Background

Hepatitis C and CKD are both highly prevalent diseases in the United States. Data has demonstrated that hepatitis C may be causally linked to some glomerular diseases, and that patients who are positive for hepatitis C have increased risk for albuminuria.

Study Design

To determine if hepatitis C infection is associated with increased likelihood of CKD, we performed retrospective cross-sectional and longitudinal analyses of a large clinical database.

Setting and Participants

Data on a study population of 13,139 African American and white patients tested for hepatitis C between 1994 and 2004 was extracted from a computerized database from a clinical population of an urban hospital and affiliated clinics.

Predictor

Hepatitis C by ELISA.

Outcome

In cross-sectional analysis, CKD was defined as a minimum estimated GFR (eGFR) value < 60 ml/min/1.73 m2, using the 4 variable MDRD Study equation, or proteinuria. In longitudinal analysis, CKD was defined as eGFR < 60 ml/min/1.73 m2.

Measurements

Potential confounders investigated included sex, age, race, HIV status, chronic hypertension, diabetes, and other laboratory abnormalities.

Results

A total of 3938 patients (30.0 %) were positive for hepatitis C, and 2549 (19.4%) had CKD. Of those with CKD, 1999 (78.4%) had eGFR < 60 ml/min/1.73 m2, 186 (7.3%) had proteinuria, and 364(14.3%) had both. In cross-sectional analysis, after controlling for diabetes, hypertension, age, alanine serotransferase (AST), and HIV status, patients who tested positive for hepatitis C had a decreased risk of CKD (OR=0.69, 95% CI 0.62–0.77). A total of 7,038 subjects without CKD were followed for a median of 3.5 years. Of these, 2243 (31.8%) were hepatitis C positive at onset of follow-up. In longitudinal analysis, after adjustment for age, baseline eGFR, diabetes, hypertension, AST and HIV, the HR (95% CI) for development of CKD compared to those who were hepatitis C negative was 1.024 (0.908 1.156).

Limitations

Retrospective design, clinical database with missing values, different hepatitis C assays used over the study time period, limited data on proteinuria.

Conclusions

Our results do not support the hypothesis that infection with the hepatitis C virus per se is associated with an increased risk of having or developing CKD.

Background/Aims

Several inflammatory biomarkers have been found to be associated with cardiovascular disease or all-cause mortality in dialysis patients, but their usefulness in clinical practice or as surrogate endpoints is not certain. The purpose of the present study was to determine the intrapatient variation of C-reactive protein, IL-6, fetuin-A and albumin in a population of dialysis patients.

Methods

Apparently healthy dialysis patients with either a tunneled dialysis catheter or fistula had monthly assessments of these biomarkers for a total of four determinations, and the intraclass correlation coefficients were calculated as measures of intersubject variance.

Results

Our results showed large within-subject variation relative to the total variation in the measurements (31-46%). Having a tunneled catheter as opposed to a fistula was not significantly associated with mean levels, suggesting that chronic subclinical catheter infection does not explain the variation seen in the biomarkers. In contrast, there was a rapid change in these biomarkers with a clinically apparent acute infection.

Conclusion

These results suggest that these biomarkers have limitations for use as surrogate endpoints in clinical trials due to wide fluctuations, even in apparently clinically healthy individuals.

Abnormalities of calcium, phosphorus and magnesium homeostasis are common, and collectively are called disorders of mineral metabolism. Normal homeostatic regulation maintains serum levels, intracellular levels, and optimal mineral content in bone. This regulation occurs at three major target organs, the intestine, kidney and bone, principally via the complex integration of two hormones, parathyroid hormone and vitamin D. An understanding of normal physiology is necessary to accurately diagnose and treat disorders of mineral metabolism and will be briefly reviewed before discussing the differential diagnosis and treatment of specific disorders.

Elevated serum phosphate has clinically been associated with vascular stiffness and cardiovascular mortality. Mechanistic studies over the past decade looking at phosphate’s local effects on the vessel wall have lent insight into various pathways that culminate in vascular calcification.Smooth muscle cell phenotype change and apoptosis play prominent roles. The sodium-phosphate cotransporter PiT-1 is required for the osteochondrogenic differentiation of smooth muscle cellsin vitro. Less is known about phosphate-driven valve interstitial cell calcification and elastin degradation.In this paper, we review the current knowledge about phosphate-induced changes in the vascular wall.

Background/Aims

We have shown that hepatitis C does not increase the risk of developing chronic kidney disease (CKD), but it is not known if hepatitis C worsens progression of existing CKD.

Methods

We retrospectively identified patients with primary glomerulonephritis on biopsy over 4 years, evaluating the progression of CKD over time.

