Early-onset type 2 diabetes: A high-risk factor for proliferative diabetic retinopathy (PDR) in patients with microalbuminuria.

We aim to explore the relationship between early-onset diabetes and proliferative diabetic retinopathy (PDR) in type 2 diabetes mellitus (T2DM) patients with microalbuminuria.A total of 461 T2DM patients with microalbuminuria were enrolled. Subjects were defined as early-onset or late-onset based on the age at which they were diagnosed with diabetes (<40 and ≥40 years, respectively). Medical history, anthropometry, and laboratory indicators were documented. PDR was defined as the presence of any of the following changes on fundus photography: neovascularization, vitreous hemorrhage, or preretinal hemorrhage.The prevalence of PDR was 6-fold higher in patients with early-onset than late-onset T2DM [(6.1% vs 1.0%), P = .004]. Univariate correlation analysis showed that early-onset diabetes, use of oral hypoglycemic drugs, and insulin therapy were risk factors for PDR. In multivariate logistic analysis, patients with early-onset diabetes exhibited a 7.00-fold [(95% confidence interval 1.40-38.26), P = .019] higher risk of PDR than subjects with late-onset diabetes after adjusting for sex; T2DM duration; systolic blood pressure; total triglyceride; glycated hemoglobin; insulin therapy; and the use of oral hypoglycemic drugs, antihypertensive drugs, and lipid-lowering drugs.In T2DM patients with microalbuminuria, early-onset diabetes is an independent risk factor for the development of PDR.

The Profile of Plasma Free Amino Acids in Type 2 Diabetes Mellitus with Insulin Resistance: Association with Microalbuminuria and Macroalbuminuria.

Altered plasma levels of branched-chain amino acids (BCAAs) and aromatic amino acids (AAAs) may predict the development of insulin resistance and other type 2 diabetes mellitus (T2DM) associated comorbidities. To elucidate the role of plasma free amino acids (PFAAs) profile as a biomarker for early detection of diabetic kidney disease, quantitative measurement of PFAAs profile was determined for 90 T2DM subjects, 30 were free of nephropathy, 30 with microalbuminuria, 30 with macroalbuminuria, and in addition to 30 healthy controls. The plasma levels of valine, leucine, isoleucine, phenylalanine, citrulline, and total BCAAs were significantly increased in diabetic normoalbuminuria group when compared to controls. However, the total BCAAs level was significantly decreased in diabetic patients with micro and macroalbuminuria. Other amino acid plasma levels as tyrosine, arginine, ornithine, glycine, and the total AAAs level were significantly decreased in all diabetic subgroups compared to controls. Significant positive correlations between total BCAAs, valine, leucine, isoleucine, serum insulin, glucose, and HOMA-IR values in the diabetic normoalbuminuria group were found. The use of altered PFAAs profile as a prognostic factor in T2DM patients at risk for microalbuminuria or macroalbuminuria might reduce or prevent the incidence of end-stage diabetic renal disease.

Proposed Imprecision Quality Goals for Urinary Albumin/Creatinine Ratio.

BACKGROUND: The urinary albumin/creatinine ratio (ACR) is an important indicator of albuminuria. We aimed to estimate ACR uncertainty and its impact on test results and proposed imprecision quality goals based on the estimated uncertainty. METHODS: The combined ACR uncertainty was calculated using the individual uncertainties of urinary albumin and creatinine. ACR confidence intervals (CIs) were estimated based on the expanded uncertainty. When the CI contained the ACR category boundary (30 or 300 mg/g), the cases were considered ambiguous. Quality goals for ACR were suggested using the number of ambiguous cases among actual patient results. RESULTS: The number of ambiguous cases resulting from the combined ACR uncertainty was higher than expected based on biological variation (BV) quality goals. When the ACR met BV quality specifications, we estimated that 4.8-15.5% of the results may have been misclassified. To minimize the number of ambiguous results, the minimum, desirable, and optimum quality goals were set at 34.0%, 18.0%, and 4.5%, respectively. CONCLUSIONS: We expressed ACR uncertainty using the uncertainties of urinary albumin and creatinine and assessed the impact of this combined uncertainty on the test results. Subsequently, we proposed imprecision quality goals for ACR based on ambiguous results.

Classification of Acute Rejection Episodes in Kidney Transplantation: a Proposal Based on Factor Analysis.

