Early Nephropathy In Type Research Articles

Clinical Utility of Urinary β2 Microglobulin in Detection of Early Nephropathy in type 2 Diabetes Mellitus Patients

Background: Diabetic nephropathy is a kidney disease associated with long-standing hyperglycemia. The main features of diabetic nephropathy include nephrotic syndrome with excessive filtration of protein into the urine (proteinuria), high blood pressure (hypertension), and progressive impairment of kidney function. Objective: To find out the clinical utility of urinary β2 microglobulin in the detection of early nephropathy in type 2 diabetes mellitus patients. Methods: This cross-sectional study was conducted in the Department of Nephrology, Dhaka Medical College Hospital, over a period of one year from January 2017 to December 2017. 50 type 2 diabetes mellitus patients as the case group and age sex-matched 50 healthy participants as the control group was included in this study as the study population. Socio-demographic, family history, history of patients, and epidemiological data were recorded. A clinical examination investigation was done for all the study population. The urinary β2 microglobulin (β2m) level was assayed using the beta- 2- macroglobulin ELISA kit, EIA 3609. Statistical analysis was done by the Statistical Package for Social Science (SPSS-22). The confidence interval was considered at the 95% level. The sensitivity and specificity of urinary β2m were calculated in detecting early DN. P-value <0.05 was considered statistically significant. Result: Mean age of the case group was 50.08±12.06 years and the control group was 46.54±9.89 years. Female was predominant in both case and control group. Hypertension, anemia, diabetic nephropathy, and diabetic peripheral neuropathy were found in 24(48%), 17(34%0, 14(28%), and 11(22%) cases. Urinary ACR was found significantly higher in the case group than that of the control group (183.32±164.11 mg/gm vs 13.60±4.40 mg/gm). Similarly, urinary β2 microglobulin was found significantly higher in the case group than in the control group (0.50±0.22 µgm/ml vs 0.14±0.05 µgm/ml). Among early nephropathy patients .....

2151-PUB: Association of Homocysteine with Early Nephropathy in Patients with Type 2 Diabetes

Early predication and intervention of diabetic nephropathy is increasingly imperative. Hyperhomocysteinemia is common and chronically induces arteriolar thickening, and tubulointerstitial and podocyte injury, therefore, could play a causative role in early renal injury in the kidney in type 2 diabetes. In this study, we for the first time investigated the relation of plasma total homocysteine concentration to early nephropathy in type 2 diabetes. We enrolled 183 type 2 diabetic patients in a cross-sectional study. Early diabetic nephropathy status was diagnosed by presence of microalbuminuria. Plasma total homocysteine levels were measured using fluorescence polarization immunoassay. Variables for diabetic nephropathy were obtained from fasting blood samples and interviewer- questionnaire. We found that plasma total homocysteine concentrations were elevated in subjects with early diabetic nephropathy than without (13.3±2.9)µmol/l vs. (8.5 ± 1.4)μmol/l, p < 0.01). The association of homocysteine with the diabetic nephropathy was independent of major traditional risk factors for diabetic nephropathy (duration of diabetes, HbA1c, and blood pressure) and determinants of higher homocysteine concentration (age, sex, serum folate and vitamin B12, Biguanide use, and serum cystatin or creatinine levels,) (OR: 1.36 (1.08-1.74), p < 0.05). Furthermore, per increase of 5.0 μmol/l plasma homocysteine was related to early nephropathy (OR: 1.15 (1.04-1.29), p < 0.05), after controlling for per unit increase of other factors: per 5 year increase of duration of diabetes, per 1% increase of HbA1c, per 10 nmol/l increase of serum folate, per 100 pmol/l increase of serum B12, per 0.1 mg/L increase of serum cystatin or per 10 μmol/l increase of creatinine, and per 10 or 5 mmHg increase of systolic or diastolic blood pressure. We concluded that plasma total homocysteine concentration was independently associated with occurrence of early diabetic nephropathy. Future prospective studies are warranted. Disclosure J. Li: None. Q. Lv: None. H. Lu: None. H. Zhang: None. J. Zhou: None. Funding National Natural Science Foundation of China (81070655); Jiangsu Provincial Natural Science Foundation of China (BK2009441)

MicroRNA-21 as an Early Marker of Nephropathy in Patients with Type 1 Diabetes.

