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Albuminuria is associated with a higher prevalence of depression in a population-based cohort study: the Maastricht Study.
Martens, RJH, Kooman, JP, Stehouwer, CDA, Dagnelie, PC, van der Kallen, CJH, Kroon, AA, Leunissen, KML, van der Sande, FM, Schaper, NC, Sep, SJS, et al
Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. 2018;(1):128-138
Abstract
BACKGROUND Depression is common in individuals with chronic kidney disease (CKD). However, data on the association of albuminuria, which together with reduced estimated glomerular filtration rate (eGFR) defines CKD, with depression are scarce and conflicting. In addition, it is not clear when in the course from normal kidney function to CKD the association with depression appears. METHODS We examined the cross-sectional associations of albuminuria and eGFR with depressive symptoms and depressive episodes in 2872 and 3083 40- to 75-year-old individuals, respectively, who completed the baseline survey of an ongoing population-based cohort study conducted in the southern part of The Netherlands between November 2010 and September 2013. Urinary albumin excretion (UAE) was the average UAE in two 24-h urine collections and eGFR was calculated with the Chronic Kidney Disease Epidemiology Collaboration equation based on creatinine and cystatin C. Depressive symptoms were assessed with the 9-item Patient Health Questionnaire (PHQ-9) and the presence of a minor or major depressive episode was assessed with the MINI-International Neuropsychiatric Interview. RESULTS In total, 5.4% had a minor or major depressive episode. UAE was <15 mg/24 h in 81.2%, 15-<30 mg/24 h in 10.3% and ≥30 mg/24 h in 8.6%. In a multivariable logistic regression analysis adjusted for potential confounders, and with UAE <15 mg/24 h as reference category, the odds ratio for a minor or major depressive episode was 2.13 [95% confidence interval (CI) 1.36-3.36] for UAE 15-<30 mg/24 h and 1.81 (95% CI 1.10-2.98) for UAE ≥30 mg/24 h. The average eGFR was 88.2 ± 14.7 mL/min/1.73 m2. eGFR was not associated with the presence of a minor or major depressive episode. Results were similar when we assessed associations with depressive symptoms or clinically relevant depressive symptoms (PHQ-9 score ≥10). CONCLUSIONS Albuminuria was associated with depressive symptoms and depressive episodes, even at levels of UAE that do not fulfil the CKD criteria. Future longitudinal studies should examine the direction of this association and whether albuminuria could serve as a biomarker to identify individuals at risk of depression.
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Use of monomeric and oligomeric flavanols in the dietary management of patients with type 2 diabetes mellitus and microalbuminuria (FLAVA trial): study protocol for a randomized controlled trial.
Rashid, M, Verhoeven, AJM, Mulder, MT, Timman, R, van Beek-Nieuwland, Y, Athumani, AA, Zandbergen, AAM, van der Wiel, HE, Sijbrands, EJG, Berk, KA
Trials. 2018;(1):379
Abstract
BACKGROUND Patients with type 2 diabetes mellitus (T2D) are prone to micro- and macro-vascular complications. Monomeric and oligomeric flavanols (MOF) isolated from grape seeds (Vitis vinifera) have been linked to improved endothelial function and vascular health. The aim of this study is to determine the effect of a daily supplementation of 200 mg MOF on renal endothelial function of patients with T2D and microalbuminuria. METHODS/DESIGN For this double-blind, placebo-controlled, randomized, multicenter trial 96 individuals (ages 40-85 years) with T2D and microalbuminuria will be recruited. Participants will be randomly assigned to the intervention group, receiving 200 mg of MOF daily for 3 months, or to the control group, receiving a placebo. The primary endpoint is the evolution over time in albumin excretion rate (AER) until 3 months of intervention as compared with placebo. Secondary endpoints are the evolution over time in established plasma markers of renal endothelial function-asymmetric dimethylarginine (ADMA), soluble vascular cell adhesion molecule-1 (sVCAM-1), soluble intercellular cell adhesion molecule-1 (sICAM-1), interleukin-6 (IL-6), and von Willebrand Factor (vWF)-until 3 months of intervention as compared with placebo. Mixed modeling will be applied for the statistical analysis of the data. DISCUSSION We hypothesize that T2D patients with microalbuminuria have a medically determined requirement for MOF and that fulfilling this requirement will result in a decrease in AER and related endothelial biomarkers. If confirmed, this may lead to new insights in the dietary management of patients with T2D. TRIAL REGISTRATION Nederlands Trial Register, NTR4669 , registered on 7 July 2014.
