Graft conditioning with fluticasone propionate reduces graft-versus-host disease upon allogeneic hematopoietic cell transplantation in mice.

Hematopoietic cell transplantation (HCT) treats many blood conditions but remains underused due to complications such as graft-versus-host disease (GvHD). In GvHD, donor immune cells attack the patient, requiring powerful immunosuppressive drugs like glucocorticoids (GCs) to prevent death. In this study, we tested the hypothesis that donor cell conditioning with the glucocorticoid fluticasone propionate (FLU) prior to transplantation could increase hematopoietic stem cell (HSC) engraftment and reduce GvHD. Murine HSCs treated with FLU had increased HSC engraftment and reduced severity and incidence of GvHD after transplantation into allogeneic hosts. While most T cells died upon FLU treatment, donor T cells repopulated in the hosts and appeared less inflammatory and alloreactive. Regulatory T cells (Tregs) are immunomodulatory and survived FLU treatment, resulting in an increased ratio of Tregs to conventional T cells. Our results implicate an important role for Tregs in maintaining allogeneic tolerance in FLU-treated grafts and suggest a therapeutic strategy of pre-treating donor cells (and not the patients directly) with GCs to simultaneously enhance engraftment and reduce GvHD upon allogeneic HCT.

Absence of CD11a Expression Identifies Embryonic Hematopoietic Stem Cell Precursors via Competitive Neonatal Transplantation Assay.

Hematopoietic stem cells (HSCs) are defined by their self-renewal, multipotency, and bone marrow (BM) engraftment abilities. How HSCs emerge during embryonic development remains unclear, but are thought to arise from hemogenic endothelium through an intermediate precursor called "pre-HSCs." Pre-HSCs have self-renewal and multipotent activity, but lack BM engraftability. They can be identified functionally by transplantation into neonatal recipients, or by in vitro co-culture with cytokines and stroma followed by transplantation into adult recipients. While pre-HSCs express markers such as Kit and CD144, a precise surface marker identity for pre-HSCs has remained elusive due to the fluctuating expression of common HSC markers during embryonic development. We have previously determined that the lack of CD11a expression distinguishes HSCs in adults as well as multipotent progenitors in the embryo. Here, we use a neonatal transplantation assay to identify pre-HSC populations in the mouse embryo. We establish CD11a as a critical marker for the identification and enrichment of pre-HSCs in day 10.5 and 11.5 mouse embryos. Our proposed pre-HSC population, termed "11a- eKLS" (CD11a- Ter119- CD43+ Kit+ Sca1+ CD144+), contains all in vivo long-term engrafting embryonic progenitors. This population also displays a cell-cycle status expected of embryonic HSC precursors. Furthermore, we identify the neonatal liver as the likely source of signals that can mature pre-HSCs into BM-engraftable HSCs.

Antiviral therapy and hepatocellular carcinoma risk in hepatitis B patients with cirrhosis.

OBJECTIVES: Our goal was to evaluate the effect of antiviral therapy on hepatocellular carcinoma incidence for cirrhotic patients with lower hepatitis B virus DNA levels. METHODS: Consecutive cirrhosis patients from a US cohort (n = 381) and 408 patients from a Taiwan cohort were enrolled. Patients were classified into a low (<20 IU/ml) and high hepatitis B virus DNA group (≥20 IU/ml), and each was further stratified into treated and untreated subgroups. RESULTS: Except for hepatitis B e antigen, baseline characteristics were similar for both hepatitis B virus DNA groups. Antiviral therapy significantly reduced hepatocellular carcinoma incidence in cirrhotic patients with hepatitis B virus DNA ≥20 IU/ml at 5-years (12.2% vs. 22.8%) and 10-years (23.3% vs. 37.2%) (P = 0.0018). For cirrhotic patients with hepatitis B virus DNA <20 IU/ml, there was no statistically significant difference in cumulative hepatocellular carcinoma incidence between the treated and untreated groups. After adjusting for age, sex, and hepatitis B e antigen status, antiviral therapy was an independent predictor (hazard ratio 0.43, P < 0.0001) for reduced hepatocellular carcinoma risk in patients with hepatitis B virus DNA ≥20 IU/ml. CONCLUSION: Antiviral therapy was associated with a 57% reduction in hepatocellular carcinoma incidence in chronic hepatitis B patients with cirrhosis and hepatitis B virus DNA as low as 20 IU/ml (but no lower). However, hepatocellular carcinoma incidence remained substantial, regardless of hepatitis B virus DNA levels and treatment status, highlighting the need for ongoing hepatocellular carcinoma surveillance for all cirrhotic hepatitis B virus patients.

