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Prediction of microalbuminuria from proteinuria in chronic kidney disease due to non-diabetic lifestyle-related diseases: comparison with diabetes.
Ogi, M, Seto, T, Wakabayashi, Y
Clinical and experimental nephrology. 2021;(7):727-750
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BACKGROUND To suppress increases in kidney failure and cardiovascular disease due to lifestyle-related diseases other than diabetes, early intervention is desirable. We examined whether microalbuminuria could be predicted from proteinuria. METHODS The participants consisted of adults who exhibited a urinary protein-to-creatinine ratio (uPCR) of < 0.5 g/gCr and an eGFR of ≥ 15 ml/min/1.73 m2 in their spot urine at their first examination for lifestyle-related disease. Urine was tested three times for each case, with microalbuminuria defined as a urinary albumin-to-creatinine ratio (uACR) of 30-299 mg/gCr, at least twice on three measurements. Youden's Index was used as an index of the cut-off value (CO) according to the ROC curve. RESULTS A single uPCR was useful for differentiating normoalbuminuria and micro- and macroalbuminuria in patients with non-diabetic lifestyle-related diseases. Regarding the GFR categories, the CO of the second uPCR was 0.09 g/gCr (AUC 0.89, sensitivity 0.76, specificity 0.89) in G1-4 (n = 197) and 0.07 g/gCr (AUC 0.92, sensitivity 0.85, specificity 0.88) in G1-3a (n = 125). Using the sum of two or three uPCR measurements was more useful than a single uPCR for differentiating microalbuminuria in non-diabetic lifestyle disease [CO, 0.16 g/gCr (AUC 0.91, sensitivity 0.85, specificity 0.87) and 0.23 g/gCr (AUC 0.92, sensitivity 0.88, specificity 0.84), respectively]. CONCLUSION Microalbuminuria in Japanese individuals with non-diabetic lifestyle-related diseases can be predicted from the uPCR, wherein the CO of the uPCR that differentiates normoalbuminuria and micro- and macroalbuminuria was 0.07 g/gCr for G1-3a, while that in G3b-4 was 0.09 g/gCr.
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Kidney, Cardiovascular, and Safety Outcomes of Canagliflozin according to Baseline Albuminuria: A CREDENCE Secondary Analysis.
Jardine, M, Zhou, Z, Lambers Heerspink, HJ, Hockham, C, Li, Q, Agarwal, R, Bakris, GL, Cannon, CP, Charytan, DM, Greene, T, et al
Clinical journal of the American Society of Nephrology : CJASN. 2021;(3):384-395
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BACKGROUND AND OBJECTIVES The kidney protective effects of renin-angiotensin system inhibitors are greater in people with higher levels of albuminuria at treatment initiation. Whether this applies to sodium-glucose cotransporter 2 (SGLT2) inhibitors is uncertain, particularly in patients with a very high urine albumin-to-creatinine ratio (UACR; ≥3000 mg/g). We examined the association between baseline UACR and the effects of the SGLT2 inhibitor, canagliflozin, on efficacy and safety outcomes in the Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) randomized controlled trial. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS The study enrolled 4401 participants with type 2 diabetes, an eGFR of 30 to <90 ml/min per 1.73 m2, and UACR of >300 to 5000 mg/g. Using Cox proportional hazards regression, we examined the relative and absolute effects of canagliflozin on kidney, cardiovascular, and safety outcomes according to a baseline UACR of ≤1000 mg/g (n=2348), >1000 to <3000 mg/g (n=1547), and ≥3000 mg/g (n=506). In addition, we examined the effects of canagliflozin on UACR itself, eGFR slope, and the intermediate outcomes of glycated hemoglobin, body weight, and systolic BP. RESULTS Overall, higher UACR was associated with higher rates of kidney and cardiovascular events. Canagliflozin reduced efficacy outcomes for all UACR levels, with no evidence that relative benefits varied between levels. For example, canagliflozin reduced the primary composite outcome by 24% (hazard ratio [HR], 0.76; 95% confidence interval [95% CI], 0.56 to 1.04) in the lowest UACR subgroup, 28% (HR, 0.72; 95% CI, 0.56 to 0.93) in the UACR subgroup >1000 to <3000 mg/g, and 37% (HR, 0.63; 95% CI, 0.47 to 0.84) in the highest subgroup (Pheterogeneity=0.55). Absolute risk reductions for kidney outcomes were greater in participants with higher baseline albuminuria; the number of primary composite events prevented across ascending UACR categories were 17 (95% CI, 3 to 38), 45 (95% CI, 9 to 81), and 119 (95% CI, 35 to 202) per 1000 treated participants over 2.6 years (Pheterogeneity=0.02). Rates of kidney-related adverse events were lower with canagliflozin, with a greater relative reduction in higher UACR categories. CONCLUSIONS Canagliflozin safely reduces kidney and cardiovascular events in people with type 2 diabetes and severely increased albuminuria. In this population, the relative kidney benefits were consistent over a range of albuminuria levels, with greatest absolute kidney benefit in those with an UACR ≥3000 mg/g. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER ClinicalTrials.gov: CREDENCE, NCT02065791. PODCAST This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2021_02_22_CJN15260920_final.mp3.