Results

The cohort consisted of 111 patients: 21% were positive for hepatitis C, 61% were negative for hepatitis C and 18% were not tested. The hepatitis C-positive subjects were more likely to be African American (p = 0.031), followed for fewer days (p = 0.007) and have diabetes and focal segmental glomerulosclerosis on biopsy (p < 0.001). Longitudinal follow-up of CKD progression using multiple creatinine measures analyzed by repeated measures ANCOVA demonstrated that patients with hepatitis C had a worsening creatinine over time compared to the hepatitis C-negative and not tested groups (p < 0.001). By Cox hazards regression analyses, risk of death/end-stage renal disease (ESRD) was decreased in patients who tested negative for hepatitis C compared to testing positive (0.46, CI 0.27–0.88), but this became nonsignificant after adjustment for mean arterial pressure and hemoglobin.

Conclusion

Our results support that infection with hepatitis C in patients with glomerulonephritis is associated with an increased risk of progression of CKD. Prospective studies are required to confirm these observations.

Chronic Kidney Disease-Mineral Bone Disorder (CKD-MBD) is a newly defined disorder that describes the interacting triad of (1) biochemical abnormalities of calcium, phosphorus, and PTH, (2) vascular calcification, and (3) abnormal bone in patients with CKD. We describe a novel animal model of slowly progressive CKD that spontaneously develops all three components of CKD-MBD while fed a normal phosphorus diet. The advantage of this model is the natural progression of the disease, allowing manipulation early in the course of CKD to better understand the pathophysiology of CKD-MBD. We further demonstrate that different sources of dietary protein, despite having similar total phosphorus contents, can have profound effects on the progression of CKD-MBD, likely due to differences in intestinal bioavailability of these phosphorus sources. Animals with early, but established, CKD fed a casein-based protein source, compared to grain-based protein source, had no differences in serum phosphorus. However, the casein protein-fed animals had increased urinary phosphorus excretion and elevated serum FGF23. Thus, this animal model will allow us to examine early changes in the course of CKD that may lead to CKD-MBD.

Background/Aims

Several inflammatory biomarkers have been found to be associated with cardiovascular disease or all-cause mortality in dialysis patients, but their usefulness in clinical practice or as surrogate endpoints is not certain. The purpose of the present study was to determine the intrapatient variation of C-reactive protein, IL-6, fetuin-A and albumin in a population of dialysis patients.

Methods

Apparently healthy dialysis patients with either a tunneled dialysis catheter or fistula had monthly assessments of these biomarkers for a total of four determinations, and the intraclass correlation coefficients were calculated as measures of intersubject variance.

Results

Our results showed large within-subject variation relative to the total variation in the measurements (31–46%). Having a tunneled catheter as opposed to a fistula was not significantly associated with mean levels, suggesting that chronic subclinical catheter infection does not explain the variation seen in the biomarkers. In contrast, there was a rapid change in these biomarkers with a clinically apparent acute infection.

Conclusion

These results suggest that these biomarkers have limitations for use as surrogate endpoints in clinical trials due to wide fluctuations, even in apparently clinically healthy individuals.

Objective

Changes in endothelial function, measured as flow-mediated dilation (FMD) of the brachial artery, has not been systematically assessed beyond 6 months of initiation of antiretroviral therapy (ART) when drug-related effects might offset initial improvements with virologic control.

Design

We assessed 6 and 12 month changes in FMD [presented as median (quartile 1, quartile 3)] and circulating HIV and cardiovascular biomarkers in 23 subjects initiating ART.

Results

There were no significant changes in FMD at 6 or 12 months overall despite significant increases in CD4 cell count and HDL-C and reductions in HIV RNA level, MCP-1, IP-10, sVCAM-1, sTNFR2, and sCD14. However, there were significant differences (P = 0.04) in the changes in FMD between those receiving efavirenz [N = 12; −3.50% (−4.90%, 0.68%)] vs. protease inhibitors at 12 months [N = 11; 1.50% (−0.86%, 4.56%)]. The differences in changes in FMD between those receiving and not receiving emtricitabine/tenofovir/efavirenz were more pronounced and were significantly different at both 6 and 12 months (P<0.02 for both). Additional studies showed no significant differences in changes in 25-(OH)-vitamin D, PTH, FGF-23, of F2-isoprostane levels between efavirenz and PI use or between those receiving and not receiving emtricitabine/tenofovir/efavirenz.

Conclusion

Efavirenz use was associated with reduced FMD at 12 months compared to PI-based regimens while emtricitabine/tenofovir/efavirenz was associated with reduced FMD at both 6 and 12 months compared to those not receiving this combination. Long-term effects of antiretrovirals on endothelial function may play an important role in the risk of cardiovascular disease in HIV-infected patients.