Research Spotlight

Gupta, S., J. J. Gao, M. Emmett and A. Z. Fenves (2017). “Topiramate and metabolic acidosis: An evolving story.” Hosp Pract (1995) 45(5): 192-195.

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Topiramate is an anticonvulsant that is being increasingly used for a number of different off-label indications. Its inhibition of carbonic anhydrase isoenzymes can lead to metabolic acidosis, elevated urine pH, reduced urine citrate, and hypercalciuria, thereby creating a milieu that is ripe for calcium phosphate stone formation. In this review, we describe a case of topiramate-induced metabolic acidosis. We review the frequency of metabolic acidosis among children and adults, as well as the mechanism of hyperchloremic metabolic acidosis and renal tubular acidosis in topiramate users. Finally, we describe the long-term effects of topiramate-induced metabolic acidosis, including nephrolithiasis, nephrocalcinosis, and bone degradation. Patients who are prescribed topiramate should be carefully monitored for metabolic derangements, and they may benefit from alkali supplementation, or in extreme cases, discontinuation of the drug altogether.

Kovesdy, C. P., L. J. Appel, M. E. Grams, L. Gutekunst, P. A. McCullough, B. F. Palmer, B. Pitt, D. A. Sica and R. R. Townsend (2017). “Potassium homeostasis in health and disease: A scientific workshop cosponsored by the national kidney foundation and the american society of hypertension.” Am J Kidney Dis 70(6): 844-858.

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While much emphasis, and some controversy, centers on recommendations for sodium intake, there has been considerably less interest in recommendations for dietary potassium intake, in both the general population and patients with medical conditions, particularly acute and chronic kidney disease. Physiology literature and cohort studies have noted that the relative balance in sodium and potassium intakes is an important determinant of many of the sodium-related outcomes. A noteworthy characteristic of potassium in clinical medicine is the extreme concern shared by many practitioners when confronted by a patient with hyperkalemia. Fear of this often asymptomatic finding limits enthusiasm for recommending potassium intake and often limits the use of renin-angiotensin-aldosterone system blockers in patients with heart failure and chronic kidney diseases. New agents for managing hyperkalemia may alter the long-term management of heart failure and the hypertension, proteinuria, and further function loss in chronic kidney diseases. In this jointly sponsored effort between the American Society of Hypertension and the National Kidney Foundation, 3 panels of researchers and practitioners from various disciplines discussed and summarized current understanding of the role of potassium in health and disease, focusing on cardiovascular, nutritional, and kidney considerations associated with both hypo- and hyperkalemia.

Muriello, M. J., S. Viall, T. Bottiglieri, K. Cusmano-Ozog and C. R. Ferreira (2017). “Confirmation that mat1a p.Ala259val mutation causes autosomal dominant hypermethioninemia.” Mol Genet Metab Rep 13: 9-12.

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Methionine adenosyltransferase (MAT) I/III deficiency is an inborn error of metabolism caused by mutations in MAT1A, encoding the catalytic subunit of MAT responsible for the synthesis of S-adenosylmethionine, and is characterized by persistent hypermethioninemia. While historically considered a recessive disorder, a milder autosomal dominant form of MAT I/III deficiency occurs, though only the most common mutation p.Arg264His has ample evidence to prove dominant inheritance. We report a case of hypermethioninemia caused by the p.Ala259Val substitution and provide evidence of autosomal dominant inheritance by showing both maternal inheritance of the mutation and concomitant hypermethioninemia. The p.Ala259Val mutation falls in the dimer interface, and thus likely leads to dominant inheritance by a similar mechanism to that described in the previously reported dominant negative mutation, that is, by means of interference with subunits encoded by the wild-type allele.

Mogensen, U. M., P. S. Jhund, W. T. Abraham, A. S. Desai, K. Dickstein, M. Packer, J. L. Rouleau, S. D. Solomon, K. Swedberg, M. R. Zile, L. Kober and J. J. V. McMurray (2017). “Type of atrial fibrillation and outcomes in patients with heart failure and reduced ejection fraction.” J Am Coll Cardiol 70(20): 2490-2500.

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BACKGROUND: Atrial fibrillation (AF) is common in heart failure (HF), but the outcome by type of AF is largely unknown. OBJECTIVES: This study investigated outcomes related to type of AF (paroxysmal, persistent or permanent, or new onset) in 2 recent large trials in patients with HF with reduced ejection fraction. METHODS: The study analyzed patients in the PARADIGM-HF (Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure) and ATMOSPHERE (Aliskiren Trial to Minimize Outcomes in Patients with Heart Failure) trials. Multivariable Cox regression models were used to estimate hazard ratios (HRs) for outcomes related to AF type. RESULTS: Of 15,415 patients, 5,481 (35.6%) had a history of AF at randomization, and of these, 1,645 (30.0%) had paroxysmal AF. Compared with patients without AF, patients with paroxysmal AF at randomization had a higher risk of the primary composite endpoint of cardiovascular death or HF hospitalization (HR: 1.20; 95% confidence interval [CI]: 1.09 to 1.32; p < 0.001), HF hospitalization (HR: 1.34; 95% CI: 1.19 to 1.51; p < 0.001), and stroke (HR: 1.34; 95% CI: 1.02 to 1.76; p = 0.037), whereas the corresponding risks in patients with persistent or permanent AF were not elevated. Neither type of AF was associated with higher mortality. New onset AF was associated with the greatest risk of adverse outcomes: primary endpoint (HR: 2.21; 95% CI: 1.80 to 2.71), HF hospitalization (HR: 2.11; 95% CI: 1.58 to 2.81), stroke (HR: 2.20; 95% CI: 1.25 to 3.88), and all-cause mortality (HR: 2.26; 95% CI: 1.86 to 2.74), all p values < 0.001, compared with patients without AF. Anticoagulants were used less often in patients with paroxysmal (53%) and new onset (16%) AF than in patients with persistent or permanent AF (71%). CONCLUSIONS: Among HF patients with a history of AF, those with paroxysmal AF were at greater risk of HF hospitalization and stroke than were patients with persistent or permanent AF, underlining the importance of anticoagulant therapy. New onset AF was associated with increased risk of all outcomes.

Miles, D., D. Cameron, M. Hilton, J. Garcia and J. O’Shaughnessy (2017). “Overall survival in meridian, a double-blind placebo-controlled randomised phase iii trial evaluating first-line bevacizumab plus paclitaxel for her2-negative metastatic breast cancer.” Eur J Cancer: 2017 Nov [Epub ahead of print].

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The MERiDiAN trial was designed to investigate prospectively plasma VEGF-A as a potential predictive biomarker for bevacizumab effect on investigator-assessed PFS in HER2-negative mBC. The co-primary objectives were met: bevacizumab significantly improved PFS in both the ITT population (stratified hazard ratio [HR] 0.68, 99% confidence interval [CI]: 0.51–0.91; log-rank p = 0.0007) and the VEGF-Ahigh population (stratified HR 0.64, 96% CI: 0.47–0.88; log-rank p = 0.0038). However, results did not support the use of baseline plasma VEGF-A level to identify the patients benefitting most from bevacizumab.