24-h Urinary Albumin Excretion Research Articles

Vitamin D receptor activator and dietary sodium restriction to reduce residual urinary albumin excretion in chronic kidney disease (ViRTUE study): rationale and study protocol.

Optimal albuminuria reduction is considered essential to halting chronic kidney disease (CKD) progression. Both vitamin D receptor activator (VDRA) treatment and dietary sodium restriction potentiate the efficacy of renin-angiotensin-aldosterone-system (RAAS) blockade to reduce albuminuria. The ViRTUE study addresses whether a VDRA in combination with dietary sodium restriction provides further albuminuria reduction in non-diabetic CKD patients on top of RAAS blockade. The ViRTUE study is an investigator-initiated, prospective, multi-centre, randomized, double-blind (paricalcitol versus placebo), placebo-controlled trial targeting stage 1-3 CKD patients with residual albuminuria of >300 mg/day due to non-diabetic glomerular disease, despite angiotensin-converting enzyme inhibitor or angiotensin receptor blocker use. During run-in, all subjects switched to standardized RAAS blockade (ramipril 10 mg/day) and blood pressure titrated to <140/90 mmHg according to a standardized protocol. Eligible patients are subsequently enrolled and undergo four consecutive study periods in random order of 8 weeks each: (i) paricalcitol (2 µg/day) combined with a liberal sodium diet (∼200 mmol Na(+)/day, i.e. mean sodium intake in the general population), (ii) paricalcitol (2 µg/day) combined with dietary sodium restriction (target: 50 mmol Na(+)/day), (iii) placebo combined with a liberal sodium diet and (iv) placebo combined with dietary sodium restriction. Data are collected at the end of each study period. The primary outcome is 24-h urinary albumin excretion. Secondary study outcomes are blood pressure, renal function (estimated glomerular filtration rate), plasma renin activity and, in a sub-population (N = 9), renal haemodynamics (measured glomerular filtration rate and effective renal plasma flow). A sample size of 50 patients provides 90% power to detect a 23% reduction in albuminuria, assuming a 25% dropout rate. Further reduction of residual albuminuria by combination of VDRA treatment and sodium restriction during single-agent RAAS-blockade will justify long-term studies on cardiorenal outcomes and safety. NTR2898 (Dutch trial register).

Urinary albumin excretion and prevalence of microalbuminuria in a general Chinese population: a cross-sectional study.

BackgroundMicroalbuminuria has been shown to be a risk factor for cardiovascular and renal disease in patients with hypertension and diabetes as well as in the general population. Urinary albumin excretion over 24 h is considered a ‘gold standard’ to detect microalbuminuria. Few studies have used 24-h urinary albumin excretion to analyze the prevalence of and related factors for microalbuminuira in a general Chinese population.MethodsThis study included 1980 adults aged 18–69 years from the Shandong-Ministry of Health Action on Salt and Hypertension (SMASH) Project 2011 survey. Blood pressure, height, weight and waist circumference were measured, and a venous blood and timed 24-h urine samples were collected from each participant. Linear and logistic regression analyses were used to test associations between established cardiovascular risk factors and microalbuminuria.ResultsThe median (25th–75th percentile) of 24-h urinary albumin excretion was 6.1 mg/d (4.5–8.7 mg/d) for all adults, 6.0 mg/d (4.4–8.5 mg/d) for men and 6.2 mg/d (4.6–8.9 mg/d) for women. The overall prevalence of microalbuminuria was 4.1% (95% confidence interval [CI]: 3.2–5.0%), 3.7% (95% CI: 2.9–4.5%) for men and 4.6% (95% CI: 3.7–5.5%) for women. Microalbuminuria was present in 8.1% (95% CI: 6.9–9.3%) of individuals with hypertension, 11.4% (95% CI: 10.0–12.8%) of those with diabetes and 15.6% (95% CI: 14.0–17.2%) of those with both. Multiple logistic regression analysis indicated that systolic blood pressure (odds ratio [OR] 1.02; 95% CI: 1.01–1.03) and fasting blood glucose (OR 1.19; 95% CI: 1.05–1.35) were the independent risk factors for microalbuminuria.ConclusionsAdults in the general population of Shandong Province have a moderate prevalence of microalbuminuria. Those with hypertension and diabetes are at high risk of having microalbuminuria, suggesting the need for screening and early intervention for microalbuminuria among these individuals.

