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Reduction of urinary connective tissue growth factor by Losartan in type 1 patients with diabetic nephropathy.Background.Connective tissue growth factor (CTGF) is an important profibrotic cytokine implicated in development of diabetic glomerulosclerosis. Urinary CTGF is reported to be significantly increased in patients with diabetic nephropathy. The present study aimed to investigate the short- and long term effects of angiotensin II receptor blockade by Losartan on urinary CTGF levels in hypertensive type 1 diabetic patients with diabetic nephropathy.Methods.Seventy-one hypertensive type 1 diabetic patients with diabetic nephropathy were included in the study. After a washout period of 4 weeks, the patients received Losartan 50 mg, 100 mg, and 150 mg once daily in treatment periods each lasting 2 months. Thereafter, patients were followed prospectively during treatment with Losartan 100 mg o.d. with a total mean follow-up time of 36 months. At baseline, after 2, 4, and 6 months and then biannually, urinary and plasma CTGF levels[enzyme linked immunosorbent assay (ELISA) fibroGen], albuminuria (Turbidimetry), glomerular filtration rate (GFR)[51-creatinine ethylenediaminetetraacetic acid (51Cr-EDTA plasma clearance)] and 24 hours blood pressure (TM2420)) were determined.Results.Baseline levels of urinary and plasma CTGF were 7076 (5708 to 8770) ng/24 hours[geometric mean (95% CI)] and 12.7 (7.3) ng/mL[mean (SD)], respectively. Albuminuria, GFR, and arterial blood pressure at baseline were 1152 (937 to 1416) mg/24 hours, 88 (24) mL/min/1.73 m2, and 153/80 (17/9) mm Hg, respectively. Losartan significantly reduced urinary CTGF by 21% (9 to 31) (95% CI) initially (P<0.05 vs. baseline), with no further reduction after increasing dose. The sustained reduction in urinary CTGF was 22% (12 to 32) (P<0.05 vs. baseline). Rate of decline in GFR during the study was 3.2 (−1.6 to 15.9) mL/min/year[median (range)]. Reduction in urinary CTGF was correlated with a lower rate of decline in GFR (r= 0.23,P= 0.05). Plasma CTGF remained unchanged throughout the study.Conclusion.Our 3-year study demonstrates that Losartan persistently reduces urinary CTGF excretion, which is associated with a slower rate of decline in GFR. [ABSTRACT FROM AUTHOR]

Renoprotection with and without blood pressure reduction. AT1-receptor blockade dose dependently lowers blood pressure (BP) and albuminuria. Reduction of BP and albuminuria are independent treatment targets for renoprotection, but whether this requires similar dose titration is unknown. We tested this in two studies designed to find the optimal antialbuminuric dose of losartan in type 1 diabetic (DM, N = 50) and nondiabetic renal patients (ND, N = 12). After baseline, treatment followed with losartan 50, 100, and 150 mg/day, each dose for eight (DM) or six weeks (ND). At the end of each period, albuminuria (24-hour samples) and mean arterial pressure (MAP) were measured. Patients were divided into "good" and "poor" BP responders (BP+, BP-) according to BP response above or below group median. Baseline MAP in the BP- groups was 102 (97, 104) mm Hg in DM (median, 95% CI) and 91 (80, 108) mm Hg in ND. The top of the dose response for BP (obtained at losartan 100 mg) in the BP- groups was -2 (-4, 3) mm Hg in DM and –1 (-6, 2) mm Hg in ND, versus -15 (-18, -12) mm Hg and -16 (-26, -18) mm Hg in BP+ groups (both P < 0.05). Albuminuria was reduced dose dependently both in BP- and BP+: with 100 mg, the reduction in albuminuria in DM BP- was -32% (-49, 13) versus -45% (-60, -38) in DM BP+ and -45% (-70,-7) versus –25% (-58, -6) in ND BP- and BP+ (all P > 0.05). Moreover, in patients in whom BP fell below the recommended treatment target of 130/80 mm Hg (13 in DM and 10 in ND), albuminuria was progressively reduced, with further increasing the dose of losartan in most patients. Absence of BP response to losartan does not preclude a reduction in albuminuria, and optimal reduction of albuminuria may require titration beyond the predefined BP target. [ABSTRACT FROM AUTHOR]

