Research Spotlight

Asrani, S. K., L. W. Jennings, W. R. Kim, P. Kamath, J. Levitsky, M. K. Nadim, G. Testa, M. Leise, J. F. Trotter and G. Klintmalm (2019). “Meld-Grail-Na: Glomerular Filtration Rate and Mortality on Liver-Transplant Waiting List.” Hepatology Sep 16. [Epub ahead of print].

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BACKGROUND & AIMS: Among patients with cirrhosis awaiting liver transplantation, prediction of waitlist (WL) mortality is adjudicated by Model for End Stage liver disease-sodium (MELD-Na) score. Replacing serum creatinine (Scr) with estimated glomerular filtration rate (eGFR) in the MELD-Na score may improve prediction of WL mortality, especially for women and highest disease severity. METHODS: We developed (2014) and validated (2015) a model incorporating eGFR using national data (n=17,095) to predict WL mortality. Glomerular Filtration Rate (GFR) was estimated using GfR Assessment In Liver disease (GRAIL) developed amongst patients with cirrhosis (Asrani SK Hepatology.2018; www.bswh.md/grail). Multivariate Cox proportional hazards analysis models were utilized to compare predicted 90-day WL mortality between MELD-GRAIL-Na (re-estimated bilirubin, INR, sodium and GRAIL) vs. MELD-Na. RESULTS: Within 3 months, 27.8% were transplanted, 4.3% died on the WL and 4.7% were delisted for other reasons. GFR as estimated by GRAIL (HR 0.382, 95% CI 0.344-0.424) and the re-estimated model MELD-GRAIL-Na (HR 1.212, 95% CI 1.199-1.224) were significant predictors of mortality or being delisted on the WL within 3 months. MELD-GRAIL-Na was a better predictor of observed mortality at highest deciles of disease severity (>/=27-40). For score >/=32 (observed mortality 0.68), predicted mortality was 0.67 (MELD-GRAIL-Na) and 0.51 (MELD-Na). For women score >/=32 (observed mortality 0.67), predicted mortality was 0.69 (MELD-GRAIL-Na) and 0.55 (MELD-Na). In 2015, use of MELD-GRAIL-Na as compared to MELD-Na resulted in reclassification of 16.7% (n=672) of patients on the WL. CONCLUSION: Incorporation of eGFR likely captures true GFR better than Scr, especially among women. Incorporation of MELD-GRAIL-Na instead of MELD-Na may impact outcomes for 12-17% awaiting transplant and affect organ allocation.

Askar, M., A. Madbouly, L. Zhrebker, A. Willis, S. Kennedy, K. Padros, M. B. Rodriguez, C. Bach, B. Spriewald, R. Ameen, S. A. Shemmari, K. Tarassi, A. Tsirogianni, N. Hamdy, G. Mossallam, G. Honger, R. Spinnler, G. Fischer, I. Fae, R. Charlton, A. Dunk, T. A. Vayntrub, M. Halagan, K. Osoegawa and M. Fernandez-Vina (2019). “Hla Haplotypes in 250 Families: The Baylor Laboratory Results and a Perspective on a Core Ngs Testing Model for the 17(Th) International Hla and Immunogenetics Workshop.” Hum Immunol Sep 23. [Epub ahead of print].

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Since their inception, the International HLA & Immunogenetics Workshops (IHIW) served as a collaborative platform for exchange of specimens, reference materials, experiences and best practices. In this report we present a subset of the results of human leukocyte antigen (HLA) haplotypes in families tested by next generation sequencing (NGS) under the 17th IHIW. We characterized 961 haplotypes in 921 subjects belonging to 250 families from 8 countries (Argentina, Austria, Egypt, Jamaica, Germany, Greece, Kuwait, and Switzerland). These samples were tested in a single core laboratory in a high throughput fashion using 6 different reagents/software platforms. Families tested included patients evaluated clinically as transplant recipients (kidney and hematopoietic cell transplant) and their respective family members. We identified 486 HLA alleles at the following loci HLA-A, -B, -C, -DRB1, -DRB3, -DRB4, -DRB5, -DQA1, -DQB1, -DPA1, -DPB1 (77, 115, 68, 69, 10, 6, 4, 44, 31, 20 and 42 alleles, respectively). We also identified nine novel alleles with polymorphisms in coding regions. This approach of testing samples from multiple laboratories across the world in different stages of technology implementation in a single core laboratory may be useful for future international workshops. Although data presented may not be reflective of allele and haplotype frequencies in the countries to which the families belong, they represent an extensive collection of 3rd and 4th field resolution level 11-locus haplotype associations of 486 alleles identified in families from 8 countries.

