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1.  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
2.  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
3.  Chronic Kidney Disease and Risk of Death from Infection 
American Journal of Nephrology  2011;34(4):330-336.
Background
Infection, bacteremia and sepsis are major sources of morbidity and mortality in patients with end-stage renal disease. This study sought to determine the association between predialysis chronic kidney disease (CKD) and infection-related mortality.
Methods
We analyzed participants in the Third National Health and Nutrition Examination Survey (NHANES III). The study included adults ≥45- years-old without end-stage renal disease. Estimated glomerular filtration rate (eGFR) was categorized as ≥60, 45–59.9 and <45 ml/min per 1.73 m2, and urinary albumin-to-creatinine ratio (ACR) as <30, 30–299.9 and ≥300 mg/g. The study identified infection-related mortality, including septicemia, respiratory, abdominal and gastrointestinal, cardiac, kidney and genitourinary, neurologic, and other infections over a median of 13 years using the National Death Index.
Results
Of 7,400 participants included in the study, 206 died from infections. Compared to individuals with eGFR ≥60 ml/min per 1.73 m2, infection-related mortality was higher for those with lower eGFR [adjusted HR = 1.36 (95% CI: 0.81, 2.30) and 2.36 (1.04, 5.38) for eGFR of 45–59.9 and <45 ml/min per 1.73 m2, respectively; p trend = 0.06]. Compared to individuals with ACR <30 mg/g, infection-related mortality was higher for ACR levels of 30–299 and ≥300 mg/g [adjusted HR = 1.68 (95% CI: 0.97, 2.92) and 2.84 (0.92, 8.74), p trend = 0.02].
Conclusions
Reduced eGFR and albuminuria are associated with increased risk for infection-related mortality. Efforts are needed to reduce its incidence and mitigate the effects of infections among individuals with CKD.
doi:10.1159/000330673
PMCID: PMC3169360  PMID: 21860228
Chronic kidney disease; Infection; Sepsis; Mortality
4.  Blood Cadmium and Estimated Glomerular Filtration Rate in Korean Adults 
Environmental Health Perspectives  2011;119(12):1800-1805.
Background: Cadmium is a nephrotoxicant at high exposure levels. Few studies have evaluated the role of cadmium in kidney function at low-exposure levels.
Objective: We evaluated the association of blood cadmium with estimated glomerular filtration rate (eGFR) in the Korean adult population.
Methods: We evaluated 1,909 adults ≥ 20 years of age who participated in the 2005 Korean National Health and Nutrition Examination Survey and had blood cadmium determinations. eGFR was calculated using the Modification of Diet in Renal Disease equation.
Results: Blood cadmium geometric means were 1.57 μg/L for men and 1.49 μg/L for women. The difference in eGFR levels that compared participants in the highest versus lowest cadmium tertiles, after multivariable adjustment, was –1.85 [95% confidence interval (CI): –3.55, –0.16] mL/min per 1.73 m2 in women and 0.67 (–1.16, 2.50) mL/min per 1.73 m2 in men. Among men, the association between blood cadmium and eGFR was modified by blood lead levels (p-value for interaction = 0.048). The fully adjusted differences in eGFR levels for a 2-fold increase in blood cadmium levels were –1.14 (–3.35, 1.07) and 1.84 (0.54, 3.14) mL/min per 1.73 m2 in men with blood lead levels below and above the median (2.75 μg/dL), respectively.
Conclusion: Elevated blood cadmium levels were associated with lower eGFR in women, which supports the role of cadmium as a risk factor for chronic kidney disease. In men, there was no overall association, although elevated blood cadmium levels were associated with higher eGFR levels in men with high blood lead levels and nonstatistically associated with lower eGFR levels in men with low blood lead levels.
doi:10.1289/ehp.1003054
PMCID: PMC3261971  PMID: 21835726
cadmium; chronic kidney disease; glomerular filtration rate; Korean; survey
5.  Kidney function as an underestimated factor for reduced health related quality of life in patients with Fabry disease 
BMC Nephrology  2014;15(1):188.
Background
Impairments of health related quality of life (HRQoL) are frequently observed in Fabry disease (FD) and are known to be related to neuropathic pain and cardiovascular events. This study aimed to explore the role of chronic kidney disease (CKD) in a large cohort of patients with FD.
Methods
In 96 patients (53% female; age 40 ± 12 yrs) with genetically proven FD, HRQoL was assessed by the Medical Outcomes Study (SF-36) questionnaire. All patients were naïve to enzyme replacement therapy. Three categories for kidney dysfunction were chosen, eGFR ≥/<60 ml/min/1.73 m2 or need of renal replacement therapy (RRT). Minor (e.g. arrhythmia, angina pectoris, etc.) and major (e.g. myocardial infarction, coronary artery bypass, stroke or implantable cardioverter-defibrillator) vascular events as well as pain and pain therapy were considered in linear regression analyses with the dimensions of HRQoL.
Results
Ten patients (10%) had impaired kidney function and a further nine were on RRT (9.4%). Kidney function and pain emerged as the main factors associated with lower scores on the SF 36, in particular on physical components (PCS beta-coefficients for CKD −6.2, for RRT −11.8, for pain −9.1, p < 0.05, respectively), while controlling for gender, vascular event and pain-therapy. Relationships were found for mental aspects of HRQoL. Age and history of vascular events were not related to HRQoL.
