Excretion Of Retinol-binding Protein Research Articles

Urinary RBP as an Independent Predictor of Renal Outcome in Diabetic Nephropathy.

Background Renal tubular impairment is prevalent in diabetic nephropathy (DN) and the histological severity predicted renal outcome. Biomarkers of tubular injury also increased in the urine of DN patients. The retrospective study aimed to assess the prognostic value of clinically widely applied urinary tubular injury markers, retinol-binding protein (RBP), β2-microglobulin (β2-MG) and N-acetyl-β-D-glucosaminidase (NAG) in DN. Method A total of 305 patients with biopsy-proven DN were enrolled. The baseline urine total protein and components including albumin, IgG, RBP, β2-MG and NAG were retrieved from medical records. The primary outcome was end stage renal disease (ESRD). Cox proportional hazard analysis and restricted cubic splines were performed to evaluate the association of parameters with ESRD. Nomograms were constructed and concordance index (C-index) was used to measure the prediction ability. Result The levels of urinary RBP, β2-MG and NAG were positively correlated with the severity of interstitial fibrosis and tubular atrophy (IFTA). Positive correlations were also observed among β2-MG, NAG and mesangial expansion. Urinary RBP was not correlated with any glomerular lesions. Urinary RBP, β2-MG and NAG were risk factors for ESRD in hazard analysis with adjustment for age, gender and body mass index (BMI). The hazard ratios increased with the increment of baseline levels. In the multivariate Cox model including serum creatinine (SCr), total urinary protein, urinary albumin, urinary IgG and the tubular injury biomarkers, urinary RBP (with every g/mol.Cr increase: HR 1.06, 95% CI 1.03-1.10, p =0.001) remained as an independent risk factor for ESRD in DN patients. Patients were divided by the medium value of urinary RBP into the low RBP and high RBP groups. Survival analysis showed that significantly more patients in the high RBP progressed to ESRD compared to those in the low RBP group (p =0.02) when urinary total protein was less than 3.5 g/g. The C-index of the nomogram incorporating age, gender, BMI, SCr and total urine protein was 0.757. The value increased to 0.777 after adding urinary RBP to the model. Conclusions Urinary RBP excretion was only correlated with the severity of IFTA and independently predicted ESRD in DN patients.

Urinary DPP4 correlates with renal dysfunction, and DPP4 inhibition protects against the reduction in megalin and podocin expression in experimental CKD.

This study investigated the molecular mechanisms underlying the antiproteinuric effect of DPP4 inhibition in 5/6 renal ablation rats and tested the hypothesis that the urinary activity of DPP4 correlates with chronic kidney disease (CKD) progression. Experiments were conducted in male Wistar rats who underwent 5/6 nephrectomy (Nx) or sham operation followed by 8 wk of treatment with the DPP4 inhibitor (DPP4i) sitagliptin or vehicle. Proteinuria increased progressively in Nx rats throughout the observation period. This increase was remarkably mitigated by sitagliptin. Higher levels of proteinuria in Nx rats compared to control rats were accompanied by higher urinary excretion of retinol-binding protein 4, a marker of tubular proteinuria, as well as higher urinary levels of podocin, a marker of glomerular proteinuria. Retinol-binding protein 4 and podocin were not detected in the urine of Nx + DPP4i rats. Tubular and glomerular proteinuria was associated with the reduced expression of megalin and podocin in the renal cortex of Nx rats. Sitagliptin treatment partially prevented this decrease. Besides, the angiotensin II renal content was significantly reduced in the Nx rats that received sitagliptin compared to vehicle-treated Nx rats. Interestingly, both urinary DPP4 activity and abundance increased progressively in Nx rats. Additionally, urinary DPP4 activity correlated positively with serum creatinine levels, proteinuria, and blood pressure. Collectively, these results suggest that DPP4 inhibition ameliorated both tubular and glomerular proteinuria and prevented the reduction of megalin and podocin expression in CKD rats. Furthermore, these findings suggest that urinary DPP4 activity may serve as a biomarker of renal disease and progression.

