Effectiveness of lumacaftor/ivacaftor initiation in children with cystic fibrosis aged 2 through 5 years on disease progression: Interim results from an ongoing registry-based study.

BACKGROUND: Lumacaftor/ivacaftor (LUM/IVA) has been shown to be safe and efficacious in people with cystic fibrosis (CF) ≥1 year of age. To assess the impact of early LUM/IVA initiation on CF disease progression, a 6-year observational study leveraging data from existing CF patient registries is being conducted in children with CF homozygous for F508del (F/F genotype) who were aged 2 through 5 years at treatment initiation. Here we present interim results from this study focusing on data from the European CF Society Patient Registry (ECFSPR). METHODS: The LUM/IVA cohort included children in the ECFSPR who started LUM/IVA between 15 January 2019 and 31 December 2020. Longitudinal trends in growth parameters, pulmonary exacerbations, hospitalizations, safety outcomes, and other effectiveness outcomes in the LUM/IVA cohort were compared to those in two modulator-naïve cohorts: (i) matched concurrent cohort heterozygous for F508del and a minimal function mutation (F/MF concurrent comparator cohort) and (ii) matched concurrent cohort with the F/F genotype from countries without commercial access to LUM/IVA as of 2020 (F/F concurrent comparator cohort). RESULTS: The LUM/IVA cohort matched to the F/MF concurrent comparator cohort had 681 children and the LUM/IVA cohort matched to the F/F concurrent comparator cohort had 183 children. LUM/IVA cohorts had increases in body mass index percentiles relative to the matched F/MF and F/F concurrent comparator cohorts (mean difference in change from baseline: 8.4 [95% CI: 5.5, 11.3] and 11.8 [95% CI: 5.9, 17.7], respectively). Increases in height and weight percentiles were also observed in the LUM/IVA cohort relative to the F/MF and F/F concurrent comparator cohorts. Reductions in pulmonary exacerbations and hospitalizations relative to baseline and the F/F concurrent comparator cohort were seen in 2021. CONCLUSIONS: This interim analysis showed favorable trends in clinical outcomes, including growth parameters, pulmonary exacerbations, and hospitalizations, suggesting an early beneficial effect of LUM/IVA treatment in children aged 2 through 5 years at treatment initiation.

Elexacaftor/Tezacaftor/Ivacaftor Treatment and Depression-related Events.

Rationale: Elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) has been shown to be safe and efficacious in people with cystic fibrosis (pwCF) aged 2 years and older with at least one F508del-CFTR allele or more. After U.S. approval in 2019, reports emerged of depression-related adverse events in pwCF treated with ELX/TEZ/IVA. Objectives: To review available evidence on depression-related events in pwCF treated with ELX/TEZ/IVA in the context of background epidemiology in pwCF. Methods: Safety data from 14 ELX/TEZ/IVA clinical trials and 10 trials of CF transmembrane conductance regulator (CFTR) modulators in which placebo was administered, along with data from CF registries in the United States and Germany and cumulative postmarketing adverse event data from 61,499 pwCF who initiated ELX/TEZ/IVA after initial approval in the United States (October 2019) through October 2022, were reviewed and used to calculate exposure-adjusted rates of depression-related adverse events and prevalence of depression. In addition, a scientific literature review was conducted to identify ELX/TEZ/IVA publications reporting depression-related events or changes in depressive symptoms after treatment initiation. Measurements and Main Results: In clinical trials, the exposure-adjusted rate of any depression-related adverse event was 3.32/100 person years (PY) in the pooled ELX/TEZ/IVA group (n = 1,711) and 3.24/100 PY in the pooled placebo group (n = 1,369). The exposure-adjusted rates of suicidal ideation and suicide attempt were also similar between the pooled ELX/TEZ/IVA group and pooled placebo group (ideation: 0.23/100 PY vs. 0.28/100 PY; attempt: 0.08/100 PY vs. 0.14/100 PY). In the postmarketing setting, the exposure-adjusted reporting rates of depression-related events were low in context of the background prevalence in pwCF (all depression-related events: 1.29/PY; suicidal ideation: 0.12/100 PY; and suicide attempt: 0.05/100 PY). Assessments of individual case reports were confounded by preexisting mental health conditions, intercurrent psychosocial stressors (including coronavirus disease [COVID-19] lockdowns), and the heterogeneous and fluctuating nature of depression. Data from CF registries in the United States and Germany showed that patterns of depression prevalence in pwCF exposed to ELX/TEZ/IVA did not change after treatment initiation. Published studies utilizing the nine-item Patient Health Questionnaire did not show evidence of worsening depression symptoms in pwCF treated with ELX/TEZ/IVA. Conclusions: Our review of data from clinical trials, postmarketing reports, an ongoing registry-based ELX/TEZ/IVA postauthorization safety study, and peer-reviewed literature suggests that depression symptoms and depression-related events reported in pwCF treated with ELX/TEZ/IVA are generally consistent with background epidemiology of these events in the CF population and do not suggest a causal relationship with ELX/TEZ/IVA treatment.

