Mechanisms of Impaired Potassium Handling With Dual Renin-Angiotensin-Aldosterone Blockade in Chronic Kidney Disease

Preston, Richard A.; Afshartous, David; Garg, Dyal C.; Medrano, Sergio; Alonso, Alberto B.; Rodrı́guez, Rolando

doi:10.1161/hypertensionaha.108.125252

Cited by 47 publications

(40 citation statements)

References 27 publications

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“…Hyperkalemia stimulates aldosterone secretion, which also increases the fractional potassium excretion (27). Patients who have CKD and have been given a potassium load actually maintain their S K levels when compared with control subjects, strongly supporting the presence of compensatory extrarenal mechanisms of potassium loss (28). Patients with …”

Section: Discussionmentioning

confidence: 98%

Serum Potassium and Outcomes in CKD

Korgaonkar¹,

Tilea²,

Gillespie³

et al. 2010

Clinical Journal of the American Society of Nephrology

201

159

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Background and objectives:The relationship between serum potassium (S K ) and mortality in chronic kidney disease (CKD) has not been systematically investigated.Design, setting, participants, & measurements: We examined the predictors and mortality association of S K in the Renal Research Institute CKD Study cohort, wherein 820 patients with CKD were prospectively followed at four US centers for an average of 2.6 years. Predictors of S K were investigated using linear and repeated measures regression models. Associations between S K and mortality, the outcomes of ESRD, and cardiovascular events in time-dependent Cox models were examined.Results: The mean age was 60.5 years, 80% were white, 90% had hypertension, 36% had diabetes, the average estimated GFR was 25.4 ml/min per 1.73 m 2 , and mean baseline S K was 4.6 mmol/L. Higher S K was associated with male gender, lower estimated GFR and serum bicarbonate, absence of diuretic and calcium channel blocker use, diabetes, and use of angiotensinconverting enzyme inhibitors and/or statins. A U-shaped relationship between S K and mortality was observed, with mortality risk significantly greater at S K <4.0 mmol/L compared with 4.0 to 5.5 mmol/L. Risk for ESRD was elevated at S K <4 mmol/L in S K categorical models. Only the composite of cardiovascular events or death as an outcome was associated with higher S K (>5.5).Conclusions: Although clinical practice usually emphasizes greater attention to elevated S K in the setting of CKD, our results suggest that patients who have CKD and low or even low-normal S K are at higher risk for dying than those with mild to moderate hyperkalemia.

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Section: Discussionmentioning

confidence: 98%

Serum Potassium and Outcomes in CKD

Korgaonkar¹,

Tilea²,

Gillespie³

et al. 2010

Clinical Journal of the American Society of Nephrology

201

159

View full text Add to dashboard Cite

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“…Taken together, our current findings indicate that renal dysfunction greatly puts patients at risk for hyperkalemia irrespective of the dosage of TMP-SMX. In kidney diseases, an impaired production of aldosterone results in abdominal potassium excretion (25,26). Accordingly, the potassium-sparing effects of TMP-SMX are presumably accentuated in patients with kidney insufficiency even at low-dose TMP-SMX.…”

Section: Discussionmentioning

confidence: 99%

Renal Insufficiency in Concert with Renin-angiotensin-aldosterone Inhibition Is a Major Risk Factor for Hyperkalemia Associated with Low-dose Trimethoprim-sulfamethoxazole in Adults

et al. 2016

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Objective Low-dose trimethoprim-sulfamethoxazole (TMP-SMX) is commonly used to prevent pneumocystis pneumonia in daily practice. Previous reports have shown a relationship between high-or standard-dose of TMP-SMX and hyperkalemia, however it remains unclear whether this is true for low-dose TMP-SMX. In this study we sought to determine the risk factors for hyperkalemia associated with low-dose TMP-SMX. Methods In this retrospective cohort study, 186 consecutive adult patients who received TMP-SMX as prophylaxis for pneumocystis pneumonia from January 2014 to January 2015 were evaluated. Data on the patients' age, gender, baseline estimated glomerular filtration rate (eGFR), baseline serum potassium, maximum serum potassium, duration reaching the maximal serum potassium level, dosage, and concomitant use of angiotensin-converting enzyme inhibitors (ACEi)/angiotensin receptor blockers (ARB), β-blockers, nonsteroidal anti-inflammatory drugs and potassium-sparing diuretics were retrospectively collected. Hyperkalemia was defined as a serum potassium level ! 5 mEq/L. Univariate and multivariate analyses were performed. Results The median age of the patients was 66 years and 51.1% were men. Hyperkalemia associated with low-dose TMP-SMX was observed in 32 patients (17.2%). The median duration to reach the maximal serum potassium level was 12 days. The multivariate logistic regression analysis identified renal insufficiency to be a major risk factor for hyperkalemia associated with low-dose TMP-SMX (eGFR <60 mL/min/1.73 m 2 , adjusted OR 4.62). Moreover, in the subpopulation of patients with renal insufficiency, ACEi/ARB use was considered to be a major risk factor for hyperkalemia (adjusted OR 3.96). Conclusion Renal insufficiency in concert with ACEi/ARB use is a major risk factor for hyperkalemia induced by low-dose TMP-SMX.

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“…Specifically, as illustrated in Tables 2 and 3, there were no between-group differences in 24-hour urine sodium or potassium excretion and no between-group differences in fractional excretion of potassium or potassium excretion rate. Other investigators found that the effects of lisinopril and spironolactone therapy on renal potassium excretion do not fully account for the observed increase in serum potassium that this regimen induces in patients with CKD (23), but no studies have compared different regimens. Even while adjusting for urinary sodium, potassium, and creatinine clearance in our study, the significant differences in serum potassium change between losartan and placebo and between spironolactone and placebo persisted.…”

Section: Discussionmentioning

confidence: 99%

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

Buren

Adams‐Huet

Nguyen³

et al. 2014

Clinical Journal of the American Society of Nephrology

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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.

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Mechanisms of Impaired Potassium Handling With Dual Renin-Angiotensin-Aldosterone Blockade in Chronic Kidney Disease

Cited by 47 publications

References 27 publications

Serum Potassium and Outcomes in CKD

Serum Potassium and Outcomes in CKD

Renal Insufficiency in Concert with Renin-angiotensin-aldosterone Inhibition Is a Major Risk Factor for Hyperkalemia Associated with Low-dose Trimethoprim-sulfamethoxazole in Adults

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

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