Association of Kidney Function with Changes in the Endothelial Surface Layer

Background and objectives

ESRD is accompanied by endothelial dysfunction. Because the endothelial glycocalyx (endothelial surface layer) governs interactions between flowing blood and the vessel wall, perturbation could influence disease progression. This study used a novel noninvasive sidestream–darkfield imaging method, which measures the accessibility of red blood cells to the endothelial surface layer in the microcirculation (perfused boundary region), to investigate whether renal function is associated with endothelial surface layer dimensions.

Design, setting, participants, & measurements

Perfused boundary region was measured in control participants (n=10), patients with ESRD (n=23), participants with normal kidney function after successful living donor kidney transplantation (n=12), and patients who developed interstitial fibrosis/tubular atrophy after kidney transplantation (n=10). In addition, the endothelial activation marker angiopoietin-2 and shed endothelial surface layer components syndecan-1 and soluble thrombomodulin were measured using ELISA.

Results

Compared with healthy controls (1.82±0.16 µm), ESRD patients had a larger perfused boundary region (+0.23; 95% confidence interval, 0.46 to <0.01; P<0.05), which signifies loss of endothelial surface layer dimensions. This large perfused boundary region was accompanied by higher circulating levels of syndecan-1 (+57.71; 95% confidence interval, 17.38 to 98.04; P<0.01) and soluble thrombomodulin (+12.88; 95% confidence interval, 0.29 to 25.46; P<0.001). After successful transplantation, the perfused boundary region was indistinguishable from healthy controls (without elevated levels of soluble thrombomodulin or syndecan-1). In contrast, however, patients who developed interstitial fibrosis and tubular atrophy showed a large perfused boundary region (+0.36; 95% confidence interval, 0.09 to 0.63; P<0.01) and higher levels of endothelial activation markers. In addition, a significant correlation between perfused boundary region, angiopoietin-2, and eGFR was observed (perfused boundary region versus GFR: Spearman’s ρ=0.31; P<0.05; perfused boundary region versus angiopoietin-2: Spearman’s ρ=−0.33; P<0.05).

Conclusion

Reduced renal function is strongly associated with low endothelial surface layer dimensions. After successful kidney transplantation, the endothelial surface layer is indistinguishable from control.     

Ratio of hepatic arterial flow to recipient body weight predicts biliary complications after deceased donor liver transplantation

ObjectivesAdequate hepatic arterial (HA) flow to the bile duct is essential in liver transplantation. This study was conducted to determine if the ratio of directly measured HA flow to weight is related to the occurrence of biliary complications after deceased donor liver transplantation.MethodsA retrospective review of 2684 liver transplants carried out over a 25-year period was performed using data sourced from a prospectively maintained database. Rates of biliary complications (biliary leaks, anastomotic and non-anastomotic strictures) were compared between two groups of patients with HA flow by body weight of, respectively, <5 ml/min/kg (n = 884) and ≥5 ml/min/kg (n = 1800).ResultsPatients with a lower ratio of HA flow to weight had higher body weight (92 kg versus 76 kg; P < 0.001) and lower HA flow (350 ml/min versus 550 ml/min; P < 0.001). A lower ratio of HA flow to weight was associated with higher rates of biliary complications at 2 months, 6 months and 12 months (19.8%, 28.2% and 31.9% versus 14.8%, 22.4% and 25.8%, respectively; P < 0.001).ConclusionsA ratio of HA flow to weight of < 5 ml/min/kg is associated with higher rates of biliary complications. This ratio may be a useful parameter for application in the prevention and early detection of biliary complications.     

End stage liver disease etiology & transplantation referral outcomes of major ethnic groups in British Columbia,Canada: A cohort study