Registry-based study in people with cystic fibrosis and an R117H variant treated with ivacaftor.

BACKGROUND: Ivacaftor approval was extended to people with cystic fibrosis (CF) and an R117H variant in 2014 in the USA. This observational, real-world, postapproval study evaluated long-term outcomes among people with CF and an R117H variant on ivacaftor using data from the US Cystic Fibrosis Foundation Patient Registry. METHODS: Key outcomes were evaluated in ivacaftor-treated people with CF and an R117H variant for up to 36 months before and after treatment initiation using within-group comparisons. Analyses were descriptive in nature, focused on evaluation of observed outcome patterns over time and were performed both overall and for age groups ≥2 to <6 years, ≥6 to <18 years and ≥18 years. Key outcomes included lung function, body mass index (BMI), pulmonary exacerbations (PEx) and hospitalisations. RESULTS: The ivacaftor cohort included 369 people with CF and an R117H variant who initiated therapy between 1 January 2015 and 31 December 2016. During each of the 12-month intervals following treatment initiation, the mean observed percent predicted forced expiratory volume in 1 s (ppFEV1) and BMI values were higher and the mean annualised number of PEx and hospitalisation events were lower than pretreatment values. Mean change in ppFEV1 from pretreatment baseline was an increase of 1.5 (95% CI 0.8 to 2.3), 1.7 (95% CI 0.7 to 2.7) and 1.8 (95% CI 0.6 to 3.0) percentage points in the first, second and third years of treatment, respectively. Similar trends were observed in adult and paediatric subgroups. CONCLUSIONS: The results support the clinical effectiveness of ivacaftor in people with CF and an R117H variant, including adult and paediatric subgroups.

Real-world safety and effectiveness of elexacaftor/tezacaftor/ivacaftor in people with cystic fibrosis: Interim results of a long-term registry-based study.

BACKGROUND: Phase 3 clinical trials showed elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) was safe and efficacious in people with cystic fibrosis (CF) with ≥1 F508del-CFTR allele. To assess long-term effects of ELX/TEZ/IVA under real-world conditions of use, a 5-year observational registry-based study is being conducted. We report interim results from the first 2 years of follow-up. METHODS: The study included people with CF in the US Cystic Fibrosis Foundation Patient Registry (CFFPR) who initiated ELX/TEZ/IVA between October 2019 and December 2020. Pulmonary exacerbations (PEx), percent predicted forced expiratory volume in 1 second (ppFEV1), hospitalizations, bacterial pathogens, body mass index (BMI), CF complications and comorbidities, and liver function tests (LFTs) after treatment initiation were compared with the 5-year pre-treatment period. Death and lung transplantation were assessed relative to 2019 CFFPR data. RESULTS: 16,116 people with CF were included (mean treatment duration 20.4 months). Among those with 5 years of pre-treatment data, mean PEx/patient/year declined to 0.18 (95% CI: 0.17, 0.19) in Years 1 and 2 post-treatment from 0.86 (95% CI: 0.83, 0.88) in the baseline year (79% reduction), after a continued increase observed pre-treatment. Similarly, a decline in mean hospitalizations/patient/year was observed in Year 1 that was sustained in Year 2 (74% reduction from baseline year). The mean absolute change in ppFEV1 from baseline was +8.2 percentage points (95% CI: 8.0, 8.4) in Year 1 and +8.9 percentage points (95% CI: 8.7, 9.1) in Year 2, after a continued decline observed pre-treatment. Positive bacterial cultures decreased for all evaluated pathogens, and mean BMI increased by 1.6 kg/m2 (95% CI: 1.5, 1.6) by Year 2. No new safety concerns were identified based on evaluation of CF complications, comorbidities, and LFTs. The annualized rates of death (0.47% [95% CI: 0.39, 0.55]) and lung transplantation (0.16% [95% CI: 0.12, 0.22]) were considerably lower than reported in 2019 (1.65% and 1.08%, respectively). CONCLUSIONS: ELX/TEZ/IVA treatment was associated with sustained improvements in lung function, reduced frequency of PEx and all-cause hospitalization, increased BMI, and lower prevalence of positive bacterial cultures. Additionally, there was a 72% lower rate of death and 85% lower rate of lung transplantation relative to the year before ELX/TEZ/IVA availability. These results, from the largest cohort of ELX/TEZ/IVA-treated people to date, extend our understanding of the broad clinical benefits of ELX/TEZ/IVA.

