Normoalbuminuric Research Articles

Normoalbuminuric Diabetic Kidney Disease in the U.S. Population

BackgroundThis study sought to compare the prevalence and modifying factors of normoalbuminuric (NA) versus albuminuric (ALB) CKD in the U.S. diabetic and nondiabetic populations. MethodsNHANES 2001–2008 included 2798 diabetic and 15,743 nondiabetic participants. Age-specific prevalence of NA-CKD and ALB-CKD was calculated within each diabetes stratum and then stratified again according to gender, ethnicity, mean arterial pressure ≥105mmHg and HbA1c≥7%. Multivariate regression analyses were performed to determine odds ratios and 95% CI for NA-CKD. ResultsPrevalence of NA-CKD rose with age, with an overall mean of 9.7% in diabetic and 4.3% in nondiabetic participants. NA-CKD was less prevalent in diabetic men, OR=0.58 (95% CI: 0.39, 0.87). In comparison with whites, blacks and ‘other’ ethnic groups had an OR for NA-CKD of 0.44 (95% CI 0.29, 0.68) and 0.57 (95% CI: 0.34, 0.96), respectively. Poorly controlled blood pressure and glycemia resulted in a decreased OR for NA-CKD (OR=0.25, 95% CI: 0.13, 0.50) and (0.48, 95% CI: 0.31, 0.74), respectively. Similar results were obtained for nondiabetic participants. ConclusionsNA-CKD is more common in people with diabetes, women, non-Hispanic whites, and in the setting of well controlled blood pressure and glycemia.

The relationship among TAFI, t-PA, PAI-1 and F1 + 2 in type 2 diabetic patients with normoalbuminuria and microalbuminuria

Disturbances of coagulation and fibrinolysis in type 2 diabetes mellitus (DM2) contribute to increased rates of macrovascular complications such as myocardial infarction and ischemic stroke. The aim of the study was to investigate the relationship among plasminogen activator inhibitor 1 (PAI-1), thrombin-activable fibrinolysis inhibitor (TAFI), tissue plasminogen activator (t-PA), prothrombin fragments 1+2 (F1+2), glycemic control, hypertension, sex and body mass index (BMI) in DM2 patients with normoalbuminuria and microalbuminuria. Forty-two normoalbuminuric (NAU), 42 microalbuminuric (MAU) patients with DM2 and 42 blood donors as control group were enrolled. TAFI, PAI-1, t-PA and F1+2 were assessed by enzyme-linked immunosorbent assay (ELISA) in all patients. TAFI was significantly increased in the MAU group, PAI-1 and F1+2 were increased in both groups and t-PA was not elevated in either group compared to controls. We found positive correlations in the NAU: TAFI and fibrinogen (r=0.65, P=0.02), PAI-1 and triglycerides (r=0.67, P=0.01), in the MAU: TAFI and F1+2 (r=0.48, P=0.02), TAFI and systolic blood pressure (r=0.53, P=0.01), PAI-1 and BMI (r=0.43, P<0.05). We found decreased fibrinolysis in DM2 patients presented with increased PAI-1 in both NAU and MAU. Hypofibrinolysis in MAU is further accented by the elevation of TAFI. TAFI-mediated inhibition of fibrinolysis in DM2 is regulated independently from PAI-1. Patient[Combining Acute Accent]s sex does not affect diabetes-related changes in hemostasis and fibrinolysis.

Risk markers of future microalbuminuria and hypertension based on clinical and morphological parameters in young type 1 diabetes patients

Nephropathy is a severe complication of type 1 diabetes and develops in 30% of patients. Currently, it is not possible to identify young patients at risk prior to the development of microalbuminuria (MA) and/or hypertension (HT). To study predictors of MA and/or HT in young normoalbuminuric (NA) patients with type 1 diabetes. Forty-six NA and normotensive (NT) type 1 diabetes patients, regularly followed since onset with checks on metabolic control, kidney function, and MA, were investigated with kidney biopsies and 24-h ambulatory blood pressure measurements (ABPMs) after 10.6 yr of diabetes. The patients were followed another six and a half years with regard to the development of MA and HT. Fifteen patients developed MA and/or HT during follow-up. The strongest risk markers were poor metabolic control after puberty, high day-time systolic blood pressure (BP), and increased BMT at 10 yr, which explained 62% of the outcome for MA and/or HT at 17 yr duration with 77% sensitivity and 65% specificity. The threshold values were long-term postpubertal HbA(1c) > 8.2%, day-time systolic BP > 130 mmHg, and BMT > 490 nm/1.73 m(2). Normoalbuminuric and NT patients at risk of developing MA and HT could be identified and might benefit from an early start of antihypertensive therapy and improvement of metabolic control.

