Baseline Albumin Excretion Rate Research Articles

405-P: Glycemic Control Impacts Renal Function Decline among People with Type 1 Diabetes after the Onset of Diabetic Kidney Disease

While poor glycemic control increases the risk of diabetic kidney disease (DKD) , its impact on renal function decline among those with established DKD is unclear. To examine this, we tested the relationship between baseline HbA1c and renal outcomes in the 3-year Preventing Early Renal Loss (PERL) trial (n=530) , which included persons with type 1 diabetes (T1D) and early-to-moderate DKD (eGFR 40-100 ml/min/1.73m2 and persistent albuminuria and/or ongoing GFR decline) . In Cox regression models, baseline HbA1c was associated (p<0.0001) with a higher risk of progression to ESKD or serum creatinine doubling (HR 1.87 per HbA1c unit increment, 95% CI 1.42-2.47) , and in mixed-effects linear regression models, with 0.87 and 0.51 ml/min/1.73m2/year higher rates of estimated glomerular filtration rate (eGFR) and iohexol GFR decline (p<0.00for both) . Baseline albumin excretion rate (AER) was a modifier of the HbA1c-GFR slope relationships (p for interaction <0.05) , such that HbA1c was associated with a higher rate of GFR decline among those with AER≥200 μg/min than among those with AER<20 or 20≤AER<200 (Fig.1) . Thus, worse glycemic control in PERL was a major determinant of GFR decline and ESKD risk after DKD onset, especially in persons with overt proteinuria. Efforts to normalize HbA1c should continue among such persons. Disclosure H.Shah: None. J.B.Mcgill: Advisory Panel; Gilead Sciences, Inc., Lilly Diabetes, MannKind Corporation, Novo Nordisk A/S, Provention Bio, Inc., Salix Pharmaceuticals, Consultant; Bayer AG, Boehringer Ingelheim International GmbH, Research Support; Dexcom, Inc., Novo Nordisk. I.B.Hirsch: Consultant; Abbott Diabetes, Bigfoot Biomedical, Inc., GWave, Roche Diabetes Care, Research Support; Beta Bionics, Inc., Insulet Corporation, Medtronic. C.Wu: None. A.Galecki: None. M.Mauer: None. A.Doria: Research Support; Novo Nordisk Foundation. Perl consortium: n/a. Funding National Institutes of Health UC4DK101108Juvenile Diabetes Research Foundation 17-2012-377The Leona M. and Harry B. Helmsley Charitable Trust 2018PG-T1D014

The effect of monomeric and oligomeric FLAVAnols in patients with type 2 diabetes and microalbuminuria (FLAVA-trial): A double-blind randomized controlled trial

Microalbuminuria is an early sign of vascular complications of type 2 diabetes and predicts cardiovascular disease and mortality. Monomeric and oligomeric flavanols (MOFs) are linked to improved vascular health. The aim of this study was to assess the effect of 3 months MOFs on albuminuria and endothelial function markers in patients with type 2 diabetes and microalbuminuria. We conducted a double-blind, placebo-controlled trial among patients with type 2 diabetes and microalbuminuria. Patients with type 2 diabetes received either 200mg MOFs or placebo daily on top of their habitual diet and medication. The primary endpoint was the between-group difference of the change in 24-h Albumin Excretion Rate (AER) over three months. Secondary endpoints were the between-group differences of the change in plasma levels of different markers of endothelial dysfunction. Mixed-modelling was applied for the longitudinal analyses. Participants (n=97) were 63.0±9.5 years old; diabetes-duration was 15.7±8.5 years. Median baseline AER was 60 (IQR 20-120) mg/24h. There was no within-group difference in median change of AER from baseline to 3 months in the intervention (0 (-35-21) mg/24h, p=0.41) or the control group (0 (-20-10) mg/24h, p=0.91). There was no between-group difference in the course of AER over three months (log-transformed data: β=-0.02 (95%CI -0.23-0.20), p=0.88), nor in the plasma levels of the endothelial dysfunction markers. Daily 200mg MOFs for three months on top of habitual diet and usual care did not reduce AER and plasma markers of endothelial dysfunction compared to placebo, in patients with long-term type 2 diabetes and microalbuminuria. NTR4669, www.trialregister.nl.