Real-World Outcomes Among Patients with Cystic Fibrosis Treated with Ivacaftor: 2012-2016 Experience.

INTRODUCTION: In this long-term, postapproval, observational study, data from the US Cystic Fibrosis Foundation Patient Registry and the UK Cystic Fibrosis Registry were used to evaluate the impact of ivacaftor treatment on cystic fibrosis (CF) by comparing outcomes in ivacaftor-treated patients with those in matched untreated comparator patients. Registry data from up to 5 years of ivacaftor availability in the US and up to 4 years of availability in the UK were evaluated. METHODS: Starting in the first year of ivacaftor availability, ivacaftor-treated patients in each registry were matched 1:5 to comparator patients who never received ivacaftor. Clinical endpoints were evaluated in annual cross-sectional safety analyses. The key endpoints were death, organ transplants, pulmonary exacerbation, and hospitalization. Relative risks and 95% CIs were calculated to compare the ivacaftor and comparator cohorts in each registry. RESULTS: Here, we report the complete and final results of the annual cross-sectional safety analyses across the duration of the study, with up to 5 years of follow-up. Data show a pattern of lower risk of death, transplant, pulmonary exacerbation, and hospitalization among ivacaftor-treated patients in both registries. CONCLUSIONS: Ivacaftor-treated patients had consistently favorable clinical outcomes relative to untreated comparators, and no new safety concerns were identified. While general limitations of observational research apply, these findings support disease modification by CF transmembrane conductance regulator (CFTR) modulator therapy with ivacaftor. Future research of novel CFTR modulators will need to explore alternative methods for comparator selection for evaluation of clinical data given the evolving landscape of CF treatment.

We performed a study to better understand the long-term impact of treatment with a drug called ivacaftor for patients with cystic fibrosis (CF). Our study used data from CF patient registries in the United Kingdom and the United States. These registries collect information about patients with CF, their health, and the treatments they receive. Using data from these registries, we compared patients treated with ivacaftor with a similar group of patients (similar age, sex, and disease severity) who did not receive ivacaftor. We looked at the clinical outcomes of each group every year for up to 5 years. In the final analysis from our study, we found no new safety concerns associated with ivacaftor treatment. Additionally, we found that patients treated with ivacaftor tended to have lower risks of death, organ transplant, pulmonary exacerbations, and hospitalizations. Overall, these results demonstrate the favorable impact of ivacaftor treatment on long-term outcomes of patients with CF.

Disease progression in patients with cystic fibrosis treated with ivacaftor: Data from national US and UK registries.

