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2.  Vascular Calcification: Pathophysiology and Risk Factors 
Current hypertension reports  2012;14(3):228-237.
Vascular calcification can occur in nearly all arterial beds and in both the medial and intimal layers. The initiating factors and clinical consequences depend on the underlying disease state and the location of the calcification. The best studied manifestation is coronary artery calcification, in part because of the obvious clinical consequences, but also because of CT based imaging modalities. In the general population, the presence of coronary artery calcification increases cardiovascular risk above that predicted by traditional Framingham risk factors, suggesting the presence of non-traditional risk factors. In patients with chronic kidney disease (CKD) coronary artery calcification is more prevalent and markedly more severe than in the general population. In these CKD patients, non-traditional risk factors such as oxidative stress, advanced glycation end-products and disordered mineral metabolism are also more prevalent and more severe and offer mechanistic insight into the pathogenesis of vascular calcification.
doi:10.1007/s11906-012-0265-8
PMCID: PMC3959826  PMID: 22476974
Hypertension; diabetes; vascular calcification; Chronic kidney disease (CKD); Traditional risk factors; non-traditional risk factors; inflammation; mineral metabolism; dyslipidemia; calcium; phosphorus
3.  Hemodialysis does not alter in vitro hepatic CYP3A4 and CYP2D6 metabolic activity in uremic serum 
There is a paucity of studies evaluating the change in liver metabolism in subjects receiving hemodialysis. The purpose of this study was to compare the effect of uremic toxins on hepatic cytochrome P450 (CYP)3A4 and CYP2D6 metabolism before and after a 4-hour hemodialysis session. Midazolam and dextromethorphan were incubated with uremic serum collected from subjects before and after the 4-hour hemodialysis session. Analysis and quantification of the 1′-OH-midazolam and 4-OH-midazolam and dextrorphan metabolites were performed by high-pressure liquid chromatography/mass spectrometry. Statistical analysis using the Student’s t-test (paired) was used to compare the amount of metabolite formed. The mean amount of 1′-OH-midazolam, 4-OH-midazolam, and dextrorphan metabolites formed before and after hemodialysis did not significantly differ. There was no significant difference in CYP3A4 and CYP2D6 metabolic activity in uremic serum before and after hemodialysis.
doi:10.2147/CPAA.S54381
PMCID: PMC3862653  PMID: 24353447
hemodialysis; uremia; CYP3A4; CYP2D6; metabolism
4.  Association of Hepatitis C Virus Infection With Prevalence and Development of Kidney Disease 
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.
doi:10.1053/j.ajkd.2008.03.009
PMCID: PMC2478742  PMID: 18440680
CKD; hepatitis C; proteinuria; GFR
5.  Precision of Biomarkers to Define Chronic Inflammation in CKD 
American journal of nephrology  2008;28(5):808-812.
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.
doi:10.1159/000135692
PMCID: PMC2574778  PMID: 18506106
Biomarkers, precision; Chronic inflammation; Chronic kidney disease; CKD stage 5D; Inflammatory biomarkers, intrapatient variance; Tunneled dialysis catheter
6.  Disorders Involving Calcium, Phosphorus, and Magnesium 
Primary care  2008;35(2):215-vi.
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.
doi:10.1016/j.pop.2008.01.007
PMCID: PMC2486454  PMID: 18486714
Calcium; Phosphorus; Magnesium; Parathyroid Hormone; Vitamin D
7.  Activation of Arterial Matrix Metalloproteinases Leads to Vascular Calcification in Chronic Kidney Disease 
American Journal of Nephrology  2011;34(3):211-219.
Background
The objective of the current study was to determine if altered regulation of matrix metalloproteinases (MMPs) may predispose to extracellular matrix degradation, facilitating arterial calcification in chronic kidney disease (CKD) using a progressive model of CKD-MBD, the Cy/+ rat.
Methods
Sera were collected from normal or CKD rats at various times and MMP-2 and MMP-9 levels determined by ELISA or zymography. Aorta tissue was harvested at sacrifice for RT-PCR and immunostaining. Calcification of aorta rings was assessed with MMP inhibitors.
