Association of lactate dehydrogenase with mortality in incident hemodialysis patients.

BACKGROUND: Lactate dehydrogenase (LDH) plays a role in the glucose metabolism of the human body. Higher LDH levels have been linked to mortality in various cancer types; however, the relationship between LDH and survival in incident hemodialysis (HD) patients has not yet been examined. We hypothesized that higher LDH level is associated with higher death risk in these patients. METHODS: We examined the association of baseline and time-varying serum LDH with all-cause, cardiovascular and infection-related mortality among 109 632 adult incident HD patients receiving care from a large dialysis organization in the USA during January 2007 to December 2011. Baseline and time-varying survival models were adjusted for demographic variables and available clinical and laboratory surrogates of malnutrition-inflammation complex syndrome. RESULTS: There was a linear association between baseline serum LDH levels and all-cause, cardiovascular and infection-related mortality in both baseline and time-varying models, except for time-varying infection-related mortality. Adjustment for markers of inflammation and malnutrition attenuated the association in all models. In fully adjusted models, baseline LDH levels ≥360 U/L were associated with the highest risk of all-cause mortality (hazard ratios = 1.19, 95% confidence interval 1.14-1.25). In time-varying models, LDH >280 U/L was associated with higher death risk in all three hierarchical models for all-cause and cardiovascular mortality. CONCLUSIONS: Higher LDH level >280 U/L was incrementally associated with higher all-cause and cardiovascular mortality in incident dialysis patients, whereas LDH <240 U/L was associated with better survival. These findings suggest that the assessment of metabolic functions and monitoring for comorbidities may confer survival benefit to dialysis patients.

Melanoma incidence, stage, and survival after solid organ transplant: A population-based cohort study in Ontario, Canada.

BACKGROUND: Risk of melanoma is increased with potentially worse outcomes after solid organ transplant. OBJECTIVE: To estimate the incidence, stage, and survival in transplant recipients with melanoma. METHODS: Population-based, retrospective, observational study using linked administrative databases. Adults receiving their first solid organ transplant from 1991 through 2012 were followed to December 2013. RESULTS: We identified 51 transplant recipients with melanoma, 11 369 recipients without melanoma, and 255 matched patients with melanoma from the nontransplant population. Transplant recipients were at increased risk of melanoma (standardized incidence ratio, 2.29; 95% confidence interval [CI], 2.07-2.49) and more likely to be diagnosed at stages II through IV (adjusted odds ratio, 4.29; 95% CI, 2.04-9.00) compared with the nontransplant population. Melanoma-specific mortality was increased in transplant recipients compared with the nontransplant population (adjusted hazard ratio, 1.93; 95% CI, 1.03-3.63). Among transplant recipients, all-cause mortality was increased after melanoma compared with those without melanoma (stage T1/T2: adjusted hazard ratio, 2.18; 95% CI, 1.13-4.21; T3/T4: adjusted hazard ratio, 4.07; 95% CI, 2.36-7.04; III/IV: adjusted hazard ratio, 7.92; 95% CI, 3.76-16.70). LIMITATIONS: The databases did not contain data on immunosuppressive drugs; ascertainment of melanoma metastasis relied on pathology reports. CONCLUSION: Melanoma after solid organ transplant is more often diagnosed at a later stage and leads to increased mortality, even for early-stage tumors.

Circulating Endocannabinoids and Mortality in Hemodialysis Patients.

BACKGROUND: Mortality in patients with end-stage renal disease (ESRD) on maintenance hemodialysis (MHD) remains exceptionally high. While traditional risk factors such as obesity are paradoxically associated with better survival, nontraditional risk factors including cachexia increase the likelihood of poor outcomes. There is accumulating evidence that the endocannabinoid (ECB) system plays a major role in energy preservation and storage, factors which can prevent the deleterious effects of cachexia. Hence, in this study, we evaluated the association of circulating ECB levels with mortality in MHD patients. METHODS: Serum concentrations of anandamide (AEA) and 2-arachidonoyl-sn-glycerol (2-AG), major ECB ligands, were measured in MHD patients. Their correlation with various clinical/laboratory indices and association with 12-month all-cause mortality were examined. RESULTS: Serum 2-AG levels positively correlated with body mass index, serum triglycerides and body anthropometric measures. Meanwhile, serum AEA levels correlated positively with serum interleukin-6, and negatively with serum very low-density lipoprotein levels. While increased serum 2-AG levels were associated with reduced risk of all-cause mortality (hazard ratio [HR] 0.52, 95% CI 0.28-0.98), there was no clear association between serum AEA levels and mortality (HR 0.91, 95% CI 0.48-1.72). CONCLUSIONS: In MHD patients, the circulating levels of ECB ligand, 2-AG, may play an important role in determining body mass and risk of mortality. These observations were unique to 2-AG as similar findings were not obtained with serum AEA. Future studies need to investigate the mechanisms responsible for these associations and examine the modulation of the ECB system as a potential target for therapy in ESRD.

