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1.  High Prevalence and Diversity of Kidney Dysfunction in Patients with Type 2 Diabetes Mellitus and Coronary Artery Disease: The BARI 2D Baseline Data 
Background
We describe baseline renal function and albumin excretion rate in patients enrolled in BARI 2D, a randomized clinical trial comparing revascularization and medical therapy with medical therapy alone and deferred or no revascularization, and the impact of glycemic control with either insulin providing or insulin sensitizing drugs, on 5 year mortality.
Methods
Study participants had T2DM, documented CAD, and creatinine < 2 mg/dl. Albuminuria status (albumin/creatinine ratio [ACR]) and estimated glomerular filtration rate (eGFR), utilizing the abbreviated MDRD equation, were determined at baseline. Univariate and multivariate relationships between baseline clinical characteristics and the presence of albuminuria and reduced eGFR rate were estimated.
Results
2146 subjects were included in the analysis. 43% of the cohort had evidence of kidney dysfunction at baseline: 23% had an eGFR ≥ 60 ml/min/1.73 m2 with either micro (>30 ACR; 17%) or macro (> 300 ACR; 6%) albuminuria. 21 % had a reduced eGFR < 60 ml/min/1.73 m2; 52 % with reduced eGFR had no albuminuria; 28 % had microalbuminuria and 20 % had macroalbuminuria. Race, smoking status, duration of diabetes, hypertension, HbA1c, triglycerides, vascular disease, abnormal ejection fraction, and reduced eGFR were associated with greater albuminuria. Age, sex, duration of diabetes, ACR, HbA1c, HDL, and number of hypertensive medications were associated with reduced eGFR.
Conclusion
Kidney dysfunction is common in older patients with T2DM and CAD; Albuminuria was present in 33%. Reduced eGFR was present in 21%, and half the patients with reduced eGFR had no evidence of albuminuria.
doi:10.1097/MAJ.0b013e3181d430ad
PMCID: PMC4312489  PMID: 20375690
2.  Does albuminuria predict renal risk and/or cardiovascular risk in obese type 2 diabetic patients? 
Increased urinary albumin excretion (UAE) is a marker of renal and cardiovascular risk in patients with type 2 diabetes (DT2). What about the obese patient with DT2? Does albuminuria predict the progression of renal disease and/or cardiovascular disease? The objective of this study is to determine the link between albuminuria, renal risk and cardiovascular risk in a cohort of obese DT2 patients. This is a prospective study begun in September 2006. It included DT2 patients presenting obesity defined by a body mass index (BMI)>30 Kg/m2. Three groups of patients were defined: normo-albuminuria (Urinary Albumin Excretion UAE<30 mg/day or Albumin Creatinine Ratio ACR<30 mg/g), micro-albuminuria (UAE=30-300 mg/day or ACR=30-300 mg/g) and macro-albuminuria (UAE>300 mg/day or ACR>300 mg/g). Data on 144 obese DT2 patients were compiled: The mean age of our patients was 59 ± 9 years and the sex ratio 0.26. The incidence of ESRD was higher in the macro-albuminuria group than in the two other groups (26.5% vs. 1.2%, p<0.001). The incidence of cardiovascular events was 15.4%, 14.3% and 23.5% in the normo, micro and macro-albuminuria groups (p=0.48). A history of cardiovascular comorbidities was the main cardiovascular risk in multivariate analysis (0R=15.07; 95% CI=5.30-42.82; p<0.001) and the low admission GFR (0R=5.67; 95% CI=1.23-9.77; p=0.008) was the main factor for progression of kidney disease in multivariate analysis. Albuminuria may be a better marker of kidney disease progression than of cardiovascular risk in the obese DT2 patient, according to our results. However, to accurately demonstrate the link albuminuria - renal risk and albuminuria - cardiovascular risk in the obese DT2 patient, additional studies using very strict criteria of selection and judgment are needed.
PMCID: PMC3925884  PMID: 24551483
Diabete type 2; obesity; albuminuria; renal risk; cardiovascular risk
3.  Discordant associations of lipid parameters with albuminuria and chronic kidney disease: a population-based study 
Background
Although dyslipidemia is related to the pathogenesis of renal insufficiency, which routinely available lipid measure is more applicable in estimation of kidney function is still uncertain. Our objective was to evaluate inconsistent associations of lipid profiles with both albuminuria and chronic kidney disease (CKD).
Methods
We performed a population-based study in 9730 subjects aged 40 years or older. Definitions of abnormalities in albumin excretion were according to the latest guidelines of American Diabetes Association’s Standards of Medical Care. CKD was defined as estimated glomerular filtration rate (eGFR) < 60 mL/min per 1.73 m2 or the presence of albuminuria.
Results
There were 2274 (23.4 %) participants categorized as low-grade albuminuria, 639 (6.6 %) participants categorized as increased urinary albumin excretion and 689 (7.1 %) participants categorized as CKD. Triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), Non HDL-C to HDL-C ratio, TG to HDL-C ratio were significantly correlated with urinary albumin to creatinine ratio (ACR), serum creatinine and eGFR (all P < 0.0001). Compare with other lipid parameters, TG to HDL-C ratio have shown the strongest correlation with increased odds of both increased urinary albumin excretion and CKD. No significant associations between lipid parameters and low-grade albuminuria were observed after adjustments for potential confounding factors.
Conclusion
Our study lends support to discordant associations of lipid parameters with albuminuria and renal function. TG to HDL-C ratio is a better marker than other routine lipid measures for identifying renal insufficiency and should be given more consideration in the clinical practice.
doi:10.1186/s12944-015-0153-8
PMCID: PMC4660634  PMID: 26607500
Dyslipidemia; Low-grade albuminuria; Increased urinary albumin excretion; Chronic kidney disease; TG to HDL-C ratio
4.  Prevalence of chronic kidney disease across levels of glycemia among adults in Pudong New Area, Shanghai, China 
BMC Nephrology  2013;14:253.
Background
Few population-based studies have examined the relationship between glycemic status and chronic kidney disease (CKD) in China. We examined the prevalence of CKD across categories of glycemia [diagnosed diabetes, undiagnosed diabetes (fasting plasma glucose [FPG] ≥ 126 mg/dL), prediabetes (FPG 100–126 mg/dL) and normal glycemia (FPG <100 mg/dL)] among Chinese adults and assessed the relative contribution of dysglycemia (prediabetes and/or diabetes) to the burden of CKD.
Methods
5,584 Chinese adults aged 20–79 years were selected from the Pudong New Area of Shanghai through a multistage random sampling. Demographic and lifestyle characteristics, anthropometry and blood pressure were measured. Biochemical assays included FPG, serum creatinine and lipids, urinary creatinine and albumin. Prevalence of albuminuria [urine albumin-to-creatinine ratio (ACR) ≥ 30 mg/g], decreased kidney function and CKD (either decreased kidney function or albuminuria) across levels of glycemia were estimated.
