Implication of transcription factor FOXD2 dysfunction in syndromic congenital anomalies of the kidney and urinary tract (CAKUT).

Congenital anomalies of the kidney and urinary tract (CAKUT) are the predominant cause for chronic kidney disease below age 30 years. Many monogenic forms have been discovered due to comprehensive genetic testing like exome sequencing. However, disease-causing variants in known disease-associated genes only explain a proportion of cases. Here, we aim to unravel underlying molecular mechanisms of syndromic CAKUT in three unrelated multiplex families with presumed autosomal recessive inheritance. Exome sequencing in the index individuals revealed three different rare homozygous variants in FOXD2, encoding a transcription factor not previously implicated in CAKUT in humans: a frameshift in the Arabic and a missense variant each in the Turkish and the Israeli family with segregation patterns consistent with autosomal recessive inheritance. CRISPR/Cas9-derived Foxd2 knockout mice presented with a bilateral dilated kidney pelvis accompanied by atrophy of the kidney papilla and mandibular, ophthalmologic, and behavioral anomalies, recapitulating the human phenotype. In a complementary approach to study pathomechanisms of FOXD2-dysfunction-mediated developmental kidney defects, we generated CRISPR/Cas9-mediated knockout of Foxd2 in ureteric bud-induced mouse metanephric mesenchyme cells. Transcriptomic analyses revealed enrichment of numerous differentially expressed genes important for kidney/urogenital development, including Pax2 and Wnt4 as well as gene expression changes indicating a shift toward a stromal cell identity. Histology of Foxd2 knockout mouse kidneys confirmed increased fibrosis. Further, genome-wide association studies suggest that FOXD2 could play a role for maintenance of podocyte integrity during adulthood. Thus, our studies help in genetic diagnostics of monogenic CAKUT and in understanding of monogenic and multifactorial kidney diseases.

Associations between Total Immunoglobulin E Levels and Urinary Albumin Excretion: A Cross-Sectional Study.

INTRODUCTION: The association between total immunoglobulin E (IgE) levels and urinary albumin excretion has not been fully established. Current study aimed to evaluate the association between total IgE levels and urinary albumin-to-creatinine ratio (UACR) among adult Americans. METHODS: Current cross-sectional study utilized data from the 2005 to 2006 National Health and Nutrition Examination Survey, including individuals aged 20 years and above. To assess the relationships between total IgE levels and UACR, both multivariable linear regression models and smooth curve fitting were employed. RESULTS: The study included a total of 3,400 participants (weighted mean age: 46.6 ± 0.8 years), with 1,625 females (weighted percentage: 47.8%). After adjusting for potential confounders, we observed a positive association between higher total IgE levels on a log2 scale and increased UACR (ß = 3.34; 95% CI: 1.40-5.28, p = 0.002). Furthermore, the association displayed a non-linear dose-response pattern. The interaction test revealed a significant distinction in the correlation between total IgE and UACR when stratified by hyperlipidemia (p for interaction <0.001). The results remained robust in sensitivity analyses. CONCLUSION: Our study revealed a significant and independent association between elevated total IgE levels and an increased UACR, which also exhibited a distinct non-linear pattern, highlighting the intricate nature of the connection between IgE levels and UACR.

Association between 1-year changes in urinary albumin-to-creatinine ratio and kidney disease progression in Japanese individuals with diabetes: a historical cohort study.

BACKGROUND: The National Kidney Foundation recently proposed a ≥ 30% decrease in urinary albumin-to-creatinine ratio (UACR) over 0.5-2 years as a surrogate endpoint for chronic kidney disease (CKD) progression in individuals with baseline UACR > 30 mg/g. This historical cohort study aimed to determine the applicability of a decrease in UACR, within as little as 1 year, as a surrogate endpoint for Japanese individuals with type 2 diabetes mellitus (T2D). METHODS: A total of 5067 individuals with T2D were divided into three groups based on 1-year change in UACR: ≥ 30% decrease (UACR decreased group), < 30% decrease and < 30% increase (UACR unchanged group), or ≥ 30% increase (UACR increased group). The primary endpoint was a composite of a ≥ 30% decline in estimated glomerular filtration rate (eGFR) or the initiation of kidney replacement therapy, whichever occurred first. RESULTS: At baseline, the proportions of individuals with normoalbuminuria, microalbuminuria, and eGFR ≥ 60 mL/min/1.73 m2 were 68.1%, 22.1%, and 75.5%, respectively. During a median follow-up of 6.8 years, 926 individuals (18.3%) reached the composite endpoint. Adjusted hazard ratios (vs. the UACR unchanged group) for the UACR decreased and increased groups were 0.758 (95% confidence interval [CI], 0.636-0.905; P = 0.002) and 1.304 (95% CI, 1.108-1.536; P = 0.001), respectively. CONCLUSIONS: These findings support the use of 1-year changes in UACR as a surrogate endpoint for the progression of CKD and the implementation of a ≥ 30% decrease in UACR as a positive efficacy endpoint in Japanese individuals with T2D and early-stage kidney disease.