Anker, S. D., J. Butler, G. S. Filippatos, W. Jamal, A. Salsali, J. Schnee, K. Kimura, C. Zeller, J. George, M. Brueckmann, F. Zannad and M. Packer (2019). “Evaluation of the Effects of Sodium-Glucose Co-Transporter 2 Inhibition with Empagliflozin on Morbidity and Mortality in Patients with Chronic Heart Failure and a Preserved Ejection Fraction: Rationale for and Design of the Emperor-Preserved Trial.” Eur J Heart Fail Sep 16. [Epub ahead of print].

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BACKGROUND: The principal biological processes that characterize heart failure with a preserved ejection fraction (HFpEF) are systemic inflammation, epicardial adipose tissue accumulation, coronary microcirculatory rarefaction, myocardial fibrosis and vascular stiffness; the resulting impairment of left ventricular and aortic distensibility (especially when accompanied by impaired glomerular function and sodium retention) causes increases in cardiac filling pressures and exertional dyspnoea despite the relative preservation of left ventricular ejection fraction. Independently of their actions on blood glucose, sodium-glucose co-transporter 2 (SGLT2) inhibitors exert a broad range of biological effects (including actions to inhibit cardiac inflammation and fibrosis, antagonize sodium retention and improve glomerular function) that can ameliorate the pathophysiological derangements in HFpEF. Such SGLT2 inhibitors exert favourable effects in experimental models of HFpEF and have been found in large-scale trials to reduce the risk for serious heart failure events in patients with type 2 diabetes, many of whom were retrospectively identified as having HFpEF. STUDY DESIGN: The EMPEROR-Preserved Trial is enrolling approximately 5750 patients with HFpEF (ejection fraction >40%), with and without type 2 diabetes, who are randomized to receive placebo or empagliflozin 10 mg/day, which is added to all appropriate treatments for HFpEF and co-morbidities. STUDY AIMS: The primary endpoint is the time-to-first-event analysis of the combined risk for cardiovascular death or hospitalization for heart failure. The trial will also evaluate the effects of empagliflozin on renal function, cardiovascular death, all-cause mortality and recurrent hospitalization events, and will assess a wide range of biomarkers that reflect important pathophysiological mechanisms that may drive the evolution of HFpEF. The EMPEROR-Preserved Trial is well positioned to determine if empagliflozin can have a meaningful impact on the course of HFpEF, a disorder for which there are currently few therapeutic options.

Agbim, U. and S. K. Asrani (2019). “The Path Chosen Matters for Patients with Cirrhosis and the Acute Kidney Injury to Chronic Kidney Disease Continuum.” Clin Gastroenterol Hepatol 17(11): 2182-2184.