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Effect of dapagliflozin on urinary albumin excretion in patients with chronic kidney disease with and without type 2 diabetes: a prespecified analysis from the DAPA-CKD trial.
Jongs, N, Greene, T, Chertow, GM, McMurray, JJV, Langkilde, AM, Correa-Rotter, R, Rossing, P, Sjöström, CD, Stefansson, BV, Toto, RD, et al
The lancet. Diabetes & endocrinology. 2021;(11):755-766
Abstract
BACKGROUND Reductions in albuminuria are associated with a subsequent lower risk of kidney failure in patients with chronic kidney disease. The SGLT2 inhibitor dapagliflozin significantly reduced albuminuria in patients with type 2 diabetes and normal or near-normal kidney function. Whether this effect persists in patients with chronic kidney disease with and without type 2 diabetes is unknown. We assessed the effects of dapagliflozin on albuminuria in patients with chronic kidney disease with and without type 2 diabetes in the dapagliflozin and prevention of adverse outcomes in chronic kidney disease (DAPA-CKD) trial. METHODS DAPA-CKD was a multicentre, double-blind, placebo-controlled, randomised trial done at 386 sites in 21 countries. Patients were eligible for the trial if they had chronic kidney disease, defined as an estimated glomerular filtration rate (eGFR) between 25 mL/min per 1·73 m2 and 75 mL/min per 1·73 m2 and a urinary albumin-to-creatinine ratio (UACR) between 200 mg/g and 5000 mg/g (22·6 to 565·6 mg/mmol). Participants were randomly assigned to dapagliflozin 10 mg (AstraZeneca; Gothenburg, Sweden) once daily or matching placebo, in accordance with the sequestered, fixed randomisation schedule, using balanced blocks to ensure an approximate 1:1 ratio. Change in albuminuria was a pre-specified exploratory outcome of DAPA-CKD. Regression in UACR stage, defined as a transition from macroalbuminuria (≥300 mg/g) to microalbuminuria or normoalbuminuria (<300 mg/g), and progression in UACR stage, defined as a transition from less than 3000 mg/g to 3000 mg/g or greater, were additional discrete endpoints. The trial is registered with ClinicalTrials.gov, NCT03036150. FINDINGS Between Feb 2, 2017, and April 3, 2020, 4304 patients were recruited and randomly assigned to either dapagliflozin (n=2152) or placebo (n=2152). Median UACR was 949 mg/g (IQR 477 to 1885). Overall, compared with placebo, dapagliflozin reduced geometric mean UACR by 29·3% (95% CI -33·1 to -25·2; p<0·0001); relative to placebo, treatment with dapagliflozin resulted in a geometric mean percentage change of -35·1% (95% CI -39·4 to -30·6; p<0·0001) in patients with type 2 diabetes and -14·8% (-22·9 to -5·9; p=0·0016) in patients without type 2 diabetes over the follow-up visits (pinteraction<0·0001) Among 3860 patients with UACR of 300 mg/g or greater at baseline, dapagliflozin increased the likelihood of regression in UACR stage (hazard ratio 1·81, 95% CI 1·60 to 2·05). Among 3820 patients with UACR less than 3000 mg/g at baseline, dapagliflozin decreased the risk of progression in UACR stage (0·41, 0·32 to 0·52). Larger reductions in UACR at day 14 during dapagliflozin treatment were significantly associated with attenuated eGFR decline during subsequent follow-up (β per log unit UACR change -3·06, 95% CI -5·20 to -0·90; p=0·0056). INTERPRETATION In patients with chronic kidney disease with and without type 2 diabetes, dapagliflozin significantly reduced albuminuria, with a larger relative reduction in patients with type 2 diabetes. The similar effects of dapagliflozin on clinical outcomes in patients with or without type 2 diabetes, but different effects on UACR, suggest that part of the protective effect of dapagliflozin in patients with chronic kidney disease might be mediated through pathways unrelated to reduction in albuminuria. FUNDING AstraZeneca.
