Research Spotlight

Wesson, D. E., J. M. Buysse and D. A. Bushinsky (2020). “Mechanisms of Metabolic Acidosis-Induced Kidney Injury in Chronic Kidney Disease.” J Am Soc Nephrol 31(3): 469-482.

Full text of this article.

Retrospective analyses and single-center prospective studies identify chronic metabolic acidosis as an independent and modifiable risk factor for progression of CKD. In patients with CKD, untreated chronic metabolic acidosis often leads to an accelerated reduction in GFR. Mechanisms responsible for this reduction include adaptive responses that increase acid excretion but lead to a decline in kidney function. Metabolic acidosis in CKD stimulates production of intrakidney paracrine hormones including angiotensin II, aldosterone, and endothelin-1 (ET-1) that mediate the immediate benefit of increased kidney acid excretion, but their chronic upregulation promotes inflammation and fibrosis. Chronic metabolic acidosis also stimulates ammoniagenesis that increases acid excretion but also leads to ammonia-induced complement activation and deposition of C3 and C5b-9 that can cause tubule-interstitial damage, further worsening disease progression. These effects, along with acid accumulation in kidney tissue, combine to accelerate progression of kidney disease. Treatment of chronic metabolic acidosis attenuates these adaptive responses; reduces levels of angiotensin II, aldosterone, and ET-1; reduces ammoniagenesis; and diminishes inflammation and fibrosis that may lead to slowing of CKD progression.

Wang, C. H., W. T. Chang, K. I. Su, C. H. Huang, M. S. Tsai, E. Chou, T. C. Lu, W. J. Chen, C. C. Lee and S. C. Chen (2020). “Neuroprognostic accuracy of blood biomarkers for post-cardiac arrest patients: A systematic review and meta-analysis.” Resuscitation 148: 108-117.

Full text of this article.

AIM: To summarise and compare the prognostic accuracy of the blood biomarkers of brain injury, including NSE and S-100B, for neurological outcomes in adult post-cardiac arrest patients. METHODS: We systematically searched PubMed and Embase databases from their inception to March 2019. We selected studies providing sufficient data of prognostic values of NSE or S-100B to predict neurological outcomes in adult post-cardiac arrest patients. We adopted QUADAS-2 to assess risk of bias and a Bayesian bivariate random-effects meta-analysis model to synthesise the prognostic data. The study protocol was registered with PROSPERO (CRD42018084933). RESULTS: We included 42 studies involving 4806 patients in the meta-analysis. The NSE was associated with a pooled sensitivity of 0.56 (95% credible interval [CrI], 0.47-0.65) and pooled specificity of 0.99 (95% CrI, 0.98-1.00). The S-100B was associated with a pooled sensitivity of 0.63 (95% CrI, 0.46-0.78) and pooled specificity of 0.97 (95% CrI, 0.92-1.00). The heterogeneity for NSE (I(2), 22.4%) and S-100B (I(2), 16.1%) was low and publication bias was not significant. In subgroup analyses, both biomarkers were associated with high specificity across all subgroups with regard to different populations (i.e. whether patients were out-of-hospital cardiac arrest or whether patients received targeted temperature management), different timings of measurement, and different timings of outcome assessment. CONCLUSIONS: The prognostic performance was comparable between NSE and S-100B. Both biomarkers may be integrated into a multimodal neuroprognostication algorithm for post-cardiac arrest patients and institution-specific cut-off points for both biomarkers should be established.

Tondo, M., B. Wasek, J. C. Escola-Gil, D. de Gonzalo-Calvo, C. Harmon, E. Arning and T. Bottiglieri (2020). “Altered Brain Metabolome Is Associated with Memory Impairment in the rTg4510 Mouse Model of Tauopathy.” Metabolites Feb 14: 10(2) [Epub ahead of print.].

Full text of this article.