Altered Underlying Renal Tubular Function in Patients With Chronic Hepatitis B Receiving Nucleos(t)ide Analogs in a Real-World Setting: The MENTE Study.

Cases of renal tubular dysfunction have been reported in patients with hepatitis B and in patients with human immunodeficiency virus who are undergoing tenofovir treatment. However, little is known about the impact on tubular function in patients with chronic hepatitis B (CHB) under long-term use of entecavir (ETV) and tenofovir disoproxil fumarate (TDF). We evaluated markers of renal tubular function and bone turnover in patients with CHB treated with ETV or TDF. A multicenter, cross-sectional study was performed on markers of renal tubular function and bone turnover in hepatitis B virus-monoinfected patients on long-term treatment with Entecavir or Tenofovir (the MENTE study). The analyzed parameters were: retinol-binding protein/creatinine, neutrophil gelatinase-associated lipocalin/creatinine, excretion of phosphates, uric acid excretion, glomerular filtrate, protein/creatinine, albumin/creatinine, serum creatinine, phosphate, CTX, P1NP, vitamin D, and parathormone. A total of 280 patients (ETV: 89, TDF: 69, control: 122) were included in this study. The TDF group was associated with altered levels of retinol-binding protein (RBP)/creatinine (TDF 25% vs. 7% ETV and control; P<0.001). Protein/creatinine, uric acid excretion, P1NP1, and parathormone were higher in the TDF group. The proportion of patients with serum phosphate <2.5 mg/dL was higher in both the ETV and the TDF groups compared with the control. The multivariate analysis showed that the use of TDF was independently associated with a higher risk of altered excretion of RBP/creatinine (4.4; interquartile range: 1.4 to 14; P=0.013). We found an independent association between TDF use and altered RBP excretion. This finding indicates subclinical tubular damage. Because tubular dysfunction can precede the decline of renal function, close monitoring of RBP levels in patients with CHB on nucleos(t)ide analog treatment must be performed for early detection of TDF-related renal toxicity. In this study, these differences in tubular function were not associated with concomitant changes in markers of bone turnover.

66 Renal long-term follow up after pregnancy and risk of chronic kidney disease

Introduction Glomerular filtration rate (GFR) increases during pregnancy and some incipient nephropathies may appear after this period, especially when gestational hypertension (GH) is present. Objectives Renal evaluation in women over 10 years after pregnancy. Methods Total of 30 volunteer patients whose last childbirth was 10–20years ago. Renal parameters assessed were: urinary excretion of retinol-binding protein (RBP), urine protein/creatinine ratio (PCR), Urine albumin/creatinine ratio (ACR), serum creatinine, serum C cystatin, vitamin D (25OHD), serum uric acid, vascular endothelial growth factor (VEGF), estimated GFR (eGFR) based on Modification of Diet in Renal Disease (MDRD) Study and the Chronic Kidney Disease Epidemiology Collaboration equation – CKD-EPI Creatinine, 2009 (CKD-EPI crea), CKD-EPI Cystatin C, 2012 (CKD-EPI cys) and CKD-EPI Creatinine-Cystatin C, 2012 (CKD-EPI crea-cys) equations. Results The average age was 45.5years old, 56.6% were afro descendant, and mean time after last labor was 13.7years. Approximately 6.6% had type 2 diabetes and 30.3% had chronic hypertension (CH) after pregnancy (among them 90% had GH). Mean body mass index (BMI) was 29.1kg/m 2 (overweight), although all patients with CAH were obese. Mean value of cystatin C was 1.45mg/L (elevated in 20%), RBP 0.30mg/L (high level in only one case), PCR 0.02g/g, ACR 6.91mg/g creatinine (high level in only one case), 25OHD 24.34ng/mL (deficiency in 33.3%), serum uric acid 4.50mg/dL (high level in only one case), serum creatinine 0.73mg/dL (normal level in all cases), VEGF 312.04pg/mL (high level in two cases). Mean clearance of creatinine using MDRD was 93.5mL/min/1.73m 2 , CKD-EPI crea 101.7mL/min/1.73m 2 , CKD-EPI cys 49.0mL/min/1.73m 2 and CKD-EPI crea-cys 68.3mL/min/1.73m 2 (about 30% less when compared with the equations without cystatin C, then 26.6% had eGFR 2 ). None of the patients had ever been assisted by a nephrologist. Conclusions Obesity, CH, 25OHD deficiency, high levels of serum cystatin C and low eGFR may appear years after pregnancy, especially if GH was present. Women who had GH should have long-term follow up with nephrologist to have a more complete and regular renal evaluation. The eGFR by combined creatinine-cystatin C equation seems to be better than other formulas and it could be useful to detect early chronic kidney disease. Fapesp n° 2014/00213-7