Serum Endocannabinoid Levels in Patients With End-Stage Renal Disease.

CONTEXT: Previous studies have shown that the endocannabinoid system plays a major role in energy metabolism through the actions of its main mediators, 2-arachidonoyl-sn-glycerol (2-AG) and anandamide (AEA). OBJECTIVE: We examined serum levels of major endocannabinoid mediators and their association with clinical parameters in patients with end-stage renal disease (ESRD). DESIGN AND SETTING: Serum concentrations of 2-AG and AEA were measured in patients on maintenance hemodialysis (MHD) and controls, and correlations with various clinical and laboratory indices were examined. 2-AG was also measured in age and sex-matched healthy subjects for comparison of levels in patients undergoing MHD. MAIN OUTCOME MEASURE: Serum 2-AG. RESULTS: Serum 2-AG levels were significantly elevated in patients with ESRD compared with healthy controls. Higher levels of 2-AG were found in patients on MHD compared to healthy subjects, and similar findings were seen in a second set of subjects in independent analyses. Among 96 patients on MHD, 2-AG levels correlated significantly and positively with serum triglycerides (ρ = 0.43; P < 0.0001), body mass index (ρ = 0.40; P < 0.0001), and body anthropometric measures and negatively with serum high-density lipoprotein cholesterol (ρ = -0.33; P = 0.001) following adjustment for demographic and clinical variables. CONCLUSIONS: In patients on MHD, levels of serum 2-AG, a major endocannabinoid mediator, were increased. In addition, increasing serum 2-AG levels correlated with increased serum triglycerides and markers of body mass. Future studies will need to evaluate the potential mechanisms responsible for these findings.

Incidence and Risk Factors of Keratinocyte Carcinoma After First Solid Organ Transplant in Ontario, Canada.

IMPORTANCE: Keratinocyte carcinoma (KC), also known as nonmelanoma skin cancer, is the most common malignancy after solid organ transplant. Epidemiologic data on posttransplant KC in North America are limited by a lack of KC capture in cancer and transplant registries. OBJECTIVE: To estimate the incidence and identify risk factors for posttransplant KC. DESIGN, SETTING, AND PARTICIPANTS: This population-based inception cohort study in Ontario, Canada, used linked administrative databases and a health insurance claims-based algorithm. Participants were adult recipients of a first kidney, liver, heart, or lung transplant from January 1, 1994, to December 31, 2012. The cohort (n = 10 198) was followed up to December 31, 2013. Data were analyzed from May 31, 2016, to April 21, 2017. EXPOSURES: Solid organ transplant with functioning graft. MAIN OUTCOMES AND MEASURES: Age- and sex-adjusted standardized incidence ratio for KC in the transplant cohort was compared with that in the general population. Cumulative incidence of posttransplant KC was estimated using cumulative incidence functions, accounting for the competing risks of death or kidney graft loss. The association between KC and patient-, transplant-, and health services-related factors was evaluated with a multivariable cause-specific hazards model. RESULTS: A total of 10 198 transplant recipients were included in the study. The median (interquartile range [IQR]) age at transplant was 51 (41-59) years, with most recipients being male (6608 [64.8%]) and white (5964 [58.5%]). Posttransplant KC was diagnosed in 1690 patients (16.6%) after a median (IQR) of 3.96 (1.94-7.09) years, with an incidence rate of 2.63 per 100 patient-years (95% CI, 2.51-2.76). The rate of KC was significantly higher after transplant compared with the general population (standardized incidence ratio, 6.61; 95% CI, 6.31-6.93). The highest 10-year cumulative incidence was in the subsets of patients with a history of pretransplant skin cancer (66.5%), older than 50 years at transplant (27.5% for 51-65 years; 40.5% for >65 years), and of the white race (24.1%). The strongest independent risk factors for KC included older age at transplant (adjusted hazard ratio [aHR], 9.27; 95% CI, 7.08-12.14 for >65 years vs 18-35 years), white vs black race (aHR, 8.50; 95% CI, 4.03-17.91), pretransplant invasive skin cancer (aHR, 4.30; 95% CI, 3.72-4.98), and posttransplant precancerous skin lesions (aHR, 4.32; 95% CI, 3.77-4.95). CONCLUSIONS AND RELEVANCE: The incidence of KC appeared to be substantially increased after transplant, particularly in patients who were older at transplant, were white, and had a history of cancerous or precancerous skin tumors; intensified skin cancer screening, education, and early use of chemopreventive interventions may be warranted for these high-risk patient subsets.