BACKGROUND: Ivacaftor is the first in a class of drugs, CFTR modulators, that target the underlying defect in cystic fibrosis (CF). This long-term observational safety study evaluated CF disease progression in patients treated with ivacaftor in a real-world setting for up to 5 years. METHODS: Data from existing US and UK CF patient registries were used to assess longitudinal patterns in lung function, nutritional status, pulmonary exacerbations and hospitalizations, CF-related diabetes (CFRD), and Pseudomonas aeruginosa in ivacaftor-treated vs untreated comparator cohorts matched by age, sex, and disease severity. RESULTS: US analyses included 635 ivacaftor-treated patients and 1874 comparators followed for 5 years from year 1 of market availability (2012-2016). Evaluation of outcome patterns from pretreatment baseline (2011) through year 5 (2016), showed that relative to comparators, ivacaftor-treated patients had better preserved lung function (mean change in percent predicted FEV1, -0.7 percentage points with ivacaftor vs -8.3 percentage points in comparators) and improved nutritional status (mean body mass index change +2.4 kg/m2 with ivacaftor vs +1.6 kg/m2 in comparators). US patients treated with ivacaftor had significantly lower frequencies of exacerbations and hospitalizations in each of the 5 years of follow-up relative to pretreatment baseline and comparators. Favorable trends in CFRD and P. aeruginosa prevalence were also observed. Findings from the smaller UK registry were directionally similar to and consistent with US findings. CONCLUSIONS: This observational study represents the largest longitudinal analysis of patients treated with ivacaftor in a real-world setting. The findings support disease modification by CFTR modulation with ivacaftor.

Data from the US and UK cystic fibrosis registries support disease modification by CFTR modulation with ivacaftor.

BACKGROUND: Ivacaftor is the first cystic fibrosis transmembrane conductance regulator (CFTR) modulator demonstrating clinical benefit in patients with cystic fibrosis (CF). As ivacaftor is intended for chronic, lifelong use, understanding long-term effects is important for patients and healthcare providers. OBJECTIVE: This ongoing, observational, postapproval safety study evaluates clinical outcomes and disease progression in ivacaftor-treated patients using data from the US and the UK CF registries following commercial availability. METHODS: Annual analyses compare ivacaftor-treated and untreated matched comparator patients for: risks of death, transplantation, hospitalisation, pulmonary exacerbation; prevalence of CF-related complications and microorganisms and lung function changes in a subset of patients who initiated ivacaftor in the first year of commercial availability. Results from the 2014 analyses (2 and 3 years following commercial availability in the UK and USA, respectively) are presented here. RESULTS: Analyses included 1256 ivacaftor-treated and 6200 comparator patients from the USA and 411 ivacaftor-treated and 2069 comparator patients from the UK. No new safety concerns were identified based on the evaluation of clinical outcomes included in the analyses. As part of safety evaluations, ivacaftor-treated US patients were observed to have significantly lower risks of death (0.6% vs 1.6%, p=0.0110), transplantation (0.2% vs 1.1%, p=0.0017), hospitalisation (27.5% vs 43.1%, p<0.0001) and pulmonary exacerbation (27.8% vs 43.3%, p<0.0001) relative to comparators; trends were similar in the UK. In both registries, ivacaftor-treated patients had a lower prevalence of CF-related complications and select microorganisms and had better preserved lung function. CONCLUSIONS: While general limitations of observational research apply, analyses revealed favourable results for clinically important outcomes among ivacaftor-treated patients, adding to the growing body of literature supporting disease modification by CFTR modulation with ivacaftor. EU PAS REGISTRATION NUMBER: EUPAS4270.

Diagnosed cataracts in patients with cystic fibrosis in a United States administrative database.

BACKGROUND: We estimated the incidence and prevalence of diagnosed cataracts among patients with cystic fibrosis (CF) versus the general population (GP). METHODS: Using a large US health insurance claims database, we identified a CF cohort and a GP cohort matched with respect to age, gender, and calendar year. The prevalence and incidence of diagnosed cataract (primary outcome) for both cohorts were calculated, as well as the incidence rate ratios (IRRs). RESULTS: The prevalence of diagnosed cataracts among patients with CF alive and enrolled in the health plan on August 31, 2012 was 4.8% versus 2.8% in the GP. The incidence in the CF cohort was higher than in the GP and increased with age in both cohorts. The adjusted IRR comparing the CF and GP cohorts was 1.5 (95% CI: 1.2-1.8). CONCLUSIONS: The study suggests that the risk of developing cataract was higher among patients with CF than among the GP.

Poverty and racial disparities in kidney disease: the REGARDS study.

