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1.  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.
Objective
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.
Methods
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.
Results
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.
Conclusion
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.
doi:10.1097/QAD.0b013e328357f5ed
PMCID: PMC3531628  PMID: 22824630
antiretroviral therapy; chronic kidney disease; tenofovir
2.  Tenofovir Treatment Duration Predicts Proteinuria in a Multi-Ethnic United States Cohort of Children and Adolescents with Perinatal HIV-1 Infection 
Background
Tenofovir is associated with renal proximal tubule injury. Such toxicity has not been extensively studied in HIV-1-infected children, in whom tenofovir is increasingly used.
Methods
History, urine and blood were collected at regular intervals from 448 children and adolescents with perinatal HIV-1 infection followed in the Pediatric HIV/AIDS Cohort study. Relationships between tenofovir use and proteinuria and chronic kidney disease (CKD) outcomes were examined using multivariable logistic regression models. Proteinuria was defined as at least one urine protein/creatinine ratio (uPCR) ≥0.2, and CKD as ≥2 sequential uPCR ≥0.2 or estimated glomerular filtration rates (eGFR) <60 mL/min/1.73 m2 with no subsequent resolution, or a clinical diagnosis not contradicted by a normal uPCR. Subjects with ≥2 uPCR <0.2, and no abnormal uPCR and eGFR comprised the comparison group.
Results
Subjects were 47% male, 72% black, 24% Hispanic, with entry mean age (±standard deviation) of 11.5±2.5 years. Proteinuria prevalence at entry, and annually during 3 years, ranged from 10.3%–13.7%. The cumulative prevalence of proteinuria was 22% (94/434, 95% CI: 18%–26%) and CKD 4.5% (20/448, 95% CI: 2.7%–6.8%). Duration of tenofovir use was an independent predictor of proteinuria, with >3 years of exposure having the highest risk compared with no exposure (OR: 2.53, 95% CI: 1.23- 5.22, overall p=0.01). Overall, duration of tenofovir use did not significantly predict the presence of CKD.
Conclusions
Rates of proteinuria and CKD were lower than those seen in the pre-HAART era. However, prolonged exposure to tenofovir increases risk of renal injury.
doi:10.1097/INF.0b013e31827f4eff
PMCID: PMC3800277  PMID: 23249917
Tenofovir; proteinuria; chronic kidney disease; proximal tubules; nephrotoxicity; urine protein/creatinine ratio
3.  Factors associated with renal dysfunction within an urban HIV-infected cohort in the era of highly active antiretroviral therapy 
HIV medicine  2009;10(6):343-350.
Background
Kidney disease remains a prevalent problem in HIV care. The contribution of highly active antiretroviral therapy (HAART), HIV disease factors and traditional factors needs further evaluation.
Methods
A cross-sectional study of all patients seen at an HIV outpatient clinic during 2005 was performed. All data were collected from medical record review. Multivariate regression modelling was used to identify independent predictors of lower glomerular filtration rate (eGFR) and chronic renal failure (CRF) from factors significant in univariate analysis. eGFR was calculated using the simplified modification of diet in renal disease equation. Results were compared with those for persons from the National Health and Nutrition Examination Survey (NHANES) matched for age, race and gender.
Results
Of 845 HIV-infected persons, 64% were men and 34% were Caucasian, and the mean age was 39.8 years. Thirty per cent of the patients had proteinuria and 43% had eGFR<90 mL/min/1.73 m2. Persons on HAART (63%) had a lower mean eGFR than those not on HAART (92.0 vs. 101.6). In multivariate analyses, significant predictors of eGFR decline were diagnoses of hypertension, hyperlipidaemia, proteinuria, use of tenofovir or stavudine, and lower viral load. Compared with those in NHANES, HIV-infected persons had a lower mean eGFR (94.9 vs. 104.2) and a higher prevalence of CRF (8% vs. 2%).
Conclusion
In this cohort, the prevalence of CRF is low, but remains higher than that of the general population. Clinicians should routinely screen for early asymptomatic kidney disease to address risk factors that can be treated.
doi:10.1111/j.1468-1293.2009.00693.x
PMCID: PMC3918930  PMID: 19490182
AIDS; chronic kidney disease; highly active antiretroviral therapy; HIV
4.  Association of Non-alcoholic Fatty Liver Disease with Chronic Kidney Disease: A Systematic Review and Meta-analysis 
PLoS Medicine  2014;11(7):e1001680.
In a systematic review and meta-analysis, Giovanni Musso and colleagues examine the association between non-alcoholic fatty liver disease and chronic kidney disease.
Please see later in the article for the Editors' Summary
Background
Chronic kidney disease (CKD) is a frequent, under-recognized condition and a risk factor for renal failure and cardiovascular disease. Increasing evidence connects non-alcoholic fatty liver disease (NAFLD) to CKD. We conducted a meta-analysis to determine whether the presence and severity of NAFLD are associated with the presence and severity of CKD.
Methods and Findings
English and non-English articles from international online databases from 1980 through January 31, 2014 were searched. Observational studies assessing NAFLD by histology, imaging, or biochemistry and defining CKD as either estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m2 or proteinuria were included. Two reviewers extracted studies independently and in duplicate. Individual participant data (IPD) were solicited from all selected studies. Studies providing IPD were combined with studies providing only aggregate data with the two-stage method. Main outcomes were pooled using random-effects models. Sensitivity and subgroup analyses were used to explore sources of heterogeneity and the effect of potential confounders. The influences of age, whole-body/abdominal obesity, homeostasis model of insulin resistance (HOMA-IR), and duration of follow-up on effect estimates were assessed by meta-regression. Thirty-three studies (63,902 participants, 16 population-based and 17 hospital-based, 20 cross-sectional, and 13 longitudinal) were included. For 20 studies (61% of included studies, 11 cross-sectional and nine longitudinal, 29,282 participants), we obtained IPD. NAFLD was associated with an increased risk of prevalent (odds ratio [OR] 2.12, 95% CI 1.69–2.66) and incident (hazard ratio [HR] 1.79, 95% CI 1.65–1.95) CKD. Non-alcoholic steatohepatitis (NASH) was associated with a higher prevalence (OR 2.53, 95% CI 1.58–4.05) and incidence (HR 2.12, 95% CI 1.42–3.17) of CKD than simple steatosis. Advanced fibrosis was associated with a higher prevalence (OR 5.20, 95% CI 3.14–8.61) and incidence (HR 3.29, 95% CI 2.30–4.71) of CKD than non-advanced fibrosis. In all analyses, the magnitude and direction of effects remained unaffected by diabetes status, after adjustment for other risk factors, and in other subgroup and meta-regression analyses. In cross-sectional and longitudinal studies, the severity of NAFLD was positively associated with CKD stages. Limitations of analysis are the relatively small size of studies utilizing liver histology and the suboptimal sensitivity of ultrasound and biochemistry for NAFLD detection in population-based studies.