Introduction:Diabetic nephropathy (DN) is the most common cause of chronic kidney disease worldwide. A major challenge is to identify early diabetic nephropathy. microRNAs (miRNAs) are short noncoding RNA sequences and regulate a wide range of biological processes as cell differentiation, proliferation, cell metabolism and apoptosis. miRNAs may have a role in molecular mechanisms linked to cellular pathways of DN. The aim of this study was to investigate the level of microRNA-21 as a potential marker of early nephropathy in type 1 diabetes mellitus (T1DM).Methods:A total number of 340 participants were included and classified into 3 groups; Group I included 100 healthy participants, Group II included 120 patients with T1DM with <5 years duration, and Group III included 120 patients with T1DM with >5 years duration. All participants were submitted to detail clinical examination, laboratory investigations, urinary albumin/creatinine ratio (ACR), estimated glomerular filtration rate (eGFR) as well as plasma microRNA-21 assays.Results:Blood pressure and ACR were significantly higher in group III than groups I and II. Further, microRNA-21 was significantly higher in group III than groups I and II, and more in group II than group I. microRNA-21 starts to rise in group II before microalbuminuria. miRNA-21 at a level of 0.01 had a greater sensitivity 94.1% and specificity 100% for identifying DN than ACR at level 45 mg/gm with sensitivity 88.2% and specificity 89%.Conclusion:Plasma microRNA-21 can serve as an early marker for diagnosis and identifying diabetic nephropathy in T1DM.

YKL-40: A biomarker for early nephropathy in type 2 diabetic patients and its association with inflammatory cytokines

Diabetic Nephropathy (DN) is an important cause of morbidity and death amongst diabetes. Persistent micro and macroalbuminuria are well known predictors of DN leading to progressive end-stage renal disease. However, albuminuria has several limitations. Increasing evidences show that YKL-40 is highly expressed in variety of inflammatory diseases and also recognized as a non-invasive prognostic biomarker for inflammation. In the present study, we measured plasma YKL-40 levels in different stages of albuminuria and assessed its diagnostic accuracy as a biomarker for DN and correlated with different families of circulatory cytokines. A total of 306 subjects were recruited and divided into three groups [Group-I, control (n = 83), Group-II, Normoalbuminuria (n = 81), Group-III, DN (n = 142)]. Group-III is further subdivided into: Group-IIIa, microalbuminuria (n = 73), Group-IIIb, macroalbuminuria (n = 69). The median levels of YKL-40 (p = 0.001) showed a marked stepwise increase from normo to macroalbuminuria and positively correlated with eGFR. The AUCROC for YKL-40 was found to be high [0.95; (95% CI: 0.88–1.0)], when compared to other acute phase markers. Plasma YKL-40 showed a positive correlation with LIGHT/TNFSF14, sIL-6Ra, gp130/sIL-6Rβ, IFN-β, IL-8, TNFSF14, sCD-30 and eGFR meanwhile a negative correlation with TWEAK/TNFSF12, IL-7 like cytokine and IFN-λ2. Plasma YKL-40 could be a potential biomarker for early diagnosis of incipient DN among South Indian population.

