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Mechanism of Hyperkalemia-Induced Metabolic Acidosis.
Harris AN, Grimm PR, Lee HW, Delpire E, Fang L, Verlander JW, Welling PA, Weiner ID
(2018) J Am Soc Nephrol 29: 1411-1425
MeSH Terms: Acidosis, Aldosterone, Amiloride, Ammonia, Animals, Cation Transport Proteins, Diuretics, Glutaminase, Hydrochlorothiazide, Hydrogen-Ion Concentration, Hyperkalemia, Kidney Tubules, Distal, Kidney Tubules, Proximal, Membrane Glycoproteins, Mice, Mice, Knockout, Protein-Serine-Threonine Kinases, Proton-Translocating ATPases, Urinalysis
Show Abstract · Added April 3, 2018
Hyperkalemia in association with metabolic acidosis that are out of proportion to changes in glomerular filtration rate defines type 4 renal tubular acidosis (RTA), the most common RTA observed, but the molecular mechanisms underlying the associated metabolic acidosis are incompletely understood. We sought to determine whether hyperkalemia directly causes metabolic acidosis and, if so, the mechanisms through which this occurs. We studied a genetic model of hyperkalemia that results from early distal convoluted tubule (DCT)-specific overexpression of constitutively active Ste20/SPS1-related proline-alanine-rich kinase (DCT-CA-SPAK). DCT-CA-SPAK mice developed hyperkalemia in association with metabolic acidosis and suppressed ammonia excretion; however, titratable acid excretion and urine pH were unchanged compared with those in wild-type mice. Abnormal ammonia excretion in DCT-CA-SPAK mice associated with decreased proximal tubule expression of the ammonia-generating enzymes phosphate-dependent glutaminase and phosphoenolpyruvate carboxykinase and overexpression of the ammonia-recycling enzyme glutamine synthetase. These mice also had decreased expression of the ammonia transporter family member Rhcg and decreased apical polarization of H-ATPase in the inner stripe of the outer medullary collecting duct. Correcting the hyperkalemia by treatment with hydrochlorothiazide corrected the metabolic acidosis, increased ammonia excretion, and normalized ammoniagenic enzyme and Rhcg expression in DCT-CA-SPAK mice. In wild-type mice, induction of hyperkalemia by administration of the epithelial sodium channel blocker benzamil caused hyperkalemia and suppressed ammonia excretion. Hyperkalemia decreases proximal tubule ammonia generation and collecting duct ammonia transport, leading to impaired ammonia excretion that causes metabolic acidosis.
Copyright © 2018 by the American Society of Nephrology.
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19 MeSH Terms
Combined Angiotensin Receptor Antagonism and Neprilysin Inhibition.
Hubers SA, Brown NJ
(2016) Circulation 133: 1115-24
MeSH Terms: Abnormalities, Drug-Induced, Aminobutyrates, Angioedema, Angiotensin Receptor Antagonists, Biphenyl Compounds, Bradykinin, Contraindications, Drug Combinations, Drug Costs, Drug Synergism, Enalapril, Enzyme Inhibitors, Female, Follow-Up Studies, Heart Failure, Humans, Hyperkalemia, Hypertension, Kidney, Multicenter Studies as Topic, Natriuretic Peptides, Neprilysin, Pregnancy, Prodrugs, Prospective Studies, Pyridines, Randomized Controlled Trials as Topic, Stroke Volume, Tetrazoles, Thiazepines, Valsartan
Show Abstract · Added April 6, 2017
Heart failure affects ≈5.7 million people in the United States alone. Angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, β-blockers, and aldosterone antagonists have improved mortality in patients with heart failure and reduced ejection fraction, but mortality remains high. In July 2015, the US Food and Drug Administration approved the first of a new class of drugs for the treatment of heart failure: Valsartan/sacubitril (formerly known as LCZ696 and currently marketed by Novartis as Entresto) combines the angiotensin receptor blocker valsartan and the neprilysin inhibitor prodrug sacubitril in a 1:1 ratio in a sodium supramolecular complex. Sacubitril is converted by esterases to LBQ657, which inhibits neprilysin, the enzyme responsible for the degradation of the natriuretic peptides and many other vasoactive peptides. Thus, this combined angiotensin receptor antagonist and neprilysin inhibitor addresses 2 of the pathophysiological mechanisms of heart failure: activation of the renin-angiotensin-aldosterone system and decreased sensitivity to natriuretic peptides. In the Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) trial, valsartan/sacubitril significantly reduced mortality and hospitalization for heart failure, as well as blood pressure, compared with enalapril in patients with heart failure, reduced ejection fraction, and an elevated circulating level of brain natriuretic peptide or N-terminal pro-brain natriuretic peptide. Ongoing clinical trials are evaluating the role of valsartan/sacubitril in the treatment of heart failure with preserved ejection fraction and hypertension. We review here the mechanisms of action of valsartan/sacubitril, the pharmacological properties of the drug, and its efficacy and safety in the treatment of heart failure and hypertension.
© 2016 American Heart Association, Inc.
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31 MeSH Terms
Is there a new dawn for selective mineralocorticoid receptor antagonism?