Protective effect of total flavonoids extracted from the leaves of Murraya paniculata (L.) Jack on diabetic nephropathy in rats

This study was designed to evaluate the effects of total flavonoids extracted from the leaves of Murraya paniculata (L.) Jack (TFMP) on diabetic nephropathy.High fat diet and streptozotocin-induced diabetic rats were treated with the TFMP (35 or 70mg/kg) for 13weeks. Changes of renal function parameters were examined at the end of administration. Some kidneys were collected for histological and immunohistochemistry studies, the other ones for biochemical parameters analysis.TFMP significantly decreased the levels of serum blood urea nitrogen, serum creatinine, creatinine clearance, interleukin-6, urinary albumin, 24h-urinary albumin excretion rate, kidney weight to body weight ratio and fasting blood glucose in diabetic rats. Meanwhile, the levels of triglycerides, total and LDL cholesterols in the TFMP treated diabetic rats were lower and the high-density lipoprotein cholesterol level was higher than that in the diabetic rats. TFMP treatment significantly blocked the decrease of superoxide dismutase and glutathione peroxidase and increase of malondialdehyde levels in diabetic rats. Furthermore, the TFMP not only decreased the expression of TGF-β1 and CTGF protein, but also reduced diabetes-induced morphological alterations of the kidney. These results suggest that TFMP is a protective agent against renal damage in diabetic nephropathy.

Fractalkine in type 2 Egyptian diabetics with and without nephropathy

Abstract Background Diabetes mellitus is a group of metabolic diseases characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both. Diabetic nephropathy is the major microvascular complication of diabetes mellitus; one of the earliest clinical signs of diabetic nephropathy is an elevated urinary albumin excretion (UAE), referred to as microalbuminuria. Fractalkine is a large cytokine protein of 373 amino acids; it contains multiple domains. Fractalkine (CX3CL1) is a unique chemokine and the only representative of the CX3C group. It exists as a membrane-bound and soluble form. It interacts with cells expressing CX3CR1, a G-coupled protein receptor. It is also commonly known by the names fractalkine (in humans) and neurotactin (in mice). Aim Our study aimed to assess fractalkine levels in type 2 Egyptian diabetic patients with and without diabetic nephropathy and its role as a marker in the development of diabetic nephropathy. Patients and methods Our study was carried out on 75 individuals: 25 controls, 25 type 2 diabetic patients without diabetic nephropathy, and 25 type 2 diabetic patients with diabetic nephropathy. These patients were subjected to a full laboratory workup including fasting and postprandial blood glucose, glycated hemoglobin A1C, serum urea and creatinine, 24-h UAE, and fractalkine level. Results and conclusion Our study showed that the serum fractalkine concentration was significantly elevated in type 2 diabetic patients with nephropathy (1153.14±261.1) compared with type 2 diabetic patients without nephropathy (705.78±150.59) and the control group (251.5±64) (both P=0.000). There was a significant correlation between serum fractalkine level and 24-h UAE, HBA1C, and serum creatinine. Thus, this positive correlation between serum fractalkine level and UAE could be an early predictor of microvascular complications in diabetic patients. We can conclude that serum fractalkine plays a pathogenic role in the development of diabetic nephropathy.

The Comparison of 24-Hour Urinary Sodium, Albumin, and Protein Excretion in Chronic Kidney Disease Patients with Type 2 Diabetes Mellitus Using Insulin Detemir or Insulin Glargine

Insulin detemir induces bodyweight loss or less weight gain in patients with type 2 diabetes mellitus. However, in contrast to insulin detemir, insulin glargine has no weight loss effect. Increased sodium excretion has been speculated to be one of the mechanisms of weight loss by insulin detemir. However, there are no studies in the literature comparing sodium excretion between patients using insulin detemir and those using insulin glargine. There are also no studies comparing the excretion of urinary albumin and urinary protein in chronic kidney disease (CKD) patients using insulin detemir or insulin glargine. Thus, the aim of the current study was to compare the effects of insulin detemir and insulin glargine on sodium, albumin, and protein excretion in patients with various stages of CKD and concomitant type 2 diabetes. Demographic, clinical, and laboratory data were evaluated for all patients. Hypoglycemic attacks, appetite score, 24-h urinary sodium, albumin, and protein excretion were also measured. A total of 47 patients (23 taking insulin detemir, 24 taking insulin glargine) were included in the study. There were no differences with respect to 24-h sodium (p = 0.694), albumin (p = 0.297), or protein excretion (p = 0.202) between patient groups. Appetite and hypoglycemic attacks also did not differ between groups. Use of insulin detemir or insulin glargine was not related to sodium, albumin, and protein excretion in stepwise regression analysis. There was no difference between insulin detemir and insulin glargine with respect to sodium, albumin, and protein excretion in type 2 diabetic CKD patients. Studies are needed both in CKD patients and those with normal renal function to highlight mechanisms regarding the weight loss effect unique to insulin detemir.