INTRODUCTION: Kidney transplantation is considered the ideal treatment for end-stage renal disease. Acute rejection can influence graft survival. The aim of this study was to propose a classification system for acute rejection based on factor analysis. MATERIALS AND METHODS: Data were collected from kidney transplant recipients with acute rejection diagnosis based on standard histological variables, the presence of peritubular eosinophils, and immunolabeling for lysozyme and myeloperoxidase in kidney tissue. Factor analysis was employed for data reduction and generation of a new case classification, with orthogonal rotation as a strategy to simplify factors, and principal component analysis was used as an extraction method. RESULTS: Seventy-nine kidney biopsies were obtained from 74 patients. The total population was divided into humoral rejection (39.2%), cellular rejection (34.1%), and mixed acute rejection (26.7%). No significant differences were found between the three groups in clinical and biochemical variables. We extracted 4 factors using factor analysis. The 1st factor was characterized by the presence of capillaritis, plasma cells infiltration, tubulitis, and inflammation. The 2nd factor included positivity for lysozyme and myeloperoxidase, while the 3rd factor included the presence of eosinophils and glomerulitis. The 4th component consisted of the presence of C4d and endarteritis. The cases belonging to the 3rd factor showed the greatest increase in serum creatinine. The cases belonging to the 4th factor exhibited greater urinary excretion of proteins. CONCLUSIONS: This proposal of classification of acute rejection could contribute to evaluate the prognosis of kidney transplant recipients.

Determining the Optimal Protocol for Measuring an Albuminuria Class Transition in Clinical Trials in Diabetic Kidney Disease.

Albuminuria class transition (normo- to micro- to macroalbuminuria) is used as an intermediate end point to assess renoprotective drug efficacy. However, definitions of such class transition vary between trials. To determine the most optimal protocol, we evaluated the approaches used in four clinical trials testing the effect of renin-angiotensin-aldosterone system intervention on albuminuria class transition in patients with diabetes: the BENEDICT, the DIRECT, the ALTITUDE, and the IRMA-2 Trial. The definition of albuminuria class transition used in each trial differed from the definitions used in the other trials by the number (one, two, or three) of consecutively collected urine samples at each study visit, the time interval between study visits, the requirement of an additional visit to confirm the class transition, and the requirement of a percentage increase in albuminuria from baseline in addition to the class transition. In Cox regression analysis, neither increasing the number of urine samples collected at a single study visit nor differences in the other variables used to define albuminuria class transition altered the average drug effect. However, the SEM of the treatment effect increased (decreased precision) with stricter end point definitions, resulting in a loss of statistical significance. In conclusion, the optimal albuminuria transition end point for use in drug intervention trials can be determined with a single urine collection for albuminuria assessment per study visit. A confirmation of the end point or a requirement of a minimal percentage change in albuminuria from baseline seems unnecessary.

Epidemiological study of chronic kidney disease progression: a large-scale population-based cohort study.

The prognostic information about CKD progression, particularly for GFR categories 1 and 2, is still limited. This cohort was therefore conducted to determine the CKD progression using a competing risk approach. We conducted a retrospective cohort study linking community health screening with hospitals and death registry data in a province of Thailand, from 1997 to 2011. A competing risk model was applied by treating death as a competing risk factor to estimate 2-, 5-, and 10-year probability of kidney failure and median time for CKD progression from lower to higher GFR category. There were 17,074 non-diabetic and 15,032 diabetic CKD subjects. Diabetic subjects progressed more rapidly through GFR categories with the median times for CKD progression from GFR categories G1 to G2, G2 to G3a, G3a to G3b, G3b to G4, and G4 to G5 of 4.4, 6.1, 4.9, 6.3, and 9.0 years, respectively. Non-diabetic subjects took longer to progress with the corresponding median time of 9.4, 14.0, 11.0, 13.8, and >14.3 years. After adjusting for confounders, diabetic subjects were 49% (cause-specific hazard ratio ((c)HR) = 1.49, 95% CI: 1.37, 1.62) more likely to develop kidney failure than non-diabetic subjects. Albuminuria categories A3 and A2 were, respectively, 3.40 (95% CI: 3.07, 3.76) and 1.71 (95% CI: 1.53, 1.92) higher risk of kidney failure when compared to A1. For each albumin category, death rate increased as albuminuria increased particularly in diabetic subjects, which was approximately 2 times higher in A3 compared to A1. Considering GFR category, it gradually increased from G1 to G4 and sharply increased from G4 to G5 in both non-diabetic and diabetic subjects. This study has quantified CKD progression in an Asian population within ordinary practice. Diabetic subjects progress through GFR and albuminuria categories and reach kidney failure about twice as rapidly as non-diabetic subjects.