Conclusion
Cardiovascular events and pain are important factors related to HRQoL, social functioning and depression. Our study highlights impaired chronic kidney disease, in particular after initiation of RRT, as a strong determinant of reduced HRQoL in FD.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2369-15-188) contains supplementary material, which is available to authorized users.
doi:10.1186/1471-2369-15-188
PMCID: PMC4280765  PMID: 25432518
Quality of life; SF-36; Chronic kidney disease; Fabry disease
6.  A Low Baseline Glomerular Filtration Rate Predicts Poor Clinical Outcome at 3 Months after Acute Ischemic Stroke 
Background and Purpose
Chronic kidney disease (CKD) is an established risk factor for numerous cardiovascular diseases including stroke. The relationship between the baseline estimated glomerular filtration rate (eGFR) and clinical 3-month outcomes in patients with acute ischemic stroke were evaluated in this study.
Methods
This was a prospective cohort study involving a hospital-based stroke registry; 1373 patients with acute ischemic stroke were enrolled. Patients were divided into the following four groups according their eGFR (calculated using the CKD Epidemiology Collaboration equations): ≥60, 45-59, 30-44, and <30 mL/min/1.73 m2. The primary endpoint of poor functional outcome was defined as 3-month death or dependency (modified Rankin Scale score ≥3); secondary endpoints were neurological deterioration (increase in National Institutes of Health Stroke Severity score of ≥4 at discharge compared to baseline) during hospitalization and in-hospital mortality.
Results
The overall eGFR was 84.5±20.8 mL/min/1.73 m2 (mean±SD). The distribution of baseline renal impairment was as follows: 1,218, 82, 40, and 33 patients had eGFRs of ≥60, 45-59, 30-44, and <30 mL/min/1.73 m2, respectively. At 3 months after the stroke, 476 (34.7%) patients exhibited poor functional outcome. Furthermore, a poor functional outcome occurred more frequently with increasingly advanced stages of CKD (rates of 31.9%, 53.7%, 55.0%, and 63.6% for CKD stages 1/2, 3a, 3b, and 4/5, respectively; p<0.001). Multivariate analysis revealed that a baseline eGFR of <30 mL/min/1.73m2 increased the risk of a poor functional outcome by 2.37-fold (p=0.047). In addition, baseline renal dysfunction was closely associated with neurological deterioration during hospitalization and with in-hospital mortality.
Conclusions
A low baseline eGFR was strongly predictive of both poor functional outcome at 3 months after ischemic stroke and neurological deterioration/mortality during hospitalization.
doi:10.3988/jcn.2015.11.1.73
PMCID: PMC4302182  PMID: 25628740
chronic kidney disease; functional outcome; mortality; stroke
7.  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
8.  Albuminuria, Kidney Function, and the Incidence of Cognitive Impairment Among Adults in the United States 
Background
Albuminuria and estimated glomerular filtration rate (eGFR) are each associated with increased risk for cognitive impairment, but their joint association is unknown.
Study Design
Prospective cohort study.
Setting and Participants
A US national sample of 19,399 adults without cognitive impairment at baseline participating in the REGARDS )REasons for Geographic And Racial Disparities in Stroke) study.
Predictors
Albuminuria was assessed by the urine albumin-creatinine ratio (UACR) and GFR was estimated using the CKD-EPI (CKD Epidemiology Collaboration) equation.
Outcomes
Incident cognitive impairment was defined as a score of 4 or less on the Six-item Screener at the last follow-up visit.
Results
Over a mean follow-up of 3.8 ± 1.5 years, UACR 30 – 299 and ≥300 mg/g were independently associated with 31% and 57% higher risk for cognitive impairment, respectively, relative to individuals with UACR <10 mg/g. This finding was strongest among those with high eGFR and attenuated at lower levels (P=0.04 for trend). Relative an eGFR ≥60 ml/min/1.73m2, eGFR <60 ml/min/1.73m2 was not independently associated with cognitive impairment. However, after stratifying by UACR, eGFR <60 ml/min/1.73m2 was associated with 30% higher risk for cognitive impairment among participants with UACR <10 mg/g but not higher UACR levels (P=0.04 for trend).
Limitations
single measure of albuminuria and eGFR, screening test of cognition
Conclusions
When eGFR was preserved, albuminuria independently associated with incident cognitive impairment. When albuminuria was <10 mg/g, low eGFR independently associated with cognitive impairment. Albuminuria and low eGFR are complementary but not additive risk factors for incident cognitive impairment.
doi:10.1053/j.ajkd.2011.05.027
PMCID: PMC3199339  PMID: 21816528
albuminuria; chronic kidney disease; cognitive impairment
9.  High Prevalence and Diversity of Kidney Dysfunction in Patients with Type 2 Diabetes Mellitus and Coronary Artery Disease: The BARI 2D Baseline Data 
Background
We describe baseline renal function and albumin excretion rate in patients enrolled in BARI 2D, a randomized clinical trial comparing revascularization and medical therapy with medical therapy alone and deferred or no revascularization, and the impact of glycemic control with either insulin providing or insulin sensitizing drugs, on 5 year mortality.
Methods
Study participants had T2DM, documented CAD, and creatinine < 2 mg/dl. Albuminuria status (albumin/creatinine ratio [ACR]) and estimated glomerular filtration rate (eGFR), utilizing the abbreviated MDRD equation, were determined at baseline. Univariate and multivariate relationships between baseline clinical characteristics and the presence of albuminuria and reduced eGFR rate were estimated.
