Berit R. Jensen

Predictors for the development of microalbuminuria and macroalbuminuria in patients with type 1 diabetes: inception cohort study

Abstract ObjectiveTo evaluate baseline predictors for the development of persistent microalbuminuria and macroalbuminuria prospectively in patients with type 1 diabetes. DesignProspective observational study of an inception cohort. SettingOutpatient diabetic clinic in a tertiary referral centre, Gentofte, Denmark. Participants286 patients (216 adults) newly diagnosed with type 1 diabetes consecutively admitted to the clinic between 1 September 1979 and 31 August 1984. Main outcome measuresPersistent microalbuminuria and persistent macroalbuminuria. ResultsDuring the median follow up of 18.0 years (range 1.0-21.5 years), total of 4706 patient years of follow up, 79 of 277 (29%) patients developed persistent microalbuminuria. 27 of 79 progressed further to persistent macroalbuminuria. The cumulative incidence of persistent microalbuminuria and persistent macroalbuminuria was 33.6% (95% confidence interval 27.2% to 40.0%) and 14.6% (8.9% to 20.3%), respectively. Significant predictors for the development of persistent microalbuminuria were a 10-fold increase in urinary albumin excretion rate (relative risk 3.78, 1.57 to 9.13), being male (2.41, 1.43 to 4.06), a 10 mm Hg increase in mean arterial blood pressure (1.38, 1.20 to 1.57), a 1% increase in haemoglobin A1c(1.18, 1.04 to 1.32), and a 1 cm increase in height (0.96, 0.95 to 0.98). 28 patients with microalbuminuria (35%) regressed to normoalbuminuria either transiently (n = 15) or permanently (n = 13). ConclusionsAround one third of patients newly diagnosed with type 1 diabetes develop persistent microalbuminuria within the first 20 years of diabetes. Several potentially modifiable risk factors predict the development of persistent microalbuminaria and persistent macroalbuminuria.

Additive Effect of ACE Inhibition and Angiotensin II Receptor Blockade in Type I Diabetic Patients with Diabetic Nephropathy

Albuminuria and hypertension are predictors of poor renal and cardiovascular outcome in diabetic patients. This study tested whether dual blockade of the renin-angiotensin system (RAS) with both an angiotensin-converting enzyme (ACE) inhibitor (ACE-I) and an Angiotensin-II receptor blocker (ARB) is superior to either drug alone in type I diabetic patients with diabetic nephropathy (DN). A randomized double-blind crossover trial was performed with 8-wk treatment with placebo, 20 mg of benazepril once daily, 80 mg of valsartan once daily, and the combination of 20 mg of benazepril and 80 mg of valsartan. Twenty type I diabetic patients with DN were included. At the end of each treatment period, albuminuria, 24-h BP, and GFR were measured. Eighteen patients completed the study. Placebo values were: albuminuria [mean (95% CI)], 701 (490 to 1002) mg/24 h; BP [mean (SEM)], 144 (4)/79 (2) mmHg, and GFR [mean (SEM)], 82 (7) ml/min per 1.73 m(2). Treatment with benazepril, valsartan, or dual blockade significantly reduced albuminuria and BP compared with placebo. Benazepril and valsartan were equally effective. Dual blockade induced an additional reduction in albuminuria of 43 % (29 to 54 %) compared with any type of monotherapy, and a reduction in systolic BP of 6 (0 to 13) mmHg and 7 (1 to 14) mmHg (versus benazepril and valsartan, respectively) and a reduction of 7 (4 to 10) mmHg diastolic compared with both monotherapies. GFR was reversibly reduced on dual blockade compared with monotherapy and placebo. All treatments were safe and well tolerated. In conclusion, dual blockade of the RAS may offer additional renal and cardiovascular protection in type I diabetic patients with DN.

PLASMA LIPOPROTEINS AND RENAL FUNCTION DURING SIMVASTATIN TREATMENT IN DIABETIC NEPHROPATHY

SummaryThe aim of this study was to assess the effect of simvastatin on plasma lipoproteins and renal function in hypercholesterolaemic Type 1 (insulin-dependent) diabetic patients with diabetic nephropathy. Twenty-six hypercholesterolaemic (total cholesterol ≽ 5.5 mmol/l) Type 1 diabetic patients with nephropathy were enrolled in a double-blind randomized placebo-controlled study for 12 weeks. The active treatment group (n -14) received simvastatin (10–20 mg/day) for 12 weeks while the remaining 12 patients received treatment with placebo. The results during simvastatin treatment (baseline vs 12 weeks): total cholesterol 6.6 vs 4.8 mmol/1 (p < 0.01), LDL-cholesterol 4.25 vs 2.57 mmol/l (p < 0.01) and apolipoprotein B 1.37 vs 1.06 mmol/l (p < 0.01). HDL-cholesterol, and apolipoprotein A-I remained unchanged. Total cholesterol, LDL-cholesterol, HDL-cholesterol, apolipoprotein A–I, apolipoprotein B remained unchanged during placebo treatment. Albuminuria measured during the simvastatin and the placebo treatment (baseline vs 12 weeks) (the data are logarithmically transformed before analysis because of their positively skewed transformation; geometric mean (×/÷ antilog SE) is indicated) was 458 (×/÷ 1.58) vs 393 (×/÷ 1.61) and 481 (×/÷ 1.62) vs 368 (×/÷ 1.78 μg/min (NS). Glomerular filtration rate during simvastatin and placebo treatment (baseline vs 12 weeks) was 64 vs 63 and 72 vs 74 ml·min−1·1.73 m−2, respectively. Two patients receiving simvastatin treatment were withdrawn, one due to gastrointestinal side effects and one due to myalgia. In conclusion, our short-term study in Type 1 diabetic patients with diabetic nephropathy did not reveal any beneficial effect on albuminuria despite a striking lipid-lowering effect of simvastatin in diabetic nephropathy.

