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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.
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.
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
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
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
PMCID: PMC2628400  PMID: 19166266
2.  Serum Bicarbonate Concentrations and Kidney Disease Progression in Community-Living Elders: The Health, Aging, and Body Composition (Health ABC) Study 
In populations with prevalent chronic kidney disease (CKD), lower serum bicarbonate is associated with more rapid CKD progression, but whether lower bicarbonate is also associated with risk of incident estimated glomerular filtration rate (eGFR) <60 mL/min/1.73m2 and progression among community-living persons with predominantly preserved kidney function is unknown.
Study Design
Longitudinal observational cohort study.
Setting & Participants
Well functioning community living elders aged 70–79 years at inception.
Serum bicarbonate measured at the time of collection by arterialized venous blood sample using an arterial blood gas analyzer.
Change in eGFR, and new eGFR < 60 ml/min/1.73m2 and loss of ≥1 ml/min/1.73m2 per year at follow-up.
Linear and logistic regressions were used to evaluate associations of baseline serum bicarbonate with change in eGFR and incident eGFR <60 mL/min/1.73m2.
At baseline, mean eGFR was 84±16 (SD) mL/min/1.73m2, and serum bicarbonate was 25.2±1.9 mmol/L. Compared to participants with higher bicarbonate concentrations (23.0–28.0 mmol/L), those with bicarbonate concentrations < 23 mmol/L (n=85 [8%]) lost eGFR 0.55 (95%CI, 0.13–0.97) mL/min/1.73m2 per year faster in models adjusted for demographics, CKD risk factors, baseline eGFR, and urine albumin-creatinine ratio. Among the 989 (92%) participants with baseline eGFR>60 mL/min/1.73m2, 252 (25%) developed incident eGFR <60 mL/min/1.73m2 at follow-up. Adjusting for the same covariates, participants with bicarbonate concentrations < 23 mmol/L had nearly 2-fold greater odds of incident eGFR <60 mL/min/1.73m2 (OR, 1.72; 95% CI, 0.97–3.07) compared to those with higher bicarbonate concentrations.
Only two measurements of kidney function separated by seven years and loss to follow up due to intervening mortality in this elderly population.
Lower serum bicarbonate concentrations are independently associated with decline in eGFR and incident eGFR <60 mL/min/1.73m2 in community-living older persons. If confirmed, serum bicarbonate levels may give insights into kidney tubule health among persons with preserved eGFR and suggest a possible new target for intervention to prevent CKD development.
PMCID: PMC4177317  PMID: 24953890
Acidosis; alkalosis; kidney disease; aging; risk factor; renal disease; disease progression; kidney disease trajectory
3.  Rate of Kidney Function Decline in Older Adults: A Comparison Using Creatinine and Cystatin C 
American Journal of Nephrology  2009;30(3):171-178.
The aim of this study was to determine the decline in the estimated glomerular filtration rate (eGFR) in elderly persons and to compare estimates based on creatinine and cystatin C.
In the Cardiovascular Health Study, GFR changes in an elderly cohort were estimated from serum creatinine and cystatin C measured at baseline, year 3 and year 7 in 4,380 participants (age 72 ± 5 years at entry). Outcomes were mean eGFR decline, incident chronic kidney disease (CKD) and rapid decline in eGFR (annual loss >3 ml/min/1.73 m2).
Mean annual eGFR loss as estimated from creatinine was 0.4 ± 3.6 ml/min/1.73 m2, with 16% of the participants experiencing a rapid decline. Mean eGFR loss as estimated from cystatin C was 1.8 ± 2.6, with 25% of the participants experiencing a rapid decline (p < 0.001 for both). Among participants without baseline CKD, incident CKD was detected at year 7 in 10% (n = 263) using creatinine and 19% (n = 544) using cystatin C (p < 0.001). Increasing age was the strongest predictor of rapid decline; adjusted odds ratios were 1.38 (1.16–1.65), 1.62 (1.31–1.99) and 2.96 (2.28–3.84) for participants aged 70–74, 75–79 and 80+ at baseline, compared with those aged 65–69.
In elderly persons, cystatin C estimated substantially larger declines in kidney function than creatinine did. Defining the optimal measurement of kidney function in elderly persons should be a high priority for future research.
PMCID: PMC2820322  PMID: 19349699
Glomerular filtration rate; Creatinine; Cystatin C; Chronic kidney disease
4.  Low Serum Bicarbonate and Kidney Function Decline: The Multi-Ethnic Study of Atherosclerosis (MESA) 
Among populations with established chronic kidney disease (CKD), metabolic acidosis is associated with more rapid progression of kidney disease. The association of serum bicarbonate concentrations with early declines in kidney function is less clear.
Study Design
Retrospective cohort study.
Setting & Participants
6380 participants in the Multi-Ethnic Study of Atherosclerosis (MESA) with a baseline estimated glomerular filtration rate (eGFR) >60 mL/min/1.73m2 using the CKD-EPI (CKD Epidemiology Collaboration) creatinine–cystatin C equation.
Serum bicarbonate concentrations.
Rapid kidney function decline (eGFR decline >5% per year) and incident reduced eGFR (eGFR<60 mL/min/1.73 m2 with minimum rate of eGFR loss of 1 mL/min/1.73 m2 per year).
The average bicarbonate concentration was 23.2 ± 1.8 mEq/L. 1730 (33%) participants had rapid kidney function decline, and 487 had incident reduced eGFR during follow-up. Each 1-SD lower baseline bicarbonate concentration was associated with 12% higher adjusted odds of rapid kidney function decline (95% CI, 6%–20%) and higher risk of incident reduced eGFR (adjusted incidence rate ratio, 1.11; 95% CI, 1.03–1.20) in models adjusting for demographics, baseline eGFR, albuminuria, and CKD risk factors. The OR for the associations of bicarbonate <21mEq/L relative to 23–24 mEq/L was 1.35 (95% CI, 1.05–1.73) for rapid kidney function decline, and the incidence rate ratio was 1.16 (95% CI, 0.83–1.62) for incident reduced eGFR.
Etiology of metabolic acidosis cannot be determined in this study.
Lower serum bicarbonate concentrations are independently associated with rapid kidney function decline independent of eGFR or albuminuria in community-living persons with a baseline eGFR >60 mL/min/1.73 m2. If confirmed, our findings suggest that metabolic acidosis may indicate either early kidney disease that is not captured by eGFR or albuminuria, or may have a causal role in the development of an eGFR <60 mL/min/1.73 m2.
PMCID: PMC4177290  PMID: 24953891
serum bicarbonate; metabolic acidosis; chronic kidney disease (CKD); kidney function; renal disease; disease progression; kidney disease trajectory
5.  Longitudinal Study of the Decline in Renal Function in Healthy Subjects 
PLoS ONE  2015;10(6):e0129036.