UNLABELLED: There are pronounced disparities among black compared to white Americans for risk of end-stage renal disease. This study examines whether similar relationships exist between poverty and racial disparities in chronic kidney disease (CKD) prevalence. METHODS: We studied 22,538 participants in the REasons for Geographic And Racial Differences in Stroke (REGARDS) cohort study. We defined individual poverty as family income below USD 15,000 and a neighborhood as poor if 25% or more of the households were below the federal poverty level. RESULTS: As the estimated glomerular filtration rate (GFR) declined from 50-59 to 10-19 ml/min/ 1.73 m2, the black:white odds ratio (OR) for impaired kidney function increased from 0.74 (95% CI 0.66, 0.84) to 2.96 (95% CI 1.96, 5.57). Controlling for individual income below poverty, community poverty, demographic and comorbid characteristics attenuated the black:white prevalence to an OR of 0.65 (95% CI 0.57, 0.74) among individuals with a GFR of 59-50 ml/min/1.73 m2 and an OR of 2.21 (95% CI 1.25, 3.93) among individuals with a GFR between 10 and 19 ml/min/ 1.73 m2. CONCLUSION: Household, but not community poverty, was independently associated with CKD and attenuated but did not fully account for differences in CKD prevalence between whites and blacks.

Neighborhood poverty and racial disparities in kidney transplant waitlisting.

Racial disparities persist in the United States renal transplantation process. Previous studies suggest that the distance between a patient's residence and the transplant facility may associate with disparities in transplant waitlisting. We examined this possibility in a cohort study using data for incident, adult ESRD patients (1998 to 2002) from the ESRD Network 6, which includes Georgia, North Carolina, and South Carolina. We linked data with the United Network for Organ Sharing (UNOS) transplant registry through 2005 and with the 2000 U.S. Census geographic data. Of the 35,346 subjects included in the analysis, 12% were waitlisted, 57% were black, 50% were men, 20% were impoverished, 45% had diabetes as the primary etiology of ESRD, and 73% had two or more comorbidities. The median distance from patient residence to the nearest transplant center was 48 mi. After controlling for multiple covariates, distance from patient residence to transplant center did not predict placement on the transplant waitlist. In contrast, race, neighborhood poverty, gender, age, diabetes, hypertension, body mass index, albumin, and the use of erythropoietin at dialysis initiation was associated with waitlisting. As neighborhood poverty increased, the likelihood of waitlisting decreased for blacks compared with whites in each poverty category; in the poorest neighborhoods, blacks were 57% less likely to be waitlisted than whites. This study suggests that improving the allocation of kidneys may require a focus on poor communities.

Neighborhood poverty and racial differences in ESRD incidence.

Poverty is associated with increased risk of ESRD, but its contribution to observed racial differences in disease incidence is not well-defined. To explore the contribution of neighborhood poverty to racial disparity in ESRD incidence, we analyzed a combination of US Census and ESRD Network 6 data comprising 34,767 patients that initiated dialysis in Georgia, North Carolina, or South Carolina between January 1998 and December 2002. Census tracts were used as the geographic units of analysis, and the proportion of the census tract population living below the poverty level was our measure of neighborhood poverty. Incident ESRD rates were modeled using two-level Poisson regression, where race, age and gender were individual covariates (level 1), and census tract poverty was a neighborhood covariate (level 2). Neighborhood poverty was strongly associated with higher ESRD incidence for both blacks and whites. Increasing poverty was associated with a greater disparity in ESRD rates between blacks and whites, with the former at greater risk. This raises the possibility that blacks may suffer more from lower socioeconomic conditions than whites. The disparity persisted across all poverty levels. The reasons for increasingly higher ESRD incidence among US blacks as neighborhood poverty increases remain to be explained.

Functional hepatic recovery after xenotransplantation of cryopreserved fetal liver cells or soluble cell-factor administration in a cirrhotic rat model: are viable cells necessary?

BACKGROUND AND AIM: Chronic liver failure results in the decrease of the number of functioning hepatocytes. It dictates the necessity of using exogenous viable cells or/and agents that can stimulate hepatic regenerative processes. Fetal liver contains both hepatic and hematopoietic stem cells with high proliferative potential, which may replace damaged cells. Also, immature cells produce fetal-specific factors which may support the injured liver. Our aim was to test the ability of human fetal liver cells and cell-free fetal-specific factors of non-hepatic origin to stimulate recovery processes in an experimental model of carbon tetrachloride-induced cirrhosis in rats. METHODS: Cirrhotic rats were intrasplenically injected with fetal liver cells (1 x 10(7) cells/0.3 mL medium) or cell-free fetal-specific factors (0.3 mL/1 mg protein). Control groups received medium alone. Serum indexes, hepatic functions, and morphology were evaluated for 15 days. RESULT: Human fetal liver cell transplantation was shown to abrogate the mortality of cirrhotic animals, to improve serum markers, and to restore liver mitochondrial function and detoxification. Morphological patterns of liver recovery were observed by histology. In comparison, an injection of fetal-specific factors produced similar functional recovery, whilst a more limited liver regeneration was observed by histology. CONCLUSIONS: The positive effects of fetal liver cell and cell-free fetal-specific factors in experimental cirrhosis may result from the presence of stage-specific factors activating hepatocellular repair.

