Elevated Albumin Excretion Rate Research Articles

Complications during Adolescence Predict Mortality in Young Adults with Childhood Onset Type 1 Diabetes

Objective. Microvascular complications increase the risk of cardiovascular disease and premature death in adults with type 1 diabetes. We examined the association between microvascular complications during adolescence, including cardiac autonomic nerve dysfunction and subsequent mortality. Research Design and Methods. We undertook data linkage with the Australian National Death Index in a cohort of 409 adolescents (diagnosed between 1973 and 1993), 48% male, median age at final complications assessment 17.4 years (interquartile range: 16.0–18.9), followed longitudinally for median 22.3 years (21.0–23.4) from diagnosis. Generalized estimating equations (GEE) were used to examine associations between mortality and adolescent complications. Mortality risk was calculated as standardized mortality ratio (SMR). Results. At final adolescent visit, 20% had CAN abnormality, 30% abnormal pupillary response, 20% albuminuria, 40% early elevation of albumin excretion rate (AER) and 45% retinopathy. Data linkage 8–13 years later showed 14 were deceased (3% of cohort), 57% male, median age 28.3 years (24.8–32.9). Acute or chronic diabetes complications accounted for 25% of deaths. In multivariable GEE, elevated AER (OR 4.54, 1.23–16.80, p=0.030), pupillary abnormality (OR 4.27, 1.20–15.22, p=0.023), systolic blood pressure SDS (OR 2.17, 1.26–3.74, p=0.005) and CAN (OR 4.65, 1.03–21.0, p=0.045) predicted mortality. HbA1c was not significant. SMR was 2.5 (1.4–4.2) and was higher in females (SMR 3.5, 1.3–7.8) but not in males (SMR 2.1, 0.9–4.0). Conclusion. Mortality in young adults with type 1 diabetes is predicted by subclinical markers of autonomic neuropathy and elevated AER during adolescence, but not glycemia. Mortality was over twice that of the background population in females but not in males.

Risk Factors, Complications and Management of Diabetes Mellitus

Diabetes mellitus can be a complex disorder described by chronic progressive metabolic disorder and chronic hyperglycemia arising from dysregulation of carbohydrate, lipid and protein metabolism. Verapamil is a class of non-dihydropyridine calcium channel blockers, which prevents the second phase of glucose stimulated insulin release by inhibiting the intake of calcium into the cytosol of beta cells and also prevents sulfonylurea and glucagon-induced insulin release. The complications of diabetes mellitus are categorized as microvascular (nephropathy, neuropathy, and retinopathy) or macrovascular (cardiovascular and cerebrovascular disease). Diabetic nephropathy is a microvascular complication described by elevated urinary albumin excretion (proteinuria) or lowered kidney glomerular filtration rate in both types of diabetic mellitus. The objective of diabetes mellitus management is to inhibit the mortality and to delay the onset of disease complications and to hinder its progression by improving patients’ blood sugar level and controlling the risk of cardiovascular disease. Metformin enhances liver, muscle & adipose tissues sensitivity to the insulin and elevate peripheral glucose utilization and also prevents gluconeogenesis and obviates glucose absorption from gastrointestinal tract.

Serum Cystatin C as a Biomarker for Early Diabetic Kidney Disease and Dyslipidemia in Young Type 1 Diabetes Patients.

Background and objectives: This study aimed to assess the clinical significance of serum cystatin C in the early diagnosis of renal injury and its association with dyslipidemia in young T1D patients. Materials and Methods: A total of 779 subjects were evaluated for kidney function by estimating glomerular filtration rate (eGFR) based on serum creatinine (eGFRcreat) and cystatin C (eGFRcys). Results: The median age of study subjects was 16.2 years (2.1;26.4), diabetes duration—5.3 years (0.51;24.0). The median of HbA1c was 8% (5.2;19.9) (64 mmol/mol (33.3;194)); 24.2% of participants had HbA1c < 7% (53 mmol/mol). Elevated albumin excretion rate was found in 13.5% of subjects. The median of cystatin C was 0.8 mg/L (0.33;1.71), the median of creatinine—63 µmol/L (6;126). The median of eGFRcys was lower than eGFRcreat (92 mL/min/1.73 m2 vs. 101 mL/min/1.73 m2, p < 0.001). A total of 30.2% of all patients were classified as having worse kidney function when using cystatin C vs. creatinine for eGFR calculation. Linear correlations were found between cystatin C and HbA1c, r = −0.088, p < 0.05, as well as cystatin C and HDL, r = −0.097, p < 0.01. Conclusions: This study showed that cystatin C might be used as an additional biomarker of early kidney injury in young patients with T1D.

