Improved pregnancy outcome in type 1 diabetic women with microalbuminuria or diabetic nephropathy: effect of intensified antihypertensive therapy?
ABSTRACT: OBJECTIVE: To describe pregnancy outcome in type 1 diabetic women with normoalbuminuria, microalbuminuria, or diabetic nephropathy after implementation of an intensified antihypertensive therapeutic strategy. RESEARCH DESIGN AND METHODS: Prospective study of 117 pregnant women with type 1 diabetes. Antihypertensive therapy, mainly methyldopa, was given to obtain blood pressure <135/85 mmHg and urinary albumin excretion <300 mg/24 h. Blood pressure and A1C were recorded during pregnancy. The pregnancy outcome was compared with recently published studies of pregnant women with microalbuminuria or diabetic nephropathy. RESULTS: Antihypertensive therapy was given in 14 of 100 women with normoalbuminuria, 5 of 10 women with microalbuminuria, and all 7 women with diabetic nephropathy. Mean systolic blood pressure during pregnancy was 120 mmHg (range 101-147), 122 mmHg (116-135), and 135 mmHg (111-145) in women with normoalbuminuria, microalbuminuria, and diabetic nephropathy, respectively (P = 0.0095). No differences in mean diastolic blood pressure or A1C were detected between the groups. No women with microalbuminuria developed preeclampsia. The frequency of preterm delivery was 20% in women with normoalbuminuria and microalbuminuria in contrast to 71% in women with diabetic nephropathy (P < 0.01) where the median gestational age was 258 days (220-260). Compared with previous studies using less stringent antihypertensive therapeutic strategy and less strict metabolic control, gestational age was longer and birth weight was larger in our study. CONCLUSIONS: With intensified antihypertensive therapy and strict metabolic control, comparable pregnancy outcome was seen in type 1 diabetic women with microalbuminuria and normoalbuminuria. Although less severe than in previous studies, diabetic nephropathy was associated with more adverse pregnancy outcome.
Project description:<h4>Aims/hypothesis</h4>The aim of the study was to determine the transition rate and factors associated with the progression of normo- and low microalbuminuria to diabetic nephropathy (overt proteinuria).<h4>Methods</h4>For 8 years we prospectively observed 1,558 Japanese patients with type 2 diabetes mellitus whose basal urinary albumin:creatinine ratio (UACR) had been measured as <17.0 mg/mmol at entry. The incidence of nephropathy (UACR >33.9 mg/mmol) was determined by measuring UACR twice a year.<h4>Results</h4>Progression to nephropathy occurred in 74 patients. The annual transition rate was 0.67%, and was substantially higher for the low-microalbuminuric group than for the normoalbuminuric group (1.85% and 0.23%, respectively; hazard ratio for the low-microalbuminuric group 8.45, p < 0.01). The hazard ratio for an HbA(1c) of 7-9% or ≥9% was 2.72 (p < 0.01) or 5.81 (p < 0.01) relative to HbA(1c) <7.0%, respectively. In comparison with individuals with a systolic blood pressure (SBP) of <120 mmHg, the hazard ratios for patients with an SBP of 120-140 mmHg or ≥140 mmHg were 2.31 (p = 0.06) and 3.54 (p < 0.01), respectively. Smoking also affected progression to proteinuria (hazard ratio 1.99, p < 0.01). In contrast, 30.3% of the low-microalbuminuric group returned to normoalbuminuria (i.e. were in remission).<h4>Conclusions/interpretation</h4>These results suggest that if patients with type 2 diabetes mellitus are receiving treatment from diabetologists for hyperglycaemia and hypertension when they are in the early stages of nephropathy (i.e. normo- or low microalbuminuria), their rate of transition to proteinuria is considerably lowered, and that differentiating patients with low microalbuminuria from those with high microalbuminuria might be clinically useful.<h4>Trial registration</h4>UMIN Clinical Trials Registry C000000222.