Rising Inpatient Encounters and Economic Burden for Patients with Nonalcoholic Fatty Liver Disease in the USA.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is the fastest-growing chronic liver disease. However, little is known about NAFLD inpatient resource utilization and clinical outcomes. AIMS: The aim of this study was to quantify inpatient NAFLD encounters using patient-level data over time. METHODS: This was a retrospective analysis of de-identified data for NAFLD patients from the California Patient Discharge Database from 2006 to 2013. NAFLD patients were identified by ICD9 codes 571.40, 571.41, 571.49, 571.8, and 571.9. RESULTS: NAFLD patients (n = 91,558) were predominantly female (60%), 45-65 years old (44%), and white (53%). Inpatient encounters increased from 8153 in 2006 to 16,457 in 2013 and were associated with a 207% increase in charges ($686 million in 2006 to $1.42 billion in 2013) and average increase in charges of 9.8% per year adjusting for inflation. Comorbidities (obesity, diabetes, hyperlipidemia, cardiovascular disease, other cancer, and renal disease) increased significantly over time (all P < 0.05). From 2006 to 2011, there were 11,463 deaths (1849 for liver-related hospitalizations) (mean follow-up 4.00 ± 2.13 years). The most significant predictors of death were age > 75 (aHR 3.9, P < 0.0001), male gender (aHR 1.10, P < 0.0001), white race (aHR 1.2, P < 0.0001), decompensated cirrhosis (aHR 2.1, P < 0.0001), and cancer other than HCC (aHR 3.2, P < 0.0001). Within the liver-related hospitalization cohort, mortality predictors were similar, except for Hispanic race (aHR 0.92, P < 0.0096) and renal disease (aHR 1.50, P < 0.0001). CONCLUSIONS: The number of NAFLD inpatient encounters increased significantly from 2006 to 2013, as did the inflation-adjusted inpatient charges. The most significant predictors of death were non-liver cancers (HR 3.11, P < 0.0001, CI 3.06-3.16) and age > 75 years (HR 3.94, P < 0.0001, HR 3.86-4.03).

Clinical Features Associated with Survival Outcome in African-American Patients with Hepatocellular Carcinoma.

BACKGROUND: African-Americans (AA) have a higher incidence of hepatocellular carcinoma (HCC) and lower survival. We characterized survival rates and clinical features associated with survival in AA vs. Caucasians with HCC over the past two decades. METHODS: HCC patients from three US medical centers were matched by year of diagnosis (1991-2016): AA (n = 578)/Caucasian (n = 578) and placed in one of two groups-HCC diagnosed prior to 2010 or 2010 and after. Data were obtained from chart review and the National Death Index. Multivariate and survival analysis controlling for key predictors were conducted. RESULTS: Prior to 2010, there was no difference in survival between Caucasians and AA (p = 0.61). After 2010, AA patients had poorer survival compared to Caucasians (35% vs. 44%, respectively, p = 0.044). Over time, survival improved for Caucasians (32% before 2010 vs. 44% after 2010, p = 0.003), but not AA (36% vs. 35%, p = 0.50). AA on presentation (in the after 2010 cohort) were more likely to have BCLC (Barcelona Clinic Liver Cancer) stage C (24% vs. 15%, p = 0.010) and less likely to receive treatment (85% vs. 93%, p = 0.002) compared to matched Caucasians. BCLC beyond stage A (aHR: 1.75, 95% CI: 1.26-2.43, p = 0.001) and child's class C (aHR 2.05, 95% CI: 1.23-3.41, p = 0.006) were the strongest predictors of mortality, while race was not. CONCLUSIONS: African-Americans presented with more advanced HCC and had poorer survival compared to Caucasians after 2010. Tumor stage was an independent predictor of mortality, but ethnicity was not. Further efforts are needed to improve early HCC diagnosis for AA.