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Effect of Vitamin D therapy on urinary albumin excretion, renal functions, and plasma renin among patients with diabetic nephropathy: A randomized, double-blind clinical trial.
Liyanage, P, Lekamwasam, S, Weerarathna, TP, Liyanage, C
Journal of postgraduate medicine. 2018;(1):10-15
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Abstract
BACKGROUND Despite different management strategies, progression of proteinuria occurs in a sizable category of patients with diabetic nephropathy (DN). Increase in serum renin levels induced by the renin-angiotensin system (RAS) may contribute to this. Vitamin D therapy is found to have an inhibitory effect on the RAS. We aimed to study the effects of Vitamin D therapy on renal functions of patients with DN. METHODS This was a double-blind, randomized, placebo-controlled study. Patients with DN (urinary albumin [UA] >30 mg/g of creatinine) whose estimated glomerular filtration rate (eGFR) was more than 30 mL/min were selected and their plasma renin, parathyroid hormone, serum Vitamin D, serum calcium, serum creatinine, fasting blood sugar were done as baseline measurements. Subjects were randomized into two groups and treatment group was given Vitamin D, 50000 IU (0.25 ml) intramuscularly (IM) monthly for 6 months; control group received distilled water IM. Investigations were repeated after 6 months of therapy. RESULTS Of 155 patients invited, 85 were randomly assigned to two groups. After 6 months, mean reduction of UA to creatinine ratio in the treatment and control group was 51.8 mg/g (95% confidence interval [CI]; 66.1--37.5, P ≤ 0.001); 22.4 mg/g (95% CI; -45.7-0.8, P = 0.06), respectively (between group difference P = 0.001). Significant increase in the eGFR observed in the treatment group while eGFR remained unchanged in the control group (P = 0.03 for the between-group difference). Mean reduction in plasma renin in treatment group and control group was 5.85 pg/mL (95% CI; -6.7--4.6) (P < 0.001) and 0.95 pg/mL (95% CI; -1.4--0.14, P = 0.02), respectively. CONCLUSIONS Vitamin D 50000 IU given IM monthly for 6 months reduces urine albumin, serum creatinine, and renin levels in patients with DN.
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Changes in Albuminuria and the Risk of Major Clinical Outcomes in Diabetes: Results From ADVANCE-ON.
Jun, M, Ohkuma, T, Zoungas, S, Colagiuri, S, Mancia, G, Marre, M, Matthews, D, Poulter, N, Williams, B, Rodgers, A, et al
Diabetes care. 2018;(1):163-170
Abstract
OBJECTIVE To assess the association between 2-year changes in urine albumin-to-creatinine ratio (UACR) and the risk of clinical outcomes in type 2 diabetes. RESEARCH DESIGN AND METHODS We analyzed data from 8,766 participants in the Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation Post-Trial Observational Study (ADVANCE-ON). Change in UACR was calculated from UACR measurements 2 years apart, classified into three groups: decrease in UACR of ≥30%, minor change, and increase in UACR of ≥30%. By analyzing changes from baseline UACR groups, categorized into thirds, we repeated these analyses accounting for regression to the mean (RtM). The primary outcome was the composite of major macrovascular events, renal events, and all-cause mortality; secondary outcomes were these components. Cox regression models were used to estimate hazard ratios (HRs). RESULTS Over a median follow-up of 7.7 years, 2,191 primary outcomes were observed. Increases in UACR over 2 years independently predicted a greater risk of the primary outcome (HR for ≥30% UACR increase vs. minor change: 1.26; 95% CI 1.13-1.41), whereas a decrease in UACR was not significantly associated with lower risk (HR 0.93; 95% CI 0.83-1.04). However, after allowing for RtM, the effect of "real" decrease in UACR on the primary outcome was found to be significant (HR 0.84; 95% CI 0.75-0.94), whereas the estimated effect on an increase was unchanged. CONCLUSIONS Changes in UACR predicted changes in the risk of major clinical outcomes and mortality in type 2 diabetes, supporting the prognostic utility of monitoring albuminuria change over time.