Liver disease etiology and transplantation outcomes may vary by ethnicity. We aimed to determine if disparities exist in our province.We reviewed the provincial database for liver transplant referrals. We stratified cohorts by ethnicity and analyzed disease etiology and outcomes.Four thousand nine hundred sixteen referrals included 220 South Asians, 413 Asians, 235 First Nations (Indigenous), and 2725 Caucasians. Predominant etiologies by ethnicity included alcohol (27.4%) and primary sclerosing cholangitis (PSC) (8.8%) in South Asians, hepatitis B (45.5%) and malignancy (13.9%) in Asians, primary biliary cholangitis (PBC) (33.2%) and autoimmune hepatitis (AIH) (10.8%) in First Nations, and hepatitis C (35.9%) in Caucasians. First Nations had lowest rate of transplantation (30.6%, P = .01) and highest rate of waitlist death (10.6%, P = .03). Median time from referral to transplantation (268 days) did not differ between ethnicities (P = .47). Likelihood of transplantation increased with lower body mass index (BMI) (hazard ratio [HR] 0.99, P = .03), higher model for end stage liver disease (MELD) (HR 1.02, P < .01), or fulminant liver failure (HR 9.47, P < .01). Median time from referral to ineligibility status was 170 days, and shorter time was associated with increased MELD (HR 1.01, P < .01), increased age (HR 1.01, P < .01), fulminant liver failure (HR 2.56, P < .01) or South Asian ethnicity (HR 2.54, P < .01). Competing risks analysis revealed no differences in time to transplant (P = .66) or time to ineligibility (P = .91) but confirmed increased waitlist death for First Nations (P = .04).We have noted emerging trends such as alcohol related liver disease and PSC in South Asians. First Nations have increased autoimmune liver disease, lower transplantation rates and higher waitlist deaths. These data have significance for designing ethnicity specific interventions.     

Gut-liver axis improves with meloxicam treatment after cirrhotic liver resection

AIM: To investigate the effect of meloxicam on the gut-liver axis after cirrhotic liver resection.METHODS: Forty-four male Wistar rats were assigned to three groups: (1) control group (CG); (2) bile duct ligation with meloxicam treatment (BDL + M); and (3) bile duct ligation without meloxicam treatment (BDL). Secondary biliary liver cirrhosis was induced via ligature of the bile duct in the BDL + M and BDL groups. After 2 wk, the animals underwent a 50% hepatectomy. In the BDL + M group 15 min prior to the hepatectomy, one single dose of meloxicam was administered. Parameters measured included: microcirculation of the liver and small bowel; portal venous flow (PVF); gastrointestinal (GI) transit; alanine aminotransferase (ALT); malondialdehyde; interleukin 6 (IL-6), transforming growth factor beta 1 (TGF-β1) and hypoxia-inducible factor 1 alpha (HIF-1α) levels; mRNA expression of cyclooxigenase-2 (COX-2), IL-6 and TGF-β1; liver and small bowel histology; immunohistochemical evaluation of hepatocyte and enterocyte proliferation with Ki-67 and COX-2 liver expression.RESULTS: Proliferative activity of hepatocytes after liver resection, liver flow and PVF were significantly higher in CG vs BDL + M and CG vs BDL group (P < 0.05), whereas one single dose of meloxicam ameliorated liver flow and proliferative activity of hepatocytes in BDL + M vs BDL group. COX-2 liver expression at 24 h observation time (OT), IL-6 concentration and mRNA IL-6 expression in the liver especially at 3 h OT, were significantly higher in BDL group when compared with the BDL + M and CG groups (P < 0.01, P < 0.001, P < 0.01, respectively). Liver and small bowel histology, according to a semi quantitative scoring system, showed better integrity in BDL + M and CG as compared to BDL group. ALT release and HIF-1α levels at 1 h OT were significantly higher in BDL + M compared to CG and BDL group (P < 0.001 and P < 0.01, respectively). Moreover, ALT release levels at 3 and 24 h OT were significantly higher in BDL group compared to CG, P < 0.01. GI transit, enterocyte proliferative activity and number of goblet cells were in favor of meloxicam treatment vs BDL group (P < 0.05, P < 0.001, P < 0.01, respectively). Additionally, villus length were higher in BDL + M as compared to BDL group.CONCLUSION: One single dose of meloxicam administered after cirrhotic liver resection was able to cause better function and integrity of the remaining liver and small bowel.     

Morbid obesity in liver transplant recipients adversely affects longterm graft and patient survival in a single-institution analysis

Objective

The effects of obesity in liver transplantation remain controversial. Earlier institutional data demonstrated no significant difference in postoperative complications or 1-year mortality. This study was conducted to test the hypothesis that obesity alone has minimal effect on longterm graft and overall survival.

Methods

A retrospective, single-institution analysis of outcomes in patients submitted to primary adult orthotopic liver transplantation was conducted using data for the period from 1 January 2002 to 31 December 2012. Recipients were divided into six groups by pre-transplant body mass index (BMI), comprising those with BMIs of <18.0 kg/m², 18.0–24.9 kg/m², 25.0–29.9 kg/m², 30.0–35.0 kg/m², 35.1–40.0 kg/m² and >40 kg/m², respectively. Pre- and post-transplant parameters were compared. A P-value of <0.05 was considered to indicate statistical significance. Independent predictors of patient and graft survival were determined using multivariate analysis.