Luther JM
(2014) Curr Opin Nephrol Hypertens 23: 456-61
MeSH Terms: Animals, Antihypertensive Agents, Blood Pressure, Blood Vessels, Drug Design, Humans, Hyperkalemia, Hypertension, Mineralocorticoid Receptor Antagonists, Receptors, Mineralocorticoid, Risk Factors, Signal Transduction, Treatment Outcome
Show Abstract · Added October 27, 2014
PURPOSE OF REVIEW - Aldosterone and the mineralocorticoid receptor contribute to resistant hypertension and cardiovascular mortality, and mineralocorticoid receptor antagonists effectively reduce these complications. Their use is limited in certain populations with a higher risk of hyperkalemia or renal dysfunction. This review will highlight recent developments in extra-renal mineralocorticoid receptor research and the development of novel mineralocorticoid receptor antagonists.
RECENT FINDINGS - Tissue-specific knockout-out models provide definitive evidence that the vascular mineralocorticoid receptor directly contributes to hypertension and vascular remodeling, independent of renal effects. Several nonsteroidal mineralocorticoid receptor antagonists are in preclinical development or early-stage clinical trials. Several nonsteroidal mineralocorticoid receptor antagonists have demonstrated preserved cardiovascular benefit with a reduced incidence of hyperkalemia in preclinical studies.
SUMMARY - Novel, potent nonsteroidal mineralocorticoid receptor antagonists are in development, although their effect on cardiovascular and adverse drug events requires further investigation.
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13 MeSH Terms
Potential side effects of renin inhibitors--mechanisms based on comparison with other renin-angiotensin blockers.
Cheng H, Harris RC
(2006) Expert Opin Drug Saf 5: 631-41
MeSH Terms: Abnormalities, Drug-Induced, Amides, Angiotensin Receptor Antagonists, Angiotensin-Converting Enzyme Inhibitors, Animals, Clinical Trials as Topic, Fumarates, Humans, Hyperkalemia, Hypertension, Hypotension, Inappropriate ADH Syndrome, Male, Mice, Renin
Show Abstract · Added August 21, 2013
Angiotensin (Ang) II plays important roles in the development of hypertension and cardiovascular and renal injury. Pharmaceutical approaches to block its activity led to the development of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. Numerous trials have documented their efficacy in controlling blood pressure, minimising left ventricular remodelling, preventing progression to heart failure, ameliorating proteinuria and retarding renal disease progression. Although they are considered safe in general, there remain concerns about the potential for adverse events in certain target populations. Recently, several novel, low molecular weight renin inhibitors without the extended peptide-like backbone of previous renin inhibitors were developed with favourable pharmacokinetic properties. They have been shown to successfully reduce Ang II levels in normal volunteers and to lower blood pressure in patients with mild-to-moderate hypertension. In this review, the authors summarise current knowledge about these renin inhibitors.
1 Communities
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15 MeSH Terms
Acute tumor lysis syndrome in patients with high-grade non-Hodgkin's lymphoma.
Hande KR, Garrow GC
(1993) Am J Med 94: 133-9
MeSH Terms: Acute Disease, Allopurinol, Antineoplastic Combined Chemotherapy Protocols, Blood Urea Nitrogen, Burkitt Lymphoma, Creatinine, Humans, Hyperkalemia, Hypocalcemia, L-Lactate Dehydrogenase, Leukemia, Lymphocytic, Chronic, B-Cell, Lymphoma, Large B-Cell, Diffuse, Lymphoma, Non-Hodgkin, Lymphoma, T-Cell, Phosphates, Renal Insufficiency, Retrospective Studies, Risk Factors, Tumor Lysis Syndrome, Uric Acid
Show Abstract · Added March 5, 2014
PURPOSE - To identify patients with lymphoma at risk for tumor lysis after chemotherapy.
PATIENTS AND METHODS - The case records of 102 patients receiving combination chemotherapy for non-Hodgkin's lymphoma (intermediate to high-grade histology) were reviewed. Patients were considered to have "laboratory tumor lysis" if two of the following metabolic changes occurred within 4 days of treatment: a 25% increase in the serum phosphate, potassium, uric acid, or urea nitrogen concentrations, or a 25% decline in the serum calcium concentration. "Clinical tumor lysis" was defined as laboratory tumor lysis plus one of the following: a serum potassium level greater than 6 mmol/L, a creatinine level greater than 221 mumol/L, or a calcium level less than 1.5 mmol/L, the development of a life-threatening arrhythmia, or sudden death.
RESULTS - Laboratory tumor lysis occurred in 42% of patients and clinical tumor lysis in 6%. There was no statistical difference in the frequency of either tumor lysis syndrome among lymphoma subgroups. Clinical tumor lysis occurred more frequently in patients with pretreatment renal insufficiency (serum creatinine level greater than 132 mumol/L) than in patients with normal renal function (36% versus 2%; p = 0.01). The development of azotemia correlated with high pretreatment serum lactate dehydrogenase concentrations (p < 0.01; r2 = 0.11).
CONCLUSION - Clinically significant tumor lysis is a rare occurrence in patients with lymphoma when they are receiving allopurinol. However, tumor lysis can occur in patients with all types of moderate to high-grade non-Hodgkin's lymphoma. Patients with a high serum lactate dehydrogenase level or renal insufficiency are at increased risk for metabolic complications after chemotherapy and should be closely monitored.
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20 MeSH Terms