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The Long-Term Impact of Renin-Angiotensin System (RAS) Inhibition on Cardiorenal Outcomes (LIRICO): A Randomized, Controlled Trial.
Saglimbene, V, Palmer, SC, Ruospo, M, Natale, P, Maione, A, Nicolucci, A, Vecchio, M, Tognoni, G, Craig, JC, Pellegrini, F, et al
Journal of the American Society of Nephrology : JASN. 2018;(12):2890-2899
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BACKGROUND The comparative effectiveness of treatment with angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or their combination in people with albuminuria and cardiovascular risk factors is unclear. METHODS In a multicenter, randomized, open label, blinded end point trial, we evaluated the effectiveness on cardiovascular events of ACE or ARB monotherapy or combination therapy, targeting BP<130/80 in patients with moderate or severe albuminuria and diabetes or other cardiovascular risk factors. End points included a primary composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, and hospitalization for cardiovascular causes and a revised end point of all-cause mortality. Additional end points included ESRD, doubling of serum creatinine, albuminuria, eGFR, BP, and adverse events. RESULTS Because of slow enrollment, the trial was modified and stopped 41% short of targeted enrollment of 2100 participants, corresponding to 35% power to detect a 25% reduced risk in the primary outcome. Our analysis included 1243 adults, with median follow-up of 2.7 years. Efficacy outcomes were similar between groups (ACE inhibitor versus ARB, ACE inhibitor versus combination, ARB versus combination) as were rates of serious adverse events. The rate of permanent discontinuation for ARB monotherapy (6.3%) was significantly lower than for ACE inhibitor monotherapy (15.7%) or combined therapy (18.3%). CONCLUSIONS Patients may tolerate ARB monotherapy better than ACE inhibitor monotherapy. However, data from this trial and similar trials, although as yet inconclusive, show no trend suggesting differences in mortality and renal outcomes with ACE inhibitors or ARBs as dual or monotherapy in patients with albuminuria and diabetes or other cardiovascular risk factors.
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Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease: an exploratory analysis from the EMPA-REG OUTCOME randomised, placebo-controlled trial.