Conclusion
The presence and severity of NAFLD are associated with an increased risk and severity of CKD.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Chronic kidney disease (CKD)—the gradual loss of kidney function—is becoming increasingly common. In the US, for example, more than 10% of the adult population (about 26 million people) and more than 25% of individuals older than 65 years have CKD. Throughout life, the kidneys perform the essential task of filtering waste products (from the normal breakdown of tissues and from food) and excess water from the blood to make urine. CKD gradually destroys the kidneys' filtration units, the rate of blood filtration decreases, and dangerous amounts of waste products build up in the blood. Symptoms of CKD, which rarely occur until the disease is very advanced, include tiredness, swollen feet, and frequent urination, particularly at night. There is no cure for CKD, but progression of the disease can be slowed by controlling high blood pressure and diabetes (two risk factors for CKD), and by adopting a healthy lifestyle. The same interventions also reduce the chances of CKD developing in the first place.
Why Was This Study Done?
CKD is associated with an increased risk of end-stage renal (kidney) disease and of cardiovascular disease. These life-threatening complications are potentially preventable through early identification and treatment of CKD. Because early recognition of CKD has the potential to reduce its health-related burden, the search is on for new modifiable risk factors for CKD. One possible new risk factor is non-alcoholic fatty liver disease (NAFLD), which, like CKD is becoming increasingly common. Healthy livers contain little or no fat but, in the US, 30% of the general adult population and up to 70% of patients who are obese or have diabetes have some degree of NAFLD, which ranges in severity from simple fatty liver (steatosis), through non-alcoholic steatohepatitis (NASH), to NASH with fibrosis (scarring of the liver) and finally cirrhosis (extensive scarring). In this systematic review and meta-analysis, the researchers investigate whether NAFLD is a risk factor for CKD by looking for an association between the two conditions. A systematic review identifies all the research on a given topic using predefined criteria, meta-analysis uses statistical methods to combine the results of several studies.
What Did the Researchers Do and Find?
The researchers identified 33 studies that assessed NAFLD and CKD in nearly 64,000 participants, including 20 cross-sectional studies in which participants were assessed for NAFLD and CKD at a single time point and 13 longitudinal studies in which participants were assessed for NAFLD and then followed up to see whether they subsequently developed CKD. Meta-analysis of the data from the cross-sectional studies indicated that NAFLD was associated with a 2-fold increased risk of prevalent (pre-existing) CKD (an odds ratio [OR]of 2.12; an OR indicates the chance that an outcome will occur given a particular exposure, compared to the chance of the outcome occurring in the absence of that exposure). Meta-analysis of data from the longitudinal studies indicated that NAFLD was associated with a nearly 2-fold increased risk of incident (new) CKD (a hazard ratio [HR] of 1.79; an HR indicates often a particular event happens in one group compared to how often it happens in another group, over time). NASH was associated with a higher prevalence and incidence of CKD than simple steatosis. Similarly, advanced fibrosis was associated with a higher prevalence and incidence of CKD than non-advanced fibrosis.
What Do These Findings Mean?
These findings suggest that NAFLD is associated with an increased prevalence and incidence of CKD and that increased severity of liver disease is associated with an increased risk and severity of CKD. Because these associations persist after allowing for established risk factors for CKD, these findings identify NAFLD as an independent CKD risk factor. Certain aspects of the studies included in this meta-analysis (for example, only a few studies used biopsies to diagnose NAFLD; most used less sensitive tests that may have misclassified some individuals with NAFLD as normal) and the methods used in the meta-analysis may limit the accuracy of these findings. Nevertheless, these findings suggest that individuals with NAFLD should be screened for CKD even in the absence of other risk factors for the disease, and that better treatment of NAFLD may help to prevent CKD.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001680.
The US National Kidney and Urologic Diseases Information Clearinghouse provides information about all aspects of kidney disease; the US National Digestive Diseases Information Clearinghouse provides information about non-alcoholic liver disease
The US National Kidney Disease Education Program provides resources to help improve the understanding, detection, and management of kidney disease (in English and Spanish)
The UK National Health Service Choices website provides information for patients on chronic kidney disease, including some personal stories, and information on non-alcoholic fatty liver disease
The US National Kidney Foundation, a not-for-profit organization, provides information about chronic kidney disease (in English and Spanish)
The not-for-profit UK National Kidney Federation provides support and information for patients with kidney disease and for their carers
The British Liver Trust, a not-for-profit organization, provides information about non-alcoholic fatty liver disease, including a patient story
doi:10.1371/journal.pmed.1001680
PMCID: PMC4106719  PMID: 25050550
5.  Risk Factors for ESRD in HIV-Infected Individuals: Traditional and HIV-Related Factors 
Background
Despite improvements in survival with HIV infection, kidney disease remains an important complication. Few studies have evaluated risk factors associated with development of end-stage renal disease (ESRD) in HIV-infected individuals. We sought to identify traditional and HIV-related risk factors for ESRD in HIV-infected individuals, and to compare ESRD risk by eGFR and proteinuria levels.
Study design
Retrospective cohort study.
Setting and Participants
22,156 HIV-infected veterans without preexisting ESRD receiving healthcare in the Veterans’ Affairs medical system between 1996 and 2004.
Predictors
Hypertension, diabetes, cardiovascular disease, hypoalbuminemia (serum albumin<3.5mg/dL), CD4 lymphocyte count, HIV viral load, hepatitis C virus coinfection, proteinuria, and estimated glomerular filtration rate (eGFR) were identified using the Veterans’ Affairs electronic record system.
Outcomes
ESRD was ascertained by the United States Renal Data System.
Results
366 cases of ESRD occurred, corresponding to 3 cases per 1,000 person-years. Hypertension (HR, 1.9; 95% CI, 1.5–2.4), diabetes (HR, 1.7; 95% CI, 1.3–2.2), and cardiovascular disease (HR, 2.2; 95% CI, 1.7–2.7) were independently associated with ESRD risk in multivariate-adjusted models, as were CD4 lymphocyte count <200 cells/mm3 (HR, 1.5; 95% CI, 1.2–2.0), HIV viral load ≥30,000 copies/mL (HR, 2.0; 95% CI, 1.5–2.8), hepatitis C virus coinfection (HR, 1.9; 95% CI, 1.5–2.4), and hypoalbuminemia (HR, 2.1; 95% CI, 1.8–2.5). Compared to persons without chronic kidney disease (CKD), defined as eGFR>60mg/min/1.73m2 and no proteinuria, lower eGFR and higher proteinuria categories were jointly associated with exponentially higher ESRD rates, ranging from 6.6 per 1000 person-years for persons with proteinuria 30–100 mg/dL and eGFR>60ml/min/1.73m2, to 193 per 1000 person-years for persons with proteinuria ≥300mg/dL and eGFR<30ml/min/1.73m2.