Circulating vascular endothelial growth factor in the normo- and/or microalbuminuric patients with type 2 diabetes mellitus

Relationship between serum vascular endothelial growth factor (VEGF) level and parameters of endothelial injury and/or dysfunction in patients with diabetes mellitus type 2 with or without microalbuminuria was investigated. Eighty-four diabetic patients were divided in two subgroups (42 each): normoalbuminuric (NAU) and microalbuminuric (MAU). Forty-two blood donors were in control group. Serum VEGF and plasma von Willebrand factor, soluble thrombomodulin, plasminogen activator inhibitor 1, thrombin-activatable fibrinolysis inhibitor (TAFI) and tissue plasminogen activator (t-PA) were measured using enzyme-linked immunosorbent assay in all subjects. VEGF was significantly higher in NAU compared to controls. The difference between MAU and controls was not statistically significant, but there was a trend toward significance. Only TAFI correlated with VEGF in MAU. An observed significant increase of serum VEGF level already in NAU suggests that serum VEGF could be a sensitive predictor of endothelial dysfunction in type 2 diabetes.

Arterial Stiffness and Cognition in Elderly Persons With Impaired Glucose Tolerance and Microalbuminuria

Cognitive decline that occurs frequently in impaired glucose tolerance (IGT) may be largely due to endothelial dysfunction. We assessed: (i) the relationships between impact of urinary albumin excretion rate (UAER), as marker of generalized endothelial dysfunction, and cognition; (ii) if cognitive decline could be explained by arterial stiffening using pulse wave velocity (PWV). One hundred forty older patients (age range 70-85 years) with IGT and no dementia were selected. Patients were classified according to 24-hour UAER: normoalbuminuric (NA) (UAER<20 microg/min) or microalbuminuric (MA) (UAER between 20 and 199 microg/min). Cognitive abilities were assessed by the Mini-Mental State Examination (MMSE) and a composite score of executive and attention functioning (CCS) at baseline and after 12 months of follow-up. In MA patients (n=80), increased UAERs correlated with intimal media thickness (IMT) (r=0.268; p=02) and PWV (r=0.310; p=004). In the same group, increased UAERs were correlated with MMSE and CCS even after adjusting for age and mean arterial blood pressure (MABP). After adding PWV, the associations among UAERs, MMSE, and CCS were no longer significant. In MA patients, PWV correlated with IMT, MMSE, and CCS. In NA patients, no significant correlations were found among UAERs, MMSE, and CCS. At follow-up, baseline UAERs predicted an approximately 20% risk of poor cognition (according to MMSE and CCS) after adjusting for confounders. After adding PWV, UAERs no longer predicted cognitive performance. MA older persons with IGT showed a decline in cognition performance that may be partially explained by arterial stiffness.

Detailed glomerular ultrastructure in Japanese type 2 diabetic patients by the quick-freezing and deep-etching method

