Higher doses of spironolactone can prevent the need for dialysis in selected heart failure patients

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Higher doses of spironolactone, a diuretic (water pill), can prevent the need for dialysis in selected heart failure patients, a UT Health San Antonio study found.

The aggressive approach relieved fluid overload safely and effectively in patients who were not responding to conventional diuretics.

The findings are in the journal Annals of Internal Medicine. UT Health San Antonio kidney and cardiovascular specialists conducted a pilot study in 19 patients to show that the higher doses of spironolactone, which prevents reabsorption of excess salt in the kidneys and maintains potassium levels, could be used safely in these very-ill patients, who admit to the hospital with heart failure exacerbation and don’t respond to conventional diuretics.

Spironolactone is usually given to these types of patients in doses of 25-50 milligrams.

In this study, the dose was increased to 100 and, at some administrations, even 200 milligrams.

Symptoms

Heart failure patients come into our care with excessive fluid (salt plus water) on their body, making them short of breath, unable to walk and unable to lie flat,” said Shweta Bansal, M.D., associate professor in the Division of Nephrology at UT Health San Antonio.

“They are miserable because of shortness of breath and distension in their abdomen and legs.”

Generally the treatment is a low-salt diet and diuretics.

Furosemide (brand name Lasix) is one of the frequently used medications.

When patients are admitted to the hospital, they are monitored on this regimen and usually improve.

But about 15% to 20% of patients do not get better, Dr. Bansal said. They continue to have fluid overload.

“The reason is they get resistant to the commonly used loop diuretics, and a very high aldosterone level is one of the main reasons for this resistance,” she said.

Targeting a different mechanism

Kidneys are made up of millions of tiny tubules called nephrons.

Nephrons consist of four main segments, including a part called the loop of Henle, where 20% to 25% of salt reabsorption happens.

Loop diuretics target this section.

Spironolactone inhibits the action of aldosterone, a hormone that makes the kidney excrete too much potassium and retain salt in the distal segment, another part of nephrons.

‘Significant improvement’

Study participants who didn’t respond to standard therapy were given high-dose spironolactone and monitored for urine output and breathing.

“Most of them had a dramatic increase in their urine output and significant improvement in their shortness of breath,” Dr. Bansal said.

“We think some patients could avoid needing dialysis if treated in this manner.”


Chronic kidney disease (CKD), having an increasing prevalence rate of about 10% worldwide as a result of longevity and ongoing epidemic of diabetes mellitus (DM), is an emerging global health concern and associated with the risk of premature cardiovascular disease (CVD) and mortality [1,2].

The above-expected cardiovascular risk may be attributed to some unique features in CKD, comprising anemia, endothelial dysfunction, oxidative stress, abnormalities in calcium and phosphorus metabolism and metabolic acidosis.

These derangements can further accelerate coronary calcification, coronary atherosclerosis, left ventricular hypertrophy and eventually heart failure [3].

Among the available treatment options to retard renal function decline, blockade of renin-angiotensin-aldosterone system (RAAS) by angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) has been widely used for their potentially beneficial effects on renal and cardiovascular outcomes in both diabetic and non-diabetic patients [4,5].

The renoprotective impact takes effects mainly as a result of reduction of intra-glomerular pressure and inhibition of angiotensin-II induced mesangial cell proliferation and fibrosis [6].

The phenomenon of aldosterone synthesis escape had been proposed to explain that neither ACEI nor ARB can completely abrogate or retard the progression of kidney disease [7].

Therefore, mineralocorticoid receptor antagonists (MRA) have been evaluated for their promising role in conjunction with ACEI or ARB afterwards.

Several studies on the effects of MRA were conducted amongst CKD patients in the past one decade.

A 2014 meta-analysis, updated from a 2009 meta-analysis, included 1549 patients of 27 studies and demonstrated that addition of MRA to ACEI or ARB (or both) in mild to moderate CKD patients resulted in the reduction of proteinuria and blood pressure, but precluded conclusive evidence regarding the risk of major cardiovascular events or end-stage renal disease (ESRD) [8].

