More information about PROSPER is available on the Web site of the Vascular Biochemistry Department of the University of Glasgow
doi:10.1371/journal.pmed.1000016
PMCID: PMC2628400  PMID: 19166266
8.  CKD and Cardiovascular Disease in the Atherosclerosis Risk in Communities (ARIC) Study: Interactions With Age, Sex, and Race 
Background
Estimated glomerular filtration rate (eGFR) and albuminuria are central for diagnosis, staging, and risk evaluation in chronic kidney disease (CKD). Universal thresholds regardless of age, sex, and race are recommended, but relatively little is known about how these demographic factors alter the relationship of eGFR and albuminuria to cardiovascular outcomes.
Study Design
Observational cohort study.
Setting & Participants
11,060 whites and blacks aged 52–75 years in the Atherosclerosis Risk in Communities (ARIC) Study with median follow-up of 11.2 years.
Predictors
eGFR by the CKD Epidemiology Collaboration (CKD-EPI) creatinine equation (reference, 95 ml/min/1.73 m2) and urinary albumin-creatinine ratio (ACR) (reference, at 5 mg/g).
Outcomes
Cardiovascular events (coronary disease, stroke, and heart failure) and all-cause mortality.
Measurements
Adjusted HRs associated with eGFR and ACR in subgroups according to age, sex and race.
Results
Cardiovascular risk significantly increased at eGFR <70 ml/min/1.73 m2 in all subgroups according to age (< 65 vs. ≥65 years), sex, and race (P for interaction >0.2 for these subgroups; e.g., at eGFR 30 ml/min/1.73 m2, the adjusted HR was 2.19 [95% CI, 1.10–4.35] at age 52–64 years vs. 2.23 [95% CI, 1.33–3.72] at age 65–75 years). Results were similar for mortality. Log(ACR) was linearly associated with cardiovascular risk without threshold effects in all subgroups, with some quantitative interactions. HRs according to ACR tended to be lower in men vs. women (e.g., at ACR 40 mg/g, 1.18 [95% CI, 0.98–1.41] vs. 1.77 [95% CI, 1.45–2.15]) and in older vs. younger population (1.24 [95% CI, 1.04–1.49] vs. 1.73 [95% CI, 1.42–2.12]) (P for interaction <0.01 for sex and age). Less evident interactions were observed for mortality.
Limitations
Single measurement of eGFR with creatinine and ACR and relatively narrow age range.
Conclusions
The associations of eGFR and ACR with cardiovascular events were largely similar, with some quantitative interactions, among age, sex, and racial subgroups, generally supporting universal thresholds of GFR and ACR for CKD definition/staging.
doi:10.1053/j.ajkd.2013.04.010
PMCID: PMC3783539  PMID: 23769137
Chronic kidney disease; estimated glomerular filtration rate (eGFR); urinary albumin-creatinine ratio (ACR); cardiovascular disease; all-cause mortality
9.  The prevalence and predictive value of dipstick urine protein in HIV-positive persons in Europe 
Journal of the International AIDS Society  2014;17(4Suppl 3):19561.
Introduction
Proteinuria (PTU) is an important marker for the development and progression of renal disease, cardiovascular disease and death, but there is limited information about the prevalence and factors associated with confirmed PTU in predominantly white European HIV+ persons, especially in those with an estimated glomerular filtration rate (eGFR) of 60 mL/min/1.73 m2.
Patients and methods
Baseline was defined as the first of two consecutive dipstick urine protein (DPU) measurements during prospective follow-up >1/6/2011 (when systematic data collection began). PTU was defined as two consecutive DUP >1+ (>30 mg/dL) >3 months apart; persons with eGFR <60 at either DPU measurement were excluded. Logistic regression investigated factors associated with PTU.
Results
A total of 1,640 persons were included, participants were mainly white (n=1,517, 92.5%), male (n=1296, 79.0%) and men having sex with men (n=809; 49.3%). Median age at baseline was 45 (IQR 37–52 years), and CD4 was 570 (IQR 406–760/mm3). The median baseline date was 2/12 (IQR 11/11–6/12), and median eGFR was 99 (IQR 88–109 mL/min/1.73 m2). Sixty-nine persons had PTU (4.2%, 95% CI 3.2–4.7%). Persons with diabetes had increased odds of PTU, as were those with a prior non-AIDS [1] or AIDS event and those with prior exposure to indinavir. Among females, those with a normal eGFR (>90) and those with prior abacavir use had lower odds of PTU (Figure 1).
There was no significant association between past or current use of tenofovir, lopinavir, atazanvir (boosted or unboosted) or any other boosted PI and PTU (p>0.2). During 688.2 person-years of follow up (PYFU), three persons developed chronic kidney disease (CKD; confirmed [>3 months apart] eGFR<60); 2/685 (0.3%) without PTU and 1/38 (2.8%) with PTU (p=0.032). The crude incidence of CKD in those with baseline PTU and eGFR>60 was almost 10 times higher than in those without baseline PTU and eGFR>60 (rate ratio 9.61; 95% CI 0.87–105.9, p=0.065).