Results

A total of 785 patients met the study inclusion criteria. A BMI of >35 kg/m² was associated with non-alcoholic steatohepatitis (NASH) cirrhosis (P < 0.0001), higher Model for End-stage Liver Disease (MELD) score, and longer wait times for transplant (P = 0.002). There were no differences in operative time, intensive care unit or hospital length of stay, or perioperative complications. Graft and patient survival at intervals up to 3 years were similar between groups. Compared with non-obese recipients, recipients with a BMI of >40 kg/m² showed significantly reduced 5-year graft (49.0% versus 75.8%; P < 0.02) and patient (51.3% versus 78.8%; P < 0.01) survival.

Conclusions

Obesity increasingly impacts outcomes in liver transplantation. Although the present data are limited by the fact that they were sourced from a single institution, they suggest that morbid obesity adversely affects longterm outcomes despite providing similar short-term results. Further analysis is indicated to identify risk factors for poor outcomes in morbidly obese patients.     

Long-term impact of certain coexisting extrahepatic unisystem and multisystem manifestations on trends in incidence of liver cirrhosis in treatment-naïve patients with chronic hepatitis C: A nested case-control study

Diabetes mellitus (DM) was found to be more common in hepatitis C virus (HCV)-related cirrhotic males. However, the association between DM, or other extrahepatic manifestations (EHMs), and liver cirrhosis is still undetermined. We used a large-scale long-term study to analyze the cirrhosis risk of treatment-naïve HCV patients with EHMs as compared to those without.In this retrospective nested case-control study, we identified 11 872 treatment-naïve patients with chronic HCV between 2001 and 2013 from Taiwan National Health Insurance Research Database and divided them into patients with (cases) and without cirrhosis (controls). All patients were followed up from the index month (exact month of diagnosis) to the end of 2013, death, or study outcome, whichever occurred first. The cases and controls were 1:6 propensity score matched for age, sex, and exact month of diagnosis; finally, 8078 patients (1154 with and 6924 without cirrhosis) were included in the analysis. The presence of coexisting EHMs and a new diagnosis of cirrhosis was analyzed. Adjusted hazard ratios (HRs) and cumulative incidence for cirrhosis were calculated in conditional Cox regression models after propensity score matching.Patients with high-cirrhosis-risk EHMs, such as DM (HR: 1.72, 95% CI: 1.51–1.96, P < .001), HCD (HR: 1.45, 95% CI: 1.27–1.67, P < .007), CKD (HR: 1.21, 95% CI: 1.05–1.38, P < .001), hyperlipidemia (HR: 0.53, 95% CI: 0.46–0.60, P < .001), lichen planus (HR: 2.71, 95% CI: 1.56–4.72, P < .001), and palpable purpura (HR: 2.67, 95% CI: 2.13–3.35, P < .001) exhibited significantly higher risk of liver cirrhosis than those without. Cumulative incidence (P < .001) of liver cirrhosis by pairwise comparisons of multiple high-cirrhosis-risk EHMs, and that of lichen planus was the highest.Our study provided direct estimates of specific HCV-associated EHM time trends of cirrhosis risk, with an upward trend in incidence. Lichen planus was at the top of the list of single-EHM comparisons, and the maximum combination of certain EHMs was the greatest risk factor across a different array of multi-EHM comparisons for liver cirrhosis development.     

Neutrophil/Lymphocyte Ratio,Lymphocyte/Monocyte Ratio,and Absolute Lymphocyte Count/Absolute Monocyte Count Prognostic Score in Diffuse Large B-Cell Lymphoma: Useful Prognostic Tools in the Rituximab Era

The neutrophil/lymphocyte ratio (NLR), lymphocyte/monocyte ratio (LMR), and absolute lymphocyte count/absolute monocyte count prognostic score (ALC/AMC PS) have been described as the most useful prognostic tools for patients with diffuse large B-cell lymphoma (DLBCL). We retrospectively analyzed 148 Taiwanese patients with newly diagnosed diffuse large B-cell lymphoma under rituximab (R)-CHOP-like regimens from January 2001 to December 2010 at the Tri-Service General Hospital and investigated the utility of these inexpensive tools in our patients. In a univariate analysis, the NLR, LMR, and ALC/AMC PS had significant prognostic value in our DLBCL patients (NLR: 5-year progression-free survival [PFS], P = 0.001; 5-year overall survival [OS], P = 0.007. LMR: PFS, P = 0.003; OS, P = 0.05. ALC/AMC PS: PFS, P < 0.001; OS, P < 0.001). In a separate multivariate analysis, the ALC/AMC PS appeared to interact less with the other clinical factors but retained statistical significance in the survival analysis (PFS, P = 0.023; OS, P = 0.017). The akaike information criterion (AIC) analysis produced scores of 388.773 in the NLR, 387.625 in the LMR, and 372.574 in the ALC/AMC PS. The results suggested that the ALC/AMC PS appears to be more reliable than the NLR and LMR and may provide additional prognostic information when used in conjunction with the International Prognostic Index.     