Positive effects of cryopreserved adult or fetal liver cell transplants on hypercholesterolemia and hepatic antioxidant defenses in cholesterol-fed rabbits.

The liver plays a central role in lipid metabolism and the pathophysiology of many lipid disorders leads in turn to liver cell injury. Adult hepatocyte transplants provide well-recognized metabolic support, whilst hepatic stem cells may promote liver regeneration and repair, but in both cases, any clinical application would require low temperature banking of the cells. A model of dietary hypercholesterolemia was established in rabbits over 5 months, and transplants of cryopreserved adult hepatocytes (CH) and cryopreserved fetal liver cells (CFLC) were compared to Sham transplants. Cryopreservation was performed by a two-step freezing protocol using 1.5mol/l dimethyl sulfoxide (Me(2)SO). Serum contents of cholesterol lipid classes were measured during the subsequent 4 weeks, in addition to markers of serum and liver oxidative stress. Both CH and CFLC transplantation resulted in a decrease of serum lipids during the 1st week after transplantation. The effect of CH was limited to the 1st week, but CFLC provided a sustained lipid-lowering effect over the 4 weeks. The ultimate outcome of CFLC transplantation by the end of 4 weeks was more pronounced and statistically significant for both serum total cholesterol (0.15+/-0.05 versus 3.65+/-1.4mmol/l) and high-density lipoprotein-cholesterol (0.04+/-0.01 versus 0.56+/-0.06mmol/l) compared to Sham transplants (p<0.05 in both cases). CFLC transplantation also normalized hepatic tissue antioxidant defenses, namely an increase in reduced glutathione content, and enzyme activities for catalase and glutathione reductase (all significantly higher at p<0.05 than in Sham transplants) by 4 weeks.

Obesity is associated with family history of ESRD in incident dialysis patients.

BACKGROUND: Obesity is an established risk factor for chronic kidney disease and aggregates in families. The objective of this study is to examine the relationship between obesity and family history of end-stage renal disease (ESRD). METHODS: Data were collected from 25,883 incident patients with ESRD in US ESRD Network 6 (Georgia, North Carolina, and South Carolina) dialysis clinics between 1995 and 2003. Family history is defined as a first- or second-degree relative with ESRD. Body mass index (BMI) at dialysis therapy initiation was classified as underweight (BMI < 18.5 kg/m2), normal (BMI, 18.5 to <25 kg/m2), overweight (BMI, 25 to < 30 kg/m2), obese (BMI, 30 to <35 kg/m2), or morbidly obese (BMI > or = 35 kg/m2). RESULTS: Twenty-three percent of patients reported a family history of ESRD. Of patients reporting a family history of ESRD, 5.5% were underweight, 32.5% had normal BMI, 28.0% were overweight, 17.3% were obese, and 16.7% were morbidly obese. After controlling for age, race, sex, primary cause of ESRD, history of diabetes, history of hypertension, and estimated glomerular filtration rate at dialysis therapy initiation, reported family history of ESRD was associated with being overweight (odds ratio [OR], 1.17; 95% confidence interval [CI], 1.08 to 1.26), obese (OR, 1.25; 95% CI, 1.14 to 1.37), and morbidly obese (OR, 1.40; 95% CI, 1.27 to 1.55). CONCLUSION: Obesity at dialysis therapy initiation was associated independently with reported family history of ESRD. This finding suggests that behavioral factors, adiposity-related genes, and gene-by-BMI interaction may contribute to familial risk for ESRD. This finding also suggests that management of obesity may be even more important for patients with a family history of ESRD than for the general population.

Cryopreserved fetal liver cell transplants support the chronic failing liver in rats with CCl4-induced cirrhosis.

