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1.  Renoprotective effects of a selective estrogen receptor modulator, Raloxifene in an animal model of diabetic nephropathy 
American journal of nephrology  2007;27(2):120-128.
Our previous studies have shown that supplementation with 17-β estradiol (E2) from the onset of diabetes attenuates diabetic nephropathy. But, E2 is accompanied by feminizing effects as well as adverse side effects on other organs. The current study examined the renoprotective effects of a selective estrogen receptor modulator, raloxifene (RAL), in an experimental model of diabetic nephropathy. RAL activates estrogen receptors and estrogen receptor-mediated cellular events without the side effects of E2.
The study was performed in Sprague-Dawley non-diabetic (ND), streptozotocin (STZ)-induced diabetic (D) and STZ-induced diabetic+raloxifene (D+RAL) rats (n=6/group).
After 12 weeks of treatment, D was associated with increased albumin excretion (UAE; ND, 4.2±0.4; ND, 41.3±9.0 mg/day), glomerulosclerosis (GSI; ND, 0.26±0.04; D, 1.86±0.80 AU), tubulointerstitial fibrosis (TIFI; ND, 0.37±0.05; D, 2.12±0.50 AU), increased collagen type I (CI; ND, 1.31±0.07; D, 4.65±0.09 ROD), collagen type IV (CIV; ND, 0.64±0.03; D, 1.37±0.11 ROD) and transforming growth factor beta protein expression (TGF-β; ND, 0.65±0.08; D, 1.25±0.10 ROD), increased density of CD68-positive cells (CD68; ND, 1.37±3.02; D, 29.2±1.74 cells/mm2) and increased plasma levels of interleukin-6 (IL-6; ND, 14.8±5.0; D, 51.3±14.0 pg/ml). Treatment with RAL partially or fully attenuated these processes (UAE, 21.0±5.0 mg/day; GSI, 0.40±0.06 AU; TIFI, 0.20±0.04 AU; CI, 2.55±0.49 ROD; CIV, 0.70±0.09 ROD; TGF-β, 0.91±0.08 ROD; CD68, 6.03±2.38 cells/mm2; IL-6, 31.2±5.0 pg/ml).
Our data indicate that treatment with RAL attenuates albuminuria and renal structural changes associated with diabetes.
PMCID: PMC3179626  PMID: 17308373
diabetes; kidney; raloxifene; glomerulosclerosis; tubulointerstitial fibrosis
2.  Creatinine-Based Glomerular Filtration Rates and Microalbuminuria for Detecting Metabolic Abnormalities in US Adults: The National Health and Nutrition Examination Survey 2003–2004 
American Journal of Nephrology  2007;28(3):431-437.
Guidelines suggest searching for metabolic complications of chronic kidney disease when glomerular filtration rates (GFR) or urinary albumin tests are abnormal. This study aimed to quantify diagnostic test characteristics of these measures for detecting metabolic abnormalities.
Subjects were participants aged ≥20 years (n = 7,778) in the US National Health and Nutrition Examination Survey 2003–2004. Low GFR was defined as creatinine-based estimate <60 ml/min per 1.73 m2; abnormal urinary albumin-creatinine ratio as ≥20 mg/dl in men, ≥30 mg/dl in women; and metabolic abnormalities as abnormal potassium, hemoglobin, bicarbonate, phosphorus, or parathyroid hormone levels.
Of adults, 5.66% had low GFR and 8.14% abnormal urinary albumin-creatinine ratio. Overall, 15.09% had ≥ one metabolic abnormality, as did 34.07% with low GFR (p < 0.0001) and 24.27% with abnormal urinary albumin-creatinine ratio (p = 0.0021). Considered as a diagnostic test, the sensitivity, specificity, and positive and negative predictive values of low GFR for detecting ≥1 metabolic abnormality were 0.13, 0.96, 0.34, and 0.86, respectively. Corresponding values for abnormal urinary albumin-creatinine ratio were 0.13, 0.92, 0.24, and 0.86.
A policy of searching for metabolic complications in every adult with low GFR or microalbuminuria has limited diagnostic yield.