Renoprotection with and without blood pressure reduction.Background.AT1-receptor blockade dose dependently lowers blood pressure (BP) and albuminuria. Reduction of BP and albuminuria are independent treatment targets for renoprotection, but whether this requires similar dose titration is unknown.Methods.We tested this in two studies designed to find the optimal antialbuminuric dose of losartan in type 1 diabetic (DM,N= 50) and nondiabetic renal patients (ND,N= 12). After baseline, treatment followed with losartan 50, 100, and 150 mg/day, each dose for eight (DM) or six weeks (ND). At the end of each period, albuminuria (24-hour samples) and mean arterial pressure (MAP) were measured. Patients were divided into“good” and“poor” BP responders (BP+, BP−) according to BP response above or below group median.Results.Baseline MAP in the BP− groups was 102 (97, 104) mm Hg in DM (median, 95% CI) and 91 (80, 108) mm Hg in ND. The top of the dose response for BP (obtained at losartan 100 mg) in the BP− groups was−2 (−4, 3) mm Hg in DM and–1 (−6, 2) mm Hg in ND, versus−15 (−18,−12) mm Hg and−16 (−26,−18) mm Hg in BP+ groups (bothP<0.05). Albuminuria was reduced dose dependently both in BP− and BP+: with 100 mg, the reduction in albuminuria in DM BP− was−32% (−49, 13) versus−45% (−60,−38) in DM BP+ and−45% (−70,−7) versus–25% (−58,−6) in ND BP− and BP+ (allP>0.05). Moreover, in patients in whom BP fell below the recommended treatment target of 130/80 mm Hg (13 in DM and 10 in ND), albuminuria was progressively reduced, with further increasing the dose of losartan in most patients.Conclusion.Absence of BP response to losartan does not preclude a reduction in albuminuria, and optimal reduction of albuminuria may require titration beyond the predefined BP target. [ABSTRACT FROM AUTHOR]

OBJECTIVE — Irbesartan is renoprotective in patients with type 2 diabetes and microalbuminuria. Whether the observed reduction in microalbuminuria is reversible (hemodynamic) or persistent (glomerular structural/biochemical normalization) after prolonged antihypertensive treatment is unknown. Therefore, the present substudy of the Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria Study (IRMA-2) investigated the reversibility of kidney function changes after withdrawal of 2 years' antihypertensive treatment. RESEARCH DESIGN AND METHODS — The substudy included 133 hypertensive type 2 diabetic patients with persistent microalbuminuria in IRMA-2, randomized to doublemasked treatment with either placebo, irbesartan 150 mg, or irbesartan 300 mg o.d. for 2 years. Arterial blood pressure, overnight urinary albumin excretion rate, and glomerular filtration rate (GFR) were determined repeatedly. RESULTS — Baseline characteristics were similar in the placebo, irbesartan 150-mg, and irbesartan 300-mg groups. At the end of the study, mean arterial blood pressure (MABP) was similarly lowered to 105 ± 2 (mean ± SE), 103 ± 2, and 102 ± 2 mmHg, respectively (P < 0.05 versus baseline), and urinary albumin excretion rate reduced by 8% (-16 to 27) (NS), 34% (95% CI 8-53), and 60% (46-70) (P < 0.05). Rates of decline in GFRwere 1.3 ± 0.7, 1.2 ± 0.7, and 1.0 ± 0.8 ml · min[sup -1] · 1.73 m[sup -2] per month, respectively, during the initial 3 months of the study and 0.3 ± 0.1, 0.3 ± 0.1, and 0.4 ± 0.1 ml · min[sup -2] · 1.73 m[sup -2] per month in the remaining study period. One month after withdrawal of all antihypertensive medication, MABP remained unchanged in the placebo group, 105 ± 2 mmHg, but increased significantly in the irbesartan groups, to 109 ± 2 and 108 ± 2 mmHg, respectively. Compared with baseline, urinary albumin excretion rate was increased by 14% (-17 to 54) in the placebo group and by 11% (-26 to 65) in the irbesartan 150-mg group but was persistently reduced by 47% (24-73) in the irbesartan 300-mg group (P < 0.05). GFR levels increased to baseline values in the placebo group and approached initial levels in irbesartan groups. CONCLUSIONS — Persistent reduction of microalbuminuria after withdrawal of all antihypertensive treatment suggests that high-dose irbesartan treatment confers long-term renoprotective effects. [ABSTRACT FROM AUTHOR]