Elevated postprandial triglyceride-rich lipoproteins in patients with diabetes and stable coronary artery disease correlated with early renal damage and systemic inflammation.

BACKGROUND: Dyslipidaemia is key in the development of coronary heart disease (CHD) in patients with diabetes mellitus (DM). Accumulated evidence supports that diabetic nephropathy increases the mortality risk of patients with CHD, while the influence of diabetic dyslipidaemia on renal damage in patients with DM and CHD remains unknown. Moreover, recent data indicate that postprandial dyslipidaemia has predictive value in terms of CHD prognosis, especially in patients with DM. The study aimed to determine the relationship of triglyceride-rich lipoproteins (TRLs) after daily Chinese breakfast on systemic inflammation and early renal damage in Chinese patients with DM and SCAD. METHODS: Patients with DM diagnosed with SCAD while in the Department of Cardiology of Shengjing Hospital from September 2016 to February 2017 were enrolled in this study. Fasting and 4-h postprandial blood lipids, fasting blood glucose, glycated haemoglobin, urinary albumin-to-creatinine ratio (UACR), serum interleukin-6 (IL-6) and tumour necrosis factor-α (TNF-α) concentrations, and other parameters were measured. Fasting and postprandial blood lipid profiles and inflammatory cytokines were analysed using a paired t-test. The association between variables was analysed using Pearson or Spearman bivariate analysis. P < 0.05 was considered to be statistically significant. RESULTS: The study enrolled 44 patients in total. Compared with fasting state, postprandial total cholesterol high-density lipoprotein-cholesterol (HDL-C),low-density lipoprotein-cholesterol (LDL-C) and non-high-density lipoprotein-cholesterol (non-HDL-C) all showed no significant change. Postprandial serum triglyceride (TG) concentration increased significantly compared with that at fasting (1.40 ± 0.40 vs. 2.10 ± 0.94 mmol/L, P < 0.001), as did serum remnant lipoprotein-cholesterol (RLP-C) (0.54 ± 0.18 mmol/L vs. 0.64 ± 0.25 mmol/L). Pearson analysis revealed that serum TG and RLP-C positively correlated before and after breakfast. Moreover, during fasting, positive correlations were observed between TG and serum IL-6, TNF-α, and UACR. Positive correlations were observed between RLP-C and IL-6, UACR under fasting condition, while both TG and RLP-C were positively correlated with postprandial serum IL-6, TNF-α, and UACR concentrations. Finally, positive correlations were observed between UACR and IL-6 and TNF-α concentration under both fasting and postprandial conditions. CONCLUSIONS: An increase in postprandial TRLs was observed in Chinese patients with DM and SCAD after daily breakfast, and this increase may be related to early renal injury via the induction of systemic inflammation.

The association of thyroid parameters with markers of chronic kidney disease in euthyroid patients with type 2 diabetes.

This study was established to explore the association of thyroid parameters including thyroid hormone and thyroid sensitivity indices with chronic kidney disease (CKD) in euthyroid patients with type 2 diabetes (T2D). CKD markers were defined by estimated glomerular filtration rate (eGFR) based on serum creatinine (Scr) (eGFRcr), eGFR based on cystatin C (cys C) (eGFRcys), and urinary albumin-to-creatinine ratio (UACR). Thyroid parameters, including triiodothyronine (FT3), free thyroxin (FT4), thyroid-stimulating hormone (TSH), FT3/FT4 ratio, TSH index (TSHI), and thyrotroph T4 resistance index (TT4RI), were measured. The prevalence rates of CKD defined by eGFRcys, eGFRcr, and UACR was 19.9%, 14.1%, and 50.6%, respectively. The eGFRcys and eGFRcr levels increased with increasing FT3 and FT3/FT4 tertiles, while the UACR levels increased with decreasing FT3 tertiles. Spearman's analysis demonstrated that FT3 and FT3/FT4 were positively associated with eGFRcys and eGFRcr, and negatively associated with UACR. In logistic regression analyses, compared with the lowest FT3 tertile (≤4.12 pmol/L), the adjusted ORs for CKD (eGFRcys <60 mL/min/1.73 m2) in the middle FT3 tertile (4.12-4.74 pmol/L) and higher FT3 tertile (>4.74 pmol/L) were 0.248 and 0.153, respectively, but prominent associations of thyroid parameters with eGRFcr <60 mL/min/1.73 m2 and UACR were not observed after adjustment. Linear regression analysis demonstrated that eGFRcys was more strongly associated with FT3 than eGFRcr or UACR in the adjusted model. Among euthyroid patients with T2D, FT3 in the normal range was the independent factor most strongly related to CKD. Additionally, eGFRcys rather than eGFRcr or UACR was the CKD marker most associated with FT3.