Utility of urinary biomarkers as a diagnostic tool for early diabetic nephropathy in patients with type 2 diabetes mellitus

IntroductionRenal tubulo-interstitial damage has an important role in the pathogenesis of early diabetic nephropathy. Urinary biomarkers can help in the detection of early nephropathy in type 2 diabetic patients. The aim of this study was to estimate the levels of urinary neutrophil gelatinase associated lipocalin (NGAL) and cystatin-C in type 2 diabetic patients with early diabetic nephropathy & to compare them with diabetic patients without nephropathy and to correlate urinary NGAL and cystatin-C levels with microalbuminuria in them. Study designCross-sectional comparative study. Material and methodsThe study was conducted on 126 patients with type 2 diabetes along with 30 control subjects attending the outpatient care department of a tertiary care teaching hospital. There were 3 study groups-diabetic patients with microalbuminuria, diabetic patients without albuminuria and control subjects who were non-diabetic without any renal disease. Details on duration of diabetes and glycemic status were obtained from the patients. Urine examination was done for subjects in all the groups to look for microalbuminuria along with estimation of NGAL and cystatin-C levels. Samples were stored at −20 °C in the deep freezer. ResultsUrinary NGAL and cystatin-C levels were significantly elevated in patients with microalbuminuria (228.18 & 3.23 ng/ml) as compared to those without albuminuria (146.12 & 2.61 ng/ml) and in control subjects (26.56 & 0.30 ng/ml). Urinary NGAL and cystatin-C levels showed a linear correlation with microalbuminuria in diabetic patients. ConclusionUrinary NGAL and cystatin-C levels were increased in type 2 diabetic patients with early diabetic nephropathy as compared to patients without nephropathy. Urine NGAL and cystatin-C levels also showed a positive correlation with microalbuminuria (urine albumin-creatinine ratio) in patients with type 2 diabetes mellitus.

Clinical Utility of Urinaryβ2-Microglobulin in Detection of Early Nephropathy in African Diabetes Mellitus Patients

Background. Studies have indicated that diabetic tubulopathy may occur earlier than glomerulopathy, therefore providing a potential avenue for earlier diagnosis of diabetic nephropathy. Urinary beta-2-microglobulin (β2m) was investigated in this study as a potential biomarker in the detection of early nephropathy in type 2 diabetics. Methods. One hundred and two diabetic subjects and 103 controls that met the inclusion criteria had data (sociodemographic, medical history, physical examination, and laboratory) collected. Urinary β2m levels and urinary albumin concentration (UAC) were determined. Results. Elevated urinary β2m was more frequent among the diabetics (52%, 95% CI: 42.1–61.8%) than among the controls (32%, 95% CI: 22.9–41.2%). The frequency of microalbuminuria was higher in the diabetics (35.3%, 95% CI: 25.9–44.7%) than in the controls (15.5%, 95% CI: 8.4–22.6%). There was a positive correlation between urinary β2m and UAC (rho = 0.38, p < 0.001). Multivariate analysis showed BMI (OR: 1.23, 95% CI: 1.05–1.45), eGFR (OR: 0.97, 95% CI: 0.94–0.99), and presence of microalbuminuria (OR: 3.94, 95% CI: 1.32–11.77) as independent predictors of elevated urinary beta-2-microglobulin among the diabetics. Conclusion. Urinary β2m may be useful, either as a single test or as a component of a panel of tests, in the early detection of diabetic nephropathy.

Cystatin C - A Biomarker for Early Nephropathy in Type 2 Diabetic Patients

Diabetic nephropathy (DN) is a serious complication of diabetes associated with an increased risk of mortality, and cardiovascular and renal outcomes. Cystatin C, a 13 kD non-glycosylated basic protein, may be elevated in diabetic patients even before the appearance of microalbuminuria, and can be used as useful marker for detecting nephropathy in patients with normoalbuminuria (early nephropathy). We reviewed the recent literatures to determine if serum or urine cystatin C measurements could be useful as a marker to detect early DN in type 2 diabetic patients. Our search identified a total of 23 studies that have been published to date. Cystatin C measurement was carried out using immunoturbidimetric assays, Dade Behring Cystatin C assay, particle enhanced nephlometric immnuno assays, ELISA kits, or latex agglutination tests. Serum or urinary levels of cystatin C were elevated in type 2 diabetic patients compared to non-diabetic controls, including in patients who had no signs indicating nephropathy (without microalbuminuria). A significant positive correlation was found between cystatin C levels and albuminuria, suggesting its ability as a marker reflecting the degree of renal impairment in type 2 DN. Despite the promise of cystatin C as a biomarker, further large, multicenter prospective studies are still needed to confirm its clinical utility as a screening tool for early type 2 DN in every day practice.