Results
The prevalence of albuminuria, decreased kidney function and CKD each increased with higher glycemic levels (P < 0.001). Based on the MDRD Study equation, the unadjusted CKD prevalence was 30.9%, 28.5%, 14.1% and 9.2% in those with diagnosed diabetes, undiagnosed diabetes, prediabetes and normoglycemia, respectively. The corresponding age-, gender- and hypertension-adjusted CKD prevalence were 25.8%, 25.0%, 12.3% and 9.1%, respectively. In a multivariable analysis, the factors associated with CKD were hypertension (Odds ratio [OR] 1.70, 95% confidence interval [CI]: 1.42-2.03), dysglycemia (OR 1.65, 95% CI: 1.39-1.95), female gender (OR 1.48, 95% CI: 1.25-1.75), higher triglycerides (OR 1.14, 95% CI: 1.08-1.20 per mmol/L), higher body mass index (OR 1.08, 95% CI: 1.05-1.10 per kg/m2), and older age (OR 1.02, 95% CI: 1.01 -1.03 per year). The population attributable risks (PARs) associated with diabetes, prediabetes, dysglycemia (diabetes and prediabetes) and hypertension were 18.4%, 19.7%, 30.3% and 44.5% for CKD as defined by the MDRD study equation, and 15.8%, 24.4%, 29.2% and 10.0% with the CKD-EPI equation. Estimates of prevalence and ORs of the relative contribution of various risk factors to CKD obtained with the CKD-EPI equation were similar.
Conclusions
As much as 30% of the CKD burden may be associated with dysglycemia among Chinese adults, independent of age, gender and hypertension status. Prevention and control of diabetes and prediabetes should be a high priority in reducing the CKD burden in China.
doi:10.1186/1471-2369-14-253
PMCID: PMC4225706  PMID: 24238578
Chronic kidney disease; Glycemia; Epidemiology
5.  Serum Adiponectin and Glomerular Filtration Rate in Patients with Type 2 Diabetes 
PLoS ONE  2015;10(10):e0140631.
High serum adiponectin has been increased in several conditions of kidney disease. Only sparse and conflicting results have been reported in patients with type 2 diabetes (T2D), a subgroup of individuals who are at high risk for renal dysfunction. The aim of this study was to fill up this gap of knowledge by investigating such association in a large sample of Italian diabetic patients. The association between serum adiponectin levels and estimated glomerular filtration rate (eGFR by Chronic Kidney Disease-Epidemiology Collaboration CKD-EPI equation) was investigated in 1,243 patients with T2D from two cross-sectional Italian studies: 878 from San Giovanni Rotondo (SGR) and 365 from Foggia (FG). Serum adiponectin was inversely associated with eGFR in SGR [β (standard error, SE) for 1 standard deviation (SD) of adiponectin = -3.26 (0.64)] and in FG [β(SE)=-5.70(1.28)] sample, as well as in the two studies combined [β(SE)=-3.99(0.59)];(p<0.0001 for all). In this combined analysis, the association was still significant after adjusting for sex, smoking habits, body mass index (BMI), waist circumference, diabetes duration, glycated hemoglobin (HbA1c), albumin creatinine ratio (ACR) and anti-hyperglycemic, anti-hypertensive and anti-dyslipidemic treatments [β (SE)= -2.19 (0.59), p = 0.0001]. A stronger association between each SD adiponectin increment and low eGFR was observed among patients with micro-/macro-albuminuria, as compared to those with normo-albuminuria [adjusted β(SE)=-4.42(1.16) ml/min/1.73m2 vs. -1.50 (0.67) ml/min/1.73m2, respectively; p for adiponectin-by-albuminuric status = 0.022]. For each adiponectin SD increment, the odds of having eGFR < 60 ml/min/1.73m2 increased by 41% (odds ratio, OR = 1.41; 95% confidence interval, CI 1.21–1.64) in SGR sample, 53% (OR = 1.53; 95% CI 1.21–1.94) in FG sample, and 44% (OR = 1.44; 95%CI 1.27–1.64) in the two studies considered together (p<0.0001 for all). In the combined sample, further adjustment for the above mentioned covariates did not change the observed association (OR = 1.36; 95%CI 1.16–1.60; p<0.0001). Our study, so far the largest addressing the relationship between serum adiponectin and GFR in T2D, strongly suggests that the paradoxical inverse association, previously reported in different clinical sets, is also observed in diabetic patients. Further studies are needed to unravel the biology underlying this counterintuitive relationship.
doi:10.1371/journal.pone.0140631
PMCID: PMC4605700  PMID: 26465607
6.  Inflammation and Albuminuria in HIV-infected Patients Receiving Combination Antiretroviral Therapy 
Background:
The observed higher prevalence of albuminuria among HIV-infected patients has been strongly associated with cardiovascular disease and higher mortality. In HIV-seronegative patients with metabolic syndrome, malignancies and infections, pro-inflammatory cytokines, and acute phase reactants have been associated with albuminuria. However, the pathophysiology of albuminuria in HIV-seropositive individuals is poorly understood. We investigated the association of albuminuria with inflammatory biomarkers among HIV-infected patients on combination antiretroviral therapy.
Methods:
This is a cross-sectional analysis of the entry data of the participants enrolled in the Hawai‘i Aging with HIV-Cardiovascular Cohort. Participants were ≥ 40 years old, lived in Hawai‘i, documented HIV-positive, and had been on antiretroviral therapy for at least 6 months prior to recruitment. Albuminuria was defined as urine albumin-to-creatinine ratio (ACR) of 30 mg/g or higher, as assessed from single random urine collection. Microalbuminuria was defined as urine ACR between 30 and 300 mg/g and macroalbuminuria as urine ACR more than 300 mg/g. Plasma inflammatory biomarkers were assessed by multiplexing using Milliplex Human Cardiovascular Disease panels. Differences in clinical and laboratory characteristics between subjects with and without albuminuria were compared using a non-parametric Wilcoxon rank test for continuous variables and a chi-squared test for categorical variables. Univariate and multivariate logistic regression analyses were utilized to assess the association between presence of albuminuria as the dependent variable and plasma biomarkers as independent variables. Log-transformed plasma inflammatory biomarkers with P-value less than .1 in univariate logistic regression analysis were selected for examination in separate multivariate logistic regression models, adjusting for previously reported risk factors for albuminuria (age, gender, race, diabetes, hypertension, CD4 percent, current ritonavir, and tenofovir use).
Results:
Among a cohort of 111 HIV-infected patients (median age of 52 (Q1: 46, Q3: 57); male 86%; diabetes 6%; hypertension 33%; median CD4 count of 489 cells/mm3(Q1:341, Q3: 638); HIV RNA PCR < 48 copies/ml 85%), eighteen subjects (16.2%) had microalbuminuria, and two subjects (1.8%) had macroalbuminuria. There was no significant difference in CD4 count and HIV viral loads between patients with and without albuminuria. In univariate logistic regression analysis, higher levels of log-transformed soluble E-selectin (sE-selectin), soluble vascular cell adhesion molecule 1 (sVCAM-1), tissue plasminogen activator inhibitor-1 (tPAI-1), C-reactive protein (CRP), serum amyloid A (SAA), serum amyloid P (SAP), interleukin-1β, interleukin-8, and tumor necrosis factor-α (TNF-α) were associated with albuminuria (P < .10). In multivariate logistic regression models, sE-selectin, sVCAM-1, tPAI-1, CRP, and SAP remained significant (P < .05) even after adjustment for previously reported risk factors for albuminuria.