Effect on blood pressure of combined inhibition of endothelin-converting enzyme and neutral endopeptidase with daglutril in patients with type 2 diabetes who have albuminuria: a randomised, crossover, double-blind, placebo-controlled trial

Effective reduction of albuminuria and blood pressure in patients with type 2 diabetes who have nephropathy is seldom achieved with available treatments. We tested the effects of treatment of such patients with daglutril, a combined endothelin-converting enzyme and neutral endopeptidase inhibitor. We did this randomised, crossover trial in two hospitals in Italy. Eligibility criteria were: age 18 years or older, urinary albumin excretion 20-999 μg/min, systolic blood pressure (BP) less than 140 mm Hg, and diastolic BP less than 90 mm Hg. Patients were randomly assigned (1:1) with a computer-generated randomised sequence to receive either daglutril (300 mg/day) then placebo for 8 weeks each or vice versa, with a 4-week washout period. Patients also took losartan throughout. Participants and investigators were masked to treatment allocation. The primary endpoint was 24-h urinary albumin excretion in the intention-to-treat population. Secondary endpoints were median office and ambulatory (24 h, daytime, and night-time) BP, renal haemodynamics and sieving function, and metabolic and laboratory test results. This study is registered with ClinicalTrials.gov, number NCT00160225. We screened 58 patients, of whom 45 were enrolled (22 assigned to daglutril then placebo, 23 to placebo then daglutril; enrolment from May, 2005, to December, 2006) and 42 (20 vs 22) were included in the primary analysis. Daglutril did not significantly affect 24-h urinary albumin excretion compared with placebo (difference in change -7·6 μg/min, IQR -78·7 to 19·0; p=0·559). 34 patients had complete 24-h BP readings; compared with placebo, daglutril significantly reduced 24-h systolic (difference -5·2 mm Hg, SD 9·4; p=0·0013), diastolic (-2·5, 6·2; p=0·015), pulse (-3·0, 6·3; p=0·019), and mean (-3·1, 6·2; p=0·003) BP, as well as all night-time BP readings and daytime systolic, pulse, and mean BP, but not diastolic BP. Compared with placebo, daglutril also significantly reduced office systolic BP (-5·4, 15·4; p=0·028), but not diastolic (-1·8, 9·9; p=0·245), pulse (-3·1, 10·6; p=0·210), or mean (-2·1, 10·4; p=0·205) BP, and increased big endothelin serum concentration. Other secondary outcomes did not differ significantly between treatment periods. Three patients taking placebo and six patients taking daglutril had mild treatment-related adverse events--the most common was facial or peripheral oedema (in four patients taking daglutril). Daglutril improved control of BP in hypertensive patients with type 2 diabetes and nephropathy and had an acceptable safety profile. Combined endothelin-converting enzyme and neutral endopeptidase inhibition could provide a new approach to hypertension in this high-risk population. Solvay Pharmaceuticals.

Urinary albumin, protein excretion and circadian blood pressure in patients with fibromyalgia

Recent evidence suggests that patients with fibromyalgia (FM) have increased oxidative stress, inflammation, endothelial dysfunction and autonomic dysfunction. These factors are also shown to be responsible for increased urinary albumin and protein excretion and deranged circadian blood pressure (BP). However, no study has examined the 24-h urinary albumin excretion (UAE), 24-h urinary protein excretion (UPE) and 24-h ambulatory BP measurements in FM patients. The sociodemographic, laboratory parameters, depressive symptoms, sleep problems and 24-h ambulatory BPs were measured for all patients. Diagnosis of FM was based on the criteria for the classification of FM by the American College of Rheumatology. After diagnosis of FM, these patients underwent to complete the Fibromyalgia Impact Questionnaire (FIQ). In total, 30 patients with FM and 61 patients without FM were included. Among FM patients, the average number of tender points was 13.1 ± 1.57 and the mean FIQ score was 57.9 ± 8.86. The number of tender points did not show any correlation with office and ambulatory BPs. There were also no correlations between the number of tender points, UPE and UAE. The stepwise linear regression did not show any relation between UPE and FM. However, 24-h UAE was independently correlated with office systolic BP (P 0.008) and the presence of FM (P 0.045). The logistic regression analysis revealed no association between FM and non-dipping status. We suggest that circadian blood pressure and UPE are not independently associated with FM. However, UAE was related with the presence of FM. Studies are needed to confirm our findings and to highlight pathophysiologic mechanisms.