Mesangial expansion and glomerular basement membrane (GBM) thickening did not correlate with urinary albumin excretion (UAE) in type 2 diabetic patients in our previous studies; therefore, it was necessary to elucidate more detailed ultrastructural changes in the early stages of diabetic nephropathy (DN) in type 2 diabetic patients. The quick-freezing and deep-etching (QF–DE) method allows us to examine three-dimensional ultrastructures of human renal glomeruli in vivo at high resolution. The QF–DE method was applied to six type 2 diabetic patients without definable renal diseases other than DN. Four patients were normoalbuminuric (NA) and the other two were microalbuminuria (MA). Three control specimens were the normal parts from nephrectomies due to renal cell carcinomas. Electron microscopic morphometric analyses provided quantitative glomerular structural changes. Replica membranes were prepared by the QF–DE method, and diameters of mesh structures at the GBM and mesangial matrix (MM) were measured on electron micrographs as previously described. By the QF–DE method, both the GBM middle layer and MM were composed of polygonal meshwork structures. The mesh pores of the GBM and MM were more enlarged and irregular in shape in NA diabetic patients than those of the controls, and these ultrastructural changes became more obvious in MA patients. The mesh diameters of the GBM and MM in the diabetic patients were also larger than those of the controls. Such a mesh diameter of the GBM was well correlated with the amount of UAE, while the mesh diameter of MM showed a slight correlation with UAE. Although there were small number of subjects in the present study, the detailed ultrastructural changes in NA and MA type 2 diabetic patients, which had not been disclosed by conventional electron microscopy, were revealed by the QF–DE method. Increased mesh diameters of GBM might be related with the increase of UAE.

Correlation between Increased Serum sFas Levels and Microalbuminuria in Type 1 Diabetic Patients

Objective: The aim of this study was to elucidate if apoptosis dysregulation is present in type 1 diabetic patients with microalbuminuria. Subjects and Methods: The following variables were determined in 29 type 1 diabetic patients: the duration of diabetes, soluble Fas (sFas), Bcl-2, hemoglobin A_1c levels, glomerular filtration rate (GFR) and microalbuminuria, using the urine albumin to urine creatinine ratio (ACR). Age and gender were assessed and patients were categorized into two groups, according to their ACR: the microalbuminuric (MA) group with an ACR ≧30 mg/g, and the normoalbuminuric (NA) group with an ACR <30 mg/g. Results: The differences between the two groups regarding sFas, Bcl-2 and GFR were not statistically significant. However, in the MA group, a significant positive relationship between sFas and ACR was observed (r = 0.736, p = 0.015). Dividing patients into two subgroups – mild versus severe (ACR ≧150 mg/g) microalbuminuric patients – significant differences in sFas (60.4 vs. 87.2 pg/ml; p = 0.047) and GFR (113 vs. 69.5 ml min^–1 1.73 m^–2; p = 0.021) were observed, whereas in Bcl-2, the difference was not significant (77.96 vs. 71.13 ng/ml). Conclusions: At the early stages of diabetic nephropathy in type 1 diabetic patients, there seems to be a dysregulation of apoptosis, as expressed by enhanced sFas levels, leading to the speculation that the prevalence of antiapoptotic mechanisms (sFas) may promote mesangial proliferation.

Clinical applications of the quick-freezing and deep-etching method to human diabetic nephropathy

Mesangial expansion and glomerular basement membrane (GBM) thickening were not different between normoalbuminuric (NA) and microalbuminuric (MA) type 2 diabetic patients. The quick-freezing and deep-etching (QF-DE) method allows us to examine three-dimensional ultrastructures of human renal glomeruli in vivo at high resolution. In the present study, the QF-DE method was applied to the renal biopsy from 6 type 2 diabetic patients without definable renal diseases other than diabetic nephropathy. Four patients were NA and the other two were MA. Three control specimens were normal parts in surgically resected kidneys of renal cell carcinoma. Replica membranes were prepared by the QF-DE method as previously described. By the QF-DE method, both GBM middle layer and mesangial matrix (MM) were composed of polygonal meshwork structures. The mesh pores of GBM and MM were more enlarged in size and irregular in shape in NA diabetic patients than those of the controls, and these ultrastructural changes became more obvious in MA patients. The diameters of mesh pores in the diabetic patients were significantly larger than those in the control subjects. In conclusion, the QF-DE method could be applied to needle renal biopsy and the present study has firstly clarified the difference of ultrastructural changes between NA and MA type 2 diabetic patients, which had not been disclosed by the conventional electron microscopy, were revealed by the QF-DE method.

Effect of angiotensin-converting enzyme inhibition on survival in 3773 Chinese type 2 diabetic patients.