Ductal carcinoma in situ on core needle biopsy only with no residual disease at surgery.

BACKGROUND: The treatment of ductal carcinoma in situ (DCIS) remains controversial and may be particularly difficult for patients with minimal disease. There is a dearth of information regarding patients who have been diagnosed with DCIS on core needle biopsy (CNB), who have no residual disease in the lumpectomy specimen. The purpose of this study was to explore the frequency of this presentation and short-term outcomes in these patients. METHODS: Our institutional Breast Cancer Database was queried for all women who were diagnosed with pure DCIS from 2010 to 2016 and treated with lumpectomy. Variables included patient and tumor characteristics, adjuvant treatment, and ipsilateral breast tumor recurrence (IBTR). Statistical analyses included Pearson's chi-square, Fisher's exact tests, and Kaplan-Meier analysis. RESULTS: Of 547 patients with pure DCIS, 50 (14%) had DCIS on CNB only. Of the patients with DCIS on CNB only, 15 were treated with lumpectomy and radiation therapy (RT), while 35 underwent lumpectomy without RT. At a median follow-up of 4 years, there were 3 (6%) IBTR all within the same quadrant as the original lumpectomy site. None of the patients who recurred received adjuvant RT or hormonal therapy. CONCLUSIONS: Despite the minimal extent of disease exhibited in these cases, 6% of patients with DCIS on CNB only had IBTR at a median follow-up of 4 years. These data suggest that even minimal DCIS represents a significant risk of recurrence to the patient. Size and margins are not sufficient criteria to stratify risk and guide decisions for adjuvant therapies.

Higher mortality and hospital charges in patients with cirrhosis and acute respiratory illness: a population-based study.

Both cirrhosis and acute respiratory illness (ARI) carry substantial disease and financial burden. To compare hospitalized patients with cirrhosis with ARI to cirrhotic patients without ARI, a retrospective cohort study was conducted using the California Office of Statewide Health Planning and Development database. To balance the groups, propensity score matching (PSM) was used. We identified a total of 46,192 cirrhotic patients during the three study periods (14,049, 15,699, and 16,444 patients, respectively). Among patients hospitalized with cirrhosis, the ARI prevalence was higher in older age groups (p < 0.001), the Asian population (p = 0.002), non-Hispanic population (p = 0.001), and among Medicare patients (p < 0.001). Compared to controls, patients with ARI had 53.8% higher adjusted hospital charge ($122,555 vs. $79,685 per patient per admission, p < 0.001) and 35.0% higher adjusted in-hospital mortality (p < 0.001). Older patients, patients with alcoholic liver disease or liver cancer were at particularly higher risk (adjusted hazard ratio = 2.94 (95% CI: 2.26-3.83), 1.22 (95% CI: 1.02-1.45), and 2.17 (95% CI: 1.76-2.68) respectively, p = 0.028 to <0.001). Mortality rates and hospital charges in hospitalized cirrhotic patients with ARI were higher than in cirrhotic controls without ARI. Preventive efforts such as influenza and pneumococcal vaccination, especially in older patients and those with liver cancer, or alcoholic liver disease, would be of value.

Economic and clinical burden of viral hepatitis in California: A population-based study with longitudinal analysis.

BACKGROUND: Economic burden of HBV and HCV infection are trending upwards. AIMS: Compare hepatitis B virus (HBV) and hepatitis C virus (HCV) related hospital admission rates, charges, mortality rates, causes of death in a US population-based study. METHODS: Retrospective cohort analysis of HBV and HCV patients from the California Office of Statewide Health Planning and Development (2006-2013) database. RESULTS: A total of 23,891 HBV and 148,229 HCV patients were identified. Across the 8-year period, the mean increase for all-cause ($1,863 vs $1,388) and liver-related hospitalization charges ($1,175 vs $675) were significantly higher for the HBV cohort compared to the HCV cohort. HBV patients had significantly higher liver-related hospital charges per person per year than HCV patients after controlling for covariates ($123,239 vs $111,837; p = 0.002). Compared to HCV patients, adjusted mortality hazard ratio was slightly lower in HBV patients (relative risk = 0.96; 95% CI 0.94-0.99). The major causes and places of death were different. The three major causes of death for HBV were: other malignant neoplasms (35%), cardiovascular disease/other circulatory disorders (17%), and liver-related disease (15%) whereas for HCV patients were: liver-related disease (22%), other malignant neoplasms (20%), and cardiovascular disease (16%). Regarding the place of death, 53% of HBV patients and 44% of HCV patients died in hospital inpatient, respectively. CONCLUSIONS: HBV patients incurred higher liver-related hospital charges and higher mean increase for all-cause and liver-related hospitalization charges over the 8-year period compared to HCV patients. HBV patients had slightly lower mortality rate and their major causes and places of death were noticeably different from HCV patients.