Inherited or Acquired in Hipertension and Cronic Kidney Disease in Diabetes Mellitus Patients?

Abstract Diabetic kidney disease (DKD) is a common and serious microvascular complication of diabetes mellitus (DM), which is characterized by an elevated urinary albumin excretion rate, elevated blood pressure, and declined renal function. Approximately 30-40% of DM patients will develop DKD, which is the leading cause of end-stage renal disease (ESRD) and renal failure. Genetic factors appear critical in DKD pathogenesis based upon the evidence including aggregation in families, variable incidence rates of DKD between different races, and the highly heritable nature of diabetic renal clinic and histologic changes. Each 10 mmHg increase in mean systolic blood pressure (BP) was associated with a 15% increase in the hazard ratio for development of both micro- and macroalbuminuria and impaired kidney function defined as eGFR &lt;60 ml/min per 1.73 m2 or doubling of the blood creatinine level. Broadly, a baseline systolic BP &gt;140 mmHg in patients with DM2 has been associated with higher risk of ESRD and death. The ACE genes may predict diabetic nephropathy in some groups, the rate of progression and the antiproteinuric response to ACE inhibitors.

Interference with TGFβ1-Mediated Inflammation and Fibrosis Underlies Reno-Protective Effects of the CB1 Receptor Neutral Antagonists AM6545 and AM4113 in a Rat Model of Metabolic Syndrome.

The role of cannabinoid receptors in nephropathy is gaining much attention. This study investigated the effects of two neutral CB1 receptor antagonists, AM6545 and AM4113, on nephropathy associated with metabolic syndrome (MetS). MetS was induced in rats by high-fructose high-salt feeding for 12 weeks. AM6545, the peripheral silent antagonist and AM4113, the central neutral antagonist were administered in the last 4 weeks. At the end of study, blood and urine samples were collected for biochemical analyses while the kidneys were excised for histopathological investigation and transforming growth factor beta 1 (TGFβ1) measurement. MetS was associated with deteriorated kidney function as indicated by the elevated proteinuria and albumin excretion rate. Both compounds equally inhibited the elevated proteinuria and albumin excretion rate while having no effect on creatinine clearance and blood pressure. In addition, AM6545 and AM4113 alleviated the observed swelling and inflammatory cells infiltration in different kidney structures. Moreover, AM6545 and AM4113 alleviated the observed histopathological alterations in kidney structure of MetS rats. MetS was associated with a ten-fold increase in urine uric acid while both compounds blocked this increase. Furthermore, AM6545 and AM4113 completely prevented the collagen deposition and the elevated expression of the TGFβ1 seen in MetS animals. In conclusion, AM6545 and AM4113, possess reno-protective effects by interfering with TGFβ1-mediated renal inflammation and fibrosis, via peripheral action.

Liraglutide suppresses production of extracellular matrix proteins and ameliorates renal injury of diabetic nephropathy by enhancing Wnt/β-catenin signaling.

The Wnt/β-catenin signaling pathway is involved in production of the extracellular matrix (ECM) by mesangial cells (MCs). Recent studies by us and others have demonstrated that glucagon-like peptide-1 receptor agonists (GLP-1RAs) have protective effects against diabetic nephropathy. The purpose of the present study was to investigate whether the Wnt/β-catenin signaling in MCs contributes to GLP-1RA-induced inhibition of ECM accumulation and mitigation of glomerular injury in diabetic nephropathy. In cultured human mesangial cells, liraglutide (a GLP-1RA) treatment significantly reduced high glucose (HG)-stimulated production of fibronectin, collagen type IV, and α-smooth muscle actin, and the liraglutide effects were significantly attenuated by XAV-939, a selective inhibitor of Wnt/β-catenin signaling. Furthermore, HG treatment significantly decreased protein abundance of Wnt4, Wnt5a, phospho-glycogen synthase kinase-3β, and β-catenin. These HG effects on Wnt/β-catenin signaling proteins were significantly blunted by liraglutide treatment. For in vivo experiments, we administered liraglutide (200 μg·kg-1·12 h-1) by subcutaneous injection to streptozocin-induced type 1 diabetic rats for 8 wk. Administration of liraglutide significantly improved elevated blood urine nitrogen, serum creatinine, and urinary albumin excretion rate and alleviated renal hypertrophy, mesangial expansion, and glomerular fibrosis in type 1 diabetic rats, whereas blood glucose level and body weight did not have significant changes. Consistent with the in vitro experiments, liraglutide treatment significantly reduced the diabetes-induced increases in glomerular fibronectin, collagen type IV, and α-smooth muscle actin and decreases in glomerular Wnt/β-catenin signaling proteins. These results suggest that liraglutide alleviated glomerular ECM accumulation and renal injury in diabetic nephropathy by enhancing Wnt/β-catenin signaling.