Hepatocyte transplantation is a promising method for supporting hepatic function in a broad spectrum of liver diseases. The aim of this work was to test the efficacy of human fetal liver cells to support the chronic failing liver in an experimental model of carbon tetrachloride (CCl4)-induced cirrhosis in rats. Liver cirrhosis was induced by intraperitoneal administration of CCl4 at a dose of 0.2 ml (50% v/v solution)/100 g body weight, twice a week for 3 months in rats. Ten days after stopping CCl4 administration (experimental day 0), rats received intrasplenic injection of cryopreserved fetal liver cells (FLC, 1 x 10(7) cells in 0.3 ml medium). As a cirrhotic control group, CCl4-induced cirrhotic rats were used with intrasplenic injection of an equal volume of medium alone. Animals were sacrificed on experimental day 15. Human fetal liver cell transplantation almost completely prevented the death of cirrhotic animals during the 2 weeks after treatment, while high ongoing mortality was seen in the cirrhotic control group. Cell transplantation into the spleen normalized total bilirubin and TBARSs levels and increased albumin levels in blood serum, as well as restoring mitochondrial function and liver detoxification function (assessed by cytochrome P450 contents and activity) compared with the activities seen in the cirrhosis control group. In parallel with this restoration of biochemical and functional liver indices, morphological patterns of liver recovery or regeneration after liver cell transplantation were demonstrated in day 15 samples by light microscopy. These were absent in the group that had received only medium alone.

Racial disparities in the prevalence of cardiovascular disease among incident end-stage renal disease patients.

BACKGROUND: Prevalence of coronary heart disease (CHD) and heart failure (HF) is higher among blacks as compared with whites in general population. This study describes unexpected racial differences in the prevalence of CHD and HF among incident dialysis patients, with whites being at a disadvantage. METHODS: Data were obtained from Centers for Medicare and Medicaid Services (CMS) 2728 form for incident dialysis patients in Georgia, North Carolina and South Carolina in 1995-2003. The CHD and HF prevalence between races were compared using adjusted odds ratios (ORs). The potential for case ascertainment bias was assessed. RESULTS: Compared with whites (n = 23 951), black patients (n = 32 642) had lower prevalence of CHD (15.7 vs 31.2%) and HF (28.1 vs 34.1%). After controlling for age, gender, diabetes, hypertension and smoking, the association of race with CHD varied by gender and diabetes status: OR ranged from 0.36 (0.34-0.39) for non-diabetic males to 0.57 (0.53-0.61) for diabetic females. Racial differences were not fully explained by case ascertainment bias. The race-HF association varied by age, gender and diabetes: among patients aged <55, blacks tended to have higher prevalence than whites (OR ranged from 0.99 (0.90-1.09) for diabetic males to 1.25 (1.13-1.39) for non-diabetic females), but among those aged above 55, blacks were less likely to HF (OR ranged from 0.62 (0.58-0.67) for diabetic males to 0.79 (0.73-0.85) for non-diabetic females). CONCLUSIONS: Substantial racial disparities exist in CHD/HF prevalence among incident dialysis patients that persist after controlling for confounders and cannot be fully explained by disease misclassification.

Evidence-based systematic literature review of hemoglobin/hematocrit and all-cause mortality in dialysis patients.

BACKGROUND: An evidence-based evaluation of peer-reviewed original research published during 1980 to 2004 and examining the relationship between hemoglobin and/or hematocrit values and all-cause mortality in dialysis patients was conducted to compare the studies' designs, analytic strategies, and results. METHODS: The search targeted MEDLINE and EMBASE and included publications referenced in the National Kidney Foundation-Kidney Disease Outcomes Quality Initiative Anemia Guidelines. Both randomized clinical trials (RCTs) and observational studies were considered. RESULTS: Of 7 RCTs and 20 observational studies identified, 5 trials and 13 studies were included in evidence tables. The trials were underpowered to study mortality and enrolled different patient populations, limiting their generalizability. Although none reached statistical significance, trials focusing on a general dialysis population tended to show either no effect or a benefit of greater hemoglobin level target, whereas trials enrolling cardiac patients suggested increased mortality associated with greater hemoglobin levels. The observational studies were heterogeneous in design, used varying exposure categorizations, and controlled for different covariates, but generally were supportive of increased mortality associated with a hemoglobin level less than the reference range. Evidence of benefits or risks of hemoglobin levels greater than the reference was variable. CONCLUSION: RCT-based evidence relating hemoglobin and/or hematocrit values to mortality in dialysis patients is limited. The relationship may be modified by the presence of preexisting conditions (cardiac disease). The published literature is insufficient for generalization of risks or benefits of a hemoglobin level greater than 11 to 12 g/dL (>110 to 120 g/L). There is a need for better designed RCTs focusing on mortality as a primary outcome and enrolling patients without cardiac disease. Observational studies should adequately control for relevant confounders (eg, baseline comorbidities) and assess effect modification in the analysis.

