Effects of chronic exposure to low-level cadmium on renal tubular function and CYP2A6-mediated coumarin metabolism in healthy human subjects

Relationships between cadmium (Cd) body burden, kidney function and coumarin metabolism were investigated using two groups of 197 and 200 healthy Thais with men and women in nearly equal numbers. A mean age of one group was 30.5 years and it was 39.3 years for the other group. Of 397, 20 subjects (5%) excreted urine Cd between 1.4 mug/g and 3.8 mug/g creatinine and these subjects faced 10-15% increase in the probability of having abnormal urinary excretion of N-acetyl-beta-D-glucosaminidase (NAG-uria). The prevalence of NAG-uria varied with Cd body burden in a dose-dependent manner (chi(2) = 22, P < 0.008). Also NAG-nuria was one of the three kidney effect markers tested that showed the greatest strength of correlation with urine Cd in both men and women (r = 0.48 P < 0.001). In addition, urine Cd excretion of men and women showed a positive correlation (r = 0.46 to 0.54. P < 0.001) with urine 7-hydroxycoumarin (7-OHC) excretion which was used as a marker of liver cytochrome P450 2A6 (CYP2A6) enzyme activity. Urinary CA excretion accounted for 25% of the total variation in urine 7-OHC excretion (P < 0.001). These data suggest that Cd may increase the expression of CYP2A6 in liver, resulting in enhanced coumarin metabolism in subjects with high Cd body burden. (C) 2003 Elsevier Ireland Ltd. All rights reserved.

Effect of pravastatin on cardiovascular events in people with chronic kidney disease

Background - Limited data describe the cardiovascular benefit of HMG-CoA reductase inhibitors (statins) in people with moderate chronic kidney disease (CKD). The objective of this analysis was to determine whether pravastatin reduced the incidence of cardiovascular events in people with or at high risk for coronary disease and with concomitant moderate CKD. Methods and Results - We analyzed data from the Pravastatin Pooling Project (PPP), a subject-level database combining results from 3 randomized trials of pravastatin ( 40 mg daily) versus placebo. Of 19 700 subjects, 4491 ( 22.8%) had moderate CKD, defined by an estimated glomerular filtration rate of 30 to 59.99 mL/min per 1.73 m(2) body surface area. The primary outcome was time to myocardial infarction, coronary death, or percutaneous/surgical coronary revascularization. Moderate CKD was independently associated with an increased risk of the primary outcome ( adjusted HR 1.26, 95% CI 1.07 to 1.49) compared with those with normal renal function. Among the 4491 subjects with moderate CKD, pravastatin significantly reduced the incidence of the primary outcome ( HR 0.77, 95% CI 0.68 to 0.86), similar to the effect of pravastatin on the primary outcome in subjects with normal kidney function ( HR 0.78, 95% CI 0.65 to 0.94). Pravastatin also appeared to reduce the total mortality rate in those with moderate CKD ( adjusted HR 0.86, 95% CI 0.74 to 1.00, P = 0.045). Conclusions - Pravastatin reduces cardiovascular event rates in people with or at risk for coronary disease and concomitant moderate CKD, many of whom have serum creatinine levels within the normal range. Given the high risk associated with CKD, the absolute benefit that resulted from use of pravastatin was greater than in those with normal renal function.

The influence of viral genotypes and rejection episodes on the recurrence of hepatitis C after liver transplantation

Purpose. The aim of this study was to report the influence of hepatitis C virus (HCV) genotype and rejection episodes on the outcome of orthotopic liver transplantation (OLT), hepatitis recurrence, and progression to graft cirrhosis after OLT. Methods. Fifty-three patients who all had undergone OLT for end-stage liver cirrhosis were selected for this study. Hepatitis C genotype was determined. Recurrent hepatitis and rejection were diagnosed based on elevated liver function tests and a liver biopsy. Results. The patients were followed up for a mean of 51.9 +/- 34.3 months. The cumulative survival rate was no different in OLT for hepatitis C and OLT for all other liver diseases. After OLT, serum HCV RNA was detected in 93%. Histological recurrence occurred in 85% of all patients. The 1-, 3-, and 5-year recurrence rates were 48%, 77%, and 85%, respectively. Of the 41 patients with recurrent hepatitis C, 4 (10%) had cirrhosis, 18 (44%) had hepatitis with fibrosis, and 91 (46%) had hepatitis without fibrosis at the end of follow-up. A total of 32% of the patients were infected by HCV genotype 1b and 68% by other HCV genotypes. The recurrence rates were significantly higher in patients infected with genotype 1b than in those with other genotypes (p = 0.04). Twenty of 48 patients (42%) experienced acute rejection. There was a strong association between the number of rejection episodes and the incidence of HCV-related cirrhosis (p < 0.01). Conclusion. Our findings showed the genotype 1b to result in a higher recurrence rate after OLT. On the other hand, rejection episodes were associated with a more rapid progression to graft cirrhosis.