Risk Factors for Retinopathy in Type 1 Diabetes: The DCCT/EDIC Study.

The Diabetes Control and Complications Trial (DCCT) demonstrated that intensive therapy reduced the development and progression of retinopathy in type 1 diabetes (T1D) compared with conventional therapy. The Epidemiology of Diabetes Interventions and Complications (EDIC) study observational follow-up showed persistent benefits. In addition to glycemia, we now examine other potential retinopathy risk factors (modifiable and nonmodifiable) over more than 30 years of follow-up in DCCT/EDIC. The retinopathy outcomes were proliferative diabetic retinopathy (PDR), clinically significant macular edema (CSME), and ocular surgery. The survival (event-free) probability was estimated using the Kaplan-Meier method. Cox proportional hazards models assessed the association between risk factors and subsequent risk of retinopathy. Both forward- and backward-selection approaches determined the multivariable models. Rate of ocular events per 1,000 person-years was 12 for PDR, 14.5 for CSME, and 7.6 for ocular surgeries. Approximately 65%, 60%, and 70% of participants remained free of PDR, CSME, and ocular surgery, respectively. The greatest risk factors for PDR in descending order were higher mean HbA1c, longer duration of T1D, elevated albumin excretion rate (AER), and higher mean diastolic blood pressure (DBP). For CSME, risk factors, in descending order, were higher mean HbA1c, longer duration of T1D, and greater age and DBP and, for ocular surgeries, were higher mean HbA1c, older age, and longer duration of T1D. Mean HbA1c was the strongest risk factor for the progression of retinopathy. Although glycemic control is important, elevated AER and DBP were other modifiable risk factors associated with the progression of retinopathy.

Epicardial, pericardial and total cardiac fat and cardiovascular disease in type 2 diabetic patients with elevated urinary albumin excretion rate.

Background We evaluated the association of cardiac adipose tissue including epicardial adipose tissue and pericardial adipose tissue with incident cardiovascular disease and mortality, coronary artery calcium, carotid intima media thickness and inflammatory markers. Design A prospective study of 200 patients with type 2 diabetes and elevated urinary albumin excretion rate (UAER). Methods Cardiac adipose tissue was measured from baseline echocardiography. The composite endpoint comprised incident cardiovascular disease and all-cause mortality. Coronary artery calcium, carotid intima media thickness and inflammatory markers were measured at baseline. Cardiac adipose tissue was investigated as continuous and binary variable. Analyses were performed unadjusted (model 1), and adjusted for age, sex (model 2), body mass index, low-density lipoprotein cholesterol, smoking, glycated haemoglobin, and systolic blood pressure (model 3). Results Patients were followed-up after 6.1 years for non-fatal cardiovascular disease ( n = 29) or mortality ( n = 23). Cardiac adipose tissue ( p = 0.049) and epicardial adipose tissue ( p = 0.029) were associated with cardiovascular disease and mortality in model 1. When split by the median, patients with high cardiac adipose tissue had a higher risk of cardiovascular disease and mortality than patients with low cardiac adipose tissue in unadjusted (hazard ratio 1.9, confidence interval: 1.1; 3.4, p = 0.027) and adjusted (hazard ratio 2.0, confidence interval: 1.1; 3.7, p = 0.017) models. Cardiac adipose tissue ( p =  0.033) was associated with baseline coronary artery calcium (model 1) and interleukin-8 (models 1-3, all p < 0.039). Conclusions In type 2 diabetes patients without coronary artery disease, high cardiac adipose tissue levels were associated with increased risk of incident cardiovascular disease or all-cause mortality even after accounting for traditional cardiovascular disease risk factors. High cardiac adipose tissue amounts were associated with subclinical atherosclerosis (coronary artery calcium) and with the pro-atherogenic inflammatory marker interleukin-8.