The higher risk of hyperkalemia and gynecomastia limits its prescription in clinical practice. A later meta-analysis by Ng et al. in 2015 also drew similar conclusions, but the impact of MRA on CVD morbidity and mortality was unable to evaluate due to insufficiency data [9].

The major flaws in the studies of these meta-analyses were relatively small patient numbers and short follow-up period relatively.

, a non-selective MRA, can protect against cardiac fibrosis and left ventricular dysfunction, and improve endothelial dysfunction and proteinuria [10].

Therefore, we conducted this retrospective cohort study using representative national data to evaluate the effects of spironolactone on all-cause mortality, CVD mortality, ESRD, hospitalization for heart failure (HHF), major adverse cardiovascular events (MACE) and hyperkalemia-associated hospitalization (HKAH) in predialysis stage 3–4 CKD patients.


Chronic kidney disease (CKD), having an increasing prevalence rate of about 10% worldwide as a result of longevity and ongoing epidemic of diabetes mellitus (DM), is an emerging global health concern and associated with the risk of premature cardiovascular disease (CVD) and mortality [1,2].

The above-expected cardiovascular risk may be attributed to some unique features in CKD, comprising anemia, endothelial dysfunction, oxidative stress, abnormalities in calcium and phosphorus metabolism and metabolic acidosis.

These derangements can further accelerate coronary calcification, coronary atherosclerosis, left ventricular hypertrophy and eventually heart failure [3].

Among the available treatment options to retard renal function decline, blockade of renin-angiotensin-aldosterone system (RAAS) by angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) has been widely used for their potentially beneficial effects on renal and cardiovascular outcomes in both diabetic and non-diabetic patients [4,5].

The renoprotective impact takes effects mainly as a result of reduction of intra-glomerular pressure and inhibition of angiotensin-II induced mesangial cell proliferation and fibrosis [6].

The phenomenon of aldosterone synthesis escape had been proposed to explain that neither ACEI nor ARB can completely abrogate or retard the progression of kidney disease [7].

Therefore, mineralocorticoid receptor antagonists (MRA) have been evaluated for their promising role in conjunction with ACEI or ARB afterwards.

Several studies on the effects of MRA were conducted amongst CKD patients in the past one decade.

A 2014 meta-analysis, updated from a 2009 meta-analysis, included 1549 patients of 27 studies and demonstrated that addition of MRA to ACEI or ARB (or both) in mild to moderate CKD patients resulted in the reduction of proteinuria and blood pressure, but precluded conclusive evidence regarding the risk of major cardiovascular events or end-stage renal disease (ESRD) [8].

The higher risk of hyperkalemia and gynecomastia limits its prescription in clinical practice. A later meta-analysis by Ng et al. in 2015 also drew similar conclusions, but the impact of MRA on CVD morbidity and mortality was unable to evaluate due to insufficiency data [9].

The major flaws in the studies of these meta-analyses were relatively small patient numbers and short follow-up period relatively. Spironolactone, a non-selective MRA, can protect against cardiac fibrosis and left ventricular dysfunction, and improve endothelial dysfunction and proteinuria [10].

Therefore, we conducted this retrospective cohort study using representative national data to evaluate the effects of spironolactone on all-cause mortality, CVD mortality, ESRD, hospitalization for heart failure (HHF), major adverse cardiovascular events (MACE) and hyperkalemia-associated hospitalization (HKAH) in predialysis stage 3–4 CKD patients.


More information: Shweta Bansal et al, High-Dose Spironolactone When Patients With Acute Decompensated Heart Failure Are Resistant to Loop Diuretics: A Pilot Study, Annals of Internal Medicine (2019). DOI: 10.7326/M18-3285

Journal information: Annals of Internal Medicine
Provided by University of Texas Health Science Center at San Antonio

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