Renal Tubular Dysfunction in Pediatric Urolithiasis: Proteomic Evidence

To investigate whether inflammation, oxidation, and tubular injury are present in children with stones (RS) compared with healthy controls (HC) by measuring urinary proteins involved in these processes. Quantitative proteomic comparison of pooled urine from RS (N = 30, 24 females, mean age 12.95 ± 4.03 years) versus age- and gender-matched HC (N = 30), using liquid chromatography-mass spectrometry. Relative protein abundance was estimated using spectral counting. Proteins of interest were selected using the following criteria: (1) ≥5 spectral counts; (2) ≥2-fold difference in spectral counts; and (3) P-value ≤.05 for Fisher's exact test. Of the 1813 proteins identified, 230 met the above criteria, with 163 proteins upregulated in the RS group and 67 upregulated in HC. Functional analysis revealed 19 inflammatory proteins, 5 proteins involved in oxidative stress, and 5 involved in tubular injury. Of those proteins, NADPH-oxidase, a major source of reactive oxygen species, was only found in the RS group, whereas glutathione S-transferase A2, an important antioxidant enzyme, was more abundant in controls. ELISA analysis confirmed statistically significant differences in the urinary excretion of retinol-binding protein 4, a marker of proximal tubular dysfunction, between stone patients with hypercalciuria and controls. We provide proteomic evidence of oxidative stress, inflammation, and tubular injury in children with renal stones. We speculate that inflammation and changes in the oxidant-antioxidant balance may cause tubular damage in these patients. Targeting these proteins may have therapeutic benefits.

The effects of palladium nanoparticles on the renal function of female Wistar rats

A number of studies have shown that palladium nanoparticles are able to exert some adverse health effects, such as concentration-dependent cytotoxicity, induction of apoptosis and alterations of the release and expression of numerous cytokines. Nevertheless, our current knowledge of the potential toxic effects induced by exposure to these nanoparticles is far from being complete. For this reason, the present study assessed the possible renal toxicity of palladium nanoparticles by investigating urinary excretion of retinol binding protein, β2-microglobulin and albumin in female Wistar rats intravenously exposed to different nanoparticle concentrations (0.012, 0.12, 1.2 and 12 µg/kg) and by carrying out a morphological observation of the kidneys of treated animals. Results showed a significant increase in urinary retinol binding protein and β2-microglobulin levels in rats that were administered 12 µg/kg compared to controls. Moreover, an ultrastructural study of the kidneys revealed significant alterations in the proximal and distal tubular epithelium were observed, with a range of severity, in all experimental conditions. Collectively, our findings suggest that exposure to palladium nanoparticles is able to induce a significant renal tubular dysfunction, whereas it does not seem to affect kidney glomerular filtration. However, further studies are needed to confirm our results, to understand the molecular mechanisms of toxic action and to evaluate the potential adverse effects of these nanoparticles also on the glomerular section of the kidney.

Changes in Kidney Functions during Middle-distance Triathlon in Male Athletes.