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Normal-range urinary albumin excretion associates with blood pressure and renal electrolyte handling in pregnancy.
Birukov, A, Andersen, MS, Jørgensen, JS, Kitlen, G, Rakova, N, Nielsen, JH, Andersen, LB, Dechend, R, Jensen, BL
American journal of physiology. Renal physiology. 2020;(1):F1-F7
Abstract
Albuminuria in the pathological range is a significant predictor of preeclampsia. In healthy persons, high normal urinary albumin predicts a later incidence of hypertension and is associated with salt sensitivity of blood pressure. We hypothesized that in pregnancy urinary albumin in the normal range associates with blood pressure through activation of distal Na+ reabsorption and renal salt retention by plasma factors cofiltered with albumin. We analyzed 24-h urine collections and plasma samples from gestational week 29 of 560 pregnant women from the Odense Child Cohort, a Danish population-based cohort. Plasma and urinary aldosterone were measured by ELISA. Plasma and urinary Na+, K+, Cl-, and creatinine were also determined. Predictive values of urinary albumin were assessed by linear mixed, multiple, and Cox regression analyses. Primary outcomes were blood pressure and renal electrolyte handling. Twenty-four-hour urinary albumin excretion at gestational week 29 associated with gestational blood pressure trajectory, with adjusted β coefficients (95% confidence intervals) for each 10-fold increase in urinary albumin as follows: 5.71 (1.60 to 9.81) mmHg for systolic blood pressure and 4.39 (1.41 to 7.38) mmHg for diastolic blood pressure. Urinary albumin was inversely associated with fractional excretion rates of Na+, K+, and Cl-, with adjusted β coefficients (95% confidence intervals) for each 10-fold increase in urine albumin as follows: -0.25 (-0.35 to -0.14), -5.06 (-6.81 to -3.30), and -0.28 (-0.41 to -0.15), respectively. In conclusion, at gestational week 29, urinary albumin excretion in the normal range associated with blood pressure and renal electrolyte handling independent of potential confounders.
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Urinary Albumin, Sodium, and Potassium and Cardiovascular Outcomes in the UK Biobank: Observational and Mendelian Randomization Analyses.
Zanetti, D, Bergman, H, Burgess, S, Assimes, TL, Bhalla, V, Ingelsson, E
Hypertension (Dallas, Tex. : 1979). 2020;(3):714-722
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Urinary biomarkers are associated with cardiovascular disease, but the nature of these associations is not well understood. We performed multivariable-adjusted regression models to assess associations of random spot measurements of the urine sodium-potassium ratio (UNa/UK) and urine albumin adjusted for creatinine with cardiovascular risk factors, cardiovascular disease, and type 2 diabetes mellitus (T2D) in 478 311 participants of the UK Biobank. Further, we assessed the causal relationships of these kidney biomarkers, used as proxies for kidney function, with cardiovascular outcomes using the 2-sample Mendelian randomization approach. In observational analyses, UNa/UK showed significant inverse associations with atrial fibrillation, coronary artery disease, ischemic stroke, lipid-lowering medication, and T2D. In contrast, urine albumin adjusted for creatinine showed significant positive associations with atrial fibrillation, coronary artery disease, heart failure, hemorrhagic stroke, lipid-lowering medication, and T2D. We found a positive association between UNa/UK and albumin with blood pressure (BP), as well as with adiposity-related measures. After correcting for potential horizontal pleiotropy, we found evidence of causal associations of UNa/UK and albumin with BP (β systolic BP ≥2.63; β diastolic BP ≥0.85 SD increase in BP per SD change in UNa/UK and urine albumin adjusted for creatinine; P≤0.04), and of albumin with T2D (odds ratio=1.33 per SD change in albumin, P=0.02). Our comprehensive study of urinary biomarkers performed using state-of-the-art analyses of causality mirror and extend findings from randomized interventional trials which have established UNa/UK as a risk factor for hypertension. In addition, we detect a causal feedback loop between albumin and hypertension, and our finding of a bidirectional causal association between albumin and T2D reflects the well-known nephropathy in T2D.
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Frequency of alcohol drinking modifies the association between salt intake and albuminuria: a 1-year observational study.