[Estimation of the glomerular filtration rate in 2014 by tests and equations: strengths and weaknesses]. / L'estimation de la filtration glomérulaire en 2014: intérêts et limites des tests et formules.

The accurate estimation of the glomerular filtration rate (GFR) is a goal of multiple interests regarding clinical, research and public health aspects. The strong relationship between progressive loss of renal function and mortality underlines the need for early diagnosis and close follow-up of renal diseases. Creatinine is the commonest biomarker of GFR in use. By reason of non-renal determinants of GFR, it is required to integrate creatinine values within equations that take in account its most important determinants (i.e., age, sex). The CKD-EPI 2009 equation is now recommended as the first line equation to estimate GFR within the general population. In this indication, it should replace MDRD that tends to overestimate the prevalence of stage 3 chronic kidney disease with GFR around 60 ml/min. However, many questions remain about the accuracy of GFR equations in specific situations such as extremes of age or body weight. The identification of new biomarkers, less determined by non-renal determinants, is of importance. Among these biomarkers, cystatin-C is more accurate to estimate GFR when it is combined to creatinine (i.e., equation CKD-EPI 2012). However the indica. tions for using cystatin-C instead of creatinine alone are still unclear and its use remains limited in routine practice. In conclusion, neither biomarker nor equation gives an accurate estimation for the whole range of GFR and for all patient populations. Limits of prediction are relying on both biomarker's properties and the range of GFR that is concerned, but also rely on the measurement methods. Therefore, it is crucial to interpret the estimated GFR according to the strengths and weaknesses of the equation in use.

[Albuminuria in the diabetic patient: practical management]. / Albuminurie beim Diabetiker: praktisches Management.

Diabetic Nephropathy is the most common cause of end stage renal disease in Western countries. An increased urinary albumin excretion represents a characteristic sign of diabetic kidney damage. Regular screening for microalbuminuria allows early detection and timely intervention. In overt diabetic nephropathy, quantification of albuminuria helps monitoring disease progression. Therapeutic interventions to reduce albuminuria retard progression of nephropathy and reduce cardiovacular mortality, since albuminuria represents an independent cardiovascular risk factor. This review article describes the natural history of diabetic nephropathy and discusses practical issues for the measurement of albuminuria. Available prophylactic and therapeutic measures, particularly glycemic control and inhibition of the renin-angiotensin-aldosteron system, are reviewed using an evidence based approach.

La néphropathie diabétique est la cause la plus commune d'insuffisance rénale terminale dans les pays occidentaux. Une augmentation de l'excrétion urinaire d'albumine représente un signe caractéristique de l'atteinte rénale diabétique. La recherche régulière de microalbuminurie permet la détection précoce et une intervention à temps. En cas de néphropathie diabétique déclarée, la quantification de l'albuminurie aide à suivre la progression de la maladie. Les interventions visant à diminuer l'albuminurie retardent la progression de la néphropathie et réduisent la mortalité cardiovasculaire, puisque l'albuminurie représente un facteur de risque cardiovasculaire indépendant. Cette revue décrit l'histoire naturelle de la néphropathie diabétique et discute des aspects pratiques de la mesure de l'albuminurie. Les mesures prophylactiques et thérapeutiques disponibles aujourd'hui, en particulier le contrôle glycémique et l'inhibition du système rénine-angiotensine-aldostérone, sont revues selon une approche fondée sur des preuves.

Determining the optimal cut-off value of the urinary albumin-to-creatinine ratio to detect atherosclerotic vascular diseases.