The relationship between self-reported nocturnal sleep duration, daytime sleepiness and 24-h urinary albumin and protein excretion in patients with newly diagnosed type 2 diabetes

AimIn the current study the relationship between self-reported nocturnal sleep duration (NSD) and daytime sleepiness with 24-h urinary protein excretion (UPE) and 24-h urinary albumin excretion (UAE) were investigated in patients with newly diagnosed type 2 diabetes mellitus. MethodsAll patients underwent history taking, physical examination, blood pressure (BP) measurement, 12 lead electrocardiographic evaluation, routine urine analysis, biochemical analysis, 24-h urine collection to measure UAE, UPE and creatinine clearance. Self reported NSD and daytime sleepiness (using Epworth Sleepiness Scale (ESS)) were recorded for all patients. ResultsIn total 110 patients (56 male and 54 female) were included. Self reported NSD was 7.17±1.07h. Mean ESS score was 5.59±2.48. Stepwise linear regression of independent factors revealed that logarithmically converted 24-h UAE (as a dependent parameter) was related with clinical systolic BP (b: 0.01, p: 0.003), HbA1c (b: 0.082, p: 0.033), self reported NSD (b: −0.152, p: 0.004) and ESS score (b: 0.044, p: 0.043). Additionally, on the other hand, 24-h UPE was related with clinical systolic BP (b: 0.011, p: 0.001) and self reported NSD (b: −0.179, p<0.0001) in regression analysis. ConclusionIn conclusion, 24-h UAE were independently related with self reported NSD and daytime sleepiness where as 24-h UPE was related with only NSD in patients with newly diagnosed type 2 diabetic patients.

Treatment of Lipoxin A4 and its analogue on low-dose endotoxin induced preeclampsia in rat and possible mechanisms

Preeclampsia (PE) is known to represent an exaggerated maternal inflammatory response to pregnancy. Lipoxin A4 (LXA4), considered as an endogenous stop signal in inflammation, has been extensively studied pre clinically for its inflammatory pro-resolving effects. Thus, in the current study, we tested the effect of BML-111 (synthetic analogue of LXA4) on experimental PE rats induced by low-dose endotoxin (LPS) and of LXA4 on human extravillous trophoblast cell line (TEV-1). In vivo experiment results showed that systolic blood pressure, 24h-urinary albumin excretion, serum TNF-α and IL-8 levels and morphologic damage of placenta and kidney caused by LPS were all effectively alleviated by BML-111. LXA4 also inhibited LPS-triggered apoptosis, activation of NF-κB, TNF-α and IL-8 mRNA and protein expression in TEV-1 cells. At the same time, BML-111 protected the cells from LPS-reduced proliferation. The current study demonstrated for the first time that LXA4 could alleviate the symptoms of PE in endotoxin exposed rats.

Replacing 24-h Albumin Excretion with a Shorter Collection Period in Preeclampsia.

To evaluate whether the gold standard of 24-h urinary albumin excretion in preeclamptic women could be substituted by a shorter collection period. From each woman, three spot, two 12-h, and one 24-h urine samples were collected. For each sample, urine albumin concentrations in milligram per liter were analyzed by the immunoturbidimetric method. The albumin concentrations in the spot and 12-h collections (day and night) were compared with the 24-h urine collection. Albumin concentrations in both 12-h collections were fitted closely with the concentrations of the 24-h collection. The median difference between the 24-h collection and the day collection was 43mg/L and the correlation coefficient was 0.96 (p<0.0001). The median difference between the night collection and the 24-h collection was -31mg/L and the correlation coefficient was 0.98 (p<0.0001). The gold standard of 24-h urinary albumin concentrations in preeclamptic women can be substituted with a 12-h collection. Spot samples were weaker as compared to the 12-h collection.