Population-based screening for family history of end-stage renal disease among incident dialysis patients.

BACKGROUND: We determined the familial aggregation of end-stage renal disease (ESRD) in a large, population-based sample of incident ESRD cases to assess the feasibility of developing a targeted screening and prevention program directed at members of families at high risk for kidney disease. METHODS: Between January 1, 1995, and December 31, 2003, incident dialysis patients in ESRD Network 6 facilities were asked to complete a voluntary questionnaire on family history (FH) of ESRD. Cases with ESRD attributed to Mendelian diseases or urologic causes were excluded. FH was considered present if first- or second-degree relatives had ESRD. De-identified FH data were collated with demographic data at dialysis initiation. RESULTS: More than 46% of eligible patients (25,883/55,929) provided FH information and 22.8% (5,901/25,883) of these reported having a FH of ESRD. FH of ESRD was positively associated with female gender, earlier age at ESRD onset, and primary cause of ESRD, and negatively associated with white race. FH associations with age, race, gender, and primary cause of renal failure remained statistically significant after simultaneous adjustment in a multivariate logistic regression model. CONCLUSIONS: Approximately 23% of incident dialysis patients have close relatives with ESRD. Far more are likely to have relatives with clinically silent proteinuria or chronic kidney disease (CKD), both risk factors for future cardiovascular events and ESRD. Physicians caring for patients with CKD should be aware of the marked familial aggregation of ESRD and consider focusing screening efforts on high-risk family members in an attempt to slow the exponential growth rate of kidney disease.

Does antimicrobial resistance cluster in individual hospitals?

Factors that affect the resistance rates for an organism-drug combination in a given hospital also might influence resistance rates for other organism-drug combinations. We examined correlations between resistance prevalence in non-intensive care inpatient areas of 41 hospitals participating in phase 3 (1998-1999) of Project ICARE (Intensive Care Antimicrobial Resistance Epidemiology). We focused on statistically significant (P<.05) Pearson correlation coefficients for methicillin-resistant Staphylococcus aureus, coagulase-negative staphylococci, vancomycin-resistant enterococci, and resistance to third-generation cephalosporins, imipenem, and fluoroquinolones in Escherichia coli, Klebsiella pneumoniae, Enterobacter species, and Pseudomonas aeruginosa. Resistance prevalence rates in individual hospitals were not strongly correlated among gram-positive organisms, and few correlations were seen between rates in gram-positive and gram-negative organisms. More frequent significant associations were found among resistance rates for gram-negative organisms. Resistance to third-generation cephalosporins in K. pneumoniae was significantly correlated with the majority of other sentinel antimicrobial-resistant organisms. High prevalence of this organism may serve as a marker for more generalized resistance problems in hospital inpatient areas.

Temporal changes in prevalence of antimicrobial resistance in 23 US hospitals.

Antimicrobial resistance is increasing in nearly all health-care-associated pathogens. We examined changes in resistance prevalence during 1996-1999 in 23 hospitals by using two statistical methods. When the traditional chi-square test of pooled mean resistance prevalence was used, most organisms appear to have increased in prevalence. However, when a more conservative test that accounts for changes within individual hospitals was used, significant increases in prevalence of resistance were consistently observed only for oxacillin-resistant Staphylococcus aureus, ciprofloxacin-resistant Pseudomonas aeruginosa, and ciprofloxacin- or ofloxacin-resistant Escherichia coli. These increases were significant only in isolates from patients outside intensive-care units (ICU). The increases seen are of concern; differences in factors present outside ICUs, such as excessive quinolone use or inadequate infection-control practices, may explain the observed trends.