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1.  Iron Sucrose Promotes Endothelial Injury and Dysfunction and Monocyte Adhesion/Infiltration 
American Journal of Nephrology  2011;35(2):114-119.
Intravenous (IV) iron preparations are widely used in the management of anemia in ESRD populations. Recent changes in reimbursement policy have dramatically increased the use of IV iron to lower the use of costly erythropoiesis-stimulating agents. These preparations are frequently administered with insufficient attention to the total body iron stores or presence of inflammation which is aggravated by excess iron. Endothelial injury and dysfunction are critical steps in atherosclerosis, thrombosis and cardiovascular disease. IV iron preparations raise plasma non-transferrin-bound iron which can promote oxidative stress, endothelial damage and dysfunction. We explored the effect of an IV iron preparation on endothelial cells, monocytes and isolated arteries.
Primary cultures of human aortic endothelial cells (HAEC) were treated with pharmacologically relevant concentrations of iron sucrose (10–100 μg/ml) for 4–24 h. Endothelial cell morphology, viability, and monocyte adhesion were tested. Endothelial function was assessed by measuring the vasorelaxation response to acetylcholine in normal rat thoracic aorta rings preincubated with iron sucrose (200 μg/ml).
In contrast to the control HAEC which showed normal cobblestone appearance, cells treated with iron sucrose (50–100 μg/ml) for 4 h showed loss of normal morphological characteristics, cellular fragmentation, shrinkage, detachment, monolayer disruption and nuclear condensation/fragmentation features signifying apoptosis. HAEC exposure to iron sucrose (10–100 μg/ml) increased monocyte adhesion 5- to 25-fold. Incubation in media containing 200 μg/ml iron sucrose for 3 h caused marked reduction in the acetylcholine-mediated relaxation in phenylephrine-precontracted rat aorta.
Pharmacologically relevant concentration of iron sucrose results in endothelial injury and dysfunction and marked increase in monocyte adhesion.
PMCID: PMC3265804  PMID: 22212390
Iron sucrose; Endothelial function; Atherosclerosis; End-stage renal disease; Cardiovascular disease; Oxidative stress
2.  Increased Presence of Cognitive Impairment in Hemodialysis Patients in the Absence of Neurological Events 
American Journal of Nephrology  2011;35(2):120-126.
Cognitive impairment (CI) is highly prevalent among hemodialysis (HD) patients and is associated with increased morbidity and mortality. The aim was to compare cognitive function in HD patients with no history of stroke or dementia and well-matched controls. Studies are required to determine the impact of HD and chronic kidney disease-specific risks on CI.
76 outpatients (50 receiving outpatient HD and 26 with normal kidney function matched for age and comorbidity) underwent a cross-sectional observational study. HD patients were well dialyzed and had optimal hemoglobin levels. A battery of eight neuropsychological tests was used. Outcomes included assessment scores of neurocognitive testing and prevalence and subtype of CI.
Compared to controls, HD subjects had significantly lower composite scores for each tested cognitive domain. In each domain except memory, the percentage of subjects with impairment was significantly higher in HD subjects than controls. Differences between the groups were independent of vascular and dementia risk factors. 82% of HD subjects met criteria for CI versus 50% of controls. Non-amnestic subtype of CI was more prevalent in both groups.
Well-dialyzed HD patients with optimized hemoglobin levels and with no history of stroke or dementia performed significantly worse on multiple measures of cognition compared to controls. A higher prevalence of non-memory impairment may suggest an underlying vascular versus neurodegenerative mechanism. HD and chronic kidney disease-specific risk factors may contribute to early CI not readily detected by routine screening methods.
PMCID: PMC3711004  PMID: 22212437
Cognitive impairment; Chronic kidney disease; Hemodialysis
3.  Pretransplant Physical Activity Predicts All-Cause Mortality in Kidney Transplant Recipients 
American Journal of Nephrology  2011;35(1):17-23.