Positive correlation between hypertensive retinopathy and albuminuria in hypertensive adults.

PURPOSE: We investigated the association between albuminuria and hypertensive retinopathy (HR) in hypertensive adults. METHODS: This was a cross-sectional subgroup analysis of data from the China Stroke Primary Prevention Trial. We enrolled 2,964 hypertensive adults in this study. Keith-Wagener-Barker stages was used to assess HR. The urinary albumin to creatinine ratio (UACR) was calculated to evaluate albuminuria. RESULTS: HR was found in 76.6% (n = 2, 271) of the participants, albuminuria was found in 11.1% (n = 330). The UACR levels were significantly higher in subjects with HR than in those without HR (grade 1, ß = 1.42, 95% confidence intervals [CI]: -0.12, 2.95, p = 0.070; grade 2, ß = 2.62, 95% CI: 0.56, 4.67, p = 0.013; grade 3, ß = 5.17, 95% CI: 1.13, 9.20, p = 0.012). In the subgroup analyses, the association between HR and UACR was stronger in current smokers (p for interaction = 0.014). The correlation between HR grades 1 and 2 and UACR was stronger in subjects with higher triglyceride levels (≥ 1.7 mmol/L), but for grade 3 HR, this correlation was stronger in subjects with lower triglycerides levels (< 1.7 mmol/L, p for interaction = 0.023). The odds of albuminuria were significantly higher in subjects with HR than in those without HR (grade 1, odds ratio [OR] = 1.57, 95% CI: 1.08, 2.29, p = 0.019; grade 2, OR = 2.02, 95% CI: 1.28, 3.18, p = 0.002; grade 3, OR = 2.12, 95% CI: 0.99, 4.55, p = 0.053). In the subgroup analyses, the association between HR grades 1 and 2 and albuminuria was stronger in subjects with higher triglycerides levels (≥ 1.7 mmol/L), but for grade 3 HR, this correlation was stronger in subjects with lower triglyceride levels (< 1.7 mmol/L, p for interaction = 0.014). CONCLUSION: HR was positively correlated with albuminuria in hypertensive Chinese adults. This correlation was more remarkable when the population was stratified by triglycerides levels and smoking status. HR can be used as an indicator of early renal injury.

Rationale, design and baseline characteristics of the effect of canagliflozin in patients with type 2 diabetes and microalbuminuria in the Japanese population: The CANPIONE study.

AIM: To evaluate the effect of canagliflozin, a sodium-glucose co-transporter-2 (SGLT2) inhibitor, on albuminuria and the decline of estimated glomerular filtration rate (eGFR) in participants with type 2 diabetes and microalbuminuria. METHODS: The CANPIONE study is a multicentre, randomized, parallel-group and open-labelled study consisting of a unique 24-week preintervention period, during which the rate of eGFR decline before intervention is estimated, followed by a 52-week intervention and a 4-week washout period. Participants with a geometric mean urinary albumin-to-creatinine ratio (UACR) of 50 and higher and less than 300 mg/g in two consecutive first-morning voids at two different time points, and an eGFR of 45 ml/min/1.73m2 or higher, are randomly assigned to receive canagliflozin 100 mg daily or to continue guideline-recommended treatment, except for SGLT2 inhibitors. The first primary outcome is the change in UACR, and the second primary outcome is the change in eGFR slope. RESULTS: A total of 258 participants were screened and 98 were randomized at 21 sites in Japan from August 2018 to May 2021. The mean baseline age was 61.4 years and 25.8% were female. The mean HbA1c was 7.9%, mean eGFR was 74.1 ml/min/1.73m2 and median UACR was 104.2 mg/g. CONCLUSIONS: The CANPIONE study will determine whether the SGLT2 inhibitor canagliflozin can reduce albuminuria and slow eGFR decline in participants with type 2 diabetes and microalbuminuria.

Effect of continuous positive airway pressure on albuminuria in patients with obstructive sleep apnea: a meta-analysis.