Yoshimura, R, Yamamoto, R, Shinzawa, M, Tomi, R, Ozaki, S, Fujii, Y, Ito, T, Tanabe, K, Moriguchi, Y, Isaka, Y, et al
Hypertension research : official journal of the Japanese Society of Hypertension. 2020;(11):1249-1256
Abstract
Albuminuria is an important risk factor for end-stage kidney disease and cardiovascular mortality. This 1-year observational study aimed to assess the effect modification of alcohol drinking on the association between salt intake and albuminuria. Overall, 448 employees at a pharmaceutical company in Japan who underwent annual health checkups in both 2017 and 2018 were evaluated. The main exposure of interest was drinking frequency at their first checkups categorized as rarely, occasionally, and daily. To assess the association between the changes in salt intake and albuminuria, the differences in salt intake estimated from single-spot urine specimens and the urinary albumin-to-creatinine ratio (UACR) between 2017 and 2018 were calculated for each subject. A multivariable-adjusted linear regression model showed a significant association between ∆salt intake and ∆Log UACR (per 1 g/day of ∆salt intake, adjusted ß 0.16 [95% confidence interval 0.14, 0.19]) and an effect modification between drinking frequency and ∆salt intake (P for interaction = 0.088). The association between ∆salt intake and ∆Log UACR was enhanced by drinking frequency in a dose-dependent manner (per 1 g/day of ∆salt intake, adjusted ß 0.13 [0.06, 0.19], 0.16 [0.12, 0.20], and 0.20 [0.13, 0.27] in rare, occasional, and daily drinkers, respectively). In conclusion, the results of the present study indicated that salt-induced albuminuria was enhanced in subjects with higher drinking frequency, suggesting that salt restriction may have a stronger renoprotective effect in subjects with higher drinking frequency.
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Chronic kidney disease in psoriasis: a cohort study.
Conti, A, Giovannini, L, Mandel, VD, Odorici, G, Lasagni, C, Bigi, L, Pellacani, G, Cappelli, G
Journal der Deutschen Dermatologischen Gesellschaft = Journal of the German Society of Dermatology : JDDG. 2020;(5):438-445
Abstract
BACKGROUND Psoriasis is a chronic, relapsing disease often associated with comorbidities. While its associations with cardiovascular and metabolic factors have been investigated, little is known about its association with impairment of renal function. MATERIALS AND METHODS We performed a cohort study of 219 psoriatic patients in which we evaluated chronic kidney disease (CKD) and eGFR as well as albuminuria according to their KDIGO stratification risk criteria. We also evaluated circulating immunoglobulins (IgG, IgA, IgM), C3-C4 levels and the urinary albumin-to-creatinine ratio. We divided the patients into two groups, according to the presence or absence of known and established CKD risk factors. RESULTS In our population, the risk of CKD was moderate in 17.35 % of patients, high in 5.02 % and very high in 3.66 %. The risk prevalence for CKD was slightly greater in the group without established risk factors than the risk prevalence reported in NHANES 1999-2006. The presence of psoriatic arthritis, duration of psoriasis (≥ 21 years) and magnitude of the PASI score showed a positive correlation with the urinary albumin-to-creatinine ratio. CONCLUSIONS We found an association between microalbuminuria and the duration of psoriasis, as well as with psoriatic arthritis. Moreover, patients with microalbuminuria exhibited a higher Kidney Disease Improving Global Outcome stratification risk.
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The Effect of Antioxidant Vitamins on Patients With Diabetes and Albuminuria: A Meta-Analysis of Randomized Controlled Trials.
Chen, J, Wu, J, Kong, D, Yang, C, Yu, H, Pan, Q, Liu, W, Ding, Y, Liu, H
Journal of renal nutrition : the official journal of the Council on Renal Nutrition of the National Kidney Foundation. 2020;(2):101-110
Abstract
OBJECTIVE This study aimed to investigate the effect of antioxidant vitamins, including vitamins E and C, on patients with diabetes and albuminuria by conducting a meta-analysis of randomized controlled trials. DESIGN The PubMed, Embase, CENTRAL (the Cochrane Central Register of Controlled Trials at the Cochrane Library), Web of Science, OVID, and www.clinicaltrials.gov (latest search: December 10, 2018) databases were searched. This study was limited to randomized controlled trials. Patients with diabetes and albuminuria were included regardless of diabetic type, and patients must have received treatment with vitamins C or E. RESULTS Ten studies, representing 445 participants, were identified for analysis. Antioxidant vitamins had significant effects on serum creatinine levels (mean difference = -0.11 mg/dL, 95% confidence interval -0.19 to -0.03, P = .007) and systolic pressure (mean difference = -6.02 mm Hg, 95% confidence interval -9.65 to -2.40, P = .001) with low heterogeneity. Antioxidant vitamins had no effect on albuminuria or proteinuria, diastolic blood pressure, glucose, or lipid metabolism. CONCLUSION This meta-analysis indicated that antioxidant vitamins can benefit kidney function and systolic blood pressure in patients with diabetes and albuminuria. Further studies with larger sample sizes and longer follow-up are needed to completely understand the effect of antioxidant vitamins in these patients.