Project description:AIMS/INTRODUCTION:The maximum value of home systolic blood pressure is correlated with damage to target organs, including diabetic nephropathy. However, the precise relationship between the development of diabetic nephropathy and maximum home systolic blood pressure has not been elucidated. MATERIALS AND METHODS:In this prospective 2-year cohort subanalysis of the KAMOGAWA-HBP study, the patient population was 477 Japanese patients with normoalbuminuria. We investigated the effects of mean and maximum home blood pressure on the development of diabetic nephropathy, which we defined as a urinary albumin excretion value ≥30 mg/g creatinine. Among the 477 patients, 67 developed diabetic nephropathy. RESULTS:In our multivariate logistic regression analyses, the maximum morning home systolic blood pressure was significantly positively associated with the development of diabetic nephropathy after adjusting for patient sex and age, smoking status, the diabetes mellitus duration, body mass index, creatinine, total cholesterol, hemoglobin A1c, and antihypertensive medication use (odds ratio 1.21, 95% confidence interval 1.03-1.42, P = 0.021). CONCLUSIONS:Maximum home blood pressure can be identified at a glance, and its measurement would thus be helpful to healthcare providers who treat patients with diabetes and normoalbuminuria.
Project description:OBJECTIVE: To estimate the direct medical costs of hypertensive patients with type 2 diabetes by the level of proteinuria and to evaluate the differences between patients whose nephropathy did and did not progress. RESEARCH DESIGN AND METHODS: We identified 7,758 patients with diabetes and hypertension who had a urine albumin-to-creatinine ratio (UACR) during 2001-2003 and at least one follow-up UACR 3-5 years later. Patients were followed for up to 8 years for progression of nephropathy, which was defined by increasing levels of proteinuria: normoalbuminuria (UACR < 30 mg/g), microalbuminuria (30-299 mg/g), macroalbuminuria (?300 mg/g), and end-stage renal disease (dialysis or transplant). We calculated annualized inpatient, outpatient, pharmaceutical, and total medical costs incurred by patients after the baseline measure through 2008, comparing patients who did and did not progress to a higher nephropathy stage. We also compared pre- and postprogression costs among those whose nephropathy progressed. RESULTS: Patients with normoalbuminuria who progressed to microalbuminuria experienced an annualized change in baseline costs that was $396 higher (P < 0.001) than those who maintained normal albuminuria ($902 vs. $506). Among those with microalbuminuria, progression was significantly associated with a $747 difference (P < 0.001) in annualized change in outpatient costs compared with no progression ($1,056 vs. $309). Among patients who progressed, costs were 37% higher following progression from normoalbuminuria to microalbuminuria ($10,188 vs. $7,424; P < 0.001), and 41% higher following progression from microalbuminuria to macroalbuminuria ($12,371 vs. $8,753; P < 0.001). CONCLUSIONS: Progression of nephropathy was strongly associated with higher subsequent medical care costs in hypertensive patients with diabetes. Greater prevention efforts may reduce the substantial economic burden of diabetic nephropathy.