Limitations
Results may not be generalizable to female and nonveteran populations.
Conclusions
In HIV-infected persons, ESRD risk appears attributable to a combination of traditional and HIV-related risk factors for kidney disease. Combining eGFR and proteinuria for CKD staging is most effective for stratifying risk for ESRD.
doi:10.1053/j.ajkd.2011.10.050
PMCID: PMC3324595  PMID: 22206742
End-stage renal disease; HIV; chronic kidney disease; risk factors
6.  A clinically useful risk-score for chronic kidney disease in HIV infection 
Journal of the International AIDS Society  2014;17(4Suppl 3):19514.
Introduction
Development of a simple, widely applicable risk score for chronic kidney disease (CKD) allows comparisons of risks or benefits of starting potentially nephrotoxic antiretrovirals (ARVs) as part of a treatment regimen.
Materials and Methods
A total of 18,055 HIV-positive persons from the Data on Adverse Drugs (D:A:D) study with >3 estimated glomerular filtration rates (eGFRs) >1/1/2004 were included. Persons with use of tenofovir (TDF), atazanavir (ritonavir boosted (ATV/r) and unboosted (ATV)), lopinavir (LPV/r) and other boosted protease inhibitors (bPIs) before baseline (first eGFR >60 ml/min/1.73 m2 after 1/1/2004) were excluded. CKD was defined as confirmed (>3 months apart) eGFR <60. Poisson regression was used to develop a score predicting low (<0 points), medium (1–4 points) and high (>5 points) risk of developing CKD. Increased incidence of CKD associated with starting ARVs was modelled by including ARVs as time-updated variables. The risk score was externally validated on two independent cohorts.
Results
A total of 641 persons developed CKD during 103,278.5 PYFU (incidence 6.2/1000 PYFU, 95% CI 5.7–6.7). Older age, intravenous drug use, HCV+ antibody status, lower baseline eGFR, female gender, lower CD4 nadir, hypertension, diabetes and cardiovascular disease predicted CKD and were included in the risk score (Figure 1). The incidence of CKD in those at low, medium and high risk was 0.8/1000 PYFU (95% CI 0.6–1.0), 5.6 (95% CI 4.5–6.7) and 37.4 (95% CI 34.0–40.7) (Figure 1). The risk score showed good discrimination (Harrell's c statistic 0.92, 95% CI 0.90–0.93). The number needed to harm (NNTH) in patients starting ATV or LPV/r was 1395, 142 or 20, respectively, among those with low, medium or high risk. NNTH were 603, 61 and 9 for those with a low, medium or high risk starting TDF, ATV/r or bPIs. The risk score was externally validated on 2603 persons from the Royal Free Hospital clinic cohort (94 events, incidence 5.1/1000 PYFU; 95% CI 4.1–6.1) and 2013 persons from the control arms of SMART/ESPRIT (32 events, incidence 3.8/1000 PYFU; 95% CI 2.5–5.1). External validation showed consistent CKD rates across risk groups (Figure 2).
Interpretation
Traditional and HIV-related risk factors were predictive of CKD; all are routinely available, making the risk score easy to incorporate into clinical practise and of direct relevance for clinical decision making. NNTH in persons starting potentially nephrotoxic ARVs at high risk of CKD were low, and alternative ARVs may be more appropriate.
doi:10.7448/IAS.17.4.19514
PMCID: PMC4224906  PMID: 25394023
7.  Role of Traditional Risk Factors and Antiretroviral Drugs in the Incidence of Chronic Kidney Disease, ANRS CO3 Aquitaine Cohort, France, 2004–2012 
PLoS ONE  2013;8(6):e66223.
Objective
To examine the role of antiretroviral drugs (ART), HIV-related and traditional risk factors on the incidence of chronic kidney disease (CKD) in HIV-infected patients.
Design
Prospective hospital-based cohort of HIV-infected patients from 2004 to 2012.
Methods
CKD was defined using MDRD equation as an estimated glomerular filtration rate (eGFR) less than 60 ml/mn/1.73 m2 at 2 consecutive measurements ≥3 months apart. Poisson regression models were used to study determinants of CKD either measured at baseline or updated. ART exposure was classified as ever or never. We additionally tested the role of tenofovir (TDF), whether or not prescribed concomitantly with a Protease Inhibitor (PI), taking into account the cumulative exposure to the drug.
Results
4,350 patients (74% men) with baseline eGFR>60 ml/mn/1.73 m2 were followed for a median of 5.8 years. At the end of follow-up, 96% had received ART, one third of them (35%) jointly received TDF and a PI. Average incidence rate of CKD was 0.95% person-years of follow-up. Incidence of CKD was higher among women (IRR = 2.2), older patients (>60 y vs <45 y: IRR = 2.5 and 45–60 y: IRR = 1.7), those with diabetes (IRR = 1.9), high blood pressure (IRR = 1.5), hyperlipidemia (IRR = 1.5), AIDS stage (IRR = 1.4), low baseline eGFR (IRR = 15.8 for 6090 and IRR = 7.1 for 70500/mm3 (IRR = 2.5), and exposure to TDF (IRR = 2.0). Exposure to TDF was even strongly associated with CKD when co-administered with PIs (IRR = 3.1 vs 1.3 when not, p<0,001). A higher risk of CKD was found when tenofovir exposure was >12 months [IRR = 3.0 with joint PIs vs 1.3 without (p<0.001)]. A vast majority of those developing CKD (76.6%) had a baseline eGFR between 60 and 80 ml/mn/1.73 m2.
Conclusion
In patients with eGFR between 60 and 80 mL/min/1.73 m2, a thorough control of CKD risk factors is warranted. The use of TDF, especially when co-administered with PIs, should be mentioned as a relative contraindication in presence of at least one of these risk factors.
doi:10.1371/journal.pone.0066223
PMCID: PMC3680439  PMID: 23776637
8.  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
9.  The Impact of Kidney Function at HAART Initiation on Mortality in HIV-infected Women 
Background
In the early highly active antiretroviral therapy (HAART) era, kidney dysfunction was strongly associated with death among HIV-infected individuals. We re-examined this association in the later HAART period to determine whether chronic kidney disease (CKD) remains a predictor of death after HAART-initiation.