Differences Between Nisoldipine and Lisinopril on Glomerular Filtration Rates and Albuminuria in Hypertensive IDDM Patients With Diabetic Nephropathy During the First Year of Treatment

Our objective was to compare the effect of a long-acting calcium antagonist (nisoldipine) versus an ACE inhibitor (lisinopril) on albuminuria, arterial blood pressure, and glomerular filtration rate (GFR) in hypertensive IDDM patients with diabetic nephropathy. We performed a 1-year, double-blind, doubledummy, randomized, controlled study comparing nisoldipine (20–40 mg once daily) with lisinopril (10–20 mg once daily) in 52 hypertensive IDDM subjects with diabetic nephropathy. Three patients dropped out, and results for the remaining 49 (25 nisoldipine, 24 lisinopril) are presented. Diuretics were required in 10 nisoldipineand 8 lisinopril-treated patients. Every 3 months, 24-h ambulatory blood pressure (TM2420, A&D, Tokyo, Japan) and albuminuria in three 24-h samples (enzyme immunoassay) were measured; GFR (51Cr-EDTA plasma clearance) was recorded every 6 months. Mean arterial blood pressure (24 h) was reduced from (mean ± SE) 108 ± 3 mmHg at baseline to 101 ± 2 in average during treatment in the lisinopril group and from 105 ± 2 to 103 ± 2 in the nisoldipine group (P = 0.06 comparing changes in the two groups). Albuminuria was reduced 47% (95% CI 21–65) in the lisinopril group versus an increase of 11% (−3 to 27) in the nisoldipine group (P = 0.001). Fractional albumin clearance was reduced 37% (95% CI 4–59%) in the lisinopril versus an increase of 35% (8–69%) in the nisoldipine group (P < 0.01). GFR decreased from 85 ± 5 ml · min−1 · 1.73 m−2 to 73 ± 5 in the lisinopril group and from 84 ± 6 to 80 ± 7 in the nisoldipine group (P < 0.05). The effect of study medication on albuminuria and GFR was independent of changes in systemic blood pressure and baseline variables in multiple regression analyses. In summary, lisinopril reduced albuminuria, but also GFR, to a greater extent than did nisoldipine in hypertensive IDDM patients with diabetic nephropathy during the 1st year of treatment. Longer follow-up is required to clarify whether these drugs have different renoprotective effects.

The acute effect of smoking on systemic haemodynamics, kidney and endothelial functions in insulin-dependent diabetic patients with microalbuminuria

The acute effect of smoking upon arterial blood pressure, urinary albumin excretion rate, glomerular filtration rate and transcapillary escape rate of albumin were investigated in nine normotensive insulin-dependent diabetic patients with microalbuminuria, who had been smoking for 19 (range 4-30) years. In a prospective, open randomized cross-over design, patients were investigated with and without smoking three cigarettes per hour during a 5.5-h period. A rise in systolic blood pressure and heart rate (Takeda TM2420, median (range)) was observed during the smoking day (10(-11 to 14) mmHg and 8 (-1 to 19) beats min-1), compared to the non-smoking day (1 mmHg (-7 to 13) (p = 0.05) and 0 beats min-1 (-2 to 4) (p < 0.01)). Urinary albumin excretion rate (ELISA), glomerular filtration rate (plasma clearance of 51Cr-EDTA) and transcapillary escape rate of albumin (125I-albumin) remained the same with or without smoking. Our study suggests that heavy smoking induces an abrupt rise in systolic blood pressure and heart rate, while vascular leakage of albumin and glomerular filtration rate remain unaltered in normotensive insulin-dependent diabetic patients with microalbuminuria who had been smoking for several years.