Matrix Metalloproteinase-2 as Potential Marker of Early Nephropathy in Type 1 Diabetes

Background: Early detection of diabetic nephropathy (DN) is important. Matrix metalloproteinases-2 (MMP-2) regulates a variety of cellular functions including apoptosis and angiogenesis. Diabetic environment stimulates the secretion of MMP-2 that is considered to participate in DN. Objectives: We conducted this study to investigate the level of MMP-2 as a potential marker of early nephropathy in type 1 diabetes. Methods: The total number of the study was 300 participants, among them 100 participants, were healthy volunteers control group with comparable age and sex to other participants (Group 1). The remaining 200 participants were suffering from type 1 diabetes and were categorized according to duration of diabetes into 100 patients had disease duration less than 5 years and all of them non microalbuimnuric (Group 2) and the last 100 patients had disease duration more than 5 years (Group 3). All subjects were submitted to complete clinical examination; routine laboratory investigations, including; random blood sugar (RBS); glycosylated hemoglobin (HbA1C) and quantitative determination of microalbuminuria (MA) for DN. Specific laboratory investigation for MMP-2 by enzyme-linked immunosorbent assay. Results: RBS and HbA-1c were significantly higher in group 3 than group 2. MA significantly detected only in group 3. MMP-2 was significantly higher in group 3 than the other groups 1, 2 and in the meantime significantly higher in group 2 than 1. MMP-2 starts to rise early before the onset of MA in group 2. Eventually duration of diabetes, RBS, HbA1c and MA were positively correlated with the MMP-2 level. (r=0. 44; P<0.05), (r=0. 43; P<0.05), (r=0. 58; P<0.05) and (r=0. 71; P<0.001) respectively. MMP-2 cutoff level of ≥ 311 ng/ml had a greater sensitivity and specificity for identifying MA (P<0.001). Conclusion: MMP-2 level pre-date the clinical evidence of MA, may serve as an important predictor for early development of DN and a potential marker of severity.

Markers of and Risk Factors for the Development and Progression of Diabetic Kidney Disease

Diabetic kidney disease (DKD) occurs in 25%-40% of patients with diabetes. Given the dual problems of a significant risk of progression from DKD to end-stage renal disease (ESRD) and increased cardiovascular morbidity and mortality, it is important to identify patients at risk of DKD and ESRD and initiate protective renal and cardiovascular therapies. The importance of preventive therapy is emphasized further by worldwide increases in the incidence of diabetes. This review summarizes the evidence regarding the prognostic value and benefits of targeting established and novel risk markers for DKD development and progression. Family history of DKD, smoking history, and glycemic, blood pressure, and plasma lipid level control are established factors for identifying people at greatest risk of DKD development and progression. Absolute albumin excretion rate (AER) and glomerular filtration rate (GFR) measurements also are important, although AER categorization generally lacks the necessary specificity and sensitivity, and estimates of declining GFR are compromised by methodological limitations for GFRs in the normal-to-high range. Emerging risk markers for progressive loss of kidney function include markers of oxidation and inflammation, profibrotic cytokines, uric acid, advanced glycation end products, functional and structural markers of vascular dysfunction, kidney structural changes, and tubular biomarkers. Among these, the most promising are serum uric acid and soluble tumor necrosis factor receptor (type 1 and type 2) levels, especially in relation to GFR changes. At present, these can only be considered as risk markers because they only identify an individual at increased risk of progressive DKD and not necessarily related to the causal pathway promoting kidney damage. Further work is needed to establish whether modulating these factors improves the prognosis in DKD. Although change in urinary peptidome levels also is a promising marker, there currently is neither a clinical assay nor adequate studies defining its prognostic value. Until these or other novel markers become available for clinical use, predictive accuracy often may be increased with greater attention to established markers.