Results
There was an increase in MMP-2, MMP-9, TIMP-1, and RUNX-2 expression in the aorta with progressive CKD, and increased MMP-2 activity in the serum. Immunostaining revealed increased expression of MMP-2 and MMP-9 in areas of aorta calcification. There was also an upregulation of MMP-2 and MMP-9 in vascular smooth muscle cells (VSMC) from CKD rats. MMP inhibitors decreased calcification of aorta rings from normal and CKD rats. High phosphorus increased MMP-2 and MMP-9 expressions in VSMC from normal rats but not from CKD rats.
Conclusion
MMP-2 and MMP-9 expression and activity are increased with progressive CKD, and blockade of MMP activity can inhibit arterial calcification. These data suggest degradation of the extracellular matrix is a critical step in the pathogenesis of arterial calcification in CKD.
doi:10.1159/000330175
PMCID: PMC3712810  PMID: 21791917
Matrix metalloproteinase; Gelatinase; Vascular calcification; Chronic kidney disease
8.  Direct Effects of Phosphate on Vascular Cell Function 
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.
doi:10.1053/j.ackd.2010.12.002
PMCID: PMC3086393  PMID: 21406295
Vascular calcification; phosphate; chronic kidney disease; smooth muscle cell; elastin degradation
9.  Hepatitis C Increases the Risk of Progression of Chronic Kidney Disease in Patients with Glomerulonephritis 
American Journal of Nephrology  2010;32(4):311-316.
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.
doi:10.1159/000319456
PMCID: PMC2969148  PMID: 20714136
Hepatitis C; Chronic kidney disease; Glomerulonephritis; Diabetic nephropathy; Dialysis; Focal segmental glomerulosclerosis
10.  A Rat Model of Chronic Kidney Disease-Mineral Bone Disorder (CKD-MBD) and The Effect of Dietary Protein Source 
Kidney international  2008;75(2):176-184.
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.
doi:10.1038/ki.2008.456
PMCID: PMC2716076  PMID: 18800026
11.  Precision of Biomarkers to Define Chronic Inflammation in CKD 
American Journal of Nephrology  2008;28(5):808-812.
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.
doi:10.1159/000135692
PMCID: PMC2574778  PMID: 18506106
Biomarkers, precision; Chronic inflammation; Chronic kidney disease; CKD stage 5D; Inflammatory biomarkers, intrapatient variance; Tunneled dialysis catheter
12.  Decreased MicroRNA Is Involved in the Vascular Remodeling Abnormalities in Chronic Kidney Disease (CKD) 
PLoS ONE  2013;8(5):e64558.
Patients with CKD have abnormal vascular remodeling that is a risk factor for cardiovascular disease. MicroRNAs (miRNAs) control mRNA expression intracellularly and are secreted into the circulation; three miRNAs (miR-125b, miR-145 and miR-155) are known to alter vascular smooth muscle cell (VSMC) proliferation and differentiation. We measured these vascular miRNAs in blood from 90 patients with CKD and found decreased circulating levels with progressive loss of eGFR by multivariate analyses. Expression of these vascular miRNAs miR-125b, miR-145, and miR-155 was decreased in the thoracic aorta in CKD rats compared to normal rats, with concordant changes in target genes of RUNX2, angiotensin II type I receptor (AT1R), and myocardin. Furthermore, the expression of miR-155 was negatively correlated with the quantity of calcification in the aorta, a process known to be preceded by vascular de-differentiation in these animals. We then examined the mechanisms of miRNA regulation in primary VSMC and found decreased expression of miR-125b, 145, and 155 in VSMC from rats with CKD compared to normal littermates but no alteration in DROSHA or DICER, indicating that the low levels of expression is not due to altered intracellular processing. Finally, overexpression of miR-155 in VSMC from CKD rats inhibited AT1R expression and decreased cellular proliferation supporting a direct effect of miR-155 on VSMC. In conclusion, we have found ex vivo and in vitro evidence for decreased expression of these vascular miRNA in CKD, suggesting that alterations in miRNAs may lead to the synthetic state of VSMC found in CKD. The decreased levels in the circulation may reflect decreased vascular release but more studies are needed to confirm this relationship.
doi:10.1371/journal.pone.0064558
PMCID: PMC3661525  PMID: 23717629
13.  Worsening Endothelial Function with Efavirenz Compared to Protease Inhibitors: A 12-Month Prospective Study 
PLoS ONE  2012;7(9):e45716.
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.
doi:10.1371/journal.pone.0045716
PMCID: PMC3447812  PMID: 23029197

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