PURPOSE: A relationship between albuminuria and obstructive sleep apnea (OSA) has been documented in previous studies. Nevertheless, the impact of continuous positive airway pressure (CPAP) treatment on albuminuria in subjects with OSA is debated. This meta-analysis was carried out to investigate whether or not CPAP treatment affected urinary albumin-to-creatinine ratio (UACR) in subjects with OSA. METHODS: A comprehensive literature search was conducted on Web of Science, Embase, and PubMed from January 1990 to December 2020. Information on patients' characteristics, features of the studies, and UACR of pre- and post-CPAP treatment was collected. For estimation of the pooled effects, standardized mean difference (SMD) was applied. RESULTS: This meta-analysis included 6 articles and 211 subjects. The pooled analysis suggested that CPAP therapy exerted a favorable effect on the decrease of UACR in subjects with OSA (SMD = 0.415, 95% CI = 0.026 to 0.804, z = 2.09, p = 0.037). Subgroup analyses revealed that the CPAP treatment effect was not influenced by sample size, BMI, age, or AHI. CONCLUSION: The present meta-analysis indicated that UACR was significantly reduced by CPAP therapy in subjects with OSA. Further well-designed randomized controlled trials with large sample size are required to confirm the benefits.

The relationship between urinary albumin to creatinine ratio and all-cause mortality in the elderly population in the Chinese community: a 10-year follow-up study.

BACKGROUND: In patients with diabetes and hypertension, proteinuria is independently associated with all-cause death. However, in the general population, urinary albumin to creatinine ratio (UACR) is less used to predict all-cause mortality. When the urinary albumin to creatinine ratio is within the normal range (UACR< 30 mg/g), the clinical relevance of an increased urinary albumin excretion rate is still debated. We studied the relationship between UACR and all-cause mortality in community populations, and compared UACR groups within the normal range. METHODS: The participants were the inhabitants from the Wanshoulu community in Beijing, China. The average age is 71.48 years, and the proportion of women is 60.1%. A total of 2148 people completed random urine samples to determine the urinary albumin to creatinine ratio (UACR). The subjects were divided into three groups according to UACR: Group 1 (UACR< 10 mg/g), Group 2 (10 mg/g < UACR< 30 mg/g), Group 3 (UACR> 30 mg/g). We used Kaplan-Meier survival analysis and Cox regression model to verify the relationship between UACR and all-cause mortality. RESULTS: At an average follow-up of 9.87 years (718,407.3 years), the total mortality rate were 183.4/1000. In the Cox proportional hazards model, after adjusting for possible confounders, those with normal high-value UACR (group 2) showed a higher all-cause mortality than those with normal low-value UACR (group 1) [hazard ratio (HR) 1.289, 95% confidence interval (CI) 1.002 ~ 1.659 for all-cause mortality]. Those with proteinuria (group 3) showed a higher all-cause mortality than those with normal low-value UACR (group 1) [hazard ratio (HR) 1.394, 95% confidence interval (CI) 1.020 ~ 1.905 for all-cause mortality]. CONCLUSION: Urinary albumin to creatinine ratio is an important risk factor for all-cause death in community population. Even if it is within the normal range (UACR< 30 mg/g), it occurs in people with high normal value (10 mg/g < UACR< 30 mg/g), the risk of all-cause death will also increase.

Cardiovascular Risk Based on ASCVD and KDIGO Categories in Chinese Adults: A Nationwide, Population-Based, Prospective Cohort Study.

BACKGROUND: The Kidney Disease Improving Global Outcomes (KDIGO) clinical practice guideline used eGFR and urinary albumin-creatinine ratio (ACR) to categorize risks for CKD prognosis. The utility of KDIGO's stratification of major CVD risks and predictive ability beyond traditional CVD risk prediction scores are unknown. METHODS: To evaluate CVD risks on the basis of ACR and eGFR (individually, together, and in combination using the KDIGO risk categories) and with the atherosclerotic cardiovascular disease (ASCVD) score, we studied 115,366 participants in the China Cardiometabolic Disease and Cancer Cohort study. Participants (aged ≥40 years and without a history of cardiovascular disease) were examined prospectively for major CVD events, including nonfatal myocardial infarction, nonfatal stroke, and cardiovascular death. RESULTS: During 415,111 person-years of follow-up, 2866 major CVD events occurred. Incidence rates and multivariable-adjusted hazard ratios of CVD events increased significantly across the KDIGO risk categories in ASCVD risk strata (all P values for log-rank test and most P values for trend in Cox regression analysis <0.01). Increases in c statistic for CVD risk prediction were 0.01 (0.01 to 0.02) in the overall study population and 0.03 (0.01 to 0.04) in participants with diabetes, after adding eGFR and log(ACR) to a model including the ASCVD risk score. In addition, adding eGFR and log(ACR) to a model with the ASCVD score resulted in significantly improved reclassification of CVD risks (net reclassification improvements, 4.78%; 95% confidence interval, 3.03% to 6.41%). CONCLUSIONS: Urinary ACR and eGFR (individually, together, and in combination using KDIGO risk categories) may be important nontraditional risk factors in stratifying and predicting major CVD events in the Chinese population.