Effect of ethanol extract of Rhodiola rosea on the early nephropathy in type 2 diabetic rats

This study aimed to investigate the therapeutical effects of Rhodiola rosea extract on rats with type 2 diabetic nephropathy (DN). The rat type 2 DN model was established by high fat and high calorie feeding and intravenous injection of streptozocin (STZ). Wistar rats were randomly divided into normal group, control group, low dose Rhodiola rosea group, high dose Rhodiola rosea group and Captopril group. Oral glucose tolerance test (OGTT) was performed to determine the impairment of glucose tolerance in the established animal model. A series of parameters including fasting blood glucose (FBG), total cholesterol (TC), triglyceride (TG), creatinine clearance rate (Ccr), 24-h urinary albumin (UA), the ratio of kidney mass/body weight (renal index) and glomerular area were examined after 8 weeks. Moreover, the expression of transforming growth factor (TGF)-β1 in renal tissues was detected by using immunohistochemisty. At the end of the eighth week, FBG, TC, TG, Ccr, 24-h urinary albumin, the ratio of kidney mass/body weight and glomerular area were significantly reduced in Rhodiola rosea extract treatment groups as compared with those in control group. TGF-β1 expression in renal tissues of Rhodiola rosea extract treatment groups was also significantly decreased as compared with that of control group. These results indicate that Rhodiola rosea extract may have a protective effect on early nephropathy in diabetic rats, which might be related to the decrease of the renal expression of TGF-β1.

Effect of the Best Compatibility of Components in Corni Fructus on WT1 Expression in Glomerular Podocytes of Type 2 Diabetic Rats with Early Nephropathy

Our previous studies have shown that the best compatibility of components in Corni Fructus (PC) had a protective effect on vascular endothelial cells. In this study, the effect of PC on WT1 expression in glomerular podocytes and the mechanism of PC on early nephropathy in type 2 diabetic rats have been investigated. Type 2 diabetic rats were generated by high-fat diet combined with intraperitoneal injection of 30 mg/kg streptozotocin (STZ), then fed aminoguanidine (100 mg/kg), glimepiride (0.4 mg/kg), low-dose (60 mg/kg) or high-dose (120 mg/kg) of PC once a day for 12 weeks. Fasting blood glucose (FBG) was examined regularly. Insulin (INS) was measured by a radioimmunoassay. Microalbuminuria (mALB) was measured by an ELISA assay. Urinary creatinine (UCr), blood urea nitrogen (BUN) and N-acetyl-β-D-glucosaminidase (NAG) were measured by colorimetric assays. Renal morphological changes were observed by optical microscopy. The expression index of Wilms tumor 1 (WT1EI) in glomeruli was examined by immunohistochemistry. The results showed that PC led to a decrease in FBG (p < 0.01), NAG (p < 0.05) and mALB (p < 0.05) and an increase in INS (p < 0.01) and WT1EI (p < 0.05) compared to the diabetic group. PC could improve renal damage and greatly reduce the renal morphology score (p < 0.05). These results suggested that PC had the protective effect on early nephropathy in type 2 diabetic rats, which was closely related to the regulation of podocytes.