Alzheimer’s disease (AD) is characterized, amongst other features, by the pathologic accumulation of abnormally phosphorylated tau filaments in neurons that lead to neurofibrillary tangles. However, the molecular mechanisms by which the abnormal processing of tau leads to neurodegeneration and cognitive impairment remain unknown. Metabolomic techniques can comprehensively assess disturbances in metabolic pathways that reflect changes downstream from genomic, transcriptomic and proteomic systems. In the present study, we undertook a targeted metabolomic approach to determine a total of 187 prenominated metabolites in brain cortex tissue from wild type and rTg4510 animals (a mice model of tauopathy), in order to establish the association of metabolic pathways with cognitive impairment. This targeted metabolomic approach revealed significant differences in metabolite concentrations of transgenic mice. Brain glutamine, serotonin and sphingomyelin C18:0 were found to be predictors of memory impairment. These findings provide informative data for future research on AD, since some of them agree with pathological alterations observed in diseased humans.

Tolcher, A. W., R. Kurzrock, V. Valero, R. Gonzalez, R. S. Heist, A. R. Tan, J. Means-Powell, T. L. Werner, C. Becerra, C. Wang, C. Leonowens, S. Kalyana-Sundaram, J. F. Kleha, J. Gauvin, A. M. D’Amelio, Jr., C. Ellis, N. Ibrahim and L. Yan (2020). “Phase I dose-escalation trial of the oral AKT inhibitor uprosertib in combination with the oral MEK1/MEK2 inhibitor trametinib in patients with solid tumors.” Cancer Chemother Pharmacol Feb 15. [Epub ahead of print].

Full text of this article.

PURPOSE: This study aimed to determine the safety, tolerability, and recommended phase II doses of trametinib plus uprosertib (GSK2141795) in patients with solid tumors likely to be sensitive to MEK and/or AKT inhibition. METHODS: This was a phase I, open-label, dose-escalation, and dose-expansion study in patients with triple-negative breast cancer or BRAF-wild type advanced melanoma. The primary outcome of the expansion study was investigator-assessed response. Among 126 enrolled patients, 63 received continuous oral daily dosing of trametinib and uprosertib, 29 received various alternative dosing schedules, and 34 were enrolled into expansion cohorts. Doses tested in the expansion cohort were trametinib 1.5 mg once daily (QD) + uprosertib 50 mg QD. RESULTS: Adverse events (AEs) were consistent with those reported in monotherapy studies but occurred at lower doses and with greater severity. Diarrhea was the most common dose-limiting toxicity; diarrhea and rash were particularly difficult to tolerate. Overall, 59% and 6% of patients reported AEs with a maximum severity of grade 3 and 4, respectively. Poor tolerability prevented adequate delivery of uprosertib with trametinib at a concentration predicted to have clinical activity. The study was terminated early based on futility in the continuous-dosing expansion cohorts and a lack of pharmacological or therapeutic advantage with intermittent dosing. The objective response rate was < 5% (1 complete response, 5 partial responses). CONCLUSIONS: Continuous and intermittent dosing of trametinib in combination with uprosertib was not tolerated, and minimal clinical activity was observed in all schedules tested.

Szerlip, M., D. N. Feldman, H. D. Aronow, J. C. Blankenship, J. W. Choi, I. Y. Elgendy, S. Elmariah, S. Garcia, B. H. Goldstein, H. Herrmann, R. S. Hira, M. R. Jaff, A. Kalra, E. Kaluski, C. J. Kavinsky, D. M. Kolansky, D. F. Kong, J. C. Messenger, D. Mukherjee, R. A. G. Patel, R. Piana, E. Senerth, M. Shishehbor, G. Singh, V. Singh, P. K. Yadav and D. Cox (2020). “SCAI publications committee manual of standard operating procedures.” Catheter Cardiovasc Interv 2020 Feb 14. [Epub ahead of print].

Full text of this article.

Evidence-based recommendations for clinical practice are intended to help health care providers and patients make decisions, minimize inappropriate practice variation, promote effective resource use, improve clinical outcomes, and direct future research. The Society for Cardiovascular Angiography and Interventions (SCAI) has been engaged in the creation and dissemination of clinical guidance documents since the 1990s. These documents are a cornerstone of the society’s education, advocacy, and quality improvement initiatives. The publications committee is charged with oversight of SCAI’s clinical documents program and has created this manual of standard operating procedures to ensure consistency, methodological rigor, and transparency in the development and endorsement of the society’s documents. The manual is intended for use by the publications committee, document writing groups, external collaborators, SCAI representatives, peer reviewers, and anyone seeking information about the SCAI documents program.