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Association of smoking and cardiometabolic parameters with albuminuria in people with type 2 diabetes mellitus: a systematic review and meta-analysis.
Kar, D, Gillies, C, Nath, M, Khunti, K, Davies, MJ, Seidu, S
Acta diabetologica. 2019;(8):839-850
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AIMS: Smoking is a strong risk factor for albuminuria in people with type 2 diabetes mellitus (T2DM). However, it is unclear whether this sequela of smoking is brought about by its action on cardiometabolic parameters or the relationship is independent. The aim of this systematic review is to explore this relationship. METHODS Electronic databases on cross-sectional and prospective studies in Medline and Embase were searched from January 1946 to May 2018. Adult smokers with T2DM were included, and other types of diabetes were excluded. RESULTS A random effects meta-analysis of 20,056 participants from 13 studies found that the odds ratio (OR) of smokers developing albuminuria compared to non-smokers was 2.13 (95% CI 1.32, 3.45). Apart from smoking, the odds ratio of other risk factors associated with albuminuria were: age 1.24 (95% CI 0.84, 1.64), male sex 1.39 (95% CI 1.16, 1.67), duration of diabetes 1.78 (95% CI 1.32, 2.23), HbA1c 0.63 (95% CI 0.45, 0.81), SBP 6.03 (95% CI 4.10, 7.97), DBP 1.85 (95% CI 1.08, 2.62), total cholesterol 0.06 (95% CI - 0.05, 0.17) and HDL cholesterol - 0.01 (95% CI - 0.04, 0.02), triglyceride 0.22 (95% CI 0.12, 0.33) and BMI 0.40 (95% CI 0.00-0.80). When the smoking status was adjusted in a mixed effect meta-regression model, the duration of diabetes was the only statistically significant factor that influenced the prevalence of albuminuria. In smokers, each year's increase in the duration of T2DM was associated with an increased risk of albuminuria of 0.19 units (95% CI 0.07, 0.31) on the log odds scale or increased the odds approximately by 23%, compared to non-smokers. Prediction from the meta-regression model also suggested that the odds ratios of albuminuria in smokers after a diabetes duration of 9 years and 16 years were 1.53 (95% CI 1.10, 2.13) and 5.94 (95% CI 2.53, 13.95), respectively. CONCLUSIONS Continuing to smoke and the duration of diabetes are two strong predictors of albuminuria in smokers with T2DM. With a global surge in younger smokers developing T2DM, smoking cessation interventions at an early stage of disease trajectory should be promoted.
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Association between Sodium Intake and Urinary Fractional Albumin and Immunoglobulin G Excretion in Chronic Nondialytic Renal Disease: A Prospective Longitudinal Study.
Martinez, MG, Dos Santos Silva, V, do Valle, AP, de Oliveira, RC, Banin, VB, Hokama, NK, Martin, LC
Nephron. 2019;(1):62-67
Abstract
BACKGROUND/AIMS: Previous studies reported that fractional clearance of urinary proteins is better than total proteinuria in predicting chronic kidney disease (CKD) progression. However, the role of sodium in the fractional excretion of proteins has not been established. We aimed to evaluate the association between sodium intake and fractional albumin and immunoglobulin G (IgG) excretion in nondialytic CKD. METHODS We did a longitudinal, observational, and prospective study that included CKD patients aged 18-80. Included patients performed basal routine laboratory evaluations, urinary sodium excretion, and fractional albumin and IgG excretion that were repeated after 6-month of follow-up. RESULTS We evaluated 84 patients, mean age 55 ± 15.6 years, 40 women, and 74 whites. The change of estimated sodium intake had an association with the change of fractional albumin (R = 0.54; p < 0.001) and IgG (R = 0.56; p < 0.001) excretion in univariate analysis (increases in sodium intake were paralleled by increases in albumin and IgG excretion fractions). This association was maintained in a multiple generalized linear model even after adjusting for age and for changes in blood pressure, urinary potassium, protein intake, and blood glucose. CONCLUSION In CKD patients, changes in estimated sodium intake were associated with changes in the fractional albumin and IgG excretion regardless of confounding factors. Findings of this study support the idea that reducing salt intake, and consequently, albumin and IgG fractional excretions could help to slow CKD progression. This hypothesis must be tested in long-term interventional studies.