Project description:BACKGROUND:Non-invasive measurements of 24 hour ambulatory central aortic systolic pressure (24 h-CASP) and central pulse pressure (24 h-CPP) are now feasible. We evaluate the relationship between 24 h central blood pressure and diabetes-related complications in patients with type 1 diabetes. METHODS:The study was cross-sectional, including 715 subjects: 86 controls (C), 69 patients with short diabetes duration (< 10 years), normoalbuminuria (< 30 mg/24 h) without receiving antihypertensive treatment (SN), 211 with longstanding diabetes (? 10 years) and normoalbuminuria (LN), 163 with microalbuminuria (30-299 mg/24 h) (Mi) and 186 with macroalbuminuria (> 300 mg/24 h) (Ma).24 h-CASP and 24 h-CPP was measured using a tonometric wrist-watch-like device (BPro, HealthStats, Singapore) and derived using N-point moving average. RESULTS:In C, SN, LN, Mi and Ma mean ± SD 24 h-CASP was: 114 ± 17, 115 ± 13, 121 ± 13, 119 ± 16 and 121 ± 13 mmHg (p < 0.001); and 24 h-CPP: 38 ± 8, 38 ± 7, 44 ± 10, 46 ± 11 and 46 ± 11 mmHg, (p < 0.001).Following rigorous adjustment (24 h mean arterial pressure and conventional risk factors), 24 h-CASP and 24 h-CPP increased with diabetes, albuminuria degree, previous cardiovascular disease (CVD), retinopathy and autonomic dysfunction (p ? 0.031).Odds ratios per 1 standard deviation increase in 24 h-CASP, 24 h-CPP and 24 h systolic blood pressure (24 h-SBP) were for CVD: 3.19 (1.68-6.05), 1.43 (1.01-2.02) and 2.39 (1.32-4.33), retinopathy: 4.41 (2.03-9.57), 1.77 (1.17-2.68) and 3.72 (1.85-7.47) and autonomic dysfunction: 3.25 (1.65-6.41), 1.64 (1.12-2.39) and 2.89 (1.54-5.42). CONCLUSIONS:24 h-CASP and 24 h-CPP was higher in patients vs. controls and increased with diabetic complications independently of covariates. Furthermore, 24 h-CASP was stronger associated to complications than 24 h-SBP.The prognostic significance of 24 h-CASP and 24 h-CPP needs to be determined in follow-up studies. TRIAL REGISTRATION:ClinicalTrials.gov ID NCT01171248.
Project description:<h4>Background</h4>Improving the early detection of diabetic nephropathy remains a great challenge in disease management. Periostin is a marker of renal tubular injury and related to progressive kidney injury in animal models of chronic kidney disease. The clinical implications of urinary periostin activities in patients with type 2 diabetes have not been evaluated.<h4>Methods</h4>Urine samples were obtained from 30 healthy volunteers and 328 type 2 diabetic patients with normoalbuminuria (n=114), microalbuminuria (n=100) and macroalbuminuria (n=114). The excretion levels of urinary periostin were quantified with enzyme-linked immunosorbent assay. Immunohistochemical periostin expression was determined in kidney tissues from overt diabetic nephropathy.<h4>Results</h4>Increased periostin expression in glomeruli and tubular epithelium in diabetic renal pathology was observed. Urinary periostin levels were significantly elevated in the patients of the normoalbuminuria [3.06 (IQR: 1.12, 6.77) ng/mgCr], microalbuminuria [8.71 (IQR: 5.09, 19.29) ng/mgCr] and macroalbuminuria [13.58 (IQR: 3.99, 16.19) ng/mgCr] compared with healthy controls [1.15 (IQR: 0.60, 1.63) ng/mgCr] (P<0.01).Increased urine periostin level significantly correlated with aging, high albuminuria and decline of GFR. Urine periostin ELISA also demonstrated high performance for the diagnosis of established normoalbuminuric, microalbuminuric and macroalbuminuric type 2 diabetes (AUC 0.78 (95%CI, 0.71 to 0.86), 0.99 (95%CI, 0.98 to 1.00) and 0.95 (95%CI, 0.91 to 0.98), respectively).<h4>Conclusion</h4>The study indicates that increased urine periostin levels can be detected in patients with type 2 diabetes before the onset of significant albuminuria. Urinary periostin is an associated renal derangement in patients with established diabetic nephropathy and it may be used as an early marker of diabetic renal injury.