Conclusions
One in 25 persons with eGFR>60 had confirmed proteinuria at baseline. Factors associated with PTU were similar to those associated with CKD. The lack of association with antiretrovirals, particularly tenofovir, may be due to the cross-sectional design of this study, and additional follow-up is required to address progression to PTU in those without PTU at baseline. It may also suggest other markers are needed to capture the deteriorating renal function associated with antiretrovirals may be needed at higher eGFRs. Our findings suggest PTU is an early marker for impaired renal function.
doi:10.7448/IAS.17.4.19561
PMCID: PMC4224881  PMID: 25394068
10.  Predictivity of survival according to different equations for estimating renal function in community-dwelling elderly subjects 
Nephrology Dialysis Transplantation  2008;24(4):1197-1205.
Background. Detection of subjects with early chronic kidney disease (CKD) is important because some will progress up to stage 5 CKD, and most are at high risk of cardiovascular morbidity and mortality. While validity and precision of estimated glomerular filtration rate (eGFR) equations in tracking true GFR have been repeatedly investigated, their prognostic performance for mortality has not been hitherto compared. This is especially relevant in an elderly population in whom the risk of death is far more common than progression.
Methods. We analysed data of participants in the InCHIANTI study, a community-based cohort study of older adults. Twenty-four-hour creatinine clearance (Ccr), Cockcroft–Gault (C-G) and Modification of Diet in Renal Disease (MDRD)-derived equations (six and four input variables) were calculated at enrolment (1998–2000), and all-cause mortality and cardiovascular mortality were prospectively ascertained by Cox regression over a 6-year follow-up.
Results. Of the 1270 participants, 942 (mean age 75 years) had complete data for this study. The mean renal function ranged from 77 ml/min/1.73 m2 by Ccr to 64 ml/min/1.73 m2 by C-G. Comparisons among equations using K/DOQI staging highlight relevant mismatches, with a prevalence of CKD ranging from 22% (MDRD-4) to 40% (C-G). Reduced renal function was a strong independent predictor of death. In a Cox model–-adjusted for demographics, physical activity, comorbidities, proteinuria and inflammatory parameters—participants with Ccr 60–90 ml/min/1.73 m2 and Ccr <60 ml/min/1.73 m2 were, respectively, 1.70 (95% CI: 1.02–2.83) and 1.91 (95% CI: 1.11–3.29) times more likely to die over the follow-up compared to those with Ccr >90 ml/min/1.73 m2. For the C-G, the group with values <60 ml/min/1.73 m2 had a significant higher all-cause mortality compared to those with values >90 ml/min/1.73 m2 (HR 2.59, 95% CI: 1.13–5.91). The classification based on the MDRD formulae did not provide any significant prognostic information. The adjusted risk of all-cause mortality followed a similar pattern when Ccr and estimating equations were introduced as continuous variables or dichotomized as higher or lower than 60 ml/min. C-G was the best prognostic indicator of cardiovascular mortality. Possibly, Ccr and C-G are better prognostic indicators than MDRD-derived equations because they incorporate a stronger effect of age.
Conclusions. In a South-European elderly population, the prevalence of CKD is high and varies widely according to the method adopted to estimate GFR. Researchers and clinicians who want to capture the prognostic information on mortality related to kidney function should use the Ccr or C-G formula and not MDRD equations. These results highlight the importance of strategies for early detection and clinical management of CKD in elderly subjects.
doi:10.1093/ndt/gfn594
PMCID: PMC2721425  PMID: 18988669
Cockcroft–Gault formula; elderly; MDRD equations; mortality; population-based study
11.  CKD classification based on estimated GFR over three years and subsequent cardiac and mortality outcomes: a cohort study 
BMC Nephrology  2009;10:26.
Background
It is unknown whether defining chronic kidney disease (CKD) based on one versus two estimated glomerular filtration rate (eGFR) assessments changes the prognostic importance of reduced eGFR in a community-based population.
Methods
Participants in the Atherosclerosis Risk in Communities Study and the Cardiovascular Health Study were classified into 4 groups based on two eGFR assessments separated by 35.3 ± 2.5 months: sustained eGFR < 60 mL/min per 1.73 m2 (1 mL/sec per 1.73 m2); eGFR increase (change from below to above 60); eGFR decline (change from above to below 60); and eGFR persistently ≥60. Outcomes assessed in stratified multivariable Cox models included cardiac events and a composite of cardiac events, stroke, and mortality.
Results
There were 891 (4.9%) participants with sustained eGFR < 60, 278 (1.5%) with eGFR increase, 972 (5.4%) with eGFR decline, and 15,925 (88.2%) with sustained eGFR > 60. Participants with eGFR sustained < 60 were at highest risk of cardiac and composite events [HR = 1.38 (1.15, 1.65) and 1.58 (1.41, 1.77)], respectively, followed by eGFR decline [HR = 1.20 (1.00, 1.45) and 1.32 (1.17, 1.49)]. Individuals with eGFR increase trended toward increased cardiac risk [HR = 1.25 (0.88, 1.77)] and did not significantly differ from eGFR decline for any outcome. Results were similar when estimating GFR with the CKD-EPI equation.