Low physical activity (PA) has been associated with higher rates of cardiovascular disease (CVD) and mortality in the general population. Despite the benefits of kidney transplantation, kidney transplant recipients (KTRs) remain at elevated risk for CVD and mortality compared to individuals without kidney disease.
A prospective cohort of 507 adult KTRs from three academic centers completed the Physical Activity Scale for the Elderly (PASE) at transplantation. PASE scores were divided into tertiles.
PA was lower with older age, history of CVD, smoking, and diabetes. During the median 8-year follow-up period, 128 individuals died, among whom 101 had a functioning allograft. In multivariable Cox regression for all-cause mortality, greater PA was strongly associated with better survival (HR: 0.52 for most active vs. inactive tertiles, 95% CI: 0.31–0.87, p = 0.01). Secondary analyses, in which (1) death with a functioning graft was the primary outcome, and (2) PASE scores were converted to the metabolic equivalent of task, revealed similar results. We did not find an association between change of PA after transplantation and mortality.
PA at the time of kidney transplantation is a strong predictor of all-cause mortality and death with graft function. Evaluation of PA level among kidney transplant candidates may be a useful method to risk-stratify patients for survival after kidney transplantation. Kidney transplant candidates and recipients should also be encouraged to be physically active.
PMCID: PMC3251242  PMID: 22156548
Kidney transplantation; Mortality; Physical activity
4.  Arginine and Asymmetric Dimethylarginine in Puromycin Aminonucleoside-Induced Chronic Kidney Disease in the Rat 
American Journal of Nephrology  2011;35(1):40-48.
Reduced renal L-arginine (L-Arg) synthesis/transport, induction of arginases and increased endogenous NOS inhibitor, asymmetric dimethylarginine (ADMA) will inhibit NO production. This study investigated pathways of L-Arg synthesis/uptake/utilization, ADMA degradation and oxidant/antioxidants in puromycin aminonucleoside (PAN) chronic kidney disease (CKD).
Rats were given low- (LD) or high-dose (HD) PAN and followed for 11 weeks for proteinuria. BP was measured and blood and tissues were harvested and analyzed for abundance of argininosuccinate synthase (ASS) and lyase (ASL), arginase, cationic amino acid transporter (CAT1) and dimethylargininedimethylaminohydrolase (DDAH) in kidney, cortex, aorta and liver. Arginase and DDAH activity, plasma L-Arg and ADMA, renal pathology and creatinine clearances were also measured.
PAN caused dose-dependent kidney damage and hypertension and creatinine clearance fell in HD-PAN. Renal ASS fell in HD-PAN, renal cortex and aortic ASL and membrane CAT1 fell in both PAN groups. There was no activation of renal arginase, but aortic arginase increased in LD-PAN. Renal DDAH activity fell moderately in LD-PAN and markedly in HD-PAN where hepatic DDAH activity also fell. Plasma L-Arg was unchanged while ADMA rose moderately and dose-dependently with PAN. There were several indices of oxidative stress which was most prominent in HD-PAN.
Reduction in renal ASS/ASL and loss of renal cortex CAT1 compromises renal L-Arg synthesis and release. Loss of aortic CAT1 impairs L-Arg uptake. Increased plasma ADMA was associated with progressive loss of renal DDAH activity. However, loss of renal clearance and falls in hepatic DDAH activity in HD-PAN did not have additive effects on plasma ADMA.
PMCID: PMC3251243  PMID: 22179117
Argininosuccinate synthase; Argininosuccinate lyase; Arginase; Cationic amino acid transporter, CAT1; Dimethylarginine dimethylaminohydrolase, DDAH; Hypertension; Proteinuria; Creatinine clearance; Nitric oxide
5.  Cognitive Function and the Risk of Death in Chronic Kidney Disease 
American Journal of Nephrology  2011;35(1):49-57.
Background and Aims
Cognitive impairment is a risk factor for death in dialysis patients and the general population. We sought to determine if cognitive impairment is associated with death in people with non-dialysis-dependent chronic kidney disease (CKD), and if so, whether this relationship is greater in the CKD population compared to the general population.