Project description:<h4>Introduction</h4>Diabetic nephropathy (DN) is a progressive kidney disease resulting as a complication of diabetes mellitus. This study evaluated the disease progression and economic burden of DN among commercially insured patients with type 2 diabetes in the USA.<h4>Methods</h4>The research design was a retrospective observational study based on healthcare claims data. The Truven MarketScan Databases (2004-2014) were queried for adults with type 2 diabetes with at least one urine albumin test (index, randomly selected) after diagnosis and at least one test after the index. On the basis of the index test, patients were classified into normoalbuminuria, microalbuminuria, or macroalbuminuria groups. Nephropathy-related treatment use was measured in the 6 months after the index, disease progression was assessed from the index to the end of data availability, and annual all-cause and nephropathy-related costs and healthcare resource use (HRU) were assessed up to 2 years from the index. Outcomes were compared between any two groups, controlling for baseline demographics.<h4>Results</h4>A total of 23,235 patients were identified and classified into normoalbuminuria (N = 18,409), microalbuminuria (N = 3863), or macroalbuminuria (N = 963) groups. Patients with albuminuria were more likely to be older, male, and have a higher burden of baseline comorbidities and HRU. Within 6 months following the index, 12-20% of patients with albuminuria were not treated with any relevant recommended treatment. Compared to the normoalbuminuria group, patients with macroalbuminuria had a significantly greater risk of disease progression (hazard ratio [HR] = 1.44), and both albuminuria groups were more likely to require dialysis (HR = 4.23 and 40.14 for micro- and macroalbuminuria, respectively; all p < 0.05). Annual all-cause (2016 US dollars, $3580 and $12,830 higher for micro- and macroalbuminuria vs. normoalbuminuria, respectively) and nephropathy-related ($362 and $3716) costs increased significantly with increasing nephropathy severity, consistent with the trend in increased HRU.<h4>Conclusions</h4>Diabetic nephropathy may be undertreated or inappropriately treated. It was also associated with significantly higher costs, HRU, and risk of disease progression among commercially insured patients with type 2 diabetes in the USA.<h4>Funding</h4>Takeda Development Center Americas, Inc.
Project description:OBJECTIVE:Chronic renal insufficiency and/or proteinuria in type 2 diabetes may stem from chronic renal diseases (CKD) other than classic diabetic nephropathy in more than one-third of patients. We interrogated urine proteomic profiles generated by surface-enhanced laser desorption/ionization-time of flight/mass spectrometry with the aim of isolating a set of biomarkers able to reliably identify biopsy-proven diabetic nephropathy and to establish a stringent correlation with the different patterns of renal injury. RESEARCH DESIGN AND METHODS:Ten micrograms of urine proteins from 190 subjects (20 healthy subjects, 20 normoalbuminuric, and 18 microalbuminuric diabetic patients and 132 patients with biopsy-proven nephropathy: 65 diabetic nephropathy, 10 diabetic with nondiabetic CKD [nd-CKD], and 57 nondiabetic with CKD) were run using a CM10 ProteinChip array and analyzed by supervised learning methods (Classification and Regression Tree analysis). RESULTS:The classification model correctly identified 75% of patients with normoalbuminuria, 87.5% of those with microalbuminuria, and 87.5% of those with diabetic nephropathy when applied to a blinded testing set. Most importantly, it was able to reliably differentiate diabetic nephropathy from nd-CKD in both diabetic and nondiabetic patients. Among the best predictors of the classification model, we identified and validated two proteins, ubiquitin and ?2-microglobulin. CONCLUSIONS:Our data suggest the presence of a specific urine proteomic signature able to reliably identify type 2 diabetic patients with diabetic glomerulosclerosis.
Project description:Early prevention of diabetic nephropathy by way of blocking the renin-angiotensin system (RAS) in patients with normoalbuminuria seems rational, but trials have so far shown conflicting results. The present meta-analysis was undertaken to investigate if such treatment can prevent development of microalbuminuria.We searched MEDLINE, EMBASE and the Cochrane Library (2 June 2014) for randomised controlled trials, with a population of patients with type 2 diabetes and normoalbuminuria, comparing angiotensin-converting enzyme inhibitors (ACEis) or angiotensin receptor blockers (ARBs) to placebo. Studies had to have at least 50 participants in each arm and one year of follow-up. Random and fixed effect models were performed as well as trial sequential analysis.Six trials were included in the analysis (n=16,921). Overall risk of bias was variable. In a fixed model analysis ACE or ARB treatment was superior to placebo in relation to prevention of development of microalbuminuria, risk ratio 0.84 (95% confidence interval (CI) 0.79-0.88) p<0.001, I(2)=23%, similar to random model results. Treatment also showed a trend towards a reduction in all-cause mortality(p=0.07).We conclude that in patients with type 2 diabetes and normoalbuminuria, early intervention with ACEis or ARBs reduces the risk for development of microalbuminuria.
