Research Spotlight

Atta, M. G., M. M. Estrella, K. L. Skorecki, J. B. Kopp, C. A. Winkler, W. G. Wasser, R. Shemer, L. C. Racusen, M. Kuperman, M. C. Foy, G. M. Lucas and D. M. Fine (2015). “Association of APOL1 Genotype with Renal Histology among Black HIV-Positive Patients Undergoing Kidney Biopsy.” Clinical Journal of the American Society of Nephrology. 2015 Dec 14. [Epub ahead of print].

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BACKGROUND AND OBJECTIVES: Prior studies have shown that the APOL1 risk alleles are associated with a greater risk of HIV-associated nephropathy and FSGS among blacks who are HIV positive. We sought to determine whether the APOL1 high-risk genotype incrementally improved the prediction of these underlying lesions beyond conventional clinical factors. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In a cross-sectional study, we analyzed data from 203 blacks who are HIV positive, underwent kidney biopsies between 1996 and 2011, and were genotyped for the APOL1 G1 and G2 alleles. Predictive logistic regression models with conventional clinical factors were compared with those that also included APOL1 genotype using receiver-operating curves and bootstrapping analyses with crossvalidation. RESULTS: The addition of APOL1 genotype to HIV-related risk factors for kidney disease in a predictive model improved the prediction of non-HIV-associated nephropathy FSGS, specifically, increasing the c statistic from 0.65 to 0.74 (P=0.04). Although two risk alleles were significantly associated with higher odds of HIV-associated nephropathy, APOL1 genotype did not add incrementally to the prediction of this specific histopathology. CONCLUSIONS: APOL1 genotype may provide additional diagnostic information to traditional clinical variables in predicting underlying FSGS spectrum lesions in blacks who are HIV positive. In contrast, although APOL1 risk genotype predicts HIV-associated nephropathy, it lacked a high c statistic sufficient for discrimination to eliminate the role of kidney biopsy in the clinical care of blacks who are HIV positive with nephrotic proteinuria or unexplained kidney disease.

Anker, S. D., M. Kosiborod, F. Zannad, I. L. Pina, P. A. McCullough, G. Filippatos, P. van der Meer, P. Ponikowski, H. S. Rasmussen, P. T. Lavin, B. Singh, A. Yang and P. Deedwania (2015). “Maintenance of serum potassium with sodium zirconium cyclosilicate (ZS-9) in heart failure patients: results from a phase 3 randomized, double-blind, placebo-controlled trial.” European Journal of Heart Failure 17(10): 1050-1056.

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Aims Hyperkalaemia in heart failure patients limits use of cardioprotective renin-angiotensin-aldosterone system inhibitors (RAASi). Sodium zirconium cyclosilicate (ZS-9) is a selective potassium ion trap, whose mechanism of action may allow for potassium binding in the upper gastrointestinal tract as early as the duodenum following oral administration. ZS-9 previously demonstrated the ability to reduce elevated potassium levels into the normal range, with a median time of normalization of 2.2 h and sustain normal potassium levels for 28 days in HARMONIZEa Phase 3, double-blind, randomized, placebo-controlled trial. In the present study we evaluated management of serum potassium with daily ZS-9 over 28 days in heart failure patients from HARMONIZE, including those receiving RAASi therapies. Methods and resultsHeart failure patients with evidence of hyperkalaemia (serum potassium 5.1 mmol/L, n = 94) were treated with open-label ZS-9 for 48 h. Patients (n = 87; 60 receiving RAASi) who achieved normokalaemia (potassium 3.5-5.0 mmol/L) were randomized to daily ZS-9 (5, 10, or 15 g) or placebo for 28 days. Mean potassium and proportion of patients maintaining normokalaemia during days 8-29 post-randomization were evaluated. Despite RAASi doses being kept constant, patients on 5 g, 10 g, and 15 g ZS-9 maintained a lower potassium level (4.7 mmol/L, 4.5 mmol/L, and 4.4 mmol/L, respectively) than the placebo group (5.2 mmol/L; P<0.01 vs. each ZS-9 group); greater proportions of ZS-9 patients (83%, 89%, and 92%, respectively) maintained normokalaemia than placebo (40%; P < 0.01 vs. each ZS-9 group). The safety profile was consistent with previously reported overall study population. ConclusionCompared with placebo, all three ZS-9 doses lowered potassium and effectively maintained normokalaemia for 28 days in heart failure patients without adjusting concomitant RAASi, while maintaining a safety profile consistent with the overall study population.