Background: Albuminuria and hypertension are predictors of poor renal and cardiovascular outcome in diabetic patients. We tested whether dual blockade of the renin-angiotensin system (RAS) with both an angiotensin-converting enzyme (ACE) inhibitor and an angiotensin II receptor blocker (ARB) is superior to maximal recommended dose of ACE inhibitor in type 1 diabetic patients with diabetic nephropathy (DN).Methods: We performed a randomized, double-blind, crossover trial with 8 weeks treatment with placebo and irbesartan 300 mg (once daily), added on top of enalapril 40 mg (once daily). We included 24 type 1 patients with DN. At the end of each treatment period, albuminuria, 24-hour blood pressure, and glomerular filtration rate (GFR) were measured.Results: Values on ACE inhibitors + placebo were: albuminuria [mean (95% CI)], 519 (342 to 789) mg/24 hours; blood pressure [mean (SEM)], 131 (3)/74 (1) mm Hg, and GFR [mean (SEM)], 65 (5) mL/min/1.73 m2. Dual blockade of the RAS induced a reduction in albuminuria [mean (95% CI)] of 25% (15, 34) (P < 0.001), a reduction in systolic blood pressure of 8 mm Hg (4, 12) (P = 0.002), and a reduction of 4 mm Hg (2, 7) (P = 0.003) in diastolic blood pressure. GFR and plasma potassium remained unchanged during both treatment regimes. Dual blockade was safe and well tolerated.Conclusion: Dual blockade of the RAS is superior to maximal recommended dose of ACE inhibitors with regard to lowering of albuminuria and blood pressure in type 1 patients with DN. Long-term trials are needed to further establish the role of dual blockade of the RAS in renal and cardiovascular protection. [ABSTRACT FROM AUTHOR]

Renoprotective effects of losartan in diabetic nephropathy: Interaction with ACE insertion/deletion genotype? Background. The beneficial short- and long-term renoprotective effects of angiotensin I-converting enzyme (ACE) inhibition are lower in albuminuric diabetic patients homozygous for the deletion compared to the insertion polymorphism of the ACE gene. In an attempt to overcome this interaction, we evaluated the short-term renoprotective effect in diabetic nephropathy of the angiotensin II receptor antagonist losartan in patients homozygous for the insertion or the deletion allele. Methods. Fifty-four hypertensive type 1 diabetic patients with diabetic nephropathy homozygous for the insertion (I; N = 26) or the deletion (D; N = 28) allele of the ACE/ID polymorphism were included. After four weeks of washout, the patients received losartan 50 mg daily followed by 100 mg in two treatment periods each lasting two months. Patients and investigators were blinded to ACE genotypes. At baseline and in the end of the treatment periods, 24-hour blood pressure, albuminuria and glomerular filtration rate values were determined. Results. At baseline, blood pressure, albuminuria and glomerular filtration rate (GFR) values were similar in the two genotype groups [II vs. DD, 1134 (238 to 5302) vs. 1451 (227 to 8129) mg/24 h, median (range); 156/82 (17/9) vs. 153/80 (17/11) mm Hg, mean (SD); and 86 (22) vs. 88 (24) mL/min/1.73 m2 , respectively]. Both doses of losartan significantly lowered blood pressure, albuminuria, and GFR (P < 0.05 vs. baseline). Losartan 100 mg was more effective than 50 mg in reducing albuminuria, 51% (95% CI; 40 to 61) versus 33% (23 to 42), respectively (P < 0.01). No differences in the impact of losartan between the II and DD groups were observed: Losartan 100 mg lowered systolic/diastolic blood pressure by 12/6 and 10/4 mm Hg, whereas albuminuria decreased by 55% (35 to 68) and 46% (28 to 61), in the II and DD groups, respectively (P =... [ABSTRACT FROM AUTHOR]