Distinct roles of arginases 1 and 2 in diabetic nephropathy.

Diabetes is the leading cause of end-stage renal disease, resulting in a significant health care burden and loss of economic productivity by affected individuals. Because current therapies for progression of diabetic nephropathy (DN) are only moderately successful, identification of underlying mechanisms of disease is essential to develop more effective therapies. We showed previously that inhibition of arginase using S-(2-boronoethyl)-l-cysteine (BEC) or genetic deficiency of the arginase-2 isozyme was protective against key features of nephropathy in diabetic mouse models. However, those studies did not determine whether all markers of DN were dependent only on arginase-2 expression. The objective of this study was to identify features of DN that are associated specifically with expression of arginase-1 or -2. Elevated urinary albumin excretion rate and plasma urea levels, increases in renal fibronectin mRNA levels, and decreased renal medullary blood flow were associated almost completely and specifically with arginase-2 expression, indicating that arginase-2 selectively mediates major aspects of diabetic renal injury. However, increases in renal macrophage infiltration and renal TNF-α mRNA levels occurred independent of arginase-2 expression but were almost entirely abolished by treatment with BEC, indicating a distinct role for arginase-1. We therefore generated mice with a macrophage-specific deletion of arginase-1 (CD11bCre /Arg1fl/fl ). CD11bCre /Arg1fl/fl mice had significantly reduced macrophage infiltration but had no effect on albuminuria compared with Arg1fl/fl mice after 12 wk of streptozotocin-induced diabetes. These results indicate that selective inhibition of arginase-2 would be effective in preventing or ameliorating major features of diabetic renal injury.

ABCC8-Related Maturity-Onset Diabetes of the Young (MODY12): Clinical Features and Treatment Perspective.

Maturity-onset diabetes of the young (MODY) is a heterogeneous group of diseases associated with gene mutations leading to dysfunction of pancreatic β-cells. Thirteen identified MODY variants differ from each other by the clinical course and treatment requirement. Currently, MODY subtypes 1–5 are best-studied, descriptions of the other forms are sporadic. This article reports a MODY12 clinical case, caused by a mutation in the gene of the ATP-binding cassette transporter sub-family C member 8 (ABCC8), encoding sulfonylurea receptor 1. Diabetes manifested in a 27-year-old non-obese man with epilepsy in anamnesis. No evidence of ketosis was present, pancreatic antibodies were undetectable, and C-peptide remained within the reference range. During the initial investigation, non-proliferative diabetic retinopathy and elevated albumin excretion rate was revealed. After 4 months, diabetes was complicated by pre-proliferative retinopathy and diabetic macular edema. Recurrent hypoglycemia and an increase in body weight was observed on moderate and even small insulin doses. Taking into account the clinical features and the presence of diabetes in four generations on the maternal side, screening for all MODY subtypes was performed. A mutation in the ABCC8 gene was found in proband and in his mother. After the insulin discontinuation, gliclazide modified release combined with sodium/glucose cotransporter 2 (SGLT2) inhibitors was started. This treatment eliminated hypoglycemia and improved glycemic variability parameters. A decrease in the amplitude of glucose excursions was documented by continuous glucose monitoring. After 3 months of treatment, glycemic control was still optimal, and no hypoglycemic episodes were observed. The case report demonstrates the clinical features of ABCC8-associated MODY and the therapeutic potential of a combination of sulfonylurea with SGLT2 inhibitor in this disease.Electronic supplementary materialThe online version of this article (doi:10.1007/s13300-016-0192-9) contains supplementary material, which is available to authorized users.

Diabetic peripheral neuropathy may not be as its name suggests: evidence from magnetic resonance imaging.

Diabetic peripheral neuropathy (DPN) affects up to 50% of patients with diabetes and is a major cause of morbidity and increased mortality. Its clinical manifestations include distressing painful neuropathic symptoms and insensitivity to trauma that result in foot ulcerations and amputations. Several recent studies have implicated poor glycemic control, duration of diabetes, hyperlipidemia (particularly hypertryglyceridaemia), elevated albumin excretion rates, and obesity as risk factors for the development of DPN. However, similar data are not available for painful DPN. Moreover, although there is now strong evidence for the importance of peripheral nerve microvascular disease in the pathogenesis of DPN, peripheral structural biomarkers of painful DPN are lacking. However, there is now emerging evidence for the involvement of the central nervous system in both painful and painless DPN afforded by magnetic resonance imaging. This review will focus on this emerging evidence for central changes in DPN, hitherto considered a peripheral nerve disease only.