Conclusions:
This study has shown an association between inflammation and albuminuria independent of previously reported risk factors for albuminuria in HIV-infected subjects on stable combination antiretroviral therapy. Chronic low-grade inflammation despite potent antiretroviral treatment may be one of the factors causing higher rates of albuminuria among HIV-infected patients. Future studies are needed to further elucidate the pathophysiologic mechanisms of chronic inflammation in HIV and its impact on kidney disease.
PMCID: PMC4175929
7.  Albuminuria as a marker of arterial stiffness in chronic kidney disease patients 
World Journal of Nephrology  2015;4(3):406-414.
AIM: To access the association between albuminuria levels and arterial stiffness in non-diabetic patients with hypertension and chronic kidney disease (CKD) stages 1-2, treated with renin angiotensin blockade agents plus other hypertensive drugs when needed.
METHODS: One hundred fifteen patients [median age 52 years (68% males)] were consequently enrolled in the study. For each patient, we recorded gender, age, body mass index (BMI), peripheral systolic blood pressure (pSBP), peripheral diastolic blood pressure, peripheral pulse pressure, central systolic blood pressure (cSBP), central diastolic blood pressure (cDBP), central pulse pressure (cPP), hematocrit, hemoglobin, hsCRP, total cholesterol triglycerides, high-density lipoprotein-C, low-density lipoprotein-C, calcium, phosphorus, parathormone, and albumin, as well as 24 h urine albumin excretion. According to 24-h urine albumin collection, patients were then classified as those with moderately increased albuminuria (formerly called macroalbuminuria) (≤ 300 mg/d) and those with severely increased albuminuria (formerly called macroaluminuria (> 300 mg/d). We considered aortic stiffness (AS) indices [carotid femoral pulse wave velocity (PWVc-f) and augmentation index (AIx)] as primary outcomes of the study. We explored potential correlations between severely increased albuminuria and AS indices using a multiple linear regression model.
RESULTS: Fifty-eight patients were included in the moderately increased albuminuria group and 57 in the severely increased albuminuria. Blood pressure measurements of the study population were 138 ± 14/82 ± 1.3 mmHg (systolic/diastolic). There were no significant differences in age, sex, and BP measurements between the two groups. Patients with severely increased albuminuria had higher PWV and AIx than patients with moderately increased albuminuria (P < 0.02, P < 0.004, respectively). In addition these patients exhibited higher BMI (P < 0.03), hsCRP (P < 0.001), and fibrinogen levels (P < 0.02) compared to patients with moderately increased albuminuria. In multivariate linear regression analysis, severely increased albuminuria (β = 1.038, P < 0.010) pSBP (β = 0.028, P < 0.034) and Ht (β = 0.171, P = 0.001) remained independent determinants of the increased PWVc-f. Similarly, severely increased albuminuria (β = 4.385, P < 0.012), cSBP (β = 0.242, P < 0.001), cPP (β = 0.147, P < 0.01) and Ht levels (β = 0.591, P < 0.013) remained independent determinants of increased AIx.
CONCLUSION: These findings demonstrate an independent association between AS indices and severely increased albuminuria in non-diabetic, hypertensive patients with CKD stages 1-2 treated with renin angiotensin aldosterone system blockers.
doi:10.5527/wjn.v4.i3.406
PMCID: PMC4491932  PMID: 26167465
Arterial stiffness; Pulse wave velocity; Augmentation index; Albuminuria
8.  Vitamin D and Racial Disparity in Albuminuria: NHANES 2001–2006 
American Journal of Hypertension  2011;24(10):1114-1120.
Background
National data show unexplained racial disparity in albuminuria. We assessed whether low serum vitamin D status contributes to racial disparity in albuminuria.
Methods
We examined the association between race and albuminuria (spot urinary albumin/creatinine ratio (ACR) ≥30) among non-Hispanic black and white nonpregnant adults who were free of renal impairment in the National Health and Nutrition Examination Survey (NHANES) from 2001–2006. We conducted analyses without and with serum 25(OH)D. We adjusted for age, sex, education level, smoking, body mass index (BMI), diabetes, diagnosis of hypertension, and use of antihypertensive medication.
Results
Albuminuria was present in 10.0% of non-Hispanic blacks and 6.6% in non-Hispanic whites. Being black (odds ratio (OR) 1.46; 95% confidence interval (CI) 1.23–1.73) was independently associated with albuminuria. There was a graded, inverse association between 25(OH)D level and albuminuria. Notably, the association between race and albuminuria was no longer significant (OR 1.19; 95% CI 0.97–1.47) after accounting for participants' serum 25(OH)D. Similar results were observed when participants with macroalbuminuria (ACR ≥300 mg/g) or elevated parathyroid hormone (>74 pg/ml) were excluded or when a continuous measure of 25(OH)D was substituted for the categorical measure. There were no interactions between race and vitamin D status though racial disparity in albuminuria was observed among participants with the highest 25(OH)D levels.
Conclusion
Suboptimal vitamin D status may contribute to racial disparity in albuminuria. Randomized controlled trials are needed to determine whether supplementation with vitamin analogues reduces risk for albuminuria or reduce racial disparity in this outcome.
doi:10.1038/ajh.2011.108
PMCID: PMC3176582  PMID: 21716328
albuminuria; blood pressure; health status disparities; hypertension; vitamin D
9.  Assessment of Proteinuria in Patients with Chronic Kidney Disease Stage 3: Albuminuria and Non-Albumin Proteinuria 
PLoS ONE  2014;9(5):e98261.
Background and Objective
Proteinuria assessment is key in investigating chronic kidney disease (CKD) but uncertainty exists regarding optimal methods. Albuminuria, reflecting glomerular damage, is usually measured, but non-albumin proteinuria (NAP), reflecting tubular damage, may be important. This study investigated the prevalence and associations of albuminuria and NAP, and the optimum number of urine specimens required.
Methods
1,741 patients with CKD stage 3, recruited from primary care, underwent medical history, clinical assessment, blood sampling, and submitted three early morning urine samples for albumin to creatinine ratio (uACR) and protein to creatinine ratios (uPCR). Albuminuria was defined as uACR ≥3 mg/mmol in at least two of three samples. Isolated NAP was defined as uPCR ≥17 mg/mmol in two of three samples and uACR <3 mg/mmol in all three. Prevalence and associations of albuminuria and NAP, degree of agreement between single uACR and average of three uACRs, and urine albumin to protein ratio (uAPR = uACR/uPCR) were identified.
