Diuretic Tolerance to Repeated-Dose Furosemide in Infants Born Very Preterm with Bronchopulmonary Dysplasia.

OBJECTIVES: To assess the presence and timing of furosemide diuretic tolerance in infants with bronchopulmonary dysplasia (BPD), and to determine if tolerance is modified by thiazide co-administration. STUDY DESIGN: We performed a retrospective cohort study among infants born very preterm with BPD exposed to repeated-dose furosemide for 72 hours, measuring net fluid balance (total intake minus total output) as a surrogate of diuresis in the 3 days before and after exposure. The primary comparison was the difference in fluid balance between the first and third 24 hours of furosemide exposure. We fit a general linear model for within-subject repeated measures of fluid balance over time, with thiazide co-administration as an interaction variable. Secondary analyses included an evaluation of weight trajectories over time. RESULTS: In 83 infants, median fluid balance ranged between + 43.6 and + 52.7 ml/kg/d in the 3 days prior to furosemide exposure. Fluid balance decreased to a median of + 29.1 ml/kg/d in the first 24 hours after furosemide, but then increased to +47.5 ml/kg/d by the third 24-hour interval, consistent with tolerance (P < .001). Thiazides did not modify the change in fluid balance during furosemide exposure for any time-period. Weight decreased significantly in the first 24 hours after furosemide and increased thereafter (P < .001). CONCLUSIONS: The net fluid balance response to furosemide decreases rapidly during repeated-dose exposures in infants with BPD, consistent with diuretic tolerance. Clinicians should consider this finding in the context of an infant's therapeutic goals. Further research efforts to identify safe and effective furosemide dosage strategies are needed.

Echocardiographic Assessment of Pulmonary Arterial Hypertension Following Inhaled Nitric Oxide in Infants with Severe Bronchopulmonary Dysplasia.

OBJECTIVES: Inhaled nitric oxide (iNO) is an effective pulmonary vasodilator. However, the efficacy of iNO in former premature infants with established bronchopulmonary dysplasia (BPD) has not been studied. This study aimed to determine the efficacy of iNO in reducing pulmonary artery pressure in infants with severe BPD as measured by echocardiography. STUDY DESIGN: Prospective, observational study enrolling infants born at less than 32 weeks gestation and in whom (1) iNO therapy was initiated after admission to our institution, or (2) at the outside institution less than 48 h before transfer and received an echocardiogram prior to iNO initiation, and (3) had severe BPD. Data were collected at three time-points: (1) before iNO; (2) 12-48 h after initiation of iNO; and (3) 48-168 h after initiation of iNO. The primary outcome was the effect of iNO on pulmonary artery pressure measured by echocardiography in patients with severe BPD between 48 and 168 h after initiating iNO therapy. RESULTS: Of 37 enrolled, 81% had echocardiographic evidence of pulmonary arterial hypertension (PAH) before iNO and 56% after 48 h of iNO (p = 0.04). FiO2 requirements were significantly different between time-points (1) and (3) (p = 0.05). There were no significant differences between Tricuspid Annular Plane Systolic Excursion (TAPSE) Z-Scores, time to peak velocity: right ventricular ejection time (TPV:RVET), and ventilator changes. CONCLUSIONS: Although we found a statistically significant reduction of PAH between time-point (1) and (3), future trials are needed to further guide clinical care.

Left Atrial Strain and the Risk of Atrial Arrhythmias From Extended Ambulatory Cardiac Monitoring: MESA.

Background Abnormalities in left atrial (LA) function often occur before LA structural changes and clinically identified atrial fibrillation (AF). Little is known about the relationship between LA strain and the risk of subclinical atrial arrhythmias detected from extended ambulatory cardiac monitoring. Methods and Results A total of 1441 participants of MESA (Multi-Ethnic Study of Atherosclerosis) completed speckle-tracking echocardiography and cardiac monitoring during 2016 to 2018 (mean age, 73 years); participants in AF during echocardiography or during the entire cardiac monitoring period were excluded. Absolute values of LA reservoir, booster pump, and conduit strains were measured. We evaluated associations of LA strain with monitor-detected AF, premature atrial contractions, and supraventricular tachycardia. Primary analyses adjusted for demographic variables, blood pressure, diabetes, smoking, and clinical cardiovascular disease. Cardiac monitoring (median, 14 days) detected AF in 3%. Each SD (4.0%) lower (worse) LA booster pump strain was associated with 84% higher risk of monitor-detected AF (95% CI, 30%-162%), 39% higher premature atrial contraction frequency (95% CI, 27%-53%), and 19% higher supraventricular tachycardia frequency (95% CI, 10%-29%). Additional adjustment for NT-proBNP (N-terminal pro-B-type natriuretic peptide), LA volume index, tissue Doppler a' peak velocity, left ventricular ejection fraction, and global longitudinal strain had little impact on associations. Findings were similar for LA reservoir strain and null for LA conduit strain. Conclusions In a multiethnic community-based cohort, impaired LA strain was an important correlate of subclinical atrial arrhythmias, even after adjustment for conventional measures of LA structure and function.