Hypertension and Diabetic Nephropathy.

Diabetic nephropathy (DN) is a major complication of both type 1 and type 2 diabetes. DN is the most common cause of end-stage renal disease, and it markedly enhances the risk of cardiovascular events. An elevated urinary albumin excretion rate, increased blood pressure (BP), and a continual loss of renal function are characteristics of DN. Screening for microalbuminuria is central to diabetes care, and antihypertensive agents are used for the primary prevention and treatment of DN. Angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers play central roles and have protective properties beyond their BP-lowering effects. BP control in relation to DN is the main focus of this review, but tight control of the glucose level is equally important. There is an unmet need for new treatment options, and while a few promising candidates exist, their roles in clinical practice have not yet been determined.

Prognostic Value of Albuminuria on Cardiovascular Outcomes After Elective Percutaneous Coronary Intervention

Albuminuria is the most widely evaluated marker of kidney damage. Many previous studies have demonstrated an association between the presence of albuminuria and increased cardiovascular events. However, there are limited data regarding the impact of albuminuria in patients requiring coronary revascularization. This study investigated whether the urinary albumin excretion rate could predict cardiovascular events in such a population. We enrolled 698 consecutive patients who underwent elective percutaneous coronary intervention. The baseline urinary albumin-to-creatinine ratio (ACR; mg/gCr) was measured and patients were divided into those with normoalbuminuria (ACR <30 mg/gCr), microalbuminuria (ACR 30 to 300 mg/gCr), or macroalbuminuria (ACR >300 mg/gCr). We collected data on the incidences of cardiac death and/or nonfatal myocardial infarction. We identified 389, 230, and 79 patients with normoalbuminuria, microalbuminuria, and macroalbuminuria, respectively. During follow-up (median: 1,564 days), 41 events occurred. The event-free survival rate was 89% in patients with macroalbuminuria, 92% in those with microalbuminuria, and 97% in those with normoalbuminuria, respectively (log-rank test p = 0.002). After adjustment for conventional risk factors, Cox analysis revealed hazard ratios for cardiac death and/or nonfatal myocardial infarction were 2.56 (95% CI 1.23 to 5.32, p = 0.01) in those with microalbuminuria and 4.02 (95% CI 1.59 to 10.12, p = 0.003) in those with macroalbuminuria compared with those with normoalbuminuria. In conclusion, an elevated urinary albumin excretion rate independently predicted adverse cardiovascular outcomes, with a gradual risk increase that progressed from microalbuminuria to macroalbuminuria in patients undergoing elective percutaneous coronary intervention.

Increased Macrophage Activation Inhibited by Tacrolimus in the Kidney of Diabetic Rats

Background/Aims: Accumulating evidence suggests that macrophage-induced inflammation may be the mechanism of development and progression of diabetic nephropathy. A previous study by our group has shown that tacrolimus, like cyclosporin A, has a renoprotective effect in diabetic rats. The present study aimed to elucidate the underlying molecular events. Methods: Diabetic rats were induced by using streptozotocin. Diabetic rats were subjected to oral tacrolimus treatment at a dose of 0.5 or 1.0 mg/kg daily for 4 weeks. Body weight, blood glucose, hemoglobin A_1c(HbA_1c) and renal pathology were assessed, followed by analyses of renal calcineurin (CaN) expression, changes in renal macrophage infiltration, proliferation and activation, and detection of renal TLR2+ and TLR4+ as well as NF-κB-p-p65+ in macrophages. Results: Diabetic rats had a reduced body weight and increased blood glucose and HbA_1c levels, whereas tacrolimus treatment did not affect body weight or blood glucose and HbA_1c. Increased relative kidney weight was only significantly reduced by tacrolimus treatment at a dose of 1.0 mg/kg, while the elevated albumin excretion rate was markedly attenuated after treatment with tacrolimus (0.5 and 1.0 mg/kg) in diabetic rats. Elevated glomerular volume was significantly attenuated by tacrolimus treatment with 0.5 and 1.0 mg/kg, and increased indices for tubulointerstitial injury were only ameliorated by tacrolimus treatment with 1.0 mg/kg. Western blot data showed that expression of CaN protein was induced 2.4-fold in the kidneys of positive control diabetic rats, whereas tacrolimus treatment at 0.5 and 1.0 mg/kg doses reduced the increased expression of CaN protein by 38.0 and 73.2%, respectively. Histologically there was a marked accumulation of ED-1+ cells (macrophages) in diabetic kidneys and tacrolimus treatment failed to inhibit it. In contrast, tacrolimus treatment at 0.5 and 1.0 mg/kg doses significantly inhibited the elevated ED-1+/PCNA+ cells and ED-1+/iNOS+ cells in the kidneys of diabetic rats, while tacrolimus treatment at a dose of 0.5 or 1.0 mg/kg significantly suppressed the increased ED-1+/TLR2+ cells, ED-1+/TLR4+ cells and ED-1+/NF-κB-p-p65+ cells in the kidneys of diabetic rats. Conclusion: The data from the current study demonstrated that tacrolimus could ameliorate early renal injury through a mechanism to suppress macrophage activation.

