| Background With the industry rapidly developing and people’s lifestyle changing, the prevalence rate of diabetes mellitus(DM) among Chinese adults has been increasing in recent years. A national study from June 2007 through May 2008 to estimate the prevalence of diabetes among Chinese adults (20 years of age or older) was conducted. The age-standardized prevalences of total diabetes (which included both previously diagnosed diabetes and previously undiagnosed diabetes) and prediabetes (i.e., impaired fasting glucose or impaired glucose tolerance) were 9.7% and 15.5%, respectively, accounting for 92.4 million adults with diabetes and 148.2 million adults with prediabetes. A cross-sectional survey conducted in 2010 suggested that the estimated prevalence of diabetes among a representative sample of Chinese adults was 11.6% and the prevalence of prediabetes was 50.1%. These results indicate that diabetes has become a major public health problem in China and that strategies aimed at the prevention and treatment of diabetes are needed.Diabetes not only brings patients the physical and mental damage and leads to shortened life expectancy, but also brings a heavily economic burden to individuals and nations.The total estimated cost of diagnosed diabetes in the U.S. in 2012 is $245 billion, including $176 billion in direct medical costs and $69 billion in reduced productivity. In China, the direct medical costs of T2DM and its complications were estimated to be 26.0 billion USD in 2007 and were projected to be 47.2 billion USD in 2030. This estimate highlights the substantial burden that diabetes imposes on society. Additional components of societal burden include intangibles from pain and suffering, resources from care provided by nonpaid caregivers, and the burden associated with undiagnosed diabetes. The results indicated that DM consumes a large portion of healthcare expenditures and will continue to place a heavy burden on health budgets in the future. Preventive intervention, screening, and treatment strategies may effectively decrease the incidence and complications of diabetes and therefore save costs.Good glycemic control is essential for the longevity and quality of life in T1DM. Hyperglycemia is the initiating cause of the diabetic tissue damage,established by the DCCT (Diabetes Control and Complications Trial) and the UKPDS (U.K. Prospective Diabetes Study). In the Lainz T1DM prospective cohort study,13.0% mortality and 5.6% renal replacement therapy (RRT) were directly associated with and more frequently found in poor glycemia. Patients with the highest HbAlc values (4th quartile) had a higher mortality rate and a greater incidence of RRT (P< 0.04). In the Cox proportional hazards analysis, age, male gender, increased HbAlc, albuminuria, and reduced creatinine clearance were predictors of mortality (P<0.05). Predictors of RRT were albuminuria (P< 0.001), reduced creatinine clearance (P< 0.001), and belonging to the 4th HbAlc quartile (P= 0.06). In Kaplan-Meier analysis, mortality was linearly associated with poor glycemia, whereas RRT incidence appeared to rise at a HbAlc threshold of approximately8.5%.Diabetic kidney disease (DKD) is the leading cause of end-stage renal failure worldwide. Besides, DKD is associated with cardiovascular disease, and increases mortality of diabetic patients. DKD accounts for approximately 45%of incident cases and 55% of prevalent cases in the United States.Albuminuria is a common complication of diabetes and a leading cause of end stage renal disease(ESRD). The Australian population-based study shows that albuminuria is common among patients with established diabetes, is present before the onset of diabetes, and becomes more prevalent with worsening glucose tolerance. Overall,25.3% of patients with diabetes mellitus (known [KDM] and newly diagnosed [NDM], type 1 and type 2) had evidence of albuminuria (21.0%, microalbuminuria; 4.3%, macroalbuminuria). Prevalence increased with increasing glycemia (normal glucose tolerance [NGT],5.1%; impaired fasting glucose [IFG],9.3%; impaired glucose tolerance,11.0%; NDM,17.8%; and KDM,32.6%[type 2 only]). Patients with diabetes (KDM and NDM) and IFG had an increased risk for albuminuria compared with those with NGT independent of age, sex, and other known risk factors for albuminuria. Logistic regression modeling identified age, duration of diabetes, systolic blood pressure, current smoking, body mass index, and glycated hemoglobin level as independent risk factors for albuminuria.Diabetes may complicate chronic kidney disease, often manifesting with reduced glomerular filtration rate (GFR), albuminuria, or both. Of 42,761 participants with diabetes,8,618 (20.2%) had estimated GFR<60mL/min/1.73m2,7,715 (18.0%) had albumin-creatinine ratio (ACR)>30mg/g, and 2,641 (6.2%) had both. The unadjusted incidence (per 1,000 person-years) of all-cause mortality increased from 3.1 (95% Cl,2.4-3.8) in participants with estimated GFR>105mL/min/1.73m2 and no albuminuria to 73.7 (95% Cl,54.9-92.5) in participants with estimated GFR<30mL/min/1.73m2 and macroalbuminuria (P< 0.001). Progression to ESRD likewise increased from 0.2 (95% Cl,0-0.4) to 220.4 (95% Cl,177.2-263.6) per 1,000 person-years (P< 0.001). After adjustment for confounders, both estimated GFR and albuminuria were associated independently with mortality and progression to ESRD, with a strong synergistic interaction (P for interaction< 0.001); estimated GFR<30mL/min/1.73m2 and macroal buminuria together were associated with a 5-fold higher risk of mortality and a more than 1,000-fold higher risk of progression to ESRD (compared with patients with estimated GFR>60mL/min/1.73m2 and ACR<30mg/g;P<0.001 for both outcomes).However, the decline of glomerular function is not always associated with the development of micro-and macro-albuminuria in patients with diabetes. Increased urinary albumin excretion rate(AER) is widely accepted as the first clinical sign of diabetic kidney disease. However, it is possible that some diabetic patients could first manifest reduced glomerular filtration rate (GFR) or hypertension. Relatively advanced diabetic renal lesions can be present in some diabetic patients with long-standing normoalbuminuria, and this might indicate increased risk of progression to microalbuminuria and then to overt diabetic nephropathy. Macroalbuminuria was a strong predictor of eGFR loss and risk of developing sustained eGFR<60mL/min/1.73m2. However, screening with AER alone would have missed 24% of cases of sustained impaired eGFR. This discordance between changes in GFR and AER has resulted in a search for new markers that identify people with diabetes who are at risk of declining GFR independent of progressive increases in AER.Effective interventions in early diabetic kidney disease will control or slow the progression of kidney disease and reduce the burden of diabetic kidney disease. So early diagnosis is the key.Currently the main indicators used to assess the clinical degree of renal damage are glomerular filtration rate (GFR), blood urea nitrogen(BUN), serum creatinine(SCr) and urine regular test. However, these indicators are not good enough to reflect early renal damage in sensitivity. Therefore, to explore the pathogenesis of diabetic nephropathy, looking for sensitive and simple laboratory diagnostic marker for early diagnosis of DKD is particularly important.Type 1 diabetes, also known as insulin-dependent diabetes mellitus (IDDM), is an organ-specific autoimmune disease, resulting from the destruction of insulin-secreting pancreatic islet beta-cells by autoreactive cells and their mediators. Thl and Th2 cells and their respective mediators participate in inducing and sustaining pancreatic islet beta-cell destruction in IDDM.Diabetic kidney disease is an inflammatory disease. Inflammation plays a critical role in the pathogenesis of diabetic kidney disease. Expression of cell adhesion molecules, growth factors, chemokines and pro-inflammatory cytokines are increased in the renal tissues of diabetic patients, and serum and urinary levels of cytokines and cell adhesion molecules, correlated with albuminuria. Increased concentrations of C-reactive protein and interleukin-6 is a finding suggestive of the presence of inflammation. Low-grade inflammatory markers are associated with diabetic kidney disease in type 1 diabetic patients. Inflammatory cytokines, mainly 1L-1, IL-6, and IL-18, as well as TNF-alpha, are involved in the development and progression of diabetic kidney disease. Inflammation might contribute to early induction and amplification of the immune assault against pancreatic beta cells and, at later stages, to the stabilization and maintenance of insulitis. Inflammatory mediators probably contribute to the suppression of beta-cell function and subsequent apoptosis; they may also inhibit or stimulate beta-cell regeneration and might cause peripheral insulin resistance.An emerging amount of data suggest that the complement system plays an important role in the pathogenesis of diabetic vascular complications. A connection between the complement system and vascular dysfunction had been suggested, with a special focus on the relation to diabetic kidney disease.Mannose-binding lectin (MBL) is synthesized by hepatocytes and belongs to the family of C-type lectins. MBL may aggravate local and systemic inflammation through complement activation. Hansen et al. reported that concentrations of both MBL and high-sensitivity C-reactive protein (Hs-CRP) were associated with the progression of renal disease in type 1 diabetes.Inflammation and complement activation initiated by MBL may be implicated in the pathogenesis of diabetes and diabetic vascular complications. The relationship between MBL levels and DKD in Chinese patients with TIDM remains unknown. Thus, the