Obesity Paradox in Advanced Kidney Disease: From Bedside to the Bench.

While obesity is associated with a variety of complications including diabetes, hypertension, cardiovascular disease and premature death, observational studies have also found that obesity and increasing body mass index (BMI) can be linked with improved survival in certain patient populations, including those with conditions marked by protein-energy wasting and dysmetabolism that ultimately lead to cachexia. The latter observations have been reported in various clinical settings including end-stage renal disease (ESRD) and have been described as the "obesity paradox" or "reverse epidemiology", engendering controversy. While some have attributed the obesity paradox to residual confounding in an effort to "debunk" these observations, recent experimental discoveries provide biologically plausible mechanisms in which higher BMI can be linked to longevity in certain groups of patients. In addition, sophisticated epidemiologic methods that extensively adjusted for confounding have found that the obesity paradox remains robust in ESRD. Furthermore, novel hypotheses suggest that weight loss and cachexia can be linked to adverse outcomes including cardiomyopathy, arrhythmias, sudden death and poor outcomes. Therefore, the survival benefit observed in obese ESRD patients can at least partly be derived from mechanisms that protect against inefficient energy utilization, cachexia and protein-energy wasting. Given that in ESRD patients, treatment of traditional risk factors has failed to alter outcomes, detailed translational studies of the obesity paradox may help identify innovative pathways that can be targeted to improve survival. We have reviewed recent clinical evidence detailing the association of BMI with outcomes in patients with chronic kidney disease, including ESRD, and discuss potential mechanisms underlying the obesity paradox with potential for clinical applicability.

Lymphocyte Cell Ratios and Mortality among Incident Hemodialysis Patients.

BACKGROUND: Neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) have been previously suggested as oncologic prognostication markers. These are associated with malnutrition and inflammation, and hence, may provide benefit in predicting mortality among hemodialysis patients. METHODS: Among 108,548 incident hemodialysis patients in a large U.S. dialysis organization (2007-2011), we compared the mortality predictability of NLR and PLR with baseline and time-varying covariate Cox models using the receiver operating characteristic curve (AUROC), net reclassification index (NRI), and adjusted R2. RESULTS: During the median follow-up period of 1.4 years, 28,618 patients died. Median (IQR) NLR and PLR at baseline were 3.64 (2.68-5.00) and 179 (136-248) respectively. NLR was associated with higher mortality, which appeared stronger in the time-varying versus baseline model. PLR exhibited a J-shaped association with mortality in both models. NLR provided better mortality prediction in addition to demographics, comorbidities, and serum albumin; ΔAUROC and NRI for 1-year mortality (95% CI) were 0.010 (0.009-0.012) and 6.4% (5.5-7.3%) respectively. Additionally, adjusted R2 (95% CI) for the Cox model increased from 0.269 (0.262-0.276) to 0.283 (0.276-0.290) in the non-time-varying model and from 0.467 (0.461-0.472) to 0.505 (0.500-0.512) in the time-varying model. There was little to no benefit of adding PLR to predict mortality. CONCLUSIONS: High NLR in incident hemodialysis patients predicted mortality, especially in the short-term period. NLR, but not PLR, added modest benefit in predicting mortality along with demographics, comorbidities, and serum albumin, and should be included in prognostication approaches.

Are women who quit smoking at high risk of excess weight gain throughout pregnancy?

BACKGROUND: Smoking cessation has been reported to be associated with high total gestational weight gain (GWG), which itself is a risk factor for adverse maternal-infant outcomes. Recent studies have criticized conventional single measures of GWG, since they may lead to biased results. Therefore, we aimed to compare patterns of GWG based on serial antenatal weight measurements between women who: never smoked, quit during pregnancy, continued to smoke. METHODS: Participants (N = 509) of our longitudinal study were recruited from seven antenatal clinics in Southwestern Ontario. Serial GWG measurements were abstracted from medical charts, while information on smoking status was obtained from a self-administered questionnaire at a median gestational age of 32 (27-37) weeks. GWG patterns were assessed by fitting piecewise mixed-effects models. First trimester weight gains and weekly rates for the last two trimesters were compared by smoking status. RESULTS: During the first trimester, women who never smoked and those who quit during pregnancy gained on average 1.7 kg (95 % CI: 1.4-2.1) and 1.2 kg (0.3-2.1), respectively, whereas women who continued smoking gained more than twice as much (3.5 kg, 2.4-4.6). Weekly rate of gain in the second and third trimesters was highest in women who quit smoking (0.60 kg/week, 0.54-0.65), approximately 20 and 50 % higher than in women who never smoked and those who smoked during pregnancy, respectively. CONCLUSIONS: In this longitudinal study to examine GWG by smoking status based on serial GWG measurements, we found that women who quit smoking experienced a rapid rate of gain during the last two trimesters, suggesting that this high-risk group may benefit from targeted interventions.