Efficacy and safety of esaxerenone (CS-3150) in Japanese patients with type 2 diabetes and macroalbuminuria: a multicenter, single-arm, open-label phase III study.

BACKGROUND: Esaxerenone has potential renoprotective effects and reduces the urinary albumin-to-creatinine ratio (UACR) in patients with diabetic kidney disease and overt nephropathy. We investigated the efficacy and safety of esaxerenone in Japanese patients with type 2 diabetes (T2D) and macroalbuminuria (UACR ≥ 300 mg/g creatinine). METHODS: We conducted a multicenter, single-arm, open-label phase III study in 56 patients with T2D and UACR ≥ 300 mg/g creatinine with estimated glomerular filtration rate (eGFR) ≥ 30 mL/min/1.73 m2 and treated with a renin-angiotensin system inhibitor. Patients received esaxerenone for 28 weeks at 1.25 mg/day initially with titration to 2.5 mg/day based on serum potassium (K+) monitoring. Efficacy was evaluated as the change in UACR from baseline to week 28. Safety endpoints included adverse events (AEs), incidence of serum K+ increase, and change in eGFR from baseline. RESULTS: UACR decreased by 54.6% (95% CI 46.9%, 61.3%) on average from baseline (544.1 mg/g creatinine) to the end of treatment (246.8 mg/g creatinine); 51.8% of patients showed improvement to early nephropathy. AE incidence was 69.6%. Three patients (5.4%) had serum K+ levels ≥ 6.0 mEq/L or ≥ 5.5 mEq/L on two consecutive occasions. Hyperkalemia in two patients was transient and resolved during the treatment period. One patient discontinued following two consecutive serum K+ values ≥ 5.5 mEq/L. The maximum change from baseline in eGFR was - 8.3 mL/min/1.73 m2 at week 24. CONCLUSIONS: Esaxerenone reduced UACR in Japanese patients with T2D and UACR ≥ 300 mg/g creatinine; more than half experienced a transition from UACR ≥ 300 mg/g creatinine to UACR < 300 mg/g creatinine. CLINICAL TRIAL REGISTRATION: JapicCTI-173696.

Serum stromal cell-derived factor-1 levels are associated with diabetic kidney disease in type 2 diabetic patients.

The present study was designed to explore whether serum stromal cell-derived factor-1 (SDF-1) levels were associated with diabetic kidney disease (DKD). Serum SDF-1 levels were measured by sandwich ELISA. Patients with an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 or a urinary albumin-to-creatinine ratio (UACR) ≥30 mg/g for 3 months were identified as having DKD. Among the recruited type 2 diabetic patients, 18.71% (n = 32) were found to have DKD, and the serum SDF-1 levels of these patients were higher than those of patients without DKD (p < 0.05). Serum SDF-1 levels were positively correlated with cystatin C levels, the UACR and DKD incidence (r = 0.330, 0.183 and 0.186, respectively, p < 0.05) and inversely related to eGFR (r = -0.368, p < 0.001). After adjusting for other clinical covariates by multivariate logistic regression analyses, serum SDF-1 levels were found to be an independent contributor to DKD, and the odds ratio (95% confidence interval) was 1.438 (1.041-1.986). Furthermore, receiver operating characteristic analysis revealed that the optimal SDF-1 cutoff value for indicating DKD was 5.609 ng/mL (its corresponding sensitivity was 82.00%, and specificity was 46.90%). Our results demonstrated that serum SDF-1 levels were closely associated with DKD and could be considered a potent indicator for DKD in patients with T2D.

Dose-Response Mixed Models for Repeated Measures - a New Method for Assessment of Dose-Response.

PURPOSE: In this paper we investigated a new method for dose-response analysis of longitudinal data in terms of precision and accuracy using simulations. METHODS: The new method, called Dose-Response Mixed Models for Repeated Measures (DR-MMRM), combines conventional Mixed Models for Repeated Measures (MMRM) and dose-response modeling. Conventional MMRM can be applied for highly variable repeated measure data and is a way to estimate the drug effect at each visit and dose, however without any assumptions regarding the dose-response shape. Dose-response modeling, on the other hand, utilizes information across dose arms and describes the drug effect as a function of dose. Drug development in chronic kidney disease (CKD) is complicated by many factors, primarily by the slow progression of the disease and lack of predictive biomarkers. Recently, new approaches and biomarkers are being explored to improve efficiency in CKD drug development. Proteinuria, i.e. urinary albumin-to-creatinine ratio (UACR) is increasingly used in dose finding trials in patients with CKD. We use proteinuria to illustrate the benefits of DR-MMRM. RESULTS: The DR-MMRM had higher precision than conventional MMRM and less bias than a dose-response model on UACR change from baseline to end-of-study (DR-EOS). CONCLUSIONS: DR-MMRM is a promising method for dose-response analysis.