Results
2146 subjects were included in the analysis. 43% of the cohort had evidence of kidney dysfunction at baseline: 23% had an eGFR ≥ 60 ml/min/1.73 m2 with either micro (>30 ACR; 17%) or macro (> 300 ACR; 6%) albuminuria. 21 % had a reduced eGFR < 60 ml/min/1.73 m2; 52 % with reduced eGFR had no albuminuria; 28 % had microalbuminuria and 20 % had macroalbuminuria. Race, smoking status, duration of diabetes, hypertension, HbA1c, triglycerides, vascular disease, abnormal ejection fraction, and reduced eGFR were associated with greater albuminuria. Age, sex, duration of diabetes, ACR, HbA1c, HDL, and number of hypertensive medications were associated with reduced eGFR.
Conclusion
Kidney dysfunction is common in older patients with T2DM and CAD; Albuminuria was present in 33%. Reduced eGFR was present in 21%, and half the patients with reduced eGFR had no evidence of albuminuria.
doi:10.1097/MAJ.0b013e3181d430ad
PMCID: PMC4312489  PMID: 20375690
10.  Chronic kidney disease in US adults with type 2 diabetes: an updated national estimate of prevalence based on Kidney Disease: Improving Global Outcomes (KDIGO) staging 
BMC Research Notes  2014;7:415.
Background
Kidney Disease Improving Global Outcomes (KDIGO) 2013 updated the classification and risk stratification of chronic kidney disease (CKD) to include both the level of renal function and urinary albumin excretion (UAE). The update subclassifies the previous category of moderate renal impairment. There is currently limited information on the prevalence of CKD based on this new classification in United States (US) adults with type 2 diabetes mellitus (T2DM). The objective of this study was to provide such estimates, for T2DM both overall and in those ≥ 65 years of age. We used the continuous National Health and Nutrition Examination Survey (NHANES) 1999–2012 to identify participants with T2DM. Estimated glomerular filtration rate (eGFR) and UAE were calculated using laboratory results and data collected from the surveys, and categorized based on the KDIGO classification. Projections for the US T2DM population were based on NHANES sampling weights.
Results
A total of 2915 adults diagnosed with T2DM were identified from NHANES, with 1466 being age ≥ 65 years. Prevalence of CKD based on either eGFR or UAE was 43.5% in the T2DM population overall, and 61.0% in those age ≥ 65 years. The prevalence of mildly decreased renal function or worse (eGFR < 60/ml/min/1.73 m2) was 22.0% overall and 43.1% in those age ≥ 65 years. Prevalence of more severe renal impairment (eGFR < 45 ml/min/1.73 m2) was 9.0% overall and 18.6% in those age ≥ 65 years. The prevalence of elevated UAE (> 30 mg/g) was 32.2% overall and 39.1% in those age ≥ 65 years. The most common comorbidities were hypertension, retinopathy, coronary heart disease, myocardial infarction, and congestive heart failure.
Conclusions
This study confirms the high prevalence of CKD in T2DM, impacting 43.5% of this population. Additionally, this study is among the first to report US prevalence estimates of CKD based on the new KDIGO CKD staging system.
doi:10.1186/1756-0500-7-415
PMCID: PMC4091951  PMID: 24990184
Diabetes; Type 2 diabetes mellitus; Chronic kidney disease; Prevalence; Estimated glomerular filtration rate; Albuminuria
11.  Do Clinical Symptoms and Signs Predict Reduced Renal Function Among Hospitalized Adults? 
Background:
Reduced renal function manifests as reduced glomerular filtration rate (GFR), which is estimated using the serum creatinine levels. This condition is frequently encountered among hospitalized adults. Renal dysfunction remains clinically asymptomatic, until late in the course of disease, and its symptoms and screening strategies are poorly defined.
Aim:
We conducted this study to understand if the presence of renal dysfunction related clinical symptom and signs (either alone or in combination) can predict reduced GFR. Further, we aimed to determine if the combination of symptoms and signs are useful for prediction of different levels of reduced GFR.
Subjects and Methods:
We performed a cross-sectional clinical prediction study and included all consecutive patients admitted to the medical wards of the hospital. We used a renal dysfunction related clinical predictors as index tests and low estimated GFR ([eGFR] < 60 ml/min/1.73 m2) as a reference standard. We identified symptoms with a high likelihood ratio (LR) for prediction of low eGFR and constructed different risk score models. We plotted receiver operating curves for each score and used area under the curve (AUC) for comparison. The score with the highest AUC was considered as most discriminant. All statistical analysis was performed using the statistical software STATA (version 11.0, lake drive, Texas, USA).
Results:
A total of 341 patients participated in the study. None of the predictor variables had statistically significant LRs for eGFR less than 60 ml/min or eGFR less than 30 ml/min. Positive LRs were significant for prediction of eGFR < 15 ml/min for the presence of hypertension, vomiting pruritis, peripheral edema, hyperpigmentation, peripheral neuropathy and severe anemia. The best predictive model for eGFR less than 15 ml/min/1.73 m2, included Age > 45 years, the presence of hypertension, vomiting, peripheral edema, hyperpigmentation, and severe anemia and had AUC of 0.82.
Conclusion:
Clinical symptoms and signs are poorly predictive of reduced renal function, except for very low eGFR of less than 15 ml/min/1.73 m2.
doi:10.4103/2141-9248.122052
PMCID: PMC3868112  PMID: 24379997
Clinical predictor; Glomerular filtration rate; Renal dysfunction
12.  Benefits and Safety of Long-Term Fenofibrate Therapy in People With Type 2 Diabetes and Renal Impairment 
Diabetes Care  2012;35(2):218-225.
OBJECTIVE
Diabetic patients with moderate renal impairment (estimated glomerular filtration rate [eGFR] 30–59 mL/min/1.73 m2) are at particular cardiovascular risk. Fenofibrate’s safety in these patients is an issue because it may elevate plasma creatinine. Furthermore, guidelines regarding fenofibrate dosing in renal impairment vary internationally. We investigated fenofibrate’s effects on cardiovascular and end-stage renal disease (ESRD) events, according to eGFR, in the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) Study.