Conclusion
Individuals with persistently reduced eGFR are at highest risk of cardiovascular outcomes and mortality, while individuals with an eGFR < 60 mL/min per 1.73 m2 at any time are at intermediate risk. Use of even a single measurement of eGFR to classify CKD in a community population appears to have prognostic value.
doi:10.1186/1471-2369-10-26
PMCID: PMC2760546  PMID: 19761597
12.  Risk Factors for ESRD in HIV-Infected Individuals: Traditional and HIV-Related Factors 
Background
Despite improvements in survival with HIV infection, kidney disease remains an important complication. Few studies have evaluated risk factors associated with development of end-stage renal disease (ESRD) in HIV-infected individuals. We sought to identify traditional and HIV-related risk factors for ESRD in HIV-infected individuals, and to compare ESRD risk by eGFR and proteinuria levels.
Study design
Retrospective cohort study.
Setting and Participants
22,156 HIV-infected veterans without preexisting ESRD receiving healthcare in the Veterans’ Affairs medical system between 1996 and 2004.
Predictors
Hypertension, diabetes, cardiovascular disease, hypoalbuminemia (serum albumin<3.5mg/dL), CD4 lymphocyte count, HIV viral load, hepatitis C virus coinfection, proteinuria, and estimated glomerular filtration rate (eGFR) were identified using the Veterans’ Affairs electronic record system.
Outcomes
ESRD was ascertained by the United States Renal Data System.
Results
366 cases of ESRD occurred, corresponding to 3 cases per 1,000 person-years. Hypertension (HR, 1.9; 95% CI, 1.5–2.4), diabetes (HR, 1.7; 95% CI, 1.3–2.2), and cardiovascular disease (HR, 2.2; 95% CI, 1.7–2.7) were independently associated with ESRD risk in multivariate-adjusted models, as were CD4 lymphocyte count <200 cells/mm3 (HR, 1.5; 95% CI, 1.2–2.0), HIV viral load ≥30,000 copies/mL (HR, 2.0; 95% CI, 1.5–2.8), hepatitis C virus coinfection (HR, 1.9; 95% CI, 1.5–2.4), and hypoalbuminemia (HR, 2.1; 95% CI, 1.8–2.5). Compared to persons without chronic kidney disease (CKD), defined as eGFR>60mg/min/1.73m2 and no proteinuria, lower eGFR and higher proteinuria categories were jointly associated with exponentially higher ESRD rates, ranging from 6.6 per 1000 person-years for persons with proteinuria 30–100 mg/dL and eGFR>60ml/min/1.73m2, to 193 per 1000 person-years for persons with proteinuria ≥300mg/dL and eGFR<30ml/min/1.73m2.
Limitations
Results may not be generalizable to female and nonveteran populations.
Conclusions
In HIV-infected persons, ESRD risk appears attributable to a combination of traditional and HIV-related risk factors for kidney disease. Combining eGFR and proteinuria for CKD staging is most effective for stratifying risk for ESRD.
doi:10.1053/j.ajkd.2011.10.050
PMCID: PMC3324595  PMID: 22206742
End-stage renal disease; HIV; chronic kidney disease; risk factors
13.  Chronic Kidney Disease and Outcomes in Heart Failure With Preserved Versus Reduced Ejection Fraction 
Background
There is scant evidence on the effect that chronic kidney disease (CKD) confers on clinically meaningful outcomes among patients with heart failure with preserved left ventricular ejection fraction (HF-PEF).
Methods and Results
We identified a community-based cohort of patients with HF. Electronic medical record data were used to divide into HF-PEF and reduced left ventricular EF on the basis of quantitative and qualitative estimates. Level of CKD was assessed by estimated glomerular filtration rate (eGFR) and by dipstick proteinuria. We followed patients for a median of 22.1 months for outcomes of death and hospitalization (HF-specific and all-cause). Multivariable Cox regression estimated the adjusted relative-risk of outcomes by level of CKD, separately for HF-PEF and HF with reduced left ventricular EF. We identified 14 579 patients with HF-PEF and 9762 with HF with reduced left ventricular EF. When compared with patients with eGFR between 60 and 89 mL/min per 1.73 m2, lower eGFR was associated with an independent graded increased risk of death and hospitalization. For example, among patients with HF-PEF, the risk of death was nearly double for eGFR 15 to 29 mL/min per 1.73 m2 and 7× higher for eGFR<15 mL/min per 1.73 m2, with similar findings in those with HF with reduced left ventricular EF.