Does Chronic Use of High Dose Proton Pump Inhibitors Increase Risk for Pancreatic Cancer?

OBJECTIVES: To analyze whether use of proton pump inhibitors increase the risk for pancreatic cancer in a mouse model and human clinical cohorts. METHODS: p48-Cre/LSL-KrasG12D mice that develop precancerous pancreatic intraepithelial neoplasia (PanINs) were treated with low- or high-dose proton pump inhibitors (PPIs) orally for 1 and 4 months. The mechanism for the cholecystokinin receptor 2 (CCK-2R) activation was investigated in vitro. Two resources were employed to analyze the risk of pancreatic cancer in human subjects with PPI use. RESULTS: Serum gastrin levels were increased 8-fold (P < 0.0001) in mice treated with chronic high-dose PPIs, and this change correlated with an increase (P = 0.02) in PanIN grade and the development of microinvasive cancer. The CCK-2R expression was regulated by microRNA-148a in the p48-Cre/LSL-KrasG12D mice pancreas and in human pancreatic cancer cells in vitro. Proton pump inhibitor consumption in human subjects was correlated with pancreatic cancer risk (odds ratio, 1.54). A validation analysis conducted using the large-scale United Kingdom Biobank database confirmed the correlation (odds ratio, 1.9; P = 0.00761) of pancreatic cancer risk with PPI exposure. CONCLUSIONS: This investigation revealed in both murine models and human subjects, PPI use is correlated with a risk for development of pancreatic cancer.

Achieving adequate growth in infants with congenital diaphragmatic hernia prior to discharge.

BACKGROUND/PURPOSE: To evaluate the enteral feeding requirements, including caloric provisions, of infants with CDH in relation to growth patterns. METHODS: A retrospective observational study was conducted on infants with CDH between August 2012 and March 2017. Electronic medical records were reviewed to extract detailed infant feeding data and anthropometric measurements at monthly intervals until discharge. Statistical methods of analysis included generalized linear models, Pearson correlation coefficient, Analysis of variance (ANOVA), Kruskal-Wallis, Wilcoxon rank sum, and Fisher's Exact tests. RESULTS: Among 149 infants with CDH, 45% (n = 67) met criteria for malnutrition at discharge. Maternal human milk (HM) was initiated in 95% of infants (n = 142) and continued in 79% of infants (n = 118) at discharge. Overall, 50% received fortification of feeds, including 60% (n = 89) of formula fed infants compared to only 21% (n = 31) of HM fed infants (p<0.001). Infants fed formula had lower weight-for-length z-scores at discharge compared to those fed HM. CONCLUSIONS: Infants receiving HM demonstrated improved growth compared to formula fed infants. However, higher calorie feeding regimens need to be initiated earlier to improve growth velocity. Prompt recognition of malnutrition and growth failure with aggressive supplementation may improve the overall growth of infants with CDH and has the potential to improve long term neurodevelopmental outcomes.

Association Between Kidney Clearance of Secretory Solutes and Cardiovascular Events: The Chronic Renal Insufficiency Cohort (CRIC) Study.