Methods
To evaluate the effect of kidney function at the time of HAART initiation on time to all-cause mortality, we evaluated 1415 HIV-infected women initiating HAART in the Women’s Interagency HIV Study (WIHS). Multivariable proportional hazards models with survival times calculated from HAART initiation to death were constructed; participants were censored at the time of the last available visit or December 31, 2006.
Results
CKD (eGFR <60 ml/min/1.73 m2) at HAART initiation was associated with higher mortality risk adjusting for age, race, hepatitis C serostatus, AIDS history and CD4+ cell count (hazard ratio [HR]=2.23, 95% confidence interval [CI]: 1.45–3.43). Adjustment for hypertension and diabetes history attenuated this association (HR=1.89, CI: 0.94–3.80). Lower kidney function at HAART initiation was weakly associated with increased mortality risk in women with prior AIDS (HR=1.09, CI: 1.00–1.19, per 20% decrease in eGFR).
Conclusions
Kidney function at HAART initiation remains an independent predictor of death in HIV-infected individuals, especially in those with a history of AIDS. Our study emphasizes the necessity of monitoring kidney function in this population. Additional studies are needed to determine mechanisms underlying the increased mortality risk associated with CKD in HIV-infected persons.
doi:10.1097/QAI.0b013e3181e674f4
PMCID: PMC3243740  PMID: 20581688
kidney disease; mortality; HIV; WIHS; antiretroviral therapy
10.  Chronic kidney disease at presentation is not an independent risk factor for AIDS-defining events or death in HIV-infected persons 
Clinical nephrology  2013;79(2):93-100.
Studies have documented an association between chronic kidney disease (CKD) and increased risk of end-stage renal disease (ESRD), death and comorbidities, including cardiovascular disease and metabolic syndrome, in the general population. However, there is little data on the relationship between CKD and ADE (AIDS defining event), and to our knowledge, no studies have analyzed death as a competing risk for ADE among HIV-infected persons. An observational cohort study was performed to determine the incidence and risks for developing an ADE or death among HIV-infected persons with and without CKD from 1998 – 2005. CKD was defined as an estimated glomerular filtration rate (eGFR) less than 60 ml/min/1.73 m2 using the CKD-Epidemiology Collaboration (CKD-EPI) equation. Log rank test and Cox regression which determined time to development of ADE and/or death as combined and separate outcomes, and competing risk models for ADE versus mortality, were performed. Among the 2,127 persons that contributed to the 5,824 person years of follow-up: 22% were female, 34% African-American, 38% on HAART, and 3% had CKD at baseline. ADE occurred in 227 (11%) persons and there were 80 (4%) deaths. CKD was not significantly associated with ADE/death (HR 1.3, 95% CIs: 0.5, 3.2), ADE (HR 1.0, 95% CIs: 0.4, 3.1), or death (HR 1.6, 95% CIs: 0.4, 3.1). Competing risk analyses confirmed no statistically significant associations between CKD and these outcomes. CKD was uncommon in HIV-infected persons presenting for care in this racially diverse cohort, and was not independently associated with risk of developing an ADE or dying during follow-up.
doi:10.5414/CN107390
PMCID: PMC3726221  PMID: 23270930
HIV; CKD; AIDS defining event (ADE); mortality
11.  Chronic Kidney Disease Identification in a High-Risk Urban Population: Does Automated eGFR Reporting Make a Difference? 
Whether automated estimated glomerular filtration rate (eGFR) reporting for patients is associated with improved provider recognition of chronic kidney disease (CKD), as measured by diagnostic coding of CKD in those with laboratory evidence of the disease, has not been explored in a poor, ethnically diverse, high-risk urban patient population. A retrospective cohort of 237 adult patients (≥20 years) with incident CKD (≥1 eGFR ≥60 ml/min/1.73 m2, followed by ≥2 eGFRs <60 ml/min/1.73 m2 ≥3 months apart)—pre- or postautomated eGFR reporting—was identified within the San Francisco Department of Public Health Community Health Network (January 2005–July 2009). Patients were considered coded if any ICD-9-CM diagnostic codes for CKD (585.x), other kidney disease (580.x–581.x, 586.x), or diabetes (250.4) or hypertension (403.x, 404.x) CKD were present in the medical record within 6 months of incident CKD. Multivariable logistic regression was used to obtain adjusted odds ratios (ORs) for CKD coding. We found that, pre-eGFR reporting, 42.5 % of incident CKD patients were coded for CKD. Female gender, increased age, and non-Black race were associated with lower serum creatinine and lower prevalence of coding but comparable eGFR. Prevalence of coding was not statistically significantly higher overall (49.6 %, P = 0.27) or in subgroups after the institution of automated eGFR reporting. However, gaps in coding by age and gender were narrowed post-eGFR, even after adjustment for sociodemographic and clinical characteristics: 47.9 % of those <65 and 30.3 % of those ≥65 were coded pre-eGFR, compared to 49.0 % and 52.0 % post-eGFR (OR = 0.43 and 1.16); similarly, 53.2 % of males and 25.4 % of females were coded pre-eGFR compared to 52.8 % and 44.0 % post-eGFR (OR 0.28 vs. 0.64). Blacks were more likely to be coded in the post-eGFR period: OR = 1.08 and 1.43 (Pinteraction > 0.05). Automated eGFR reporting may help improve CKD recognition, but it is not sufficient to resolve underidentification of CKD by safety net providers.
doi:10.1007/s11524-012-9726-2
PMCID: PMC3531349  PMID: 22684427
Chronic kidney disease; Diagnostic coding; Estimated glomerular filtration rate; Female; African American
12.  Chronic kidney disease and estimates of kidney function in HIV infection: a cross-sectional study in the Multicenter AIDS Cohort Study 
Background
Cystatin C has been proposed as an alternative marker of kidney function among HIV-infected persons in whom serum creatinine is affected by extra-renal factors.
Methods
In this cross-sectional study, we compared estimated glomerular filtration rates (eGFR) using serum creatinine versus cystatin C between 150 HIV-uninfected and 783 HIV-infected men. We evaluated the prevalence of chronic kidney disease (CKD; eGFR<60 mL/min/1.73 m2) and examined the influence of extra-renal factors on GFR-estimates among HIV-infected men.
Results
Estimated GFRSCR was similar by HIV serostatus, but eGFRCYSC was lower in HIV-infected men. A higher proportion of HIV-infected men were classified as having CKD when using eGFRCYSC versus eGFRSCR (7% vs. 5%, P<0.01). In HIV-infected individuals without CKD, eGFRSCR was higher than eGFRCYSC while it was lower than eGFRCYSC in persons with CKD. In HIV-infected men, older age, proteinuria, and prior clinical AIDS were inversely associated with both GFR-estimates. Higher serum albumin levels and ACE-inhibitor/ARB use were associated with lower eGFRSCR. HIV viral load, hepatitis C co-infection, and serum alkaline phosphatase were inversely associated with eGFRCYSC.