aim of this study was to evaluate serum MBL levels in TIDM with DKD and with persistent normoalbuminuria(PN), and to evaluate the predictive value of MBL in the diagnosis of diabetic kidney disease in type 1 diabetes.Objective The aim of this study was to investigate serum levels of mannose-binding lectin(MBL) in type 1 diabetes with diabetic kidney disease (DKD) and persistent normoalbuminuria(PN), and to evaluate the predictive value of MBL in the diagnosis of diabetic kidney disease in type 1 diabetes.Method From the outpatient clinic at Linyi People’s Hospital and Qjlu Hospital of Shandong University, all patients with long-standing TIDM and DKD were recruited for this study. A total of 224 patients with DKD and 224 patients with PN [urinary albumin excretion(UAER)<30mg/24h], matched for sex, age, and duration of diabetes, were included and recruited for this study. DKD was diagnosed clinically based on the following criteria:persistent albuminuria(30-300)mg/24h in at least two of three consecutive 24h urine collections, presence of retinopathy, and no evidence of other kidney or renal tract disease. Diabetes was defined as self-report of a previous diagnosis of the disease by a clinician (excluding gestational diabetes mellitus) or hemoglobin Alc (HbAlc) of 6.5% or greater.At admission, we requested individual participant data regarding presence and severity of DKD, age, sex, ethnicity, diabetes duration, HbAlc, systolic and diastolic blood pressure, cigarette smoking status, body mass index (BMI), and current use of diabetes, antihypertensive, and lipid-lowering medications. The study followed the tenets of the Declaration of Helsinki and was approved by the Institute ethics committee of Linyi People’s Hospital, Qilu Hospital of Shandong University, with written informed consent obtained from each participant.All investigations were performed in the morning after an overnight fast. Venous blood was drawn with minimal stasis from an antecubital vein. Clotted blood was centrifuged within 1h and serum stored at -80℃ HbAlc was measured by high-performance liquid chromatography (HLC-723G7; TOSOH, Japan) with a normal range of 4-6%. The UAER was determined in 24-hour urine collections by enzyme-linked immunosorbent assay thereafter (sensitivity,0.001 mg/L). MBL was measured by time-resolved immune-fluorometricassay on serum samples. Microwells coated with anti-MBL antibody were incubated with dilutions of patient serum, were developed with europium-labeled anti-MBL antibody, and europium was quantified with time-resolved fluorometric assay (Baoman Biological Technology Co, Ltd, Shanghai, China). The detection limit was 1.5μg/L The coefficients of variation (CV) for the intra-and inter-assay reproducibility were 8.5% and 10% for a sample of 3,500μg/L,6.05% and 7.5% for a sample of 1800μg/L,4.2% and 4.9% for a sample of 750μg/L. Other biomarkers, such as Hs-CRP and creatinine were tested by standard laboratory methods.Results are expressed as percentages for categorical variables and as medians (interquartile ranges, IQRs) for the continuous variables. Univariate data on demographic and clinical features were compared by Mann-Whitney U-test or Chi-Square test as appropriate. Correlations among continuous variables were assessed by the Spearman rank correlation coefficient. To investigate whether MBL allows predicting of DKD in diabetes, different statistical methods were used. First, the relation of MBL with the DKD was investigated with the use of logistic regression models. For multivariate analysis, we included confounders, known risk factors, and other predictors as assessed in univariate analysis. Results were expressed as adjusted odds ratios (OR) with the corresponding 95% Confidence interval (Cl). Second, receiver operating characteristic (ROC) curve was used to test the overall predict accuracy of MBL, and results were reported as area under the curve (AUC). All statistical analysis was performed with SPSS for Windows, version 20.0 (SPSS Inc., Chicago, IL). Statistical significance was defined as P< 0.05.Results The serum MBL levels were significantly higher in diabetes with DKD as compared with PN (P<0.0001). Based on the receiver operating characteristic (ROC) curve, the optimal cutoff value of serum MBL levels as an indicator for diagnosis of DKD was projected to be 1680μg/L, which yielded a sensitivity of 75.4% and a specificity of 78.8%, with the area under the curve at 0.768 (95% confidence interval [Cl],0.724-0.815). Multivariate logistic regression analysis adjusted for common factors showed that serum MBL levels≥1680μg/L was an independent indicator of DKD (odds ratio [OR]=6.99; 95%CI:2.83-17.15).Conclusion In type 1 diabetic patient, elevated serum levels of MBL can be seen as an independent predicting marker of DKD even after correcting for possible confounding factors. |
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