Higher risk of hepatocellular carcinoma in Hispanic patients with hepatitis C cirrhosis and metabolic risk factors.

The effect of metabolic syndrome on chronic liver diseases other than non-alcoholic fatty liver disease has not been fully elucidated. Our goal was to evaluate if metabolic syndrome increased the risk of liver-related complications, specifically hepatocellular carcinoma (HCC) and decompensation, in cirrhotic chronic hepatitis C (CHC) patients. We conducted a retrospective cohort study of 3503 consecutive cirrhotic CHC patients seen at Stanford University from 1997-2015. HCC developed in 238 patients (8-year incidence 21%) and hepatic decompensation in 448 patients (8-year incidence 61%). The incidence of HCC and decompensation increased with Hispanic ethnicity, diabetes, and number of metabolic risk factors. Multivariate Cox regression analysis demonstrated that, independent of HCV therapy and cure and other background risks, Hispanic ethnicity with ≥2 metabolic risk factors significantly increased the risk of HCC and hepatic decompensation. There was no interaction between Hispanic ethnicity and metabolic risk factors. All in all, metabolic risk factors significantly increase the risk of liver-related complications in cirrhotic CHC patients, especially HCC among Hispanics. As the prevalence of metabolic syndrome increases globally, targeted health interventions are needed to help curb the effects of metabolic syndrome in CHC patients.

Temporal trends in disease presentation and survival of patients with hepatocellular carcinoma: A real-world experience from 1998 to 2015.

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the few cancers whose incidence continues to increase. The goal of the current study was to investigate the presentation and survival trends of patients with HCC presenting to a university hospital between 1998 and 2015. METHODS: Study data were ascertained by individual chart review with survival data also supplemented by National Death Index query up to December 31, 2015. Patients were divided into three 6-year groups by diagnosis date (1998-2003, 2004-2009, and 2010-2015). RESULTS: A total of 2106 consecutive patients with HCC were included. The majority of patients had either hepatitis C (56.7%) or hepatitis B (22.1%), but cases of nonalcoholic steatohepatitis HCC increased by 68% over the most recent time period. Screening/surveillance identified 61% of HCC cases, but only 31% of these patients underwent curative treatment, which did not increase significantly over time. The overall median survival was 29.8 months (2.48 years) and without improvement over time. On multivariable analysis, Asian or Hispanic ethnicity, meeting Milan criteria, and receiving any of the standard HCC treatments were found to be significantly associated with improved survival, but diagnosis time period and liver disease etiology were not. CONCLUSIONS: Over the last 18 years, the percentage of cases of nonalcoholic steatohepatitis HCC has increased but not overall survival. It is interesting to note that only 31% of patients with HCC identified via screening/surveillance received any curative treatment. Further research is needed to better understand the barriers to curative care for patients with HCC and the causes of the lack of improvement in survival in the more recent patient cohort. Cancer 2018;124:2588-98. © 2018 American Cancer Society.

More advanced disease and worse survival in cryptogenic compared to viral hepatocellular carcinoma.