Severe hypoglycemia and coronary artery calcification during the diabetes control and complications trial/epidemiology of diabetes interventions and complications (DCCT/EDIC) study

AimRecently, major attention has been paid to the role of hypoglycemia as a cardiovascular risk factor. While EURODIAB-investigators concluded that severe hypoglycemia is not a cardiovascular risk factor in type 1 diabetes, other investigators found the opposite. The primary purpose of this study was to investigate the role of severe hypoglycemia in atherosclerosis during the DCCT- and EDIC-years with special attention to overall glycemic levels. Research design and methodsThe effect of severe hypoglycemic rates on coronary artery calcification (CAC) was evaluated for the entire cohort (n=1205) and glycemic stratified cohorts (HbA1C<7.5% [58mmol/mol], HbA1C≥7.5%). ResultsThe association between CAC and mean DCCT-hypoglycemia rate was stronger than the association between CAC and mean EDIC-hypoglycemia rate. Although the DCCT-severe hypoglycemia rate without HbA1C-stratification was not significantly associated with a CAC-score≥100 Agatston units (p=0.093), the interaction between above glycemic ranges and DCCT-hypoglycemic rate was significant (p<0.05). A sub-analysis of patients belonging to the lower glycemic range (HbA1C<7.5%), adjusted for baseline age, gender, baseline diabetes duration, baseline neuropathy, baseline albumin excretion rate, systolic blood pressure, LDL-cholesterol, smoking status, body mass index and DCCT-A1C, indicated significant (p=0.02) associations between DCCT-severe hypoglycemia rate and CAC-score≥100. One unit increase in the natural logarithm transformed DCCT-severe hypoglycemia rate increased the risk of having a CAC≥100 by 30%. ConclusionsOur results suggest a cumulative effect of hypoglycemic events on cardiovascular risk. They provide a possible link between above mentioned contradictory reports. Our findings support the relevance of personalizing glycemic goals in diabetes management beyond HbA1C.

Estimated insulin sensitivity predicts regression of albuminuria in Type 1 diabetes.

To test the hypothesis that greater baseline insulin sensitivity would predict regression of albuminuria over 6 years in adults with Type 1 diabetes. We enrolled 81 people aged 30-48 years with albuminuria at baseline in the present study and re-examined them 6 years later. Urinary albumin excretion rate was measured and albuminuria was defined as urinary albumin excretion rate ≥ 20 μg/min. Regression of albuminuria was defined as normoalbuminuria (urinary albumin excretion rate < 20 μg/min) at follow-up. Predictors of regression of albuminuria were examined in stepwise logistic regression. The variables age, diabetes duration, sex, serum uric acid, HbA1c , systolic blood pressure, LDL cholesterol, HDL cholesterol, BMI, baseline albumin excretion rate, estimated insulin sensitivity at baseline, change in estimated insulin sensitivity from baseline to follow-up and angiotensin-converting enzyme inhibitor/angiotensin receptor blocker use were considered for inclusion in the model. Estimated insulin sensitivity was significantly higher at both baseline (4.6 ± 1.2 vs 3.4 ± 1.7; P = 0.002) and follow-up (5.2 ± 1.9 vs. 3.5 ± 1.7; P < 0.0001) in people who had regression of albuminuria vs those who did not. HbA1c (odds ratio 0.4, 95% CI 0.2-0.8; P = 0.006), estimated insulin sensitivity (odds ratio 2.5, 95% CI 1.3-4.9; P = 0.006) at baseline and change in estimated insulin sensitivity from baseline to follow-up (odds ratio 2.7, 95% CI 1.4-5.3; P = 0.003) were independently associated with regression of albuminuria in a multivariable stepwise model. In conclusion, over 6 years, higher baseline estimated insulin sensitivity and change in estimated insulin sensitivity independently predicted regression of albuminuria. Improving insulin sensitivity in people with Type 1 diabetes is a potential therapeutic target to increase rates of regression of albuminuria.

Glomerular normofiltration in hypertension may mask a state of former hyperfiltration