PMCID: PMC2786013  PMID: 18097135
Chronic kidney disease; Creatinine; Glomerular filtration rate; Microalbuminuria
3.  Effects of Renal Replacement Therapy on Plasma Lipoprotein(a) Levels 
American Journal of Nephrology  2007;28(3):361-365.
Patients with end-stage renal disease (ESRD) have significantly higher levels of lipoprotein(a) [Lp(a)] when compared to control populations. Elevated levels of Lp(a) may play a role in the high incidence of cardiovascular disease in ESRD. We conducted a prospective study to test the hypothesis that plasma levels of Lp(a) decline rapidly after renal transplantation proportional to the improvement in renal function, but are not affected by hemodialysis. All adults that initiated hemodialysis or received a renal transplant from our institution during a 10-month period were invited to participate in the study. Lp(a) levels were obtained immediately prior to the initiation of renal replacement therapy. In transplant recipients, repeat Lp(a) measures were done at 3 days, 5 days, 1 week, 2 weeks, 3 weeks and 4 weeks post-transplant. In hemodialysis patients, repeat Lp(a) measures were done after 3 months. We used a mixed effects model to analyze the effect of time, race and creatinine on Lp(a) after transplant. Lp(a) levels decreased rapidly after renal transplantation. Mean Lp(a) levels at 2 weeks were 35.3% lower than prior to transplantation. Each reduction of 50% in creatinine was associated with a 10.6% reduction in Lp(a) (p < 0.001). In contrast, there was no significant change in Lp(a) after initiation of hemodialysis. The rapid decrease of Lp(a) levels after renal transplantation provides support for a metabolic role of the kidney in Lp(a) catabolism and suggests that the increase in Lp(a) seen in chronic kidney disease is due to loss of functioning renal tissue.
PMCID: PMC2786011  PMID: 18057868
Renal transplantation; Cardiovascular risk factors; Clinical epidemiology; Lipoprotein(a)
4.  Kidney Volume Associations with Subclinical Renal and Cardiovascular Disease: The Diabetes Heart Study 
American Journal of Nephrology  2007;28(3):366-371.
The prognostic significance of total kidney volume (TKV) in subjects with type 2 diabetes mellitus (T2DM) is unknown.
One hundred and seventy unrelated Caucasians with T2DM underwent multidetector-row computed tomography of the neck, chest, and abdomen to measure calcified plaque in the coronary artery (CorCP), carotid artery (CarCP), and infrarenal aorta (AorCP). Spearman's rank correlation coefficients were used to assess associations between TKV and subclinical renal and cardiovascular disease. Partial correlation coefficients were computed to adjust for the potential confounding effects of age, sex, body mass index, glomerular filtration rate (GFR), diabetes duration, and hemoglobin A1c. Values are expressed as mean ± SD (median in parentheses).
The study group (51% female) had a mean age of 62.9 ± 8.5 (62.3) years, a T2DM duration of 11.5 ± 6.8 (10.0) years, a urinary albumin:creatinine ratio of 109.9 ± 396 (17.6) mg/g, a GFR of 63.8 ± 12.8 (63.2) ml/min, a TKV of 272.4 ± 69.7 (261.9) cm3, CorCP 2,170 ± 3,394 (653), CarCP 374 ± 673 (104), AorCP 14,569 ± 17,480 (8,370), and a carotid artery intima-media thickness of 0.70 ± 0.14 (0.68) mm. Adjusting for age, sex, body mass index, diabetes duration, GFR, and hemoglobin A1c, the TKV was significantly associated with AorCP (r = 0.20, p = 0.016), but not with CorCP, CarCP, or carotid artery intima-media thickness (all p ≥ 0.25). No significant associations were detected between TKV and blood pressure or albuminuria.
In Caucasians with T2DM, TKV and calcified atherosclerotic plaque in the infrarenal abdominal aorta are positively associated. Common mechanisms linking renal matrix deposition with aortic atherosclerosis may underlie this association and require further study.