Chronic kidney disease is an important concern in preventive medicine, but the rate of decline in renal function in healthy population is not well defined. The purpose of this study was to determine reference values for the estimated glomerular filtration rate (eGFR) and rate of decline of eGFR in healthy subjects and to evaluate factors associated with this decline using a large cohort in Japan.
Retrospective cross-sectional and longitudinal studies were performed with healthy subjects aged ≥18 years old who received a medical checkup. Reference values for eGFR were obtained using a nonparametric method and those for decline of eGFR were calculated by mixed model analysis. Relationships of eGFR decline rate with baseline variables were examined using a linear least-squares method.
In the cross-sectional study, reference values for eGFR were obtained by gender and age in 72,521 healthy subjects. The mean (±SD) eGFR was 83.7±14.7ml/min/1.73m2. In the longitudinal study, reference values for eGFR decline rate were obtained by gender, age, and renal stage in 45,586 healthy subjects. In the same renal stage, there was little difference in the rate of decline regardless of age. The decline in eGFR depended on the renal stage and was strongly related to baseline eGFR, with a faster decline with a higher baseline eGFR and a slower decline with a lower baseline eGFR. The mean (±SD) eGFR decline rate was ‒1.07±0.42ml/min/1.73m2/year (‒1.29±0.41%/year) in subjects with a mean eGFR of 81.5±11.6ml/min/1.73m2.
The present study clarified for the first time the reference values for the rate of eGFR decline stratified by gender, age, and renal stage in healthy subjects. The rate of eGFR decline depended mainly on baseline eGFR, but not on age, with a slower decline with a lower baseline eGFR.
PMCID: PMC4464887  PMID: 26061083
6.  Comparison of the Schwartz and CKD-EPI Equations for Estimating Glomerular Filtration Rate in Children, Adolescents, and Adults: A Retrospective Cross-Sectional Study 
PLoS Medicine  2016;13(3):e1001979.
Estimating kidney glomerular filtration rate (GFR) is of utmost importance in many clinical conditions. However, very few studies have evaluated the performance of GFR estimating equations over all ages and degrees of kidney impairment. We evaluated the reliability of two major equations for GFR estimation, the CKD-EPI and Schwartz equations, with urinary clearance of inulin as gold standard.
Methods and Findings
The study included 10,610 participants referred to the Renal and Metabolic Function Exploration Unit of Edouard Herriot Hospital (Lyon, France). GFR was measured by urinary inulin clearance (only first measurement kept for analysis) then estimated with isotope dilution mass spectrometry (IDMS)–traceable CKD-EPI and Schwartz equations. The participants’ ages ranged from 3 to 90 y, and the measured GFRs from 3 to 160 ml/min/1.73 m2. A linear mixed-effects model was used to model the bias (mean ratio of estimated GFR to measured GFR). Equation reliability was also assessed using precision (interquartile range [IQR] of the ratio) and accuracy (percentage of estimated GFRs within the 10% [P10] and 30% [P30] limits above and below the measured GFR). In the whole sample, the mean ratio with the CKD-EPI equation was significantly higher than that with the Schwartz equation (1.17 [95% CI 1.16; 1.18] versus 1.08 [95% CI 1.07; 1.09], p < 0.001, t-test). At GFR values of 60–89 ml/min/1.73 m2, the mean ratios with the Schwartz equation were closer to 1 than the mean ratios with the CKD-EPI equation whatever the age class (1.02 [95% CI 1.01; 1.03] versus 1.15 [95% CI 1.13; 1.16], p < 0.001, t-test). In young adults (18–40 y), the Schwartz equation had a better precision and was also more accurate than the CKD-EPI equation at GFR values under 60 ml/min/1.73 m2 (IQR: 0.32 [95% CI 0.28; 0.33] versus 0.40 [95% CI 0.36; 0.44]; P30: 81.4 [95% CI 78.1; 84.7] versus 63.8 [95% CI 59.7; 68.0]) and also at GFR values of 60–89 ml/min/1.73 m2. In all patients aged ≥65 y, the CKD-EPI equation performed better than the Schwartz equation (IQR: 0.33 [95% CI 0.31; 0.34] versus 0.40 [95% CI 0.38; 0.41]; P30: 77.6 [95% CI 75.7; 79.5] versus 67.5 [95% CI 65.4; 69.7], respectively). In children and adolescents (2–17 y), the Schwartz equation was superior to the CKD-EPI equation (IQR: 0.23 [95% CI 0.21; 0.24] versus 0.33 [95% CI 0.31; 0.34]; P30: 88.6 [95% CI 86.7; 90.4] versus 29.4 [95% CI 26.8; 32.0]). This study is limited by its retrospective design, single-center setting with few non-white patients, and small number of patients with severe chronic kidney disease.
The results from this study suggest that the Schwartz equation may be more reliable than the CKD-EPI equation for estimating GFR in children and adolescents and in adults with mild to moderate kidney impairment up to age 40 y.
In this retrospective cross-sectional study, Luciano da Silva Selistre and colleagues compare Schwartz and CDK-EPI equations for estimating glomerular filtration rate in patients of different ages and degrees of renal impairment.
Editors' Summary
Throughout life, our kidneys filter waste products (from food and from the normal breakdown of tissues) and excess water from our blood to make urine. If our kidneys stop working for any reason, the rate at which they filter the blood (the glomerular filtration rate, or GFR) decreases, and dangerous amounts of creatinine and other waste products build up in the blood. Kidneys can stop working suddenly, but in chronic kidney disease (CKD), a condition that affects more than 10% of the world’s population, kidney function declines gradually over many years. The symptoms of CKD, which rarely occur until the disease is very advanced, include tiredness, swollen feet, and frequent urination, especially at night. CKD cannot be cured, but its progression can be slowed by controlling high blood pressure and diabetes and by adopting a healthy lifestyle; the same interventions also reduce the chance of CKD developing in the first place.
Why Was This Study Done?
CKD is linked with an increased risk of end-stage renal (kidney) disease and cardiovascular disease. Early identification of CKD can prevent these life-threatening complications, so clinical practice guidelines have been proposed for the diagnosis and management of CKD in the general population. The assessment of GFR is central to these guidelines. GFR can be measured by infusing inulin, a compound that is eliminated from the body by glomerular filtration, into the blood and measuring its rate of appearance in the urine. However, in routine clinical practice, GFR is usually estimated from blood creatinine levels using a GFR estimating equation (creatinine levels vary considerably within and between individuals, so an equation is needed to convert measured creatinine levels into GFR estimates). Examples of creatinine-based GFR estimation equations include the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation and the Schwartz equation, which were developed in middle-aged adults and children, respectively. Few studies have evaluated the performance of such equations over all ages and levels of kidney impairment, so here the researchers assess the reliability of the CKD-EPI and Schwartz equations for estimating GFR in children, adolescents, and adults.