Comparison of renal resistive index among patients with Type 2 diabetes with different levels of creatinine clearance and urinary albumin excretion

To evaluate the prevalence of increased renal resistive index and related factors among patients with Type 2 diabetes with different levels of creatinine clearance and urinary albumin excretion. Laboratory analyses, including calculation of 24-h urinary albumin excretion and 24-h creatinine clearance, and renal doppler ultrasonography to measure renal resistive index, were carried out for patients newly diagnosed with Type 2 diabetes mellitus. Participants were classified into four groups according to 24-h creatinine clearance and 24-h urinary albumin excretion levels. Group 1 was composed of 73 patients (54.1%) with normal 24-h creatinine clearance and 24-h urinary albumin excretion. Group 2 was composed of 34 (25.2%) patients with normal 24-h creatinine clearance and increased 24-h urinary albumin excretion. Group 3 was composed of 14 (10.4%) patients with decreased 24-h creatinine clearance and normal 24-h urinary albumin excretion. Group 4 was composed of 14 (10.4%) patients with both decreased 24-h creatinine clearance and increased 24-h urinary albumin excretion . In total, 41 patients (30.4%) had increased renal resistive index levels. Comparison of the four groups with respect to increased renal resistive index revealed: among group 1 patients, 10 (13.7%) had increased renal resistive index levels; among group 2 patients, 14 (41.2%) had increased renal resistive index levels; among group 3 patients, eight (57.1%) had increased renal resistive index levels; among group 4 patients, nine (64.3%) had increased renal resistive index levels (P<0.0001 for trend). In multivariate regression, 24-h creatinine clearance (P<0.0001), but not 24-h urinary albumin excretion, was related to increased renal resistive index levels. Renal resistive index levels were highest in patients with Type 2 diabetes with both decreased 24-h creatinine clearance and increased 24-h urinary albumin excretion, whereas they were lowest in patients with normal creatinine clearance and normal urinary albumin excretion.

Grape seed proanthocyanidin extract ameliorates diabetic nephropathy in rats

This study examined the effects of grape seed proanthocyanidin extract (GSPE) on kidney of diabetic nephropathy rats. Male Sprague-Dawley rats were divided into three Groups: control, diabetic nephropathy, diabetic nephropathy and received GSPE 500 mg/kg for 6 weeks. At first, 24-h urinary albumin excretion (UAE) was studied two weeks after induction of diabetes then each week until the end of the experimental period in all of groups. At the end, the experimental animals were sacrificed and the right kidneys were collected and were prepared for light microscopy and electron microscopy evaluation. The results showed that the UAE and kidney weight in diabetic nephropathy rats were significantly higher than in control. Also an increase of the mesangial matrix, apoptotic cells, Bax expression, glomerular basement membrane thickness and broadening of foot process in diabetic nephropathy group rats were observed when compared to control group. These features were found to be reversed when the GSPE was administered to the experimental animals. Our results suggest that GSPE can prevent the progression of nephropathy in diabetic rats. Key words: Apoptosis, diabetic nephropathy, Bax protein, glomerular basement membrane, grape seed proanthocyanidin extract (GSPE).

Prediction of cardiovascular events, diabetic nephropathy, and mortality by albumin concentration in a spot urine sample in patients with type 2 diabetes

AimsTo analyze in a random urine spot the predictive value of urinary albumin concentration (UAC) for cardiovascular events, diabetic nephropathy (DN), and death in patients with type 2 diabetes. MethodsIn this cohort, urinary albumin (immunoturbidimetry) was measured as 24-h urinary albumin excretion (UAE) and, in a random spot urine, as UAC and albumin:creatinine ratio (ACR). Primary outcomes were: 1) cardiovascular events, 2) DN defined as a composite outcome [macroalbuminuria and/or decreased glomerular filtration rate (GFR) <60ml/min/1.73m2], and 3) death. ResultsA total of 199 type 2 diabetic patients, aged 59.9±9.9years, were followed for 6.1±2.7years. UAC ≥14.4mg/l, as determined by ROC curve, predicted DN and prediction for this and other outcomes were compared with traditional microalbuminuria cutoffs for ACR and UAE. The outcomes frequency was: cardiovascular events=26.4%, DN=31.7% (23.5% decreased GFR; 13.6% macroalbuminuria) and death=8.50%. In Cox analyses, UAC ≥14mg/l increased the risk (hazard ratio, HR) for cardiovascular events 3.25 times (95% CI 1.43–7.38; P=0.005), 4.30 for DN composite outcome (95% CI 2.22–8.32; P<0.001), and 5.51 for death (95% CI 1.16–26.22; P=0.032). Corresponding HRs of ACR ≥30mg/g were: 2.89 (95% CI 1.29–6.45; P=0.009) for cardiovascular events, 4.67 (95% CI 2.34–9.34; P<0.001) for DN composite outcome and 5.07 (95% CI 1.01–24.88; P=0.049) for death. HRs of UAE ≥30mg/24-h were: 2.20 (95% CI 2.08–2.49; P=0.030) for cardiovascular events, 6.76 (95% CI 3.32–13.77; P<0.001) for DN composite outcome, and 2.47 (95% CI 0.72–8.42; P=0.150) for death. ConclusionsIn conclusion, random UAC ≥14mg/l predicted cardiovascular events, diabetic nephropathy, and mortality just as well as ACR. UAC may be used to assess cardiovascular and renal risks in patients with type 2 diabetes.