RESEARCH DESIGN AND METHODS
Type 2 diabetic patients (aged 50–75 years) with eGFR ≥30 mL/min/1.73 m2 were randomly allocated to a fixed dose of fenofibrate (200 mg daily) (n = 4,895) or placebo (n = 4,900) for 5 years. Baseline renal function (Modification of Diet in Renal Disease equation) was grouped by eGFR (30–59, 60–89, and ≥90 mL/min/1.73 m2). The prespecified outcome was total cardiovascular events (composite of cardiovascular death, myocardial infarction, stroke, and coronary/carotid revascularization). Serious adverse events and instances of ESRD (plasma creatinine >400 μmol/L, dialysis, renal transplant, or renal death) were recorded. Analysis was by intention to treat.
RESULTS
Overall, fenofibrate reduced total cardiovascular events, compared with placebo (hazard ratio 0.89 [95% CI 0.80–0.99]; P = 0.035). This benefit was not statistically different across eGFR groupings (P = 0.2 for interaction) (eGFR 30–59 mL/min/1.73 m2: 0.68 [0.47–0.97], P = 0.035; eGFR ≥90 mL/min/1.73 m2: 0.85 [0.70–1.02], P = 0.08). ESRD rates were similar between treatment arms, without adverse safety signals of fenofibrate use in renal impairment.
CONCLUSIONS
Patients with type 2 diabetes and moderate renal impairment benefit from long-term fenofibrate, without excess drug-related safety concerns compared with those with no or mild renal impairment. Fenofibrate treatment should not be contraindicated in moderate renal impairment, suggesting that current guidelines may be too restrictive.
doi:10.2337/dc11-1109
PMCID: PMC3263870  PMID: 22210576
13.  Preventing renal and cardiovascular risk by renal function assessment: insights from a cross-sectional study in low-income countries and the USA 
BMJ Open  2012;2(5):e001357.
Objective
To assess the prevalence of microalbuminuria and kidney dysfunction in low-income countries and in the USA.
Design
Cross-sectional study of screening programmes in five countries.
Setting
Screening programmes in Nepal, Bolivia, the USA (National Health and Nutrition Examination Survey (NHANES) 2005–2008) Bangladesh and Georgia.
Participants
General population in Nepal (n=20 811), Bolivia (n=3436) and in the USA (n=4299) and high-risk subjects in Bangladesh (n=1518) and Georgia (n=1549).
Primary and secondary outcome measures
Estimated glomerular filtration rate (eGFR)<60ml/min/1.73 m2 and microalbuminuria (defined as urinary albumin creatinine ratio values of 30–300 mg/g) were the main outcome measures. The cardiovascular (CV) risk was also evaluated on the basis of demographic, clinical and blood data.
Results
The prevalence of eGFR<60ml/min/1.73 m2 was 19%, 3.2% and 7% in Nepal, Bolivia and the USA, respectively. In Nepal, 7% of subjects were microalbuminuric compared to 8.6% in the USA. The prevalence of participants with predicted 10-year CV disease (CVD) risk ≥10% was 16.9%, 9.4% and 17% in Nepal, Bolivia and in the USA, respectively. In Bangladesh and Georgia, subjects with eGFR<60 ml/min/1.73 m2 were 8.6% and 4.9%, whereas those with microalbuminuria were 45.4% and 56.5%, respectively. Predicted 10-year CVD risk ≥10% was 25.4% and 25% in Bangladesh and Georgia, respectively.
Conclusions
Renal abnormalities are common among low-income countries and in the USA. Prevention programmes, particularly focused on those with renal abnormalities, should be established worldwide to prevent CVD and progression to end-stage renal disease.
doi:10.1136/bmjopen-2012-001357
PMCID: PMC3467605  PMID: 23002161
14.  Comparison of the Sensitivity of a Pre-MRI Questionnaire and Point of Care eGFR Testing for Detection of Impaired Renal Function 
Academic radiology  2012;19(10):1181-1185.
Rationale and Objectives
The Food and Drug Administration recommends renal function estimation using laboratory testing for patients at risk for chronically reduced kidney function before the administration of gadolinium-based contrast agents (GBCAs). Point-of-care (POC) estimated glomerular filtration rate (eGFR) testing was added to the pre-magnetic resonance (MR) questionnaire at our institution in June 2008 for all patients undergoing a contrast-enhanced MR exam. This study was done to evaluate the effectiveness of a pre-MR screening questionnaire about kidney disease and to assess POC eGFR detection of additional patients at risk for nephrogenic systemic fibrosis.
Materials and Methods
This retrospective study was approved by our institutional review board and determined to be Health Insurance Portability and Accountability Act compliant. Medical records, laboratory data, and pre-MR questionnaires of all patients who presented for contrast-enhanced MR scans during October 2008 were reviewed. The National Kidney Disease Education Program isotope-dilution mass spectrometry-traceable Modification of Diet in Renal Disease equation was used to calculate eGFRs using the POC creatinine laboratory value, age, race, and gender. Sensitivity and specificity were calculated using 2 × 2 tables, and 95% confidence intervals were calculated with exact binomial confidence intervals.