Retinal Arteriolar Tortuosity is Associated With Retinopathy and Early Kidney Dysfunction in Type 1 Diabetes

To examine the association of retinal vessel tortuosity with diabetic retinopathy and early nephropathy in type 1 diabetes. Cross-sectional. A total of 1159 participants with type 1 diabetes aged 12 to 20 years, attending diabetes clinics in Children's Hospital at Westmead, Sydney, Australia between 1990 and 2002, were included. Retinal photography and clinical examinations were performed during the baseline visit to assess diabetic retinopathy and albumin excretion rate (AER). Retinal vessel tortuosity was measured from digitized retinal photographs using a semi-automated computer program by a single grader masked to participants' characteristics. Diabetic retinopathy was defined as ETDRS level ≥21 (mild nonproliferative retinopathy) and early kidney dysfunction was defined as AER ≥7.5 μg/min. Of 944 patients (81.4%), 85 (9.0%) had signs of retinopathy only, 250 (26.5%) had early kidney dysfunction only, and 85 (9.0%) had both retinopathy and early kidney dysfunction. In multivariate analysis, higher arteriolar tortuosity was associated with retinopathy (odds ratio [OR] 2.01, 95% confidence interval [CI] 1.23-3.29, the highest quartile vs the remaining 3 quartiles), early kidney dysfunction (OR 1.56, 95% CI 1.06-2.28, per standard deviation [SD] increase), or coexistence of both complications (OR 1.96, 95% CI 1.21-3.24, the highest quartile vs the remaining 3 quartiles). Greater retinal arteriolar tortuosity was independently associated with retinopathy and early stage of nephropathy in type 1 diabetes. These findings may offer the potential of quantitative measurement of retinal vessel tortuosity for diabetic complication risk assessment.

In patients with type 1 diabetes and new-onset microalbuminuria the development of advanced chronic kidney disease may not require progression to proteinuria

We sought to study new-onset microalbuminuria, its progression, and the decline of renal function in patients with type 1 diabetes. Using a cohort of 109 patients who developed new-onset microalbuminuria in the first 4 years following enrollment in the 1st Joslin Kidney Study, we simultaneously tracked the change in their renal function and urinary albumin excretion. Of these, 79 patients were followed for an average of 12 years after microalbuminuria onset, wherein their glomerular filtration rate was estimated by the Modification of Diet in Renal Disease Study formula and compared with their microalbuminuria and proteinuria. The concordance between these outcomes was weak. Only 12 of the 23 patients who progressed to advanced (stage 3-5) chronic kidney disease developed proteinuria, which, in general, did not precede but accompanied the progression to advanced chronic kidney disease. The remaining 11 patients who developed advanced disease had persistent microalbuminuria or returned to normal albuminuria. Thus, we found that one-third of patients with type 1 diabetes developed advanced chronic kidney disease relatively soon after the onset of microalbuminuria and this was not conditional on the presence of proteinuria. Contrary to the existing concept of early nephropathy in type 1 diabetes, less emphasis should be placed on the mechanisms of progression to proteinuria and more placed on mechanisms initiating and promoting the early decline of renal function that eventually progresses to advanced chronic kidney disease.

Matrix metalloproteinases in subjects with type 1 diabetes

BackgroundNephropathy is serious complication of diabetes. We have previously shown that level of the proteoglycan syndecan-1 in blood is associated with ultrastructural kidney changes in young persons with type 1 diabetes. Dysregulation of matrix metalloproteinases (MMPs) and tissue inhibitors of matrix metalloproteinases (TIMPs) may contribute to the development of nephropathy. The aim of this study was to investigate if the levels of MMPs in blood samples are potential markers of early nephropathy in type 1 diabetes.MethodsBlood samples were collected from type 1 diabetes patients after 11 years of diabetes (n = 15) and healthy volunteers (n = 12) and stored at ÷80°C until measurement. Levels and activities of serum MMP-2, MMP-9, TIMP-1 and TIMP- 2 were analyzed and compared to those of control individuals using ELISA, SDS-PAGE gelatin zymography, and Western blot analysis.ResultsThe serum levels of both MMP-9 and MMP-2 were significantly higher in subjects with type 1 diabetes, compared to controls (p = 0.016 and p = 0.008 respectively). Western blotting revealed no differences between the two groups in the levels of TIMP-1 or TIMP-2, respectively.ConclusionOur MMP analysis of serum from a limited number of patients with type 1 diabetes suggest that such analysis is potentially useful as markers in studies of people at risk of progression to chronic kidney disease.