Impacts of common factors of life style on serum liver enzymes

AIM: To investigate the impacts of gender, age and factors of life style (alcohol, overweight, coffee and smoking) on serum liver enzymes.METHODS: Serum alanine aminotransferase (ALT) and gamma-glutamyltransferase (GGT) were measured from 6269 apparently healthy individuals (2851 men, 3418 women, mean age 45 ± 12 years, range 25-74 years) in a national cross-sectional health survey. All subjects underwent detailed clinical examinations and interviews including the amount and pattern of alcohol use, coffee consumption and smoking habits.RESULTS: In this population with a mean ± SD alcohol consumption of 65 ± 105 g/wk and body mass index (BMI) of 26.1 ± 4.3 kg/m², both ALT and GGT were significantly influenced by alcohol use (P < 0.001) and BMI (P < 0.001), whereas smoking increased only GGT (P < 0.001). A significant effect of age on ALT was seen in men (P < 0.001) whereas not in women. Significant two-factor interactions of alcohol use in men were observed with age (ALT: P < 0.01; GGT: P < 0.001) and BMI (GGT: P < 0.05). For ALT, a significant interaction also occurred between BMI and age (P < 0.005). In contrast, women showed significant interactions of alcohol use with BMI (GGT: P < 0.05), smoking (GGT: P < 0.001), and coffee consumption (GGT: P < 0.001).CONCLUSION: Life-style associated changes in liver enzymes may reflect health risks, which should be considered in the definition of normal limits for liver enzymes.     

Correlation between lncRNA SNHG16 gene polymorphism and its interaction with environmental factors and susceptibility to colorectal cancer

Objective:To study the relationship between long-chain non-coding RNA small nucleolar RNA host gene 16 (lncRNA SNHG16) polymorphisms and its interaction with environmental factors and susceptibility to colorectal cancer (CRC).Methods:Sanger sequencing was used to analyze genotypes of lncRNA SNHG16 gene rs7353, rs8038, and rs15278 sites. Multifactor dimensionality reduction was used to analyze interactions between lncRNA SNHG16 gene rs7353, rs8038, rs15278 sites, and environmental factors. Haploview 4.1 software was used to analyze linkage disequilibrium of lncRNA SNHG16 gene rs7353, rs8038, and rs15278 sites. Quantitative real-time polymerase chain reaction was used to analyze plasma lncRNA SNHG16 levels of CRC patients and control subjects.Results:Variation of the lncRNA SNHG16 gene rs7353 site A>G variation was associated with decreased CRC susceptibility (Odds ratio [OR] = 0.50, 95% confidence interval [CI]: 0.40–0.62, P < .01). The rs8038 site G>A and rs15278 site A>G variation were associated with increased CRC susceptibility (OR = 1.87, 95% CI: 1.47–2.36, P < .01). The rs15278 site G>A variation was associated with increased CRC susceptibility (OR = 2.24, 95% CI: 1.61–3.11, P < .01). Interaction combinations featuring age, rs7353, rs8038, and rs15278 single nucleotide polymorphism are 13.53 times more susceptible to CRC than other interactions (95% CI: 9.43–19.41, P < .01). The rs15278, rs8038, and rs7353 site AGA haplotypes were significantly associated with a decreased CRC risk (OR = 0.65, 95% CI: 0.48–0.88, P = .01), AAG haplotypes were significantly associated with an increased CRC risk (OR = 2.00, 95% CI: 1.27–3.17, P < .01). High lncRNA SNHG16 expression was associated with tumor progression in CRC patients (χ² = 8.85, P = .03). The rs7353 site A>G variation caused a significant decrease in plasma lncRNA SNHG16 level (P < .01), while the rs8038 site G>A variation and rs15278 site A>G variation resulted in increased plasma lncRNA SNHG16 levels.Conclusion:Polymorphisms of lncRNA SNHG16 gene rs7353, rs8038, rs15278 loci and their interaction with age are significantly associated with CRC susceptibility.     