Genome-wide association study of urinary albumin excretion rate in patients with type 1 diabetes

An abnormal urinary albumin excretion rate (AER) is often the first clinically detectable manifestation of diabetic nephropathy. Our aim was to estimate the heritability and to detect genetic variation associated with elevated AER in patients with type 1 diabetes. The discovery phase genome-wide association study (GWAS) included 1,925 patients with type 1 diabetes and with data on 24 h AER. AER was analysed as a continuous trait and the analysis was stratified by the use of antihypertensive medication. Signals with a p value <10(-4) were followed up in 3,750 additional patients with type 1 diabetes from seven studies. The narrow-sense heritability, captured with our genotyping platform, was estimated to explain 27.3% of the total AER variability, and 37.6% after adjustment for covariates. In the discovery stage, five single nucleotide polymorphisms in the GLRA3 gene were strongly associated with albuminuria (p < 5 × 10(-8)). In the replication group, a nominally significant association (p = 0.035) was observed between albuminuria and rs1564939 in GLRA3, but this was in the opposite direction. Sequencing of the surrounding genetic region in 48 Finnish and 48 UK individuals supported the possibility that population-specific rare variants contribute to the synthetic association observed at the common variants in GLRA3. The strongest replication (p = 0.026) was obtained for rs2410601 between the PSD3 and SH2D4A genes. Pathway analysis highlighted natural killer cell mediated immunity processes. This study suggests novel pathways and molecular mechanisms for the pathogenesis of albuminuria in type 1 diabetes.

Kidney Disease and Related Findings in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study

OBJECTIVEKidney disease manifests clinically as elevated albumin excretion rate (AER), impaired glomerular filtration rate (GFR), or both, and is a cause of substantial morbidity and mortality in type 1 diabetes (T1D). The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study tested whether intensive diabetes therapy (INT) aimed at lowering glucose concentrations as close as safely possible to the normal range reduces the risks of kidney disease and other diabetes complications.RESEARCH DESIGN AND METHODSIn the DCCT, 1,441 participants with T1D were randomly assigned to INT or conventional diabetes therapy (CON) for a mean duration of 6.5 years. Subsequently, participants have been followed for 18 years in the ongoing observational EDIC. Standardized longitudinal measurements of AER, estimated GFR, and blood pressure were made throughout the DCCT/EDIC.RESULTSDuring the DCCT, INT reduced the risks of incident microalbuminuria (AER ≥40 mg/24 h) and macroalbuminuria (AER ≥300 mg/24 h) by 39% (95% CI 21–52%) and 54% (29–74%), respectively. During EDIC years 1–8, participants previously assigned to DCCT INT continued to experience lower rates of incident microalbuminuria and macroalbuminuria, with risk reductions of 59% (39–73%) and 84% (67–92%), respectively. Beneficial effects of INT on the development of impaired GFR (sustained estimated GFR <60 mL/min/1.73 m2) and hypertension became evident during combined DCCT/EDIC follow-up, with risk reductions of 50% (18–69%) and 20% (6–21%), respectively, compared with CON.CONCLUSIONSIn the DCCT/EDIC, INT resulted in clinically important, durable reductions in the risks of microalbuminuria, macroalbuminuria, impaired GFR, and hypertension.

