Amiloride lowers plasma TNF and interleukin-6 but not interleukin-17A in patients with hypertension and type 2 diabetes.

Interleukin (IL)-17A contributes to hypertension in preclinical models. T helper 17 and dendritic cells are activated by NaCl, which could involve the epithelial Na+ channel (ENaC). We hypothesized that the ENaC blocker amiloride reduces plasma IL-17A and related cytokines in patients with hypertension. Concentrations of IL-17A, IFN-γ, TNF, IL-6, IL-1ß, and IL-10 were determined by immunoassays in plasma from two patient cohorts before and after amiloride treatment: 1) patients with type 2 diabetes mellitus (T2DM) and treatment-resistant hypertension (n = 69, amiloride 5-10 mg/day for 8 wk) and 2) patients with hypertension and type 1 diabetes mellitus (T1DM) (n = 29) on standardized salt intake (amiloride 20-40 mg/day, 2 days). Plasma and tissue from ANG II-hypertensive mice with T1DM treated with amiloride (2 mg/kg/day, 4 days) were analyzed. The effect of amiloride and benzamil on macrophage cytokines was determined in vitro. Plasma cytokines showed higher concentrations (IL-17A ∼40-fold) in patients with T2DM compared with T1DM. In patients with T2DM, amiloride had no effect on IL-17A but lowered TNF and IL-6. In patients with T1DM, amiloride had no effect on IL-17A but increased TNF. In both cohorts, blood pressure decline and plasma K+ increase did not relate to plasma cytokine changes. In mice, amiloride exerted no effect on IL-17A in the plasma, kidney, aorta, or left cardiac ventricle but increased TNF in cardiac and kidney tissues. In lipopolysaccharide-stimulated human THP-1 macrophages, amiloride and benzamil (from 1 nmol/L) decreased TNF, IL-6, IL-10, and IL-1ß. In conclusion, inhibition of ENaC by amiloride reduces proinflammatory cytokines TNF and IL-6 but not IL-17A in patients with T2DM, potentially by a direct action on macrophages.NEW & NOTEWORTHY ENaC activity may contribute to macrophage-derived cytokine release, since amiloride exerts anti-inflammatory effects by suppression of TNF and IL-6 cytokines in patients with resistant hypertension and type 2 diabetes and in THP-1-derived macrophages in vitro.

Predicting albuminuria response to spironolactone treatment with urinary proteomics in patients with type 2 diabetes and hypertension.

Background: The mineralocorticoid receptor antagonist spironolactone significantly reduces albuminuria in patients with diabetes. Prior studies have shown large between-patient variability in albuminuria treatment response. We previously developed and validated a urinary proteomic classifier that predicts onset and progression of chronic kidney disease. Here, we tested whether the proteomic classifier based on 273 urinary peptides (CKD273) predicts albuminuria response to spironolactone treatment. Methods: We performed a post hoc analysis in a double-blind randomized clinical trial with allocation to either spironolactone 12.5-50 mg/day (n = 57) or placebo (n = 54) for 16 weeks. Patients were diagnosed with type 2 diabetes and resistant hypertension. Treatment was an adjunct to renin-angiotensin system inhibition. Primary endpoint was the percentage change in urine albumin to creatinine ratio (UACR). Capillary electrophoresis mass spectrometry was used to quantify urinary peptides at baseline. The previously validated combination of 273 known urinary peptides was used as proteomic classifier. Results: Spironolactone reduced UACR relative to placebo by 50%, although with a large between-patient variability in UACR response (5th to 95th percentile, 7 to 312%). An interaction was detected between CKD273 and treatment assignment (ß = -1.09, P = 0.026). Higher values of CKD273 at baseline were associated with a larger reduction in UACR in the spironolactone group (ß = -0.70, P = 0.049), but not in the placebo group (ß = 0.39, P = 0.25). Stratified in tertiles of baseline CKD273, reduction in UACR was greater in the highest tertile, 63% (95% confidence interval: 35-79%), as compared with the two other tertiles combined, 16% (-17 to 40%) (P = 0.011). Conclusions: A urinary proteomics classifier can be used to identify individuals with type 2 diabetes who are more likely to show an albuminuria-lowering response to spironolactone treatment. These results suggest that urinary proteomics may be a valuable tool to tailor therapy, but confirmation in a larger clinical trial is required.

Albuminuria is associated with an increased prostasin in urine while aldosterone has no direct effect on urine and kidney tissue abundance of prostasin.