National Health and Nutrition Examination Survey-III participants older than 60 years were asked to subtract 3 from 20 five times and to perform immediate and delayed recall of three items. A cognitive score of 0–11 was assigned based on the number of correct responses. Participants were categorized according to cognitive score (11, 9–10, 6–9, and 0–5) and CKD status. Survival analyses were conducted using Cox models.
Within the CKD subpopulation, those in the lowest cognitive score group had a twofold increased hazard of death compared to those with maximum score. Within the non-CKD subpopulation, those in the lowest cognitive score group had a 46% increased hazard of death compared to those with maximum score. However, the difference in the hazards of death in the CKD and non-CKD subpopulations with the lowest cognitive score was not significant (p = 0.99).
Low cognitive score is associated with an increased risk of death in elderly individuals with and without CKD; however, there was no interaction of CKD and low cognitive score in this analysis.
PMCID: PMC3254030  PMID: 22189005
Cognitive function; Cognitive score; Chronic kidney disease; Mortality
6.  Living Donor Kidney Donation: Another Form of White Coat Effect 
American Journal of Nephrology  2011;35(1):75-79.
Living donor nephrectomy can be associated with increases in blood pressure several years following the procedure, but the best method to assess blood pressure during the living donor evaluation process is unclear.
Living kidney donors underwent casual clinic and ambulatory blood pressure monitoring (ABPM) and measurement of central aortic pressures at baseline and 6 months following donor nephrectomy.
There was a significant decline in clinic systolic blood pressure (SBP; p = 0.001) and central aortic systolic pressure (p = 0.011) during the study period. However, average ABPM was unchanged and other measures of central arterial pressures and Augmentation Index were unchanged at 6 months compared to baseline.
The remarkable differences between clinic SBP and ambulatory SBP prior to donation, and the disappearance of these differences 6 months later, suggest a substantial white coat effect on SBP associated with living kidney donor evaluation. Also, ABPM represents a better way to assess blood pressure prior to kidney donation.
PMCID: PMC3254031  PMID: 22189100
Ambulatory blood pressure monitoring; Blood pressure; Living donors; Hemodynamics; Transplantation
7.  Mineralocorticoid Receptor-Dependent Proximal Tubule Injury Is Mediated by a Redox-Sensitive mTOR/S6K1 Pathway 
American Journal of Nephrology  2011;35(1):90-100.
The mammalian target of rapamycin (mTOR) is a serine kinase that regulates phosphorylation (p) of its target ribosomal S6 kinase (S6K1), whose activation can lead to glomerular and proximal tubular cell (PTC) injury and associated proteinuria. Increased mTOR/S6K1 signaling regulates signaling pathways that target fibrosis through adherens junctions. Recent data indicate aldosterone signaling through the mineralocorticoid receptor (MR) can activate the mTOR pathway. Further, antagonism of the MR has beneficial effects on proteinuria that occur independent of hemodynamics.
Accordingly, hypertensive transgenic TG(mRen2)27 (Ren2) rats, with elevated serum aldosterone and proteinuria, and age-matched Sprague-Dawley rats were treated with either a low dose (1 mg/kg/day) or a conventional dose (30 mg/kg/day) of spironolactone (MR antagonist) or placebo for 3 weeks.
Ren2 rats displayed increases in urine levels of the PTC brush border lysosomal enzyme N-acetyl-β-aminoglycosidase (β-NAG) in conjunction with reductions in PTC megalin, the apical membrane adherens protein T-cadherin and basolateral α-(E)-catenin, and fibrosis. In concert with these abnormalities, Ren2 renal cortical tissue also displayed increased Ser2448 (p)/activation of mTOR and Thr389 (p)-S6K1 and increased 3-nitrotyrosine (3-NT) content, a marker for peroxynitrite. Low-dose spironolactone had no effect on blood pressure but decreased proteinuria and β-NAG comparable to a conventional dose of this MR antagonist. Both doses of spironolactone attenuated ultrastructural maladaptive alterations and led to comparable reductions in (p)-mTOR/(p)-S6K1, 3-NT, fibrosis, and increased expression of α-(E)-catenin, T- and N-cadherin.