Risk Factors for Long-Term Mortality and Progressive Chronic Kidney Disease Associated With Acute Kidney Injury After Cardiac Surgery

The aim of the study was to evaluate risk factors for long-term mortality and progressive chronic kidney disease (CKD) after cardiac surgery in patients with normal preoperative renal function and postoperative acute kidney injury (AKI). From April 2009 to December 2012, we prospectively enrolled 3245 cardiac surgery patients of our hospital. The primary endpoints included survival rates and the secondary endpoint was the incidence of progressive chronic kidney disease (CKD) in a follow-up period of 2 years. Acute kidney injury was staged by KDIGO classification. Progressive CKD was defined as GFR ≤ 30 mL/min/1.73 m² or end-stage renal disease (ESRD) (starting renal replacement therapy or renal transplantation).The AKI incidence was 39.9% (n = 1295). The 1 and 2 year overall survival (OS) rates of AKI patients were significantly lower than that for non-AKI patients (85.9% and 82.3% vs 98.1% and 93.7%, P < 0.001), even after complete recovery of renal function during 2 years after intervention (P < 0.001). The 2-year overall survival (OS) rates of patients with AKI stage 1, 2, and 3 were 89.9%, 78.6%, and 61.4% (P < 0.001), respectively. Multivariate Cox regression analysis of factors for 2-year survival rates revealed that besides age (P < 0.001), chronic cardiac failure (P < 0.001), diabetes (P < 0.001), cardiopulmonary bypass time (P < 0.01), and length of intensive care unit (ICU) stay (P = 0.004), AKI was a significant risk factor for reducing 2-year survival rates even after complete recovery of renal function (P < 0.001). The accumulated progressive CKD prevalence was significantly higher in AKI than in non-AKI patients (6.8% vs 0.2%, P < 0.001) in the 2 years after surgery. Even with complete recovery of renal function at discharge, AKI was still a risk factor for accumulated progressive CKD (RR 1.92, 95% CI 1.37–2.69).The 2-year mortality and progressive CKD incidence even after complete recovery of renal function were significantly increased in cardiac surgery patients with postoperative AKI.     

Is the liver kinetic growth rate in ALPPS unprecedented when compared with PVE and living donor liver transplant? A multicentre analysis

Background

The clinical perspective on hepatic growth is limited. The goal of the present study was to compare hepatic hypertrophy and the kinetic growth rate(KGR) in patients after the ALPPS (Associating Liver Partition with Portal Vein Ligation for Staged Hepatectomy) procedure, portal vein embolization (PVE) and living donor liver transplantation.

Methods

Volumetry and KGR of the future liver remnant (FLR) were compared from (15) patients undergoing ALPPS, (53) patients undergoing PVE, (90) recipients of living donor liver grafts and (93) donors of living donor liver grafts.

Results

The degree of hypertrophy was significantly greater after ALPPS (84.3 ± 7.8%) than after PVE (36.0 ± 27.2%) (P < 0.001). The KGR was also significantly greater for ALPPS [32.7 ± 13.6 cubic centimetres (cc)/day] (10.8 ± 4.5%/day) compared with PVE (4.4 ± 3.2 cc/day) (0.98 ± 0.75%/day) (P < 0.001). The FLR of living donor donors had the greatest degree of hypertrophy (107.5 ± 39.2%) and was greater than after ALPPS (P = 0.02), PVE (P < 0.001) and in living donor-recipient grafts (P < 0.001). KGR (cc/day) was greater in FLR of living donor donors compared with both ALPPS (P < 0.001) and PVE (P < 0.001). The KGR in patients undergoing ALPPS and living donor liver transplantation had a linear relationship with the size of FLR.

Conclusion

FLR hypertrophy and KGR were greater after ALPPS than PVE. However, the degree of hypertrophy after ALPPS is not unprecedented, as KGR in the FLR from living donor donors is equal to or greater than after ALPPS. The KGR of the FLR in patients after ALPPS and living donor donors correlates directly with the size of the FLR.     