We assessed the effects of angiotensin-converting enzyme (ACE) inhibition on survival and cardiorenal outcomes in a consecutive cohort of Chinese type 2 diabetic patients with varying degree of albuminuria, ranging from normoalbuminuria to macroalbuminuria. A total of 3773 consecutive Chinese type 2 diabetic patients were followed prospectively for a mean period of 35.8 months. Clinical end points included all-cause mortality, with cardiovascular end point defined as first hospitalization because of ischemic heart disease, congestive heart failure, revascularization procedures, or cerebrovascular accident as well as renal end point defined as dialysis, doubling of baseline plasma creatinine, or plasma creatinine > or =500 micromol/L. The use of ACE inhibitor was 26.3% in normoalbuminuric (NA), 70.1% in microalbuminuric (MI), and 82.6% in macroalbuminuric (MA) groups. Albuminuria was a major predictor for all-cause mortality with 4-fold difference between NA and MA patients. The 7-year cumulative mortality rate was 7.1%, 10.8%, and 21.7% in the NA, MI, and MA groups, respectively. The use of ACE inhibition was associated with significant reduction of mortality (hazard ratio 0.41 and 95% confidence interval, 0.29, 0.58) in the entire group and was most evident in high-risk patients who had cardiorenal complications or retinopathy at baseline for all albuminuric groups (NA 0.76 [0.31,1.87]; MI 0.32 [0.16, 0.65]; and MA 0.20 [0.13, 0.33]). The prognostic value of albuminuria for death in type 2 diabetes and the beneficial effects of ACE inhibitors in Chinese type 2 diabetic patients with micro- or macroalbuminuria has been confirmed. The effects of ACE inhibitors in type 2 diabetic patients with normoalbuminuria require further evaluation.

Is podocyte injury relevant in diabetic nephropathy? Studies in patients with type 2 diabetes.

Podocyte structural changes have been suggested to be involved in the pathogenesis of albuminuria in diabetes. We evaluated podocytes density, number, and structure in 67 white patients with type 2 diabetes: 21 normoalbuminuric (NA), 23 microalbuminuric (MA), and 23 proteinuric (P). Kidney function and biopsy studies were performed; 20 kidney donors served as control subjects. Electron microscopic morphometric analysis was used to estimate numerical density of podocytes per glomerulus [Nv(epi/glom)], filtration slit length density per glomerulus (FSLv/glom), and foot process width (FPW). The number of podocytes per glomerulus (Epi N/glom) was obtained by multiplying Nv(epi/glom) by mean glomerular volume. Nv(epi/glom) was significantly decreased in all type 2 diabetic groups compared with control subjects and was lower in MA and P than in NA (P < 0.0001, ANOVA). Epi N/glom was lower in MA and P patients compared with control subjects (P < 0.002, ANOVA); however, there were no significant differences among the type 2 diabetic groups. In addition, MA and P had decreased FSLv/glom and increased FPW compared with NA (P < 0.005 for both, ANOVA). The albumin excretion rate was inversely related to Nv(epi/glom) and FSLv/glom and directly to FPW (P < 0.0005 for all), whereas there was no correlation with Epi N/glom. In conclusion, changes in podocyte structure and density occur since the early stages of diabetic nephropathy and might contribute to increasing albuminuria in type 2 diabetic patients. These findings also suggest that in white type 2 diabetic patients, the density of podocytes may be functionally more relevant than the absolute number.

Urinary Albumin as an Indicator of Diabetic Nephropathy Lesions in Japanese Type 2 Diabetic Patients

Caucasian type 2 diabetic patients with microalbuminuria (MA) or overt nephropathy (ON) show greater heterogeneity of renal lesions than type 1 diabetic patients. We examined whether a similar situation exists in 30 Japanese type 2 diabetic patients [21 male, age 48 ± (SD) 8 years, known duration 11 ± (SD) 8 years] without definable renal disease other than diabetic nephropathy. Six patients were normoalbuminuric (NA), 11 MA, and 13 had ON. Normal controls were 9 age-matched Japanese living-related renal transplant donors. Electron microscopic morphometry was performed on renal biopsy specimens and related to renal function. Glomerular basement membrane width and mesangial fractional volume [Vv(Mes/glom)] were increased in all type 2 diabetic patients groups (NA, MA, ON) as compared with normal controls. The Vv(Mes/glom) correlated directly with urinary albumin/creatinine. However, Vv(Mes/glom) as well as glomerular basement membrane width overlapped among the three functional categories (NA, MA, ON) and normal controls. In conclusion: (1) similar to Caucasian type 2 diabetic patients, Japanese type 2 diabetic patients have greater heterogeneity of renal structure than Caucasian type 1 diabetic patients, and (2) urinary albumin is not a reliable indicator of underlying renal structure in Japanese type 2 diabetic patients.