Results
Albuminuria prevalence was 16% and NAP 6%. Using a <1 mg/mmol threshold for uACR reduced NAP prevalence to 3.6%. Independent associations of albuminuria were: males (OR 3.06 (95% CI, 2.23–4.19)), diabetes (OR 2.14 (1.53–3.00)), lower estimated glomerular filtration rate ((OR 2.06 (1.48–2.85) 30–44 vs 45–59), and high sensitivity CRP ((OR 1.70 (1.25–2.32)). NAP was independently associated with females (OR 6.79 (3.48–13.26)), age (OR 1.62 (1.02–2.56) 80 s vs 70–79) and high sensitivity CRP ((OR 1.74 (1.14–2.66)). Of those with uPCR≥17 mg/mmol, 62% had uAPR<0.4. Sensitivity of single uACR was 95%, specificity 98%, PPV 90%. Bland Altman plot one vs average of three uACRs showed: mean difference 0.0064 mg/mmol (SD 4.69, limits of agreement −9.19 to +9.20, absolute mean difference 0.837).
Conclusions
In CKD stage 3, albuminuria has associations distinct from those of isolated NAP (except for inflammatory markers). Single uACR categorised albuminuria but average of three performed better for quantification.
doi:10.1371/journal.pone.0098261
PMCID: PMC4035283  PMID: 24867154
10.  Evaluation of Shear Wave Velocity and Human Bone Morphogenetic Protein-7 for the Diagnosis of Diabetic Kidney Disease 
PLoS ONE  2015;10(3):e0119713.
Purpose
The aim of this study was to determine the diagnostic values of kidney shear wave velocity (SWV) and bone morphogenetic protein-7 (BMP-7), and their correlation in the diagnosis of early diabetic kidney disease.
Methods
A total of 150 patients with type 2 diabetes mellitus were divided into three equal groups based on the urinary albumin-creatinine ratio (ACR): normal albuminuria (normo- group, ACR < 30 mg/g creatinine, n = 50), microalbuminuria (micro- group, 30 ≤ ACR < 300 mg/g creatinine, n = 50), and macroalbuminuria (macro- group, ACR ≥ 300 mg/g creatinine and estimated glomerular filtration rate (eGFR) ≥30 ml/min/1.73 m2, n = 50). Fifty healthy volunteers were recruited to serve as controls (control group). The levels of serum BMP-7 were detected, and virtual touch tissue quantification was used to detect the renal SWV value in all study subjects. Correlations between groups as well as SWV and BMP-7 were analyzed.
Results
Serum BMP-7 and SWV were significantly and progressively decreased and increased, respectively, during the development of renal disease, from the normo- to the micro- and to the macro- groups (all P < 0.01 between each other for BMP-7 and SWV). Moreover, no significant differences between the normo- and control groups were observed for either BMP-7 or SWV (both P > 0.05). In addition, a significant correlation was found between SWV and BMP-7, with a coefficient of -0.569 (P < 0.05).
Conclusion
The determination of SWV together with serum BMP-7 may play an important role in the diagnosis of diabetic kidney disease.
doi:10.1371/journal.pone.0119713
PMCID: PMC4366104  PMID: 25790348
11.  Serum Gamma - Glutamyltransferase Is Associated with Albuminuria: A Population-Based Study 
PLoS ONE  2014;9(12):e114970.
Background
Serum γ - glutamyltransferase (GGT) is implicated in the pathogenesis of endothelial dysfunction and atherosclerosis. Albuminuria is a marker of endothelial damage and correlated with structural and functional integrity of the vasculature. Our objective was to evaluate the association between serum GGT level and prevalence of albuminuria in a Chinese population.
Materials and Methods
We conducted a population-based cross-sectional study in 9,702 subjects aged 40 years or older. Increased urinary albumin excretion was defined according to the urinary albumin-to-creatinine ratio (ACR) ranges greater or equal than 30 mg/g. Low-grade albuminuria was defined according to the highest quartile of ACR in participants without increased urinary albumin excretion.
Results
The prevalence of low-grade albuminuria and increased urinary albumin excretion were respectively 23.4% and 6.6% in this population and gradually increased across the sex-specific serum GGT quartiles (all P for trend <0.05). In logistic regression analysis, compared with subjects in the lowest quartile of serum GGT level, the adjusted odds ratios (ORs) in the highest quartile was 1.22 [95% confidence interval (CI), 1.04–1.43] for low-grade albuminuria and 1.55 (95% CI, 1.18–2.04) for increased urinary albumin excretion. In subgroup analysis, significant relationship of serum GGT level with both low-grade albuminuria and increased urinary albumin excretion were detected in women, younger subjects, overweight subjects and in those with hypertension or glomerular filtration rate greater than 90 (all P <0.05).
Conclusion
Serum GGT level is associated with urinary albumin excretion in middle-aged and elderly Chinese.
doi:10.1371/journal.pone.0114970
PMCID: PMC4263709  PMID: 25500578
12.  Retinal Vessel Diameter and Chronic Kidney Disease in Rural China 
Medicine  2015;94(49):e2076.
Abstract
Few studies have examined the relationship between retinal microvascular abnormalities and chronic kidney disease (CKD). This study aims to examine the association between retinal vessel diameters and CKD in the rural China in order to provide the scientific basis for the early detection and diagnosis for CKD.
Participants and data were extracted from the Handan Eye Study, a population-based cross-sectional study performed from 2006 to 2007. The central retinal arteriolar equivalent (CRAE) and central retinal venular equivalent (CRVE) were summarized by the average arteriolar and venular caliber of each eye. The estimated glomerular filtration rate (eGFR) and a urinary albumin to creatinine ratio (ACR) were recorded. Multivariate logistic regression models were used to determine any associations between CRAE, CRVE, arteriole-to-venule ratio (AVR), retinopathy, and CKD in the recruited participants.
CKD was found in was 17.3% (892/5158) of this population with a 0.9% (48/5545) rate of reduced renal function and 16.7% (922/5538) rate of albuminuria. Retinopathy was present in 9.6% (571/5925) of participants. Compared to the 4th quartile of AVR, the first group was found to have a higher risk of albuminuria (odds ratio [OR] = 1.261, 95% confidence interval [95%CI]: 1.015–1.567, P = 0.037) and CKD (OR = 1.240, 95%CI: 1.000–1.537, P = 0.049) after adjustment for potential confounding variables. Retinopathy was associated with the occurrence of albuminuria (OR = 1.340, 95%CI: 1.067–1.685, P = 0.012) and CKD (OR = 1.341, 95%CI: 1.071–1.681, P = 0.010). In participants with diabetes, the ORs for the 1st and 4th quartiles of CRAE and CRVE were 2.292 (95%CI: 1.076–4.881, P = 0.032) and 2.113 (95%CI: 1.006–4.438, P = 0.048), respectively. Among the participants with hypertension, retinopathy was also observed to be associated with CKD (OR = 1.306, 95%CI: 1.003–1.699, P = 0.047).