Project description:Purpose: This meta-analysis aimed to determine the diagnostic performance of neutrophil gelatinase-associated lipocalin (NGAL) in diabetic nephropathy (DN). Methods: We searched the PubMed, Embase, Wanfang, and China National Knowledge Infrastructure databases for articles published up to 24 April 2019. The meta-analyses were conducted by Stata 11.0, and diagnostic accuracy, sensitivity, specificity, negative and positive likelihood ratios (NLR and PLR), diagnostic odds ratio (DOR), and receiver operating characteristic (ROC) curve data were pooled. Moreover, heterogeneity and small trials bias were evaluated. Results: Six cross-sectional studies were included in the meta-analysis. For the studies of microalbuminuria versus normoalbuminuria, the estimates (95% confidence interval) were as follows: sensitivity, 0.75 (0.51-0.89); specificity, 0.78 (0.70-0.84); PLR, 3.37 (2.49-4.56); NLR, 0.33 (0.16-0.69); DOR, 10.31 (4.05-26.25); and area under the ROC curve (AUC), 0.81 (0.77-0.84). For the studies of microalbuminuria?+?macroalbuminuria versus normoalbuminuria, the results were as follows: sensitivity, 0.83 (0.66-0.93); specificity, 0.88 (0.67-0.97); PLR, 7.20 (1.97-26.31); NLR, 0.19 (0.08-0.46); DOR, 37.83 (4.84-295.65); AUC, 0.92 (0.90-0.94). Deeks' funnel plot suggested that small trials bias was insignificant in this study. Conclusions: Our findings suggest that NGAL is a potential diagnostic marker for patients with DN and that its diagnostic value for microalbuminuria?+?macroalbuminuria is superior to that for microalbuminuria. Highlights The first meta-analysis to investigate NGAL diagnostic role in DN. NGAL is valuable for the early diagnosis of DN. The diagnostic value of NGAL in microalbuminuria?+?macroalbuminuria was much higher.
Project description:<h4>Background</h4>Diabetic nephropathy (DN) is a major complication of diabetes and the main cause of end-stage renal disease. Extracellular vesicles (EVs) are small cell-derived vesicles that can alter disease progression by microRNA (miRNA) transfer.<h4>Methods</h4>In this study, we aimed to characterize the cellular origin and miRNA content of EVs in plasma samples of type 2 diabetes patients at various stages of DN. Type 2 diabetes patients were classified in three groups: normoalbuminuria, microalbuminuria and macroalbuminuria. The concentration and cellular origin of plasma EVs were measured by flow cytometry. A total of 752 EV miRNAs were profiled in 18 subjects and differentially expressed miRNAs were validated.<h4>Results</h4>Diabetic patients with microalbuminuria and/or macroalbuminuria showed elevated concentrations of total EVs and EVs from endothelial cells, platelets, leucocytes and erythrocytes compared with diabetic controls. miR-99a-5p was upregulated in macroalbuminuric patients compared with normoalbuminuric and microalbuminuric patients. Transfection of miR-99a-5p in cultured human podocytes downregulated mammalian target of rapamycin (mTOR) protein expression and downregulated the podocyte injury marker vimentin.<h4>Conclusions</h4>Type 2 diabetes patients with microalbuminuria and macroalbuminuria display differential EV profiles. miR-99a-5p expression is elevated in EVs from macroalbuminuria and mTOR is its validated mRNA target.