Strenuous exercise induces proteinuria which is related to the intensity of exercise. However, renal responses to each type of exercise during a middle-distance triathlon have not been reported. The present study, carried out on 7 healthy athletes, investigated renal function at rest and after each exercise of a half-triathlon race. Blood and urine samples were collected at rest and after each specific event. Protein excretion and renal clearances were determined on each sample. Compared with resting values, albuminuria was increased by a factor of 30 (p<0.05) after swimming but did not differ from the resting value after cycling and running (p>0.05). Rates of β2-microglobulin and retinol-binding protein excretion did not change throughout the triathlon (p>0.05). Glomerular filtration rate (expressed as creatinine clearance) remained stable after each exercise event, whereas tubular reabsorption rate (expressed as urea clearance) was reduced by 50, 40 and 65% after swimming, cycling and running, respectively, compared to pre-exercise values (p<0.05). Glomerular membrane permeability (expressed as albumin clearance) was significantly increased by the swimming event (13 times, p<0.05). These results suggest that middle-distance triathlon has a noticeable impact on the glomerular membrane permeability (albumin clearance) and elimination of protein waste (urea clearance) depending on exercise type.

Scintigraphic assessment of renal function in steel plant workers occupationally exposed to lead.

Occupational exposure to lead may produce kidney damage, but existing data on the dose range associated with nephrotoxicity are inconclusive. We here assessed renal function under conditions of low to moderate lead exposure using renal scintigraphy. Fifty-three male foundrymen (exposed group) and fourty male office workers (control group) from a steel plant were included in the study. Glomerular and tubular renal function were assessed by means of (99m)Tc-DTPA and (99m)Tc-EC clearance, respectively. Urinary markers of glomerular dysfunction (albumin) and tubular damage (α1-microglobulin (α1M), β2-microglobulin (β2M), retinol-binding protein (RBP), N-acetyl-β-glucosaminidase (NAG) activity) were determined using latex beads tests or colorimetry. The lead concentration in blood was measured with atomic absorption spectrometry. The blood lead concentrations were 145.8 (121.3-175.3) and 39.3 (35.1-44.1) µg/l (geometric mean, 95(th) CI, p<0.001) in the exposed and control groups, respectively. Subjects exposed to lead presented with increased (99m)Tc-DTPA clearance (158.3 (148.4-168.8) vs. 135.9 (127.9-144.4) ml/min; p<0.01) and urinary albumin excretion (7.61 (6.28-9.22) vs. 4.78 (4.05-5.65) mg/g creatinine; p<0.001). (99m)Tc-EC clearance and excretion of α1M, β2M, RBP and NAG were not significantly different between the groups. Significant correlations between (99m)Tc-DTPA clearance and blood lead concentrations (r=0.45; p<0.01) and between urinary albumin excretion and blood lead concentrations (r=0.71; p<0.001) were noted. Use of renal scintigraphy in present study revealed measurable alterations of renal function under the conditions of low-level lead exposure and suggest that increased glomerular filtration may be an early indicator of kidney damage in subjects occupationally exposed to lead.

Cadmium, type 2 diabetes, and kidney damage in a cohort of middle-aged women

BackgroundIt has been proposed that diabetic patients are more sensitive to the nephrotoxicity of cadmium (Cd) compared to non-diabetics, but few studies have examined this in humans, and results are inconsistent. AimTo test the hypothesis that women with type 2 diabetes mellitus (DM) or impaired glucose tolerance (IGT) have higher risk of kidney damage from cadmium compared to women with normal glucose tolerance (NGT). MethodsAll 64-year-old women in Gothenburg, Sweden, were invited to a screening examination including repeated oral glucose tolerance tests. Random samples of women with DM, IGT, and NGT were recruited for further clinical examinations. Serum creatinine was measured and used to calculate estimated glomerular filtration rate (eGFR). Albumin (Alb) and retinol-binding protein (RBP) were analyzed in a 12h urine sample. Cadmium in blood (B-Cd) and urine (U-Cd) was determined using inductively coupled plasma mass spectrometry. Associations between markers of kidney function (eGFR, Alb, and RBP) and quartiles of B-Cd and U-Cd were evaluated in models, including also blood pressure and smoking habits. ResultsThe mean B-Cd (n=590) was 0.53µg/L (median 0.34µg/L). In multivariable models, a significant interaction was seen between high B-Cd (upper quartile, >0.56µg/L) and DM (point estimate +0.40mg Alb/12h, P=0.04). In stratified analyzes, the effect of high B-Cd on Alb excretion was significant in women with DM (53% higher Alb/12h, P=0.03), but not in women with IGT or NGT. Models with urinary albumin adjusted for creatinine showed similar results. In women with DM, the multivariable odds ratio (OR) for microalbuminuria (>15mg/12h) was increased in the highest quartile of B-Cd vs. B-Cd quartiles 1–3 in women with DM (OR 4.2, 95% confidence interval 1.1–12). No such effect was found in women with IGT or NGT. There were no associations between B-Cd and eGFR or excretion of RBP, and no differences between women with DM, IGT, or NGT regarding effect of B-Cd on eGFR or RBP. ConclusionThe present study provides support for the hypothesis that women with DM have higher risk of renal glomerular damage from cadmium exposure compared to women without DM.