Quantitative analysis of retinal and choroidal microvascular parameters using optical coherence tomography angiography in children with nephrotic syndrome: a pilot study.

PURPOSE: To study the retinal and choroidal microvascular parameters in children with nephrotic syndrome (NS). METHODS: This is a cross-sectional study. Optical coherence tomography angiography was used to evaluate the changes of retinal and choroidal microvessels in patients with NS. Thirty NS children and 20 normal controls were included in this study. The macular vessel density (VD) of the superficial capillary plexus (SCP), deep capillary plexus (DCP), choroid capillary plexus (CCP), and foveal avascular zone (FAZ) area of the SCP and DCP was quantitatively calculated. Clinical data including serum protein, blood lipid, uric acid, urea, serum creatinine, urinary protein concentration, urinary creatinine, 24-h urine volume, 24-h urinary total protein, 24-h creatinine clearance rate, and urinary albumin to creatinine ratio were collected. RESULTS: The VDs of the DCP and CCP in children with NS were significantly lower than those in controls (59.35 ± 2.45 vs. 61.15 ± 1.53, p = 0.002, 66.34 ± 1.43 vs. 67.16 ± 1.23, p = 0.042, respectively). The VD of the SCP in children with NS had a tendency to decrease compared with that in controls, but there were no significant differences. There were also no significant differences in FAZ area between the two groups. The VD of the SCP was positively correlated with serum total protein (ρ = 0.446, p = 0.014), serum albumin (ρ = 0.431, p = 0.017), and 24-h urine volume (ρ = 0.389, p = 0.034) but negatively correlated with triglyceride (ρ = - 0.450, p = 0.013), low-density lipoprotein cholesterol (ρ = -0.432, p = 0.017), urinary protein concentration (ρ = - 0.606, p < 0.001), and 24-h urinary total protein (ρ = - 0.517, p = 0.004). The VDs of the SCP, DCP, and CCP were negatively correlated with the urinary albumin to creatinine ratio (ρ = - 0.473, p = 0.008, ρ = - 0.438, p = 0.015, ρ = -0.467, p = 0.009, respectively). CONCLUSIONS: Retinal and choroidal VDs were decreased in children with NS and paralleled the severity of kidney disease. Optical coherence tomography angiography can be used as a noninvasive method for evaluating renal injury in patients with NS.

Elevated triglycerides rather than other lipid parameters are associated with increased urinary albumin to creatinine ratio in the general population of China: a report from the REACTION study.

BACKGROUND: Dyslipidaemia has always been regarded as the cornerstone of arteriosclerosis and is related to the pathogenesis of renal insufficiency. However, it is unclear which routinely available lipid parameter is related to urinary albumin to creatinine ratio (UACR). The purpose of this study was to examine the lipid abnormalities associated with UACR in the general population in China. METHODS: The present study was nested in an ongoing Risk Evaluation of cAncers in Chinese diabetic Individuals: A lONgitudinal (REACTION) study, which was designed to demonstrate the association of abnormal glucose metabolism with the risk of cancer in the Chinese population. This cross-sectional study included 34, 569 subjects (11, 390 males and 23, 179 females) from 8 different regional community cohorts, with an average age of 57.9 years. The UACR data were divided into the < 25% group, the 25-49% group, the 50-74% group, and the ≥ 75% group according to the quartile division of the centre where the subjects visited. The lipid classes were defined according to the guidelines for the prevention and treatment of dyslipidaemia in Chinese adults. Multiple logistic regression analysis was used to evaluate the association of the lipid parameters and UACR. RESULTS: Multivariable regression analysis revealed that compared with the other lipid parameters, triglycerides (TG) showed an adjusted odds ratio that was significant in model 1-4. This relationship was attenuated after adjusting for Haemoglobin A1c (HbA1c) and blood pressure (BP), but TG ≥ 2.3 mmol/L was still significantly associated with UACR in total subjects and in both men and women (OR: 1.131, 95% CI 1.065-1.203, P < 0.001 in total subjects; OR: 1.134, 95% CI 1.022-1.258, P = 0.017 in men; OR: 1.129, 95% CI 1.046-1.219, P = 0.002 in women). In the stratified analysis, elevated TG was significantly associated with increased urinary albumin in subjects with eGFR ≥ 90 mL/min per 1.73 m2, 5.6 ≤ FBG < 7.0 or 7.8 ≤ PBG < 11.1 mmol/L, 24 ≤ BMI < 28 kg/m2, 120 ≤ SBP < 140 and/or 80 ≤ DBP < 90 mmHg. CONCLUSIONS: We conclude that high TG levels rather than total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, or non-high-density lipoprotein cholesterol levels are associated with UACR in the general population in China.

