Levels of NT-proBNP, markers of low-grade inflammation, and endothelial dysfunction during spironolactone treatment in patients with diabetic kidney disease.

UNLABELLED: Renin-angiotensin-aldosterone system (RAAS) blockade may reduce levels of biomarkers of chronic low-grade inflammation and endothelial dysfunction. We investigated the effect of spironolactone added to standard RAAS blockade on these biomarkers in an analysis of four original studies. MATERIALS AND METHODS: The studies were double-blind, randomised, placebo-controlled studies in 46 type 1 and 23 type 2 diabetic patients with micro- or macroalbuminuria treated with angiotensin-converting enzyme inhibitor (ACE inhibitor) or angiotensin receptor blocker (ARB), and randomised to additional treatment with spironolactone 25 mg and placebo daily for 60 days. OUTCOME MEASURES: Changes in inflammatory (hsCRP, s-ICAM, TNFα, IL-6, IL-8, Serum amyloid A, IL1ß), endothelial dysfunction (sE-selectin, s-ICAM1, s-VCAM1, VWF, p-selectin, s-thrombomodulin) and NT-proBNP after each treatment period. RESULTS: During spironolactone treatment, u-albumin excretion rate was reduced from 605 (411-890) to 433 (295-636) mg/24 h, as previously reported. Markers of inflammation and endothelial dysfunction did not change; only changes in NT-proBNP (reduced by 14%, p=0.05) and serum amyloid A (reduced by 62%, p=0.10) were borderline significant. DISCUSSIONS: Our results indicate that the renoprotective effect of spironolactone when added to RAAS blockade is not mediated through anti-inflammatory pathways since markers of inflammation and endothelial dysfunction are not affected during treatment.

Tubular and glomerular injury in diabetes and the impact of ACE inhibition.

OBJECTIVE: We studied tubular and glomerular damage in type 1 diabetic patients by measuring urinary-liver fatty acid binding protein (U-LFABP) and albuminuria. Subsequently, we evaluated the effect of ACE inhibition on U-LFABP in patients with diabetic nephropathy. RESEARCH DESIGN AND METHODS: We studied Caucasians with type 1 diabetes: 58 with normoalbuminuria (urinary albumin <30 mg/24 h), 45 with persistent microalbuminuria (30-300 mg/24 h), and 45 with persistent macroalbuminuria (> or =300 mg/24 h). A control group consisted of 57 healthy individuals. The groups were matched by sex and duration of diabetes. In addition, U-LFABP was measured in 48 type 1 diabetic patients with diabetic nephropathy in a randomized crossover trial consisting of 2 months of treatment with 20, 40, and 60 mg lisinopril once daily in random order. RESULTS: In the cross-sectional study, levels of U-LFABP were significantly higher in normoalbuminuric patients versus those in the control group (median 2.6 [interquartile range 1.3-4.1] vs. 19 [0.8-3.0] microg/g creatinine, P = 0.02) and increased with increasing levels of albuminuria (microalbuminuric group 4.2 [1.8-8.3] microg/g creatinine and nephropathy group 71.2 [8.1-123.4], P < 0.05 for all comparisons). U-LFABP correlates with the urinary albumin-to-creatinine ratio (R(2) = 0.54, P < 0.001). In the intervention study, all doses of lisinopril significantly reduced urinary albumin excretion rate and U-LFABP from baseline. The reductions in U-LFABP were 43, 46, and 40% with increasing doses of lisinopril (NS). CONCLUSIONS: An early and progressive increase in tubulointerstitial damage as reflected by increased U-LFABP levels occurs in type 1 diabetic patients and is associated with albuminuria. Furthermore, ACE inhibition reduces the tubular and glomerular damage and dysfunction.

Autoregulation of glomerular filtration rate during spironolactone treatment in hypertensive patients with type 1 diabetes: a randomized crossover trial.

BACKGROUND: Autoregulation of GFR, i.e. maintenance of relative constancy of GFR despite variations in mean arterial pressure (MAP) >80 mmHg, is impaired in diabetic kidney disease; furthermore, some antihypertensive drugs may jeopardize autoregulation. The aim of our study was to establish if spironolactone affects the ability to autoregulate GFR. METHODS: Sixteen hypertensive type 1 diabetic patients with persistent normoalbuminuria (presumed normal autoregulation) completed this randomized, double-masked, crossover trial. After a 4-week wash-out period, patients received spironolactone 25 mg o.d. and matched placebo for 4 weeks in random order. After each treatment period, the ability to autoregulate GFR was determined by measuring GFR ((51)Cr-EDTA clearance) before (basal) and after acute blood pressure reduction by intravenous injection of clonidine. RESULTS: During placebo, the mean (SE) basal GFR was 115 (5) ml/min/1.73 m(2) and the BP was 146 (4)/81 (2) mmHg corresponding to a MAP of 103 (2) mmHg. Spironolactone did not significantly reduce GFR or BP. Injection of clonidine induced a significant reduction in the MAP of 17 (2) and 19 (1) mmHg during placebo and spironolactone treatment, respectively, and an overall reduction in GFR of 11 and 15 ml/min/1.73 m(2) (both comparisons NS between treatment periods). Signs of impaired autoregulation were present in nine patients during placebo and in nine patients during spironolactone treatment. Relative changes in GFR on placebo treatment correlated with diabetes duration (R = 0.67, P < 0.01) but were not related to duration of hypertension, baseline BP, GFR, HbA1c or to changes in BP. CONCLUSION: Spironolactone did not change the overall ability to autoregulate GFR in 16 hypertensive type 1 diabetic patients with normoalbuminuria. Our data are suggestive that the ability to autoregulate GFR is gradually impaired with increasing diabetes duration, a phenomenon not previously described in normoalbuminuric patients.