Early nephropathy in type 1 diabetes: the importance of early renal function decline

The results of recent clinical trials in early diabetic nephropathy demonstrate that current therapies designed to suppress microalbuminuria do not prevent renal function decline. However, recent observational studies refined the traditional model of early nephropathy in type 1 diabetes and may inform more effective therapies for the prevention of chronic kidney disease. A contemporary model of early nephropathy in type 1 diabetes has emerged in which initiation of renal function decline occurs soon after the onset of microalbuminuria and is not conditional on progression to proteinuria. Early renal function decline can be diagnosed using serial measurement of serum cystatin C. Abnormal levels of markers of protein glycation, uric acid metabolism, and chronic inflammation appear to represent mechanisms unique to early renal function decline and distinct from those involved in microalbuminuria. Recent findings refine the existing paradigm of early nephropathy in type 1 diabetes and have significant implications for research. Clinical tests--such as an algorithm for the serial determination of serum cystatin C--should be developed for monitoring early renal function decline for use as an outcome in clinical trials.

Increased syndecan-1 in serum is related to early nephropathy in type 1 diabetes mellitus patients

Increased syndecan-1 in serum is related to early nephropathy in type 1 diabetes mellitus patients

Increased syndecan-1 in serum is related to early nephropathy in type 1 diabetes mellitus patients

To the Editor: Hyperglycaemia is associated with increased inflammatory activity, endothelial dysfunction and microvascular complications in patients with type 1 diabetes mellitus. Low-grade inflammation and changes in functions of different constituents of the capillary wall may contribute to the development of complications. The endothelium is covered by a protective glycocalyx consisting of proteoglycans, hyaluronan, glycoproteins and plasma proteins. The transmembrane proteoglycan syndecan-1 is a component of this cell coat. Through its glycosaminoglycan chains, syndecan-1 has the ability to bind numerous ligands and by such interactions to modulate important cellular functions like receptor binding and regulation of inflammation [1]. The syndecan-1 ectodomain can be released from the endothelial cell surface by a highly regulated proteolytic cleavage at a juxtamembrane site of the protein core. Syndecan-1 concentrations found in sera from healthy individuals are low. Shed syndecan-1 levels are often increased in tissue injury and certain cancers. In this study we tested for associations between early kidney damage, as evidenced by persistent microalbuminuria, and shedding of syndecan-1, measured by determining serum concentrations of soluble syndecan-1 in patients with type 1 diabetes mellitus. In an initial study, patients with type 1 diabetes mellitus were recruited from Aker University Hospital and nearby paediatric Departments [2]. The inclusion criteria in this study were persistent microalbuminuria, defined as an AER between 15 and 200 μg/min in at least two out of three overnight urine samples taken during 1 year, and diabetes

Early nephropathy in type 1 diabetes: A new perspective on who will and who will not progress

Impaired renal function and end-stage renal disease (ESRD) affect up to a third of patients with type 1 diabetes. Thus, strategies for early detection and for preventative interventions are of critical importance. A model of diabetic nephropathy was developed in the 1980s that placed paramount importance on the finding of microalbuminuria as an early marker of a committed process of progressive kidney disease in diabetes. However, recent studies have provided evidence that microalbuminuria is a marker of dynamic, rather than fixed, kidney injury. Preliminary studies into early renal function decline, a process measured in early nephropathy using a simple assay for cystatin C to calculate the slope of glomerular filtration rate change over time, suggest that it is a more proximal marker than microalbuminuria of a person's trajectory toward impaired renal function and ESRD. Therefore, early renal function decline, rather than microalbuminuria, may be considered as the early marker of the committed process underlying progressive diabetic nephropathy.