RATIONALE & OBJECTIVE: The clearance of protein-bound solutes by the proximal tubules is an innate kidney mechanism for removing putative uremic toxins that could exert cardiovascular toxicity in humans. However, potential associations between impaired kidney clearances of secretory solutes and cardiovascular events among patients with chronic kidney disease (CKD) remains uncertain. STUDY DESIGN: A multicenter, prospective, cohort study. SETTING & PARTICIPANTS: We evaluated 3,407 participants from the Chronic Renal Insufficiency Cohort (CRIC) study. EXPOSURES: Baseline kidney clearances of 8 secretory solutes. We measured concentrations of secretory solutes in plasma and paired 24-hour urine specimens using liquid chromatography-tandem mass spectrometry (LC-MS/MS). OUTCOMES: Incident heart failure, myocardial infarction, and stroke events. ANALYTICAL APPROACH: We used Cox regression to evaluate associations of baseline secretory solute clearances with incident study outcomes adjusting for estimated GFR (eGFR) and other confounders. RESULTS: Participants had a mean age of 56 years; 45% were women; 41% were Black; and the median estimated glomerular filtration rate (eGFR) was 43 mL/min/1.73 m2. Lower 24-hour kidney clearance of secretory solutes were associated with incident heart failure and myocardial infarction but not incident stroke over long-term follow-up after controlling for demographics and traditional risk factors. However, these associations were attenuated and not statistically significant after adjustment for eGFR. LIMITATIONS: Exclusion of patients with severely reduced eGFR at baseline; measurement variability in secretory solutes clearances. CONCLUSIONS: In a national cohort study of CKD, no clinically or statistically relevant associations were observed between the kidney clearances of endogenous secretory solutes and incident heart failure, myocardial infarction, or stroke after adjustment for eGFR. These findings suggest that tubular secretory clearance provides little additional information about the development of cardiovascular disease events beyond glomerular measures of GFR and albuminuria among patients with mild-to-moderate CKD.

A Cholecystokinin Receptor Antagonist Halts Nonalcoholic Steatohepatitis and Prevents Hepatocellular Carcinoma.

BACKGROUND AND AIMS: Nonalcoholic steatohepatitis (NASH) is a common inflammatory liver condition that may lead to cirrhosis and hepatocellular carcinoma (HCC). Risk factors for NASH include a saturated fat diet, altered lipid metabolism, and genetic and epigenetic factors, including microRNAs. Serum levels of cholecystokinin (CCK) are elevated in mice and humans that consume a high-saturated fat diet. CCK receptors (CCK-Rs) have been reported on fibroblasts which when activated can induce fibrosis; however, their role in hepatic fibrosis remains unknown. We hypothesized that elevated levels of CCK acting on the CCK-Rs play a role in the development of NASH and in NASH-associated HCC. METHODS: We performed a NASH Prevention study and Reversal study in mice fed a saturated fat 75% choline-deficient-ethionine-supplemented (CDE) diet for 12 or 18 weeks. In each study, half of the mice received untreated drinking water, while the other half received water supplemented with the CCK-R antagonist proglumide. CCK-R expression was evaluated in mouse liver and murine HCC cells. RESULTS: CCK receptor antagonist treatment not only prevented NASH but also reversed hepatic inflammation, fibrosis, and steatosis and normalized hepatic transaminases after NASH was established. Thirty-five percent of the mice on the CDE diet developed HCC compared with none in the proglumide-treated group. We found that CCK-BR expression was markedly upregulated in mouse CDE liver and HCC cells compared with normal hepatic parenchymal cells, and this expression was epigenetically regulated by microRNA-148a. CONCLUSION: These results support the novel role of CCK receptors in the pathogenesis of NASH and HCC.

Endogenous Gastrin Collaborates With Mutant KRAS in Pancreatic Carcinogenesis.

OBJECTIVE: The KRAS gene is the most frequently mutated gene in pancreatic cancer, and no successful anti-Ras therapy has been developed. Gastrin has been shown to stimulate pancreatic cancer in an autocrine fashion. We hypothesized that reactivation of the peptide gastrin collaborates with KRAS during pancreatic carcinogenesis. METHODS: LSL-Kras; P48-Cre (KC) mutant KRAS transgenic mice were crossed with gastrin-KO (GKO) mice to develop GKO/KC mice. Pancreata were examined for 8 months for stage of pancreatic intraepithelial neoplasia lesions, inflammation, fibrosis, gastrin peptide, and microRNA expression. Pancreatic intraepithelial neoplasias from mice were collected by laser capture microdissection and subjected to reverse-phase protein microarray, for gastrin and protein kinases associated with signal transduction. Gastrin mRNA was measured by RNAseq in human pancreatic cancer tissues and compared to that in normal pancreas. RESULTS: In the absence of gastrin, PanIN progression, inflammation, and fibrosis were significantly decreased and signal transduction was reversed to the canonical pathway with decreased KRAS. Gastrin re-expression in the PanINs was mediated by miR-27a. Gastrin mRNA expression was significantly increased in human pancreatic cancer samples compared to normal human pancreas controls. CONCLUSIONS: This study supports the mitogenic role of gastrin in activation of KRAS during pancreatic carcinogenesis.