Conclusions
CKD is common and an important independent predictor of death and hospitalization in adults with HF across the spectrum of left ventricular systolic function. Our study highlights the need to develop new and effective interventions for the growing number of patients with HF complicated by CKD.
doi:10.1161/CIRCOUTCOMES.113.000221
PMCID: PMC3904800  PMID: 23685625
chronic kidney disease; heart failure; hospitalization; mortality
14.  Association of Hepatitis C Virus Infection With Prevalence and Development of Kidney Disease 
Background
Hepatitis C and CKD are both highly prevalent diseases in the United States. Data has demonstrated that hepatitis C may be causally linked to some glomerular diseases, and that patients who are positive for hepatitis C have increased risk for albuminuria.
Study Design
To determine if hepatitis C infection is associated with increased likelihood of CKD, we performed retrospective cross-sectional and longitudinal analyses of a large clinical database.
Setting and Participants
Data on a study population of 13,139 African American and white patients tested for hepatitis C between 1994 and 2004 was extracted from a computerized database from a clinical population of an urban hospital and affiliated clinics.
Predictor
Hepatitis C by ELISA.
Outcome
In cross-sectional analysis, CKD was defined as a minimum estimated GFR (eGFR) value < 60 ml/min/1.73 m2, using the 4 variable MDRD Study equation, or proteinuria. In longitudinal analysis, CKD was defined as eGFR < 60 ml/min/1.73 m2.
Measurements
Potential confounders investigated included sex, age, race, HIV status, chronic hypertension, diabetes, and other laboratory abnormalities.
Results
A total of 3938 patients (30.0 %) were positive for hepatitis C, and 2549 (19.4%) had CKD. Of those with CKD, 1999 (78.4%) had eGFR < 60 ml/min/1.73 m2, 186 (7.3%) had proteinuria, and 364(14.3%) had both. In cross-sectional analysis, after controlling for diabetes, hypertension, age, alanine serotransferase (AST), and HIV status, patients who tested positive for hepatitis C had a decreased risk of CKD (OR=0.69, 95% CI 0.62–0.77). A total of 7,038 subjects without CKD were followed for a median of 3.5 years. Of these, 2243 (31.8%) were hepatitis C positive at onset of follow-up. In longitudinal analysis, after adjustment for age, baseline eGFR, diabetes, hypertension, AST and HIV, the HR (95% CI) for development of CKD compared to those who were hepatitis C negative was 1.024 (0.908 1.156).
Limitations
Retrospective design, clinical database with missing values, different hepatitis C assays used over the study time period, limited data on proteinuria.
Conclusions
Our results do not support the hypothesis that infection with the hepatitis C virus per se is associated with an increased risk of having or developing CKD.
doi:10.1053/j.ajkd.2008.03.009
PMCID: PMC2478742  PMID: 18440680
CKD; hepatitis C; proteinuria; GFR
15.  Baseline Kidney Function as Predictor of Mortality and Kidney Disease Progression in HIV-Positive Patients 
Background
Chronic kidney disease (CKD) is associated with increased all-cause mortality and kidney disease progression. Decreased kidney function at baseline may identify human immunodeficiency virus (HIV)-positive patients at increased risk of death and kidney disease progression.
Study Design
Observational cohort study.
Setting & Participants
7 large HIV cohorts in the United Kingdom with kidney function data available for 20,132 patients.
Predictor
Baseline estimated glomerular filtration rate (eGFR).
Outcomes
Death and progression to stages 4-5 CKD (eGFR <30 mL/min/1.73 m2 for >3 months) in Cox proportional hazards and competing-risk regression models.
Results
Median age at baseline was 34 (25th-75th percentile, 30-40) years, median CD4 cell count was 350 (25th-75th percentile, 208-520) cells/μL, and median eGFR was 100 (25th-75th percentile, 87-112) mL/min/1.73 m2. Patients were followed up for a median of 5.3 (25th-75th percentile, 2.0-8.9) years, during which 1,820 died and 56 progressed to stages 4-5 CKD. A U-shaped relationship between baseline eGFR and mortality was observed. After adjustment for potential confounders, eGFRs <45 and >105 mL/min/1.73 m2 remained associated significantly with increased risk of death. Baseline eGFR <90 mL/min/1.73 m2 was associated with increased risk of kidney disease progression, with the highest incidence rates of stages 4-5 CKD (>3 events/100 person-years) observed in black patients with eGFR of 30-59 mL/min/1.73 m2 and those of white/other ethnicity with eGFR of 30-44 mL/min/1.73 m2.
Limitations
The relatively small numbers of patients with decreased eGFR at baseline and low rates of progression to stages 4-5 CKD and lack of data for diabetes, hypertension, and proteinuria.
Conclusions
Although stages 4-5 CKD were uncommon in this cohort, baseline eGFR allowed the identification of patients at increased risk of death and at greatest risk of kidney disease progression.
doi:10.1053/j.ajkd.2012.03.006
PMCID: PMC3657190  PMID: 22521282
Estimated glomerular filtration rate (eGFR); Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI); human immunodeficiency virus (HIV); chronic kidney disease; mortality; competing risk
16.  Age Is the Strongest Effector for the Relationship between Estimated Glomerular Filtration Rate and Coronary Artery Calcification in Apparently Healthy Korean Adults 
Endocrinology and Metabolism  2014;29(3):312-319.