Objective: In the majority of hypertensive subjects normofiltration represents a state of preserved renal function. However, previous research has shown that some normofilterers may represent a group of former hyperfilterers with increased risk of microalbuminuria. We did a prospective study to investigate whether in hypertensive normofilterers with former glomerular hyperfiltration, clinical characteristics differ from those of true normofilterers. Design and methods: Creatinine clearance (CrCl) and albumin excretion rate (AER) were measured at entry and after 8.5 years of follow-up, in 534 young-to-middle-age stage 1 hypertensive subjects from the HARVEST (mean age 34.6±8.3 years, 69% men). Glomerular hyperfiltration was defined as a CrCl≥150 ml/min/1.73m2. Baseline ambulatory BP, 24h urinary epinephrine, echocardiographic data, and routine blood tests were also obtained. Results: At follow-up end, 442 participants were normofilterers. Of these, 395 had normal CrCl also at baseline (true normofilterers, Group 1) whereas 47 subjects had a baseline CrCl ≥150 ml/min/1.73m2 (former hyperfilterers, Group 2). Participants of Group 2 had higher age-and-sex-adjusted systolic blood pressure (p=.007) than those of Group 1. In addition, 24h urinary epinephrine (p<.001), heart rate (p=.05), ambulatory night-time BP fall (p=.004), and left ventricular end-systolic stress (p=.01) were higher in Group 2. During the follow-up, subjects of Group 2 had a greater baseline-adjusted increase in glucose than those of Group 1 (p=.03) and a tendency to the impairment in the other metabolic data. At follow-up end, microalbuminuria was 5.3% in subjects of Group 1 and was 36.2% in those of Group 2 (p<0.0001). This difference held true in a multivariable logistic regression in which several confounders, ambulatory blood pressure, baseline AER, and other risk factors were taken into account (p<0.0001). Conclusions: These data show that hypertensive normofilterers with former hyperfiltration are a distinct subgroup characterized by higher sympatho-adrenergic activity and poorer metabolic profile. These patients are at increased risk of renal damage and should be treated earlier for hypertension

Baseline Markers of Inflammation Are Associated With Progression to Macroalbuminuria in Type 1 Diabetic Subjects

OBJECTIVEThe current study aimed to determine in the Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications cohort whether or not abnormal levels of markers of inflammation and endothelial dysfunction measured in samples collected at DCCT baseline were able to predict the development of macroalbuminuria.RESEARCH DESIGN AND METHODSLevels of inflammation and endothelial cell dysfunction biomarkers were measured in 1,237 of 1,441 patients enrolled in the DCCT study who were both free of albuminuria and cardiovascular disease at baseline. To test the association of log-transformed biomarkers with albuminuria, generalized logistic regression models were used to quantify the association of increased levels of biomarkers and development of abnormal albuminuria. Normal, micro-, and macroalbuminuria were the outcomes of interest.RESULTSIn the logistic regression models adjusted by DCCT treatment assignment, baseline albumin excretion rate, and use of ACE/angiotensin receptor blocker drugs, one unit increase in the standardized levels of soluble E-selectin (sE-selectin) was associated with an 87% increase in the odds to develop macroalbuminuria and one unit increase in the levels of interleukin-6 (IL-6), plasminogen activator inhibitor 1 (PAI-1; total and active), and soluble tumor necrosis factor receptors (TNFR)-1 and -2 lead to a 30–50% increase in the odds to develop macroalbuminuria. Following adjustment for DCCT baseline retinopathy status, age, sex, HbA1c, and duration of diabetes, significant associations remained for sE-selectin and TNFR-1 and -2 but not for IL-6 or PAI-1.CONCLUSIONSOur study indicates that high levels of inflammatory markers, mainly E-selectin and sTNRF-1 and -2, are important predictors of macroalbuminuria in patients with type 1 diabetes.

High Concentrations of AGE-LDL and Oxidized LDL in Circulating Immune Complexes Are Associated With Progression of Retinopathy in Type 1 Diabetes

OBJECTIVETo determine whether immunocomplexes (ICs) containing advanced glycation end product (AGE)–LDL (AGE-LDL) and oxidized LDL (oxLDL) contribute to the development of retinopathy over a 16-year period in subjects with type 1 diabetes.RESEARCH DESIGN AND METHODSLevels of AGE-LDL and oxLDL in ICs were measured in 517 patients of the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) cohort. Retinopathy was assessed by stereoscopic fundus photography. Cox proportional hazards models were used to assess the effect of AGE-LDL-ICs and oxLDL-ICs on retinopathy progression.RESULTSIn unadjusted models, higher baseline levels of AGE-LDL-ICs and oxLDL-ICs significantly predicted progression of diabetic retinopathy outcomes. After adjustment by study-design variables (treatment group, retinopathy cohort, duration of type 1 diabetes, and baseline albumin excretion rate [AER], hemoglobin A1c (HbA1c), and Early Treatment Diabetic Retinopathy Study [ETDRS] score), one SD increase in IC levels was associated with 47% (hazard ratio [HR] 1.47 [95% CI 1.19–1.81]; AGE-LDL-IC) and 45% (1.45 [1.17–1.80]; oxLDL-IC) increased risk of developing proliferative diabetic retinopathy (PDR) and 37% (1.37 [1.12–1.66]; to both ICs) increased risk of progressing to severe nonproliferative retinopathy. Analyses were stratified by retinopathy cohort because results differed between primary and secondary cohorts. For AGE-LDL-ICs, HR for progression to PDR was 2.38 (95% CI 1.30–4.34) in the primary cohort and attenuated in the secondary cohort (1.29 [1.03–1.62]). Similar results were observed for oxLDL-ICs.CONCLUSIONSIncreased levels of AGE-LDL and oxLDL in ICs are associated with increased risk for progression to advanced retinopathy in patients with type 1 diabetes, indicating that the antibody response to modified LDL plays a significant role in retinopathy progression.