What Did the Researchers Do and Find?
In 10,610 individuals referred to a single French hospital because of suspected or established kidney disease or before kidney donation, the researchers compared GFR measured by inulin clearance with GFR estimated using the CKD-EPI and Schwartz equations. They evaluated the reliability of each equation by calculating the average (mean) ratio of estimated GFR to measured GFR (a ratio of 1 indicates that the equation yielded GFR values identical to those from the gold-standard inulin clearance test) and by assessing the precision and accuracy of the estimated GFR values: the precision of a measurement indicates its reproducibility and reliability; the accuracy of a measurement indicates its closeness to the true value of a quantity. Across all the participants, the mean ratio of estimated GFR to measured GFR with the Schwartz equation was nearer to 1 than the mean ratio for the CKD-EPI equation. Among participants of all ages with measured GFR values indicating mild loss of kidney function, the mean ratio obtained with Schwartz equation was also nearer to 1 than that obtained with the CKD-EPI equation. Among young adults (18–40 years old) with measured GFR values indicating mild to moderate loss of kidney function, the Schwartz equation had better precision and was more accurate than the CKD-EPI equation, but, in all patients aged ≥65 years, the CKD-EPI equation performed better than the Schwartz equation. Finally, in children and adolescents, the Schwartz equation performed better than the CKD-EPI equation.
What Do These Findings Mean?
Several aspects of this study (for example, its single-site setting and the low numbers of participants with severe CKD) may limit the accuracy and generalizability of its findings. However, these findings suggest that the Schwartz equation may be more reliable than the CKD-EPI equation for estimating GFR in children and adolescents and in adults up to 40 years old with mild to moderate kidney impairment. Up to now, there has been no consensus about when physicians should switch from using the Schwartz equation (which was developed in children) to using the CKD-EPI equation (which was developed in middle-aged adults) to estimate GFR in their patients. The findings of this study might therefore help physicians decide when to make this switch, thereby improving clinical decision-making and possibly helping to reduce the global burden of CKD.
Additional Information
This list of resources contains links that can be accessed when viewing the PDF on a device or via the online version of the article at
The UK National Health Service Choices website provides information for patients on chronic kidney disease, including information on screening for and diagnosing CKD and some personal stories about the disease
The US National Kidney Foundation, a not-for-profit organization, provides information about chronic kidney disease and about the estimation of glomerular filtration rates (in English and Spanish)
The US National Institute of Diabetes and Digestive and Kidney Diseases provides links to information about all aspects of kidney disease and information on creatinine-based GFR estimation equations; the US National Kidney Disease Education Program provides resources to help improve the understanding, detection, and management of kidney disease (in English and Spanish)
World Kidney Day, a joint initiative of the International Society of Nephrology and the International Federation of Kidney Foundations, aims to raise awareness about kidneys and kidney disease
Clinical guidelines for the evaluation and management of CKD produced by the Kidney Disease Improving Global Outcomes not-for-profit foundation are available
MedlinePlus provides links to additional resources about kidney diseases
PMCID: PMC4811544  PMID: 27023756
7.  Kidney Function Decline and Apparent Treatment-Resistant Hypertension in the Elderly 
PLoS ONE  2016;11(1):e0146056.
Cross-sectional studies show a strong association between chronic kidney disease and apparent treatment-resistant hypertension, but the longitudinal association of the rate of kidney function decline with the risk of resistant hypertension is unknown.
The population-based Three-City included 8,695 participants older than 65 years, 4265 of them treated for hypertension. We estimated the odds ratios (OR) of new-onset apparent treatment-resistant hypertension, defined as blood pressure ≥ 140/90 mmHg despite use of 3 antihypertensive drug classes or ≥ 4 classes regardless of blood pressure, associated with the mean estimated glomerular filtration rate (eGFR) level and its rate of decline over 4 years, compared with both controlled hypertension and uncontrolled nonresistant hypertension with ≤ 2 drugs. GFR was estimated with three different equations.
Baseline prevalence of apparent treatment-resistant hypertension and of controlled and uncontrolled nonresistant hypertension, were 6.5%, 62.3% and 31.2%, respectively. During follow-up, 162 participants developed apparent treatment-resistant hypertension. Mean eGFR decline with the MDRD equation was 1.5±2.9 mL/min/1.73 m² per year: 27.7% of the participants had an eGFR ≥3 and 10.1% ≥ 5 mL/min/1.73 m² per year. After adjusting for age, sex, obesity, diabetes, and cardiovascular history, the ORs for new-onset apparent treatment-resistant hypertension associated with a mean eGFR level, per 15 mL/min/1.73m² drop, were 1.23 [95% confidence interval 0.91–1.64] compared to controlled hypertension and 1.10 [0.83–1.45] compared to uncontrolled nonresistant hypertension; ORs associated with a decline rate ≥ 3 mL/min/1.73m² per year were 1.89 [1.09–3.29] and 1.99 [1.19–3.35], respectively. Similar results were obtained when we estimated GFR with the CKDEPI and the BIS1 equations. ORs tended to be higher for an eGFR decline rate ≥ 5 mL/min/1.73m² per year.
The speed of kidney function decline is associated more strongly than kidney function itself with the risk of apparent treatment-resistant hypertension in the elderly.
PMCID: PMC4726557  PMID: 26807712
8.  Longitudinal changes in hematocrit in hypertensive chronic kidney disease: results from the African-American Study of Kidney Disease and Hypertension (AASK) 
Nephrology Dialysis Transplantation  2015;30(8):1329-1335.
Anemia is common in chronic kidney disease (CKD) and associated with poor outcomes. In cross-sectional studies, lower estimated glomerular filtration rate (eGFR) has been associated with increased risk for anemia. The aim of this study was to determine how hematocrit changes as eGFR declines and what factors impact this longitudinal association.
We followed 1094 African-Americans with hypertensive nephropathy who participated in the African-American Study of Kidney Disease and Hypertension. Mixed effects models were used to determine longitudinal change in hematocrit as a function of eGFR. Interaction terms were used to assess for differential effects of age, gender, baseline eGFR, baseline proteinuria, malnutrition and inflammation on eGFR-associated declines in hematocrit. In sensitivity analyses, models were run using iGFR (by renal clearance of I125 iothalamate) in place of eGFR.