Conclusion
Among HIV-uninfected and HIV-infected men of similar social risk behaviors, GFR estimates differed by biomarker and kidney function level. Estimated GFRCYSC classified a larger proportion of HIV-infected men with CKD compared to eGFRSCR. Differences between these GFR-estimating methods may be due to the effects of extra-renal factors on serum creatinine and cystatin C. Until GFR-estimating equations are validated among HIV-infected individuals, current GFR estimates based on these biomarkers should be interpreted with care in this patient population.
doi:10.1097/QAI.0b013e318222f461
PMCID: PMC3159728  PMID: 21646913
HIV; kidney disease; serum creatinine; cystatin C; glomerular filtration rate; Multicenter AIDS Cohort Study
13.  Low documentation of chronic kidney disease among high-risk patients in a managed care population: a retrospective cohort study 
BMC Nephrology  2009;10:25.
Background
Early detection of chronic kidney disease (CKD) is sub-optimal among the general population and among high risk patients. The prevalence and impact of major CKD risk factors, diabetes (DM) and hypertension (HTN), on CKD documentation among managed care populations have not been previously reported. We examined this issue in a Kaiser Permanente Georgia (KPG) CKD cohort.
Methods
KPG enrollees were included in the CKD cohort if they had eGFRs between 60 and 365 days apart that were <90 ml/min during 1999-2006. The current analysis is restricted to participants with eGFR 10-59 ml/min/1.73 m2. CKD documentation was defined as a presenting diagnosis of CKD by a primary care physician or nephrologist using ICD-9 event codes. The association between CKD documentation and DM and HTN were assessed with multivariate logistic regression models.
Results
Of the 50,438 subjects within the overall KPG CKD cohort, 20% (N = 10,266) were eligible for inclusion in the current analysis. Overall, CKD diagnosis documentation was low; only 14.4% of subjects had an event-based CKD diagnosis at baseline. Gender and types 2 diabetes interacted on CKD documentation. The prevalence of CKD documentation increased with the presence of hypertension and/or type 2 diabetes, but type 2 diabetes had a lower effect on CKD documentation. In multivariate analysis, significant predictors of CKD documentation were eGFR, hypertension, type 2 diabetes, congestive heart failure, peripheral artery disease, statin use, age and gender. CKD documentation was lower among women than similarly affected men.
Conclusion
Among patients with an eGFR 10-59, documentation of CKD diagnosis by primary and subspecialty providers is low within a managed care patient cohort. Gender disparities in CKD documentation observed in the general population were also present among KPG CKD enrollees.
doi:10.1186/1471-2369-10-25
PMCID: PMC2753574  PMID: 19758452
14.  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
15.  Prevalence, determinants and co-morbidities of chronic kidney disease among First Nations adults with diabetes: results from the CIRCLE study 
BMC Nephrology  2012;13:57.
Background
Indigenous peoples worldwide are experiencing elevated rates of type 2 diabetes and its complications. To better understand the disproportionate burden of diabetic end stage renal disease (ESRD) among Canadian First Nations people (FN), we examined prevalence, determinants, and co-morbidities of chronic kidney disease (CKD) within this population.
Methods
The 2007 Canadian FN Diabetes Clinical Management and Epidemiologic (CIRCLE) study conducted a cross-sectional national medical chart audit of 885 FN adults with type 2 diabetes to assess quality of diabetes care. In this sub-study, participants were divided by estimated glomerular filtration rate (eGFR in ml/min/1.73 m2), as well as by albuminuria level in those with eGFRs = > 60. Those with eGFRs = > 60 and negative albuminuria were considered to have normal/near normal kidney function (non-CKD). Using univariate and logistic regression analysis, they were compared with participants having eGFRs = > 60 plus albuminuria (CKD-alb) and with participants having eGFRs <60 (CKD-eGFR <60).
Results
While 84.5% of total CIRCLE participants had eGFRs = > 60, almost 60% of the latter had CKD-alb. Of the 15.5% of total participants with CKD-eGFR <60, 80% had eGFRs 30–60 (Stage 3 CKD) but over 10% (1.6% of total participants) had ESRD. Independent determinants of CKD-alb were male gender and increasing diabetes duration, systolic BP, A1C and total cholesterol. These plus smoking rates also discriminated between FN with micro- and macro-albuminuria. Independent determinants of CKD-eGFR <60 were increasing age at diabetes diagnosis, diabetes duration, total cholesterol and systolic BP. However, participants with CKD-eGFR <60 also displayed a decreasing mean age of diabetes diagnosis as eGFR declined. Micro-vascular co-morbidities were significantly associated with CKD-alb but both micro- and macro-vascular co-morbidities were associated with CKD-eGFR <60. Only 35-40% of participants with CKD used insulin.
Conclusions
High prevalences of CKD-alb and early CKD-eGFR <60 among diabetic FN were largely related to modifiable and treatable risk factors. However, an earlier age of diabetes diagnosis and longer duration of diabetes characterized those with ESRD. These findings suggest that a failure to meet current standards of diabetes care interacting with an age-related survival benefit contribute to the disproportionate burden of ESRD among FN and possibly other Indigenous peoples.
doi:10.1186/1471-2369-13-57
PMCID: PMC3438064  PMID: 22776036
Indigenous peoples; Aboriginal; First Nations; Diabetes; Chronic kidney disease; End stage renal disease; Risk factors.
16.  Chronic Kidney Disease as a Predictor of Cardiovascular Disease (From the Framingham Heart Study) 
Chronic kidney disease (CKD) is a risk factor for cardiovascular disease (CVD), although shared risk factors may mediate much of the association. We related CKD and CVD in the setting of specific CVD risk factors and determined whether more advanced CKD was a CVD risk equivalent. The Framingham Heart Study original cohort (n=2471, mean age 68 years, 58.9% women) was studied. Glomerular filtration rate (eGFR) was estimated using the simplified Modification of Diet in Renal Disease Study equation. CKD was defined as eGFR < 59 mL/min per 1.73 m2 (women) and < 64 (men) and Stage 3b CKD defined as eGFR 30-44 (women) and 30-50 (men). Cox Proportional Hazard models adjusting for CVD risk factors were used to relate CKD to CVD. We tested for effect modification by CVD risk factors. Overall, 23.2% of the study sample had CKD (n=574; mean eGFR 50 mL/min per 1.73 m2) and 5.3% had Stage 3b CKD (n=131; mean eGFR 42 mL/min per 1.73 m2). In multivariable models (mean follow-up time 16 years), Stage 3 CKD was marginally associated with CVD (HR=1.17, 95% CI 0.99-1.38, p=0.06), whereas Stage 3b CKD was associated with CVD [HR=1.41, 95% CI 1.05-1.91, p=0.02]. Upon testing CVD risk equivalency, the risk of CVD for Stage 3b CKD among participants with prior CVD was significantly lower as compared to participants with prior CVD and no Stage 3b CKD (age- and sex-adjusted HR for CVD = 0.66 [95% CI 0.47 to 0.91], p=0.01). Low HDL modified the association between CKD and CVD (p-value=0.004 for interaction). Stage 3b CKD is associated with CVD but is not a CVD risk equivalent. In conclusion, CVD risk in the setting of CKD is higher in the setting of low HDL cholesterol.
doi:10.1016/j.amjcard.2008.02.095
PMCID: PMC2517213  PMID: 18572034
17.  Nephrotoxicity of HAART 
AIDS Research and Treatment  2011;2011:562790.
