Associations of CKD risk factors and longitudinal changes in urine biomarkers of kidney tubules among women living with HIV.

BACKGROUND: Novel urine biomarkers have enabled the characterization of kidney tubular dysfunction and injury among persons living with HIV, a population at an increased risk of kidney disease. Even though several urine biomarkers predict progressive kidney function decline, antiretroviral toxicity, and mortality in the setting of HIV infection, the relationships among the risk factors for chronic kidney disease (CKD) and urine biomarkers are unclear. METHODS: We assessed traditional and infection-related CKD risk factors and measured 14 urine biomarkers at baseline and at follow-up among women living with HIV in the Women's Interagency Health Study (WIHS). We then used simultaneously adjusted multivariable linear regression models to evaluate the associations of CKD risk factors with longitudinal changes in biomarker levels. RESULTS: Of the 647 women living with HIV in this analysis, the majority (67%) were Black, the median age was 45 years and median follow-up time was 2.5 years. Each traditional and infection-related CKD risk factor was associated with a unique set of changes in urine biomarkers. For example, baseline hemoglobin a1c was associated with worse tubular injury (higher interleukin [IL]-18), proximal tubular reabsorptive dysfunction (higher α1-microglobulin), tubular reserve (lower uromodulin) and immune response to injury (higher chitinase-3-like protein-1 [YKL-40]). Furthermore, increasing hemoglobin a1c at follow-up was associated with further worsening of tubular injury (higher kidney injury molecule-1 [KIM-1] and IL-18), as well as higher YKL-40. HCV co-infection was associated with worsening proximal tubular reabsorptive dysfunction (higher ß2-microglobulin [ß2m]), and higher YKL-40, whereas HIV viremia was associated with worsening markers of tubular and glomerular injury (higher KIM-1 and albuminuria, respectively). CONCLUSIONS: CKD risk factors are associated with unique patterns of biomarker changes among women living with HIV, suggesting that serial measurements of multiple biomarkers may help in detecting and monitoring kidney disease in this setting.

Different renoprotective effects of luseogliflozin depend on the renal function at the baseline in patients with type 2 diabetes: A retrospective study during 12 months before and after initiation.

AIMS: The safety and efficacy, particularly, the factors associated with the renal prognosis, were assessed over 12 months after the initiation of luseogliflozin therapy in Japanese patients with type 2 diabetes and renal impairment. METHODS: In total, 238 patients treated with luseogliflozin (2.5 mg, once daily) were studied as the safety analysis set. Two hundred and two subjects whose medication was continued over 12 months were investigated as the full analysis set. The subjects were divided into 3 groups based on the estimated glomerular filtration rate (eGFR): high eGFR (n = 49), normal eGFR (n = 116) and low eGFR (n = 37) groups. RESULTS: The body weight, systolic blood pressure, HbA1c and urinary protein excretion gradually decreased from baseline in all eGFR groups. While the eGFR was significantly reduced from baseline in the high and normal eGFR groups, the eGFR did not significantly differ over time in the low eGFR group. There was no marked difference in the frequency of adverse events that were specific for SGLT2 inhibitors among the 3 groups in the safety analysis set. CONCLUSIONS: Luseogliflozin can preserve the renal function in the medium term in patients with type 2 diabetes and renal impairment without an increase in specific adverse events.

Urinary megalin in association with progression factors of diabetic nephropathy.

AIM: The aim of this study is to evaluate the association between urinary megalin, renal function, blood pressure, lipid profile, vitamin D and glycemic control in patients with type 2 diabetes mellitus (T2DM). METHODS: . This was a cross-sectional study which recruited 209 patients with T2DM. Urinary megalin was positively associated with systolic blood pressure (SBP) (r=0.218, p=0.04) but negatively with glomerular filtration rate (GFR) (r=-0.16, p=0.023). The levels of urinary albumin, triglycerides (TGs) and glycosylated hemoglobin (HbA1c) were higher in the "high-megalin" group, compared to those in "low-megalin" group. Moreover, there was a significant inverse association between vitamin D3 levels and megalin levels in urine (OR=0.281, p=0.047). CONCLUSION: Our study showed for the first time that megalin is associated with progression factors of diabetic nephropathy as well as vitamin D deficiency (Tab. 3, Fig. 1, Ref. 15).

Estimated Total Albumin in Fresh Urine Samples Based on Correlation Between the Roche Immunoturbidimetric and an In-House HPLC Method.