The parameters of retinal vessel diameter may be a useful index evaluating the occurrence and development of CKD.
doi:10.1097/MD.0000000000002076
PMCID: PMC5008477  PMID: 26656332
13.  Predictors of chronic kidney disease in type 2 diabetes 
Medicine  2016;95(27):e4007.
Supplemental Digital Content is available in the text
Abstract
The identification of clinical predictors for the development of chronic kidney disease is a critical issue in the management of patients with type 2 diabetes mellitus.
We evaluated 27,029 patients with type 2 diabetes mellitus and estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m2 and normoalbuminuria from the database of the Italian Association of Clinical Diabetologists network. Primary outcomes were eGFR <60 mL/min/1.73 m2 and normoalbuminuria; albuminuria and eGFR ≥60 mL/min/1.73 m2; and eGFR <60 mL/min/1.73 m2 and albuminuria. Secondary outcomes were eGFR <60 mL/min/1.73 m2 and albuminuria. Measurements: eGFR from serum creatinine by chronic kidney disease epidemiology collaboration equation (CKD-EPI), urinary albumin excretion, HbA1c, triglycerides, high-density lipoprotein cholesterol (HDL-c) and low-density lipoprotein cholesterol (LDL-c), blood pressure, and body mass index.
Over a 4-year period, 33.2% of patients (n = 8973) developed chronic kidney disease, 10.3% (n = 2788) showed a decline in eGFR <60 mL/min/1.73 m2, 18.4% (n = 4978) developed albuminuria, and 4.5% (n = 1207) developed both features. Relative risk ratios (RRRs) for age (1.37, P < 0.001 by 5 years), sex (0.77, P < 0.001 for being male), body mass index (1.03, P < 0.001 by 1 kg/m2), triglycerides (1.02, P < 0.001 by 10 mg/dL), and LDL-c (0.97, P = 0.004 by 10 mg/dL) were independently related to the onset of eGFR reduction. Age (1.08, P < 0.001 by 5 years), sex (1.36, P < 0.001 for being male), body mass index (1.02, P < 0.001 by 1 kg/m2), triglycerides (1.01, P = 0.02 by 10 mg/dL), HDL-c, and LDL-c (0.97, P = 0.008 and 0.99, P = 0.003 by 5 and 10 mg/dL, respectively) were related to the onset of albuminuria. HbA1c and the intensity of antihypertensive treatment showed a weaker association with renal outcome.
Reduction in eGFR and albuminuria showed distinct sets of risk factors, suggesting that different mechanisms are involved in the development of these 2 components of diabetic kidney disease.
doi:10.1097/MD.0000000000004007
PMCID: PMC5058807  PMID: 27399078
albuminuria; diabetic kidney disease; glomerular filtration rate; risk factors; type 2 diabetes
14.  Estimated insulin sensitivity predicts regression of albuminuria in Type 1 diabetes 
Aim
To test the hypothesis that greater baseline insulin sensitivity would predict regression of albuminuria over 6 years in adults with Type 1 diabetes.
Method
We enrolled 81 people aged 30–48 years with albuminuria at baseline in the present study and re-examined them 6 years later. Urinary albumin excretion rate was measured and albuminuria was defined as urinary albumin excretion rate ≥20 µg/min. Regression of albuminuria was defined as normoalbuminuria (urinary albumin excretion rate <20µg/min) at follow-up. Predictors of regression of albuminuria were examined in stepwise logistic regression. The variables age, diabetes duration, sex, serum uric acid, HbA1c, systolic blood pressure, LDL cholesterol, HDL cholesterol, BMI, baseline albumin excretion rate, estimated insulin sensitivity at baseline, change in estimated insulin sensitivity from baseline to follow-up and angiotensinconverting enzyme inhibitor/angiotensin receptor blocker use were considered for inclusion in the model.
Results
Estimated insulin sensitivity was significantly higher at both baseline (4.6±1.2 vs 3.4±1.7; P=0.002) and follow-up (5.2±1.9 vs. 3.5±1.7; P<0.0001) in people who had regression of albuminuria vs those who did not. HbA1c (odds ratio 0.4, 95% CI 0.2–0.8; P=0.006), estimated insulin sensitivity (odds ratio 2.5, 95% CI 1.3–4.9; P=0.006) at baseline and change in estimated insulin sensitivity from baseline to follow-up (odds ratio 2.7, 95% CI 1.4–5.3; P=0.003) were independently associated with regression of albuminuria in a multivariable stepwise model.
Conclusions
In conclusion, over 6 years, higher baseline estimated insulin sensitivity and change in estimated insulin sensitivity independently predicted regression of albuminuria. Improving insulin sensitivity in people with Type 1 diabetes is a potential therapeutic target to increase rates of regression of albuminuria.
doi:10.1111/dme.12572
PMCID: PMC4301993  PMID: 25303233
15.  Albuminuria as a Risk Factor for Anemia in Chronic Kidney Disease: Result from the KoreaN Cohort Study for Outcomes in Patients With Chronic Kidney Disease (KNOW-CKD) 
PLoS ONE  2015;10(10):e0139747.
Background
Anemia is a common complication among patients with chronic kidney disease (CKD), and it is associated with unfavorable clinical outcomes in patients with CKD independent of the estimated glomerular filtration rate (eGFR). We assessed the association of the urinary albumin-to-creatinine ratio (ACR) and eGFR with anemia in CKD patients.
Methods
We conducted a cross-sectional study using baseline data from the KoreaN Cohort Study for Outcome in Patients With Chronic Kidney Disease (KNOW-CKD). Multiple regression analysis was performed to identify the independent association of albuminuria with anemia. Furthermore, odds ratios for anemia were calculated by cross-categorization of ACR and eGFR.
Results
Among 1,456 patients, the mean age was 53.5 ± 12.4 years, and the mean eGFR and ACR were 51.9 ± 30.5 mL/min per 1.73 m2 and 853.2 ± 1,330.3 mg/g, respectively. Anemia was present in 644 patients (40.5%). Multivariate analysis showed that the odds ratio of anemia increased according to ACR levels, after adjusting for age, sex, eGFR, body mass index, pulse pressure, cause of CKD, use of erythropoiesis stimulating agents, serum calcium and ferritin (ACR < 30 mg/g as a reference group; 30–299 mg/g, adjusted odds ratio (OR) = 1.43, 95% confidence interval (CI) = 0.88–2.33; ≥300 mg/g, adjusted OR = 1.86, 95% CI = 1.12–3.10). In addition, graded associations were observed in cross-categorized groups of a higher ACR and eGFR compared to the reference group with an ACR <30 mg/g and eGFR ≥60 mL/min per 1.73 m2.
Conclusion
The present study demonstrated that albuminuria was a significant risk factor for anemia in CKD patients independent of the eGFR.
doi:10.1371/journal.pone.0139747
PMCID: PMC4592200  PMID: 26430892
16.  Advanced Glycation Urinary Protein-Bound Biomarkers and Severity of Diabetic Nephropathy in Man 
American Journal of Nephrology  2011;34(4):347-355.