Emergence and Progression of Albuminuria in a Cohort of Egyptian Patients with Type 2 Diabetes Mellitus: a 5-year Prospective Study

Introduction: We sought to report the 5-year incidence of proteinuria and risk factors for the progression of diabetic nephropathy in Egyptians with type 2 diabetes mellitus (DM). Methods: Five-hundred and twelve Egyptians with type 2 diabetes were evaluated at baseline and after 5-years of follow-up by a timed urine sample to measure urinary albumin excretion. Baseline evaluation also included a number of potential risk factors of progression of diabetic nephropathy. Results: Patients mean age was 47.5±8.8 years and 47.6% of them were males. Their mean duration of diabetes was 8.9±6.6 years and 44.1% of them were on insulin. At baseline, 62.5% of patients had no proteinuria, 23% had microalbuminuria and 14.5% had overt proteinuria. Among patients that had no albuminuria at baseline, 173/320 still had no albuminuria after 5-years follow up (54.1%), 79/320 developed microalbuminuria (24.7%) and 68/320 developed macroalbuminuria (21.3%). Microalbuminuria progressed to macroalbuminuria in 44/118 patients (37.3%), and 45/512 patients developed end stage renal disease (8.8%). Regression from microalbuminuria to no albuminuria occurred in 49/118 patients (41.5%), regression from overt proteinuria to microalbuminuria occurred in 16/74 patients (21.6%) and regression from overt proteinuria to no albuminuria occurred in 2/74 patients (2.7%). In multivariate analysis, only higher baseline albumin excretion rate (OR 1.4, P < 0.002), higher blood cholesterol levels (OR 2.5, P < 0.02), and depression (2.3, P

Cystatin C as Predictor of Microalbuminuria in the Early Stage of Hypertension

Background/Aims: Predictors of microalbuminuria in the early stage of hypertension are not well known. We did a prospective study to investigate whether glomerular hyperfiltration assessed from serum cystatin C predicts development of microalbuminuria in hypertension. Methods: We assessed 101 treatment-naive subjects screened for stage 1 hypertension and followed-up for a median 3.1 years. Cystatin C was measured at entry and glomerular filtration rate was estimated using the Hoek formula (CystGFR). Urinary albumin and ambulatory blood pressure were measured at entry and during the follow-up. Results: Subjects in the top CystGFR tertile (>115 ml/min/1.73m²) were leaner (p = 0.002) and developed microalbuminuria more frequently (p = 0.02) than the rest of the group. In univariate Cox regression, CystGFR was associated with future microalbuminuria (hazard ratio, 1.06, 95% confidence interval (CI), 1.02–1.10, p = 0.001). After controlling for baseline albumin excretion rate and several confounders, CystGFR remained a significant predictor of microalbuminuria development (hazard ratio, 1.19, 95% CI, 1.03–1.37, p = 0.019). The association between future microalbuminuria and creatinine clearance or glomerular filtration rate estimated with the Cockroft-Gault or the Modification of Diet in Renal Disease formula did not attain the level of statistical significance in this sample. Conclusions: The present findings indicate that CystGFR is more sensitive than creatinine clearance or estimated glomerular filtration rate for predicting microalbuminuria development in the early stage of hypertension and confirm that hyperfiltration precedes microalbuminuria in this clinical entity.

The Effects of Dietary Patterns on Urinary Albumin Excretion: Results of the Dietary Approaches to Stop Hypertension (DASH) Trial

Dietary studies designed to decrease the urinary albumin excretion rate (AER) typically reduce protein by increasing lower protein plant foods and decreasing higher protein animal products. We evaluated AER while increasing protein intake in the Dietary Approaches to Stop Hypertension (DASH) Trial (randomized, parallel group, 8 week controlled feeding). 378 individuals without diabetes with prehypertension or stage I hypertension. The DASH diet, 18% energy from protein, emphasizes, among other features, low-fat dairy products; and the fruit/vegetable (FV) and control diets, each with 15% energy from protein. AER. We measured AER by using immunoassay and covariates at baseline and after 8 weeks. Baseline AER had a geometric mean value of 4.0 +/- 0.2 (SE) mg/24 h. In 285 participants with baseline AER less than 7 mg/24 h, AER was unchanged by diet treatment (geometric mean, 2.5 +/- 0.2 mg/24 h in the control diet, 3.0 +/- 0.2 mg/24 h in the FV diet, and 2.8 +/- 0.2 mg/24 h in the DASH diet). Conversely, in 93 participants with baseline AER of 7 mg/24 h or greater, end-of-feeding AER was lower in the FV diet (6.6 +/- 1.0 mg/24 h) than in the control (11.4 +/- 1.8 mg/24 h; P = 0.01) or DASH diets (11.7 +/- 1.6 mg/24 h; P = 0.005). The DASH and control diets were not different (P = 0.9). Long-term AER change not studied. The decrease in AER after 8 weeks occurred in only those with high-normal baseline AER in the FV diet, in a pattern distinct from the blood pressure decrease. The DASH diet did not increase AER despite a 3% increase in energy from protein.