Cherney, DZI, Zinman, B, Inzucchi, SE, Koitka-Weber, A, Mattheus, M, von Eynatten, M, Wanner, C
The lancet. Diabetes & endocrinology. 2017;(8):610-621
Abstract
BACKGROUND In a pooled analysis of short-term trials, short-term treatment with the sodium-glucose co-transporter-2 (SGLT2) inhibitor empagliflozin reduced albuminuria in patients with type 2 diabetes and prevalent albuminuria. In this exploratory analysis of the EMPA-REG OUTCOME trial, we report the short-term and long-term effects of empagliflozin on albuminuria in patients with type 2 diabetes and established cardiovascular disease, according to patients' baseline albuminuria status. METHODS In this randomised, double-blind, placebo-controlled trial at 590 sites in 42 countries, we randomly assigned patients aged 18 years and older with type 2 diabetes and established cardiovascular disease (1:1:1) to empagliflozin 10 mg, empagliflozin 25 mg, or placebo in addition to standard of care until at least 691 patients experienced an adjudicated event included in the primary outcome. We did the randomisation with a computer-generated random-sequence and interactive voice-response and web-response system, stratified by HbA1c, BMI, region, and estimated glomerular filtration rate. Patients, investigators, and individuals involved in analysis of trial data were masked to treatment assignment. The primary and secondary efficacy and safety endpoints of this trial have been reported previously. Here, we report urinary albumin-to-creatinine ratio (UACR) data for the pooled empagliflozin group versus placebo according to albuminuria status at baseline (normoalbuminuria: UACR <30 mg/g; microalbuminuria: UACR ≥30 to ≤300 mg/g; and macroalbuminuria: UACR >300 mg/g). We did the analysis with mixed-model repeated measures including prespecified and post-hoc tests. This study is completed and registered with ClinicalTrials.gov, number NCT01131676. FINDINGS Between Sept 1, 2010, and April 22, 2013, we randomly assigned 7028 patients to treatment groups and 7020 patients received treatment. At baseline, we had UACR data for 6953 patients: 4171 (59% of treated patients; 1382 assigned to placebo and 2789 assigned to empagliflozin) had normoalbuminuria, 2013 (29%; 675 assigned to placebo and 1338 assigned to empagliflozin) had microalbuminuria, and 769 (11%; 260 assigned to placebo and 509 assigned to empagliflozin) had macroalbuminuria. Median treatment duration was 2·6 years (IQR 2·0-3·4; 136 weeks) and median observation time was 3·1 years (2·2-3·6; 164 weeks). After short-term treatment at week 12, the placebo-adjusted geometric mean ratio of UACR change from baseline with empagliflozin was -7% (95% CI -12 to -2; p=0·013) in patients with normoalbuminuria, -25% (-31 to -19; p<0·0001) in patients with microalbuminuria, and -32% (-41 to -23; p<0·0001) in patients with macroalbuminuria. The reductions in UACR were maintained with empagliflozin in all three groups compared with placebo during long-term treatment when measured at 164 weeks. At follow-up, after cessation of treatment for a median of 34 or 35 days, UACR was lower in the empagliflozin versus placebo group in those with baseline microalbuminuria (placebo-corrected adjusted geometric mean ratio of relative change from baseline with empagliflozin: -22%, 95% CI -32 to -11; p=0·0003) or macroalbuminuria (-29%, -44 to -10; p=0·0048), but not for patients with baseline normoalbuminuria (1%, -8 to 10; p=0·8911). Patients treated with empagliflozin were more likely to experience a sustained improvement from microalbuminuria to normoalbuminuria (hazard ratio [HR] 1·43, 95% CI 1·22 to 1·67; p<0·0001) or from macroalbuminuria to microalbuminuria or normoalbuminuria (HR 1·82, 1·40 to 2·37; p<0·0001), and less likely to experience a sustained deterioration from normoalbuminuria to microalbuminuria or macroalbuminuria (HR 0·84, 0·74 to 0·95; p=0·0077). The proportions of patients with any adverse events, serious adverse events, and adverse events leading to discontinuation increased with worsening UACR status at baseline, but were similar between treatment groups. The proportion of patients with genital infections was greater with empagliflozin than placebo in all subgroups by UACR status. INTERPRETATION These results support short-term and long-term benefits of empagliflozin on urinary albumin excretion, irrespective of patients' albuminuria status at baseline. FUNDING Boehringer Ingelheim & Eli Lilly and Company Diabetes Alliance.
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Urine albumin-to-creatinine ratio is associated with the severity of liver disease, renal function and survival in patients with decompensated cirrhosis.