BACKGROUND & AIMS: Although hepatitis B virus (HBV) and hepatitis C virus (HCV) infections remain major risk factors for hepatocellular carcinoma (HCC), non-viral causes of HCC, particularly non-alcoholic fatty liver disease (NAFLD), are becoming increasingly prevalent. The aim of this study was to compare the clinical characteristics and survival of cryptogenic and viral HCC. METHODS: We conducted a retrospective cohort study involving 3878 consecutive HCC patients seen at two tertiary centres in the United States and one in Taiwan from 2004 to 2014. We compared the clinical characteristics, treatment and survival of patients by underlying aetiology: cryptogenic (n = 696), HBV (n = 1304) or HCV (n = 1878). RESULTS: Cirrhosis was present in 66.8% of the cryptogenic HCC patients, compared with 74.7% of HBV-related HCC (HBV-HCC) (P = .001) and 85.9% of HCV-HCC (P < .001). Compared to viral HCC, cryptogenic HCC patients presented with larger tumours and at later stages of disease. Five-year overall survival was 16.3% among cryptogenic HCC patients compared with 31.9% among HBV-HCC patients and 27.7% among HCV-HCC patients (P < .001 for both by the log-rank test). HCC aetiology was not an independent predictor of survival, though ethnicity, cirrhosis status, meeting Milan criteria and treatment allocation were. CONCLUSIONS: Compared with viral HCC patients, those with cryptogenic HCC had lower prevalence of cirrhosis, were diagnosed with larger tumours at more advanced stages of disease, and had poorer overall survival. Additional efforts are needed to identify patients at risk of cryptogenic HCC and to identify cryptogenic HCC at earlier stages of disease.

Open Label Study of 8 vs. 12 Weeks of Ledipasvir/Sofosbuvir in Genotype 6 Treatment Naïve or Experienced Patients.

OBJECTIVES: Hepatitis C genotype 6 (HCV-GT6) is one of the most prevalent genotypes in Southeast Asia. Ledipasvir and sofosbuvir fixed-dose combination (LDV/SOF FDC) for 12 weeks has been shown to be effective for multiple HCV genotypes including treatment-naïve HCV-6. Our goal was to examine treatment outcomes in a diverse HCV-6 population. METHODS: We prospectively enrolled 60 HCV-GT6 patients at four US centers. Treatment -naïve without cirrhosis patients received open-labeled LDV/SOF FDC orally once a day for 8 weeks; All cirrhotic and/or treatment-experienced patients received LDV/SOF FDC for 12 weeks. The primary outcome was sustained virological response 12 weeks after therapy (SVR12). Secondary outcomes were adverse events (AEs) and/or serious adverse events (SAEs). All patients gave written consent. RESULTS: Overall mean age was 58±10 and 58% were male. All patients were Asian and foreign born. The 8-week group included 20 patients (33.3%) and the 12-week included 40 patients (66.7%). There were 2 (5%) patients with decompensation, 3 with liver cancer (7.5%), and 14 with prior treatment (35%) in the 12-week group. SVR12 was 95.0% for the 8-week group (19/20) and 95.0% for the 12-week group (38/40). AEs included fatigue (5%), insomnia (3.3%), headache (1.7%), and nausea (1.7%); however, all patients completed the intended treatment duration. There were two treatment-unrelated SAEs. CONCLUSIONS: LDV/SOF FDC for 8 or 12 weeks was safe and effective for patients without cirrhosis or prior treatment failure as well as for patients with cirrhosis and/or prior treatment failure, respectively.

Increased Prevalence of Metabolic Risk Factors in Asian Americans With Hepatocellular Carcinoma.

BACKGROUND: We used metabolic risk factors to estimate the prevalence and clinical significance of nonalcoholic fatty liver disease in Asian Americans with hepatocellular carcinoma (HCC). METHODS: This is a retrospective cohort study of 824 consecutive Asian HCC patients at Stanford University Medical Center from 1998 to 2015. Patients were subdivided as: Chinese, other East Asian (Japanese and Korean), South East Asian (Vietnamese, Thai, and Laotian), Maritime South East Asian (MSEA: Malaysian, Indonesian, Filipino, and Singaporean), and South West Asian (Indian, Pakistani, and Middle Eastern). Metabolic risk factors studied were body mass index, hypertension, type II diabetes, and hyperlipidemia. RESULTS: Most patients were male (76%) with mean age 63 years. Metabolic risk factors were highly prevalent on presentation and increased over time (P<0.001), as did the prevalence of cryptogenic HCC (P<0.004). Compared with other Asian subgroups, MSEAs had the highest body mass index (26.3) and higher rates of type II diabetes (44% vs. 23% to 35%, P=0.004), hypertension (59% vs. 38% to 55%, P=0.04), and cryptogenic HCC (15% vs. 4% to 10%, P=0.01). They were more likely to be symptomatic on presentation (44% vs. 32% to 58%, P=0.07), less likely to present within Milan criteria (34% vs. 35% to 63%, P<0.0001), and trended toward decreased 10-year survival rates compared with other ethnic subgroups (9% vs. 25% to 32%, P=0.07). CONCLUSIONS: Metabolic risk factors were increasingly prevalent among Asian Americans with HCC. MSEAs, who had the highest incidence of these risk factors, had more advanced tumor stage and trended toward worse survival.

