Aldosterone Blockade in Diabetic Nephropathy
Authors: Mario F. Rubin, Raymond R. Townsend
Journal: Journal of the American Society of Nephrology (2009)

In the 1950s, electrocortin, as aldosterone was then known,1 was a relatively novel hormone, the importance of which in human pathophysiology was established by reports of cases of aldosterone excess by Conn in 1955.2 Despite more than 50 yr of study, the breadth of many actions of aldosterone continues to unfold in basic, translational, and clinical milieus. From a basic aspect, aldosterone has typical genomic effects. After receptor binding, aldosterone exposure initiates transcriptional processes, which increase protein synthesis in pathways that enhance sodium retrieval from tubular lumens, salivary and sweat glands, and colon. Nongenomic aspects have been reported in which aldosterone infusion reduces the caliber of isolated afferent and efferent arterioles3 through the activation of systems that inhibit endothelial nitric oxide action.4 From a translational aspect, the synthetic pathways detailing aldosterone production offer the opportunity for studying genes such as CYP11B2, which regulates production of 11β-hydroxylase, a key enzyme in corticosteroid production.5 Population studies of polymorphisms in the CYP11B2 gene suggest that compensation for reduced activity of CYP11B2, through modest increases in the release of ACTH, results in upregulation of other genetic pathways that can increase BP. The latter incorporates genes involved in aldosterone production, such as CYP11B1, that are also sensitive to ACTH and that also have the potential to enhance the reactivity of aldosterone responses to other factors, such as angiotensin II.6 These pursuits are shedding light on common hypertension phenotypes, such as salt sensitivity,7 and informing alternative mechanisms of action of newer mineralocorticoid system–blocking drugs.8 Encouraging, too, is the resurgence of interest in aldosterone physiology in the clinical arena, such as the investigation of Mehdi et al.9 in this issue of JASN. Mehdi et al.9 randomly assigned patients who had diabetes, were receiving 80 mg/d lisinopril, and had a urine albumin-creatinine ratio (ACR) of >300 mg/g to placebo, losartan 100 mg/d, or spironolactone 25 mg/d for 48 wk. The role of diabetic nephropathy in ESRD and the formidable cardiovascular disease associated with diabetes makes it a good clinical model for study.10 The presence of proteinuria in diabetes magnifies the risks for progression of chronic kidney disease and the likelihood of cardiovascular disease. For this reason, reducing proteinuria is thought to be salutary, particularly when accompanied by evidence of benefit on end-stage kidney disease and/or cardiovascular death.11,12 The results of the study by Mehdi et al.9 show the greatest antiproteinuric effect with spironolactone compared with placebo. This occurred despite similar degrees of BP lowering in all groups as assessed by ambulatory BP monitoring and achieved by add-on therapies (other than angiotensin-converting enzyme inhibition, angiotensin receptor blockade, or mineralocorticoid blockade) to achieve BP targets in patients with diabetes and hypertension (<130/80 mmHg). Which mechanisms can be invoked to explain their outcomes? Hyperfiltration and enhanced proteinuria are described in aldosterone excess clinical states such as primary aldosteronism,13,14 and reduced urinary protein excretion could result from lowering glomerular pressures or altering permselectivity. Alterations in glomerular permselectivity can result from inflammation, cellular hypertrophy, and enhanced collagen synthesis. Recent data suggest that aldosterone possesses proinflammatory and profibrotic properties. Rats treated with aldosterone and volume-expanded with saline showed a downregulation in the expression of slit diaphragm proteins such as nephrin and podocin and upregulation of the podocyte marker desmin,15 and at least some of the proteinuria-potentiating effect of aldosterone is attributable to podocyte injury by the induction of reactive oxygen species. Regarding the safety of aldosterone antagonism in patients who have diabetes and are already on an angiotensin-converting enzyme inhibitor, Mehdi et al.9 note that increases in potassium blood levels were most prominent in the spironolactone-treated group, compared with placebo and losartan groups. People with impaired kidney function are known to rally nonexcretory pathways such as enhanced intracellular sequestration during potassium intake to defend the serum potassium concentration.16 The use of an oral potassium chloride challenge in a controlled environment is an innovative way to identify people who may be at risk for significant hyperkalemia.17 Nonetheless, hyperkalemia remains a serious concern with aldosterone antagonism in this setting. How has the study of Mehdi et al.9 moved us forward? There are several answers. First, the dosage of lisinopril used was large enough to remove any concerns about underdosing renin-angiotensin system blockade. Second is the 48-wk duration of this study when previous studies were often in the range of 12 to 24 wk. Third, goal BP was <130/<80 mmHg as per current recommendations. Fourth, the care taken to control for dietary and 24-h BP-related factors in the outcome variable (ACR) provides assurance that the reduction noted in ACR on spironolactone compared with placebo is a real finding. Last, there is the sobering reminder of the significant incidence of asymptomatic hyperkalemia ([K+] >6.0 mEq/L on at least one occasion), which was highest in the spironolactone group (14 of 27 patients). Although manageable with dietary counseling and some use of kayexalate, it serves as a continuing reminder of the necessity for vigilance in the follow-up of patients for whom we use these potent medications. Unanswered questions from this study include whether the antiproteinuric effect of anti-aldosterone agents select a group with better prognosis, coupled with whether longer term data using aldosterone blockade will slow the rate of loss of GFR and preserve life, as shown in large heart failure studies.18,19 Disclosures None.