Early elevation of albumin excretion rate is associated with poor gluten‐free diet adherence in young people with coeliac disease and diabetes

There are conflicting data on microvascular complications in coexisting Type 1 diabetes and coeliac disease. We compared complications rates in youth with or without coeliac disease and examined the association between gluten-free diet adherence and complications. This was a comparative study of adolescents (2510 without coeliac disease, 129 with coeliac disease); 60 (47%) did not adhere to a gluten-free diet--defined as elevated anti-tissue transglutaminase or endomysial immunoglobulin A titres. Retinopathy was detected using 7-field fundal photography and albumin excretion rate by timed overnight urine collections, with early elevation defined as albumin excretion rate ≥ 7.5 μg/min. Logistic regression was used to examine the association between complications and explanatory variables, including coeliac disease vs. no coeliac disease, gluten-free diet adherence vs. non-adherence, diabetes duration and HbA1c . Median age at last assessment was 16.5 years. Those with coeliac disease vs. those without were younger at diabetes diagnosis (7.1 vs. 8.6 years, P < 0.001) and had longer diabetes duration (9.3 vs. 7.2 years, P < 0.001). HbA1c was lower in those with coeliac disease vs. those without (67 vs. 70 mmol/mol, 8.3 vs. 8.6%, P = 0.04) and adherence to a gluten-free diet vs. non-adherence (66 vs. 72 mmol/mol, 8.2 vs. 8.7%, P = 0.003). There were no differences in complication rates between those with coeliac disease vs. those without (retinopathy 22 vs. 23%, elevated albumin excretion rate 31 vs. 28%). Non-adherence to a gluten-free diet was associated with elevated albumin excretion rate (40 vs. 23%, P = 0.04). In multivariable logistic regression, elevated albumin excretion rate was associated with non-adherence to a gluten-free diet (odds ratio 2.37, 95% CI 1.04-5.40, P = 0.04) and diabetes duration (odds ratio 1.13, 95% CI 1.02-1.25, P = 0.03), but not HbA1c . While glycaemic control is better in patients with coeliac disease, non-adherence to a gluten-free diet is associated with elevated albumin excretion rate. The possible protection of a gluten-free diet on complications warrants further investigation.

Microalbuminuria, macroalbuminuria and uncontrolled blood pressure among diagnosed hypertensive patients: the aspect of racial disparity in the NHANES study

Accumulating evidence reveals that albuminuria may exacerbate uncontrolled blood pressure (BP) in hypertensive patients. However, racial differences in the associations of albuminuria with uncontrolled BP among diagnosed hypertensives have not been evaluated. A total of 6147 diagnosed hypertensive subjects aged ≥ 18 years were collected from the National Health and Nutrition Examination Survey 1999-2008 with stratified multistage sampling designs. Odds ratios (ORs), relative ORs and 95% confidence intervals (CIs) in uncontrolled BP, and the different effects of microalbuminuria and macroalbuminuria on continuous BP were estimated using weighted logistic models and linear regression models. Hypertensive subjects with microalbuminuria and macroalbuminuria were more likely to have uncontrolled BP and higher average systolic BP (SBP) in all individual racial groups. Microalbuminuria was associated with isolated uncontrolled SBP in non-Hispanic blacks and whites, and macroalbuminuria was associated with isolated uncontrolled SBP and diastolic BP (DBP) and high average DBP only in non-Hispanic blacks. Compared with non-Hispanic whites, non-Hispanic blacks and Mexicans had lower associations of microalbuminuria with uncontrolled BP (relative OR = 0.68, 95% CI = 0.48-0.97 for blacks vs whites; relative OR = 0.62, 95% CI = 0.42-0.93 for Mexicans vs. whites) and isolated uncontrolled SBP (relative OR = 0.62, 95% CI = 0.43-0.90 for blacks vs. whites; relative OR = 0.45, 95% CI = 0.29-0.71 for Mexicans vs. whites). The association of microalbuminuria with uncontrolled BP was lower in non-Hispanic blacks and Mexicans than in non-Hispanic whites. Health providers need to improve care for mildly elevated albumin excretion rates in non-Hispanic white hypertensive patients while maintaining the quality of care in non-Hispanic blacks and Mexicans.