At baseline, mean hematocrit was 39% and 441 (40%) individuals had anemia. The longitudinal relationship between eGFR and hematocrit differed by baseline eGFR and was steeper when baseline eGFR was <45 mL/min/1.73 m2. For example, the absolute decline in hematocrit per 10 mL/min/1.73 m2 decline in longitudinal eGFR was −3.7, −1.3 and −0.5% for baseline eGFR values of 20, 40 and 60 mL/min/1.73 m2, respectively (P < 0.001 comparing the longitudinal association between baseline eGFR = 40 or 60 versus baseline eGFR = 20 mL/min/1.73 m2). Similarly, male sex, younger age (<65 years) and higher baseline proteinuria (protein-to-creatinine ratio >0.22) were associated with greater hematocrit declines per unit decrease in longitudinal eGFR compared with female sex, older age and low baseline proteinuria, respectively (P-interaction <0.05 for each comparison). The longitudinal eGFR–hematocrit association did not differ by body mass index, serum albumin or C-reactive protein.
Men, younger individuals and those with low baseline eGFR (<45 mL/min/1.73 m2) or baseline proteinuria are particularly at risk for eGFR-related declines in hematocrit.
PMCID: PMC4513895  PMID: 25817226
African-American Study of Kidney Disease and Hypertension (AASK); anemia; chronic kidney disease; hematocrit
9.  Risk factors for chronic kidney disease in a large cohort of HIV-1 infected individuals initiating antiretroviral therapy in routine care 
AIDS (London, England)  2012;26(15):1907-1915.
To examine long-term effects of antiretroviral therapy (ART) on kidney function, we evaluated the incidence and risk factors for chronic kidney disease (CKD) among ART-naive, HIV-infected adults and compared changes in estimated glomerular filtration rates (eGFR) before and after starting ART.
Multicenter observational cohort study of patients with at least one serum creatinine measurement before and after initiating ART. Cox proportional hazard models, and marginal structure models examined CKD risk factors; mixed-effects linear models examined eGFR slopes.
Three thousand, three hundred and twenty-nine patients met entry criteria, contributing 10 099 person-years of observation on ART. ART was associated with a significantly slower rate of eGFR decline (from −2.18 to −1.37 ml/min per 1.73 m2 per year; P = 0.02). The incidence of CKD defined by eGFR thresholds of 60, 45 and 30 ml/min per 1.73 m2 was 10.5, 3.4 and 1.6 per 1000 person-years, respectively. In adjusted analyses black race, hepatitis C coinfection, lower time-varying CD4 cell count and higher time-varying viral load on ART were associated with higher CKD risk, and the magnitude of these risks increased with more severe CKD. Tenofovir and a ritonavir-boosted protease inhibitor (rPI) was also associated with higher CKD risk [hazard odds ratio for an eGFR threshold <60 ml/min per 1.73 m2: 3.35 (95% confidence interval (CI) = 1.40–8.02)], which developed in 5.7% of patients after 4 years of exposure to this regimen-type.
ART was associated with reduced CKD risk in association with CD4 cell restoration and plasma viral load suppression, despite an increased CKD risk that was associated with initial regimens that included tenofovir and rPI.
PMCID: PMC3531628  PMID: 22824630
antiretroviral therapy; chronic kidney disease; tenofovir
10.  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.
Little is known about normal kidney function level and the prognosis significance of low estimated glomerular filtration rate(eGFR) in the elderly.
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.
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.
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.
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
11.  The association of adiposity with kidney function decline among HIV-infected adults: Findings from the FRAM (Fat Redistribution and Metabolic Changes in HIV Infection) Study 
HIV medicine  2014;16(3):184-190.
To study the association of adiposity with longitudinal kidney function change in 544 HIV-infected persons in Study of Fat Redistribution and Metabolic Change in HIV infection (FRAM) cohort over 5 years of follow-up.
Regional distribution of muscle and adipose tissue was quantified by whole-body MRI, and total adiponectin and leptin levels were measured in serum. Kidney function was assessed by estimated glomerular filtration rate from serum cystatin C (eGFRCys), obtained at baseline and follow-up. Rapid kidney function decline was defined as annual loss of eGFRCys ≥ 3 ml/min/1.73m2, and incident chronic kidney disease (CKD) was defined at eGFRCys < 60 ml/min/1.73m2. Multivariate regression analysis was adjusted for age, race, gender, glucose, antihypertensive use, serum albumin, baseline and change in HIV viral load.
At baseline, mean age was 43 years, mean eGFRCys 86 ml/min/1.73m2, and 21% had albuminuria. Mean (standard deviation) eGFRCys decline was −0.11 ± 4.87 ml/min/1.73m2 per year; 23% of participants had rapid kidney function decline, and 10% developed incident CKD. Lowest tertile of visceral adipose tissue and highest tertile of adiponectin were both marginally associated with annual kidney function decline of −0.5 ml/min/1.73m2 each, but these associations were not statistically significant after adjustment. We found no statistically significant associations of MRI-measured regional adiposity or serum adipokines with rapid kidney function decline or incident CKD (all p-values > 0.1 in adjusted models).
Contrary to findings in the general population, adiposity did not have a substantial association with longitudinal change in kidney function among HIV-infected persons.
PMCID: PMC4320665  PMID: 25251910
adiposity; FRAM; HIV; kidney decline
12.  Inappropriate drug use and mortality in community-dwelling elderly with impaired kidney function--the Three-City population-based study 
Nephrology Dialysis Transplantation  2011;26(9):2852-2859.
Glomerular filtration rate (GFR) decline with age increases the risk of inappropriate dosing of drugs. We investigated the determinants and the mortality associated with the use of drugs that are contraindicated or require dose adjustment according to kidney function among the community-dwelling elderly.
The Three-City population-based study included 8701 participants ≥ 65 years from 1999 to 2001. Exposure to the risk of inappropriate drug dosage was defined as reported use of either a contraindicated drug or one requiring dose adjustment according to the individual baseline glomerular filtration rate estimated (eGFR) with the Modification of Diet in Renal Disease study equation. Six-year mortality was analyzed using Cox models adjusted for several sociodemographic, biologic and clinical risk factors.
The overall percentage of exposure to the risk of inappropriate drug use was 13.3% (contraindication, 0.8%): it was 52.5% (4.5%) in those with eGFR of 30–59, and 96% (48%) in those <30 mL/min/1.73 m2. Antihypertensive agents, fibrates and psycholeptics accounted for most of the drugs with dosing recommendations, and antidiabetic agents and antihistamines for those contraindicated. Individuals at risk were more likely to be men, older, and under treatment for hypertension or hypercholesterolemia. Exposure to either risk was independently related to higher all-cause mortality (Hazard Ratio1.4, 95% confidence interval 1.0–1.9) in participants with eGFR < 60 mL/min/1.73m2.
Contraindicated drug prescription was uncommon but > 10% of the population took drugs requiring renal dosing adjustments. Regular monitoring of eGFR may prevent excess mortality associated with inappropriate drug prescription in the elderly.