BACKGROUND: We examined whether low-grade albuminuria, below the conventional cut-off value for microalbuminuria, was associated with atherosclerotic vascular diseases in 8897 community-dwelling Koreans aged ≥50 years. METHODS: The urinary albumin-to-creatinine ratio (UACR) was calculated using random spot urine. Common carotid artery (CCA) intimamedia thickness (IMT) and CCA internal diameter were measured using high-resolution B-mode ultrasonography, and carotid plaque was evaluated. Brachial-ankle pulse wave velocity (BaPWV) and the ankle-brachial index (ABI) were examined, and peripheral arterial disease was defined as ABI <0.9. RESULTS: Youden's indices, predicting abnormal atherosclerotic conditions, were greatest at a UACR cut-off value of ∼15 mg/g, below the threshold conventionally used to define microalbuminuria. Compared with low normoalbuminuria (UACR <15.0 mg/g), CCA IMT, CCA diameter, and BaPWV were significantly greater in individuals with high normoalbuminuria (UACR 15.0-29.9 mg/g), who also had a significantly higher risk of carotid plaque than did those with low normoalbuminuria. CONCLUSIONS: Subclinical atherosclerotic vascular diseases developed at lower UACRs, below the conventional classification of microalbuminuria. Further longitudinal studies are needed to investigate the relationship between microalbuminuria and the development of subclinical atherosclerosis.

Urinary tubular biomarkers in short-term type 2 diabetes mellitus patients: a cross-sectional study.

The purpose of this study was to investigate the prevalence of tubular damage in short-term (less than five years) type 2 diabetes mellitus (T2DM) patients and to explore the correlation between tubular markers and their relationship with renal indices at different stages of diabetic nephropathy. A group of 101 short-term T2DM patients and 28 control subjects were recruited. Tubular markers, such as neutrophil gelatinase-associated lipocalin (NGAL), N-acetyl-ß-D: -glucosaminidase (NAG), and kidney injury molecule 1 (KIM-1), as well as urinary albumin excretion were measured in voided urine. Glomerular filtration rate (GFR) was estimated via Macisaac's formula. The patients were further categorized into three groups, namely, the normoalbuminuria, microalbuminuria, and macroalbuminuria groups, according to their urine albumin/creatinine ratio (UACR). Urinary tubular markers were compared and their correlations with renal indices [UACR and estimated GFR (eGFR)] were analyzed among the different diabetic groups. Compared with the control group, Urinary NGAL [median (IQR)][83.6(41.4-138.7) µg/gcr vs. 32.9(26.1-64.5) µg/gcr], NAG [13.5(8.7-17.9) U/gcr vs. 7.6(6.5-13.0) U/gcr] and KIM-1 [120.0(98.4-139.9) ng/gcr vs. 103.1(86.8-106.2) ng/gcr] in the T2DM were all markedly increased. For all patients, urinary NGAL had stronger positive correlations with UACR than NAG (R = 0.556 vs. 0.305, both P < 0.05). In addition, only urinary NGAL showed a negative correlation with eGFR (R = -0.215, P < 0.05). Urinary KIM-1, however, showed no significant difference among the three T2DM groups and did not correlate with either UACR or eGFR. As UACR increased from the normoalbuminuria to the last macroalbuminuria group, all of the markers increased. However, only the concentrations of NGAL were statistically different among the three diabetic groups. The correlation between the tubular markers and their relationships with the renal indices differed markedly among the three T2DM groups. In conclusion, these results suggest that tubular damage is common in short-term T2DM patients. Urinary NGAL may be a promising early marker for monitoring renal impairment in short-term T2DM patients.

Medical care costs associated with progression of diabetic nephropathy.

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.

Empirical foundations for the diagnosis of somatization: implications for DSM-5.

BACKGROUND: The aim of this study was to develop empirically validated criteria for the diagnoses of clinically relevant somatization. METHOD: This study was performed in a population-representative cohort consisting of 461 males (47.8%) and 503 females (52.2%), with an average age of 55.8 years (s.d.=11.1). Somatization, anxiety and depression were derived from the Composite International Diagnostic Interview. Mplus was used to perform confirmative factor analyses on the current DSM-IV symptom groups; on alternative symptom clusters previously suggested; and to perform latent class analysis in order to define an empirically derived cut-off for somatization. RESULTS: The existence of symptom groups as described in DSM-IV was not supported by our data, whereas a differentiation between cardiopulmonary, musculoskeletal, gastrointestinal and general somatic symptoms did fit our data. Latent class analysis revealed two classes characterized by few (n=859) and many (n=105) symptoms. The class of subjects could be approached by a simple cut-off of four functional symptoms (sensitivity 79%, specificity 98%, positive predictive value 82%, negative predictive value 97%) regardless of the number of organ systems involved. CONCLUSIONS: This study in a large population-representative cohort suggests that a simple symptom count can be used as a dimensional diagnosis of somatization. In those instances in which a categorical diagnosis is preferred, a simple cut-off of four out of 43 functional symptoms best fitted our data. We did not find any added value for incorporating the number of symptom clusters into the diagnostic criteria.