The proteinase prostasin is a candidate mediator for aldosterone-driven proteolytic activation of the epithelial sodium channel (ENaC). It was hypothesized that the aldosterone-mineralocorticoid receptor (MR) pathway stimulates prostasin abundance in kidney and urine. Prostasin was measured in plasma and urine from type 2 diabetic patients with resistant hypertension (n = 112) randomized to spironolactone/placebo in a clinical trial. Prostasin protein level was assessed by immunoblotting in (1) human and rat urines with/without nephrotic syndrome, (2) human nephrectomy tissue, (3) urine and kidney from aldosterone synthase-deficient (AS-/-) mice and ANGII- and aldosterone-infused mice, and in (4) kidney from adrenalectomized rats. Serum aldosterone concentration related to prostasin concentration in urine but not in plasma. Plasma prostasin concentration increased significantly after spironolactone compared to control. Urinary prostasin and albumin related directly and were reduced by spironolactone. In patients with nephrotic syndrome, urinary prostasin protein was elevated compared to controls. In rat nephrosis, proteinuria coincided with increased urinary prostasin, unchanged kidney tissue prostasin, and decreased plasma prostasin while plasma aldosterone was suppressed. Prostasin protein abundance in human nephrectomy tissue was similar across gender and ANGII inhibition regimens. Prostasin urine abundance was not different in AS-/- and aldosterone-infused mice. Prostasin kidney level was not different from control in adrenalectomized rats and AS-/- mice. We found no evidence for a direct relationship between mineralocorticoid receptor signaling and kidney and urine prostasin abundance. The reduction of urinary prostasin in spironolactone-treated patients is most likely the result of an improved glomerular filtration barrier function and generally reduced proteinuria.

Inflammatory-mediated atrial cardiomyopathy diagnosed using multimodality imaging and successfully treated with prednisolone: a case report.

Background: Atrial fibrillation is a common cardiac arrhythmia and often develops secondary to structural cardiac changes. Both the occurrence of atrial fibrillation and/or structural changes of the heart may lead to development of atrial cardiomyopathy and heart failure (HF). However, isolated atrial cardiomyopathy caused by focal atrial thickening is a rare condition, previously only described in case reports as a result of different aetiologies all linked to inflammation. Case summary: A patient with inflammatory-mediated atrial cardiomyopathy causing atrial fibrillation and acute decompensated HF presented as isolated left atrial wall thickening on transoesophageal echocardiography. The diagnosis was confirmed using multimodality imaging with transthoracic and transoesophageal echocardiography, cardiac magnetic resonance imaging, positron emissions tomography/computer tomography scanning and intracardiac echocardiography-guided endomyocardial biopsy. Despite no specific histological aetiology, the observed atrial cardiomyopathy might be associated with type 1 diabetes mellitus. The patient in the present case was successfully treated with prednisolone. Discussion: Diabetes mellitus is an important risk factor for developing atrial fibrillation and diabetic cardiomyopathy, due to reduced levels of anti-inflammatory and increased levels of proinflammatory cytokines causing cardiac inflammatory structural remodelling. The regression of the atrial thickening might be due to prednisolone's anti-inflammatory effects and thereby ability to suppress atrial remodelling and reduce the occurrence of atrial fibrillation. However, the effect of prednisolone might only affect the non-manifested inflammatory-mediated atrial remodelling. Due to the rare occurrence of isolated atrial cardiomyopathy a multiple imaging approach during the diagnostic process and follow-ups are essential to determine the aetiology and effect of the treatment.

Minimal dose CT for left ventricular ejection fraction and combination with chest-abdomen-pelvis CT.