Renal tubular dysfunction in children with sickle cell haemoglobinopathy

Children with sickle cell disease (SCD) are remarkably more prone than others to renal dysfunction. The kidneys, as one of the systemic long-term hazards in SCD, may be affected by both the haemodynamic changes of chronic anaemia as well as by the consequences of vaso-occlusion. The aim of this study was to evaluate the proximal tubular function in a group of Saudi children with established SCD. This study was conducted in Al-Khafji Joint Operations (KJO) Hospital, in Saudi Arabia during the period from June 2011 to August 2012. Thirty-four children: Group I (18 males and 16 females) with SCD (HBSS) and 27 children: Group II (17 males and 10 females) with sickle cell trait (HBAS) were evaluated for urinary excretion of retinol binding protein (RBP) and - Beta 2 microglobulin (β2 MG). Group I patients showed a significantly impaired urinary concentrating ability compared to that of Group II (417 ± 94 mOsm/kg vs 581 ± 165 mOsm/kg). The urinary excretions of RBP and β2-microglobulin were significantly higher in Group I than in Group II. The values were 762.01 ± 124.20 μg/L and 841.84 ± 389.02 μg/L versus 198.12 ± 42.24 μg/L and 298.3 ± 38.11 μg/L, respectively. Significant proximal tubular dysfunction was a feature in the SCD group, indicated by high urinary RBP and β2-microglobulin excretion. Assessing the urinary excretion of these low molecular weight proteins in children with sickle cell disease at different points of diagnosis may add key clinical information to the follow up of renal tubular function in patients with SCD.

Reply to Dr Gurnaney

In a cross sectional study of 88 pregnant women urinary excretion of albumin, when expressed as a ratio to creatinine concentration, was not significantly different from that in a non-pregnant control group of similar age (p greater than 0.05) and did not change significantly during pregnancy. Only when albumin excretion was expressed as a fractional clearance was the urinary excretion significantly increased in the third trimester compared with the first trimester (p less than 0.05), although it was still not significantly different from that in the non-pregnant control group. Excretion of retinol-binding protein was significantly increased during all three trimesters of pregnancy (p less than 0.01 in each case) and more so in the second and third trimesters than in the first. It is concluded that the increased total protein excretion that has been described during pregnancy is not explained by an increased excretion of albumin which remains essentially normal. In contrast, the tubular absorption of proteins is decreased.

Urinary retinol excretion in children with acute watery diarrhoea.

Children with diarrhoea due to rotavirus infection excrete retinol in urine. This study aimed at demonstrating the extent and mechanism of urinary retinol excretion in children with acute watery diarrhoea caused by pathogens other than rotavirus. Thirty-two children, aged five months to five years, hospitalized with watery diarrhoea predominantly due to enterotoxigenic Escherichia coli in Bangladesh, were studied. Their serum retinol and retinol-binding protein (RBP) were low at admission and increased significantly after recovery from illness. The mean hospital stay of these patients was four days. Forty-seven percent of the children excreted retinol in urine on day 1, and about 38% continued excreting retinol on day 3. The estimated urinary retinol loss of 3.44 micromol for the illness episode represented more than 40% of liver retinol reserve (8.25 micromol) in malnourished children. A conservative estimate of the loss would represent at least 20% of the liver reserve in relatively better-nourished children. Kidney tubular dysfunctions of increased RBP excretion significantly predicted urinary retinol excretion in children with watery diarrhoea.