Enhanced renoprotective effects of ultrahigh doses of irbesartan in patients with type 2 diabetes and microalbuminuria.

BACKGROUND: The purpose of this study was to evaluate the renoprotective effect as reflected by short-term changes in albuminuria of ultrahigh doses of irbesartan in type 2 diabetic patients with microalbuminuria. METHODS: This double-masked randomized crossover trial included 52 (41 males) hypertensive type 2 diabetic patients with microalbuminuria on ongoing antihypertensive medication. At inclusion, previous antihypertensive treatment was discontinued and replaced with bendroflumethiazide, 5 mg once daily, for the entire study. Following 2 months wash-out (baseline), patients were treated randomly with irbesartan 300, 600, and 900 mg once daily, each dose for 2 months. End points evaluated at the end of each study period included urinary albumin excretion rate (UAE) (mean of three 24-hour collections), 24-hour ambulatory blood pressure, and glomerular filtration rate (GFR) [chromium 51 ethylenediaminetetraacetic acid (51Cr-EDTA)]. RESULTS: Baseline values were: 24-hour UAE [geometric mean (95% CI)] 134 (103 to 170) mg/24 hours, ambulatory blood pressure [mean (SD)] 140 (10)/77 (7) mm Hg, and GFR 103 (19) mL/min/1.73 m2. All doses of irbesartan significantly reduced UAE, ambulatory blood pressure, and GFR from baseline. Reductions in UAE from baseline were 52% (46% to 57%), 49% (43% to 54%), and 59% (54% to 63%) with increasing doses of irbesartan (P < 0.01). UAE was reduced significantly more by irbesartan 900 mg compared with lower doses with an additional reduction in UAE of 15% (2% to 26%) by irbesartan 900 mg compared with 300 mg (P = 0.02). The greater reduction in albuminuria by irbesartan 900 vs. 300 mg was more pronounced in patients with UAE during irbesartan 300 mg above vs. below the median [31% (18% to 42%) vs. -9% (-25% to 6%), respectively (P < 0.05)]. With increasing doses systolic ambulatory blood pressure was reduced from baseline by 8 (4 to 12), 9 (5 to 13), and 9 (5 to13) mm Hg, and diastolic ambulatory blood pressure by 6 (4 to 7), 7 (6 to 9), and 7 (6 to 9) mm Hg (NS between doses). CONCLUSION: Ultrahigh dosing of irbesartan (900 mg once daily) is generally safe and offers additional renoprotection independent of changes in systemic blood pressure and GFR in comparison to the currently recommended dose of 300 mg.

Beneficial effects of adding spironolactone to recommended antihypertensive treatment in diabetic nephropathy: a randomized, double-masked, cross-over study.

OBJECTIVE: The objective of this study was to evaluate the safety and short-term effect of adding spironolactone to conventional antihypertensive treatment including diuretics and maximally recommended doses of an ACE inhibitor or an angiotensin II receptor blocker (ARB) on albuminuria and blood pressure in type 2 diabetic patients with nephropathy. RESEARCH DESIGN AND METHODS: Twenty-one type 2 diabetic patients with nephropathy were enrolled in a randomized, double-masked, cross-over study. Patients were treated in random order with spironolactone 25 mg once daily and matched placebo for 8 weeks, respectively, in addition to ongoing antihypertensive treatment including diuretics and maximally recommended doses of an ACE inhibitor and/or an ARB. At the end of each treatment period, albuminuria, 24-h ambulatory blood pressure (ABP), and glomerular filtration rate (GFR) were determined. RESULTS: During the addition of placebo, values were as follows: albuminuria (geometric mean [range]) 1,566 [655-7,762] mg/24 h, ABP (mean +/- SE) 138 +/- 3/71 +/- 1 mmHg, and GFR (mean +/- SE) 74 +/- 6 ml/min per 1.73 m2. During the addition of spironolactone, albuminuria was reduced by 33% (95% CI 25-41) (P < 0.001), fractional clearance of albumin by 40% (24-53) (P < 0.001), and 24-h ABP by 6 mmHg (2-10) for systolic and 4 mmHg (2-6) for diastolic (P < 0.001 for both). The change in albuminuria did not correlate with the change in systolic 24-h ABP (r = 0.19, P = 0.42) or diastolic 24-h ABP (r = 0.01, P = 0.96). Spironolactone treatment induced an insignificant reversible reduction in GFR of 3 ml/min per 1.73 m2 (-0.3 to 6) (P = 0.08). One patient was excluded from the study due to hyperkalemia. Otherwise treatment was well tolerated. CONCLUSIONS: Our study suggests that spironolactone safely adds to the reno- and cardiovascular protective benefits of treatment with maximally recommended doses of ACE inhibitor and ARB by reducing albuminuria and blood pressure in type 2 diabetic patients with nephropathy.