PMCID: PMC2820343  PMID: 18057869
Kidney volume; Glomerular filtration rate; Diabetes mellitus; Coronary atherosclerosis; Aorta atherosclerosis; Multidetector computed tomography, calcified plaque measurements
5.  Identification of Apolipoprotein E Guangzhou (Arginine 150 Proline), a New Variant Associated with Lipoprotein Glomerulopathy 
American Journal of Nephrology  2007;28(2):347-353.
Lipoprotein glomerulopathy (LPG) is a rare disease characterized by thrombus-like substances in markedly dilated glomerular capillaries and elevated plasma levels of apolipoprotein E (apoE). Previous studies have shown that genetic disorders of apoE may contribute to the pathogenesis of LPG, but LPG may not be caused by apoE gene mutations in Chinese patients. This study investigated the association of a new variant of apoE with LPG in a Chinese family.
The apoE gene in a family with 4 LPG patients was sequenced. The polymerase chain reaction product of coding region of apoE exon 4 was cloned into pMD 18-T vector and then sequenced.
A novel point mutation in exon 4 of the apoE gene was identified in all 4 LPG patients and 1 asymptomatic family member. Sequence analysis confirmed a nucleotide G to C point mutation in exon 4 (base 308) of the apoE gene in all patients and the asymptomatic family member. This missense mutation denotes amino acid substitution of the proline residue for arginine residue at position 150 of apoE. Those patients were all heterozygotes with apoE Guangzhou. One of 2 grandsons was a heterozygous carrier of apoE Guangzhou, although he did not have proteinuria.
The results of this study suggest that apoE (arginine 150 proline) is a novel apoE variant that etiologically related to LPG. This variant (apoE Guangzhou) may cause a marked molecular conformational change of the apoE and thus impair its binding ability to lipids.
PMCID: PMC2785906  PMID: 18046082
Lipoprotein glomerulopathy; Apolipoprotein E; Nephrotic syndrome; Gene mutation
6.  Slc26a6 (PAT1) Deletion Downregulates the Apical Na+/H+ Exchanger in the Straight Segment of the Proximal Tubule 
American Journal of Nephrology  2007;28(2):330-338.
Slc26a6 (PAT1, CFEX) is a major chloride/base exchanger located on the apical membrane of the kidney proximal tubule. The purpose of the present study was to examine the effect of Slc26a6 deletion on the apical Na+/H+ exchanger 3 (NHE3) in the straight segment (S3) of the proximal tubule, which is the major site for the reabsorption of filtered chloride in the kidney.
The proximal tubule S3 segment was perfused and the intracellular pH and apical Na+/H+ exchanger activity and expression were measured.
In the proximal tubule straight segments that were microperfused in vitro, baseline intracellular pH, measured by BCPCF-AM, was 7.10 ± 0.02 in Slc26a6–/– and 7.33 ± 0.02 in Slc26a6+/+ animals, a significant reduction in Slc26a6 mutant mice (p < 0.00001). The activity of the apical Na+/H+ exchanger was 0.49 ± 0.02 pH units/min in Slc26a6+/+ and 0.26 ± 0.03 pH units/min in Slc26a6–/– animals, a significant reduction in Slc26a6–/– mice (p < 0.0001). Formate-induced intracellular alkalinization, which is mediated via NHE3, was significantly blunted in Slc26a6–/– animals, with an alkalinization magnitude of 0.16 pH unit in Slc26a6–/– versus 0.37 in Slc26a6+/+ animals (p < 0.00001, n = 5 separate animals). Angiotensin II stimulation of NHE3 activity was intact in Slc26a6–/– animals. Buffering capacity was comparable in Slc26a6+/+ and Slc26a6–/– mice. Immunoblotting and immunofluorescent labeling demonstrated comparable NHE3 abundance and distribution in kidney proximal tubules of Slc26a6+/+ and Slc26a6–/– mice.
In conclusion, Slc26a6 deletion downregulates the apical Na+/H+ exchanger activity in the straight segment of the proximal tubule. The absence of a significant renal sodium loss in Slc26a6-null mice, despite NHE3 downregulation in the in vitro perfused tubules, points to possible activation of signaling pathways that can stimulate the apical Na+/H+ exchanger in vivo.