Vascular inflow control during hemi-hepatectomy: a comparison between intrahepatic pedicle ligation and extrahepatic vascular ligation

Background Intrahepatic pedicle ligation (IPL) is an alternative to extrahepatic portal dissection (EPD). Although IPL has been well described, concern has arisen over a possible association with increased complication rates.Methods Patients who underwent hemi-hepatectomy during January 1995 to December 2010 were reviewed and the inflow control technique (IPL versus EPD) documented. Patient, tumour, treatment and outcome variables were compared.Results A total of 798 patients underwent hemi-hepatectomy, 568 (71.2%) of the right and 230 (28.8%) of the left liver. In univariate analysis, factors associated with the choice of IPL included surgeon, right hepatectomy, preoperative portal vein embolization, diagnosis of colorectal cancer liver metastasis, and smaller tumour size (P < 0.011). In multivariate analysis, right hepatectomy [versus left: hazard ratio (HR) 3.878, 95% confidence interval (CI) 1.15–13.14; P = 0.029] and smaller tumour size (median of 4.5 cm versus 5.5 cm: HR 0.72, 95% CI 0.59–0.88; P = 0.002) were associated with IPL. Pringle manoeuvre time was longer in IPL procedures (40 min versus 29 min; P < 0.001). Complication rates (49.8% in IPL versus 48.4% in EPD; P = 0.706) were similar in both groups, as was the severity of complications; 17.6% of EPD and 22.3% of IPL patients experienced complications of grade ≥3 (P = 0.225).Conclusions Patients with small tumours undergoing right hepatectomy were more likely to undergo IPL. In selected patients, IPL was not associated with an increased complication rate and thus it should be considered a safe approach.     

Characteristics of Internal Medicine Physicians Disciplined by Professional Colleges in Canada

Physician misconduct is of serious concern to patient safety and quality of care. Currently, there are limited data on disciplinary proceedings involving internal medicine (IM) physicians.The aim of this study was to investigate the number and nature of disciplinary cases among IM physicians compared with those of other disciplined physicians.Our retrospective study reviewed information from all provincial Colleges of Physicians and Surgeons (CPS) and compiled a database of all disciplined physicians from 2000 to 2013 in Canada. Disciplinary rate differences (RDs) were calculated for IM physicians and compared with other physicians.From 2000 to 2013, overall disciplinary rates were low (9.6 cases per 10,000 physician years). There were 899 disciplinary cases, 49 of which involved 45 different IM physicians. IM physicians comprised 10.8% of all disciplined physicians and were disciplined at a lower rate than non-IM physicians, incurring 5.18 fewer cases per 10,000 physician years than other physicians (95% confidence interval [CI] 3.62–6.73; P < 0.001). They were significantly less likely to be disciplined for: unprofessional conduct (RD 1.16; CI 0.45–1.87; P = 0.001); unlicensed activity (RD 0.78; CI 0.37–1.19; P < 0.001); standard of care issues (RD 1.37; CI 0.49–2.26; P = 0.002); sexual misconduct (RD 1.65; CI 0.90–2.40; P < 0.001); miscellaneous (RD 0.80; CI 0.11–1.50; P = 0.020); mental illness (RD 0.06; CI 0.01–0.12; P = 0.025); inappropriate prescribing (RD 0.74; CI 0.15–1.33; P = 0.010); and criminal conviction (RD 0.33; CI 0.00–0.65; P = 0.048). No significant differences were found with respect to unclear violations, fraudulent behavior/prevarication, or offenses involving drugs/alcohol (all RDs less than 0.32). IM physicians were also less likely to incur the following penalties: voluntary license surrender (RD 0.53; CI 0.37–0.69; P < 0.001); suspension (RD 2.39; CI 1.26–3.51; P < 0.001); retraining/assessment (RD 1.58; CI 0.77–2.39; P < 0.001); restriction (RD 1.60; CI 0.74–2.46; P < 0.001); other (RD 0.52; CI 0.07–0.97; P = 0.030); formal reprimand (RD 2.78; CI 1.77–3.79; P < 0.001); or fine (RD 3.28; CI 1.89–4.67; P < 0.001). No significant differences were found with respect to revocation or mandated counseling/rehabilitation (all RDs less than 0.46).Generally, disciplinary rates among physicians were low. Compared with other physicians, IM physicians have significantly lower disciplinary rates overall and are less likely to incur the majority of disciplinary offenses and penalties.     

Serum Uric Acid and Risk of CKD in Type 2 Diabetes

Background and objective

Serum uric acid may predict the onset and progression of kidney disease, but it is unclear whether uric acid is an independent risk factor for diabetic nephropathy. Our aim was to study the relationship between uric acid levels and the development of CKD components in patients with type 2 diabetes.