Prediabetic Nephropathy as an Early Consequence of the High-Calorie/High-Fat Diet: Relation to Oxidative Stress

This study evaluated early renal functional, structural, and biochemical changes in high-calorie/high-fat diet fed mice, a model of prediabetes and alimentary obesity. Male C57BL6/J mice were fed normal (11 kcal% fat) or high-fat (58 kcal% fat) diets for 16 wk. Renal changes were evaluated by histochemistry and immunohistochemistry, Western blot analysis, ELISA, enzymatic assays, and chemiluminometry. High-fat diet consumption led to increased body and kidney weights, impaired glucose tolerance, hyperinsulinemia, polyuria, a 2.7-fold increase in 24-h urinary albumin excretion, 20% increase in renal glomerular volume, 18% increase in renal collagen deposition, and 8% drop of glomerular podocytes. It also resulted in a 5.3-fold increase in urinary 8-isoprostane excretion and a 38% increase in renal cortex 4-hydroxynonenal adduct accumulation. 4-hydroxynonenal adduct level and immunoreactivity or Sirtuin 1 expression in renal medulla were not affected. Studies of potential mechanisms of the high-fat diet induced renal cortex oxidative injury revealed that whereas nicotinamide adenine dinucleotide phosphate reduced form oxidase activity only tended to increase, 12/15-lipoxygenase was significantly up-regulated, with approximately 12% increase in the enzyme protein expression and approximately 2-fold accumulation of 12(S)-hydroxyeicosatetraenoic acid, a marker of 12/15-lipoxygenase activity. Accumulation of periodic acid-Schiff -positive material, concentrations of TGF-β, sorbitol pathway intermediates, and expression of nephrin, CAAT/enhancer-binding protein homologous protein, phosphoeukaryotic initiation factor-α, and total eukaryotic initiation factor-α in the renal cortex were indistinguishable between experimental groups. Vascular endothelial growth factor concentrations were reduced in high-fat diet fed mice. In conclusion, systemic and renal cortex oxidative stress associated with 12/15-lipoxygenase overexpression and activation is an early phenomenon caused by high-calorie/high-fat diet consumption and a likely contributor to kidney disease associated with prediabetes and alimentary obesity.

Total Glucosides of Paeony Regulates JAK2/STAT3 Activation and Macrophage Proliferation in Diabetic Rat Kidneys

Total glucosides of paeony (TGP) is the major active constituent of Paeonia lactiflora Pall., which has shown renoprotection in experimental diabetic nephropathy. Activation of Janus kinase/signal transducers and activators of transcription (JAK/STAT) is an important mechanism by which hyperglycemia contributes to renal damage. Macrophages also play an essential role in the pathogenesis of diabetic nephropathy. Herein, we investigated the ability of TGP to modulate JAK2/STAT3 activation and macrophage proliferation in rats with streptozotocin (STZ)-induced diabetes. TGP (50, 100, and 200 mg/kg) was administered orally once a day for eight weeks. Levels of p-JAK2 and p-STAT3 were determined by Western blot analysis. Immunohistochemistry and double immunohistochemistry were used to identify p-STAT3, ED-1, PCNA/ED-1, and p-STAT3/ED-1-positive (+) cells. The elevated 24-h urinary albumin excretion rate was markedly attenuated by treatment with 50, 100, and 200 mg/kg TGP. Western blot analysis showed that the significantly increased levels of p-JAK2, p-STAT3 proteins in the kidneys of diabetic rats were significantly inhibited by 50, 100, and 200 mg/kg TGP treatment. The marked accumulation and proliferation of macrophages in diabetic kidneys were significantly inhibited by TGP treatment. ED-1+/p-STAT3+ cells were significantly increased in the kidneys from the model group but were significantly inhibited by TGP treatment. These results show that TGP significantly inhibited diabetic nephropathy progression and suggest that these protective effects are associated with the ability of TGP to inhibit the JAK2/STAT3 pathway and macrophage proliferation and action.