PMCID: PMC3907357  PMID: 21292816
Aged; Cohort Studies; Community Health Planning; Drug Toxicity; Female; Follow-Up Studies; France; epidemiology; Glomerular Filtration Rate; Humans; Inappropriate Prescribing; adverse effects; Kidney; physiopathology; Kidney Failure, Chronic; epidemiology; mortality; pathology; Kidney Function Tests; Longitudinal Studies; Male; Prognosis; Prospective Studies; Risk Factors; Survival Rate
13.  Associations of Urinary Levels of Kidney Injury Molecule-1 (KIM-1) and Neutrophil Gelatinase-Associated Lipocalin (NGAL) With Kidney Function Decline in the Multi-Ethnic Study of Atherosclerosis (MESA) 
Whether elevations of urinary biomarkers of tubular injury (urine neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule 1 (KIM-1)) are associated with future risk of kidney disease has not been investigated.
Study Design
1:1 nested case-control study
Setting & Participants
686 participants in the Multi-Ethnic Study of Atherosclerosis (MESA).
NGAL and KIM-1 were measured at baseline and expressed as log-transformed continuous variables and categorized into deciles.
Kidney function was estimated by cystatin C using the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) equation. Incident CKD Stage 3 was defined as eGFR <60 ml/min/1.73m2 and a eGFR decline >1 ml/min/1.73m2 per year, and rapid kidney function decline (RKFD) was defined as decline of ≥3 ml/min/1.73m2 per year.
Cases were defined as persons with eGFR >60 ml/min/1.73m2 who subsequently developed incident CKD Stage 3 and/or had RKFD by MESA year 5 visit. Controls were matched for age, gender, race, diabetes, and baseline eGFR. We adjusted for age, hypertension and presence of albuminuria (ACR ≥30 mg/g).
Of the 343 cases, 145 had incident CKD Stage 3, 141 had RKFD and 57 had both. Mean eGFR for controls was 81 (±10) ml/min/1.73m2 at baseline and 80 (±10) at follow-up, compared with 82 (±13) and 58 (±10) for cases. Each doubling of KIM-1 (pg/ml) was associated with an OR of 1.15 (95% CI, 1.02-1.29) for incident CKD Stage 3 and/or RKFD. Compared to the lowest 90%, the highest decile of KIM-1 was associated with an OR of 2.02 (95% CI, 1.15-3.56) for the outcome; these associations were independent of albuminuria. NGAL levels (ng/ml) were not associated with incident CKD Stage 3 and/or RKFD (OR, 1.04; 95% CI, 0.99-1.10). Results were similar when KIM-1 and NGAL were standardized for urine creatinine.
The case-control design limits ability to account for persons who died or were not available for follow-up.
Urinary KIM-1 is associated with future risk of kidney disease independent of albuminuria. Urinary biomarkers of tubular injury are a promising tool for identifying persons at risk for CKD.
PMCID: PMC3690926  PMID: 22749388
KIM-1; NGAL; kidney function decline
14.  Blood pressure and chronic kidney disease progression in a multi-racial cohort: the Multi-Ethnic Study of Atherosclerosis 
Journal of human hypertension  2013;27(7):10.1038/jhh.2013.1.
The relationship between blood pressure (BP) and kidney function among individuals with chronic kidney disease (CKD) remains controversial. This study evaluated the association between BP and estimated glomerular filtration rate (eGFR) decline among adults with nondiabetic stage 3 CKD. The Multi-Ethnic Study of Atherosclerosis participants with an eGFR 30–59 ml min–1 per 1.73 m2 at baseline without diabetes were included. Participants were followed over a 5-year period. Kidney function change was determined by annualizing the change in eGFR using cystatin C, creatinine and a combined equation. Risk factors for progression of CKD (defined as a decrease in annualized eGFR >2.5 ml min–1 per 1.73 m2) were identified using univariate analyses and sequential logistic regression models. There were 220 participants with stage 3 CKD at baseline using cystatin C, 483 participants using creatinine and 381 participants using the combined equation. The median (interquartile range) age of the sample was 74 (68–79) years. The incidence of progression of CKD was 16.8% using cystatin C and 8.9% using creatinine (P = 0.002). Systolic BP >140 mm Hg or diastolic BP >90 mm Hg was significantly associated with progression using a cystatin C-based (odds ratio (OR), 2.49; 95% confidence interval (CI), 1.12–5.52) or the combined equation (OR, 2.07; 95% CI, 1.16–3.69), but not when using creatinine after adjustment for covariates. In conclusion, with the inclusion of cystatin C in the eGFR assessment hypertension was an important predictor of CKD progression in a multi-ethnic cohort with stage 3 CKD.
PMCID: PMC3830562  PMID: 23407373
blood pressure; glomerular filtration rate; renal disease; cystatin C; creatinine; ethnicity
15.  Antiretroviral-Treated HIV-Infected Women Have Similar Long-Term Kidney Function Trajectories as HIV-Uninfected Women 
Natural history studies suggest increased risk for kidney function decline with HIV infection, but few studies have made comparisons with HIV-uninfected women. We examined whether HIV infection treated with highly active antiretroviral therapy (HAART) remains associated with faster kidney function decline in the Women's Interagency HIV Study. HIV-infected women initiating HAART with (n=105) or without (n=373) tenofovir (TDF) were matched to HIV-uninfected women on calendar and length of follow-up, age, systolic blood pressure, hepatitis C antibody serostatus, and diabetes history. Linear mixed models were used to evaluate differences in annual estimated glomerular filtration rate (eGFR). Person-visits were 4,741 and 11,512 for the TDF-treated and non-TDF-treated analyses, respectively. Mean baseline eGFRs were higher among women initiated on TDF-containing HAART and lower among those on TDF-sparing HAART compared to their respective HIV-uninfected matches (p<0.05 for both). HIV-infected women had annual rates of eGFR changes similar to HIV-uninfected matches (p-interaction >0.05 for both). Adjusting for baseline eGFR, mean eGFRs at 1 and 3 years of follow-up among women initiated on TDF-containing HAART were lower than their uninfected matches (−4.98 and −4.26 ml/min/1.73 m2, respectively; p<0.05 for both). Mean eGFR of women initiated on TDF-sparing HAART was lower versus uninfected matches at 5 years (–2.19 ml/min/1.73 m2, p=0.03). HAART-treated HIV-infected women had lower mean eGFRs at follow-up but experienced rates of annual eGFR decline similar to HIV-uninfected women. Tenofovir use in HIV-infected women with normal kidney function did not accelerate long-term kidney function decline relative to HIV-uninfected women.
PMCID: PMC3636577  PMID: 23273313
16.  Soluble Urokinase Receptor and Chronic Kidney Disease 
The New England journal of medicine  2015;373(20):1916-1925.