Background/Aims
The formation of advanced glycation end products (AGEs) is accelerated in patients with diabetic nephropathy. The aim of this study was to ascertain if the urinary excretion of proteins modified by advanced glycation can be used as biomarkers for albuminuria in individuals with type 1 or type 2 diabetes.
Methods
Community-based patients with type 1 (n = 68) or type 2 diabetes (n = 216) attending a diabetes clinic of a tertiary referral hospital were classified as having normoalbuminuria (Normo, albumin excretion rate (AER) <20 μg/min), microalbuminuria (Micro, AER 20–200 μg/min) or macroalbuminuria (Macro, AER ≥200 μg/min). Serum and urine AGE-modified proteins were measured.
Results
In patients with both type 1 diabetes and type 2 diabetes, there was a clear association between the degree of albuminuria and urinary AGE-modified proteins (p < 0.0001). Exclusive to patients with type 1 diabetes, urinary excretion of the AGE carboxymethyllysine correlated with AER, whereas patients with type 2 diabetes and macroalbuminuria had an increase in urinary methylglyoxal, an AGE intermediate. These changes were independent of isotopic glomerular filtration rate levels. Serum concentrations of AGEs or soluble receptor for AGEs were not consistently associated with albuminuria in either type 1 or type 2 diabetes.
Conclusions
Urinary excretion of proteins modified by AGEs may be useful biomarkers of albuminuria in individuals with type 1 and type 2 diabetes, warranting prospective investigation in larger diabetic cohorts.
doi:10.1159/000331064
PMCID: PMC3182043  PMID: 21876347
Advanced glycation end products; Diabetic nephropathy; Albuminuria; Carboxymethyllysine; Methylglyoxal; Urinary biomarkers
17.  Prevalence of chronic kidney disease defined by using CKD-EPI equation and albumin-to-creatinine ratio in the Korean adult population 
Background/Aims
An updated chronic kidney disease (CKD) definition and classification were proposed by Kidney Disease: Improving Global Outcomes (KDIGO), with adoption of a new equation to estimate glomerular filtration rate (GFR) and albuminuria to evaluate kidney structural damage. This study was performed to estimate the prevalence of CKD in the Korean adult population as defined and classified by the KDIGO guidelines.
Methods
Cross-sectional samples of the fifth Korean National Health and Nutrition Examination Survey for 2011 to 2012 were examined for adults aged ≥ 19 years. CKD prevalence was determined based on decreased GFR and albuminuria. The GFR was estimated using the CKD Epidemiology Collaboration creatinine equation, and albuminuria was evaluated using the albumin-to-creatinine ratio (ACR) in spot urine.
Results
Of the 16,576 subjects participating in the survey, 10,636 (4,758 men, 5,878 women) were included in the present study. The prevalence of CKD was estimated as 7.9% (7.8% in 2011 and 8.0% in 2012, p = 0.770). The prevalence of low, moderately increased, high, and very high CKD risk prognosis was 92.0%, 6.3%, 1.1%, and 0.6%, respectively. The prevalence of albuminuria (ACR ≥ 30 mg/g) in individuals with GFR ≥ 60 mL/min/1.73 m2 has reached 5.7%. The odds ratios of hypertension and diabetes to CKD were 3.4 and 3.1 in men, and 2.9 and 2.0 in women (all p < 0.001), respectively.
Conclusions
A large percentage of CKD patients had albuminuria prior to a decrease in GFR. Regular laboratory tests for albuminuria for the high-risk group, and especially for hypertensive or diabetic patients, might improve detection of CKD at an early stage.
doi:10.3904/kjim.2015.193
PMCID: PMC5094925  PMID: 27017386
Renal insufficiency, chronic; Kidney Disease Improving Global Outcomes; Glomerular filtration rate; Albuminuria; Korea
18.  Foot insensitivity is associated with renal function decline in patients with type 2 diabetes: a cohort study 
Background
Identifying patients with diabetes at increased risk of chronic kidney disease (CKD) is essential to prevent/slow the progression to end-stage renal disease (ESRD). CKD and diabetic peripheral neuropathy (DPN) share common mechanisms. Hence, we aimed to examine the relationship between foot insensitivity and CKD in patients with Type 2 diabetes.
Methods
A prospective observational cohort study in adults with Type 2 diabetes. Patients with ESRD were excluded. Foot insensitivity was assessed using the 10-g monofilament test. Renal function was assessed using estimated glomerular filtration rate (eGFR) based on the MDRD equation. Albuminuria was defined as the presence of urinary albumin/creatinine ratio (ACR) >3.4 mg/mmol.
Results
Two hundred and twenty eight patients were recruited and followed-up for 2.5 years. One hundred and ninety patients (83.4%) had eGFR ≥ 60 ml/min/1.73 m2. Seventy six (33.3%) patients had foot insensitivity (i.e. abnormal monofilament test). Patients with foot insensitivity had lower eGFR and higher prevalence of albuminuria compared to patients with normal monofilament test. After adjustment for age, gender, ethnicity, diabetes duration, HbA1c, body mass index, insulin treatment, number of anti-hypertensives, history of peripheral vascular disease, and baseline eGFR (R2 0.87), baseline foot insensitivity was associated with study-end eGFR (B = −3.551, p = 0.036).
Conclusions
Patients with Type 2 diabetes and foot insensitivity are at increased risk of eGFR decline. Identifying these patients offers an opportunity to intensify metabolic and blood pressure control to prevent/retard the development of CKD. Future studies of larger sample size and longer follow up from multiple centres are needed to assess the diagnostic performance of our findings in predicting CKD development, and to compare the performance of the monofilament test with albuminuria.
doi:10.1186/s12902-016-0147-1
PMCID: PMC5120531  PMID: 27876022
Diabetic neuropathy; Chronic kidney disease; Diabetic nephropathy; Albuminuria; Estimated glomerular filtration rate; Foot insensitivity; 10 g monofilament
19.  Racial and Ethnic Differences in Albuminuria in Individuals With Estimated GFR Greater Than 60 mL/min/1.73 m2: Results From the Kidney Early Evaluation Program (KEEP) 
Background
Albuminuria is an important marker for chronic kidney disease and progression to end-stage renal disease in the general population; understanding racial and ethnic differences can help inform efforts to reduce health disparities. We sought to estimate independent associations of race/ethnicity with albuminuria to determine whether observed differences were attributable to known kidney disease risk factors.
Methods
This cross-sectional study included 64,161 Kidney Early Evaluation Program (KEEP) participants, 2000–2008, with estimated glomerular filtration rate ≥ 60 mL/min/1.73 m2, not on regular dialysis, and without previous kidney transplant. Albuminuria (urine albumin-creatinine ratio [ACR] ≥ 30 mg/g) was examined by self-reported race and ethnicity. Covariates were age, sex, educational level, body mass index, diabetes status or glucose level, hypertension status or blood pressure measurement, smoking status, health insurance status, and geographic region.