Design, setting, participants, & measurements

Longitudinal study of a cohort of patients with type 2 diabetes from the database of the Italian Association of Clinical Diabetologists network. From a total of 62,830 patients attending the diabetes centers between January 1, 2004, and June 30, 2008, we considered those with baseline eGFR values ≥60 ml/min per 1.73 m² and normal albumin excretion (n=20,142). Urinary albumin excretion, GFR, and serum uric acid were available in 13,964 patients. We assessed the association of serum uric acid quintiles with onset of CKD components by multinomial logistic regression model adjusting for potential confounders. We calculated the relative risk ratios (RRRs) for eGFR <60 ml/min per 1.73 m², albuminuria, and their combination at 4 years.

Results

At 4-year follow-up, 1109 (7.9%) patients developed GFR <60 ml/min per 1.73 m² with normoalbuminuria, 1968 (14.1%) had albuminuria with eGFR ≥60 ml/min per 1.73 m², and 286 (2.0%) had albuminuria with eGFR <60 ml/min per 1.73 m². The incidence of eGFR <60 ml/min per 1.73 m² increased in parallel with uric acid quintiles: Compared with the lowest quintile, RRRs were 1.46 (95% confidence interval [CI], 1.14 to 1.88; P=0.003), 1.44 (95% CI, 1.11 to 1.87; P=0.006), 1.95 (95% CI, 1.48 to 2.58; P<0.001), and 2.61 (95% CI, 1.98 to 3.42; P<0.001) for second, third, fourth, and fifth quintiles, respectively. Serum uric acid was significantly associated with albuminuria only in presence of eGFR <60 ml/min per 1.73 m².

Conclusions

Mild hyperuricemia is strongly associated with the risk of CKD in patients with type 2 diabetes.     

Hemodynamics and vasoactive substance levels during renal congestion that occurs in the anhepatic phase of liver transplantation

AIM: To explore hemodynamics and vasoactive substance levels during renal vein congestion that occurs in the anhepatic phase of liver transplantation.METHODS: New Zealand rabbits received ligation of the hepatic pedicle, supra-hepatic vena cava and infrahepatic vena cava [anhepatic phase group(APH); n = 8], the renal veins(RVL; n = 8), renal veins and hepatic pedicle [with the inferior vena cava left open)(RVHP; n = 8)], or a sham operation(SOP; n = 8). Hemodynamic parameters(systolic, diastolic, and mean arterial blood pressures) and the levels of serum bradykinin(BK) and angiotensin Ⅱ(ANGII) were measured at baseline(0 min), and 10 min, 20 min, 30 min, and 45 min after the surgery. Correlation analyses were performed to evaluate the associations between hemodynamic parameters and levels of vasoactive substances.RESULTS:All experimental groups(APH,RVL,and RVHP)showed significant decreases in hemodynamic parameters(systolic,diastolic,and mean arterial blood pressures)compared to baseline levels,as well as compared to the SOP controls(P0.05 for all).In contrast,BK levels were significantly increased compared to baseline in the APH,RVL,and RVHP groups at all time points measured(P0.05 for all),whereas no change was observed in the SOP controls.There were no significant differences among the experimental groups for any measure at any time point.Further analyses revealed that systolic,diastolic,and mean arterial blood pressures were all negatively correlated with BK levels,and positively correlated with ANGII levels in the APH,RVL,and RVHP groups(P0.05 for all).CONCLUSION:In the anhepatic phase of orthotopic liver transplantation,renal vein congestion significantly impacts hemodynamic parameters,which correlate with serum BK and ANGII levels.     

Fibroblast Growth Factor 23 and Cardiovascular Mortality after Kidney Transplantation

Background and objectives

Circulating fibroblast growth factor 23 (FGF23) is associated with adverse cardiovascular outcomes in CKD. Whether FGF23 predicts cardiovascular mortality after kidney transplantation, independent of measures of mineral metabolism and cardiovascular risk factors, is unknown.

Design, setting, participants, & measurements

The association between plasma C-terminal FGF23 and cardiovascular mortality was analyzed in a single-center prospective cohort of 593 stable kidney transplant recipients (mean age ± SD, 52±12 years; 54% male; estimated GFR, 47±16 ml/min per 1.73 m²), at a median of 6.1 (interquartile range, 2.7–11.7) years after transplantation. Multivariate Cox regression models were built, adjusting for measures of renal function and mineral metabolism; Framingham risk factors; the left ventricular wall strain markers midregional fragment of pro–A-type natriuretic peptide (MR-proANP) and N-terminal-pro brain natriuretic peptide (NT-proBNP); and copeptin, the stable C-terminal portion of the precursor of vasopressin.