Low- and high-molecular-weight urinary proteins as predictors of response to rituximab in patients with membranous nephropathy: a prospective study

Selective urinary biomarkers have been considered superior to total proteinuria in predicting response to treatment and outcome in patients with membranous nephropathy (MN). We prospectively tested whether urinary (U) excretion of retinol-binding protein (RBP), α1-microglobulin (α1M), albumin, immunoglobulin IgG and IgM and/or anti-phospholipase 2 receptor (PLA(2)R) levels could predict response to rituximab (RTX) therapy better than standard measures in MN. We also correlated changes in antibodies to PLA(2)R with these urinary biomarkers. Twenty patients with MN and proteinuria (P) >5 g/24 h received RTX (375 mg/m(2) × 4) and at 12 months, 1 patient was in complete remission (CR), 9 were in partial remission (PR), 5 had a limited response (LR) and 4 were non-responders (NR). At 24 months, CR occurred in 4, PR in 12, LR in 1, NR in 2 and 1 patient relapsed. By simple linear regression analysis, UIgG at baseline (mg/24 h) was a significant predictor of change in proteinuria at 12 months (Δ urinary protein) (P = 0.04). In addition, fractional excretion (FE) of IgG, urinary alpha 1 microglobulin (Uα1M) (mg/24 h) and URBP (μg/24 h) were also predictors of response (P = 0.05, 0.04, and 0.03, respectively). On the other hand, UIgM, FEIgM, albumin and FE albumin did not predict response (P = 0.10, 0.27, 0.22 and 0.20, respectively). However, when results were analyzed in relation to proteinuria at 24 months, none of the U markers that predicted response at 12 m could predict response at 24 m (P = 0.55, 0.42, 0.29 and 0.20). Decline in anti-PLA(2)R levels was associated with and often preceded urinary biomarker response but positivity at baseline was not a predictor of proteinuria response. The results suggest that in patients with MN, quantification of low-, medium- and high-molecular-weight urinary proteins may be associated with rate of response to RTX, but do not correlate with longer term outcomes.

The threshold level of urinary cadmium associated with increased urinary excretion of retinol-binding protein and β2-microglobulin: a re-assessment in a large cohort of nickel-cadmium battery workers

ObjectiveTo evaluate the threshold value of urinary cadmium (CdU) for renal dysfunction on the basis of relationships unconfounded by protein degradation, diuresis and the renal effects associated with chronic smoking.MethodsWe...

Randomized Comparison of Renal Effects, Efficacy, and Safety With Once-Daily Abacavir/Lamivudine Versus Tenofovir/Emtricitabine, Administered With Efavirenz, in Antiretroviral-Naive, HIV-1–Infected Adults: 48-Week Results From the ASSERT Study

Abacavir/lamivudine and tenofovir/emtricitabine fixed-dose combinations are commonly used first-line antiretroviral therapies, yet few studies have comprehensively compared their safety profiles. Forty-eight-week data are presented from this multicenter, randomized, open-label study comparing the safety profiles of abacavir/lamivudine and tenofovir/emtricitabine, both administered with efavirenz, in HLA-B*5701-negative HIV-1-infected adults. Three hundred eighty-five subjects were enrolled in the study. The overall rate of withdrawal was high (28%). Changes in estimated glomerular filtration rate from baseline were similar between arms [difference 0.953 mL.min.1.73 m (95% confidence interval: -1.445 to 3.351), P = 0.435]. Urinary excretion of retinol-binding protein and beta-2 microglobulin increased significantly more in the tenofovir/emtricitabine arm (+50%; +24%) compared with the abacavir/lamivudine arm (no change; -47%) (P < 0.0001). A lower proportion achieved viral load <50 copies per milliliter in the abacavir/lamivudine arm (114 of 192, 59%) compared with the tenofovir/emtricitabine arm (137 of 193, 71%) [difference 11.6% (95% confidence interval: 2.2 to 21.1)]. The overall virological failure rate was low. The adverse event rate was similar between arms (except drug hypersensitivity, reported more in the abacavir/lamivudine arm). The study showed no difference in estimated glomerular filtration rate between the arms, however, increases in markers of tubular dysfunction were observed in the tenofovir/emtricitabine arm, the long-term consequence of which is unclear. A significant difference in efficacy favoring tenofovir/emtricitabine was observed.

