Potassium Handling with Dual Renin-Angiotensin System Inhibition in Diabetic Nephropathy

Abstract

SummaryBackground and objectives Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers are the cornerstones of pharmacologic therapy in diabetic nephropathy. Mineralocorticoid receptor blockers reduce proteinuria as single agents or add-on therapy to other renin-angiotensin-aldosterone system-inhibiting drugs in these patients. The long-term benefits and ultimate role of mineralocorticoid receptor blockers in diabetic nephropathy remain unknown. A clinical trial previously showed that the kalemic effect of spironolactone is higher than losartan when added to lisinopril in patients with diabetic nephropathy. The purpose of this study was to investigate if renal potassium handling was primarily responsible for that observation.Design, setting, participants, & measurements In a blinded, randomized, three-arm placebo-controlled clinical trial, 80 participants with diabetic nephropathy taking lisinopril (80 mg) were randomized to spironolactone (25 mg daily), losartan (100 mg daily), or placebo (trial dates from July of 2003 to December of 2006). Serum potassium, aldosterone, and 24-hour urine sodium, potassium, and creatinine were measured over 48 weeks. Differences were analyzed with repeated measures mixed models.Results Mean follow-up serum potassium was 5.0 mEq/L for spironolactone, 4.7 mEq/L for losartan (P=0.05 versus spironolactone), and 4.5 mEq/L for placebo (P,0.001 versus spironolactone; P=0.03 versus losartan). The difference in serum potassium was 0.23 mEq/L for losartan versus placebo (P=0.02), 0.43 mEq/L for spironolactone versus placebo (P,0.001), and 0.2 mEq/L for spironolactone versus losartan (P=0.05). Serum and urine potassium excretion and secretion rates were similar between groups throughout the study.Conclusion Spironolactone raised serum potassium more than losartan in patients with diabetic nephropathy receiving lisinopril, despite similar renal sodium and potassium excretion. This finding suggests that extrarenal potassium homeostasis contributes to hyperkalemia in these patients. A better understanding of extrarenal potassium homeostasis will provide an opportunity to use this drug more safely in patients with diabetic nephropathy as well as other patient populations.

Potassium: friend or foe?

“…Interestingly, angiotensin signaling appeared to play a permissive role for potassium secretion, since treatment with losartan rendered the mice unable to handle moderate dietary potassium [88]. This is consistent with clinical data showing that dual RAAS blockade raises serum potassium more than single RAAS blockade [89, 78]. The aldosterone synthase knockout study also found that colonic potassium secretion was entirely aldosterone-dependent [88], consistent with clinical data showing that hyperkalemia complicates the use of eplerenone in patients on hemodialysis [90].…”

Spironolactone Add-on for Preventing or Slowing the Progression of Diabetic Nephropathy: A Meta-analysis

“…From a total of 236 potentially eligible studies, 220 were excluded because they were not relevant to the study objectives; were reviews, meeting abstracts, case-only studies (ie, a control group [in which control medication or placebo was added to standard AD/RP/AHT treatment] was not included); or contained no detailed, usable data necessary for the meta-analysis. A total of 16 studies 23,28,34,35,[42][43][44][45][46][47][48][49][50][51][52][53] were included in the present metaanalysis and are described in the table (see also Supplemental Tables 1A-3B in the online version 28,34,43,45,47,49,52,53 ; and hyperkalemia, 12 studies (spironolactone, 319; control, 295). 28,34,35,[43][44][45][46]48,49,50,52,53 Effects of the Addition of Spironolactone on Urinary Protein/Albumin Excretion Compared with controls, the addition of spironolactone to standard AD/RP/AHT treatment significantly reduced end-of-treatment 24-hour urinary albumin/protein excretion (MD = -61.48; 95% CI, -96.74 to -26.23; P = 0.0006) (Figure 2A).…”

Albuminuria is Not an Appropriate Therapeutic Target in Patients with CKD

“…Loop or thiazide diuretics have not been shown to be beneficial. Mineralocorticoid receptor blockers decrease risk, but in the work by Mehdi et al (44), the addition of spironolactone to 80 mg lisinopril in patients with diabetes and proteinuria significantly decreased proteinuria but caused hyperkalemia .6 mEq/L in 50% of individuals (44,45). Lower BP may be beneficial in individuals with proteinuria (46).…”