Measurement of the intrarenal arterial resistance index for the identification and prediction of diabetic nephropathy

Background and Aims High intrarenal resistance index (RI) predicts renal function in several conditions; its use in the prediction of diabetic nephropathy (DN) is little explored. We aimed (1) to compare RI in diabetic and non diabetic hypertensive patients, and (2) to evaluate whether high RI is associated with clinical signs of DN and its progression over time. Methods and Results Design: observational, prospective. Participants: 92 type 2 diabetic patients and 37 non-diabetic controls aged 40–70, with hypertension and normal renal function. We measured ultrasound RI and, among others, creatinine, estimated glomerular filtration rate and urinary albumin excretion rate (AER) at baseline and after 4.5 years follow-up. Progression of albuminuric state (i.e., transition from baseline normo-microalbuminuria to follow-up micro-macroalbuminuria) was evaluated. RI was significantly higher in diabetic than non-diabetic participants (0.69 ± 0.05 vs 0.59 ± 0.05, p < 0.001). Diabetic patients with RI ≥ 0.73, i.e., above the 80th percentile of the RI distribution, had significantly higher baseline AER and a more frequent progression of the albuminuric state compared to patients with RI < 0.73 (27.7 μg/mg [12.1–235.4] vs 15.1 μg/mg [8.6–33.4]; 52.9% vs 9.5%, respectively). AER increased significantly from baseline to follow-up in patients with RI ≥ 0.73 (from 27.7 μg/mg [12.1–235.4] to 265.0 μg/mg [23.8–1018.1], p < 0.01), but not in those with RI < 0.73 (from 15.1 μg/mg [8.6–33.4] to 16.1 μg/mg [10.7–67.2], ns). OR for progression of albuminuric state, adjusted for established predictors of DN, including baseline AER, was 5.01 (1.4–17.7, 95% CI) for patients with RI ≥ 0.73 vs <0.73. Findings were confirmed in patients with normoalbuminuria at baseline. Conclusions In diabetic patients, high RI (≥0.73) is associated with features of DN and its progression over time, independent of albuminuria.

Six-Year Incidence of Proteinuria in Type 1 Diabetic African Americans

We sought to report the 6-year incidence of proteinuria and associated risk factors in African Americans with type 1 diabetes. African Americans (n = 483) with type 1 diabetes were reexamined in a 6-year follow-up study. Proteinuria and creatinuria were measured in 4-h timed urine specimens obtained at initial and follow-up visits. Other evaluations included a structured clinical interview, ocular examination, masked grading of seven stereoscopic fundus photographs, blood pressure measurements, blood assays, and administration of the Beck Depression Inventory (BDI). Over the 6-year period, 117 (42.9%) of the 473 patients at risk developed "any" proteinuria, defined as either microalbuminuria (26.0%) or overt (16.9%) proteinuria; 87 (23.5%) progressed from micro- or no albuminuria to overt proteinuria and 39 (8.7%) to end-stage renal disease; and 40 (20.6%) regressed. Peak incidence of any proteinuria occurred for patients who were 10-14 years of age or had 5-10 years of diabetes duration at baseline. Multiple regression analysis showed that baseline albumin excretion rate (AER), systemic hypertension, blood cholesterol, and high BDI depression scores were significant and independent risk factors for incidence of any proteinuria. In African Americans with type 1 diabetes, the 6-year incidence of proteinuria is high, particularly among young patients and those with a relatively short duration of diabetes at baseline. Baseline AER is the strongest predictor for incidence of any proteinuria.