Cholongitas, E, Goulis, I, Ioannidou, M, Soulaidopoulos, S, Chalevas, P, Akriviadis, E
Hepatology international. 2017;(3):306-314
Abstract
BACKGROUND AND AIMS To investigate if urine albumin-to-creatinine ratio (UACR) is associated with the presence of glomerular filtration rate (GFR) <60 mL/min, severity of liver disease and survival in patients with stable decompensated cirrhosis. METHODS We evaluated prospectively 220 patients (73 % male, age 52.8 ± 12 years). In each patient, assessment of GFR was based on 51chromium-EDTA. Random urine samples were obtained for measurement of UACR. RESULTS Thirty-eight patients (17 %, group 1) had UACR ≥30 mg/g and 182 (83 %, group 2) had UACR <30 mg/g. Group 1, compared to group 2 patients, had significantly lower levels of "true" GFR (61 vs. 71 ml/min, p = 0.035). Patients with "true" GFR <60 mL/min (n = 93), compared to those with "true" GFR ≥60 mL/min (n = 127), had higher levels of UACR (16 vs. 11.3 mg/g, p = 0.023). In multivariate analysis, serum creatinine and UACR (ΟR 0.98, 95 % CI 0.95-0.99, p = 0.04) were independently associated with the presence of GFR <60 mL/min. Based on the area under the ROC curves, the best cut-off point for UACR was >16.51 mg/g giving a sensitivity 70 %, specificity 49 %, PPV 68 % and NPV 51 %. During the follow-up period [17 (6-52) months], the patients who died or underwent LT (n = 158), compared to those who remained alive (n = 62), had higher levels of UACR (41 vs. 13 mg/g, p = 0.025). Patients with UACR ≥30 mg/g had worse outcome, compared to those with UACR <30 mg/g (log rank p = 0.053). CONCLUSIONS We showed for the first time that UACR ≥30 mg/g was associated with more severe liver disease, lower GFR and worse LT-free survival in patients with decompensated cirrhosis. However, further studies are needed to confirm these findings.
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Comparative Efficacy and Safety of Antihypertensive Agents for Adult Diabetic Patients with Microalbuminuric Kidney Disease: A Network Meta-Analysis.
Huang, R, Feng, Y, Wang, Y, Qin, X, Melgiri, ND, Sun, Y, Li, X
PloS one. 2017;(1):e0168582
Abstract
BACKGROUND Antihypertensive treatment mitigates the progression of chronic kidney disease. Here, we comparatively assessed the effects of antihypertensive agents in normotensive and hypertensive diabetic patients with microalbuminuric kidney disease. METHODS MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials were systematically searched for randomized controlled trials (RCTs) comparing oral antihypertensive agents in adult diabetic patients with microalbuminuria. The primary efficacy outcome was reduction in albuminuria, and the primary safety outcomes were dry cough, presyncope, and edema. Random-effects pairwise and Bayesian network meta-analyses were performed to produce outcome estimates for all RCTs, only hypertensive RCTs, or only normotensive RCTs. Surface under the cumulative ranking (SUCRA) probability rankings were calculated for all outcomes. Sensitivity analyses on type 2 diabetes status, age, or follow-up duration were also performed. RESULTS A total of 38 RCTs were included in the meta-analyses. The angiotensin-converting enzyme inhibitor-calcium channel blocker (ACEI-CCB) combination therapy of captopril+diltiazem was most efficacious in reducing albuminuria irrespective of blood pressure status. However, the ACEI-angiotensin receptor blocker (ACEI-ARB) combination therapy of trandolapril+candesartan was the most efficacious in reducing albuminuria for normotensive patients, while the ACEI-CCB combination therapy of fosinopril+amlodipine was the most efficacious in reducing albuminuria for hypertensive patients. The foregoing combination therapies displayed inferior safety profiles relative to ACEI monotherapy with respect to dry cough, presyncope, and edema. With respect to type 2 diabetic patients with microalbuminuria, the Chinese herbal medicine Tangshen formula followed by the ACEI ramipril were the most efficacious in reducing albuminuria. CONCLUSIONS Trandolapril+candesartan appears to be the most efficacious intervention for reducing albuminuria for normotensive patients, while fosinopril+amlodipine appears to be the most efficacious intervention for reducing albuminuria for hypertensive patients. For practitioners opting for monotherapy, our SUCRA analysis supports the use of trandolapril and fosinopril in normotensive and hypertensive adult diabetic patients with microalbuminuria, respectively.