Studies the glomerular permselectivity in early stages of overt diabetic neuropathy. Development of pathological levels of albuminuria; Neutralization of negatively charged electrostatic barrier within the glomerular capillary wall; Basis of an albumin excretion rate.

Objective: To investigate the association between treatment-induced change in continuous glucose monitoring (CGM) time in range (TIR) and albuminuria in persons with type 1 diabetes (T1D) treated with sensor-augmented insulin pumps (SAP).Research Design and Methods: Twenty-six out of 55 participants with albuminuria and multiple daily injection therapy (25% females; median 51 [interquartile range 46-63] years of age; glycated hemoglobin A1c (HbA1c) 75 [68-88] mmol/mol [9.0% (8.4-10.4%)]; and urinary albumin-to-creatinine ratio (UACR) 89 [37-250] mg/g) were in a randomized controlled trial assigned to SAP therapy for 1 year. Anthropometrics, CGM data, and blood and urine samples were collected every 3 months.Results: Mean change (95% CI) in percentage of TIR (%TIR) was 13.2% (6.2; 20.2), in HbA1c was -14.4 (-17.4; -10.5) mmol/mol (-1.3% [-1.6; -1.0]), and in UACR was -15% (-38; 17) (all P < 0.05). UACR decreased by 19% (10; 28) per 10% increase in %TIR (P = 0.04), 18% (1; 30) per 10 mmol/mol decrease in HbA1c (P = 0.07), and 31% per 10-mmHg decrease in mean arterial pressure (P < 0.001).Conclusions: In this longitudinal study, treatment-induced increase in %TIR was significantly associated with decrease in albuminuria in T1D. [ABSTRACT FROM AUTHOR]

Background: Individual patients show a large variability in albuminuria response to angiotensin receptor blockers (ARB). Identifying novel biomarkers that predict ARB response may help tailor therapy. We aimed to discover and validate a serum metabolite classifier that predicts albuminuria response to ARBs in patients with diabetes mellitus and micro- or macroalbuminuria.Methods: Liquid chromatography-tandem mass spectrometry metabolomics was performed on serum samples. Data from patients with type 2 diabetes and microalbuminuria (n = 49) treated with irbesartan 300 mg/day were used for discovery. LASSO and ridge regression were performed to develop the classifier. Improvement in albuminuria response prediction was assessed by calculating differences in R(2) between a reference model of clinical parameters and a model with clinical parameters and the classifier. The classifier was externally validated in patients with type 1 diabetes and macroalbuminuria (n = 50) treated with losartan 100 mg/day. Molecular process analysis was performed to link metabolites to molecular mechanisms contributing to ARB response.Results: In discovery, median change in urinary albumin excretion (UAE) was -42 % [Q1-Q3: -69 to -8]. The classifier, consisting of 21 metabolites, was significantly associated with UAE response to irbesartan (p < 0.001) and improved prediction of UAE response on top of the clinical reference model (R(2) increase from 0.10 to 0.70; p < 0.001). In external validation, median change in UAE was -43 % [Q1-Q35: -63 to -23]. The classifier improved prediction of UAE response to losartan (R(2) increase from 0.20 to 0.59; p < 0.001). Specifically ADMA impacting eNOS activity appears to be a relevant factor in ARB response.Conclusions: A serum metabolite classifier was discovered and externally validated to significantly improve prediction of albuminuria response to ARBs in diabetes mellitus. [ABSTRACT FROM AUTHOR]