Microalbuminuria could improve risk prediction of stroke in patients with transient ischaemic attacks and minor strokes

BackgroundTransient ischaemic attacks (TIA) and minor strokes are important risk factors for recurrent strokes; they precede 23% of strokes within 90 days. Identification of patients at high risk of developing further strokes is essential to allow early intervention and avoid the catastrophic outcome of strokes. Elevated urinary albumin excretion rate (AER) is a risk factor and predicts cardiovascular disease, stroke, and mortality. Elevated AER can be detected with a point-of-care bedside test. MethodsPatient demographics and the ABCD2 score were obtained for 150 consecutive patients with TIA who presented to the daily stroke clinic and the stroke unit. The ABCD2 score composite for age, blood pressure, clinical features, duration, and diabetes is the risk score presently used for stratifying patients with TIA. All patients had their albumin:creatinine ratio (ACR) measured from a urine sample obtained during their visit to the clinic or the stroke unit at Royal Devon & Exeter Hospital. Patients were followed up for any events, cardiovascular events, stroke, or death at day 7, 30, and 90. FindingsNine patients had recurrent strokes or TIAs by day 7 and 13 by day 9. Patients who had a recurrent stroke or TIA at day 7 and day 90 had a significantly higher ACR than those who did not have an event (4·00 mg/mmol [95% CI 1·89–8·40] vs 1·89 [95% CI 1·58–2·25]; p=0·03 and 3·73 [95% CI 2·12–6·56] vs 1·85 [95% CI 1·55–2·22]; p=0·02, respectively). After adjustment for sex and ABCD2 score, the 90-day predictive role of ACR persisted for those with versus those without subsequent events (adjusted ACR 3·48 mg/mmol [95% CI 1·96–6·19] vs 1·87 [95% CI 1·56–2·24], p=0·04). Stratification of the population at an ACR of 3.0 mg/mmol identified 39 patients at higher risk. Cox proportional hazards of progressing to stroke by day 90 if ACR was more than 3·0 mg/mmol was 3·2 (95% CI 1·07–9·45, p<0·04). InterpretationIncreased urinary albumin excretion, as detected by urinary ACR, is significantly elevated in patients who present with TIA or minor strokes and go on to have further strokes. The use of clinic urinary ACR test could improve the risk prediction of currently available stroke risk scores such as the ABCD2 score. FundingNational Institute for Health Research and Stroke Research Network.

Serum amyloid A and C-reactive protein levels may predict microalbuminuria and macroalbuminuria in newly diagnosed type 1 diabetic patients

BackgroundIn this study we evaluated the association of baseline levels of six different candidate proteins for the development of microalbuminuria and macroalbuminuria in type 1 diabetic patients, who were followed for approximately 30years. Two of the proteins are markers of inflammation: serum amyloid A (SAA) and C-reactive protein (CRP), three are involved in lipid metabolism: apolipoprotein A1, apolipoprotein E and adiponectin and the last protein, fibronectin, is related to structural changes. MethodsA nested case control study population of 60 patients from an inception cohort of type 1 diabetic patients where 20 developed microalbuminuria followed by macroalbuminuria and 40 stayed normoalbuminuric during approximately 30years of follow-up time was used to evaluate baseline levels of the six candidate biomarkers. The proteins were quantified by multiplexed immunoassays. ResultsLog SAA levels were borderline predictor of microalbuminuria, HR 2.31 (1–5.4) p=0.053 in a univariate Cox regression model and predicted the development of macroalbuminuria HR 2.432 (1–6) p=0.049, also univariate. When adjusting for covariates, log SAA predicted the development of microalbuminuria with an HR 4.131 (1.1–15) p=0.03. Log CRP predicted the development of microalbuminuria, HR 2.928 (1.4–6.1) p=0.004, and macroalbuminuria, HR 2.785 (1.3–5.8) p=0.007 in univariate models. When adjusting for covariates, log CRP predicted the development of microalbuminuria with an HR 5.882 (1.7–20.9) p=0.006 and macroalbuminuria with an HR 3.233 (1.1–9.8) p=0.038. Apolipoprotein A1, apolipoprotein E, fibronectin and adiponectin were not associated with development of elevated albumin excretion rate. ConclusionsSAA and CRP baseline levels predicted development of micro- and macroalbuminuria during 30years of follow up, supporting the theory that inflammation is involved in the progression of diabetic nephropathy. Further studies are needed to fully establish the two proteins’ potential as additional biomarkers for the development of diabetic nephropathy.