A higher ratio of refined grain to whole grain is associated with a greater likelihood of chronic kidney disease: a population-based study.

A growing number of studies suggest that diet and renal function are related. However, little is known about the link between both whole grain (WG) and refined grain (RG) consumption and kidney function parameters. Thus, we investigated the association of WG and RG with urinary albumin to creatinine ratio (ACR) and prevalent chronic kidney disease (CKD). Data from participants of the National Health and Nutrition Examination Surveys (NHANES) from 2005 to 2010 were collected. Estimated glomerular filtration rate (eGFR) was calculated by the CKD Epidemiology Collaboration equation. Survey design and sample weights were taken into consideration for statistical analyses. Finally, we included 16 325 participants from NHANES, 6·9 % of whom had prevalent CKD. In models adjusted for age, sex, race, fasting blood glucose, blood pressure, adiposity, hypertension and diabetes status, mean eGFR significantly increased across increasing quartiles of WG (Q1: 88·2 v. Q4: 95·4 ml/min per 1·73 m2, P<0·001), whereas it significantly decreased across increasing quartiles of RG (Q1: 97·2 v. Q4: 88·4 ml/min per 1·73 m2, P<0·001). Furthermore, serum uric acid levels and ACR significantly decreased across quartiles of WG (both P<0·001). In multivariable-adjusted logistic regression models, the likelihood of prevalent CKD was 21 % lower in the highest WG quartile compared with the lowest one. In conclusion, our results shed light on the beneficial impact of WG on kidney function and CKD, whereas RG is adversely associated with eGFR.

An Exploratory Study of Dapagliflozin for the Attenuation of Albuminuria in Patients with Heart Failure and Type 2 Diabetes Mellitus (DAPPER).

BACKGROUND AND AIMS: Sodium-dependent glucose transporter-2 (SGLT-2) inhibitors, which are anti-diabetic drugs, reportedly decrease the incidence of cardiovascular events in high-risk patients with cardiovascular diseases, and thus chronic heart failure (CHF). SGLT-2 inhibitors also decrease albuminuria in patients with type 2 diabetes mellitus (T2D). Since albuminuria is a biomarker of not only chronic kidney disease but also cardiovascular events, we hypothesized that, among T2D patients with CHF, SGLT-2 inhibitors will decrease the extent of albuminuria and also improve CHF concomitantly. METHODS: DAPPER (UMIN000025102) is a multicenter, randomized, open-labeled, parallel-group, standard treatment-controlled study, which is designed to evaluate whether dapagliflozin, one of the SGLT-2 inhibitors, decreases albuminuria in T2D patients with CHF and exerts cardioprotective effects on the failing heart. The patients are randomized to either of the dapagliflozin (5 or 10 mg, once daily orally) or control group (administration of anti-diabetic drugs administered other than SGLT 2 inhibitors). The estimated number of patients that need to be enrolled is 446 in total (223 in each group). The primary objective is the changes in the urinary albumin-to-creatinine ratio from the baseline after 2-year treatment. The key secondary objectives are (1) the safety of dapagliflozin and (2) the cardiovascular and renal efficacies of dapagliflozin. CONCLUSION AND PERSPECTIVES: DAPPER study investigates whether dapagliflozin decreases albuminuria and exerts beneficial effects on the failing heart in T2D patients. (UMIN000025102).

Visit-to-visit blood pressure variability in children and adolescents with renal disease.