Adjei, A. A., D. Richards, A. B. El-Khoueiry, F. Braiteh, C. Becerra, J. Stephenson, A. F. Hezel, M. Sherman, L. E. Garbo, D. P. Leffingwell, C. Iverson, J. N. Miner, Z. Shen, L. T. Yeh, S. Gunawan, D. M. Wilson, K. J. Manhard, P. Rajagopalan, H. Krissel and N. J. Clendeninn (2015). “A Phase I Study of the Safety, Pharmacokinetics, and Pharmacodynamics of Combination Therapy with Refametinib plus Sorafenib in Patients with Advanced Cancer.” Clinical Cancer Research. 2015 Dec 7. [Epub ahead of print]

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PURPOSE: To assess the safety and tolerability of the small-molecule allosteric MEK inhibitor refametinib combined with sorafenib, in patients with advanced solid malignancies. METHODS: This phase I dose-escalation study included an expansion phase at the maximum tolerated dose (MTD). Patients received refametinib/sorafenib twice daily (BID) for 28 days, from a dose of refametinib 5 mg plus sorafenib 200 mg to a dose of refametinib 50 mg plus sorafenib 400 mg. Plasma levels of refametinib, refametinib metabolite M17, and sorafenib were measured for pharmacokinetic assessments. Tumors were biopsied at the MTD for analysis of MEK pathway mutations and ERK phosphorylation. RESULTS: Thirty-two patients were enrolled in the dose-escalation cohort. The MTD was refametinib 50 mg BID plus sorafenib 400 mg BID. The most common treatment-related toxicities were diarrhea and fatigue. Refametinib was readily absorbed following oral administration (plasma half-life of ~16 hours at the MTD), and pharmacokinetic parameters displayed near-dose proportionality, with less than 2-fold accumulation after multiple dosing. Another 30 patients were enrolled in the MTD cohort; 19 had hepatocellular carcinoma. The combination was associated with significantly reduced ERK phosphorylation in 5 out of 6 patients biopsied, with the greatest reductions in those with KRAS or BRAF mutations. Disease was stabilized in approximately half of patients, and 1 patient with colorectal cancer achieved a partial response at the MTD lasting approximately 1 year. CONCLUSIONS: In this phase I study, refametinib plus sorafenib was well tolerated, with good oral absorption, near-dose proportionality, and target inhibition in a range of tumor types.

Warren, A. M., A. Boals, T. R. Elliott, M. Reynolds, R. J. Weddle, P. Holtz, Z. Trost and M. L. Foreman (2015). “Mild traumatic brain injury increases risk for the development of posttraumatic stress disorder.” J Trauma Acute Care Surg 79(6): 1062-1066.

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BACKGROUND: Traumatic brain injury (TBI) and posttraumatic stress disorder (PTSD) occur in individuals who sustain physical injury and share a significant overlap in symptoms. PTSD rates in the civilian injury population range from 20% to 40%. The current study examined the presence of PTSD symptoms at multiple time points (3 months and 6 months after injury) among individuals with and without TBI after admission to a Level I trauma center. METHODS: This prospective cohort study included patients 18 years and older admitted to a Level I trauma center for 24 hours or greater. Demographic and injury-related data were gathered in addition to assessments of PTSD during initial hospitalization after injury, as well as 3 months and 6 months later. The Primary Care PTSD Screen and PTSD Checklist-Civilian version were used to determine probable PTSD. International Classification of Diseases, 9th Rev. codes were used to determine mild TBI (MTBI). RESULTS: A total of 494 patients were enrolled at baseline, 311 (63%) completed 3-month follow-up, and 231 (47%) completed 6-month follow-up at the time of analysis. Preinjury PTSD was reported by 7% of the participants. At 3 months, patients with MTBI evidenced a probable PTSD rate of 18%, compared with a rate of 9% for patients with no MTBI (p = 0.04), although this relationship became a nonsignificant trend (p = 0.06) when demographics were included. At 6 months, patients with MTBI evidenced a probable PTSD rate of 26%, compared with a rate of 15% for patients with no MTBI (p = 0.04), and this relationship remained significant when demographics were included. Preinjury history of TBI did not predict PTSD, but incidence of TBI for the injury in which they were hospitalized did predict PTSD. CONCLUSION: TBI at time of injury demonstrated a nonsignificant trend toward higher rates of PTSD at 3 months and significantly predicted PTSD at 6 months after injury. This important finding may help clinicians identify patients at high risk for PTSD after injury and target these patients for screening, intervention, and referral for treatment. LEVEL OF EVIDENCE: Prognostic study, level III.

Schiffmann, R. (2015). “A genetic form of achlorhydria and gastritis.” American Journal of Clinical Nutrition 102(6): 1615-1615.

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The recent review article on the connection between achlorhydria and iron deficiency anemia concludes that gastritis-induced achlorhydria can be an independent cause of iron deficiency anemia. I would like to attract your attention to a little-known autosomal recessive genetic disease, mucolipidosis type IV (MLIV), in which all patients have constitutive achlorhydria. MLIV is caused by mutation of the MCOLN1 gene that encodes the endosomal/lysosomal transient receptor potential channel protein mucolipin 1 (TRPML1). The exact mechanism by which this nonselective cation channel deficiency prevents hydrochloric acid secretion is incompletely understood. Parietal cells in MLIV are present in seemingly normal numbers, are full of large vacuoles, yet produce normal amounts of intrinsic factor. All patients tested thus far were achlorhydric with up to 10-fold elevations in blood gastrin, which is useful for disease screening (5). Mucosal atrophy was present in biopsy samples, with increasing chronic inflammation with age. Fifty percent of patients with MLIV have iron deficiency anemia, which can be corrected with oral iron preparations. Because the achlorhydria is congenital, it is likely that it leads over time to both gastritis and iron deficiency but that the presence of gastritis is not necessary for abnormal absorption of food iron. To our knowledge, MLIV is the only single-gene disorder associated with a selective defect of gastric hydrochloric acid secretion.