Background: Many studies have reported higher values of urinary albumin measured by high performance liquid chromatography (HPLC) in comparison with immunochemical methods. The aims of our study were the implementation of the HPLC method for albuminuria, testing the hypothesis about coeluting proteins, comparison of albuminuria assessed by HPLC and immunoturbidimetric (IT) methods in diabetic and non-diabetic patient samples. Methods: We compared albuminuria assessed by HPLC with albuminuria assessed by the IT method in fresh urine samples of 636 diabetics and 456 non-diabetics. We investigated relationships between albuminuria and blood glycated hemoglobin HbA1c. Results: We found significant differences between the parameters of linear regressions between albuminuria determined using HPLC and IT among patients with and without DM, and even between patients with DM type 1 and type 2. We confirmed the underestimation of albuminuria assessed by IT. We did not reveal any significant correlation between blood glycated hemoglobin and any of the parameters derived from albuminuria. Conclusions: We excluded non-specificity of the HPLC method. Despite of a little bit lower analytical sensitivity of the HPLC method in comparison with IT method the diagnostic sensitivity of HPLC method is higher, because it measures the total albuminuria (immunoreactive plus immunounreactive). We developed three formulas (for nondiabetics, for diabetics type 1 and diabetics type 2) for the estimation of the total albuminuria from IT values. We also confirmed that albuminuria and HbA1c are independent biomarkers.

Is there a J-shaped relationship between the fatty liver index and risk of microalbuminuria in the general population?

BACKGROUND: We investigated whether the fatty liver index (FLI), as a clinical indicator of hepatic fat accumulation based on body mass index, gamma-glutamyl-transferase, triglycerides, and waist circumference, has an association with microalbuminuria. METHODS: We analyzed anthropometric and biochemical data from a nation-wide, population-based, cross-sectional study. A total of 1605 participants included were healthy native Korean 40years or older and divided into quintiles according to their log-FLI and sex. Microalbuminuria was defined as urine albumin/creatinine ratio (UACR) between 30 and 300mg/g. RESULTS: Participants in higher quintiles of log-FLI were more obese and hypertensive and had greater glycemic exposure, poorer lipid profiles, and greater increases in log-UACR compared with lower quintiles. Linear regression analysis demonstrated that log-FLI was associated with systolic and diastolic blood pressure, body mass index, waist circumference, fasting plasma glucose, glycated hemoglobin, and log-UACR. In logistic regression adjusted for age, sex, body mass index, waist circumference, and fasting plasma glucose, the OR of microalbuminuria was elevated in quintile 1 (adjusted OR=2.161, 95% CI=0.453-10.31) and quintile 5 (adjusted OR=6.387, 95% CI=1.317-51.58), when compared to quintile 2. CONCLUSIONS: There appears to be a J-shaped association between FLI and UACR in healthy general population.

Outcome of laparoscopic gastric bypass in obese and diabetic patients: when surgery fails.

BACKGROUND: The beneficial effects of bariatric surgery on diabetes and obesity have been widely demonstrated in the literature. The aim of our study was to evaluate the rate of failure of laparoscopic gastric bypass both in terms of weight loss and metabolic remission after one follow-up year. METHODS: A longitudinal, multicenter prospective study was carried out on 771 patients affected by pathological obesity. The following parameters were recorded for each patient before surgery: anthropometric, metabolic, social, smoking habits and previous failure of other bariatric procedures. After 1 follow-up year, final weight, final Body Mass Index (BMI), final percentage of lost excess body weight and percentage of lost BMI were evaluated. RESULTS: Statistical analysis showed a correlation between BMI>50 kg/m2, presence of metabolic syndrome, presence of diabetes, gastric pouch volume greater than 60 mL and failure of weight loss outcome. Statistical analysis of metabolic failure has recognized a high preoperative glycated hemoglobin percentage (HbA1c%) value as a statistically significant negative predictive factor. CONCLUSIONS: Bariatric Surgery is the most effective treatment for weight loss and metabolic improvement. However, in our study, surgery did not achieve the expected outcome in patients with specific metabolic, anthropometric and surgical characteristics (BMI>50 kg/m2, presence of metabolic syndrome, presence of T2DM with high preoperative HbA1c% level and gastric pouch volume greater than 60 mL).

Endothelial monocyte activating polypeptide II in children and adolescents with type 1 diabetes mellitus: Relation to micro-vascular complications.