The early natural history of nephropathy in type 1 diabetes: I. Study design and baseline characteristics of the study participants.

This report describes the design and baseline demographic and clinical data in the study of the early natural history of diabetic nephropathy (DN) in type 1 diabetes carried out by the International Diabetic Nephropathy Study Group. The study enrolled 243 patients ages 10-40 years (16.8 +/- 6.0, mean +/- SD) with type 1 diabetes for 2-20 years (8.0 +/- 4.2) at centers in the United States (Minneapolis), Canada (Montreal), and France (Paris). At baseline, all patients were normotensive, none had reduced glomerular filtration rate (GFR), and all but eight were normoalbuminuric (NA). All patients had baseline renal biopsies. During the study, patients will have multiple measurements of blood pressure (BP), renal function, albumin excretion rate (AER), glycemia, and other variables, with repeat renal biopsies planned at 5 years after baseline. The 31.3% of the approached patients who agreed to participate were similar in age, diabetes duration, HbA(1c), AER, and sex to those refusing participation. Age, diabetes duration, HbA(1c), and AER were similar among the three centers, but systolic BP, GFR, renal plasma flow (RPF), and filtration fraction were lower in the Paris center. The 153 patients with hyperfiltration (GFR >130 ml x min(-1) x 1.73 m(-2)) had greater RPF than those with normal GFR. The eight microalbuminuric patients tended to have longer duration of diabetes but were otherwise similar to the NA patients. The role of these and other variables in determining the development rate of the early lesions of DN over the 5 years between biopsies is the central issue under study.

Proteinuria is still useful for the screening and diagnosis of overt diabetic nephropathy.

To assess the performance of urinary total protein measurements in timed 24-h urine collection (24-h UP) and in a diurnal random urine specimen (RUS) for the screening and diagnosis of overt diabetic nephropathy. A total of 167 diabetic patients (20 type 1 and 147 type 2 diabetic patients; 78 women and 89 men), aged 20-84 years, collected 217 timed 24-h urine specimens. Albumin was measured by immunoturbidimetry, total protein by sulfosalicylic acid technique, and creatinine by Jaffe's method. According to the timed 24-h urinary albumin excretion rate (UAER), samples were divided into three groups: normoalbuminuric (NORMO) (UAER < 20 micrograms/min; n = 84), microalbuminuric (MICRO) (UAER 20-200 micrograms/min; n = 78), and macroalbuminuric (MACRO) (UAER > or = 200 micrograms/min; n = 55). Eighty-six patients also collected 105 RUSs (NORMO, n = 47; MICRO, n = 37; MACRO, n = 21), and urinary protein concentration (UPC) and urinary protein-to-creatinine ratio (UPCR) were measured. The receiver operating characteristics (ROC) curve approach was used to analyze the performance of the diagnostic tests. Spearman's coefficient of correlation of 24-h UAER versus 24-h UP was 0.95 (P < 0.001), and of 24-h UAER versus UPC and UPCR were 0.77 and 0.72, respectively (P < 0.001). The calculated areas (+/- SEM) under the ROC curve for the diagnosis of over diabetic nephropathy were 0.9987 +/- 0.001 for 24-h UP, 0.9926 +/- 0.006 for UPC, and 0.9751 +/- 0.014 for UPCR. In the ROC curves, the first points with 100% sensitivity were 541 mg (95.7% specificity) for 24-h UP, 431 mg/l (92.9% specificity) for UPC, and 0.2 (76.2% specificity) for UPCR. Measurements of proteinuria presented almost perfect accuracy for the screening and diagnosis of overt diabetic nephropathy. Protein measurement in spot urine is a reliable and simple method for the screening and diagnosis of overt diabetic nephropathy.