Highly active antiretroviral therapy (HAART) and other medical therapies for HIV-related infections have been associated with toxicities. Antiretroviral therapy can contribute to renal dysfunction directly by inducing acute tubular necrosis, acute interstitial nephritis, crystal nephropathy, and renal tubular disorders or indirectly via drug interactions. With the increase in HAART use, clinicians must screen patients for the development of kidney disease especially if the regimen employed increases risk of kidney injury. It is also important that patients with chronic kidney disease (CKD) are not denied the best combinations, especially since most drugs can be adjusted based on the estimated GFR. Early detection of risk factors, systematic screening for chronic causes of CKD, and appropriate referrals for kidney disease management should be advocated for improved patient care. The interaction between immunosuppressive therapy and HAART in patients with kidney transplants and the recent endorsement of tenofovir/emtricitabine by the Centers for Disease Control (CDC) for preexposure prophylaxis bring a new dimension for nephrotoxicity vigilance. This paper summarizes the common antiretroviral drugs associated with nephrotoxicity with particular emphasis on tenofovir and protease inhibitors, their risk factors, and management as well as prevention strategies.
doi:10.1155/2011/562790
PMCID: PMC3157198  PMID: 21860787
18.  Renal Function in Ghanaian HIV-Infected Patients on Highly Active Antiretroviral Therapy: A Case-Control Study 
PLoS ONE  2014;9(6):e99469.
Background
HAART is anticipated to result in an increase in long-term survival, but may present with the development of associated complications. The aim of this study was to assess the renal function of HIV-infected patients on antiretroviral therapy.
Methods
A case-control study (January to May 2013) conducted at the Suntreso Government Hospital, Kumasi, Ghana. A total of 163 HIV-infected patients (mean age 39.9±10.22) were studied, of which 111 were on HAART (HIV-HAART) and 52 were not (HIV-Controls). Serum urea, creatinine, potassium, sodium, chloride and CD4 counts were measured with the determination of eGFR (CKD-EPI and MDRD). Data was analysed using GraphPad Prism. The Chi-square, t-test, one-way ANOVA and Spearman's correlation were used. P values <0.05 were considered significant.
Results
Mean CD4 count of HIV-Controls was higher than that of HIV-HAART but was not significant (p = 0.304). But for sodium levels which were higher in HIV-Controls (p = 0.0284), urea (p = 0.1209), creatinine (p = 0.7155), potassium (p = 0.454) and chloride (p = 0.6282) levels did not differ significantly between both groups. All serum biochemical parameters did not differ significantly, irrespective of duration on therapy and CD4 counts. Based on regimen, sodium, chloride, urea and creatinine did not differ significantly between TDF, EVF and NVP-based therapies. Prevalence of CKD (eGFR <60 ml/min/1.73 m2) in the total population was 9.9% and 3.7% with the MDRD and EPI-CKD equations respectively.
Conclusions
Renal insufficiency remains prevalent in HIV patients. Changes in renal function occur in HIV infection and over the course of HAART but the difference at either stage is not significant. This suggests the role of HIV infection, HAART and the presence of traditional risk factors but not HAART in itself, in renal dysfunction. We however recommend a close monitoring of patients before and during HAART, to aid in evaluating drug combinations and implement dose modifications when necessary.
doi:10.1371/journal.pone.0099469
PMCID: PMC4055675  PMID: 24921259
19.  Chronic Kidney Disease Associated with Perinatal HIV infection in Children and Adolescents 
Background
This study describes the incidence, clinical and demographic characteristics, and spectrum of chronic kidney disease (CKD) in youths with perinatal HIV-1 infection.
Methods
Retrospective analysis between May 1993 and December 2006 of subjects with renal disease followed in the Pediatric AIDS Clinical Trials Group 219/219C multicenter study examining long-term consequences of perinatal HIV infection. Diagnosis confirmation was made utilizing a questionnaire mailed to research sites. Participants with CKD of other etiology than HIV were excluded. Outcome measures were biopsy-diagnosed CKD and, in absence of biopsy, HIV-associated nephropathy (HIVAN) using established clinical criteria.
Results
Questionnaires on 191 of 2,102 participants identified 27 cases of CKD: 14 biopsy-diagnosed and six clinical cases of HIVAN, and seven biopsy-diagnosed cases of immune complex-mediated kidney disease (lupus-like nephritis, three; IgA nephropathy, two; membranous nephropathy, two). Incidence rates for CKD associated with HIV in pre-HAART (1993–1997) and HAART (1998–2002, 2003–2006) eras were 0.43, 2.84 and 2.79 events per 1000 person years, respectively. In multivariable analysis, Black race and viral load ≥ 100,000 copies/ml (rate ratios 3.28 and 5.05, p ≤ 0.02) were associated with CKD.
Conclusions
A variety of immune complex-mediated glomerulonephritides and HIVAN occurs in this population. Black race and uncontrolled viral replication are risk factors for CKD associated with HIV.
doi:10.1007/s00467-011-2097-1
PMCID: PMC3715373  PMID: 22366874
HIVAN; HIV immune complex kidney disease; FSGS; renal; youth; proteinuria; biopsy
20.  Re-evaluating the predictive roles of metabolic complications and clinical outcome according to eGFR levels — a four-years prospective cohort study in Taiwan 
BMC Nephrology  2013;14:92.
Background
Metabolic complications are associated with clinical outcomes in patients with chronic kidney disease (CKD). These outcomes differ among patients according to the different stages of disease. The prevalence and association of type and number of metabolic complications with renal progression and death in patients having different eGFR levels has high clinical value, but this fact has been rarely evaluated in prospective studies.