Thereby, MR antagonism improves proximal tubule integrity by targeting mTOR/S6K1 signaling and redox status independent of changes in blood pressure.
PMCID: PMC3316484  PMID: 22205374
Cadherin; Megalin; β-NAG; Proteinuria
8.  Kidney Function Decline in the Elderly: Impact of Lipoprotein-Associated Phospholipase A2 
American Journal of Nephrology  2011;34(6):512-518.
Background: Whether lipoprotein-associated phospholipase A2 (Lp-PLA2) levels are associated with kidney function decline has not been well studied. Methods: We investigated associations of Lp-PLA2 antigen and activity with kidney function decline and rapid decline over 5.7 years in the Cardiovascular Health Study (n = 4,359). We estimated kidney function by cystatin C (eGFRcys) in repeated measures, and defined rapid decline as ≥3 ml/min/1.73 m2 per year. We stratified by baseline preserved GFR (≥60 ml/min/1.73 m2). Results: Mean age was 72 ± 5 years. Average eGFRcys decline was −1.79 ml/min/1.73 m2 (SD = 2.60) per year. Among persons with preserved GFR, compared to the lowest quartile of Lp-PLA2 antigen, eGFRcys decline was faster among persons in the second, β −0.31 (95% CI −0.52, −0.10), third −0.19 (–0.41, 0.02) and fourth quartiles −0.26 (–0.48, −0.04) after full adjustment. Persons in the highest quartile of Lp-PLA2 antigen had increased odds of rapid decline 1.34 (1.03, 1.75), compared to the lowest. There was no significant association between levels of Lp-PLA2 activity and eGFRcys decline or rapid decline. Associations were not statistically significant among persons with low eGFR (<60 ml/min/1.73 m2) at baseline. Conclusion: Higher levels of Lp-PLA2 antigen but not activity were significantly associated with faster rates of kidney function decline. These findings may suggest a novel vascular pathway for kidney disease progression.
PMCID: PMC3225232  PMID: 22056971
Chronic kidney disease; Elderly; Estimated GFR; Kidney decline; Lipoprotein-associated phospholipase A2
9.  Natural Recovery from Antiglomerular Basement Membrane Glomerulonephritis Is Associated with Glomeruli-Infiltrating CD8α+CD11c+MHC Class II+ Cells 
American Journal of Nephrology  2011;34(6):519-528.
Background/Aims: In an antiglomerular basement membrane glomerulonephritis (GN) model, GN-resistant Lewis (LEW) rats naturally recover from early glomerular inflammation (days 21–23). We have previously identified a glomeruli-infiltrating CD8α+CD11highMHC II+ cell (GIL CD8α+ cell) in GN-prone Wistar Kyoto (WKY) rats, which terminates glomerular inflammation through inducing T cell apoptosis prior to glomerular fibrosis at days 35–40. We investigated if GIL CD8α+ cells were also associated with the recovery in LEW rats. Methods: GIL CD8α+ cells in LEW rats were characterized; their infiltration was observed in connection with T cell apoptosis in glomeruli. Results: An influx of GIL CD8α+ cells into inflamed glomeruli was confirmed in the immunized LEW rats at days 17–22, which was much earlier than days 28–35 in WKY rats. Notably, LEW rats had a GIL CD8α+CD11high subpopulation after day 17, while WKY rats lacked this population until after day 30. Analyses further revealed a large number of clustered apoptotic CD4+ or CD3+ T cells in the glomeruli during recovery (day 23) in LEW rats, as compared to day 35 (transition to fibrosis) in WKY rats. Thus, infiltration of GIL CD8α+ cells coincided with decline of glomerular inflammation and T cell apoptosis during recovery in LEW rats. Isolated GIL CD8α+ cells were able to infiltrate glomeruli in both WKY and LEW rats at day 20. Conclusion: Our data revealed a strong association between GIL CD8a+ cells and recovery from early glomerular inflammation. It raises a possibility of involvement of GIL CD8a+ cells in the recovery.