Results
A total of 1167 individuals presented for contrast-enhanced MR scans. Of 13 individuals on dialysis, 2 did not report renal disease. Of 1154 individuals not on dialysis, 25 had an eGFR <30 mL/min/1.73 m2 (95% CI 1.41%–3.18%). Of these 25, 13 did and 12 did not report renal disease. The sensitivity of the questionnaire for identifying patients with an eGFR <30 mL/min/1.73 m2 was 63.2%. POC eGFR estimations identified a prevalence of 2.17% (95% CI: 1.41%–3.18%) of the total individuals not on dialysis, with an eGFR <30 mL/min/1.73 m2. Patients who denied kidney dysfunction had a 1.08% (95% CI: 0.56%–1.88%) posttest probability of having an eGFR <30 mL/min/1.73 m2.
Conclusions
POC eGFR testing identified a significant number of individuals with renal dysfunction not found by the pre-MR imaging questionnaire alone.
doi:10.1016/j.acra.2012.04.016
PMCID: PMC3600374  PMID: 22831822
Estimated glomerular filtration rate (eGFR); gadolinium-based contrast agents (GBCAs); point-of-care (POC); nephrogenic systemic fibrosis (NSF); screening questionnaires
15.  Decline in renal functioning is associated with longitudinal decline in global cognitive functioning, abstract reasoning and verbal memory 
Nephrology Dialysis Transplantation  2012;28(7):1810-1819.
Background
Decreased estimated glomerular filtration rate (eGFR) and higher serum creatinine (sCR) levels have been associated with longitudinal decline in global mental status measures. Longitudinal data describing change in multiple domains of cognitive functioning are needed in order to determine which specific abilities are most affected in individuals with impaired renal function.
Methods
We conducted a 5-year longitudinal study with 590 community-living individuals (mean age 62.1 years, 60.2% female, 93.2% white, 11.4% with diabetes mellitus, mean eGFR 78.4 mL/min/1.73 m²) free from dementia, acute stroke and end-stage renal disease. To measure longitudinal change-over-time, cognitive performance measures were regressed on eGFR adjusting for baseline eGFR and cognitive performance, comorbidity and vascular risk factors. Outcome measures were scores from 17 separate tests of cognitive abilities that were used to index 5 theoretically relevant domains: verbal episodic memory, visual-spatial organization and memory, scanning and tracking, working memory and similarities (abstract reasoning).
Results
Declines in eGFR values were associated with cognitive declines, when adjusted for eGFR and cognitive function scores at baseline. Change in renal functioning over time was related to change observed in global cognitive ability [b = 0.21SD decline per unit ln(eGFR), 95% CI: 0.04–0.38, P = .018], verbal episodic memory [b = 0.28 SD decline per unit ln(eGFR), 95% CI: 0.02–0.54, P = 0.038] and abstract reasoning [b = 0.36 SD decline per unit ln(eGFR), 95% CI: 0.04–0.67, P = 0.025]. Decline in cognitive functioning in association with declining renal functioning was observed despite statistical adjustment for demographic variables and CVD risk factors and the exclusion of persons with dementia or a history of acute stroke.
Conclusions
Early detection of mild to moderate kidney disease is an important public health concern with regard to cognitive decline.
doi:10.1093/ndt/gfs470
PMCID: PMC3707524  PMID: 23166308
cardiovascular disease; chronic kidney disease; cognitive performance; estimated glomerular filtration rate; renal disease
16.  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
17.  Development and Progression of Renal Insufficiency With and Without Albuminuria in Adults With Type 1 Diabetes in the Diabetes Control and Complications Trial and the Epidemiology of Diabetes Interventions and Complications Study 
Diabetes Care  2010;33(7):1536-1543.
OBJECTIVE
This multicenter study examined the impact of albumin excretion rate (AER) on the course of estimated glomerular filtration rate (eGFR) and the incidence of sustained eGFR <60 ml/min/1.73 m2 in type 1 diabetes up to year 14 of the Epidemiology of Diabetes Interventions and Complications (EDIC) study (mean duration of 19 years in the Diabetes Control and Complications Trial [DCCT]/EDIC).
RESEARCH DESIGN AND METHODS
Urinary albumin measurements from 4-h urine collections were obtained from participants annually during the DCCT and every other year during the EDIC study, and serum creatinine was measured annually in both the DCCT and EDIC study. GFR was estimated from serum creatinine using the abbreviated Modification of Diet in Renal Disease equation.
RESULTS
A total of 89 of 1,439 subjects developed an eGFR <60 ml/min/1.73 m2 (stage 3 chronic kidney disease on two or more successive occasions (sustained) during the DCCT/EDIC study (cumulative incidence 11.4%). Of these, 20 (24%) had AER <30 mg/24 h at all prior evaluations, 14 (16%) had developed microalbuminuria (AER 30–300 mg/24 h) before they reached stage 3 chronic kidney disease, and 54 (61%) had macroalbuminuria (AER >300 mg/24 h) before they reached stage 3 chronic kidney disease. Macroalbuminuria is associated with a markedly increased rate of fall in eGFR (5.7%/year vs. 1.2%/year with AER <30 mg/24 h, P < 0.0001) and risk of eGFR <60 ml/min/1.73 m2 (adjusted hazard ratio 15.3, P < 0.0001), whereas microalbuminuria had weaker and less consistent effects on eGFR.
CONCLUSIONS
Macroalbuminuria was a strong predictor of eGFR loss and risk of developing sustained eGFR <60 ml/min/1.73 m2. However, screening with AER alone would have missed 24% of cases of sustained impaired eGFR.
doi:10.2337/dc09-1098
PMCID: PMC2890355  PMID: 20413518
18.  More Impact of Microalbuminuria on Retinopathy Than Moderately Reduced GFR Among Type 2 Diabetic Patients 
Diabetes Care  2012;35(4):803-808.