PMCID: PMC2785905  PMID: 18046080
Chloride absorption; Bicarbonate absorption; Na+/H+ exchanger 3; SLC26A6 (PAT1, CFEX) anion exchanger
7.  Renal Function and Cardiovascular Response to Mental Stress 
American Journal of Nephrology  2007;28(2):304-310.
Cardiovascular reactivity (CVR), defined as an exaggerated hemodynamic response to mental stress, is a putative vascular risk factor and may reflect sympathetic hyperactivity. Chronic kidney disease (CKD) is also associated with sympathetic hyperactivity and vascular risk, but its relationship with CVR is unknown.
CVR was assessed in 107 individuals without overt cardiovascular disease or diabetes. Blood pressure and heart rate responses were elicited by three experimental tasks designed to evoke mental stress. Glomerular filtration rate (eGFR) was estimated using the MDRD formula. General linear models estimated the association between renal function and CVR, adjusting for potential confounders.
Mean age was 66 years and 11% had eGFR of <60 ml/min/1.73 m2. After multivariate adjustment, a low eGFR was associated with a greater stress response of systolic blood pressure, heart rate, and pulse pressure. Associations were only partially attenuated after adjustment for lipids and glucose tolerance. When considered as a continuous variable, lower eGFR was associated with a greater blood pressure response after adjustment for glycemia.
Although there were relatively few participants with CKD, these results suggest a relationship between CKD and greater CVR. Further investigation is warranted into factors that mediate this relationship and potential clinical consequences of this exaggerated response to stress in CKD.
PMCID: PMC2785907  PMID: 18025779
Renal function; Cardiovascular reactivity; Blood pressure
8.  Effects of Sevelamer and Calcium-Based Phosphate Binders on Lipid and Inflammatory Markers in Hemodialysis Patients 
American Journal of Nephrology  2007;28(2):275-279.
Cardiovascular disease accounts for almost half of all deaths in individuals with chronic kidney disease stage 5 despite advances in both dialysis treatment and cardiology. A combination of lipid-lowering and anti-inflammatory effects along with avoidance of hypercalcemia should be taken into account when choosing phosphorus binders for maintenance hemodialysis (MHD) patients.
We examined the association of sevelamer versus calcium-based phosphorus binders with lipid profile, inflammatory markers including C-reactive protein (CRP), and mineral metabolism in MHD patients who participated in the Nutritional and Inflammatory Evaluation of Dialysis Patients (NIED) study from October 2001 to July 2005.
Of the 787 MHD patients in the NIED study, 697 were on either sevelamer, a calcium-based binder, or both and eligible for this study. We compared the groups based on taking sevelamer monotherapy (n = 283) or calcium binder monotherapy (n = 266) for serum phosphate control. There were no differences between the groups on dialysis vintage. There were significant differences in age, serum calcium and phosphorus levels, as well as intact parathyroid hormone levels. Using a logistic regression models, the sevelamer group had a higher odds of serum CRP <10 mg/l [odds ratio (OR): 1.06, 95% CI: 1.02–1.11] and LDL cholesterol <70 mg/dl (OR: 1.33, 95% CI: 1.19–1.47) when compared to the calcium binder group independent of age, vintage, body mass index, statin use or other variables.
The improvements in multiple surrogate markers of inflammation and lipids in the NIED study make sevelamer a promising therapy for treatment in MHD patients with high risk of cardiovascular disease and mortality.
PMCID: PMC2785908  PMID: 17992011
End-stage renal disease; Cardiac computed tomography; Coronary calcium; Phosphate binders
9.  Mechanisms of Homocysteine-Induced Glomerular Injury and Sclerosis 
American Journal of Nephrology  2007;28(2):254-264.