Sex differences in disease presentation, treatment and clinical outcomes of patients with hepatocellular carcinoma: a single-centre cohort study.

BACKGROUND: Although sex differences in hepatocellular carcinoma (HCC) risk are well known, it is unclear whether sex differences also exist in clinical presentation and survival outcomes once HCC develops. METHODS: We performed a retrospective cohort study of 1886 HCC patients seen in a US medical centre in 1998-2015. Data were obtained by chart review with survival data also by National Death Index search. RESULTS: The cohort consisted of 1449 male and 437 female patients. At diagnosis, men were significantly younger than women (59.9±10.7 vs 64.0±11.6, p<0.0001). Men had significantly higher rates of tobacco (57.7% vs 31.0%, p<0.001) and alcohol use (63.2% vs 35.1%, p<0.001). Women were more likely to be diagnosed by routine screening versus symptomatically or incidentally (65.5% vs 58.2%, p=0.03) and less likely to present with tumours >5 cm (30.2% vs 39.8%, p=0.001). Surgical and non-surgical treatment utilisation was similar for both sexes. Men and women had no significant difference in median survival from the time of diagnosis (median 30.7 (range=24.5-41.3) vs 33.1 (range=27.4-37.3) months, p=0.84). On multivariate analysis, significant predictors for improved survival included younger age, surgical or non-surgical treatment (vs supportive care), diagnosis by screening, tumour within Milan criteria and lower Model for End-Stage Liver Disease score, but not female sex (adjusted HR=1.01, CI 0.82 to 1.24, p=0.94). CONCLUSIONS: Although men have much higher risk for HCC development, there were no significant sex differences in disease presentation or survival except for older age and lower tumour burden at diagnosis in women. Female sex was not an independent predictor for survival.

Effects of Cirrhosis on Short-term and Long-term Survival of Patients With Hepatitis B-related Hepatocellular Carcinoma.

BACKGROUND & AIMS: Hepatitis B virus (HBV) is the most common cause of hepatocellular carcinoma (HCC) worldwide. Unlike other liver diseases, HBV can cause HCC in the absence of cirrhosis. We investigated whether features of HCC in patients with HBV infection without cirrhosis and survival times differ from those of patients who develop HCC after cirrhosis. METHODS: We performed a retrospective cohort study of 487 consecutive cases of HBV-related HCC who were seen from 2000 through 2014 at a tertiary care center. Laboratory values, imaging results, and treatment information were obtained from subjects' medical records. Symptoms of HCC included weight loss, abdominal pain, or new hepatic decompensation. The primary outcome was overall survival, which was categorized as short-term survival (up to 3 years after the diagnosis of HCC) or long-term survival (3-10 years after diagnosis). RESULTS: The mean tumor size at diagnosis was significantly larger in patients without cirrhosis (6.4 ± 4.3 cm) than in patients with cirrhosis (5.0 ± 3.8 cm) (P = .0009). A significantly larger proportion of patients without cirrhosis had symptoms at diagnosis (43.8% vs 35.4% in patients without cirrhosis, P = .09). A significantly higher proportion of patients without cirrhosis survived for the long-term (P = .003), but there was no significant difference between groups in short-term survival (P = .37). Notably, the same proportions of asymptomatic patients with and without cirrhosis survived for the short-term (64.3% vs 64.2%, P = .73), but a lower proportion of asymptomatic patients with cirrhosis survived for the long-term (P = .015). In multivariate Cox regression analysis, cirrhosis was an independent predictor of death in 3-10 years (hazard ratio, 3.76; P = .003) but not in less than 3 years (P = .48). Symptoms at diagnosis predicted death within 3 years (hazard ratio, 1.76; P =.006) but not in 3-10 years (P = .15). CONCLUSIONS: Patients with HBV infection and HCC without cirrhosis present with larger tumors, and a larger percentage have symptoms of cancer than patients with cirrhosis. This may indicate that HCC surveillance is less than optimal for patients with HBV infection without cirrhosis. Despite this suboptimal surveillance, patients without cirrhosis have higher long-term survival than those with cirrhosis, especially when asymptomatic at diagnosis.