Methods
We prospectively followed a cohort of 1157 CKD patients from 2006 to death or until 2010, and evaluated the prevalence of CKD-related complications and their association with renal progression (defined as a decline in eGFR by > 50% from baseline, or end-stage renal disease requiring dialysis) and death in patients with eGFRs above and below 45 mL/min/1.73 m2 using Cox-proportional hazard models.
Results
The estimated rate (per 100 patient-years) of renal progression and death were 11.9 and 4.9, respectively. The eGFR thresholds determined by ROC analysis with a sensitivity of 90% for any metabolic complication were 60.8 mL/min/1.73 m2 and 74.3 mL/min/1.73 m2 using the MDRD and CKD Epidemiology Collaboration equations, respectively. CKD-related complications associated with renal progression in patients having eGFR < 45 mL/min/1.73 m2 were hyperphosphatemia, anemia, microinflammation and hypoalbuminemia. Those CKD-related complications associated with death were hypoalbuminemia and hyperuricemia. Hypoalbuminemia predicted renal progression, and, hypoalbuminemia and microinflammation predicted death in patients with eGFR ≥ 45 mL/min/1.73 m2. The number of complications (≥ 3) independently predicted both endpoints in patients with eGFR < 45 mL/min/1.73 m2.
Conclusions
Hypoalbuminemia was a unique and strong predictor of renal progression and all-cause mortality in CKD patients, independent of their demographic characteristics, traditional risk factors, renal function severity, the presence of cardiovascular disease and other metabolic abnormalities. Most other metabolic complications and the number of complications (≥3) were associated with the clinical outcomes of patients with eGFR < 45 mL/min/1.73 m2 rather than in those with higher eGFRs. The findings from the present study offer a novel insight into the association between metabolic complications and patient outcomes and may help to refine risk stratification according to disease stage.
doi:10.1186/1471-2369-14-92
PMCID: PMC3643890  PMID: 23607513
Anemia; Chronic kidney disease; Death; Hyperphosphatemia; Hypoalbuminemia; Metabolic complications; Renal progression
21.  Factors Affecting Glomerular Filtration Rate, as Measured by Iohexol Disappearance, in Men with or at Risk for HIV Infection 
PLoS ONE  2014;9(2):e86311.
Objective
Formulae used to estimate glomerular filtration rate (GFR) underestimate higher GFRs and have not been well-studied in HIV-infected (HIV(+)) people; we evaluated the relationships of HIV infection and known or potential risk factors for kidney disease with directly measured GFR and the presence of chronic kidney disease (CKD).
Design
Cross-sectional measurement of iohexol-based GFR (iGFR) in HIV(+) men (n = 455) receiving antiretroviral therapy, and HIV-uninfected (HIV(−)) men (n = 258) in the Multicenter AIDS Cohort Study.
Methods
iGFR was calculated from disappearance of infused iohexol from plasma. Determinants of GFR and the presence of CKD were compared using iGFR and GFR estimated by the CKD-Epi equation (eGFR).
Results
Median iGFR was higher among HIV(+) than HIV(−) men (109 vs. 106 ml/min/1.73 m2, respectively, p = .046), and was 7 ml/min higher than median eGFR. Mean iGFR was lower in men who were older, had chronic hepatitis C virus (HCV) infection, or had a history of AIDS. Low iGFR (≤90 ml/min/1.73 m2) was associated with these factors and with black race. Other than age, factors associated with low iGFR were not observed with low eGFR. CKD was more common in HIV(+) than HIV(−) men; predictors of CKD were similar using iGFR and eGFR.
Conclusions
iGFR was higher than eGFR in this population of HIV-infected and -uninfected men who have sex with men. Presence of CKD was predicted equally well by iGFR and eGFR, but associations of chronic HCV infection and history of clinically-defined AIDS with mildly decreased GFR were seen only with iGFR.
doi:10.1371/journal.pone.0086311
PMCID: PMC3917840  PMID: 24516530
22.  Estimated Glomerular Filtration Rate Decline Is a Better Risk Factor for Outcomes of Systemic Disease-Related Nephropathy than for Outcomes of Primary Renal Diseases 
PLoS ONE  2014;9(4):e92881.
Background
Currently, the contribution of kidney function decline in renal and patient outcomes is unclear. There are few data on the associations of different etiologies of estimated glomerular filtration rate (eGFR) decline with outcomes in multidisciplinary care. The purpose of this investigation was to establish whether eGFR decline in patients with disease is an important risk factor for developing end-stage renal disease (ESRD) and death.
Methods
From December 1, 2001 to December 31, 2011, 5097 adults with chronic kidney disease (CKD) received biochemical tests, physical examinations, a pathological examination, and a comprehensive questionnaire. We used linear regression models and multivariate Cox proportional hazards model to examine the outcome of eGFR decline in renal diseases with different etiologies.
Results
Mean age was 68.1±16.1 (standard deviation, SD) years, and 63.3% patients were male. In the studied cohort, 58.2% of the patients had systemic disease-related nephropathy (SDRN), 29.4% had primary renal diseases (PRDs), and 12.4% had other etiologies. The eGFR decline in SDRN had a significant association with dialysis in the Cox proportional hazards model [crude hazard ratio (HR) = 1.07, 95% confidence interval (CI), 1.04 to 1.10; adjusted HR 1.05, 95% CI, 1.02 to 1.08]. Diabetic nephropathy (DN) had the most severe eGFR decline in CKD stages 3, 4, and 5, and all contributed to the initiation of dialysis and death regardless of whether DN with or without eGFR decline was considered to be the cause. Although hypertensive nephropathy (HN) was related to significant acceleration of eGFR decline, it did not lead to poor outcome. There were still discrepancies between eGFR decline and outcomes in PRDs, hypertensive nephropathy, and lupus nephritis.
Conclusions
eGFR decline and CKD staging provide an informative guide for physicians to make proper clinical judgments in the treatment of CKD, especially SDRN. Poor control of the underlying systemic disease will thus lead to more rapid progression of SDRN.
doi:10.1371/journal.pone.0092881
PMCID: PMC3973643  PMID: 24695125
23.  A comparison of estimated glomerular filtration rates using Cockcroft−Gault and the Chronic Kidney Disease Epidemiology Collaboration estimating equations in HIV infection 
HIV Medicine  2013;15(3):144-152.
Objectives
The aim of this study was to determine whether the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI)- or Cockcroft−Gault (CG)-based estimated glomerular filtration rates (eGFRs) performs better in the cohort setting for predicting moderate/advanced chronic kidney disease (CKD) or end-stage renal disease (ESRD).
Methods
A total of 9521 persons in the EuroSIDA study contributed 133 873 eGFRs. Poisson regression was used to model the incidence of moderate and advanced CKD (confirmed eGFR < 60 and < 30 mL/min/1.73 m2, respectively) or ESRD (fatal/nonfatal) using CG and CKD-EPI eGFRs.