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Renal dysfunction is the penultimate expression of end-stage liver disease; cirrhotic patients with renal failure have a 7-fold increase in mortality compared with patients without renal failure. Surrogates of renal dysfunction, serum sodium and serum creatinine, albeit imperfect, are featured prominently in prognostic models (model for end-stage liver disease [MELD] and MELD-sodium [MELD-Na]) and decisions regarding organ allocation. However, the risk attributed to renal dysfunction is currently not differentiated as being due to acute kidney injury (AKI), chronic kidney disease (CKD), or even related to decompensated liver disease. Increasingly, cirrhotic patients awaiting liver transplantation in the current era have or are at risk for CKD: they are sicker, older, and have more comorbidities such as obesity and diabetes. In addition, cirrhotic patients with nonalcoholic fatty liver disease, a patient population enriched with these comorbidities, continues to increase. Furthermore, little is known about the interplay between AKI and CKD in cirrhotic patients; it increasingly is recognized that the 2 entities should not be considered in isolation and are more interconnected on the spectrum of renal impairment. Among patients listed for liver transplantation, Cullaro et al. examined the impact of AKI, CKD, and AKI on CKD on waitlist mortality. By using data from the United Network for Organ Sharing/Organ Procurement and Transplantation Network database from 2007 to 2014, they identified adult registrants (excluding those with exception points) listed for more than 3 months and categorized them into 4 groups according to renal function: AKI (defined as ≥0.3 mg/dL or ≥50% from previous value or <72 days of renal replacement therapy), CKD (defined as estimated glomerular filtration rate [GFR] <60 mL/min/1.73 m 2 for ≥90 days and a current estimated GFR of ≤30 mL/min/1.73 m 2 or ≥72 days of renal replacement therapy), AKI on CKD (meeting both AKI and CKD), or normal (meeting neither of the aforementioned definitions). Of 22,680 included waitlist registrants, 13% had episodes of AKI and 31% had CKD; approximately 29% died or were removed from the waitlist for being too sick. Cirrhotic patients with CKD had an increased cumulative incidence of death (subdistribution hazard risk, 1.56) while on the waitlist compared with registrants with normal renal function. However, the cumulative incidence of death on the waitlist was much more pronounced for any form of AKI, with those with AKI on CKD having the highest cumulative incidence of waitlist mortality (subdistribution hazard risk, 2.86) compared with those with normal renal function. The impact of renal dysfunction, especially AKI on CKD, increased for higher levels of MELD-Na. In a model predicting 6-month waitlist mortality, adding the pattern of renal injury to MELD-Na increased the area under the receiver operating curve from 0.71 to 0.80. The study notably raised several important issues. (Excerpt from text, p. 2182; no abstract available.)

Zhao, Y., W. Fan, T. Xu, F. R. Tay, J. L. Gutmann and B. Fan (2019). “Evaluation of several instrumentation techniques and irrigation methods on the percentage of untouched canal wall and accumulated dentine debris in C-shaped canals.” Int Endod J 52(9): 1354-1365.

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AIM: To evaluate the effect of instrumentation using Reciproc Blue (RB; VDW, Munich, Germany) and XP-endo Shaper (XP-S; FKG Dentaire, La Chaux-deFonds, Switzerland) systems on the area of untouched canal wall (AUCW), accumulated hard-tissue debris (AHTD) and the efficacy of three irrigation protocols on percentage reductions (red%) of AHTD within C-shaped canals of mandibular molars. METHODOLOGY: Seventy mandibular molars with C-shaped canals were scanned, matched and assigned to two shaping groups (n = 35): RB and XP-S. Following instrumentation, specimens were triple-matched with respect to the amount of remaining debris and assigned to three irrigation subgroups (n = 10): syringe-and-needle irrigation (SNI), XP-endo Finisher (XP-F; FKG Dentaire) and passive ultrasonic irrigation (PUI). The AUCW% and AHTD% after instrumentation and the red% of AHTD after irrigation were calculated from micro-computed tomography. Data were analysed using comparisons for two groups (RB vs. XP-S) or multiple subgroups followed by pairwise comparison procedures (SNI vs. XP-F vs. PUI) at alpha = 0.05. RESULTS: For RB and XP-S, 33.04% and 30.45%, respectively, of the canal wall remained untouched (P > 0.05). For both groups, the apical third had larger AUCW% than the coronal third (P < 0.05). Instrumentation with RB left more debris (2.8%) than XP-S (1.1%) (P < 0.05). The PUI and XP-F subgroups had higher mean red% of AHTD than the SNI subgroup; the difference was significant for RB (P < 0.05) but not for XP-S. CONCLUSIONS: Both RB and XP-S systems were associated with similar AUCW after instrumenting C-shaped canals. RB left significantly greater levels of AHTD compared with XP-S. PUI and XP-F irrigation removed more debris than SNI when using the RB system.