Nephropathy in Type 1 diabetes is associated with increased circulating activated platelets and platelet hyperreactivity

Patients with diabetes mellitus (DM) have increased platelet activation compared to non-diabetic controls. Platelet hyperreactivity has been associated with adverse cardiovascular outcomes in Type 2 DM, and with diabetic nephropathy. We investigated the relationship between platelet activation and nephropathy in Type 1 DM. Patients with Type 1 DM and diabetic nephropathy (n = 35), age- and sex-matched Type 1 DM patients with persistent normoalbuminuria (n = 51), and healthy age- and sex-matched controls (n = 30) were studied. Platelet surface P-selectin, platelet surface activated GPIIb/IIIa, monocyte-platelet aggregates (MPAs) and neutrophil-platelet aggregates (NPAs) were measured by whole blood flow cytometry as markers of platelet activation. Platelet reactivity was assessed in response to exogenously added ADP and thrombin receptor activating peptide (TRAP). Platelet surface P-selectin (basal and in response to 0.5 or 20 µM ADP) was higher in nephropathy patients compared with normoalbuminuric patients (P = 0.027), and non-diabetic controls (P = 0.0057). NPAs were higher in nephropathy patients compared to normoalbuminuric patients (P = 0.0088). MPAs were higher in nephropathy patients compared to non-diabetic controls (P = 0.0075). There were no differences between groups in activated GPIIb/IIIa or in response to TRAP at any end-point. More patients with nephropathy received aspirin (71.4%) compared to normoalbuminuric patients (27.4%) (P < 0.0001). Type 1 diabetic nephropathy, as compared with normoalbuminuria, is associated with circulating activated platelets and platelet hyperreactivity to ADP, despite the confounding variable of more nephropathy patients receiving aspirin. This platelet activation is likely to contribute to the known increased risk of cardiovascular events in patients with diabetic nephropathy.

Urinary Neutrophil Gelatinase-Associated Lipocalin and Progression of Diabetic Nephropathy in Type 1 Diabetic Patients in a Four-Year Follow-Up Study

Background: Neutrophil gelatinase-associated lipocalin (NGAL), a marker of renal tubular damage, predicts progression in non-diabetic chronic kidney. We evaluated urinary (u)-NGAL as a predictor of progression in diabetic nephropathy in type 1 diabetic (T1D) patients. Methods: As a substudy of a 4-year randomized, intervention study evaluating low-protein diet in T1D patients with diabetic nephropathy, 78 patients were studied with yearly measurements of u-NGAL (ELISA, BioPorto). Outcome: Decline in glomerular filtration rate (GFR) (51Cr-EDTA), and end-stage renal disease (ESRD) or death. Results: Mean age 40.7 (8.2) years and 50 men. 13 patients developed ESRD or died. Baseline GFR (mean, SD): 68 (31) ml/min/1.73 m2. Baseline u-NGAL [geometric mean (95% CI)] and GFR were 15.6 ng/24 h (11.8–20.7) and 68 (31) ml/min/1.73 m2. During follow-up, an increase in u-NGAL [geometric mean (95% CI)] of 15%/year (4–27) and a decline in GFR of 3.7 (3.0) ml/min/year were observed. Baseline u-NGAL was not associated with the decline in GFR. Elevated u-NGAL at baseline (log-transformed) predicted death and ESRD (HR 3.8, 95% CI 1.04–14.0), however not after adjustment for known progression promoters (HR 2.0, p = 0.6). Conclusion: Elevated u-NGAL was not related to decline in GFR during a 4-year follow-up. Elevated u-NGAL was associated with the development of ESRD and death, but not after adjustment.

The effect of RAAS blockade on markers of renal tubular damage in diabetic nephropathy: u-NGAL, u-KIM1 and u-LFABP

Abstract Aim. Blockade of the renin-angiotensin-aldosterone system (RAAS) affects both the glomerulus and tubules. We aimed to investigate the effect of irbesartan on the tubular markers: urinary (u) neutrophil gelatinase associated protein (NGAL), Kidney injury molecule 1 (KIM1) and liver-fatty acid-binding protein (LFABP). Methods. A substudy of a double-masked, randomized, cross-over study including 52 patients with type 2 diabetes, hypertension and microalbuminuria. After 2 months washout of all antihypertensive medication except bendroflumethiazid, patients were treated in random order with irbesartan 300, 600 and 900 mg for 2 months. End points. Urinary tubular markers at baseline and after each treatment period (ELISA), 24-h blood pressure, glomerular filtration rate (GFR, 51CrEDTA) and 24-h urine albumin excretion (UAER). Results. Fifty-two patients completed the study (41 male). Age (mean (SD)): 58(10) years and diabetes duration 13(8) years. Baseline GFR was 101(24) and UAER (geometric mean [95%CI]) 133 (103–172) mg/24 h. With increasing doses of irbesartan (300, 600, 900 mg) u-KIM1 was reduced with 15%, 10% and 15% (p = 0.07 between 300 mg vs. baseline and no difference between doses). Patients with high u-KIM1 at baseline (above median) had a 32% reduction in u-KIM1 during treatment (p = 0.01). No significant decline in U-NGAL compared to baseline. U-LFABP increased during treatment (p < 0.01). Conclusions. Irbesartan treatment reduced levels of the tubular marker u-KIM1 in patients with type 2 diabetes and microalbuminuria. u-NGAL changed insignificantly and u-LFABP increased. More studies with longer follow up are needed to determine the role of tubular markers in monitoring treatment effect and prediction of prognosis in diabetic nephropathy.