Results
Albuminuria prevalence was 8% (n = 2303) in whites, 11% (n = 2310) in African Americans, 9% (n = 730) in Hispanics, 10% (n = 381) in Asians, and 15% (n = 344) in American Indians/Alaska Natives. Compared with whites, odds of albuminuria were higher for all groups after multivariate adjustment. Odds were highest for American Indians/Alaska Natives (adjusted odds ratio 1.93, 95% confidence interval 1.70–2.20), then Asians (1.42, 1.26–1.61), African Americans (1.38, 1.29–1.47), and Hispanics (1.19, 1.08–1.31).
Conclusions
In the KEEP study population, albuminuria prevalence was higher among African Americans, Hispanics, Asians, and American Indians/Alaska Natives than among non-Hispanic whites, suggesting a need for screening for early detection of kidney damage, especially among people at increased risk, in the community primary care setting.
doi:10.1053/j.ajkd.2009.09.034
PMCID: PMC3507474  PMID: 20172444
20.  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.
21.  Hyperuricemia Is an Independent Risk Factor for New Onset Micro-Albuminuria in a Middle-Aged and Elderly Population: A Prospective Cohort Study in Taiwan 
PLoS ONE  2013;8(4):e61450.
Background
Hyperuricemia is now regarded as a risk factor for cardiovascular disease. Micro-albuminuria is associated with increased risk for cardiovascular disease and chronic kidney disease. We hypothesized that elevated serum uric acid (UA) is associated with development of micro-albuminuria in the general population.
Methodology/Principal Findings
We conducted a community-based prospective cohort study. A total of 1862 subjects from southern Taiwan, all older than 40 years, were screened and 993 of these participants without micro-albuminuria were followed for 4 years. Urinary albumin-to-creatinine ratio was measured two times per year. A multiple linear regression model indicated that serum UA was independently associated with ln(ACR) after adjustment for 8 factors (age, sex, and 6 metabolic metrics) (β = 0.194, p<0.01). Logistic regression analysis indicated that each 1 mg/dL increase of UA was associated with a 1.42-fold increased risk of micro-albuminuria after adjustment for the same 8 factors (OR = 1.42, 95% CI: 1.27–1.59, p<0.01). A Cox regression model using subjects with serum UA less than 5 mg/dL as reference group indicated higher hazard ratios (HRs) only found in subjects with serum UA more than 7 mg/dL (HR = 3.54, 95% CI: 2.11–5.93, p<0.01) and not in subjects with serum UA of 5 to 7 mg/dL (HR = 1.30, 95% CI: 0.82–2.07, p = 0.15).
Conclusion
Hyperuricemia is significantly associated with micro-albuminuria in middle-aged and elderly males and females from a general population in Taiwan. Elevated serum UA is an independent predictor for development of micro-albuminuria in this population.
doi:10.1371/journal.pone.0061450
PMCID: PMC3634806  PMID: 23637835
22.  Chronic Kidney Disease in Primary Care: Outcomes after Five Years in a Prospective Cohort Study 
PLoS Medicine  2016;13(9):e1002128.
Background
Chronic kidney disease (CKD) is commonly managed in primary care, but most guidelines have a secondary care perspective emphasizing the risk of end-stage kidney disease (ESKD) and need for renal replacement therapy. In this prospective cohort study, we sought to study in detail the natural history of CKD in primary care to better inform the appropriate emphasis for future guidance.
Methods and Findings
In this study, 1,741 people with CKD stage 3 were individually recruited from 32 primary care practices in Derbyshire, United Kingdom. Study visits were undertaken at baseline, year 1, and year 5. Binomial logistic regression and Cox proportional hazards models were used to model progression, CKD remission, and all-cause mortality. We used Kidney Disease: Improving Global Outcomes (KDIGO) criteria to define CKD progression and defined CKD remission as the absence of diagnostic criteria (estimated glomerular filtration rate [eGFR] >60 ml/min/1.73 m2 and urine albumin-to-creatinine ratio [uACR] <3 mg/mmol) at any study visit. Participants were predominantly elderly (mean ± standard deviation (SD) age 72.9 ± 9.0 y), with relatively mild reduction in GFR (mean ± SD eGFR 53.5 ± 11.8 mL/min/1,73 m2) and a low prevalence of albuminuria (16.9%). After 5 y, 247 participants (14.2%) had died, most of cardiovascular causes. Only 4 (0.2%) developed ESKD, but 308 (17.7%) evidenced CKD progression by KDIGO criteria. Stable CKD was observed in 593 participants (34.1%), and 336 (19.3%) met the criteria for remission. Remission at baseline and year 1 was associated with a high likelihood of remission at year 5 (odds ratio [OR] = 23.6, 95% CI 16.5–33.9 relative to participants with no remission at baseline and year 1 study visits). Multivariable analyses confirmed eGFR and albuminuria as key risk factors for predicting adverse as well as positive outcomes. Limitations of this study include reliance on GFR estimated using the Modification of Diet in Renal Disease study (MDRD) equation for recruitment (but not subsequent analysis) and a study population that was predominantly elderly and white, implying that the results may not be directly applicable to younger populations of more diverse ethnicity.
Conclusions
Management of CKD in primary care should focus principally on identifying the minority of people at high risk of adverse outcomes, to allow intervention to slow CKD progression and reduce cardiovascular events. Efforts should also be made to identify and reassure the majority who are at low risk of progression to ESKD. Consideration should be given to adopting an age-calibrated definition of CKD to avoid labelling a large group of people with age-related decline in GFR and low associated risk as having CKD.
In this prospective cohort study, Adam Shardlow and colleagues report on the progression of chronic kidney disease over 5 years among patients in primary care.
Author Summary
Why Was This Study Done?
Chronic kidney disease affects 10%–20% of adults in most countries and is associated with multiple adverse outcomes, including increased risk of death, progression to end-stage kidney disease (requiring dialysis or kidney transplantation), and increased risk of diseases of the heart and arteries.
The risk of these adverse outcomes varies considerably, and previous studies indicate that most people with chronic kidney disease are at low risk.
Many previous studies have been conducted in large teaching hospitals and have understandably emphasized the risk of end-stage kidney disease, but the results may not be applicable to the majority with chronic kidney disease because most have mild disease, are cared for by family doctors, and are never referred to a kidney specialist.
We conducted this study to better understand the risks associated with chronic kidney disease in people cared for by family doctors in order to provide a perspective that is applicable to the majority of people affected.
What Did the Researchers Do and Find?
We individually assessed 1,741 people with mild (stage 3) chronic kidney disease at 32 family doctors’ clinics and reassessed them after 1 and 5 y.
We found that most people (34%) had stable kidney function, only a very small minority (4 people or 0.2%) developed end-stage kidney disease, and 18% evidenced less severe progression after 5 y.
Surprisingly, kidney function improved in some people (19%) to the extent that they no longer had evidence of chronic kidney disease.
What Do These Findings Mean?
Our data emphasize that the management of chronic kidney disease by family doctors should focus on identifying the minority of people who are at high risk of adverse outcomes for more intensive treatment and referral to a kidney specialist.