PMCID: PMC3237105  PMID: 22068125
Glomerulonephritis; Immunosuppression; Animal models; Apoptosis
10.  Poor Outcomes in Elderly Kidney Transplant Recipients Receiving Alemtuzumab Induction 
American Journal of Nephrology  2011;34(6):534-541.
Alemtuzumab and rabbit antithymocyte globulin (rATG) are being used with increasing frequency as induction agents in kidney transplantation. Using the US Renal Data Base System, we analyzed the safety profile of these agents in the elderly.
In a cohort of patients transplanted from January 2000 to July 2009 and followed through 2009, we assessed the effect of induction on allograft loss and death among elderly recipients. Recipients were censored at dates of allograft loss, death or the end of study. Independent associations between induction agents and allograft loss or death were examined using multivariate analysis with forward stepwise Cox regression.
Among 130,402 patients with first transplants, 14,907 were age 65 years or older. 4,466 (30%), 3,049 (20.5%), 1,501 (10.1%), and 999 (6.7%) were induced with thymoglobulin, basiliximab, daclizumab, and alemtuzumab, respectively. After adjusting for baseline differences, induction with alemtuzumab was associated with an increased risk of graft loss and death, with an adjusted hazard ratio (AHR) of 1.26 (95% CI 1.08–1.48). Risk was also present at other age cutoffs [age >60 (AHR 1.16; 95% CI 1.03–1.31; p = 0.014), age >70 (AHR 1.43; 95% CI 1.13–1.81; p = 0.003) and age >75 (AHR 1.68; 95% CI 1.07–2.63; p = 0.024)].
In the elderly, alemtuzumab is associated with an escalating risk of death and graft loss in recipients of kidney transplantations.
PMCID: PMC3237278  PMID: 22104284
Alemtuzumab; Kidney transplantation; Elderly recipients; Induction agents, complications; Kidney transplants, outcomes
11.  Use of Diffusion Tensor MRI to Identify Early Changes in Diabetic Nephropathy 
American Journal of Nephrology  2011;34(5):476-482.
Currently available clinical indicators of kidney disease lack the sensitivity and/or specificity to identify early-stage diabetic nephropathy (DN). Quantitative diffusion magnetic resonance imaging (MRI), specifically diffusion tensor imaging (DTI), has been used to quantify pathophysiologic changes in other organs but has not been well studied in kidney diseases, including DN. The goal of this pilot study was to examine differences in kidney DTI parameters in diabetic subjects versus healthy controls.
16 diabetic and 5 healthy control subjects were recruited for this institutional review board-approved/Health Insurance Portability and Accountability Act-compliant study. Kidneys were scanned using DTI to generate apparent diffusion coefficient (ADC) and fractional anisotropy (FA) data. Mean cortical and medullary ADC and FA values were calculated by selecting multiple regions of interest. Diabetics were stratified by estimated glomerular filtration rate (eGFR) into 2 groups: eGFR ≥60 (n = 10) and eGFR <60 (n = 6) ml/min/1.73 m2. Mean diffusion parameters and eGFRs were compared between these groups of diabetic subjects and healthy controls.
Medullary FA, ADC and cortical ADC values were significantly lower in diabetics with eGFR <60 compared to controls. Notably, both mean medullary FA and ADC were significantly lower in diabetics with eGFR ≥60 compared to controls (p = 0.001 and p = 0.042, respectively). For the study subjects in aggregate, medullary FA correlated significantly with eGFR (R = 0.69, p < 0.01); the other diffusion parameters showed no significant correlations.