OBJECTIVES: Endothelial monocyte-activating polypeptide II (EMAP II) is a multifunctional polypeptide with proinflammatory and antiangiogenic activity. Hyperglycemia and dyslipidemia appears to be significant factors contributing to increased EMAP-II levels. We determined serum EMAP II in children and adolescents with type 1 diabetes as a potential marker for micro-vascular complications and assessed its relation to inflammation and glycemic control. METHODS: Eighty children and adolescents with type 1 diabetes were divided into 2 groups according to the presence of micro-vascular complications and compared with 40 healthy controls. High-sensitivity C-reactive protein (hs-CRP), hemoglobin A1c (HbA1c) and EMAP II levels were assessed. RESULTS: Serum EMAP II levels were significantly increased in patients with micro-vascular complications (1539 ± 321.5 pg/mL) and those without complications (843.6 ± 212.6 pg/mL) compared with healthy controls (153.3 ± 28.3 pg/mL; p<0.001). EMAP II was increased in patients with microalbuminuria than normoalbuminuric group (p<0.001). Significant positive correlations were found between EMAP II levels and body mass index, fasting blood glucose, HbA1c, serum creatinine, triglycerides, total cholesterol, urinary albumin creatinine ratio (UACR) and hs-CRP (p<0.05). A cutoff value of EMAP II at 1075 pg/mL could differentiate diabetic patients with and without micro-vascular complications with a sensitivity of 93% and specificity of 82%. CONCLUSIONS: We suggest that EMAP II is elevated in type 1 diabetic patients, particularly those with micro-vascular complications. EMAP II levels are related to inflammation, glycemic control, albuminuria level of patients and the risk of micro-vascular complications.

Reliability of biological variation data available in an online database: need for improvement.

BACKGROUND: Biological variation (BV) data enable assessment of the significance of changes in serial measurements observed within a subject and are used to set analytical quality specifications. This data is available in a database held in Westgard website (http://www.westgard.com/biodatabase1.htm). Some limitations of this data, however, have been identified in recent published reviews. The aim of this paper is to show the reliability of the published BV data and to identify ongoing works to address some of its limitations. METHODS: The BV data currently hosted on the Westgard website was examined. Distribution of measurands stratified by the number of cited references upon which the database entry is based and the distribution of papers stratified by publication year, are shown. Moreover, BV data available in literature for glycated hemoglobin, C-reactive protein, glycated albumin, alanine aminotransferase, aspartate aminotransferase and γ-glutamyl transferase are evaluated. RESULTS: The results obtained show that most BV data come just from a few papers or only one paper and that a lot of publications are dated, therefore this data is too obsolete to be used. Furthermore critical review of the BV database highlights a number of factors that might impact on the reliability of the BV data entries and translation into current practice. CONCLUSIONS: A number of issues clearly undermine the value of the current database. These issues are being considered by the European Federation of Clinical Chemistry and Laboratory Medicine, biological variation working group, in collaboration with a Spanish group responsible for the database updating.

1H NMR-based metabolomics studies of urine reveal differences between type 1 diabetic patients with high and low HbAc1 values.

The aim of this study was to investigate relation between level of HbAc1 and concentration of metabolites in urine of T1D patients. To test this hypothesis the (1)H NMR (proton nuclear magnetic resonance) target analysis of crucial urine metabolites combined with chemometric approach were applied. Urine samples were collected from 30 children and teenagers aged 4-19 with T1D and 12 healthy children, aged 9, as control group. Patients were divided into two groups according to their level of glycated hemoglobin (HbA1c): below (L-T1D) and above 6.5% (H-T1D). The multivariate data analysis (OPLS-DA) was used to explore data and generate the models for selected groups of patients. Two tailed unpaired t-test was used for statistical analysis of quantified metabolites. Comparing to L-T1D patients, H-T1D group exhibited increased levels of alanine, pyruvate and branched amino acid valine that might be related with endogenous glucose production pathway from proteins as well as in the case of T2D. Application of (1)H NMR spectroscopy together with target analysis and chemometric tools based on urine metabolite concentration enable to monitor T1D patients. This methodology can be used as supporting tool for marker HbA1c analysis providing comprehensive information about T1D progression and treatment efficiency.

Vegetables and PUFA-rich plant oil reduce DNA strand breaks in individuals with type 2 diabetes.