Background
Chronic kidney disease (CKD) is considered one of the most common risk factors for cardiovascular disease. Coronary artery calcification (CAC) is a potential mechanism that explains the association between renal function and cardiovascular mortality. We aimed to evaluate the association between renal function and CAC in apparently healthy Korean subjects.
Methods
A total of 23,617 participants in a health-screening program at Kangbuk Samsung Hospital were included in the study. Estimated glomerular filtration rate (eGFR) was assessed using the Cockcroft-Gault equation. Coronary artery calcium score (CACS) was measured via multidetector computed tomography. Subjects were divided into three groups according to the CKD Staging system with eGFR grade: stage 1, eGFR ≥90 mL/min/1.73 m2; stage 2, eGFR 60 to 89 mL/min/1.73 m2; and stage 3, eGFR 30 to 59 mL/min/1.73 m2.
Results
The mean age of the participants was 41.4 years and the mean eGFR was 103.6±21.7 mL/min/1.73 m2. Hypertension and diabetes were noted in 43.7% and 5.5% of the participants, respectively. eGFR showed a weakly negative but significant association with CACS in bivariate correlation analysis (r=-0.076, P<0.01). Mean CACS significantly increased from CKD stage 1 to 3. The proportion of subjects who had CAC significantly increased from CKD stage 1 to 3. Although the odds ratio for CAC significantly increased from stage 1 to 3 after adjustment for confounding factors, this significance was reversed when age was included in the model.
Conclusion
In early CKD, renal function negatively correlated with the degree of CAC in Korean subjects. Age was the strongest effector for this association.
doi:10.3803/EnM.2014.29.3.312
PMCID: PMC4192818  PMID: 25309790
Coronary artery calcification; Glomerular filtration rate; Renal insufficiency, chronic
17.  Systolic Blood Pressure and Mortality Among Older, Community-Dwelling Adults With CKD 
Background
Chronic kidney disease (CKD) is an increasingly common condition, especially among older adults. CKD manifests differently in older versus younger patients, with a risk of death that far outweighs the risk of CKD progressing to the point that dialysis is required. Current CKD guidelines recommend a blood pressure target of <130/80 mmHg for all CKD patients, but it is unknown how lower versus higher baseline blood pressures may affect older adults with CKD.
Study Design
Retrospective cohort study
Setting and Participants
Older patients (age 75+ years) with CKD (eGFR <60 ml/min/1.73 m2) in a community-based health maintenance organization.
Predictor
Baseline systolic blood pressure (SBP) <130, 130-160 (reference group), and >160 mm Hg.
Outcomes
Subjects followed for 5 years to examine rates of mortality (primary outcome) and cardiovascular disease hospitalizations (secondary outcome).
Results
At baseline, 3099 subjects (38.5%) had SBP <130 mm Hg, 3772 (46.9%) had SBP 131-160 mm Hg, and 1171 (14.6%) had SBP >160 mm Hg. A total of 3734 (46.4%) died and 2881 (35.8%) were hospitalized. Adjusted hazard ratios (HR) and 95% confidence intervals (CI) for mortality in SBP <130 and >160 mm Hg group were 1.22 (1.11-1.34) and 0.99 (0.89-1.10), respectively. Adjusted HR (CI) for cardiovascular hospitalization in these groups were 1.10 (1.09-1.45) and 1.26 (1.09-1.45), respectively.
Limitations
While causality should not be implied from this retrospective analysis, the results from this study can generate hypotheses for future randomized controlled trials to investigate the relationship between blood pressure and outcomes in older CKD patients.
Conclusions
Our study suggests that lower baseline SBP (≤130 mmHg) may predict poorer outcomes in terms of both mortality and cardiovascular hospitalizations among older adults with CKD. Conversely, higher baseline SBP (>160 mmHg) may predict increased risk of cardiovascular hospitalizations but does not predict mortality. Clinical trials are required to test this hypothesis.
doi:10.1053/j.ajkd.2010.07.018
PMCID: PMC2997762  PMID: 20961677
aging; elderly; chronic kidney disease; blood pressure
18.  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
19.  Impact of chronic kidney disease on the prevalence of cardiovascular disease in patients with type 2 diabetes in Spain: PERCEDIME2 study 
BMC Nephrology  2014;15(1):150.
Background
The presence of chronic kidney disease (CKD) in type 2 diabetes mellitus (T2DM) increases the risk of cardiovascular disease (CVD) regardless of the presence of traditional cardiovascular risk factors. There is controversy about the impact of each of the manifestations of CKD on the prevalence of CVD, whether it is greater with decreased estimated glomerular filtration rate (eGFR) or increased urine albumin creatinine ratio (UACR).