Objectives: This prospective study tested the diagnostic accuracy, and absolute agreement with MRI of a low-dose CT protocol for left ventricular ejection fraction (LVEF) measurement. Furthermore we assessed its potential for combining it with Chest-Abdomen-Pelvis CT (CAP-CT) for a one-stop examination. Materials & methods: Eighty-two patients underwent helical low-dose CT. Cardiac magnetic resonance imaging (MRI) was the reference standard. In fifty patients, CAP-CT was performed concurrently, using a modified injection protocol. In these, LVEF was measured with radioisotope cardiography (MUGA). Patients >18 years, without contrast media or MRI contraindications, were included. Bias was measured with Bland-Altman analysis, classification accuracy with Receiver Operating Characteristics, and inter-reader agreement with Intra-Class Correlation Coefficient (ICC). Correlation was examined using Pearson's correlation coefficients. CAP image quality was compared to previous scans with visual grading characteristics. Results: The mean CT dose-length-product (DLP) was 51.8 mGycm, for an estimated effective dose of 1.4 mSv, compared to 5.7 mSv for MUGA. CT LVEF bias was between 2 % and 10 %, overestimating end-diastolic volume. When corrected for bias, sensitivity and specificity of 100 and 98.5 % for classifying reduced LVEF (50 % MRI value) was achieved. ICC for MUGA was significantly lower than MRI and CT. Distinction of renal medulla and cortex was reduced in the CAP scan, but proportion of diagnostic scans was not significantly different from standard protocol. Conclusion: When corrected for inter-modality bias, CT classifies patients with reduced LVEF with high accuracy at a quarter of MUGA dose and can be combined with CAP-CT without loss of diagnostic quality.

Management of amlodipine-induced ankle oedema.

Pedal oedema is a well-known adverse effect of amlodipine, but significantly less frequent if only half of the maximum recommended dosage is used. Diuretics are ineffective. To cause as few side effects as possible, options for managing are prioritised in this review: Reduce dosage, switch to lercanidipine/lacidipine, switch to another group, add/increase dosage of an ACE-inhibitor/angiotensin II-receptor blocker, administer at night, or switch to verapamil/diltiazem. Non-pharmacologic actions or observation may be considered when the oedemas are mild and not bothersome.

The mineralocorticoid receptor blocker spironolactone lowers plasma interferon-γ and interleukin-6 in patients with type 2 diabetes and treatment-resistant hypertension.

BACKGROUND: The mineralocorticoid receptor antagonist spironolactone lowers blood pressure in patients with resistant hypertension despite antihypertensive treatment with angiotensin-converting inhibitors (ACEi) and angiotensin-II receptor blockers (ARB). In preclinical studies, spironolactone suppresses pro-hypertensive interleukin 17A (IL-17A). OBJECTIVES: Plasma samples were analysed from a randomized, double-blind placebo-controlled trial with spironolactone given to patients with type 2 diabetes mellitus (T2DM) and resistant hypertension on three antihypertensive drugs. We tested the hypothesis that spironolactone-induced antihypertensive effects are associated with suppression of IL-17A and related cytokines. METHODS: Interferon-γ (IFN-γ), IL-17A, tumor necrosis factor-α (TNF-α), IL-6, IL-1ß and IL-10 were assessed in plasma with immunoassay in samples before and after 16 weeks of treatment with placebo or spironolactone (12.5-25-50 mg/day). RESULTS: Spironolactone significantly reduced plasma IFN-γ and IL-6 while IL-17A, TNF-α, IL-1ß and IL-10 were unchanged. IL-6 was more sensitive to higher doses of spironolactone. At baseline, serum aldosterone correlated positively with diastolic night blood pressure. Urine albumin/creatinine-ratios correlated positively with plasma IL-6 at baseline. There were no relations between aldosterone and cytokine concentrations at baseline; between cytokine concentration and blood pressure at baseline; and between cytokine concentration decrease and blood pressure decrease, except for IFN-γ, after treatment. The spironolactone-induced elevation in plasma potassium related inversely to blood pressure but not to changes in cytokines. In macrophages in vitro, spironolactone suppressed lipopolysaccharide (LPS)-induced TNF-α, IL-6, IL-1ß and IL-10 levels. CONCLUSION: The antihypertensive action of spironolactone in resistant hypertensive patients is associated with suppressed IFN-γ and IL-6 and not IL-17A. Spironolactone exerts anti-inflammatory actions in vivo on macrophages and T-cells.

Progressive valvular calcifications with critical aortic stenosis in a 25-year-old woman with end-stage renal disease on haemodialysis: a case report.