Relatively high plasma levels of soluble urokinase-type plasminogen activator receptor (suPAR) have been associated with focal segmental glomerulosclerosis and poor clinical outcomes in patients with various conditions. It is unknown whether elevated suPAR levels in patients with normal kidney function are associated with future decline in the estimated glomerular filtration rate (eGFR) and with incident chronic kidney disease.
We measured plasma suPAR levels in 3683 persons enrolled in the Emory Cardiovascular Biobank (mean age, 63 years; 65% men; median suPAR level, 3040 pg per milliliter) and determined renal function at enrollment and at subsequent visits in 2292 persons. The relationship between suPAR levels and the eGFR at baseline, the change in the eGFR over time, and the development of chronic kidney disease (eGFR <60 ml per minute per 1.73 m2 of body-surface area) were analyzed with the use of linear mixed models and Cox regression after adjustment for demographic and clinical variables.
A higher suPAR level at baseline was associated with a greater decline in the eGFR during follow-up; the annual change in the eGFR was −0.9 ml per minute per 1.73 m2 among participants in the lowest quartile of suPAR levels as compared with −4.2 ml per minute per 1.73 m2 among participants in the highest quartile (P<0.001). The 921 participants with a normal eGFR (≥90 ml per minute per 1.73 m2) at baseline had the largest suPAR-related decline in the eGFR. In 1335 participants with a baseline eGFR of at least 60 ml per minute per 1.73 m2, the risk of progression to chronic kidney disease in the highest quartile of suPAR levels was 3.13 times as high (95% confidence interval, 2.11 to 4.65) as that in the lowest quartile.
An elevated level of suPAR was independently associated with incident chronic kidney disease and an accelerated decline in the eGFR in the groups studied. (Funded by the Abraham J. and Phyllis Katz Foundation and others.)
PMCID: PMC4701036  PMID: 26539835
17.  Hepatitis C Seropositivity and Kidney Function Decline Among Women With HIV: Data From the Women's Interagency HIV Study 
How co-infection with hepatitis C virus (HCV) impacts on the trajectory of kidney function among HIV-infected patients is unclear. This study examined the effect of HCV on kidney function over time among women infected with HIV.
Study Design
Retrospective observational cohort
Setting and Participants
Study sample included participants from the Women's Interagency HIV Study who were HIV-infected and had received HCV antibody testing and serum creatinine measurement at baseline.
HCV seropositivity
Outcomes and Measurement
Estimated glomerular filtration rate (eGFR) calculated from semi-annual serum creatinine measurements using the 4-variable Modification of Diet in Renal Diseases (MDRD) Study equation. Linear mixed models were used to evaluate the independent effect of being HCV seropositive on eGFR over time, adjusting for demographic factors, co-morbid conditions, illicit drug use, measures of HIV disease status, use of medications, and interactions with baseline low eGFR (<60 mL/min/1.73m2).
Of the 2,684 HIV-infected women, 952 (35%) were found to be HCV seropositive. For 180 women with CKD at baseline (eGFR <60 mL/min/1.73m2), being HCV seropositive was independently associated with a fully-adjusted net decline in eGFR of about 5% per year (95% CI: 3.2 to 7.2%), relative to women who were seronegative. In contrast, HCV was not independently associated with decline in eGFR among women without low eGFR at baseline (p<0.001 for interaction).
The MDRD Study equation has not been validated as a measure of GFR among persons with HIV or HCV. Proteinuria was not included in the study analysis. Because the study is observational, the effects of residual confounding cannot be excluded.
Among HIV-infected women with CKD, co-infection with HCV is associated with a modest, but statistically significant decline in eGFR over time. More careful monitoring of kidney function may be warranted for HIV-infected patients with CKD who are also co-infected with HCV.
PMCID: PMC2997705  PMID: 19394735
hepatitis C virus; HIV; kidney diseases; women
18.  Kidney function is associated with the rate of cognitive decline in the elderly 
Neurology  2009;73(12):920-927.
We tested the hypothesis that impaired kidney function in the elderly is associated with a more rapid rate of cognitive decline.
Baseline serum was used to calculate estimated glomerular filtration rate (eGFR), using the Modification of Diet in Renal Disease formula, for 886 elderly without dementia participating in the Rush Memory and Aging Project, a prospective, observational cohort study. Kidney function was also dichotomized into impairment or no impairment based on eGFR < or ≥60 mL/min/1.73 m2. Structured cognitive testing was performed at baseline and at annual evaluations, using a battery of 19 cognitive tests summarized into global cognition and 5 cognitive domains.
In mixed-effects models adjusted for age, sex, and education, a lower eGFR at baseline was associated with a more rapid rate of cognitive decline (estimate 0.0008, SE <0.001, p = 0.017). The increased rate of cognitive decline associated with a 15-mL/min/1.73 m2 lower eGFR at baseline (approximately 1 SD) was similar to the effect of being 3 years older at baseline. Impaired kidney function at baseline was associated with a more rapid rate of cognitive decline (estimate −0.028, SE <0.009, p = 0.003). The increased rate of cognitive decline associated with impaired kidney function at baseline was approximately 75% the effect of ApoE4 allele on the rate of cognitive decline. Baseline kidney function was associated with declines in semantic memory, episodic memory, and working memory but not visuospatial abilities or perceptual speed.
Impaired kidney function is associated with a more rapid rate of cognitive decline in old age.
= Alzheimer disease;
= body mass index;
= creatinine;
= estimated glomerular filtration rate.
PMCID: PMC2754333  PMID: 19657107
19.  Relationship between low Ankle-Brachial Index and rapid renal function decline in patients with atrial fibrillation: a prospective multicentre cohort study 
BMJ Open  2015;5(5):e008026.
To investigate the relationship between Ankle-Brachial Index (ABI) and renal function progression in patients with atrial fibrillation (AF).
Observational prospective multicentre cohort study.
Atherothrombosis Center of I Clinica Medica of ‘Sapienza’ University of Rome; Department of Medical and Surgical Sciences of University Magna Græcia of Catanzaro; Atrial Fibrillation Registry for Ankle-Brachial Index Prevalence Assessment-Collaborative Italian Study.
897 AF patients on treatment with vitamin K antagonists.
Main outcome measures
The relationship between basal ABI and renal function progression, assessed by the estimated Glomerular Filtration Rate (eGFR) calculated with the CKD-EPI formula at baseline and after 2 years of follow-up. The rapid decline in eGFR, defined as a decline in eGFR >5 mL/min/1.73 m2/year, and incident eGFR<60 mL/min/1.73 m2 were primary and secondary end points, respectively.