Innovation in Oncology Drug Development.

Significant progress has been made in our understanding of the molecular lesions responsible for tumor cells to exhibit uncontrolled growth while circumventing normal mechanisms of apoptosis and their ability to migrate and invade normal tissues while evading recognition and destruction by the immune system. This understanding has enabled the development of therapies specifically targeted to these lesions coupled to innovative treatment regimens to most effectively use these new targeted therapies with precision in selected subpopulations of patients. Innovation at the scientific and clinical levels has been appropriately embraced and supported at the FDA, resulting in regulatory innovation to facilitate and adapt to the Precision Medicine environment.

Epidemiology, outcomes, and management of acute kidney injury in the vascular surgery patient.

OBJECTIVE: Conventional clinical wisdom has often been nihilistic regarding the prevention and management of acute kidney injury (AKI), despite its being a frequent and morbid complication associated with both increased mortality and cost. Recent developments have shown that AKI is not inevitable and that changes in management of patients can reduce both the incidence and morbidity of perioperative AKI. The purpose of this narrative review was to review the epidemiology and outcomes of AKI in patients undergoing vascular surgery using current consensus definitions, to discuss some of the novel emerging risk stratification and prevention techniques relevant to the vascular surgery patient, and to describe a standardized perioperative pathway for the prevention of AKI after vascular surgery. METHODS: We performed a critical review of the literature on AKI in the vascular surgery patient using the PubMed and MEDLINE databases and Google Scholar through September 2017 using web-based search engines. We also searched the guidelines and publications available online from the organizations Kidney Disease: Improving Global Outcomes and the Acute Dialysis Quality Initiative. The search terms used included acute kidney injury, AKI, epidemiology, outcomes, prevention, therapy, and treatment. RESULTS: The reported epidemiology and outcomes associated with AKI have been evolving since the publication of consensus criteria that allow accurate identification of mild and moderate AKI. The incidence of AKI after major vascular surgery using current criteria is as high as 49%, although there are significant differences, depending on the type of procedure performed. Many tools have become available to assess and to stratify the risk for AKI and to use that information to prevent AKI in the surgical patient. We describe a standardized clinical assessment and management pathway for vascular surgery patients, incorporating current risk assessment and preventive strategies to prevent AKI and to decrease its complications. Patients without any risk factors can be managed in a perioperative fast-track pathway. Those patients with positive risk factors are tested for kidney stress using the urinary biomarker TIMP-2•IGFBP7, and care is then stratified according to the result. Management follows current Kidney Disease: Improving Global Outcomes guidelines. CONCLUSIONS: AKI is a common postoperative complication among vascular surgery patients and has a significant impact on morbidity, mortality, and cost. Preoperative risk assessment and optimal perioperative management guided by that risk assessment can minimize the consequences associated with postoperative AKI. Adherence to a standardized perioperative pathway designed to reduce risk of AKI after major vascular surgery offers a promising clinical approach to mitigate the incidence and severity of this challenging clinical problem.

Cardiovascular-Specific Mortality and Kidney Disease in Patients Undergoing Vascular Surgery.

IMPORTANCE: Acute kidney injury (AKI) affects as many as 40% of patients undergoing surgery and is associated with increased all-cause mortality. Chronic kidney disease (CKD) is a well-known risk factor for cardiovascular mortality. OBJECTIVE: To determine the association between kidney disease and long-term cardiovascular-specific mortality after vascular surgery. DESIGN, SETTING, AND PARTICIPANTS: A single-center cohort of 3646 patients underwent inpatient vascular surgery from January 1, 2000, to November 30, 2010, at a tertiary care teaching hospital. To determine cause-specific mortality for patients undergoing vascular surgery, a proportional subdistribution hazards regression analysis was used to model long-term cardiovascular-specific mortality while treating any other cause of death as a competing risk. Kidney disease constituted the main covariate after adjusting for baseline patient characteristics, surgery type, and admission hemoglobin level. Final follow-up was completed July 2014 to assess survival through January 31, 2014, and data were analyzed from June 1, 2014, to September 7, 2015. MAIN OUTCOMES AND MEASURES: Perioperative AKI, presence of CKD, and overall and cause-specific mortality. RESULTS: Among the 3646 patients undergoing vascular surgery, perioperative AKI occurred in 1801 (49.4%) and CKD was present in 496 (13.6%). The top 2 causes among the 1577 deaths in our cohort were cardiovascular disease (845 of 1577 [53.6%]) and cancer (173 of 1577 [11.0%]). Adjusted cardiovascular mortality estimates at 10 years were 17%, 31%, 30%, and 41%, respectively, for patients with no kidney disease, AKI without CKD, CKD without AKI, and AKI with CKD. Adjusted hazard ratios (95% CIs) for cardiovascular mortality were significantly elevated among patients with AKI without CKD (2.07 [1.74-2.45]), CKD without AKI (2.01 [1.46-2.78]), and AKI with CKD (2.99 [2.37-3.78]) and were higher than those for other risk factors, including increasing age (1.03 per 1-year increase; 1.02-1.04), emergent surgery (1.47; 1.27-1.71), and admission hemoglobin levels lower than 10 g/dL (1.39; 1.14-1.69) compared with a hemoglobin level of 12 g/dL or higher. CONCLUSIONS AND RELEVANCE: Perioperative AKI is common in patients undergoing vascular surgery and is associated with a high risk for cardiovascular-specific mortality comparable to that seen with CKD. These findings reinforce the importance of preoperative and postoperative risk stratification for kidney disease and the implementation of strategies now available to help prevent perioperative AKI.

