Publications

Renal failure not only alters the renal elimination, but also the non-renal disposition of drugs that are extensively metabolized by the liver. Although reduced metabolic enzyme activity in some cases can be responsible for the reduced drug clearance, alterations in the transporter systems may also be involved in the process. With the development of renal failure, the renal secretion of organic ions mediated by organic anion transporters (OATs) and organic cation transporters (OCTs) is decreased. 3-Carboxy-4-methyl-5-propyl-2-furanpropanoic acid (CMPF) and other organic anionic uremic toxins may directly inhibit the renal excretion of various drugs and endogenous organic acids by competitively inhibiting OATs. In addition, the expression of OAT1 and OCT2 was reduced in chronic renal failure (CRF) rats. Renal failure also impairs the liver uptake of drugs and organic anions, such as bromosulphophthalein (BSP), indocyanine green (ICG), and thyroxine, where organic anion transport polypeptides (OATPs) are the major transporters. Most previous studies have been done in animals or cell culture, very often in rat models, but these are presumed to reflect the presentation of advanced renal disease in humans as well. Recent studies demonstrate that the uremic toxins CMPF and indoxyl sulfate (IS) can directly inhibit rOatp2 and hOATP-C in hepatocytes. The protein content of the liver uptake transporters Oatp1, 2, and 4 were significantly decreased in CRF rats. Decreased activity of the intestinal efflux transporter, P-glycoprotein (P-gp), was also observed in CRF rats, with no significant change of protein content, suggesting that uremic toxins may suppress P-gp function. However, increased protein levels of multidrug resistance-associated protein (MRP) 2 in the kidney and MRP3 in the liver were found in CRF rats, suggesting an adaptive response that may serve as a protective mechanism. Increases in drug areas under the curve (AUCs) in subjects with advanced renal disease for drugs that are not renally excreted are consistent with uremic toxin effects on either intestinal or hepatic cell transporters, metabolizing enzymes, or both. In conclusion, alterations of drug transporters, as well as metabolic enzymes, in patients with renal failure can be responsible for reduced drug clearance.

Liver disease in patients coinfected with HIV and hepatitis C virus (HCV) has received increasing attention in recent years. Steatosis is accepted as an important contributor to liver disease in patients with HCV, but despite coinfected patients having several reasons to have steatosis, the prevalence and significance of such changes has received scant attention. We examined steatosis in an unselected cohort of coinfected patients and compared its prevalence and predictors with findings in monoinfected patients, where these relationships have been established. We studied 92 coinfected and 372 monoinfected patients undergoing staging liver biopsy. Baseline characteristics of the two groups differed significantly, pointing at different contributors to steatosis in each. Histological inflammation and fibrosis were very similar in the two groups, but steatosis was less in coinfected patients. Steatosis had a univariate association with fibrosis in both groups, but retained a multivariate association only in monoinfected patients. Other multivariate predictors of steatosis in monoinfected patients were the accepted variables of elevated body mass index, male sex, and genotype 3a infection, as well as age. In coinfected patients, however, age was the only multivariate predictor. Undetectable HIV viral load was associated with steatosis in coinfected patients in univariate analysis, but highly active antiretroviral therapy or its individual components could not be initially linked to steatosis. In conclusion, steatosis is less common in HIV/HCV coinfected patients than similar HCV monoinfected patients, and predictors of steatosis differ between the two groups.

BACKGROUND

Low bone mineral density (BMD) is common in dialysis patients. Low BMD predicts the fracture risk in the general population. Bisphosphonate therapy improves BMD and lowers the fracture risk in many populations, but has not been tested in dialysis patients because of concerns about toxicity. In this investigation, the effect of a short course of alendronate on BMD in haemodialysis (HD) patients is evaluated.

METHODS

Thirty-one healthy HD patients were randomized to placebo versus 40 mg alendronate, taken once a week for 6 weeks. Hip and lumbar spine BMD were measured by dual energy X-ray absorptiometry at baseline and at 6 months. Osteocalcin, parathyroid hormone, calcium, phosphorous and alkaline phosphatase levels were assayed at baseline and at 1, 3 and 6 months.

RESULTS

The BMD and T-scores in specific regions of the hip were stable in the treatment group and decreased in the placebo group (P=0.05). The lumbar spine density increased minimally in both groups. In the treatment group, osteocalcin levels declined significantly at 1 month (P<0.05) and remained low. The main side-effect in the alendronate group was occurrence of gastroesophageal reflux symptoms in three subjects.

CONCLUSIONS

Low-dose alendronate, administered for a limited duration, appears to be well tolerated in dialysis patients. The BMD and T-scores declined at certain hip regions in the placebo group over 6 months, while remaining stable in the treatment group, suggesting a bone-preserving effect of alendronate. Further studies of longer duration, and including examination of bone histology, are needed to assess whether bisphosphonates can be used to preserve BMD in dialysis patients.