Research Spotlight

Wesson, D. E. (2019). “Does Egfr by Any Number Mean the Same?” J Am Soc Nephrol 30(10): 1806-1807.

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The development of a consensus strategy for classification and stratification of CKD was a major advance for clinicians managing individuals with CKD, for individuals with CKD under their care, and for those at CKD risk. This strategy allowed for the development of CKD stage–guided practice guidelines governed by level of remaining GFR and degree, if any, of kidney injury determined by urine indices, such as albuminuria. An individual’s stage helped determine whether and if so, how clinicians would investigate them for the cause of reduced eGFR and/or underlying kidney injury. This staging system subsequently allowed investigators to help predict outcomes, including mortality, according to stage and therefore, help guide the approach to individuals with CKD. Our evolving understanding of the contributors to GFR as well as CKD and its progression prompts the kidney community to consider if we need to modify this comparatively recent classification and stratification system. For example, individual race/ethnicity factors into the eGFR calculation,4 and some question the appropriateness of this inclusion.5 Do different eGFRs derived for individuals with different race/ethnicity mean that the different derived eGFRs indicate different outcomes for individuals with identical parameters except for race/ethnicity? However, does the generally lower eGFR of individuals habitually eating a primarily vegetarian diet6 predict the same outcome as the identical eGFR in individuals habitually eating a primarily meat-based diet? Relatedly, is progressive nephron loss of aging7 a consequence of “healthy” aging or due, at least in part, to the comparatively high meat content of diets typical of developed societies? If progressive nephron loss is indeed a consequence of healthy aging, does the lower eGFR of a healthy aged individual indicate the same outcome(s) as the identical lower eGFR in a younger individual? These and possibly, other insights question whether our CKD classification system should evolve to help clinicians better assess the consequence(s) of a given lower eGFR through the lens of its cause and context. In a perspectives article in this issue of JASN, Delanaye et al. propose that “the CKD definition be amended to include age-specific thresholds for GFR.” (Excerpt from text of this commentary on Delanaye P, et al.: Chronic kidney disease: Call for an age-adapted definition, in this same issue of Journal of the American Society of Nephrology.)

Wen, P. Y., D. A. Reardon, T. S. Armstrong, S. Phuphanich, R. D. Aiken, J. C. Landolfi, W. T. Curry, J. J. Zhu, M. Glantz, D. M. Peereboom, J. M. Markert, R. LaRocca, D. M. O’Rourke, K. Fink, L. Kim, M. Gruber, G. J. Lesser, E. Pan, S. Kesari, A. Muzikansky, C. Pinilla, R. G. Santos and J. S. Yu (2019). “A Randomized Double-Blind Placebo-Controlled Phase Ii Trial of Dendritic Cell Vaccine Ict-107 in Newly Diagnosed Patients with Glioblastoma.” Clin Cancer Res 25(19): 5799-5807.

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PURPOSE: To evaluate the results of the randomized, double-blind, placebo-controlled phase II clinical trial of ICT-107 in patients with newly diagnosed glioblastoma. PATIENTS AND METHODS: We conducted a double-blinded randomized phase II trial of ICT-107 in newly diagnosed patients with glioblastoma (GBM) and tested efficacy, safety, quality of life (QoL), and immune response. HLA-A1(+) and/or -A2(+)-resected patients with residual tumor less-than-or-equal-to 1 cm(3) received radiotherapy and concurrent temozolomide. Following completion of radiotherapy, 124 patients, randomized 2:1, received ICT-107 [autologous dendritic cells (DC) pulsed with six synthetic peptide epitopes targeting GBM tumor/stem cell-associated antigens MAGE-1, HER-2, AIM-2, TRP-2, gp100, and IL13Ralpha2] or matching control (unpulsed DC). Patients received induction ICT-107 or control weekly x 4 followed by 12 months of adjuvant temozolomide. Maintenance vaccinations occurred at 1, 3, and 6 months and every 6 months thereafter. RESULTS: ICT-107 was well tolerated, with no difference in adverse events between the treatment and control groups. The primary endpoint, median overall survival (OS), favored ICT-107 by 2.0 months in the intent-to-treat (ITT) population but was not statistically significant. Progression-free survival (PFS) in the ITT population was significantly increased in the ICT-107 cohort by 2.2 months (P = 0.011). The frequency of HLA-A2 primary tumor antigen expression was higher than that for HLA-A1 patients, and HLA-A2 patients had higher immune response (via Elispot). HLA-A2 patients achieved a meaningful therapeutic benefit with ICT-107, in both the MGMT methylated and unmethylated prespecified subgroups, whereas only HLA-A1 methylated patients had an OS benefit. CONCLUSIONS: PFS was significantly improved in ICT-107-treated patients with maintenance of QoL. Patients in the HLA-A2 subgroup showed increased ICT-107 activity clinically and immunologically.