Mean age was 71.8±9.0 years and 41.8% were women. Low ABI (ie, ≤0.90) was present in 194 (21.6%) patients. Baseline median eGFR was 72.7 mL/min/1.73 m2, and 28.7% patients had an eGFR<60 mL/min/1.73 m2. Annual decline of eGFR was −2.0 (IQR −7.4/−0.4) mL/min/1.73 m2/year, and 32.4% patients had a rapid decline in eGFR. Multivariable logistic regression analysis showed that ABI ≤0.90 (OR 1.516 (95% CI 1.075 to 2.139), p=0.018) and arterial hypertension (OR 1.830 95% CI 1.113 to 3.009, p=0.017) predicted a rapid eGFR decline, with an inverse association for angiotensin converting enzyme (ACE) inhibitors/angiotensin receptor blockers (OR 0.662 95% CI 0.464 to 0.944, p=0.023). Among the 639 patients with AF with eGFR >60 mL/min/1.73 m2, 153 (23.9%) had a reduction of the eGFR <60 mL/min/1.73 m2. ABI ≤0.90 was also an independent predictor for incident eGFR<60 mL/min/1.73 m2 (HR 1.851, 95% CI 1.205 to 2.845, p=0.005).
In patients with AF, an ABI ≤0.90 is independently associated with a rapid decline in renal function and incident eGFR<60 mL/min/1.73 m2. ABI measurement may help identify patients with AF at risk of renal function deterioration.
Trial registration number
PMCID: PMC4442172  PMID: 25998039
20.  Metformin initiation and renal impairment: a cohort study in Denmark and the UK 
BMJ Open  2015;5(9):e008531.
To estimate prevalence of renal impairment, rate of decline in kidney function and changes in metformin use after decline in kidney function, in metformin initiators.
Design, setting and participants
We conducted this 2-country cohort study using routine data from northern Denmark and the UK during 2000–2011. We included metformin initiators among patients aged ≥30 years with medically treated diabetes.
Main outcome measures
We described patients’ demographics, comorbidity, co-medications and their estimated glomerular filtration rates (eGFR). Furthermore, we described the patients’ characteristics according to eGFR level. Finally, we examined the rate of any decline in eGFR and changes in metformin use within 90 days after first decline in eGFR during follow-up.
We included 124 720 metformin initiators in the 2 countries. Prevalence of eGFR <60 mL/min/1.73 m2 among metformin initiators was 9.0% in Denmark and 25.2% in the UK. In contrast, prevalence of eGFR values <30 mL/min/1.73 m2 among metformin initiators was 0.3% in Denmark and 0.4% in the UK. Patients with renal impairment were older and more likely to have received cardiovascular drugs. Incidence rate of decline in renal function was 4.92 per 100 person-years (95% CI 4.76 to 5.09) in Denmark and 7.48 per 100 person-years (95% CI 7.39 to 7.57) in the UK. The proportion of patients continuing metformin use, even after a first decline brought the eGFR below 30 mL/min/1.73 m2, was 44% in Denmark and 62% in the UK. There was no clinically significant dose reduction with decreasing baseline eGFR level discernible from the data.
Mild to moderate renal impairment was common among metformin initiators, while severe renal impairment was uncommon. Patients with severe renal impairment frequently continued receiving/redeeming metformin prescriptions even 90 days after eGFR decline.
PMCID: PMC4563232  PMID: 26338686
21.  Serum Albumin and Kidney Function Decline in HIV-Infected Women 
Serum albumin concentrations are a strong predictor of mortality and cardiovascular disease in HIV-infected individuals. We studied the longitudinal associations between serum albumin levels and kidney function decline in a population of HIV-infected women.
Study Design
Retrospective cohort analysis.
Setting & Participants
The study participants were recruited from the Women’s Interagency HIV Study (WIHS), a large observational study designed to understand risk factors for the progression of HIV infection in women living in urban communities. 908 participants had baseline assessment of kidney function and two follow-up measures over an average of 8 years.
The primary predictor was serum albumin concentration.
We examined annual change in kidney function. Secondary outcomes included rapid kidney function decline and incident reduced estimated glomerular filtration rate (eGFR).
Kidney function decline was determined by cystatin C–based (eGFRcys) and creatinine-based eGFR (eGFRcr) at baseline and follow up. Each model was adjusted for kidney disease and HIV-related risk factors using linear and relative risk regression.
After multivariate adjustment, each 0.5-g/dL decrement in baseline serum albumin concentration was associated with a 0.56-mL/min faster annual decline in eGFRcys (P<0.001), which was only slightly attenuated to 0.55-mL/min/1.73 m2 after adjustment for albuminuria. Results were similar whether using eGFRcys or eGFRcr. In adjusted analyses, each 0.5-g/dL lower baseline serum albumin was associated with a 1.71-fold greater risk of rapid kidney function decline (p<0.001) and a 1.72-fold greater risk of incident reduced eGFR (p<0.001).
The cohort is composed of only female participants from urban communities within the United States.
Lower levels of serum albumin were strongly associated with kidney function decline and incident reduced eGFR in HIV-infected women, independent of HIV disease status, BMI and albuminuria.
PMCID: PMC4177337  PMID: 25059222
albumin; kidney function; HIV; incident reduced eGFR; albuminuria; disease trajectory; chronic kidney disease (CKD) progression
22.  Removal of Kidney Stones by Extracorporeal Shock Wave Lithotripsy Is Associated with Delayed Progression of Chronic Kidney Disease 
Yonsei Medical Journal  2012;53(4):708-714.
This study aimed to elucidate whether stone removal by extracorporeal shock wave lithotripsy (ESWL) is associated with delayed chronic kidney disease (CKD) progression.
Materials and Methods
We conducted a retrospective analysis of 131 nephrolithiasis patients with stage 3 and 4 CKD. We collected baseline clinical and laboratory data, kidney stone characteristics, and history of receiving ESWL. We classified study patients into two groups according to whether they underwent ESWL or not (Non-ESWL group vs. ESWL group). We initially compared annual estimated glomerular filtration rate (eGFR) changes of Non-ESWL group with those of ESWL group before undergoing ESWL. In the next step, we sought to compare annual eGFR changes in the same patients before and after ESWL. Finally, we compared annual eGFR changes between success and failure groups among patients undergoing ESWL.
The mean age of the patients was 62 years and 72.5% were male. The mean observation period was 3.2 years. Non-ESWL group and ESWL group before undergoing ESWL showed similar annual eGFR changes (-1.75±6.5 vs. -1.63±7.2 mL/min/1.73 m2/year, p=0.425). However, eGFR declined slower after undergoing ESWL than before ESWL (annual eGFR changes, -0.29±6.1 vs. -1.63±7.2 mL/min/1.73 m2/year, p<0.05). In addition, among patients in ESWL group, eGFR declined faster in the failure group than in the success group (annual eGFR change, -1.01±4.7 vs. -0.05±5.2 mL/min/1.73 m2/year, p<0.05).