This pilot study suggests that changes in medullary DTI assessments may serve as indicators of early DN. Further studies are needed to determine if these findings could serve as biomarkers to identify diabetics at risk of DN progression.
PMCID: PMC3214881  PMID: 22024476
Diabetic nephropathy; Chronic kidney disease; Magnetic resonance imaging; Diffusion parameters; Diffusion tensor imaging
12.  Amelioration of Albuminuria in ROCK1 Knockout Mice with Streptozotocin-Induced Diabetic Kidney Disease 
American Journal of Nephrology  2011;34(5):468-475.
Although blockade of Rho kinase with pharmacologic inhibitors ameliorates renal fibrosis and diabetic kidney disease (DKD), the underlined mechanisms remain largely unclear. The present study tested the hypothesis that ROCK1 may regulate the early development of albuminuria via the megalin/cubilin-dependent mechanism.
A DKD model was induced in ROCK1 knockout and wild-type mice by streptozotocin (STZ). The effect of deleted ROCK1 on urinary albumin excretion and the expression of megalin/cubilin were examined. In addition, the effect of blocking ROCK activities with an inhibitor (Y-27632) on tubular albumin reabsorption was tested in a normal rat tubular epithelial cell line (NRK52E) under high-glucose conditions. Expression of transforming growth factor (TGF)-β1, interleukin-1β and collagen-1 was also been examined.
Urinary albumin excretion was significantly increased in ROCK1 WT mice at 8 weeks after STZ injection. In contrast, mice lacking ROCK1 gene were protected against the development of albuminuria. This was associated with the protection against the loss of megalin/cubilin and an increase in TGF-β1, IL-1β, and fibrosis in the kidney. In vitro, we also found that blockade of Rho kinase with inhibitor Y-27632 prevented high-glucose-induced loss of megalin expression and an increase of TGF-β1, thereby increasing the absorption rate of FITC-labeled albumin by tubular epithelial cells.
ROCK1 may play a role in the development of albuminuria in DKD by downregulating the endocytosis receptors complex – megalin/cubilin.
Copyright © 2011 S. Karger AG, Basel
PMCID: PMC3691875  PMID: 21986457
Diabetic kidney disease; Tubular cells, albuminuria; ROCK; Megalin; Cubilin
13.  Trefoil Factor 3 Predicts Incident Chronic Kidney Disease: A Case-Control Study Nested within the Atherosclerosis Risk in Communities (ARIC) Study 
American Journal of Nephrology  2011;34(4):291-297.
Early detection of individuals at high risk for chronic kidney disease (CKD) may aid prevention. Urinary levels of trefoil factor 3 (TFF3) are associated with acute kidney injury in animal models, but the association of TFF3 levels with incident CKD in humans is unknown.
We conducted a case-control study nested within the Atherosclerosis Risk in Communities (ARIC) Study and the ARIC Carotid MRI Study to determine whether urinary TFF3 levels predict incident CKD over 8.6 years of follow-up. A total of 143 participants with incident CKD (eGFR decreasing by ≥25% to <60 ml/min/1.73 m2) were matched on age, sex and race to 143 non-cases.
Higher TFF3 levels at baseline were strongly associated with Black race, diabetes (both p = 0.002), and antihypertensive medication use (p = 0.02). Compared to participants with TFF3 levels in the lowest quartile, the odds ratio (OR) of incident CKD was 1.84 (95% confidence interval (CI): 0.80, 4.22) for individuals with TFF3 levels in the second quartile, 2.43 (95% CI: 1.06, 5.53) for the third quartile, and 2.77 (95% CI: 1.22, 6.28) for the fourth quartile (p trend = 0.02). Adjustment for covariates, including urinary albumin: creatinine ratio, did not markedly change the associations. Twofold higher TFF3 levels were strongly associated with incident CKD after adjustment for CKD risk factors (adjusted OR = 1.35; 95% CI: 1.11, 1.64).