BACKGROUND: The increased risk of cardiovascular morbidity and mortality in chronic kidney disease (CKD) and end-stage renal disease (ESRD) seems particularly pronounced in patients with concomitant aortic and mitral valvular calcifications. Valvular calcification (VC) is accelerated in patients with CKD and even more so with ESRD and haemodialysis (HD) due to premature endothelial cell dysfunction. Mineral and bone disorder (CKD-MBD) is a common complication of CKD/ESRD and may play a pivotal role in VC. CASE SUMMARY: A 25-year-old woman with congenital hypoplastic kidneys and ESRD on HD from the age of 19 was admitted to the emergency department suffering from chest pain and dyspnoea. Transthoracic echocardiogram (TTE) revealed critical aortic stenosis (AS) with indexed aortic valve area 0.4 cm2/m2, a mean gradient 58 mmHg and a moderate mitral stenosis with a mean gradient 6-8 mmHg developed over the course of 2 years, as a normal TTE was performed at that time. During HD, the patient had longstanding alterations in calcium and phosphate metabolism including secondary hyperparathyroidism that eventually progressed into tertiary hyperparathyroidism. Efforts were made to treat CKD-MBD but patient compliance was low. Subtotal parathyroidectomy was performed 6 months prior to admission. The patient had dual mechanical valve replacement. DISCUSSION: Valvular calcification is common in patients with CKD/ESRD and in particular in patients on HD. Rapid progression of valve disease in this case may be related to the combination of low patient adherence and sustained disturbed calcium and phosphate metabolism with tertiary hyperparathyroidism. Transthoracic echocardiogram should be performed in patients on HD even with minor suspicion of VC and in patients with low adherence and disturbance of calcium and phosphate metabolism.

Baseline urinary metabolites predict albuminuria response to spironolactone in type 2 diabetes.

The mineralocorticoid receptor antagonist spironolactone significantly reduces albuminuria in subjects with diabetic kidney disease, albeit with a large variability between individuals. Identifying novel biomarkers that predict response to therapy may help to tailor spironolactone therapy. We aimed to identify a set of metabolites for prediction of albuminuria response to spironolactone in subjects with type 2 diabetes. Systems biology molecular process analysis was performed a priori to identify metabolites linked to molecular disease processes and drug mechanism of action. Individual subject data and urine samples were used from 2 randomized placebo controlled double blind clinical trials (NCT01062763, NCT00381134). A urinary metabolite score was developed to predict albuminuria response to spironolactone therapy using penalized ridge regression with leave-one-out cross validation. Bioinformatic analysis identified a set of 18 metabolites linked to a diabetic kidney disease molecular model and potentially affected by spironolactone mechanism of action. Spironolactone reduced UACR relative to placebo by median -42% (25th to 75% percentile -65 to 6) and -29% (25th to 75% percentile -37 to -1) in the test and replication cohorts, respectively. In the test cohort, UACR reduction was higher in the lowest tertile of the baseline urinary metabolite score compared with middle and upper tertiles -58% (25th to 75% percentile -78 to 33), -28% (25th to 75% percentile -46 to 8), -40% (25th to 75% percentile -52% to 31), respectively, P = 0.001 for trend). In the replication cohort, UACR reduction was -54% (25th to 75% percentile -65 to -50), -41 (25th to 75% percentile -46% to 30), and -17% (25th to 75% percentile -36 to 5), respectively, P = 0.010 for trend). We identified a set of 18 urinary metabolites through systems biology to predict albuminuria response to spironolactone in type 2 diabetes. These data suggest that urinary metabolites may be used as a tool to tailor optimal therapy and move in the direction of personalized medicine.

The acute blood pressure-lowering effect of amiloride is independent of endothelial ENaC and eNOS in humans and mice.

AIMS: The epithelial sodium channel (ENaC) is expressed in cultured endothelial cells and inhibitory coupling to eNOS activity has been proposed. The present study tested the hypothesis that ENaC blockers increase systemic NO-products and lower blood pressure in patients and mice, depending on eNOS. METHODS: NO-products and cGMP were measured in diabetes patient urine and plasma samples before and after amiloride treatment (20-40 mg for two days, plasma n = 22, urine n = 12 and 5-10 mg for eight weeks, plasma n = 52, urine n = 55). Indwelling catheters were implanted in the femoral artery and vein in mice for continuous arterial blood pressure and heart rate recordings and infusion. RESULTS: Treatment with amiloride for two days increased plasma and urine NO-products, while plasma cGMP decreased and urinary cGMP was unchanged in patient samples. Eight weeks of treatment with amiloride did not alter NO-products and cGMP. In mice, amiloride boli of 5, 50, and 500 µg/kg lowered heart rate and arterial blood pressure significantly and acutely. Benzamil had no effect on pressure and raised heart rate. In hypertensive eNOS-/- and L-NAME-treated mice, amiloride lowered blood pressure significantly. L-NAME infusion significantly decreased NO-products in plasma; amiloride and eNOS-deletion had no effect. An acetylcholine bolus resulted in acute blood pressure drop that was attenuated in eNOS-/- and L-NAME mice. ENaC subunit expressions were not detected consistently in human and mouse arteries and endothelial cells. CONCLUSION: Amiloride has an acute hypotensive action not dependent on ENaC and eNOS and likely related to the heart.