People at low risk should also be identified so that they can be reassured and spared unnecessary treatment or referral.
An internationally agreed definition for “remission” of chronic kidney disease is needed so that this outcome can be studied in more detail in other populations.
Our findings may not be directly applicable to populations with younger age or greater ethnic diversity.
doi:10.1371/journal.pmed.1002128
PMCID: PMC5029805  PMID: 27648564
23.  Combined Association of Albuminuria and Cystatin C–Based Estimated GFR With Mortality, Coronary Heart Disease, and Heart Failure Outcomes: The Atherosclerosis Risk in Communities (ARIC) Study 
Background
Serum cystatin C level has been shown to have a stronger association with clinical outcomes than serum creatinine level. However, little is known about the combined association of cystatin C–based estimated glomerular filtration rate (eGFRcys) and albuminuria with clinical outcomes, particularly at levels lower than current chronic kidney disease (CKD) cutoffs.
Study Design
Prospective cohort.
Setting & Participants
10,403 ARIC (Atherosclerosis Risk in Communities) Study participants followed up for a median of 10.2 years.
Predictor
eGFRcys, albuminuria.
Outcomes
Mortality, coronary heart disease (CHD), and heart failure, as well as a composite of any of these separate outcomes.
Results
Both decreased eGFRcys and albuminuria were associated independently with the composite outcome, as well as mortality, CHD, and heart failure. Although eGFRcys of 75-89 mL/min/1.73 m2 in the absence of albuminuria (albumin-creatinine ratio [ACR] <10 mg/g) or albuminuria with ACR of 10-29 mg/g with normal eGFRcys (90-104 mL/min/1.73 m2) was not associated significantly with any outcome compared with eGFRcys of 90-104 mL/min/1.73 m2 and ACR <10 mg/g, the risk of each outcome was significantly higher in those with both eGFRcys of 75-89 mL/min/1.73 m2 and ACR of 10-29 mg/g (for mortality, HR of 1.4 [95% CI, 1.1-2.0]; for CHD, HR of 1.9 [95% CI, 1.4-2.6]; for heart failure, HR of 1.8 [95% CI, 1.2-2.7]). Combining the 2 markers improved risk classification for all outcomes (P < 0.001), even in those without overt CKD.
Limitations
Only one measurement of cystatin C.
Conclusions
Mildly decreased eGFRcys and mild albuminuria independently contributed to the risk of mortality, CHD, and heart failure. Even minimally decreased eGFRcys (75-89 mL/min/1.73 m2) is associated with increased risk in the presence of mild albuminuria. Combining the 2 markers is useful for improved risk stratification even in those without clinical CKD.
doi:10.1053/j.ajkd.2012.03.011
PMCID: PMC3582350  PMID: 22537422
Epidemiology; kidney; outcomes
24.  Glomerular Filtration Rate and Albuminuria for Detection and Staging of Acute and Chronic Kidney Disease in Adults: A Systematic Review 
JAMA  2015;313(8):837-846.
Importance
Because early stage kidney disease is asymptomatic and is associated with both, morbidity and mortality, laboratory measurements are required for its detection.
Objective
To summarize evidence supporting the use of laboratory tests for glomerular filtration rate (GFR) and albuminuria to detect and stage acute kidney injury (AKI), acute kidney diseases and disorders (AKD), and chronic kidney disease (CKD) in adults.
Evidence Review
We reviewed recent guidelines from various professional groups and systematically searched for other sources of evidence for selected topics.
Findings
The Kidney Disease Improving Global Outcomes KDIGO guidelines define and stage acute and chronic kidney diseases by GFR and albuminuria. For initial assessment of GFR, measuring serum creatinine and reporting estimated GFR (eGFRcr) based on serum creatinine using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) 2009 equation is recommended. If confirmation of GFR is required because of conditions that affect serum creatinine independent of GFR, such as extremes of muscle mass or diet, or interference with the assay, cystatin C should be measured and estimated GFR should be calculated and reported using both serum creatinine and cystatin C (eGFRcys and eGFRcr-cys) or GFR should be measured directly using a clearance procedure. Initial assessment of albuminuria includes measuring urine albumin and creatinine in an untimed “spot” urine collection and reporting albumin-to-creatinine ratio (ACR). If confirmation of albuminuria is required because of diurnal variation or conditions that affect creatinine excretion, such as extremes of muscle mass or diet, the albumin excretion rate (AER) should be measured from a timed urine collection.
Conclusions and Relevance
Detection and staging of acute and chronic kidney diseases can be relatively simple. Because of the morbidity and mortality associated with kidney disease, early diagnosis is important and should be pursued in at-risk populations.
doi:10.1001/jama.2015.0602
PMCID: PMC4410363  PMID: 25710660
25.  The association of chronic kidney disease complications by albuminuria and glomerular filtration rate: a cross-sectional analysis  
Clinical Nephrology  2013;80(1):29-39.
Background: Albuminuria is strongly associated with future risk for cardiovascular and kidney outcomes, and has been proposed to be included in the classification of chronic kidney disease (CKD) along with glomerular filtration rate (GFR). Few data are available on whether albuminuria is associated with concurrent complications of CKD. Methods: A cross-sectional analysis of 1,665 participants screened for the Modification of Diet in Renal Disease (MDRD) study was performed to examine the association between albuminuria (determined using urine albumin-creatinine ratio (ACR)) and measured GFR (determined using urinary clearance of iothalamate) with anemia, acidosis, hyperphosphatemia, and hypertension. Results: Mean GFR (± SD) was 39 ml/min/1.73 m2 (± 21) and the median (25 – 75th percentile) ACR was 161 (38 – 680) mg/g. In multivariable models adjusted for age, sex, race, kidney disease etiology, and GFR, higher ACR levels were not associated with any complication. For example, comparing ACR > 300 mg/g vs. < 30 mg/g, the prevalence ratio (95% CI) for anemia was 0.98 (0.81 – 1.20), acidosis 1.13 (0.86 – 1.48), hyperphosphatemia 1.69 (0.91 – 3.17), and hypertension 1.04 (0.97 – 1.12). Lower levels of GFR were associated with all complications. For example, GFR levels < 30 ml/min/1.73 m2 vs. GFR levels 60 – 89 ml/min/1.73 m2 were associated with prevalence ratios (95% CI) of anemia 4.35 (3.18 – 5.96), acidosis 5.31 (3.41 – 8.29), hyperphosphatemia 23.8 (7.71 – 73.6), and hypertension 1.21 (1.10 – 1.32). Conclusions: Albuminuria is not associated with complications after controlling for GFR in patients younger than 70 years of age with non-diabetic CKD and GFR less than 90 ml/min/1.73 m2 and thus would not affect clinical action plans for decisions regarding evaluation and treatment of complications in similar populations.
doi:10.5414/CN107842
PMCID: PMC4108165  PMID: 23803596
albuminuria; chronic kidney disease; complications; glomerular filtration rate

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