Higher urinary TFF3 levels may indicate ongoing repair of damage in the kidney. Additional studies are needed to confirm whether TFF3 can be useful as a marker of increased risk for CKD.
PMCID: PMC3169359  PMID: 21829008
Kidney disease; Tubulointerstitual disease; Biomarkers
14.  Chronic Kidney Disease and Risk of Death from Infection 
American Journal of Nephrology  2011;34(4):330-336.
Infection, bacteremia and sepsis are major sources of morbidity and mortality in patients with end-stage renal disease. This study sought to determine the association between predialysis chronic kidney disease (CKD) and infection-related mortality.
We analyzed participants in the Third National Health and Nutrition Examination Survey (NHANES III). The study included adults ≥45- years-old without end-stage renal disease. Estimated glomerular filtration rate (eGFR) was categorized as ≥60, 45–59.9 and <45 ml/min per 1.73 m2, and urinary albumin-to-creatinine ratio (ACR) as <30, 30–299.9 and ≥300 mg/g. The study identified infection-related mortality, including septicemia, respiratory, abdominal and gastrointestinal, cardiac, kidney and genitourinary, neurologic, and other infections over a median of 13 years using the National Death Index.
Of 7,400 participants included in the study, 206 died from infections. Compared to individuals with eGFR ≥60 ml/min per 1.73 m2, infection-related mortality was higher for those with lower eGFR [adjusted HR = 1.36 (95% CI: 0.81, 2.30) and 2.36 (1.04, 5.38) for eGFR of 45–59.9 and <45 ml/min per 1.73 m2, respectively; p trend = 0.06]. Compared to individuals with ACR <30 mg/g, infection-related mortality was higher for ACR levels of 30–299 and ≥300 mg/g [adjusted HR = 1.68 (95% CI: 0.97, 2.92) and 2.84 (0.92, 8.74), p trend = 0.02].
Reduced eGFR and albuminuria are associated with increased risk for infection-related mortality. Efforts are needed to reduce its incidence and mitigate the effects of infections among individuals with CKD.
PMCID: PMC3169360  PMID: 21860228
Chronic kidney disease; Infection; Sepsis; Mortality
15.  Advanced Glycation Urinary Protein-Bound Biomarkers and Severity of Diabetic Nephropathy in Man 
American Journal of Nephrology  2011;34(4):347-355.
The formation of advanced glycation end products (AGEs) is accelerated in patients with diabetic nephropathy. The aim of this study was to ascertain if the urinary excretion of proteins modified by advanced glycation can be used as biomarkers for albuminuria in individuals with type 1 or type 2 diabetes.
Community-based patients with type 1 (n = 68) or type 2 diabetes (n = 216) attending a diabetes clinic of a tertiary referral hospital were classified as having normoalbuminuria (Normo, albumin excretion rate (AER) <20 μg/min), microalbuminuria (Micro, AER 20–200 μg/min) or macroalbuminuria (Macro, AER ≥200 μg/min). Serum and urine AGE-modified proteins were measured.
In patients with both type 1 diabetes and type 2 diabetes, there was a clear association between the degree of albuminuria and urinary AGE-modified proteins (p < 0.0001). Exclusive to patients with type 1 diabetes, urinary excretion of the AGE carboxymethyllysine correlated with AER, whereas patients with type 2 diabetes and macroalbuminuria had an increase in urinary methylglyoxal, an AGE intermediate. These changes were independent of isotopic glomerular filtration rate levels. Serum concentrations of AGEs or soluble receptor for AGEs were not consistently associated with albuminuria in either type 1 or type 2 diabetes.
Urinary excretion of proteins modified by AGEs may be useful biomarkers of albuminuria in individuals with type 1 and type 2 diabetes, warranting prospective investigation in larger diabetic cohorts.
PMCID: PMC3182043  PMID: 21876347
Advanced glycation end products; Diabetic nephropathy; Albuminuria; Carboxymethyllysine; Methylglyoxal; Urinary biomarkers
16.  Epidemiology of Interdialytic Ambulatory Hypertension and the Role of Volume Excess 
American Journal of Nephrology  2011;34(4):381-390.