Nonalcoholic fatty liver disease: a potential consequence of tumor necrosis factor-inhibitor therapy.

INTRODUCTION: Although tumor necrosis factor inhibitors (TNFi) might be expected to protect against nonalcoholic fatty liver disease (NAFLD), we have seen patients who appeared to develop NAFLD during TNFi treatment. We aimed to explore risk factors for this TNFi complication in a case-control study. METHODS: We reviewed clinic records at our VA hospital to identify patients with inflammatory diseases who developed aminotransferase elevations during TNFi therapy and who had liver biopsies showing NAFLD. These patients were matched with patients in each of three control groups: (i) inflammatory disease controls: patients on TNFi treatment with normal aminotransferase levels, (ii) nonalcoholic steatohepatitis (NASH) controls: patients with biopsy-proven NASH with no other inflammatory disease, and (iii) healthy controls. Genotyping was performed for PNPLA3, a gene predisposing to NASH. RESULTS: We identified eight cases (five steatohepatitis, three steatosis); elevated aminotransferase levels were first observed 1-63 months into TNFi therapy (average 12 months). TNFi therapy was stopped in five patients, whose aminotransferase levels then normalized within 2-8 months. There were no significant differences between cases and inflammatory disease controls in the frequency of features of metabolic syndrome. Cases had more methotrexate exposure than inflammatory controls (50 vs. 12.5%, P=0.28). PNPLA3 genotyping revealed mutations in 75% of cases, 38% of inflammatory controls, 88% of NASH controls, and 63% of healthy controls (P=NS). CONCLUSION: Our findings suggest that NAFLD can be a side effect of TNFi therapy, and that methotrexate exposure and PNPLA3 gene mutations might be risk factors. Further studies are needed to determine how TNFi causes NAFLD and to confirm these risk factors.

Helicobacter gastritis induces changes in the oxyntic mucosa indistinguishable from the effects of proton pump inhibitors.

A causal relationship between oxyntic glands dilatation with protruding parietal cells, referred to as proton pump inhibitor (PPI) effects, and PPI use has been suspected but not established. We designed this study to evaluate the association between these changes and the use of PPIs and histamine2-receptor blockers (H2-blockers). We obtained five Sydney System-compliant biopsy specimens from patients recruited into a therapeutic trial for H. pylori. Medication history with details on PPI and H2-blockers use was collected. Two blinded pathologists graded gastritis and the intensity of putative PPI effects using a 0 to 3 scale. PPI and H2-blocker use was then disclosed and the accuracy of pathologists' assessment was analyzed. There were 138 H. pylori-negative and 104 positive patients. In H. pylori-negative patients the histologic assessment for PPI use had 77.5% sensitivity and 51.8% specificity, with a positive predictive value of 86.9% and a negative predictive value of 35.9%. In H. pylori-positive patients, sensitivity was 74.1% and specificity 26.1%. Positive and negative predictive values were 55.8% and 44.4%, respectively. Neither glandular dilatations nor parietal cell protrusions related to H2-blocker use. We conclude that these changes are associated with PPI use only in H. pylori-negative subjects. In H. pylori gastritis, so-called PPI-effects were equally prevalent in PPI-users and non-users, indicating that other factors are involved in the induction of oxyntic cell hyperplasia. We suggest that comments regarding the supposed evidence of PPI use are too often wrong to be useful and should be avoided in the diagnosis of gastric biopsy specimens.

Routine assessment of family and community health risks: parent views and what they receive.

OBJECTIVE: To examine the prevalence of parent-provider discussions of family and community health risks during well-child visits and the gaps between which issues are discussed and which issues parents would like to discuss. METHODS: Data came from the National Survey of Early Childhood Health, a nationally representative sample of parents of 2068 children aged 4 to 35 months. The outcome measures were 1) the reported discussions with pediatric clinicians about 7 family and community health risks and 2) whether the parent believes that pediatric clinicians should ask parents about each risk. RESULTS: Most parents believe that pediatric providers should discuss topics such as smoking in the household, financial difficulties, and emotional support available to the parent. However, with the exception of "household smoking," fewer than half of parents have been asked about these topics by their child's clinician. Parents of black and Hispanic children were more likely than parents of white children to be asked about several of these issues, as were parents of the youngest children and those with publicly financed health insurance. The greatest gap between parents' views and their reports of discussion with the clinician occur for parents of white children and older children. Among parents who hold the view that a topic should be discussed, parents of white and older children are less likely than others to report discussing some or all family and community health risks. CONCLUSION: The low frequency of discussions for many topics indicates potential unmet need. More universal surveillance of parents with young children might ensure that needs are not missed, particularly given that strong majorities of parents view family and community topics, with the exception of community violence, as appropriate for discussion in clinic visits.