Body Mass Index, Intensive Blood Pressure Management, and Cardiovascular Events in the SPRINT Trial.

BACKGROUND: It is unclear whether intensive blood pressure management is well-tolerated and affects risk uniformly across the body mass index (BMI) spectrum. METHODS: The randomized, controlled Systolic Blood Pressure Intervention Trial (SPRINT) included 9361 individuals ≥50 years of age at high cardiovascular risk, without diabetes mellitus, with systolic blood pressure between 130 and 180 mmHg. Participants were randomized to intensive vs standard antihypertensive treatment and evaluated for the primary composite efficacy endpoint of acute coronary syndromes, stroke, heart failure, or cardiovascular death. The primary safety endpoint was serious adverse events. We used restricted cubic splines to determine the relationship between BMI, response to intensive blood pressure lowering, and clinical outcomes in SPRINT. RESULTS: Body mass index could be calculated for 9284 (99.2%) individuals. Mean BMI was similar between the 2 treatment groups (intensive group 29.9±5.8 kg/m2 vs standard group 29.8± 5.7 kg/m2; P = 0.39). Median follow-up was 3.3 years (range 0-4.8 years). Body mass index had a significant, J-shaped association with risk of all-cause mortality, stroke, and serious adverse events (P < .05 for all), but these were no longer significant after accounting for key clinical factors (P > .05 for all). Intensive blood pressure lowering reduced the primary efficacy endpoint and increased the primary safety endpoint compared with standard targets, consistently across the BMI spectrum (Pinteraction > .05). CONCLUSION: The overall efficacy and safety of intensive blood pressure lowering did not appear to be modified by baseline BMI among high-risk older adults.

A case report: haemodynamic instability due to true dynamic left ventricular outflow tract obstruction and systolic anterior motion following resuscitation: reversal of haemodynamics on supportive veno-arterial extracorporeal membrane oxygenation.

BACKGROUND: Obstruction of the left ventricular outflow tract (LVOT) as seen in hypertrophic cardiomyopathy is a dynamic condition with a wide range of clinical presentations and symptoms. CASE SUMMARY: We report the use of veno-arterial extracorporeal membrane oxygenation in a female patient who was resuscitated after out-of-hospital cardiac arrest. Soon after admission the patient developed critical haemodynamic compromise due to severe obstruction of the left ventricle outflow tract and systolic anterior motion (SAM) of the mitral valve. Veno-arterial extracorporeal membrane oxygenation restored haemodynamics and was weaned after 4 days without any haemodynamic compromise due to SAM. The patient was discharged from the intensive care unit at Day 13, and after 3 days at the coronary care unit, she was discharged to ambulatory follow-up with no sequelae. DISCUSSION: Veno-arterial extracorporeal membrane oxygenation restored haemodynamic stability in this patient with dynamic severe LVOT obstruction following cardiac arrest.

Amiloride lowers blood pressure and attenuates urine plasminogen activation in patients with treatment-resistant hypertension.

In conditions with albuminuria, plasminogen is aberrantly filtered across the glomerular barrier and activated along the tubular system to plasmin. In the collecting duct, plasmin activates epithelial sodium channels (ENaC) proteolytically. Hyperactivity of ENaC could link microalbuminuria/proteinuria to resistant hypertension. Amiloride, an ENaC inhibitor, inhibits urokinase-type plasminogen activator. We hypothesized that amiloride (1) reduces blood pressure (BP); (2) attenuates plasminogen-to-plasmin activation; and (3) inhibits urine urokinase-type plasminogen activator in patients with resistant hypertension and type 2 diabetes mellitus (T2DM).In an open-label, non-randomized, 8-week intervention study, a cohort (n = 80) of patients with resistant hypertension and T2DM were included. Amiloride (5 mg/d) was added to previous triple antihypertensive treatment (including a diuretic and an inhibitor of the renin-angiotensin-aldosterone system) and increased to 10 mg if BP control was not achieved at 4 weeks. Complete dataset for urine analysis was available in 60 patients. Systolic and diastolic BP measured by ambulatory BP monitoring and office monitoring were significantly reduced. Average daytime BP was reduced by 6.3/3.0 mm Hg. Seven of 80 cases (9%) discontinued amiloride due to hyperkalemia >5.5 mol/L, the most frequent adverse event. Urinary plasmin(ogen) and albumin excretions were significantly reduced after amiloride treatment (P < .0001). Urokinase activity was detectable in macroalbuminuric urine, with a tendency toward reduction in activity after amiloride treatment. Amiloride lowers BP, urine plasminogen excretion and activation, and albumin/creatinine ratio, and is a relevant add-on medication for the treatment of resistant hypertension in patients with T2DM and microalbuminuria.