Simvastatin protects diabetic rats against kidney injury through the suppression of renal matrix metalloproteinase-9 expression

To observe the effects of simvastatin on urinary excretion of matrix metalloproteinase-9 (MMP- 9), renal expression of MMP-9, and investigate its possible renoprotective mechanisms in streptozotocin (STZ)-induced diabetic rats. Twenty-four Wistar rats were divided into 3 groups: control healthy rats (group C, no.=8), untreated diabetic rats (group D, no.=8), and diabetic rats treated with simvastatin (20 mg/kg/d) (group S, no.=8). Peripheral blood glucose was tested weekly, glycosylated hemoglobin A1c (HbA1c), total cholesterol (TC), LDL cholesterol (LDL-C) levels, and urinary albumin (ALB) excretion rate as well as the urinary excretion rates of retinol-binding protein (RBP) and MMP-9 were tested at 8th week. The renal tissues of diabetic rats were obtained for evaluating kidney/ body weight ratio, observing renal pathological changes by electron microscope and examining the expression of renal MMP-9 mRNA by RT-PCR. There was no statistical difference on the change of peripheral blood TC and LDL-C between group C and group D. Peripheral blood glucose, HbA1c levels kidney/body weight ratio urinary excretion rates of ALB, RBP, and MMP-9 concurrently with the expression of renal MMP-9 mRNA were significantly higher in groups D and S compared with group C (p<0.01). Treatment with simvastatin significantly lowered peripheral blood TC, LDL-C, kidney/body weight ratio, urinary excretion rates of ALB, RBP, and MMP-9 as well as the expression of renal MMP-9 mRNA (p<0.01); however, there was no evident effect on the change of blood glucose and HbA1c levels between group D and group S. In addition, urinary excretion rate of MMP-9 showed positive correlations with the urinary ALB excretion and urinary RBP excretion. Pathological lesions of the glomeruli and epithelial cells foot processes (FP) was lightened by simvastatin. Simvastatin may has a potential therapeutic target in diabetic nephropathy, which may be partly attributed to down-regulating over-expression of MMP-9 in renal tissue.

The tubulointerstitium in early diabetic nephropathy: Prime target or bystander?

Diabetic nephropathy (DN) is a major microvascular complication of diabetes and a leading cause of end-stage renal disease (ESRD) worldwide. DN is classically understood as a glomerular disease. However, this understanding is currently being contested with recent studies suggesting a pivotal role of the tubulointerstitium in the initiation and progression of DN. We performed a review of the current literature as detailed below. The literature suggests that chronic hyperglycemia may orchestrate several structural and functional abnormalities of the tubulointerstitium before significant glomerular changes. Abnormalities such as increased advanced glycation end products, oxidative stress, cytokine activation, inflammatory markers, and enhanced hypoxic milieu may result in progressive tubulointerstitial damage as reflected by dysfunction of tubular protein receptors such as megalin and loss of charge-dependent tubular protein reabsorption, resulting in higher excretion of tubular injury markers such as N-acetyl-β-glucosaminidase (NAG) and retinol-binding protein (RBP), and overflow microproteinuria in the presence of intact glomerulus and before the onset of microalbuminuria. In addition, people with diabetes may have higher excretion of NAG and RBP and low levels of tubular hormones such as erythropoietin and 1,25-dihydroxyvitamin D, before the onset of microalbuminuria, suggesting that tubulointerstitial changes are present before the onset of microalbuminuria. These abnormalities are highly suggestive of DN being of tubular, rather than glomerular origin.