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Estimated Glomerular Filtration Rate and Albuminuria Are Associated with Biomarkers of Cardiac Injury in a Population-Based Cohort Study: The Maastricht Study.
Martens, RJ, Kimenai, DM, Kooman, JP, Stehouwer, CD, Tan, FE, Bekers, O, Dagnelie, PC, van der Kallen, CJ, Kroon, AA, Leunissen, KM, et al
Clinical chemistry. 2017;(4):887-897
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BACKGROUND Chronic kidney disease (CKD) is associated with an increased cardiovascular disease mortality risk. It is, however, less clear at what point in the course from normal kidney function to CKD the association with cardiovascular disease appears. Studying the associations of estimated glomerular filtration rate (eGFR) and albuminuria with biomarkers of (subclinical) cardiac injury in a population without substantial CKD may clarify this issue. METHODS We examined the cross-sectional associations of eGFR and urinary albumin excretion (UAE) with high-sensitivity cardiac troponin (hs-cTn) T, hs-cTnI, and N-terminal probrain natriuretic-peptide (NT-proBNP) in 3103 individuals from a population-based diabetes-enriched cohort study. RESULTS After adjustment for potential confounders, eGFR and UAE were associated with these biomarkers of cardiac injury, even at levels that do not fulfill the CKD criteria. For example, eGFR 60-<90 mL · min-1 ·(1.73 m2)-1 [vs ≥90 mL · min-1 · (1.73 m2)-1] was associated with a [ratio (95% CI)] 1.21 (1.17-1.26), 1.14 (1.07-1.20), and 1.19 (1.12-1.27) times higher hs-cTnT, hs-cTnI, and NT-proBNP, respectively. The association of eGFR with hs-cTnT was statistically significantly stronger than that with hs-cTnI. In addition, UAE 15-<30 mg/24 h (vs <15 mg/24 h) was associated with a 1.04 (0.98-1.10), 1.08 (1.00-1.18), and 1.07 (0.96-1.18) times higher hs-cTnT, hs-cTnI, and NT-proBNP, respectively. CONCLUSIONS eGFR and albuminuria were already associated with biomarkers of (subclinical) cardiac injury at levels that do not fulfill the CKD criteria. Although reduced renal elimination may partly underlie the associations of eGFR, these findings support the concept that eGFR and albuminuria are, over their entire range, associated with cardiac injury.
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Predictive ability of visit-to-visit variability in HbA1c and systolic blood pressure for the development of microalbuminuria and retinopathy in people with type 2 diabetes.
Takao, T, Suka, M, Yanagisawa, H, Matsuyama, Y, Iwamoto, Y
Diabetes research and clinical practice. 2017;:15-23
Abstract
AIMS: We explored whether visit-to-visit variability in both glycated hemoglobin (HbA1c) and systolic blood pressure (SBP) simultaneously predicted the development of microalbuminuria and retinopathy, and whether the predictive ability of these measurements changed according to mean HbA1c and SBP levels in people with type 2 diabetes. METHODS A retrospective observational cohort study was conducted on 243 type 2 diabetes patients with normoalbuminuria and 486 without retinopathy at the first visit and within 1year thereafter. The two cohorts were followed up from 1995 until 2012. Multivariate and stratified analyses were performed using Cox proportional hazard models. RESULTS Microalbuminuria developed in 84 patients and retinopathy in 108. Hazard ratios (HRs) for the development of microalbuminuria associated with the coefficient of variation (CV) and variation independent of mean (VIM) of both HbA1c and SBP significantly increased. In participants with a mean SBP <130mmHg, the HRs for the development of retinopathy associated with CV and VIM of HbA1c were abruptly elevated and significant compared with those with a mean SBP ≥130mmHg. CONCLUSIONS Visit-to-visit variability in both HbA1c and SBP simultaneously predict the development of microalbuminuria. HbA1c variability may predict the development of retinopathy when the mean SBP is normal (<130mmHg).