Circadian blood pressure classification scheme and the health of patients with chronic kidney disease.

BACKGROUND: In health, a sinusoidal rhythm is observed in systolic blood pressure (BP) that peaks (acrophase) during the waking hours (in-phase), but in those with chronic kidney disease (CKD) the acrophase is often observed during sleeping hours (out-of-phase). Yet in others the amplitude of the variation may be so blunted that acrophase may not be definable (phase-less). Circadian rhythms in systolic BP are often described by the dichotomous dipper classification but may not be adequate to fully characterize derangements in cyclical variation in BP. METHODS: To compare classification of circadian BP variation by phase-based classification to dipper-status we examined the cross-sectional relationship of these classification patterns to several markers of health such as health-related quality of life (Kidney Disease Quality of Life Survey, KDQOL) and physical activity (actigraphy over 2 weeks). We also assessed the relationship of circadian BP variation with circadian variation in urine electrolyte and albumin excretion rates. RESULTS: Among 103 veterans with CKD (97% men, age 69, diabetes mellitus 30%, eGFR 38.8 ml/min/1.73 m(2)) no differences were seen between dippers and non-dippers (n = 77, 75%) in eGFR, urinary Na and Cl excretion rates, or KDQOL. However, non-dippers had lower levels of physical activity and greater albuminuria compared to dippers. The same patients were classified to be in-phase (n = 36, 35%), phase-less (n = 19, 18%) or out-of-phase (n = 48, 47%). Patients in-phase had a higher eGFR and somewhat surprisingly also had the highest Na and Cl excretion rates compared to others. Those with out-of-phase systolic BP had the lowest physical composite score on KDQOL, the lowest level of physical activity, and the greatest amount of albuminuria. CONCLUSIONS: Among patients with CKD, circadian BP profile described by either dipper-based or phase-based classification is related to the level of physical activity and the severity of kidney damage. The circadian BP profile is related to overall health and nutritional intake only when using the phase-based classification. The value of these classification schemes to profile circadian BP will require longitudinal studies.

[Microalbuminuria and albuminuria: differential diagnosis and consequences for treatment]. / Mikroalbuminurie und Albuminurie: Differenzialdiagnose und therapeutische Konsequenzen.

The occurrence of microalbuminuria or albuminuria indicates a disturbance of the barrier function of endothelial cells, basement membrane or of a structural-renal disease (including diseased podocytes). The prevalence of microalbuminuria in the general population is about 8 %, however, in high risk groups, prevalence rates of 50 % and more have been observed. Its incidence is strongly associated with increased cardiovascular morbidity and mortality. Blood pressure control and the blockade of the renin-angiotensin-aldosteron-system (RAAS), respectively, is the central mechanism to reduce cardio-vascular-renal end points as well as mortality.

Oxidative stress parameters as possible urine markers in patients with diabetic nephropathy.

OBJECTIVE: Reactive oxygen species play a crucial role in the pathogenesis of diabetic nephropathy (DN). The present study was performed to assess oxidative stress parameters-thiobarbituric acid reactive substances (TBARS), reactive carbonyl derivates (RCDs), and total sulfhydryl groups (TSHGs)-in serum and urine of patients with DN. METHODS: All parameters were determined in patients with type 2 and type 1 diabetes mellitus and microalbuminuria (DMT2-MIA, DMT1-MIA, respectively) and patients with type 2 diabetes mellitus and macroalbuminuria (DMT2-MAA) compared to healthy controls. RESULTS: Serum and urine TBARS levels were higher in all patients with DN and microalbiminuria compared to the control group. RCD levels significantly increased in serum of patients with DMT2 relative to the controls as well as in urine of patients with DMT2-MAA and DMT1-MIA. In all groups of patients, TSHGs decreased in serum but not in urine of patients with DMT2-MAA. CONCLUSION: Urine TBARS, RCDs, and TSHGs could be proposed as possible markers for oxidative damage of kidney in DN.