OBJECTIVE
The current study aimed to investigate whether microalbuminuria or moderately decreased glomerular filtration rate (GFR) is a better predictor for the development and progression of retinopathy in type 2 diabetic patients.
RESEARCH DESIGN AND METHODS
Type 2 diabetic patients without cardiovascular diseases, malignancy, pregnancy, and acute intercurrent illness were enrolled between 1 August 2001 and 31 December 2002. All participants provided their detailed medical history and underwent an eye fundus examination. They were followed up in outpatient clinics, and serum creatinine, urinary albumin-to-creatinine ratio (UACR), and retinal photographs were followed up annually until 31 December 2009. The primary outcomes were development and progression of diabetic retinopathy and nephropathy. The secondary outcomes were cardiovascular events and all-cause mortality.
RESULTS
Among 487 participants, 81 subjects had normoalbuminuria and moderate renal impairment (baseline eGFR 30–59.9 mL/min/1.73 m2), and 106 subjects had microalbuminuria and baseline eGFR ≥60 mL/min/1.73 m2. Patients with microalbuminuria and eGFR ≥60 mL/min/1.73 m2 had a significantly greater risk for development and progression of diabetic retinopathy (HR 3.34 [95% CI 1.04–10.70]) compared with those with moderate renal impairment and normoalbuminuria after multivariate adjustment. Risks for renal outcome, cardiovascular events, and all-cause mortality were not significantly different between the two groups.
CONCLUSIONS
Microalbuminuria has a greater impact on predicting the development and progression of diabetic retinopathy compared with moderate decline in GFR among type 2 diabetic patients.
doi:10.2337/dc11-1955
PMCID: PMC3308275  PMID: 22338100
19.  Reduced Glomerular Function and Prevalence of Gout: NHANES 2009–10 
PLoS ONE  2012;7(11):e50046.
Background
The renal tubule is a major route of clearance of uric acid, a product of purine metabolism. The links between reduced glomerular filtration rate (GFR), hyperuricemia, and gout in the general population are not well understood. The objective of the present study was to estimate prevalence of gout and hyperuricemia among people with impaired GFR in the US general population.
Study Design
Cross-sectional, survey-weighted analyses of data on adults (age>20 years) in the 2009–10 cycle of the US National Health and Nutrition Examination Surveys (n = 5,589). Associations between self-reported physician diagnosis of gout and degrees of renal impairment were the primary focus of the present analyses.
Results
In the 2009–2010 period, there was an estimated 7.5 million people with gout in the US. There were 1.25 million men and 0.78 million women with moderate or severe renal impairment and gout. The age standardized prevalence of gout was 2.9% among those with normal GFR compared to 24% among those with GFR<60 ml/min/1.73 m2.In multivariable logistic regression analyses that adjusted for age, gender, body mass index, hypertension, diabetes, hypertension medications, including diuretics, blood lead levels, and hyperlipidemia, the odds ratios of gout and hyperuricemia were 5.9 (2.2, 15.7) and 9.58 (4.3, 22.0) respectively among those with severe renal impairment compared to those with no renal impairment. Approximately 2–3 fold increase in prevalence of gout was observed for each 30 ml/min/1.73 m2 decrease in GFR, after accounting for the above factors.
Conclusions
Renal glomerular function is an important risk factor for gout. The prevalence of hyperuricemia and gout increases with decreasing glomerular function independent of other factors. This association is non-linear and an eGFR of 60 ml/min/1.73 m2 appears to be a threshold for the dramatic increase in the prevalence of gout.
doi:10.1371/journal.pone.0050046
PMCID: PMC3507834  PMID: 23209642
20.  Associations of blood lead with estimated glomerular filtration rate using MDRD, CKD-EPI and serum cystatin C-based equations 
Nephrology Dialysis Transplantation  2011;26(9):2786-2792.
Background. Low-level lead exposure is widespread and has been implicated as a chronic kidney disease (CKD) risk factor. However, studies evaluating associations of lead dose with newer, potentially more accurate, estimates of kidney function, in participants with a wide range of glomerular filtration rates (GFRs), are scarce.
Methods. We compared associations of blood lead and estimated glomerular filtration rate (eGFR) using the Modification of Diet in Renal Disease (MDRD), Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) and cystatin C single variable, multivariable and combined creatinine/cystatin C equations in 3941 adults who participated in the 1999–2002 National Health and Nutrition Examination Survey cystatin C subsample.
Results. Geometric mean blood lead was 1.7 μg/dL. After multivariable adjustment, differences [95% confidence interval (CI)] in mean eGFR for a doubling of blood lead were −1.9 (−3.2, −0.7), −1.7 (−3.0, −0.5) and −1.4 (−2.3, −0.5) mL/min/1.73 m2, using the cystatin C single variable, multivariable and combined creatinine/cystatin C equations, respectively, reflecting lower eGFR with increased blood lead. The corresponding differences (95% CI) were −0.9 (−1.9, 0.02) and −0.9 (−1.8, 0.01) using the creatinine-based MDRD and CKD-EPI equations, respectively. In participants aged ≥60 years, differences in mean eGFR ranged from −3.0 to −4.5 mL/min/1.73 m2, and odds of reduced eGFR (<60 mL/min/1.73 m2) were increased for all estimates of GFR.
Conclusions. These results support the inclusion of cystatin C-based eGFR in future lead research and provide additional evidence for environmental lead exposure as a CKD risk factor.
doi:10.1093/ndt/gfq773
PMCID: PMC3203408  PMID: 21248295
blood lead; kidney function; lead exposure; NHANES
21.  Effectiveness and safety of metformin in 51 675 patients with type 2 diabetes and different levels of renal function: a cohort study from the Swedish National Diabetes Register 
BMJ Open  2012;2(4):e001076.