Relationship between Reduced BCL-2 Expression in Circulating Mononuclear Cells and Early Nephropathy in Type 1 Diabetes

Microalbuminuria is the earliest clinical evidence of diabetic nephropathy, but the mechanisms linking hyperglycemia and kidney complications are not clear. The aim of this study was to evaluate whether enhanced oxidative stress in patients with microalbuminuria can contribute to diabetic nephropathy development through downregulation of the antiapoptotic gene Bcl-2 that promotes in turn a pro-inflammatory status. We studied 30 patients with type 1 diabetes (15 with and 15 without microalbuminuria) compared to 15 matched healthy controls. Plasma oxidant status, and expression of Bcl-2, activated NF-kB, inducible Nitric Oxide synthase (iNOS), and monocyte chemoattractant protein (MCP)-1 in circulating monocytes were evaluated at baseline and after 8-week oral vitamin E treatment (600 mg b.i.d.). Bcl-2 expression was significantly reduced in microalbuminuric diabetic patients as a consequence of increased oxidant burden secondary to persistent hyperglycemia. Bcl-2 down-regulation was associated with enhanced expression of NF-kB, iNOS and MCP-1, and showed a strong correlation with the albumin excretion rate. Low Bcl-2 expression and high inflammatory status were normalized by vitamin E both in vivo and in vitro. Our study showed that Bcl-2 down-regulation in diabetic patients with poor glycemic control results in the activation of the NF-kB pathway leading to the development of nephropathy. Vitamin E might provide a novel form of therapy for prevention of nephropathy in diabetic patients in which an acceptable glycemic control is difficult to achieve despite insulin therapy.

Urinary alpha1-microglobulin as a marker of nephropathy in type 2 diabetic Asian subjects in Singapore.

This study examines urinary alpha(1)-microglobulin as a marker of early nephropathy in type 2 diabetic Chinese, Malays, and Asian Indians in Singapore. A cross-sectional study was performed on 590 consecutive type 2 diabetic patients (296 males, 294 females) who were on routine follow-up at a primary care clinic. Information was obtained from interviews, case notes, and blood and urine samples. Because the distribution of urinary alpha(1)-microglobulin levels was highly skewed, these levels were log-transformed, and geometric means were calculated. There was correction for variability in urine flow by dividing by urine creatinine levels, given as mg/mmol urine creatinine, and adjustment for confounding variables. Urinary alpha(1)-microglobulin was higher in men than in women and was directly related to age, but no ethnic differences were apparent. It was directly related to duration of diabetes, with adjusted geometric means of 1.19 and 1.43 mg/mmol urine creatinine for a duration of <10 and > or =10 years, respectively (P = 0.07). Urinary alpha(1)-microglobulin was highest in patients on insulin, followed by those on oral medication and then those on diet alone (adjusted geometric means: 1.47, 1.36, and 0.86 mg/mmol urine creatinine, respectively; P = 0.01). Levels were also higher in patients with poor glucose control, as measured by HbA(1c), fasting plasma glucose, and 2-h postprandial plasma glucose (P < 0.01 for each). Urinary alpha(1)-microglobulin was directly related to albuminuria, with adjusted geometric means for normoalbuminuria, microalbuminuria, and macroalbuminuria of 1.06, 1.47, and 4.72 mg/mmol urine creatinine, respectively (P < 0.01). However, of patients with normoalbuminuria, 33.6% had raised urinary alpha(1)-microglobulin. Likewise, of patients with normal urinary alpha(1)-microglobulin, 27.6% had albuminuria. Urinary alpha(1)-microglobulin was related to duration, severity, and control of diabetes. Urinary alpha(1)-microglobulin and albumin were directly related, but in some patients, one was present in the absence of the other. Hence, in addition to albuminuria (which measures glomerular dysfunction), urinary alpha(1)-microglobulin (which measures proximal tubular dysfunction) is useful for the early detection of nephropathy in diabetic subjects.