SCOPE: Type 2 diabetes is a multifactorial disease associated with increased oxidative stress, which may lead to increased DNA damage. The aim of this study was to investigate the effect of a healthy diet on DNA oxidation in diabetics and nondiabetics. METHODS AND RESULTS: Seventy-six diabetic and 21 nondiabetic individuals participated in this study. All subjects received information about the benefits of a healthy diet, while subjects randomly assigned to the intervention group received additionally 300 g of vegetables and 25 mL PUFA-rich plant oil per day. DNA damage in mononuclear cells (Comet Assay), urinary excretion of 8-oxo-7-hydro-2'-deoxyguanosine (8-oxodG) and 8-oxo-7,8-dihydroguanosine (8-oxoGuo) and glycated hemoglobin (HbA1c) were measured at baseline, after 4, 8 (end of intervention), and 16 weeks. The intervention with vegetables and PUFA-rich oil led to a significant increase in plasma antioxidant concentrations. Diabetic individuals of the intervention group showed a significant reduction in HbA1c and DNA strand breaks. Levels of HbA1c were also improved in diabetics of the information group, but oxidative damage to DNA was not altered. Urinary 8-oxodG and 8-oxoGuo excretion remained unchanged in both groups. CONCLUSIONS: This study provides evidence that a healthy diet rich in antioxidants reduces levels of DNA strand breaks in diabetic individuals.

Association between total bilirubin and hemoglobin A1c in Korean type 2 diabetic patients.

Recent studies have shown that bilirubin is negatively associated with hemoglobin A1c (HbA1c) in the general population. The association between bilirubin and HbA1c in serum of diabetes patients has not yet been studied. The aim of the present study was to evaluate the association between total bilirubin and HbA1c in Korean patients with type 2 diabetes. A total of 690 of the 1,275 type 2 diabetes patients registered with the public health centers in Seo-gu, Gwangju and Gokseong-gun, Jeollanam-do participated in this study. Following an overnight fast, venous blood and urine samples were collected and analyzed. The mean HbA1c values differed significantly according to total bilirubin (≤ 0.4 mg/dL, 7.6%; 0.5 mg/dL, 7.3%; 0.6-0.7 mg/dL, 7.2%; and ≥ 0.8 mg/dL, 7.1%; P for trend = 0.016) after we adjusted for other confounding factors. When the odds ratio (OR) was adjusted for other confounding factors, there was a significant association between total bilirubin and HbA1c (OR, 0.4 [95% confidence interval, 0.2-0.8] for total bilirubin ≥ 0.8 mg/dL versus ≤ 0.4 mg/dL. In conclusion, total bilirubin concentrations in serum are negatively associated with HbA1c levels after adjustment for sex, age, and other confounding factors in type 2 diabetes patients.

Urine C-peptide creatinine ratio is an alternative to stimulated serum C-peptide measurement in late-onset, insulin-treated diabetes.

AIMS: Serum C-peptide measurement can assist clinical management of diabetes, but practicalities of collection limit widespread use. Urine C-peptide creatinine ratio may be a non-invasive practical alternative. The stability of C-peptide in urine allows outpatient or community testing. We aimed to assess how urine C-peptide creatinine ratio compared with serum C-peptide measurement during a mixed-meal tolerance test in individuals with late-onset, insulin-treated diabetes. METHODS: We correlated the gold standard of a stimulated serum C-peptide in a mixed-meal tolerance test with fasting and stimulated (mixed-meal tolerance test, standard home meal and largest home meal) urine C-peptide creatinine ratio in 51 subjects with insulin-treated diabetes (diagnosis after age 30 years, median age 66 years, median age at diagnosis 54, 42 with Type 2 diabetes, estimated glomerular filtration rate > 60 ml min(-1) 1.73 m(-2) ). RESULTS: Ninety-minute mixed-meal tolerance test serum C-peptide is correlated with mixed-meal tolerance test-stimulated urine C-peptide creatinine ratio (r = 0.82), urine C-peptide creatinine ratio after a standard breakfast at home (r = 0.73) and urine C-peptide creatinine ratio after largest home meal (r = 0.71). A stimulated (largest home meal) urine C-peptide creatinine ratio cut-off of 0.3 nmol/mmol had a 100% sensitivity and 96% specificity (area under receiver operating characteristic curve = 0.99) in identifying subjects without clinically significant endogenous insulin secretion (mixed-meal tolerance test-stimulated C-peptide < 0.2 nmol/l). In detecting a proposed serum C-peptide threshold for insulin requirement (stimulated serum C-peptide < 0.6 nmol/l), a stimulated (largest home meal) urine C-peptide creatinine ratio cut-off of 0.6 nmol/mmol had a sensitivity and specificity of 92%. CONCLUSION: In patients with insulin-treated diabetes diagnosed after age 30 years, urine C-peptide creatinine ratio is well correlated with serum C-peptide and may provide a practical alternative measure to detect insulin deficiency for use in routine clinical practice.

Dapagliflozin treatment in patients with different stages of type 2 diabetes mellitus: effects on glycaemic control and body weight.