The Epidemiology of Hemoglobin Levels in Patients With Type 2 Diabetes

Anemia is a common finding in patients with diabetes, for whom it constitutes an additional burden. The aim of this study is to clarify the natural history of anemia in patients with type 2 diabetes and describe factors that predict a decrease in hemoglobin (Hb) levels. A 5-year prospective cohort study was designed as a follow-up of 503 individuals with type 2 diabetes in a single diabetes clinic. In addition to standard management, a full blood count was obtained at each routine visit. No intervention was undertaken to modify Hb levels. At baseline, 12% of patients had anemia, and an additional 13% developed anemia during follow-up. Overall Hb levels decreased by -0.07 +/- 0.01 g/dL/y, suggesting that anemia is the end point of a process that begins more than 10 years previously with the initiation of vascular damage. The greatest decreases in Hb levels were seen in patients with macroalbuminuria, renal impairment, or established macrovascular disease at baseline (all P < 0.01). In patients with microvascular disease, decreasing Hb levels tracked with decreasing glomerular filtration rates (GFRs). Patients with an estimated GFR greater than 90 mL/min/1.73 m2 (>1.5 mL/s) or normoalbuminuria had stable Hb levels during the 5-year follow-up. In patients with anemia in our cohort who were managed conservatively, Hb levels decreased by 0.09 +/- 0.03 g/dL/y. This decrease was associated with HbA1c levels, but not renal function. This study defines the natural history of Hb levels in patients with type 2 diabetes. Early identification of anemia may be achieved by means of annual or biannual screening in high-risk groups with nephropathy, advanced age, or macrovascular disease. These data are important for developing a rational response to the prevention and management of anemia.

Novel predictors of overt nephropathy in subjects with type 1 diabetes. A nested case control study from the Pittsburgh Epidemiology of Diabetes Complications cohort

Predictors of diabetic nephropathy are only partly known and traditional risk factors do not adequately explain disease risk. We thus examined novel risk factors for overt nephropathy (ON) in type 1 diabetes. The EDC is a prospective study of childhood-onset type 1 diabetes. When first seen (1986-1988), mean age was 28 and diabetes duration 19 years. In the subsequent 10 years, 56 of 485 subjects without ON in 1986-88 developed ON. An age, duration (+/-3 years), and sex-matched control was identified for 47 cases. Forty-two matched pairs had available stored plasma samples obtained prior to ON onset in cases, and complete standard risk factor data. Cases had a higher baseline albumin excretion rate (AER), HbA1, pulse rate, non-HDL cholesterol, fibrinogen, small LDL and lower eGDR and LDL particle size compared to controls (all P values<0.05). Multiple measures of immune complexes were increased in cases (P<0.05), whereas borderline elevations were seen for total antioxidant reserve (P=0.06) and retinol (P=0.08). Multivariably, other than AER, LDL particle size and IgG-IC were predictive beyond the standard predictors. Besides AER, the immunecomplexes and lipoprotein subclasses may provide additional information in the assessment of ON risk in type 1 diabetes.

Regression of microalbuminuria in type 1 diabetic patients: results of a sequential intervention with improved metabolic control and ACE inhibitors

The objective was to evaluate the effect of improved metabolic control and ACE inhibition used sequentially in the treatment of type 1 diabetic patients with microalbuminuria. We studied 44 consecutive type 1 diabetic patients with microalbuminuria not previously treated with ACE inhibitors. Improved metabolic control (optimisation period) was attempted for 6-12 months and patients with persistent microalbuminuria were subsequently treated with ACE inhibitors. Stepwise logistic regression analysis included the variables age, age at diabetes onset, duration of diabetes, HbA1c, initial albumin excretion rate (AER) and mean blood pressure as predictors of final AER. Thirty per cent of patients regressed to normoalbuminuria after the optimisation period, and 58% of them maintained normal AER 4.5+/-1.3 years later (3-7 years). Patients achieving normoalbuminuria had lower baseline AER (53+/-22 vs. 94+/-63 mg/24 h, p=0.012). The initial AER level was the only factor associated with final AER (r=0.58, p=0.021). Thirty patients with persistent microalbuminuria were treated with ACE inhibitors for two years, 35.5% of whom regressed to normal AER. Patients achieving normoalbuminuria after ACE inhibitor treatment had lower baseline AER (55+/-24 vs. 132+/-75 mg/24 h, p=0.03). The initial AER was the sole predictor of final AER (r=0.51, p<0.013). Overall, the sequential use of improved metabolic control and ACE inhibitor therapy resulted in long-term normalisation of AER in 47.4% of patients. The sequential implementation of improved metabolic control and ACE inhibitor therapy had a long-term beneficial effect in type 1 diabetic patients with microalbuminuria. We propose that type 1 diabetic patients with microalbuminuria could benefit from a period of metabolic improvement before the initiation of ACE inhibitor therapy.

Should all patients with type 1 diabetes mellitus and microalbuminuria receive angiotensin-converting enzyme inhibitors? A meta-analysis of individual patient data.