Methods
This study is a national cross-sectional study performed in primary care consults. We selected participants of both sexes who were aged 40 years or older, had been diagnosed with T2DM and had complete information on the study variables recorded in their medical records. The participants were classified according to eGFR : ≥ 60; 45–59; 30–44; <30 mL/min/1.73 m2 and UACR : < 30; 30–299; ≥300 mg/gr. The results were adjusted to compare the prevalence of CVD across all categories.
Results
A total of 1141 participants were included. Compared to participants with eGFR > 60 mL/min/1.73 m2 those with eGFR between 30–44 mL/min/m2, (OR = 2.3; 95% CI, 1.4-3.9); and eGFR < 30 mL/min/1.73 m2 (OR = 4.1 95% CI 1.6-10.2) showed increased likelihood of having CVD. Participants with UACR ≥ 30 mg/g compared to participants with UACR < 30 mg/g increased significantly the likelihood of having CVD, especially with UACR above 300 mg/g, (OR = 1.6; 95% CI 1.1-2.4 for UACR = 30–299 mg/g; OR = 3.9; CI 1.6-9.5 for UACR ≥ 300 mg/g).
Conclusion
The decrease in eGFR and increase in UACR are independent risk factors that increase the prevalence of CVD in participants with T2DM and these factors are independent of each other and of other known cardiovascular risk factors. In our study the impact of mild decreased eGFR in T2DM on CVD was lower than the impact of increased UACR. It is necessary to determine not only UACR but also eGFR for all patients with T2DM, both at the time of diagnosis and during follow-up, to identify those patients at high risk of cardiovascular complications.
doi:10.1186/1471-2369-15-150
PMCID: PMC4181296  PMID: 25227555
Type 2 diabetes; Chronic kidney disease; Cardiovascular disease
20.  Serum Carboxymethyl-lysine, a Dominant Advanced Glycation End Product, is Associated with Chronic Kidney Disease: the Baltimore Longitudinal Study of Aging 
Objective:
Advanced glycation end products (AGEs) are modifiable risk factors for renal disease that have been primarily studied in persons with diabetes or end-stage renal disease. The objective was to characterize the relationship between AGEs and renal function in community-dwelling adults.
Design:
Serum L-carboxymethyl-lysine (CML), a dominant AGE, was compared with renal function in a cross-sectional analysis.
Setting:
The Baltimore Longitudinal Study of Aging (BLSA) in Baltimore, Maryland.
Patients or Other Participants:
Community-dwelling men and women, aged 26-93 years, seen in a regular BLSA follow-up visit between 2002 and 2007.
Main outcome measure:
Chronic kidney disease (CKD), ≥stage 3 of National Kidney Foundation classification (estimated glomerular filtration rate [eGFR] <60 mL/min/1.73 m2), and eGFR.
Results:
Of 750 adults, 121 (16.1%) had CKD. Serum CML was associated with CKD (Odds Ratio [O.R.] expressed per 1 Standard Deviation [S.D.], 1.37, 95% Confidence Interval [C.I.] 1.11-1.67, P = 0.003) in a multivariate logistic regression model adjusting for age, race, smoking, and chronic diseases. Serum CML was associated with eGFR (mL/min/1.73 m2) (beta = −2.21, standard error = 0.57, P = 0.0001) in multivariate linear regression model adjusting for age, race, smoking, and chronic diseases. After excluding patients with diabetes, serum CML was associated with CKD (O.R. per 1 S.D., 1.38, 95% C.I. 1.12-1.70, P = 0.003) and eGFR (beta = −2.09, standard error = 0.59, P = 0.0005), adjusting for the same covariates.
Conclusion:
Serum CML, a dominant AGE, is independently associated with CKD and eGFR.
doi:10.1053/j.jrn.2009.08.001
PMCID: PMC2829356  PMID: 19853477
advanced glycation end products; aging; chronic kidney disease; glomerular filtration rate
21.  Chronic Kidney Disease Identification in a High-Risk Urban Population: Does Automated eGFR Reporting Make a Difference? 