Plasmin in urine from patients with type 2 diabetes and treatment-resistant hypertension activates ENaC in vitro.

BACKGROUND: Aberrant filtration of plasminogen from plasma and subsequent activation to plasmin in the urinary space may activate proteolytically the epithelial sodium channel, ENaC. In conditions with chronic albuminuria, this may cause hypertension. It was hypothesized that patients with type 2 diabetes mellitus (T2DM) and treatment-resistant hypertension excrete plasmin(ogen) in urine in proportion to albumin and that plasmin confers to urine the ability to activate ENaC. METHOD: Patients (n = 113) with T2DM and resistant hypertension, defined as systolic blood pressure (SBP) more than 130 mmHg and/or diastolic blood pressure (DBP) more than 80 mmHg despite use of at least three drugs with one diuretic and one renin-angiotensin system inhibitor, were included. Urine was analyzed for albumin, creatinine, plasmin(ogen), protease activity, and ability to activate inward current in single collecting duct cells. RESULTS: Mean ambulatory SBP/DBP was 143 ±â€Š1/77 ±â€Š0.7 mmHg; HbA1c 7.35%; and eGFR 81.0 ml/min per 1.73 m (geometric means). Patients with microalbuminuria (39%) and macroalbuminuria (13%) displayed significantly elevated levels of urinary plasmin(ogen) normalized to urine creatinine compared with patients with normal excretion of albumin (48%). Urinary plasminogen correlated significantly to urine albumin. Western immunoblotting and gelatine zymography confirmed active plasmin in urine samples from patients with microalbuminuria and macroalbuminuria. Single collecting duct cells displayed significantly increased, amiloride-sensitive, inward current when superfused with urine from albuminuric patients compared with patients with normal albumin excretion. Urinary plasminogen/creatinine ratio correlated significantly with 24-h ambulatory blood pressure. CONCLUSION: Aberrant presence of plasmin in preurine may inappropriately activate ENaC in patients with type 2 diabetes and microalbuminuria. This may contribute to treatment-resistant hypertension.

Low dose spironolactone reduces blood pressure in patients with resistant hypertension and type 2 diabetes mellitus: a double blind randomized clinical trial.

BACKGROUND: The increased risk of cardiovascular morbidity and mortality associated with arterial hypertension is particularly pronounced in patients with type 2 diabetes mellitus. Blood pressure control is, therefore, decisively important but often not sufficiently achieved. OBJECTIVE: The primary objective of this study was to evaluate the antihypertensive effect of low dose spironolactone added to triple therapy for resistant hypertension in patients with type 2 diabetes measured by ambulatory monitoring. Secondary objectives were to evaluate the effects on glycaemic control and urinary albumin excretion as well as adverse effects. METHODS: In a multicentre, double-blind, randomized, placebo-controlled study 119 patients with blood pressure at or above 130/80 mmHg despite triple antihypertensive therapy were included. One tablet of 25 mg spironolactone or placebo was added to previous treatment and increased to two if blood pressure below 130/80 mmHg was not achieved after 4 weeks. Blood pressure was measured by ambulatory monitoring at baseline and after 16 weeks. RESULTS: The study was completed by 112 patients, 57 randomized to spironolactone and 55 to placebo. Average daytime placebo-corrected blood pressure was reduced by 8.9 (4.7-13.2)/3.7 (1.5-5.8) mmHg. Also office blood pressure, night-time, 24-h and pulse pressures were reduced significantly. Urinary albumin/creatinine ratio was significantly reduced in the spironolactone group. Glycaemic control remained unchanged. Hyperkalemia was the most frequent adverse event leading to dose reduction in three cases and discontinuation in one, whereas gynaecomastia was not reported. CONCLUSION: Low dose spironolactone exerts significant BP and urinary albumin creatinine ratio lowering effects in high-risk patients with resistant hypertension and type 2 diabetes mellitus.