Spironolactone diminishes urinary albumin excretion in patients with type 1 diabetes and microalbuminuria: a randomized placebo-controlled crossover study
ABSTRACT Adding aldosterone receptor blockade to standard renoprotective treatment may provide additional renoprotection in patients with overt nephropathy. We expected an impact of spironolactone in early diabetic nephropathy, and for this hypothesis we studied the effect on markers of glomerular and tubular damage in patients with Type 1 diabetes and persistent microalbuminuria.
A double-blind, randomized, placebo-controlled crossover study in 21 patients with Type 1 diabetes and microalbuminuria using spironolactone 25 mg or placebo once daily, for 60 days added to standard antihypertensive treatment. After each treatment period, the primary endpoint were evaluated: urinary(u)-albumin excretion/24 hour(h) and secondary endpoints; 24 h blood pressure, glomerular filtration rate (GFR) and markers of tubular damage: urinary liver-type fatty-acid binding protein (LFABP), neutrophil gelatinase associated lipocalin (NGAL) and kidney injury molecule 1 (KIM1).
All patients completed the study. During spironolactone treatment, urinary albumin excretion rate was reduced by 60% (range 21-80%), from 90 mg/24 h to 35 mg/24 h (P=0.01). Blood pressure (24 h) did not change during spironolactone treatment (P>0.2 for all comparisons). The GFR (SD) decreased from 78 (6) mL/min/1.73 m(2) to 72 (6) mL/min/1.73 m(2) (P=0.003). Urinary liver-type fatty-acid binding protein, neutrophil gelatinase-associated lipocalin and kidney injury molecule 1 did not change during treatment (P>0.3 for all comparisons). Treatment was well-tolerated, but two patients had severe hyperkalaemia (plasma potassium = 5.7 mmol/l), which was sufficiently treated with diuretics and dietary intervention.
Spironolactone treatment in addition to standard renoprotective treatment lowers urinary albumin excretion in microalbuminuric patients with Type 1 diabetes, and thus may offer additional renoprotection independent of blood pressure.
- SourceAvailable from: Muhammad Umar Cheema[Show abstract] [Hide abstract]
ABSTRACT: Renal tubules are highly active transporting epithelia and are at risk of protein aggregation due to high protein turnover and/or oxidative stress. We hypothesized that the risk of aggregation was increased upon hormone stimulation and assessed the state of the intracellular protein degradation systems in the kidney from control rats and rats receiving aldosterone or angiotensin II treatment for 7 days. Control rats formed both aggresomes and autophagosomes specifically in the proximal tubules, indicating a need for these structures even under baseline conditions. Fluorescence sorted aggresomes contained various rat keratins known to be expressed in renal tubules as assessed by protein mass spectrometry. Aldosterone administration increased the abundance of the proximal tubular aggresomal protein keratin 5, the ribosomal protein RPL27, ataxin-3, and the chaperone heat shock protein 70-4 with no apparent change in the aggresome-autophagosome markers. Angiotensin II induced aggregation of RPL27 specifically in proximal tubules, again without apparent change in antiaggregating proteins or the aggresome-autophagosome markers. Albumin endocytosis was unaffected by the hormone administration. Taken together, we find that the renal proximal tubules display aggresome formation and autophagy. Despite an increase in aggregation-prone protein load in these tubules during hormone treatment, renal proximal tubules seem to have sufficient capacity for removing protein aggregates from the cells.09/2013; 1(4):e00064. DOI:10.1002/phy2.64
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ABSTRACT: Mineralocorticoid receptors (MR) exist in many tissues, in which they mediate diverse functions crucial to normal physiology, including tissue repair and electrolyte and fluid homeostasis. However, inappropriate activation of MR within these tissues, and especially in the brain, causes hypertension and pathological vascular, cardiac, and renal remodeling. MR binds aldosterone, cortisol and corticosterone with equal affinity. In aldosterone-target cells, co-expression with the 11β-hydroxysteroid dehydrogenase 2 (HSD2) allows aldosterone specifically to activate MR. Aldosterone levels are excessive in primary aldosteronism, but in conditions with increased oxidative stress, like CHF, obesity and diabetes, MR may also be inappropriately activated by glucocorticoids. Unlike thiazide diuretics, MR antagonists are diuretics that do not cause insulin resistance. Addition of MR antagonists to standard treatment for hypertension and cardiac or renal disease decreases end-organ pathology and sympathetic nerve activation (SNA), and increases quality of life indices.Current Hypertension Reports 07/2012; 14(6). DOI:10.1007/s11906-012-0297-0
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ABSTRACT: Background: Microalbuminuria (MA) has long been associated with development of chronic kidney diseases in diabetic or hypertensive patients. However, its value in predicting acute kidney injury (AKI) in an intensive care unit (ICU) setting has never been reported. This study aimed to investigate the link between MA and AKI. Methods: Septic patients without AKI on entry to the ICU were enrolled from October 2010 to December 2011 in an 18-bed ICU. Urinary albumin to creatinine ratio (ACR) was measured in the morning on day 2. Patients were then followed up for the development of AKI, ICU length of stay (LOS) and hospital mortality, and the associations of those with initial ACR were tested. Diagnostic performance of ACR in predicting AKI was evaluated using receiver operating characteristic curves. Results: A total of 84 septic patients were enrolled during the study period, of whom 36 developed AKI and 48 did not. ACR on ICU entry was an independent predictor of AKI (odds ratio [OR] = 1.02; p<0.01). The area under the curve of ACR in predicting AKI was 0.86 (95% confidence interval [95% CI], 0.77-0.94), with a sensitivity and specificity of 91.7% and 79.2%, respectively, at a cutoff of 143 mg/g. ACR was significantly higher in nonsurvivors than in survivors (198 vs. 133 mg/g; p = 0.02). In a linear regression model, ACR values significantly correlated to ICU length of stay (LOS = 0.02 × ACR + 8.19; 95% CI for the coefficient: 0.007-0.033; p = 0.002). Conclusion: ACR obtained on entry to ICU was highly predictive of AKI, and was also associated with mortality rate and ICU length of stay.Journal of nephrology 10/2012; 26(4). DOI:10.5301/jn.5000231