BACKGROUND: Increase in blood pressure (BP) variability (BPV) is associated with cardiovascular events, target organ damage, and arterial stiffness in adults. We previously reported that 24-h BPV may be associated with arterial stiffness and underlie white-coat hypertension (WCH). In this study, we examined whether visit-to-visit variability (VVV) could predict WCH and whether VVV correlated with eGFR, eGFR slope, and albuminuria/proteinuria in children and adolescents with renal diseases. METHODS: VVV was determined as average real variability of office BP measurements between visits, and 24-h BPV as the standard deviation of 24-h ambulatory BP. In 35 renal patients (25 boys and 10 girls, 7-18 years of age), divided into normotension (NT), WCH, and hypertension (HTN), the relationships between VVV and 24-h BPV and VVV in each BP category were studied. In separate 48 renal patients (24 boys and 24 girls, 2-18 years of age), the correlation between VVV and eGFR, eGFR slope, urine albumin or protein excretion was examined. RESULTS: Systolic VVV was significantly correlated with systolic office BP index. There was no correlation between VVV and 24-h BPV or 24-h pulse pressure. In addition, VVV was not different among NT, WCH, and HTN. Systolic VVV was significantly negatively correlated with eGFR but not with eGFR slope, albuminuria, or proteinuria. A cut-off value of systolic VVV for detecting eGFR < 60 ml/min per 1.73 m2 was 8.5. CONCLUSION: VVV could not predict WCH. Systolic VVV correlated with eGFR but not with eGFR slope, albuminuria/proteinuria. Increased VVV could be a marker of decreased eGFR.

Can both normal and mildly abnormal albuminuria and glomerular filtration rate be a danger signal for diabetic peripheral neuropathy in type 2 diabetes mellitus?

We aimed to investigate the potential association between urinary albumin-to-creatinine ratio (UACR) and estimated glomerular filtration rate (eGFR) and diabetic peripheral neuropathy (DPN). We were especially interested in the relationship between normal or mildly abnormal UACR and eGFR with DPN. A retrospective study was performed in 1059 patients with type 2 diabetes patients from Fuzhou, China, who were seen between 2010 and 2015. The DPN population demonstrated higher UACR and lower eGFR than the non-DPN population. Nerve conduction velocities (NCVs) were negatively correlated with UACR and were positively correlated with eGFR. UACR and eGFR were associated with the risk of DPN. Even in the UACR < 30 mg/g and eGFR ≥ 60 ml/min/1.73 m2 groups, the relationship above still existed and patients in the highest tertiles of UACR and lowest tertiles of eGFR demonstrated a greater risk of DPN (OR = 2.456, 95% CI 1.461-4.127; OR = 2.021, 95% CI 1.276-3.203). Receiver operating characteristic (ROC) analysis revealed that the area under curve (AUC) of UACR, eGFR, and joints indicates that DPN was 0.749, 0.662, and 0.731, respectively. Lower eGFR and higher UACR may be associated with the risk of DPN, even though normal or mildly abnormal UACR and eGFR have already been found to be predictive factors of DPN. Further, UACR is more sensitive than eGFR. Separately, UACR was a moderate indication of DPN, and combining it with eGFR did not increase its effect of indication to DPN.

Reduced Kidney Function, Albuminuria, and Risks for All-cause and Cardiovascular Mortality in China: A Population-based Cohort Study.

BACKGROUND: Previous studies have indicated that reduced kidney function and albuminuria are associated with increased risk of mortality and adverse cardiovascular outcomes, however, the evidence from the Asian population is limited. We investigated the association between the indicators of chronic kidney disease (CKD) and all-cause mortality, as well as cardiovascular mortality among a general population in China. METHODS: We conducted an observational study among 47,204 Chinese adults, from a cross-sectional survey, whose survival status is identified through December 31, 2013. Estimated glomerular filtration rate (eGFR) and urinary albumin-to-creatinine ratio (ACR) were used as indicators of CKD. We determined the rates of all-cause and cardiovascular mortality. RESULTS: The incidence rates for both all-cause and cardiovascular mortality increased with the advanced stages of reduced eGFR or elevated ACR. Elevated ACR levels were found to be significantly associated with increased risk of both all-cause and cardiovascular mortality, as shown in the Cox proportional hazards regression model. The multivariable adjusted hazard ratios (HR) associated with all-cause mortality were 1.26 (95% confidence interval [CI]: 1.04-1.53) for those with ACR 30-299 mg/g and 2.07 (95% CI: 1.40-3.04) with ACR ≥ 300 mg/g, compared to those with ACR <30 mg/g. The corresponding HRs for the above ACR levels associated with cardiovascular mortality were 1.08 (95% CI: 0.77-1.50) and 2.32 (95% CI: 1.31-4.12), respectively. We did not identify reduced eGFR as a risk predictor in the multivariable adjusted model for the adverse outcomes in the population, however, an interaction between eGFR and age were detected. Stratified analyses revealed that the associations of reduced eGFR (<60 mL/min/1.73 m2) with all-cause mortality were prominent among participants aged less than 65 years. CONCLUSIONS: Albuminuria was associated with an elevated risk of all-cause and cardiovascular mortality among the Chinese population, however, the association of reduced kidney function with all-cause mortality was not clear.