Urinary proteins in children with urinary tract infection

The aim of this study was to test our hypothesis that the urinary excretion of C-reactive protein (CRP), alpha 1-microglobulin (A1M), retinol-binding protein (RBP) and Clara cell protein (CC16) is increased in children with urinary tract infection (UTI) and relates to renal damage as measured by acute dimercaptosuccinic acid (DMSA) scintigraphy. Fifty-two children <2 years of age with UTI were enrolled in the study, 44 of whom were febrile. The control group consisted of 23 patients with non-UTI infection and elevated serum CRP (s-CRP) levels. Thirty-six patients had abnormal DMSA uptake, classified as mild, moderate or severe damage (DMSA class 1, 2, 3, respectively). There was a significant association between DMSA class and the excretion of urinary RBP (u-RBP) and u-CC16. There was also a significant difference in u-CRP levels between children with UTI and control children with non-UTI infections, although u-CRP excretion was not significantly correlated to DMSA class. In conclusion, the urinary excretion of the low-molecular-weight proteins RBP and CC16 showed a strong association with uptake defects on renal DMSA scans. The urinary level of CRP seems to distinguish between children with UTI and other febrile conditions. A combination of these biomarkers may be useful in the clinical assessment of children with UTI.

Are low erythropoietin and 1,25-dihydroxyvitamin D levels indicative of tubulo-interstitial dysfunction in diabetes without persistent microalbuminuria?

Aims To investigate the relationship between Erythropoietin (EPO) and 1,25-dihydroxyvitamin D levels, and tubular damage in patients with diabetes mellitus (DM) without persistent microalbuminuria. Methods We measured serum EPO and 1,25-dihydroxyvitamin D levels and tubular injury markers such as urinary N-acetyl-β- d-glucosaminidase (NAG) and retinol binding protein (RBP) levels in 41 non-diabetic controls, 40 patients with Type 1 and 40 with Type 2 DM. Results Median serum EPO levels were lower in Type 1 (2.57 mIU/ml: p < 0.001) and Type 2 DM (5.69 mIU/ml: p = 0.044) than in controls (8.76 mIU/ml), though haemoglobin levels did not differ. Median 1,25-dihydroxyvitamin D levels were lower in Type 1 (41.0 pmol/l: p = 0.001) and Type 2 DM (41.8 pmol/l: p = 0.035) than in controls (56.1 pmol/l), though serum creatinine, calcium, phosphate and PTH levels did not differ. Median RBP excretion was higher in Type 2 DM (0.35 mg/l vs. 0.23 mg/l: p = 0.013) than in controls. Median NAG excretion was higher in Type 1 DM (1079 μmol/h vs.1030 μmol/h: p = 0.048) compared to controls. Conclusions Tubulo-interstitial damage with low levels of EPO and 1,25-dihydroxyvitamin D occurs early in Type 1 and Type 2 DM before persistent microalbuminuria.

Effect of nicorandil on proteinuria in well controlled hypertensive patients

Proteinuria is an important risk factor for cardiovascular and renal morbidity and mortality. The effect of nicorandil on proteinuria in hypertensive patients well controlled by antihypertensive agents containing a low dose of valsartan has not been studied. A total of 136 proteinuric (300-3000 mg/day), valsartan-treated hypertensive patients with blood pressure less than 140/90 mmHg were randomized into three groups to receive placebo, isosorbide dinitrate (30 mg/day), or nicorandil (15 mg/day) for 6 months. The average dose of valsartan given to the patients was similar in the three groups. Creatinine clearance remained stable throughout the study in the three groups. Nicorandil, but not isosorbide dinitrate, significantly reduced proteinuria by 44% after 6 months (P < 0.0001). Urinary endothelin-1 levels significantly decreased after administration of nicorandil (P = 0.002), whereas placebo and isosorbide dinitrate had no effect. Urinary excretion of endothelin-1 was significantly correlated with improvement in urinary protein excretion in nicorandil-treated patients (r = 0.69, P < 0.0001). The urinary excretion of retinol-binding protein decreased after nicorandil administration, probably reflecting an improvement in tubular function. In contrast, the urinary excretion of immunoglobulin G did not change significantly throughout the study in the three groups. Multivariate analysis revealed that proteinuria was only significantly correlated with the use of nicorandil (model adjusted r = 0.35, P < 0.0001). The addition of nicorandil to treatment for patients with well controlled hypertension may have an additive effect on reducing proteinuria independent of hemodynamics and nitric oxide effects, possibly through inhibiting renal endothelin-1 synthesis and improving tubular function.