Netrin-1 Attenuates the Progression of Renal Dysfunction by Inhibiting Peritubular Capillary Loss and Hypoxia in 5/6 Nephrectomized Rats

Background/Aims: The aim of this study was to investigate the effect of netrin-1 on peritubular capillary (PTC) loss and hypoxia in 5/6 nephrectomized (Nx) rats. Methods: Male Sprague-Dawley rats were divided into three groups (n = 10 rats/group): sham-operated rats treated with control adenovirus; 5/6 Nx rats treated with control adenovirus; and 5/6 Nx rats treated with recombinant adenovirus mediated netrin-1 gene (Ad-netrin-1) therapy. Rats were killed 12 weeks after surgery. Blood urea nitrogen (BUN), serum creatinine (Scr) and 24-h urinary albumin excretion rates were measured. Pathological changes in renal tissues were analyzed histologically. The concentration of netrin-1, CD34, and hypoxia-inducible factor-1α (HIF-1α) were analyzed by immunohistochemistry, Western blotting and real-time PCR. Results: Renal function and histopathological damage were significantly improved in Adnetrin-1 treated 5/6 Nx rats, compared with rats treated with the control adenovirus in the 5/6 Nx group. Furthermore, Ad-netrin-1 treatment induced a significant increase in renal PTC density, accompanied by a significant decrease in HIF-1α expression. Conclusion: Adenovirus mediated netrin-1 treatment attenuates PTC damage, relieves tissues hypoxia and improves renal function, thus alleviating renal pathological changes and interstitial fibrosis in 5/6 Nx rats.

Clinical significance of plasma CD146 and P-selectin in patients with type 2 diabetic nephropathy

ObjectiveTo investigate the levels of plasma CD146 and P-selectin in patients with type 2 diabetic nephropathy at different stages. MethodsA total of 80 patients with type 2 diabetes mellitus were enrolled in the present study. According to 24h urinary albumin excretion ratio and renal function, they were further divided into group of diabetes without microalbuminuria (DN0, n=20), microalbuminuria group (DN1, n=20), macroalbuminuria group (DN2, n=20) and renal insufficiency group (DN3, n=20). Another 20 healthy subjects were enrolled as control group (non-DM). Plasma CD146 and P-selectin were measured by ELISA. ResultsPlasma CD146 and P-selectin were significantly increased in patients with type 2 diabetes with microalbuminuria (DN1) compared with health control (CD146: 415.3±29.0 vs. 243.5±14.7ng/ml, P<0.05; P-selectin: 66.8±3.4 vs. 45.3±2.7ng/ml, P<0.001). With the development of diabetic nephropathy, both plasma CD146 and P-selectin level progressively rise, with the highest levels in patients with significant renal insufficiency (DN3: 515.9±36.9 and 81.5±5.1ng/ml respectively, P<0.001). Moreover, the increase in CD146 is positively co-related to the rise of P-selectin in patients with type 2 diabetes. ConclusionExpression of CD146 and P-selectin in patients with type 2 diabetes is elevated, and they are positively correlated with severity of diabetic nephropathy.

Angelica Acutiloba Root Alleviates Advanced Glycation End‐Product‐Mediated Renal Injury in Streptozotocin‐Diabetic Rats