Hyperhomocysteinemia (hHcys) has been recognized as a critical risk or pathogenic factor in the progression of end-stage renal disease (ESRD) and in the development of cardiovascular complications related to ESRD. Recently, evidence is accumulating that hHcys may directly act on glomerular cells to induce glomerular dysfunction and consequent glomerular sclerosis, leading to ESRD. In this review, we summarize recent findings that reveal the contribution of homocysteine as a pathogenic factor to the development of glomerular sclerosis or ESRD. In addition, we discuss several important mechanisms mediating the pathogenic action of homocysteine in the glomeruli or in the kidney, such as lo- cal oxidative stress, endoplasmic reticulum stress, homocysteinylation, and hypomethylation. Understanding these mechanisms may help design new approaches to develop therapeutic strategies for treatment of hHcys-associated end-organ damage and for prevention of deterioration of kidney function and ultimate ESRD in patients with hypertension and diabetes mellitus or even in aged people with hHcys.
PMCID: PMC2820346  PMID: 17989498
Hyperhomocysteinemia; Glomerulus; Sulfur amino acids; Oxidative stress; Mesangial cells; Podocytes; Proteinuria
10.  Location Not Quantity of Blood Pressure Measurements Predicts Mortality in Hemodialysis Patients 
American Journal of Nephrology  2007;28(2):210-217.
Blood pressure (BP) measurements obtained outside the dialysis unit are prognostically superior. Whether it is the greater number of measurements made outside the dialysis unit that correlates with prognosis or whether BPs outside dialysis units are ecologically more valid is unknown.
Methods and Results
A prospective cohort study was conducted in 133 patients on chronic hemodialysis. BP was measured by the patients at home for 1 week, over an interdialytic interval by ambulatory recording, and by ‘routine’ and standardized methods in the dialysis unit for 2 weeks. Up to 6 BPs were randomly selected from a 44-hour recording of ambulatory or 1-week recording of home BPs, such that the dialysis unit BPs were exactly matched to the number of ambulatory or home BPs. The relationship with left ventricular hypertrophy and all-cause mortality was analyzed using receiver-operating characteristic curves and Cox proportional hazards analysis, respectively. Over a median follow-up of 24 months, 46 patients (31%) died. A BP change of 10/5 mm Hg increased the risk of all-cause mortality by 1.22 (95% CI 1.07–1.38)/1.18 (95% CI 1.05–1.31) with the average of the 44-hour recording and 1.20 (95% CI 1.07–1.34)/1.15 (95% CI 1.03–1.27) when up to 6 random BPs from the same ambulatory recording were drawn and averaged. With home BPs the hazard ratios were 1.17/1.15 per 10/5 mm Hg increase in BP with the average of 1-week recording and 1.18/1.13 when up to 6 random BPs were drawn and averaged. Limited duration ambulatory BP monitoring of any 6-hour interval during the first 24 h or 4-day home BP recorded after the midweek dialysis was similarly predictive of all-cause mortality.
In patients on hemodialysis, the location, not the quantity, of the BP recordings obtained outside the dialysis unit is associated with target organ damage and mortality.
PMCID: PMC2785904  PMID: 17960059
Blood pressure, self-measured; Ambulatory blood pressure; End-stage renal disease
11.  Asymmetrical Dimethylarginine in Renal Disease: Limits of Variation or Variation Limits? 
American Journal of Nephrology  2007;28(2):224-237.
Asymmetrical dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, is increasingly recognized as a putative biomarker in cardiovascular and renal disease. Elevated plasma levels of ADMA are the consequence of increased synthesis, reduced renal clearance or reduced enzymatic degradation. Based upon the metabolic fate the highest plasma concentrations of ADMA have been reported in patients with renal failure in whom this molecule accumulates. However, the range of published ADMA levels in patients with chronic renal failure as well as in patients with end-stage renal failure undergoing maintenance hemodialysis, peritoneal dialysis or kidney transplant recipients is widely scattered and overlaps with the levels reported in healthy individuals. This wide distribution can in part be explained by different bioanalytical techniques and the lack of standardization of such assays. This review summarizes available literature on ADMA in patients with kidney disease and stresses the urgent need for a consensus regarding reference values for different analytical methods in order to appreciate the prognostic significance of elevated ADMA levels. At present, one cannot advocate this molecule for risk assessment or individual patient prognosis in the clinical work-up of patients with renal impairment.
PMCID: PMC2820345  PMID: 17960061
Asymmetrical dimethylarginine; Symmetric dimethylarginine

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