Progression of coronary artery calcification and thoracic aorta calcification in kidney transplant recipients.

BACKGROUND: Vascular calcification independently predicts cardiovascular disease, the major cause of death in kidney transplant recipients (KTRs). Longitudinal studies of vascular calcification in KTRs are few and small and have short follow-up. We assessed the evolution of coronary artery (CAC) and thoracic aorta calcification and their determinants in a cohort of prevalent KTRs. STUDY DESIGN: Longitudinal. SETTING & PARTICIPANTS: The Agatston score of coronary arteries and thoracic aorta was measured by 16-slice spiral computed tomography in 281 KTRs. PREDICTORS: Demographic, clinical, and biochemical parameters were recorded simultaneously. OUTCOMES & MEASUREMENTS: The Agatston score was measured again 3.5 or more years later. RESULTS: Repeated analyzable computed tomographic scans were available for 197 (70%) KTRs after 4.40 ± 0.28 years; they were not available for the rest of patients because of death (n = 40), atrial fibrillation (n = 1), other arrhythmias (n = 4), refusal (n = 35), or technical problems precluding confident calcium scoring (n = 4). CAC and aorta calcification scores increased significantly (by a median of 11% and 4% per year, respectively) during follow-up. By multivariable linear regression, higher baseline CAC score, history of cardiovascular event, use of a statin, and lower 25-hydroxyvitamin D(3) level were independent determinants of CAC progression. Independent determinants of aorta calcification progression were higher baseline aorta calcification score, higher pulse pressure, use of a statin, older age, higher serum phosphate level, use of aspirin, and male sex. Significant regression of CAC or aorta calcification was not observed in this cohort. LIMITATIONS: Cohort of prevalent KTRs with potential survival bias; few patients with diabetes and nonwhites, limiting the generalizability of results. CONCLUSION: In contrast to previous small short-term studies, we show that vascular calcification progression is substantial within 4 years in prevalent KTRs and is associated with several traditional and nontraditional cardiovascular risk factors, some of which are modifiable.

Serum fetuin-A levels are associated with vascular calcifications and predict cardiovascular events in renal transplant recipients.

BACKGROUND AND OBJECTIVES: Vascular calcifications predict cardiovascular disease, the major cause of death in renal transplant recipients (RTRs). We studied the determinants of fetuin-A, a potent circulating calcification inhibitor encoded by the AHSG gene, and tested its association with vascular calcifications and long-term survival and cardiovascular events (CVEs) in RTRs. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Two hundred seventy-seven prevalent RTRs from a single center were included. CVEs and deaths were prospectively recorded during a 5-year follow-up. RESULTS: Independent determinants of lower serum fetuin-A levels were lower plasma cholesterol, the AHSG rs4918 G allele, and history of smoking. Low serum fetuin-A level was a determinant of aortic calcifications (assessed using spiral CT). Low fetuin-A levels (≤0.47 g/L, first quintile) were independently associated with CVEs and deaths (hazard ratio=1.83; 95% confidence interval, 1.07 to 3.04). The association was confirmed for all-cause mortality, and the major adverse cardiovascular endpoints were analyzed separately. Patients with low fetuin-A and high high-sensitivity C-reactive protein (>4.36 mg/L, fourth quintile) levels had a 3.5-fold increased risk of all-cause mortality and CVEs. In the presence of inflammation, CVE-free survival was influenced by common variants in the AHSG gene. CONCLUSIONS: These data show that low fetuin-A levels are independently associated with aortic calcifications and a higher risk of CVEs and mortality. They support fetuin-A as a circulating biomarker able to identify RTRs at risk for vascular calcifications and CVEs.