Our results suggest that stone removal by ESWL is associated with delayed deterioration of renal function in CKD patients with nephrolithiasis.
PMCID: PMC3381494  PMID: 22665335
Nephrolithiasis; chronic kidney disease; extracorporeal shock wave lithotripsy (ESWL); glomerular filtration rate (GFR)
23.  The Chronic Kidney Disease-Epidemiology Collaboration (CKD-EPI) equation does not improve the underestimation of Glomerular Filtration Rate (GFR) in people with diabetes and preserved renal function 
BMC Nephrology  2015;16:198.
Our hypothesis was that both the Chronic Kidney Disease-Epidemiology Collaboration (CKD-EPI) and Modification of Diet in Renal Disease (MDRD) equations would underestimate directly measured GFR (mGFR) to a similar extent in people with diabetes and preserved renal function.
In a cross-sectional study, bias (eGFR – mGFR) was compared for the CKD-EPI and MDRD equations, after stratification for mGFR levels. We also examined the ability of the CKD-EPI compared with the MDRD equation to correctly classify subjects to various CKD stages. In a longitudinal study of subjects with an early decline in GFR i.e., initial mGFR >60 ml/min/1.73 m2 and rate of decline in GFR (ΔmGFR) > 3.3 ml/min/1.73 m2 per year, ΔmGFR (based on initial and final values) was compared with ΔeGFR by the CKD-EPI and MDRD equations over a mean of 9 years.
In the cross-sectional study, mGFR for the whole group was 80 ± 2.2 ml/min/1.73 m2 (n = 199, 75 % type 2 diabetes). For subjects with mGFR >90 ml/min/1.73 m2 (mGFR: 112 ± 2.0, n = 76), both equations significantly underestimated mGFR to a similar extent: bias for CKD-EPI: -12 ± 1.4 ml/min/1.73 m2 (p < 0.001) and for MDRD: -11 ± 2.1 ml/min/1.73 m2 (p < 0.001). Using the CKD-EPI compared with the MDRD equation did not improve the number of subjects that were correctly classified to a CKD-stage. No biochemical or clinical patient characteristics were identified to account for the under estimation of mGFR values in the normal to high range by the CKD-EPI equation. In the longitudinal study (n = 30, 66 % type 1 diabetes), initial and final mGFR values were 102.8 ± 6 and 54.6 ± 6.0 ml/min/1.73 m2, respectively. Mean ΔGFR (ml/min/1.73 m2 per year) was 6.0 by mGFR compared with only 3.0 by MDRD and 3.2 by CKD-EPI (both p < 0.05 vs mGFR)
Both the CKD-EPI and MDRD equations underestimate reference GFR values >90 ml/min/1.73 m2 as well as an early decline in GFR to a similar extent in people with diabetes. There is scope to improve methods for estimating an early decline in GFR.
PMCID: PMC4668645  PMID: 26630928
Diabetes; Chronic; Kidney Disease; Nephropathy; CKD-EPI equation; Glomerular filtration rate
24.  Associations of N-terminal pro–B-type natriuretic peptide with kidney function decline in persons without clinical heart failure in the Heart and Soul Study 
American heart journal  2014;168(6):931-939.e2.
Subclinical volume overload in the absence of diagnosed heart failure (HF) may be an underrecognized contributor to kidney function decline in coronary artery disease (CAD) patients. We evaluated associations of circulating N-terminal pro–B-type natriuretic peptide (NT-proBNP), a marker of ventricular stretch, with change in estimated glomerular filtration rate (eGFR).
We evaluated 535 patients with stable CAD and no history of HF, who were enrolled in the Heart and Soul Study and followed up for 5 years. N-terminal pro–B-type natriuretic peptide was measured at baseline. We evaluated the associations of NT-proBNP with change in kidney function over 5 years: (a) annual percent change in eGFR, (b) rapid kidney function loss (>3% per year for 5 years), and (c) incident eGFR <60 mL/min per 1.73 m2. In multivariable models, we adjusted for demographics, comorbid conditions, echocardiographic parameters, medications, and baseline kidney function.
Among 535 participants, median NT-proBNP was 130.6 (interquartile range 61.8-280.9) pg/mL, and median B-type natriuretic peptide (BNP) was 32.5 (14.4-75.9) pg/mL. Individuals with NT-proBNP levels in the highest quartile (>280.9 pg/mL) had a greater odds of rapid kidney function loss after full adjustment (odds ratio 2.95; 95% CI 1-8.65; P = .0492). Associations with incident eGFR <60 mL/min per 1.73 m2 were also significant (adjusted odds ratio 4.23; 95% CI 1.05-16.98; P = .0422). Results were similar when analyzed using BNP as the predictor.
N-terminal pro–B-type natriuretic peptide and BNP are strongly and independently associated with accelerated kidney function loss, even in the absence of clinical HF. These findings suggest that subclinical cardiovascular dysfunction may contribute to elevated kidney disease risk in persons with CAD.
PMCID: PMC4254643  PMID: 25458658
25.  Progression of Kidney Disease in Moderately Hypercholesterolemic, Hypertensive Patients Randomized to Pravastatin Versus Usual Care: A Report From the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) 
Dyslipidemia is common in patients with chronic kidney disease. The role of statin therapy on the progression of kidney disease is unclear.
Study Design
Prospective randomized clinical trial, post hoc analyses.
Setting and participants
10,060 participants in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) (lipid-lowering component) stratified by baseline eGFR: <60, 60–89, ≥90 mL/min/1.73 m2. Mean follow-up was 4.8 years.
Randomized, pravastatin 40 mg/day or usual care.
Outcomes and measurements
Total cholesterol, HDL- and LDL-cholesterol; end stage renal disease (ESRD), estimated glomerular filtration rate (eGFR).
Through year six, total cholesterol declined in the pravastatin (−20.7%) and usual care groups (−11.2%). No significant differences were seen between the groups for rates of ESRD (1.36 vs 1.45/100 patient years, P=0.9), composite endpoints of ESRD and 50% or 25% decline in eGFR, or rate of change of eGFR. Findings were consistent across eGFR strata. In patients with eGFR≥90 mL/min/1.73 m2, the pravastatin arm tended to have a higher eGFR.
Proteinuria data unavailable, post hoc analyses, unconfirmed validity of the Modification of Diet in Renal Disease Study equation in normal eGFR range, statin drop-in rate in usual care group with small cholesterol differential between groups.
In hypertensive patients with moderate dyslipidemia and reduced eGFR, pravastatin was not superior to usual care in preventing clinical renal outcomes. This was consistent across the strata of baseline eGFR. However, benefit from statin therapy may depend on degree of cholesterol reduction achieved.
PMCID: PMC2897819  PMID: 18676075
hyperlipidemia; glomerular filtration rate; pravastatin

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