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]) 1,566 762] mg/24 h, ABP (mean Ϯ SE) 138 Ϯ 3/71 Ϯ 1 mmHg, and GFR (mean Ϯ SE) 74 Ϯ 6 ml/min per 1.73 m 2 . During the addition of spironolactone, albuminuria was reduced by 33% (95% CI 25-41) (P Ͻ 0.001), fractional clearance of albumin by 40% (24 -53) (P Ͻ 0.001), and 24-h ABP by 6 mmHg (2-10) for systolic and 4 mmHg (2-6) for diastolic (P Ͻ 0.001 for both). The change in albuminuria did not correlate with the change in systolic 24-h ABP (r ϭ 0.19, P ϭ 0.42) or diastolic 24-h ABP (r ϭ 0.01, P ϭ 0.96). Spironolactone treatment induced an insignificant reversible reduction in GFR of 3 ml/min per 1.73 m 2 (Ϫ0.3 to 6) (P ϭ 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. Diabetes Care 28:2106 -2112, 2005A ldosterone, the end product of the renin-angiotensin-aldosterone system (RAAS), has attracted renewed attention as an important mediator of both cardiovascular and renal disease (1,2). Accumulating experimental evidence suggests that circulating aldosterone per se contributes directly to renal and cardiovascular disease by inducing inflammation, fibrosis, and necrosis in end-organ tissues such as the heart, brain, and kidney (3). Moreover, aldosterone blockade has been shown to greatly improve survival in patients with chronic heart failure (4,5).Angiotensin II has long been considered the main mediator of the pathophysiological effects of the RAAS, and in diabetic nephropathy the renoprotective effects of treatment with an ACE inhibitor or an angiotensin receptor blocker (ARB) are well established (6 -9). Both ACE inhibitor and ARB treatments initially suppress plasma aldosterone. Eventually, however, plasma aldosterone may return to pretreatment levels, i.e., the aldosterone escape phenomenon. Aldosterone e...

Our results suggest that spironolactone treatment on top of recommended antihypertensive treatment reduces blood pressure and may offer additional renoprotection in type 1 diabetic patients with diabetic nephropathy.

Aims/hypothesis. It has been suggested that aldosterone plays a role in the initiation and progression of renal disease independently of arterial blood pressure and plasma angiotensin II levels. We evaluated the influence of plasma aldosterone levels on progression of diabetic nephropathy during long-term blockade of the renin-angiotensin-aldosterone system. Methods. A total of 63 hypertensive patients with type 1 diabetes and diabetic nephropathy were treated with losartan, 100 mg once daily, for a mean follow-up period of 35 months. Plasma aldosterone, GFR, albuminuria and 24-h blood pressure were determined at baseline and at regular intervals during the study. Results. Patients were divided according to their increasing or decreasing levels of plasma aldosterone during long-term losartan treatment in an escape group (n=26) and a non-escape group (n=37). In the escape group, aldosterone levels increased from (geometric mean [95% CI]) 57 pg/ml (43-76 pg/ml) at 2 months, to 102 pg/ml (78-134 pg/ml) at the end of the study (p<0.01). The corresponding levels in the non-escape group were 83 pg/ml (69-102 pg/ml) and 49 pg/ml (40-60 pg/ml; p<0.01). The median rate of decline in GFR was 5.0 ml·min −1 ·year −1 (range 0.4-15.9 ml·min − 1 ·year −1 ) in the escape group, compared with 2.4 ml·min −1 ·year −1 (−1.6 to 11.0 ml·min −1 ·year −1 ) in the non-escape group (p<0.005). The increase in plasma aldosterone correlated with the rate of decline in GFR (r 2 =0.19, p<0.001), corresponding to a decline in GFR of 1.5 ml·min −1 ·year −1 for every two-fold increase in plasma aldosterone. Pre-treatment and treatment values of plasma aldosterone were not related to albuminuria or to changes in albuminuria during the study. Conclusions/interpretation. Our data suggest that aldosterone escape during long-term blockade of the renin-angiotensin-aldosterone system is associated with an enhanced decline in GFR in patients with type 1 diabetes and diabetic nephropathy.

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.

Reduction of nephrotic range albuminuria is associated with markedly improved renal and cardiovascular outcome in patients with diabetic nephropathy. Aldosterone has been suggested to play a role in the progression of diabetic nephropathy. We therefore aimed to evaluate the short-term effect of aldosterone antagonism with spironolactone on nephrotic range albuminuria and blood pressure in diabetic nephropathy. Twenty Caucasian patients with diabetic nephropathy and nephrotic range albuminuria (>2500 mg/24 h) despite recommended antihypertensive treatment completed this double-masked, randomized crossover trial. Patients were treated in random order with spironolactone 25 mg once daily and matched placebo for 2 months, on top of ongoing antihypertensive treatment, including an angiotensin-converting enzyme inhibitor or an angiotensin II receptor blocker in maximally recommended doses. Median (range) number of antihypertensive drugs was 3 (2-5). After each treatment period, albuminuria, 24-h ambulatory blood pressure, and glomerular filtration rate (GFR) were determined. Spironolactone on top of recommended renoprotective treatment induced a 32% (95% confidence interval (CI): 21-42%) reduction in albuminuria from (geometric mean (95% CI)) 3718 (2910-4749) mg/24 h on placebo treatment (P<0.001). There was a significant reduction in 24-h blood pressure of 6 (2-10)/4 (2-6) mm Hg and day blood pressure of 7 (3-12)/5 (3-7) mm Hg (P<0.01), whereas night blood pressure remained unchanged. Spironolactone induced an insignificant reversible reduction in GFR of 3 ml/min/1.73 m2 from 64 (27) ml/min/1.73 m2. No patients were excluded due to adverse events. Our results suggest that spironolactone treatment on top of recommended renoprotective treatment including maximal renin-angiotensin system blockade may offer additional renoprotection in patients with diabetic nephropathy and nephrotic range albuminuria.

Urine-NGAL and urine-KIM1 (u-KIM1) are elevated in Type1 diabetic patients, with or without albuminuria, indicating tubular damage at an early stage. Urine-NGAL increases significantly with increasing albuminuria. The ACE inhibitor lisinopril reduced urine-NGAL, but this was not statistically significant.

Inhibition of renin with an active site inhibitor, aliskiren, lowers blood pressure (BP) in diabetic patients. Here, we studied the time course of the antihypertensive and antiproteinuric effect of renin inhibition in 15 patients with type 2 diabetes and elevated urinary albumin/creatinine ratios (UACRs) to check whether aliskiren can decrease proteinuria. After a 4-week washout of previous medications, patients received aliskiren and furosemide daily for 28 days followed by a 4-week withdrawal period. Twenty-four-hour BPs were measured at baseline throughout treatment and withdrawal periods. The UACR was significantly reduced after 2-4 days of treatment with another significant reduction after 28 days. Systolic blood pressure (SBP) was significantly lower after 7 days with no further reduction after 28 days. The BP returned toward baseline 3 days after withdrawal, whereas the UACR was still significantly reduced compared with baseline 12 days after withdrawal. Our study shows that aliskiren reduced 24 h SBP, and this was associated with a reduction in albuminuria in type 2 diabetic patients.

OBJECTIVEWe 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 METHODSWe 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 (≥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.RESULTSIn 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] μg/g creatinine, P = 0.02) and increased with increasing levels of albuminuria (microalbuminuric group 4.2 [1.8–8.3] μg/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 (R2 = 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).CONCLUSIONSAn 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.