AIM: Dapagliflozin is a stable, competitive, reversible, and highly selective inhibitor of sodium-glucose co-transporter 2, the major transporter responsible for renal glucose reabsorption. With an insulin-independent mechanism of action, dapagliflozin is currently being developed for the treatment of type 2 diabetes mellitus (T2DM). This work aims to compare the efficacy of dapagliflozin, as measured by the change in hemoglobin A1c concentration (A1c) and body weight, and to determine the pharmacodynamic effects of dapagliflozin, as measured by urinary glucose excretion in early-stage and late-stage T2DM patient populations. METHODS: A total of 151 early-stage patients and 58 late-stage patients with T2DM randomly assigned 10 or 20 mg once daily (QD) dapagliflozin treatment or placebo for 12 weeks from two phase 2 studies were included in the analysis. A1c, body weight, and urinary glucose were compared between the two patient populations. RESULTS: Compared with the early-stage population, patients in the late-stage population had a longer duration of T2DM and higher baseline levels of A1c, body weight, fasting plasma glucose, and urinary glucose excretion. After 12 weeks of dapagliflozin treatment, A1c reduction, weight loss, and increased urinary glucose excretion from baseline were observed in both populations. Baseline A1c level impacted the A1c reduction after dapagliflozin treatment with a comparable effect in patients with early and late stage disease. Late-stage patients had greater reduction in body weight. There was no statistically significant difference in the amount of urinary glucose excretion between the early-stage and late-stage patients. CONCLUSIONS: Dapagliflozin treatment at 10 and 20 mg QD for 12 weeks resulted in significant improvement in glycaemic control and body weight reduction in both early-stage and late-stage patients with T2DM. The findings suggest that dapagliflozin could be a promising treatment option for a wide range of patients with T2DM.

Tubular function in diabetic children assessed by Tamm-Horsfall protein and glutathione S-transferase.

In a previous study, we found urinary excretion of Tamm-Horsfall protein (THP) to be persistently decreased in 25% of patients during the first year after diagnosis of diabetes mellitus. We thus wanted to study another marker for distal tubular function, pi glutathione S-transferase (pi-GST) and compare this and THP with proximal tubular function evaluated with alpha-GST and alpha-1-microglobulin (HC) in patients with longer duration of diabetes. One hundred and eighty-four diabetic and 16 control children were studied with timed overnight urine collections. Median age was 14 years, and median age at diagnosis was 8 years. The urinary excretion of alpha- and pi-GST was significant lower in diabetic than control children. There were no differences in the excretion of HC and THP. Diabetic children with decreased alpha-GST had higher albumin excretion, HbA 1c levels, and longer diabetes duration but decreased THP excretion and cystatin-C clearance compared with those with normal excretion. In contrast, a decreased pi-GST or THP excretion was not associated with such differences. Diabetic children with increased HC excretion had increased HbA 1c levels. Diabetic children, before the stage of microalbuminuria, may have signs of both proximal and distal tubular dysfunction, which is related to diabetes duration and poor metabolic control. Alpha-GST and pi-GST seem to be more sensitive than other parameters studied.

Renal handling of uric acid in patients with type 1 diabetes in relation to glycemic control.

BACKGROUND: The aim of the study was to compare the renal handling of uric acid (UA) in 16 patients with type 1 diabetes without renal failure (age 34.8 +/- 13.3 years) and in 15 healthy subjects (age 34.9 +/- 12.6 years). METHODS: Creatinine clearance (Cr-Cl), clearance of uric acid (UA-Cl), fractional excretion of uric acid (UA-FE), and 24-h urinary UA excretion (UA-U) were determined. Glycemic control was assessed using fasting glucose, glycated hemoglobin and fructosamine tests. RESULTS: Patients with diabetes had significantly (p < 0.0001) lower serum UA concentrations compared to control group (2.8 +/- 0.7 vs. 5.7 +/- 0.8 mg/dl), and higher urinary UA excretion (813 +/- 107 vs. 423 +/- 40 mg/day), UA clearance (21.9 +/- 7.1 vs. 5.2 +/- 0.9 mL/min) and fractional UA excretion (17.1 +/- 5.5 vs. 4.8 +/- 1.3%), with higher creatinine clearance (129 +/- 16 vs. 111 +/- 12 mL/min, p < 0.005). In patients with diabetes there was a strong negative correlation between serum UA concentration and UA 24-h excretion (R = -0.79; p < 0.001). Fractional UA excretion correlated with fasting glycemia and HbA1c (R = +0.51 and +0.53; p < 0.05). CONCLUSIONS: In type 1 diabetes there is significant UA renal clearance increase, which is higher with poor glycemic control. It leads to hypouricemia despite an approximately twofold UA excretion increase and therefore despite increased UA synthesis.