Whether automated estimated glomerular filtration rate (eGFR) reporting for patients is associated with improved provider recognition of chronic kidney disease (CKD), as measured by diagnostic coding of CKD in those with laboratory evidence of the disease, has not been explored in a poor, ethnically diverse, high-risk urban patient population. A retrospective cohort of 237 adult patients (≥20 years) with incident CKD (≥1 eGFR ≥60 ml/min/1.73 m2, followed by ≥2 eGFRs <60 ml/min/1.73 m2 ≥3 months apart)—pre- or postautomated eGFR reporting—was identified within the San Francisco Department of Public Health Community Health Network (January 2005–July 2009). Patients were considered coded if any ICD-9-CM diagnostic codes for CKD (585.x), other kidney disease (580.x–581.x, 586.x), or diabetes (250.4) or hypertension (403.x, 404.x) CKD were present in the medical record within 6 months of incident CKD. Multivariable logistic regression was used to obtain adjusted odds ratios (ORs) for CKD coding. We found that, pre-eGFR reporting, 42.5 % of incident CKD patients were coded for CKD. Female gender, increased age, and non-Black race were associated with lower serum creatinine and lower prevalence of coding but comparable eGFR. Prevalence of coding was not statistically significantly higher overall (49.6 %, P = 0.27) or in subgroups after the institution of automated eGFR reporting. However, gaps in coding by age and gender were narrowed post-eGFR, even after adjustment for sociodemographic and clinical characteristics: 47.9 % of those <65 and 30.3 % of those ≥65 were coded pre-eGFR, compared to 49.0 % and 52.0 % post-eGFR (OR = 0.43 and 1.16); similarly, 53.2 % of males and 25.4 % of females were coded pre-eGFR compared to 52.8 % and 44.0 % post-eGFR (OR 0.28 vs. 0.64). Blacks were more likely to be coded in the post-eGFR period: OR = 1.08 and 1.43 (Pinteraction > 0.05). Automated eGFR reporting may help improve CKD recognition, but it is not sufficient to resolve underidentification of CKD by safety net providers.
doi:10.1007/s11524-012-9726-2
PMCID: PMC3531349  PMID: 22684427
Chronic kidney disease; Diagnostic coding; Estimated glomerular filtration rate; Female; African American
22.  Glomerular Filtration Rate and Proteinuria: Association with Mortality and Renal Progression in a Prospective Cohort of a Community-Based Elderly Population 
PLoS ONE  2014;9(4):e94120.
Limited prospective data are available on the importance of estimated glomerular filtration rate (GFR) and proteinuria in the prediction of all-cause mortality (ACM) in community-based elderly populations. We examined the relationship between GFR or proteinuria and ACM in 949 randomly selected community-dwelling elderly subjects (aged ≥65 years) over a 5-year period. A spot urine sample was used to measure proteinuria by the dipstick test, and GFR was estimated using the chronic kidney disease-epidemiology collaboration (CKD-EPI) equation. Information about mortality and causes of death was collected by direct enquiry with the subjects and from the national mortality data. Compared to subjects without proteinuria, those with proteinuria of grade ≥1+ had a 1.725-fold (1.134–2.625) higher risk of ACM. Compared to subjects with GFR ≥90 ml/min/1.73 m2, those with GFR<45 ml/min/1.73 m2 had a 2.357 -fold (1.170–4.750) higher risk for ACM. Among the 403 subjects included in the analysis of renal progression, the annual rate of GFR change during follow-up period was −0.52±2.35 ml/min/1.73 m2/year. The renal progression rate was 7.315-fold (1.841–29.071) higher in subjects with GFR<60 ml/min/1.73 m2 than in those with GFR ≥60 ml/min/1.73 m2. Among a community-dwelling elderly Korean population, decreased GFR of <45 ml/min/1.73 m2 and proteinuria were independent risk factors for ACM.
doi:10.1371/journal.pone.0094120
PMCID: PMC3978007  PMID: 24709896
23.  Association of apolipoprotein A1 and B with kidney function and chronic kidney disease in two multiethnic population samples 
Nephrology Dialysis Transplantation  2012;27(7):2839-2847.
lipoprotein risk factors for atherosclerosis, i.e., increased LDL cholesterol, increased triglycerides and decreased HDL cholesterol, also are associated with progression of loss of kidney function...Goek and coworkers describe the association of the apoliproteins A1 and B and eGFR in two large cohorts derived from the general polulation [the NHANES III (N=7,023) and the ARIC study (n=10,292)]. The results were similar in both cohorts...
Background
Circulating lipoproteins and their protein constituents, apolipoproteins, are risk factors for chronic kidney disease (CKD). The associations between apolipoprotein A1, apolipoprotein B and their ratio with glomerular filtration rate estimated from the new CKD Epidemiology Collaboration (CKD-EPI) equation (eGFR) are not well studied in the general population.
Methods
Associations between apolipoprotein A1, B and their ratio with the outcomes of eGFR, CKD (eGFR <60 mL/min/1.73m2) and albuminuria were examined in the Atherosclerosis Risk in Communities study (ARIC, n = 10 292, 1996–98) and the Third National Health and Nutrition Examination Survey (NHANES III, n = 7023, 1988–91). Cross-sectional multivariable-adjusted analyses were performed using linear and logistic regression. Prospective analyses related baseline apolipoprotein levels to subsequent CKD incidence over 10 years using the ARIC Carotid MRI follow-up cohort (n = 1659).