Results
Of 133 873 eGFR values, the ratio of CG to CKD-EPI was ≥ 1.1 in 22 092 (16.5%) and the difference between them (CG minus CKD-EPI) was ≥ 10 mL/min/1.73 m2 in 20 867 (15.6%). Differences between CKD-EPI and CG were much greater when CG was not standardized for body surface area (BSA). A total of 403 persons developed moderate CKD using CG [incidence 8.9/1000 person-years of follow-up (PYFU); 95% confidence interval (CI) 8.0–9.8] and 364 using CKD-EPI (incidence 7.3/1000 PYFU; 95% CI 6.5–8.0). CG-derived eGFRs were equal to CKD-EPI-derived eGFRs at predicting ESRD (n = 36) and death (n = 565), as measured by the Akaike information criterion. CG-based moderate and advanced CKDs were associated with ESRD [adjusted incidence rate ratio (aIRR) 7.17; 95% CI 2.65–19.36 and aIRR 23.46; 95% CI 8.54–64.48, respectively], as were CKD-EPI-based moderate and advanced CKDs (aIRR 12.41; 95% CI 4.74–32.51 and aIRR 12.44; 95% CI 4.83–32.03, respectively).
Conclusions
Differences between eGFRs using CG adjusted for BSA or CKD-EPI were modest. In the absence of a gold standard, the two formulae predicted clinical outcomes with equal precision and can be used to estimate GFR in HIV-positive persons.
doi:10.1111/hiv.12095
PMCID: PMC4228765  PMID: 24118916
chronic kidney disease; end stage renal disease; eGFR; renal function
24.  Association of eGFR-Related Loci Identified by GWAS with Incident CKD and ESRD 
PLoS Genetics  2011;7(9):e1002292.
Family studies suggest a genetic component to the etiology of chronic kidney disease (CKD) and end stage renal disease (ESRD). Previously, we identified 16 loci for eGFR in genome-wide association studies, but the associations of these single nucleotide polymorphisms (SNPs) for incident CKD or ESRD are unknown. We thus investigated the association of these loci with incident CKD in 26,308 individuals of European ancestry free of CKD at baseline drawn from eight population-based cohorts followed for a median of 7.2 years (including 2,122 incident CKD cases defined as eGFR <60ml/min/1.73m2 at follow-up) and with ESRD in four case-control studies in subjects of European ancestry (3,775 cases, 4,577 controls). SNPs at 11 of the 16 loci (UMOD, PRKAG2, ANXA9, DAB2, SHROOM3, DACH1, STC1, SLC34A1, ALMS1/NAT8, UBE2Q2, and GCKR) were associated with incident CKD; p-values ranged from p = 4.1e-9 in UMOD to p = 0.03 in GCKR. After adjusting for baseline eGFR, six of these loci remained significantly associated with incident CKD (UMOD, PRKAG2, ANXA9, DAB2, DACH1, and STC1). SNPs in UMOD (OR = 0.92, p = 0.04) and GCKR (OR = 0.93, p = 0.03) were nominally associated with ESRD. In summary, the majority of eGFR-related loci are either associated or show a strong trend towards association with incident CKD, but have modest associations with ESRD in individuals of European descent. Additional work is required to characterize the association of genetic determinants of CKD and ESRD at different stages of disease progression.
Author Summary
Chronic kidney disease (CKD) affects about 6%–11% of the general population, and progression to end stage renal disease (ESRD) has a significant public health impact. Family studies suggest that the risk for CKD and ESRD is heritable. Unraveling the genetic underpinning of risk for these diseases may lead to the identification of novel mechanisms and thus diagnostic and therapeutic tools. We have previously identified 16 genetic markers in association with kidney function and prevalent CKD in general population studies. However, little is known about the relevance of these SNPs to the initial development of CKD or to ESRD risk. Therefore, we have now analyzed the association of these markers with the initiation of CKD in more than 26,000 individuals from the general population using serial estimations of kidney function, and with ESRD in four case-control studies in subjects of European ancestry (3,775 cases, 4,577 controls). We show that many of the 16 markers are also associated or show a strong trend towards association with initiation of CKD, while only 2 markers are nominally associated with ESRD. Further work is required to characterize the association of genetic determinants of different stages of CKD progression.
doi:10.1371/journal.pgen.1002292
PMCID: PMC3183079  PMID: 21980298
25.  Estimated GFR and Incident Cardiovascular Disease Events in American Indians: The Strong Heart Study 
Background
In populations with high prevalence of diabetes and obesity, estimating glomerular filtration rate (GFR) by using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation may predict cardiovascular disease risk better than by using the Modification of Diet in Renal Disease (MDRD) Study equation.
Study design
Longitudinal cohort study comparing the association of GFR estimated using either the CKD-EPI or MDRD Study equations with incident cardiovascular disease outcomes.
Setting and participants
American Indians participating in the Strong Heart Study, a longitudinal population-based cohort with high prevalences of diabetes, cardiovascular disease, and CKD.
Predictor or factor
eGFR predicted using the CKD-EPI and MDRD Study equations.
Outcomes
Fatal and nonfatal cardiovascular events, consisting of coronary heart disease, stroke, and heart failure.
Measurements
The association between eGFR and outcomes was explored in Cox proportional hazards models, adjusted for traditional risk factors and albuminuria; the net reclassification index and integrated discrimination improvement were determined for the CKD-EPI versus MDRD Study equations.
Results
Among 4549 participants, diabetes was present in 45%, cardiovascular disease in 7%, and stage 3–5 CKD in 10%. Over a median of 15 years, there were 1280 cases of incident CVD, 929 of incident coronary heart disease, 305 of incident stroke, and 381 of incident heart failure. Reduced eGFR (<90 mL/min/1.73 m2) was associated with adverse events in most models. Compared with the MDRD Study equation, the CKD-EPI equation correctly reclassified 17.0% of 2,151 participants without incident CVD to a lower risk (higher eGFR) category and 1.3% (n=28) were incorrectly reclassified to a higher risk (lower eGFR) category.
Limitations
Single measurements of eGFR and albuminuria at study visits.
Conclusions
Although eGFR based on either equation had similar associations with incident cardiovascular disease, coronary heart disease, stroke, and heart failure events, among those not having events, reclassification of participants to eGFR categories was superior using the CKD-EPI equation compared with the MDRD Study equation.
doi:10.1053/j.ajkd.2012.06.015
PMCID: PMC3473098  PMID: 22841159
cardiovascular disease risk; chronic kidney disease; estimated glomerular filtration rate; Strong Heart Study

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