Angelica acutiloba root, a Japanese species of Dong quai being cultivated in Hualien County in eastern Taiwan, is used primarily for gynecological disorders in women. Increasing evidence indicates that advanced glycation end-products (AGEs) contribute to the pathogenesis of diabetic nephropathy. We investigated whether A. acutiloba root is beneficial in the amelioration of AGE-mediated renal injury in a diabetic rat model. Streptozotocin (STZ)-diabetic rats were treated orally with A. acutiloba root extract (AARE) [50, 100, 200 mg/(kg × day)] for 8 wk. Changes in renal function-related parameters in plasma and urine were analyzed at the end of the study. Kidneys were isolated for enzyme immunoassay, pathology histology, immunohistochemistry, and Western blot analyses. Polyphenolic compounds and flavonoids were abundant in AARE. AARE [200 mg/(kg × day)] partially decreased the high plasma glucose level in diabetic rats. Diabetic-dependent alterations in urinary albumin, 24-h urinary albumin excretion rate, creatinine clearance, and glomerular mesangial matrix expansion were ameliorated by AARE treatment. The increased expression of nuclear factor-κB, transforming growth factor-β(1), and the progressive accumulation of fibronectin in kidney of diabetic rats were attenuated by AARE treatment. AARE treatment ameliorated the elevated levels of advanced glycation end products (AGEs) and mitochondrial thiobarbituric acid-reactive substance, as well as the elevated levels of Nε-(carboxymethyl)lysine and receptors for AGEs in kidneys of diabetic rats. The results show that A. acutiloba root has an anti-diabetic property that involves antihyperglycemia accompanied by amelioration of glycation-mediated renal damage.

A Comparative Study of Clinical Utility of Spot Urine Samples with 24-h Urine Albumin Excretion for Screening of Microalbuminuria in Type 2 Diabetic Patients

Twenty-four hour urinary albumin excretion (UAE) is considered as gold standard method for albuminuria measurement, but collection of 24-h urine is inconvenient. The aim of present study was to evaluate whether albumin: creatinine ratio (ACR) and urinary albumin concentration (UAC) in different spot urine samples correlate or not with 24-h UAE for screening of microalbuminuria in type 2 diabetic patients. We collected first morning void (FMV), random urine sample (RUS) and 24-h urine, separately on consecutive days from 104 type 2 diabetic patients. ACR and UAC in each spot urine sample compared with 24-h UAE with regard to Pearson correlation coefficient. Pearson's correlation of albumin: creatinine ratio (ACR) with 24-h UAE was (r=0.802 and 0.623) in first morning void (FMV) and random urine sample (RUS), respectively. Pearson's correlation coefficient of urinary albumin concentration (UAC) compared with 24-h UAE was (r=0.943 and 0.920), in FMV and RUS, respectively, P<0.01. Results revealed that values in first morning void (FMV) were better correlated with 24-h urinary albumin excretion (UAE), than the values in random urine sample (RUS). We conclude that the first morning void (FMV) may be able to replace 24-h urine collection, preferably urinary albumin concentration (UAC) in the initial screening of microalbuminuria in diabetic patients. The online version of this article (doi:10.1007/s12291-011-0136-0) contains supplementary material, which is available to authorized users.

Fractional excretions of albumin and IgG are the best predictors of progression in primary glomerulonephritis

Proteinuria is the most sensitive predictor of development of progressive renal insufficiency, with increasing focus on the composition of proteinuria, particularly high molecular weight proteins such as immunoglobulin G (IgG) (molecular weight 150 kDa). Differing methods of assessing excretion of proteinuria molecules have limited interpretation of results. We aimed to assess the utility of available indices of IgG, total proteinuria and albumin excretions as predictors of chronic kidney disease (CKD) progression in patients with primary glomerulonephritis. We recruited 97 patients with primary glomerulonephritis and measured 24-h urinary protein excretion, 24-h urinary albumin excretion, selectivity index, albumin:creatinine ratio, urinary IgG:creatinine ratio, fractional excretion of albumin (FE Alb) and fractional excretion of IgG (FE IgG) at baseline. The composite endpoint was developing stage 5 CKD, requiring RRT or death. Receiver operating characteristics curve analysis was used to assess the value of each measure in predicting outcome. From this analysis, high- and low-risk patient groups according to each measure were established. These were then tested using Kaplan-Meier and Cox survival analysis. During a median follow-up of 7.07 years, 23 patients developed the primary endpoint. FE IgG and FE Alb were the most sensitive predictive tests. The hazard ratios (HR) of developing the primary endpoint using FE IgG [HR 37.1 (95% CI 8.6-158.8)] and FE Alb [HR 35.2 (95% CI 8.2-150.8)] cut-offs were double those using the other measures. FE IgG and FE Alb are superior to conventional measures of proteinuria in predicting outcome in patients with primary glomerulonephritis, possibly because they are more accurate indicators of impairment of glomerular permselectivity. FE Alb should be used, in conjunction with other measures of proteinuria, in future studies of prediction of CKD progression.