Objective
To evaluate the effectiveness and safety of metformin use in clinical practice in a large sample of pharmacologically treated patients with type 2 diabetes and different levels of renal function.
Design
Observational study between July 2004 and December 2010, mean follow-up 3.9 years.
Setting
Hospital outpatient clinics and primary care in Sweden.
Participants
51 675 men and women with type 2 diabetes, registered in the Swedish National Diabetes Register, and on continuous glucose-lowering treatment with oral hypoglycaemic agents (OHAs) or insulin.
Main outcome measures
Risks of cardiovascular disease (CVD), all-cause mortality and acidosis/serious infection, associated with each treatment regimens, were analysed in all patients and in subgroups with different estimated glomerular filtration rate (eGFR) intervals. Covariance adjustment and propensity scores were used to adjust for several baseline risk factors and characteristics at Cox regression.
Results
Compared with metformin in monotherapy, HRs for fatal/non-fatal CVD and all-cause mortality with all other OHAs combined (approximately 80% sulphonylureas) in monotherapy were 1.02 (95% CI 0.93 to 1.12) and 1.13 (1.01 to 1.27), while 1.18 (1.07 to 1.29) and 1.34 (1.19 to 1.50) with insulin in monotherapy, adjusting using propensity scores. Metformin, compared with any other treatment, showed reduced risks of acidosis/serious infection (adjusted HR 0.85, 95% CI 0.74 to 0.97) and all-cause mortality (HR 0.87, 95% CI 0.77 to 0.99), in patients with eGFR 45–60 ml/min/1.73 m2, and no increased risks of all-cause mortality, acidosis/serious infection or CVD were found in patients with eGFR 30–45 ml/min/1.73 m2.
Conclusions
Metformin showed lower risk than insulin for CVD and all-cause mortality and slightly lower risk for all-cause mortality compared with other OHA, in these 51 675 patients followed for 4 years. Patients with renal impairment showed no increased risk of CVD, all-cause mortality or acidosis/serious infection. In clinical practice, the benefits of metformin use clearly outbalance the risk of severe side effects.
Article summary
Article focus
To evaluate the risks of CVD, acidosis/serious infection and mortality associated with metformin and other glucose-lowering treatments, in a cohort of 51 675 type 2 diabetes patients and in subgroups with different degrees of renal impairment.
Key messages
Metformin was associated with reduced risk of CVD, acidosis/serious infection and all-cause mortality compared with insulin and a reduced risk of all-cause mortality compared with other OHAs.
The effects were consistent in patients with renal impairment (eGFR 45–60 ml/min/1.73 m2), and there were no increased risk of acidosis/serious infection even in patients with low renal function (eGFR 30–45 ml/min/1.73 m2).
Strengths and limitations of this study
A large cohort with comprehensive data on patient characteristics was studied.
A composite end point including diagnosis of acidosis, shock, acute renal failure and serious infections was used to evaluate the occurrence of lactic acidosis.
doi:10.1136/bmjopen-2012-001076
PMCID: PMC3400073  PMID: 22798258
22.  A Decline in Renal Function is Associated With Loss of Bone Mass in Korean Postmenopausal Women With Mild Renal Dysfunction 
Journal of Korean Medical Science  2011;26(3):392-398.
This study was conducted to assess the relationship between estimated glomerular filtration rate (eGFR) and bone mineral density (BMD) in Korean postmenopausal women with mild renal dysfunction. A total of 328 postmenopausal women who underwent BMD measurement during health check-up was investigated. BMD was measured in lumbar spine (L1-L4), femoral neck, total proximal femur and femoral trochanteric areas by dual energy radiography absorptiometry and renal function was estimated by eGFR using Cockcroft-Gault equation. Of the 328 subjects, 317 (96.6%) had an eGFR ≥60 mL/min/1.73 m2. By using simple linear regression analysis, age, height, weight and eGFR were significantly associated with BMD for the 4 aforementioned anatomic sites, while serum levels of creatinine and blood urea nitrogen did not influence BMD. When multiple regression analyses were applied, age and body weight still had significant associations with BMD at 4 different anatomic sites (P < 0.001). A significant association of eGFR with BMD remained in the lumbar spine, femoral neck and proximal total femur (P < 0.05) but not in the trochanteric area (P = 0.300). Our study suggests that a decline of renal function is associated with lower BMD in the lumbar spine, femoral neck and total proximal femur areas in Korean menopausal women with mild renal dysfunction.
doi:10.3346/jkms.2011.26.3.392
PMCID: PMC3051087  PMID: 21394308
Association; Bone Density; Koreans; Postmenopause; Renal Insufficiency
23.  Effect of Late Revascularization of a Totally Occluded Coronary Artery After Myocardial Infarction on Mortality Rates in Patients with Renal Impairment 
The American journal of cardiology  2012;110(7):954-960.