Acceptability of short term neo-adjuvant androgen deprivation in patients with locally advanced prostate cancer

Purpose: To determine the acceptability of short term neo-adjuvant maximal androgen deprivation (MAD) to patients treated with external beam radiation for locally advanced prostate cancer. Methods: Between 1996 and 2000, 818 patients with locally advanced, but non-metastatic, prostate cancer were entered into a randomised clinical trial (TROG 96.01), which compared radiation treatment alone with the same radiation treatment and 3 or 6 months neo-adjuvant MAD with goserelin and flutamide. Relevant symptoms, and how troublesome they were to the patient, were scored using a self-assessment questionnaire. This was completed by the patient at registration, and at specified times during and after treatment. Patients taking flutamide had liver function tests checked at regular intervals. Results: All patients have completed at least 12 months follow-up after treatment. Nearly all patients completed planned treatment with goserelin, but 27% of patients in the 6-month MAD treatment arm, and 20% in the 3-month arm, had to stop flutamide early. This was mainly due to altered liver function (up to 17% patients) and bowel side effects (up to 8% patients). However, although flutamide resulted in more bowel symptoms for patients on MAD, there was significant reduction in some urinary symptoms on this treatment. Acute bowel and urinary side effects at the end of radiation treatment were similar in all treatment arms. Side effect severity was unrelated to radiation target volume size, which was reduced by MAD, but symptomatology prior to any treatment was a powerful predictor. Of the 36% of patients who were sexually active before any treatment, the majority became inactive whilst on MAD. However, sexual activity at 12 months after radiation treatment was similar in all treatment arms, indicating that the effects of short term MAD on sexual function are reversible. Conclusion: Despite temporary effects on sexual activity, and compliance difficulties with flutamide, short-term neo-adjuvant MAD was not perceived by patients to be a major inconvenience. If neo-adjuvant MAD in the way tested can be demonstrated to lead to improved biochemical control and/or survival, then patients would view these therapeutic gains as worthwhile. Compliance with short-term goserelin was excellent, confirming that LH-RH analogues have a potential role in more long-term adjuvant treatment. However, for more protracted androgen deprivation, survival advantages and deleterious effects need to be assessed in parallel, in order to determine the optimal duration of treatment. (C) 2003 Elsevier Ireland Ltd. All fights reserved.

Short-term peaks in glucose promote renal fibrogenesis independently of total glucose exposure

Postprandial hyperglycemia is implicated as a risk factor predisposing to vascular complications. This study was designed to assess recurrent short-term increases in glucose on markers of renal fibrogenesis. Human renal cortical fibroblasts were exposed to fluctuating short-term (2 h) increases to 15 mM D-glucose, three times a day over 72 h, on a background of 5 mM D-glucose. To determine whether observed changes were due to fluctuating osmolality, identical experiments were undertaken with cells exposed to L-glucose. Parallel experiments were performed in cells exposed to 5 mM D-glucose and constant exposure to either 15 or 7.5 mM D-glucose. Fluctuating D-glucose increased extracellular matrix, as measured by proline incorporation ( P < 0.05), collagen IV ( P < 0.005), and fibronectin production ( P < 0.001), in association with increased tissue inhibitor of matrix metalloproteinase (MMP) ( P < 0.05). Sustained exposure to 15 mM D-glucose increased fibronectin ( P < 0.001), in association with increased MMP-2 ( P = 0.01) and MMP-9 activity ( P < 0.05), suggestive of a protective effect on collagen matrix accumulation. Transforming growth factor-beta(1) (TGF-beta(1)) mRNA was increased after short-term (90 min) exposure to 15 mM glucose (P < 0.05) and after 24-h exposure to 7.5 mM ? ( P < 0.05). Normalization of TGF-beta(1) secretion occurred within 48 h of constant exposure to an elevated glucose. Fluctuating L-glucose also induced TGF-beta(1) mRNA and a profibrotic profile, however, to a lesser extent than observed with exposure to fluctuating D-glucose. The results suggest that exposure to fluctuating glucose concentrations increases renal interstitial fibrosis compared with stable elevations in D-glucose. The effects are, in part, due to the inherent osmotic changes.

Generalized, pruritic, ulcerating maculopapular rash necessitating cessation of sirolimus in a liver transplantation patient

The use of sirolimus as an alternative to calcineurin antagonists has enabled the continuation of immunosuppression in patients with renal impairment with preservation of kidney function. Sirolimus is generally well tolerated, with the main causes of cessation of therapy related to its effect on blood lipid profile as well as leukopenia and thrombocytopenia. We report a case of a debilitating ulcerating maculopapular rash necessitating cessation of the drug in a liver transplantation patient. A 56-year-old Caucasian liver transplantation patient presented with a diffuse, debilitating rash attributed to sirolimus use. This ultimately necessitated cessation of the immunosuppressant with subsequent resolution of her symptoms. From a review of the current literature, this is a highly unusual adverse reaction to sirolimus.

Noninvasive tests for arterial structure, function, and compliance: Do they identify risk or diagnose disease?

Background: Brachial artery reactivity (BAR), carotid intima-media thickness (IMT), and applanation tonometry for evaluation of total arterial compliance may provide information about preclinical vascular disease. We sought to determine whether these tests could be used to identify patients with coronary artery disease (CAD) without being influenced by their ability to identify those at risk ford CAD developing. Methods: We studied 100 patients and compared 3 groups: 35 patients with known CAD; 34 patients with symptoms and risk factors but no CAD identified by stress echocardiography (risk group); and 31 control subjects. BAR and IMT were measured using standard methods, and total arterial compliance was calculated by the pulse-pressure method from simultaneous radial applanation tonometry and pulsed wave Doppler of the left ventricular outflow. Ischemia was identified as a new or worsening wall-motion abnormality induced by stress. Results: In a comparison between the control subjects and patients either at risk for developing CAD or with CAD, the predictors of risk for CAD were: age (P = .01); smoking history (P = .002); hypercholesterolemia (P = .002); and hypertension (P = .004) (model R = 0.82; P = .0001). The independent predictors of CAD were: IMT (P = .001); BAR (P = .04); sex (P = .005); and hypertension (P = .005) (model R = 0.80; P = .0001). Conclusion: IMT, BAR, and traditional cardiovascular risk factors appear to identify patients at risk for CAD developing. However, only IMT was significantly different between patients at risk for developing CAD and those with overt CAD.