To determine whether response of albumin excretion rate to angiotensin-converting enzyme (ACE) inhibitors has a threshold in patients with type 1 diabetes mellitus and microalbuminuria and to examine treatment effect according to covariates. Studies were identified by searching MEDLINE and related bibliographies. Selected studies included at least 10 normotensive patients with type 1 diabetes mellitus and microalbuminuria, had a placebo or nonintervention group, and included at least 1 year of follow-up. Raw data were obtained for 698 patients from the 12 identified trials. Analysis of treatment effect at 2 years was restricted to trials with at least 2 years of follow-up (646 patients from 10 trials). In patients receiving ACE inhibitors, progression to macroalbuminuria was reduced (odds ratio, 0.38 [95% CI, 0.25 to 0.57]) and the odds ratio for regression to normoalbuminuria was 3.07 (CI, 2.15 to 4.44). At 2 years, albumin excretion rate was 50.5% (CI, 29.2% to 65.5%) lower in treated patients than in those receiving placebo (P < 0.001). Estimated treatment effect varied by baseline albumin excretion rate (74.1% and 17.8% in patients with a rate of 200 microg/min and 20 microg/min, respectively [P = 0.04]) but not by patient subgroup. Adjustment for change in blood pressure attenuated the treatment difference in albumin excretion rate at 2 years to 45.1% (CI, 18.6% to 63.1%; P < 0.001). In normotensive patients with type 1 diabetes mellitus and microalbuminuria, ACE inhibitors significantly reduced progression to macroalbuminuria and increased chances of regression. Beneficial effects were weaker at the lowest levels of microalbuminuria but did not differ according to other baseline risk factors. Changes in blood pressure cannot entirely explain the antiproteinuric effect of ACE inhibitors.

Higher normal baseline albumin excretion rate (AER) values and diabetic retinopathy are Predictors of future development of diabetic nephropathy in type 2 diabetic patients (DM2)

Higher normal baseline albumin excretion rate (AER) values and diabetic retinopathy are Predictors of future development of diabetic nephropathy in type 2 diabetic patients (DM2)

Considerations about the threshold value of microalbuminuria in patients with diabetes mellitus: lessons from an 8-year follow-up study of 599 patients

Objective: To examine the validity of the time honored threshold value for microalbuminuria of 30 mg/24 h, by analyzing an 8-year follow-up data of 599 patients with diabetes mellitus type 2, normal blood pressure and base-line albumin excretion rate (AER) ≤30 mg/24 h. Patients: The patients were allocated to three groups according to the baseline values of AER. Group I: 0–10 mg/24 h; Group II: 10.1–20 mg/24 h; Group III: 20.1–30 mg/24 h. Results: Progression to microalbuminuria during follow-up occurred in 25.3, 47.3 and 85.3% of the patients in Group I, II and III, respectively. Compared to Group I, the risk to progress to microalbuminuria was 2.34 (95% CI 1.32–4.43, P=0.029) in patients of Group II and 12.36 (95% CI 8.9–16.5, P=0.0001) in Group III. The average annual decline in glomerular filtration rate (GFR) was 1.19, 1.64 and 2.52 ml/min per year, respectively in the three groups. The correlation between baseline AER values and subsequent decline in GFR was exponential without a clear threshold value. Compared to Group I, the odds ratio for any cardiovascular end point (e.g. death, non-fatal myocardial infarction etc.) was 1.9 (95% CI 0.8–2.5, P=0.22) for patients of Group II and 9.8 (95% CI 6.7–12.3, P=0.001) for Group III. Conclusions: The present study shows that patients with baseline AER values of 20.1–30 mg/24 h show an accelerated decline in GFR and significantly higher risk for cardiovascular events than patients with AER values below 20 mg/24 h. Though AER is obviously a continuous variable, the arbitrary threshold value for screening and for preventive strategies should probably be set at 20 rather than at 30 mg/24 h.

Prospective study of development of microalbuminuria and retinopathy in Brazilian IDDM patients.