Results

In multivariate linear regression analysis, MR-proANP (β=0.20, P<0.001), NT-proBNP (β=0.18, P<0.001), and copeptin (β=0.26, P<0.001) were independently associated with FGF23. During follow-up for 7.0 (interquartile range, 6.2–7.5) years, 128 patients (22%) died, of whom 66 (11%) died due to cardiovascular disease; 54 (9%) had graft failure. FGF23 was associated with an higher risk of cardiovascular mortality in a fully adjusted multivariate Cox regression model (hazard ratio [HR], 1.88 [95% confidence interval (CI), 1.11 to 3.19]; P=0.02). FGF23 was also independently associated with all-cause mortality (full model HR, 1.86 [95% CI, 1.27 to 2.73]; P=0.001). Net reclassification improved for both cardiovascular mortality (HR, 0.07 [95% CI, 0.01 to 0.14]; P<0.05) and all-cause mortality (HR, 0.11 [95% CI, 0.05 to 0.18]; P<0.001).

Conclusions

Plasma FGF23 is independently associated with cardiovascular and all-cause mortality after kidney transplantation. The association remained significant after adjustment for measures of mineral metabolism and cardiovascular risk factors.     

Identification of mineralocorticoid target sites in the isolated rabbit cortical nephron

Previous evidence suggests that the activity of the mitochondrial enzyme citrate synthase [citrate oxaloacetate-lyase (pro-3S-CH₂COO → acetyl-CoA), EC 4.1.3.7] is increased in target tissues upon acute administration of aldosterone. Therefore, an ultramicro assay was established to determine citrate synthase levels in isolated rabbit nephron segments as a means of localizing mineralocorticoid-responsive sites within the renal cortex. The relative citrate synthase activities in normal rabbit segments (per kg of dry tissue) correlated with the metabolic activity of the segments. The order was: distal convoluted tubule > proximal convoluted tubule > cortical thick ascending limb of Henle > cortical collecting duct > pars recta. When these segments were isolated from adrenalectomized rabbits, only the citrate synthase activity in the cortical collecting duct was significantly decreased compared to normal values (3.2 mol of citrate/kg dry wt per hr compared to 7.1; P < 0.001). Furthermore, enzyme activities in segments isolated from adrenalectomized rabbits 90 min after intravenous injection of aldosterone (10 μg/kg) were unchanged from normal or adrenalectomized rabbit tubule values for all segments except the cortical collecting duct. In this segment, aldosterone significantly increased citrate synthase activity compared to adrenalectomized rabbit values (8.1 mol/kg per hr compared to 3.2; P < 0.001), in contrast to the effect of dexamethasone at 10 μg/kg (4.4 mol/kg per hr compared to 3.2; P, NS). Spirolactone SC 26304 administered 30 min prior to injection of aldosterone inhibited the increase in collecting duct citrate synthase activity seen with aldosterone alone (3.4 mol/kg per hr compared to 8.1; P < 0.001). These findings suggest that the collecting duct is the primary target for aldosterone in the renal cortex.     

Predictors of survival and incidence of hepatoblastoma in the paediatric population

Objectives

This study evaluates current trends in incidence, clinical outcomes and factors predictive of survival in children with hepatoblastoma (HB).

Methods

The Surveillance, Epidemiology and End Results (SEER) database was queried for the period 1973–2009 for all patients aged <20 years with HB.

Results

A total of 606 patients were identified. The age-adjusted incidence was 0.13 patients per 100 000 in 2009. An annual percentage change of 2.18% (95% confidence interval (CI) 1.10–3.27; P < 0.05) was seen over the study period. Overall survival rates at 5, 10 and 20 years were 63%, 61% and 59%, respectively. Ten-year survival rates significantly improved in patients with resectable disease who underwent operative treatment in comparison with those with non-resectable HB (86% versus 39%; P < 0.0001). Multivariate analysis showed surgical treatment (hazard ratio (HR) = 0.23, 95% CI 0.17–0.31; P < 0.0001), Hispanic ethnicity (HR = 0.61, 95% CI 0.43–0.89; P = 0.01), local disease at presentation (HR = 0.43, 95% CI 0.29–0.63; P < 0.0001) and age < 5 years (HR = 0.63, 95% CI 0.41–0.95; P < 0.03) to be independent prognostic factors of survival.

Conclusions

The incidence of paediatric HB has increased over time. Hepatoblastoma is almost exclusively seen in children aged < 5 years. When HB presents after the age of 5 years, the prognosis is most unfavourable. Tumour extirpation markedly improves survival in paediatric patients with local disease.