Antimicrobial components of vaginal fluid.

OBJECTIVE: We examined the antimicrobial activity and composition of vaginal fluid. STUDY DESIGN: Vaginal fluid from preweighed tampons was assayed for pH, lactic acid, and antimicrobial polypeptides. The fluid was also fractionated by molecular filtration. Antimicrobial activity of whole fluid was determined against representative resident and exogenous microbes, and its fractions were tested against Escherichia coli. RESULTS: Vaginal fluids (5/5 donors) were permissive for Lactobacillus crispatus and vaginalis and Candida albicans, but not for Escherichia coli, Streptococcus group B, and Lactobacillus jensenii in three of five donors. The antimicrobial activity against E coli was predominantly in a <3-kd fraction and correlated with both low pH and high lactic acid content. Compared with a matched pH buffer, lactic acid markedly suppressed the growth of E coli. Concentrated 2- or 5-fold, the protein-rich fraction was active against E coli. CONCLUSION: Vaginal fluid exerts selective antimicrobial activity against nonresident bacterial species. The activity is mediated by lactic acid, low pH, and antimicrobial polypeptides.

Factors associated with smoking cessation among U.S. pregnant women.

OBJECTIVES: This study examines smoking and smoking cessation behaviors among U.S. pregnant women and seeks to identify the sociodemographic correlates of smoking cessation in pregnancy. METHODS: The 1998 NHIS Pregnancy and Smoking supplement was analyzed, including 5288 U.S. women (weighted to represent 13,714,358 women) who gave birth to a liveborn infant in the past 5 years. Four categories of smoking behavior were analyzed: nonsmoking at last pregnancy, persistent smoking throughout pregnancy, attempting unsuccessfully to quit during pregnancy, and successfully quitting during pregnancy. Logistic regression was used to isolate risk factors for each of the smoking behaviors and to examine factors associated with attempted and successful cessation. RESULTS: The women most likely to attempt to quit smoking in pregnancy were Hispanic women (OR = 3.09) and women who have smoked for less than 10 years (OR = 2.75 for women aged 18-24.) In general, for the groups at highest risk of smoking at the start of pregnancy, the odds of being a persistent smoker were higher than the odds of being an unsuccessful quitter, which in turn were higher than the odds of quitting successfully. The factors associated with attempts to quit included Hispanic ethnicity, higher education, above-poverty income, and shorter duration of smoking, while the combined effect of age and smoking duration was the only one significantly associated with successful quitting. In every age group, longer smoking duration was associated with lower likelihood of attempting to quit as well as successful quitting. CONCLUSIONS: The factors most strongly associated with attempts to quit smoking were Hispanic ethnicity and the combined effect of age and smoking duration. Future smoking cessation and relapse prevention programs should be developed, taking into consideration the critical factors of age, ethnicity, income, geography, and addiction.

Black-white differences in health care utilization among US children with frequent ear infections.

OBJECTIVE: To examine differences in patterns of and barriers to health care utilization between black and white children who have frequent ear infections (FEI). METHODS: Analysis was conducted using the 1997 and 1998 National Health Interview Survey-Sample Child Files. Data on 25 497 children under 18 years of age and 1985 who were reported by the parent/guardian to have had "3 or more ear infections during the past 12 months" were analyzed. The data were weighted and analyzed to represent all black and white children nationwide, accounting for the complex survey design. RESULTS: Of white and black children under 18 years of age in the United States, 8.0 and 6.6%, respectively, had FEI in the past year. Among those with FEI, whites and blacks exhibited significantly different patterns in the type of health insurance they had and in the usual source of care. After accounting for sociodemographic factors, health insurance, and usual source of care, there were still significant differences in health care use between whites and blacks. The affected black children had an increased risk of getting delayed care because of transportation problems (odds ratio [OR]: 2.32) and a reduced likelihood of seeing a medical specialist (OR: 0.49) and having surgery (OR: 0.39) in comparison to white children. CONCLUSION: Although black children with FEI were as likely as white children to be covered by health insurance and have a usual place of health care, they were significantly more likely to face barriers in obtaining the care, especially the more specialized care.