Spechler, S. J. (2019). “Eosinophilic Esophagitis: Novel Concepts Regarding Pathogenesis and Clinical Manifestations.” J Gastroenterol 54(10): 837-844.

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This report explores two hypotheses regarding eosinophilic esophagitis (EoE): (1) that the use of proton pump inhibitors (PPIs) might contribute to the pathogenesis of EoE by preventing peptic digestion of food allergens, by increasing gastric mucosal permeability to enable gastric absorption of those undegraded food allergens, and by causing microbial dysbiosis, and (2) that EoE, like eosinophilic gastroenteritis, might have mucosal-predominant and muscle-predominant forms, and that the muscle-predominant form of EoE might cause a variety of esophageal motility disorders including achalasia.

Slaughter, K. B., E. G. Meyer, A. B. Bambhroliya, J. R. Meeks, W. Ahmed, R. Bowry, R. Behrouz, O. Mir, C. Begley, J. E. Tyson, C. Miller, S. Warach, J. C. Grotta, L. D. McCullough, S. I. Savitz and F. S. Vahidy (2019). “Direct Assessment of Health Utilities Using the Standard Gamble among Patients with Primary Intracerebral Hemorrhage.” Circ Cardiovasc Qual Outcomes Sep;12(9):e005606. Epub 2019 Sep 13.

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BACKGROUND: Standard gamble (SG) directly measures patients’ valuation of their health state. We compare in-hospital and day-90 SG utilities (SGU) among intracerebral hemorrhage patients and report a 3-way association between SGU, EuroQoL-5 dimension, and modified Rankin Scale at day 90. METHODS AND RESULTS: Patients with intracerebral hemorrhage underwent in-hospital and day-90 assessments for the modified Rankin Scale, EuroQoL-5 dimension, and SG. SG provides patients a choice between their current health state and a hypothetical treatment with varying chances of either perfect health or a painless death. Higher SGU (scale, 0-1) indicates lower risk tolerance and thus higher valuation of the current health state. Logistic regression was used to estimate the likelihood of low SGU (less-than-or-equal-to 0.6), and Wilcoxon paired signed-rank test compared in-hospital and day-90 SGU. In-hospital and day-90 SG was obtained from 381 and 280 patients, respectively, including 236 paired observations. Median (interquartile range) in-hospital and day-90 SGUs were 0.85 (0.40-0.98) and 0.98 (0.75-1.00; P<0.001). In-hospital SGUs were lower with advancing age (P=0.007), higher National Institutes of Health Stroke Scale, and intracerebral hemorrhage scores (P<0.001). Proxy-based assessments resulted in lower SGUs; median difference (95% CI), -0.2 (-0.33 to -0.07). After adjustment, higher National Institutes of Health Stroke Scale and proxy assessments were independently associated with lower SGU, along with an effect modification of age by race. Day-90 SGU and modified Rankin Scale were significantly correlated; however, SGUs were higher than the EuroQoL-5 dimension utilities at higher modified Rankin Scale levels. CONCLUSIONS: Divergence between directly (SGU) and indirectly (EuroQoL-5 dimension) assessed utilities at high levels of functional disability warrant careful prognostication of intracerebral hemorrhage outcomes and should be considered in designing early end-of-life care discussions with families and patients.

Skotko, B. G., M. A. Allyse, K. Bajaj, R. G. Best, S. Klugman, M. Leach, S. Meredith, M. Michie, K. Stoll and A. R. Gregg (2019). “Adherence of Cell-Free DNA Noninvasive Prenatal Screens to Acmg Recommendations.” Genet Med 21(10): 2285-2292.

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PURPOSE: Noninvasive prenatal screening (NIPS) for fetal aneuploidy via cell-free DNA has been commercially available in the United States since 2011. In 2016, the American College of Medical Genetics and Genomics (ACMG) issued a position statement with specific recommendations for testing laboratories. We sought to evaluate adherence to these recommendations. METHODS: We focused on commercial laboratories performing NIPS testing in the United States as of 1 January 2018. Sample laboratory reports and other materials were scored for compliance with ACMG recommendations. Variables scored for common and sex chromosome aneuploidy detection included detection rate, specificity, positive and negative predictive value, and fetal fraction. Labs that performed analysis of copy-number variants and results for aneuploidies other than those commonly reported were identified. Available patient education materials were similarly evaluated. RESULTS: Nine of 10 companies reported fetal fraction in their reports, and 8 of 10 did not offer screening for autosomal aneuploidies beyond trisomy 13, 18, and 21. There was inconsistency in the application and reporting of other measures recommended by ACMG. CONCLUSIONS: Laboratories varied in the degree to which they met ACMG position statement recommendations. No company adhered to all laboratory guidance.