Aims: To investigate the relationship between arterial stiffness and insulin treatment mode [continuous subcutaneous insulin infusion (CSII) versus multiple daily injections (MDI)] in type 1 diabetes patients. Methods: Cross-sectional study, from 2009 to 2011, including 601 Caucasian type 1 diabetes patients, 58 and 543 treated with CSII and MDI, respectively. Arterial stiffness was measured as pulse wave velocity (PWV) (SphygmoCor, AtCor Medical). Adjustment included gender, age, diabetes duration, HbA, heart rate, mean arterial pressure, P-creatinine, urinary albumin excretion rate (UAER), smoking, total daily insulin dose, antihypertensive treatment, previous cardiovascular disease (CVD), total cholesterol and statin treatment. Albuminuria was UAER ≥30 mg/24-h, and CVD included myocardial infarction, revascularization, peripheral arterial disease and stroke. Results: CSII- versus MDI-treated patients were 48 versus 57 % men, 51 ± 11 versus 54 ± 13 years old (mean ± SD), had 33 ± 12 versus 32 ± 16 years diabetes duration and HbA 7.8 ± 0.9 % (62 ± 10 mmol/mol) versus 8.0 ± 1.2 % (64 ± 13 mmol/mol) ( P ≥ 0.08 for all). PWV was lower in CSII- versus MDI-treated patients (9.3 ± 2.8 vs. 10.4 ± 3.4 m/s; P = 0.016). In fully adjusted analysis, CSII treatment was significantly ( P = 0.038) associated with lower PWV, whereas HbA-level was not ( P = 0.93). Conclusions: In type 1 diabetes patients, CSII treatment was associated with lower arterial stiffness independent of other risk factors, while HbA was not. Although glucose variability was not assessed, our results suggest that glucose variability and not HbA-level affect arterial stiffness. This needs confirmation in randomised prospective studies. [ABSTRACT FROM AUTHOR]

Background: Microalbuminuria and hypertension are risk factors for diabetic nephropathy. Blockade of the renin–angiotensin system slows the progression to diabetic nephropathy in patients with type 1 diabetes, but similar data are lacking for hypertensive patients with type 2 diabetes. We evaluated the renoprotective effect of the angiotensin-II–receptor antagonist irbesartan in hypertensive patients with type 2 diabetes and microalbuminuria. Methods: A total of 590 hypertensive patients with type 2 diabetes and microalbuminuria were enrolled in this multinational, randomized, double-blind, placebo-controlled study of irbesartan, at a dose of either 150 mg daily or 300 mg daily, and were followed for two years. The primary outcome was the time to the onset of diabetic nephropathy, defined by persistent albuminuria in overnight specimens, with a urinary albumin excretion rate that was greater than 200 μg per minute and at least 30 percent higher than the base-line level. Results: The base-line characteristics in the three groups were similar. Ten of the 194 patients in the 300-mg group (5.2 percent) and 19 of the 195 patients in the 150-mg group (9.7 percent) reached the primary end point, as compared with 30 of the 201 patients in the placebo group (14.9 percent) (hazard ratios, 0.30 [95 percent confidence interval, 0.14 to 0.61; P<0.001] and 0.61 [95 percent confidence interval, 0.34 to 1.08; P=0.08] for the two irbesartan groups, respectively). The average blood pressure during the course of the study was 144/83 mm Hg in the placebo group, 143/83 mm Hg in the 150-mg group, and 141/83 mm Hg in the 300-mg group (P=0.004 for the comparison of systolic blood pressure between the placebo group and the combined irbesartan groups). Serious adverse events were less frequent among the patients treated with irbesartan (P=0.02). Conclusions: Irbesartan is renoprotective independently of its blood-pressure–lowering effect in patients with type 2 diabetes and microalbuminuria. (N Engl J Med 2001;345:870-8.) [ABSTRACT FROM AUTHOR]