With the aim to study potential risk factors for the development of microalbuminuria and retinopathy, baseline characteristics were examined in 50 Brazilian IDDM patients followed for 4.48 years with a 2-year reexamination. During the study, 3 patients (6%) aged 25.9 +/- 4.4 years, duration of diabetes 8.1 +/- 4.2 years, died from acute complications without microalbuminuria and retinopathy after a follow-up of 2.1 +/- 0.7 years. The standardized mortality rate for the group was 0.84 per 1000 (95% CL, 0.31, 1.83) in comparison to 0.14 per 1000 in the general population. From 34 normoalbuminuric individuals at baseline (urinary albumin excretion rate (AER) < or = 20 micrograms/min in > or = 2 overnight urine collections), 10 developed microalbuminuria with an incidence density of 6.5 cases per 100 person-years (95% CL, 2.23, 10.16). Spontaneous normalization of AER was found in 2 of 4 patients with microalbuminuria at cycle 2. Multiple stepwise regression analysis demonstrated that baseline AER (p = 0.03), but not glycated hemoglobin, blood pressure or duration of diabetes, predicted end-of-study AER. From 36 patients without retinopathy, 10 developed nonproliferative retinopathy with an incidence density of 6.6 cases per 100 person-years (95% CL, 2.75, 10.54). Retinopathy was associated with duration (p = 0.05) and age at diagnosis of diabetes (p = 0.01). A tendency with baseline AER (p = 0.06) was also noted. No patient developed macroalbuminuria, proliferative retinopathy or hypertension. By the end of our study, in a cohort of young IDDM patients followed in a developing country, 6% died from acute complications and 15 patients (44.1%) developed retinopathy and/or microalbuminuria. Our results suggest that the only predictor of end-of-study AER was baseline AER. Also, duration of diabetes and age at diagnosis appear to be risk factors for retinopathy.

Course of renal function in type 2 diabetic patients with abnormalities of albumin excretion rate.

Heterogeneity in renal structure has been described in type 2 diabetic patients with both microalbuminuria and proteinuria; in fact, only a subset of type 2 diabetic patients have the typical diabetic glomerulopathy. However, it is currently unknown whether abnormalities in albumin excretion rate (AER) have a different renal prognostic value depending on the underlying renal structure. Aims of this study were: 1) to study the course of renal function in type 2 diabetic patients with altered AER; 2) to evaluate the relationship between the course of glomerular filtration rate (GFR) and renal structure; and 3) to evaluate the relationship between the course of GFR and baseline AER levels, metabolic control, and blood pressure levels during a follow-up period of 4 years. A total of 108 type 2 diabetic patients, 74 with microalbuminuria (MA) and 34 with proteinuria (P), were recruited into a prospective study that encompassed: 1) a baseline kidney biopsy with morphometric measurements of glomerular parameters; 2) intensified antihypertensive treatment for an average 4-year period (blood pressure target <140/90 mmHg); and 3) determinations of GFR at baseline and every 6 months. Mean (+/- SD) GFR significantly decreased from baseline in both MA (-1.3+/-9.4 [95% CI -3.51 to +0.86], P < 0.05) and P (-3.0+/-13.0 ml x min(-1) x 1.73 m(-2) per year [-7.71 to +1.61], P < 0.01). However, the changes in GFR were quite heterogeneous. Thus, on the basis of percent GFR change per year from baseline (delta%GFR), both MA and P patients were defined as progressors or nonprogressors when they were below or above the median, respectively. Baseline parameters of glomerular structure had a strong influence on the course of GFR. Indeed, the odds ratios of being progressors significantly increased across the quartiles of baseline glomerular basement membrane (GBM) width and mesangial fractional volume [Vv(mes/glom)], being 2.71 and 2.85 higher, respectively, in the fourth quartile than in the first quartile (P < 0.01 for both). Conversely, nonprogressors outnumbered progressors in the first quartile of GBM width (odds ratio: 2.14, P < 0.05) and in the first quartile of Vv(mes/glom) (odds ratio: 2.28, P < 0.01). Baseline albumin excretion rate (AER) did not influence delta%GFR; in fact, the number of progressors did not increase across quartiles of baseline AER among either MA or P. Similarly, mean blood pressure levels during follow-up (and intensified antihypertensive therapy) did not affect the course of GFR: the number of progressors and nonprogressors did not change across quartiles of mean blood pressure. In contrast, HbA1c during follow-up had an impact on delta%GFR: the odds ratio for being a progressor increased across quartiles of HbA1c, particularly for the highest quartile (HbA1c >9.0%). In conclusion, the course of renal function is heterogeneous in type 2 diabetic patients with microalbuminuria or proteinuria. In fact, a subset of patients has a rapid decline in GFR over a 4-year follow-up period; these patients have more advanced diabetic glomerulopathy and worse metabolic control than the remaining patients, whose GFR remains stable. These two cohorts are otherwise undistinguishable as regards the degree of AER at baseline and tight blood pressure control. Kidney biopsy has an important prognostic role in these patients. Thus, tight blood pressure control, when not associated with satisfactory glycemic control, is unable to prevent rapid GFR decline in type 2 diabetic patients with typical diabetic glomerulopathy.