Coronary artery calcification: a strong predictor of cardiovascular events in renal transplant recipients.

BACKGROUND: Coronary artery calcification (CAC) independently predicts cardiovascular events (CVE) in the general population. Whether this applies to renal transplant recipients (RTR) is unknown. This prospective study assessed the prognostic impact of CAC on CVE in RTR. METHODS: We followed up a published cohort of 281 prevalent RTR. At baseline, 16-slice chest spiral computerized tomography scan was performed and classical as well as CKD-related risk factors were recorded. Major CVE (MCVE) was defined as cardiovascular death, myocardial infarction, stroke or transient ischaemic attack. All CVE (ACVE) included MCVE and revascularizations. Prognostic factors were assessed by univariate and multivariate Cox regression. RESULTS: During 2.3 ± 0.5 years of follow-up, 16 patients died from CV (n = 8) or non-CV causes (n = 8). Thirty-one RTR developed at least one CVE (first CVE cardiac in 15, peripheral in 12 and cerebrovascular in 4) for a total of 36 CVE. Thirty-month CV survival, MCVE-free survival and ACVE-free survival was 96.4, 93.9 and 87.9%, respectively. By multivariate analysis, the independent predictors of ACVE were CAC score (hazards ratios [HR] = 1.40 [1.12; 1.75] for a 2.72-fold increase in CAC, P < 0.003) and history of CVE (HR = 2.76 [1.21; 6.39], P < 0.02). CONCLUSION: Our study shows for the first time that CAC is a strong independent predictor of CVE in RTR.

Prevalence and determinants of coronary and aortic calcifications assessed by chest CT in renal transplant recipients.

BACKGROUND: Coronary artery calcifications independently predict cardiovascular events (CVE) in the general population. We assessed the prevalence and determinants of coronary (CAC) and thoracic aorta (AoC) calcifications in renal transplant recipients (RTR). METHODS: Consecutive RTR living in Belgium, with an isolated kidney graft functioning for more than 1 year, were asked to participate. They underwent a 16-slice spiral computerized tomography in order to measure calcium mass. Demographic, clinical, biochemical and urinary parameters were recorded. RESULTS: We included 281 patients. CAC and AoC were detected in 81 and 85%, with geometric means (SD) of 52.2 (4.9) and 99.3 (8.2) mg, respectively. By multiple linear regression, independent predictors of both types of calcifications included older age, longer time on dialysis, a history of CVE, of multiple transplantations and of smoking. Other determinants of CAC were male gender, current statin use and history of parathyroidectomy, and other determinants of AoC included higher pulse pressure, shorter time under mycophenolate mofetil and current use of anti-vitamin-K. CONCLUSION: The prevalence of both CAC and AoC is substantial in RTR. We delineate independent determinants either common to both CAC and AoC or specific to one, and known as classic or chronic kidney disease related risk factors.

Identification of current smokers among renal transplant recipients.

BACKGROUND: In renal transplant recipients, smoking is associated with a high burden of cardiovascular disease and a higher risk of graft loss. Surprisingly, the results of measurement of cotinine serum level, the gold standard for the detection of active smoking, have not been confronted with self-reported smoking history in this group. The aim of our study was to identify and characterize the smoking group of renal transplant recipients. METHODS: Cotinine serum level was measured and all patients were asked to fill out an anonymous questionnaire on smoking history. RESULTS: Out of 233 renal transplant recipients, 106 (45%) reported to be lifetime and current non-smokers: cotinine serum level was below detection limit in all; among the 127 renal transplant recipients (55%) with a lifetime history of smoking, cotinine level was diagnostic of current smoking in 32 (25%). Only 21 of the current smokers (66%) declared to the nephrologist that they had continued smoking whereas 11 (34%) claimed to be non-smokers. Current smokers were younger (P=0.01) than former smokers. CONCLUSION: The identification of current smokers among renal transplant recipients should start with questioning about lifetime history of smoking and if positive, measurement of cotinine serum level. Indeed up to 34% of current smokers do not acknowledge they are active smokers and would otherwise not offer to participate in programmes to stop smoking.