Acute and Chronic Kidney Disease and Cardiovascular Mortality After Major Surgery.

OBJECTIVE: The aim of the study was to determine the long-term cardiovascular-specific mortality in patients with acute kidney injury (AKI) or chronic kidney disease (CKD) after major surgery. BACKGROUND: In surgical patients, pre-existing CKD and postoperative AKI are associated with increases in all-cause mortality. METHODS: In a single-center cohort of 51,457 adult surgical patients undergoing major inpatient surgery, long-term cardiovascular-specific mortality was modeled using a multivariable subdistributional hazards model while treating any other cause of death as a competing risk and accounting for the progression to end-stage renal disease (ESRD) after discharge. Pre-existing CKD and ESRD, and postoperative AKI were the main independent predictors. RESULTS: Before the admission, 4% and 8% of the cohort had pre-existing ESRD and CKD not requiring renal replacement therapy, respectively. During hospitalization, 39% developed AKI. At 10-year follow-up, adjusted cardiovascular-specific mortality estimates were 6%, 11%, 12%, 19%, and 27% for patients with no kidney disease, AKI with no CKD, CKD with no AKI, AKI with CKD, and ESRD, respectively (P < 0.001). This association remained after excluding 916 patients who progressed to ESRD after discharge, although it was significantly amplified among them. Compared with patients having no kidney disease, adjusted hazard ratios for cardiovascular mortality were significantly higher among patients with kidney disease, ranging from 1.95 (95% confidence interval, 1.80-2.11) for patients with de novo AKI to 5.70 (95% confidence interval, 5.00-6.49) for patients with pre-existing ESRD. CONCLUSIONS: Both AKI and CKD were associated with higher long-term cardiovascular-specific mortality compared with patients having no kidney disease.

Mortality and Cost of Acute and Chronic Kidney Disease after Vascular Surgery.

BACKGROUND: Both acute kidney injury (AKI) and chronic kidney disease (CKD) are common yet underappreciated risk factors for adverse perioperative outcomes. We hypothesize that AKI and CKD are associated with similar increases in 90-day mortality and cost in patients undergoing major vascular surgery. METHODS: We used multivariable regression analyses to evaluate the associations between AKI and CKD and incremental 90-day mortality and hospital cost in a single-center cohort of 3646 adult patients undergoing major vascular surgery. We defined AKI using Kidney Disease: Improving Global Outcomes criteria as change in creatinine ≥ 0.3 mg/dL or ≥ 50% increase from the reference value. CKD was determined from medical history. Regression models were adjusted for demographic and socioeconomic characteristics, comorbid conditions, surgery type, and postoperative complications. RESULTS: The prevalence of kidney disease among vascular surgery patients is high with 49% of patients developing AKI during hospitalization and 17% presenting with CKD on admission. In risk-adjusted logistic regression analysis, perioperative AKI (odds ratio 2.2, 95% confidence interval 1.5-3.3) was the most significant predictor of 90-day mortality. The risk-adjusted average cost was significantly higher for patients with any type of kidney disease. The incremental cost of having any type of kidney disease ranged from $9100 to $19,100, even after adjustment for underlying comorbidities and other postoperative complications. CONCLUSIONS: Kidney disease after major vascular surgery is associated with significant increases in 90-day mortality and cost with the highest risk observed among patients with AKI regardless of previous CKD.