Renal dysfunction is an independent predictor of cardiovascular events and a negative prognostic indicator after myocardial infarction (MI). Randomized data comparing percutaneous coronary intervention (PCI) to medical therapy in MI patients with renal insufficiency are needed. The Occluded Artery Trial (OAT) compared optimal medical therapy alone to PCI with optimal medical therapy in 2201 high risk patients with an occluded infarct artery >24 hours post-MI with serum creatinine ≤2.5 mg/dl. The primary endpoint was a composite of death, MI, and class IV heart failure (HF). Analyses were carried out utilizing estimated glomerular filtration rates (eGFR) as a continuous variable and by eGFR categories. Long term follow up data (maximum 9 years) were used for this analysis. Lower eGFR (ml/min/1.73m2) was associated with development of the primary outcome (6-year life-table rate 16.9% in eGFR>90; 19.2% in eGFR 60–89; 34.9% in eGFR<60; p-value <0.0001), death, and class IV HF, with no difference in rates of reinfarction. On multivariable analysis, eGFR was an independent predictor of death and HF. There was no effect of treatment assignment on the primary endpoint regardless of eGFR, and there was no significant interaction between eGFR and treatment assignment on any outcome. In conclusion, lower eGFR at enrollment was independently associated with death and HF in OAT participants. Despite this increased risk, the lack of benefit from PCI in the overall trial was also seen in patients with renal dysfunction and persistent occlusion of the infarct artery in the subacute phase post MI.
doi:10.1016/j.amjcard.2012.05.024
PMCID: PMC3439588  PMID: 22728005
Myocardial Infarction; Stents and Kidney Disease
24.  Associations of kidney disease measures with mortality and end-stage renal disease in individuals with and without hypertension: a meta-analysis 
Lancet  2012;380(9854):1649-1661.
Background
Hypertension is the most prevalent comorbidity in individuals with chronic kidney disease (CKD). It is unknown, however, whether the association of the CKD measures, estimated glomerular filtration rate (eGFR) and albuminuria, with mortality or end-stage renal disease (ESRD) differs by hypertensive status.
Methods
We performed a meta-analysis of 45 cohorts (25 general population, 7 high-risk and 13 CKD cohorts), including 1,127,656 participants (364,344 with hypertension). Adjusted hazard ratios (HRs) for all-cause mortality (84,078 deaths from 40 cohorts) and ESRD (7,587 events from 21 cohorts) by hypertensive status were obtained for each study and pooled using random-effects models.
Findings
Low eGFR and high albuminuria were associated with mortality in both non-hypertensive and hypertensive individuals in the general population and high-risk cohorts. Mortality risk was higher in hypertensives as compared to non-hypertensives at preserved eGFR but a steeper relative risk gradient among non-hypertensives than hypertensives at eGFR range 45-75 ml/min/1.73m2 led to similar mortality risk at lower eGFR. With a reference eGFR of 95 mL/min/1.73m2 in each group to explicitly assess interaction, adjusted HR for all-cause mortality at eGFR 45 mL/min/1.73m2 was 1.77 (95% CI, 1.57-1.99) in non-hypertensives versus 1.24 (1.11-1.39) in hypertensives (P for overall interaction =0.0003). Similarly, for albumin-creatinine ratio (ACR) of 300 mg/g (vs. 5 mg/g), HRs were 2.30 (1.98-2.68) in non-hypertensives versus 2.08 (1.84-2.35) in hypertensives (P for overall interaction=0.019). Similar results were observed for cardiovascular mortality. The associations of eGFR and albuminuria with ESRD, however, did not differ by hypertensive status. Results in CKD cohorts were comparable to results in general and high-risk population cohorts.
Interpretation
Low eGFR and elevated albuminuria were more strongly associated with mortality among individuals without hypertension than in those with hypertension, but the associations with ESRD were similar. CKD should be considered at least an equally relevant risk factor for mortality and ESRD in non-hypertensive as it is in hypertensive individuals.
Funding
The US National Kidney Foundation (sources include Abbott and Amgen).
doi:10.1016/S0140-6736(12)61272-0
PMCID: PMC3993095  PMID: 23013600
25.  Prevalence of Estimated GFR Reporting Among US Clinical Laboratories 
Background
Routine laboratory reporting of estimated glomerular filtration rate (eGFR) may help clinicians detect kidney disease. The current national prevalence of eGFR reporting among clinical laboratories is unknown, thus the extent of the situation of laboratories not routinely reporting eGFR with serum creatinine (SCr) results is not quantified.
Design
Observational analysis.
Setting
National Kidney Disease Education Program survey of clinical laboratory conducted in 2006-7 by mail, Web, and telephone follow up.
Participants
A national random sample, 6,350 clinical laboratories, drawn from the Federal Clinical Laboratory Improvement Amendments database and stratified by six major laboratory types/groupings.
Predictors
Laboratory reports SCr results.
Outcomes
Reporting eGFR values along with SCr results.
Measurements
Percent of laboratories reporting eGFR along with reporting SCr, reporting protocol, eGFR formula used, and style of reporting cutoff values.
Results
Among laboratories reporting SCr, 38.4% report eGFR (physician offices, 25.8%; hospitals, 43.6%; independents, 38.9%; community clinics, 47.2%; health fair/insurance/public health, 45.5%; others, 43.2%). Physician office laboratories have a reporting prevalence lower than other laboratory types (p < 0.001). Among laboratories reporting eGFR, 66.7% do so routinely with all adult SCr determinations; 71.6% use the 4-variable Modification of Diet in Renal Disease Study equation; and 45.3% use the “>60 mL/min/1.73 m2” reporting convention. Independent laboratories are least likely to routinely report eGFR, (50.6%, p < .05) and most likely to report only when specifically requested (45.4%, p < 0.05). High-volume laboratories across all strata are more likely to report eGFR (p < 0.001).
Limitations
Self-reporting by laboratories, Federal database did not have names of laboratory directors/managers (intended respondents), assumed accuracy of Federal database for sample purposes.
Conclusions
Routine eGFR reporting with SCr is not yet universal and laboratories vary in their reporting practices.
doi:10.1053/j.ajkd.2008.05.023
PMCID: PMC2572813  PMID: 18676076
eGFR; laboratory reporting; serum creatinine; kidney disease

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