Results
Higher apolipoprotein A1 quartiles were associated with a lower prevalence of CKD [Q4 versus Q1: odds ratio (OR) 0.73, P-trend = 0.02 in ARIC; Q4 versus Q1: OR 0.53, P-trend <0.01 in NHANES III] as well as with higher eGFR (P-trend <0.01 in ARIC and NHANES III). No consistent significant associations were found for apolipoprotein B in either study. The apolipoprotein B/A1 ratio was significantly associated with eGFR across quartiles in both studies (P-trend <0.01) and with CKD in ARIC (Q4 versus Q1: OR 1.23, P-trend = 0.01). Prospectively, there were trends for the association of apolipoproteins with incident CKD [Q4 versus Q1: incidence rate ratio (IRR) = 0.68 for apolipoprotein A1, P-trend = 0.1; Q4 versus Q1: IRR = 1.35 for apolipoprotein B, P-trend = 0.2]. Associations were not systematically stronger when comparing traditional lipids (total cholesterol, low-density lipoprotein or high-density lipoprotein) to apolipoproteins.
Conclusions
Higher serum apolipoprotein A1 was associated with lower prevalence of CKD and higher eGFR estimated by the CKD-EPI equation in two large multiethnic population-based samples. While apolipoprotein B showed no consistent associations, a higher apolipoprotein B/A1 ratio was significantly associated with lower eGFR in both studies. The direction and magnitude of the longitudinal associations between apolipoproteins and CKD incidence were overall similar to those observed cross-sectionally. No consistent differences became apparent between traditional lipids and apolipoproteins.
doi:10.1093/ndt/gfr795
PMCID: PMC3471548  PMID: 22287661
apolipoprotein; ARIC; chronic kidney disease; epidemiology; NHANES
24.  Metabolic Syndrome and Chronic Kidney Disease in an Adult Korean Population: Results from the Korean National Health Screening 
PLoS ONE  2014;9(5):e93795.
Background
This study was aimed to examine the prevalence of metabolic syndrome (MS) and chronic kidney disease (CKD), and the association between MS and its components with CKD in Korea.
Methods
We excluded diabetes to appreciate the real impact of MS and performed a cross-sectional study using the general health screening data of 10,253,085 (48.86±13.83 years, men 56.18%) participants (age, ≥20 years) from the Korean National Health Screening 2011. CKD was defined as dipstick proteinuria ≥1 or an estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m2.
Results
The prevalence of CKD was 6.15% (men, 5.37%; women, 7.15%). Further, 22.25% study population had MS (abdominal obesity, 27.98%; hypertriglyceridemia, 30.09%; low high-density cholesterol levels, 19.74%; high blood pressure, 43.45%; and high fasting glucose levels, 30.44%). Multivariate-adjusted analysis indicated that proteinuria risk increased in participants with MS (odds ratio [OR] 1.884, 95% confidence interval [CI] 1.867–1.902, P<0.001). The presence of MS was associated with eGFR<60 mL/min/1.73 m2 (OR 1.364, 95% CI 1.355–1.373, P<0.001). MS individual components were also associated with an increased CKD risk. The strength of association between MS and the development of CKD increase as the number of components increased from 1 to 5. In sub-analysis by men and women, MS and its each components were a significant determinant for CKD.
Conclusions
MS and its individual components can predict the risk of prevalent CKD for men and women.
doi:10.1371/journal.pone.0093795
PMCID: PMC4013132  PMID: 24807226
25.  Association Between Estimated GFR, Health-Related Quality of Life, and Depression Among Older Adults With Diabetes: The Diabetes and Aging Study 
Background
Although chronic kidney disease (CKD) is a highly prevalent condition among older adults with diabetes, the associations between health-related quality of life (HRQOL) and severity of CKD in this population are not well understood. The objective of this study was to assess HRQOL and depressive symptoms across estimated GFR (eGFR) stages.
Study Design
Cross-sectional.
Setting & Participants
Participants included 5,805 members of Kaiser Permanente Northern California age 60 or older with diabetes from the 2005–2006 Diabetes Study of Northern California (DISTANCE) survey.
Predictor
eGFR categories were defined as ≥90 (referent category), 75–89, 60–74, 45–59, 30–44 or ≤29 ml/min/1.73m2.
Outcomes
HRQOL was measured using the modified Short Form 8 Physical Component Summary (PCS) and Mental Component Summary (MCS) scores. Depressive symptoms were measured using the Patient Health Questionnaire 8.
Results
In unadjusted linear regression analyses, physical (PCS) and mental (MCS) HRQOL scores were significantly lower with worsening eGFR level. However, after adjustment for sociodemographics, diabetes duration, obesity, and cardiovascular comorbidities, and taking into account interactions with proteinuria, none of the eGFR categories were significantly or substantively associated with PCS or MCS score. In both unadjusted and adjusted analyses, higher risk of depressive symptoms was observed among respondents with eGFR ≤29 ml/min/1.73m2 (relative risk, 2.02; 95% CI,1.10–3.71; p<0.05) compared with the referent group. However, this eGFR-depression relationship was no longer significant after adjusting for hemoglobin levels.
Limitations
Participants are part of a single health care delivery system.
Conclusions
Our findings suggest the need for greater attention to and potential interventions for depression in patients with reduced eGFR.
doi:10.1053/j.ajkd.2013.03.039
PMCID: PMC3773939  PMID: 23746376

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