The epidemiology of hypertension among hemodialysis (HD) patients is difficult to describe accurately because of difficulties in the assessment of blood pressure (BP).
Using 44-hour interdialytic ambulatory BP measurements, we describe the epidemiology of hypertension in a cohort of 369 patients. To seek correlates of hypertension control, antihypertensive agents were withdrawn among patients with controlled hypertension and ambulatory BP monitoring was repeated.
Hypertension (defined as an average ambulatory systolic BP ≥135 mm Hg or diastolic BP ≥85 mm Hg, or the use of antihypertensive medications) was prevalent in 82% of the patients and independently associated with epoetin use, lower body mass index and fewer years on dialysis. Although 89% of the patients were being treated, hypertension was controlled adequately in only 38%. Poor control was independently associated with greater antihypertensive drug use. Inferior vena cava (IVC) diameter in expiration was associated with increased risk of poorly controlled hypertension both in cross-sectional analysis and after withdrawal of antihypertensive drugs.
Interdialytic hypertension is highly prevalent and difficult to control among HD patients. End-expiration IVC diameter is associated with poor control of hypertension in cross-sectional analyses as well as after washout of antihypertensive drugs. Among HD patients, an attractive target for improving hypertension control appears to be the reduction of extracellular fluid volume.
PMCID: PMC3182044  PMID: 21893975
Ambulatory blood pressure monitoring; Epidemiology; Epoetin; Hemodialysis; Hypertension; Vitamin D receptor activators
17.  Glomerular Expression of Kidney Injury Molecule-1 and Podocytopenia in Diabetic Glomerulopathy 
American Journal of Nephrology  2011;34(3):268-280.
Studies have shown that kidney injury molecule-1 (KIM-1) is upregulated in damaged renal proximal tubules. In this study, we examined KIM-1 expression in glomerular epithelial cells in diabetic glomerulopathy.
Renal histology, immunostaining and Western blot for protein level, and real-time PCR for mRNA expression of KIM-1 and podocyte markers were evaluated in untreated or losartan-treated Zucker lean (Fa/+) and Zucker diabetic fatty (Fa/Fa) rats.
The diabetic rats showed an increased glomerular expression of KIM-1. KIM-1 staining was localized primarily in the hyperplastic parietal epithelium of Bowman's capsule in the early stages of diabetes with subsequent increase in KIM-1-positive cells in the glomerular tuft in the more advanced stages. The increase in glomerular KIM-1 was associated with a decrease in podocytes in Fa/Fa rats. Antiproteinuric treatment with losartan attenuated podocytopenia and decreased renal expression of KIM-1 in treated diabetic rats. In an in vitro study, albumin overload increased KIM-1 protein in the primary cultures of rat glomerular epithelial cells.
These results show that glomerular KIM-1 expression was increased, in proportion to the extent of proteinuria and podocytopenia in the diabetic animals, supporting that KIM-1 could be used as a potential biomarker for glomerular injury in proteinuric kidney disease.
PMCID: PMC3169370  PMID: 21822010
Albuminuria; Kidney injury molecule-1; Parietal epithelial cells; Podocytes; Glomerulopathy
18.  Activation of Arterial Matrix Metalloproteinases Leads to Vascular Calcification in Chronic Kidney Disease 
American Journal of Nephrology  2011;34(3):211-219.
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.
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.
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.
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.
PMCID: PMC3712810  PMID: 21791917
Matrix metalloproteinase; Gelatinase; Vascular calcification; Chronic kidney disease
19.  Angiotensin II Activation of mTOR Results in Tubulointerstitial Fibrosis through Loss of N-Cadherin 
American Journal of Nephrology  2011;34(2):115-125.
Angiotensin (Ang) II contributes to tubulointerstitial fibrosis. Recent data highlight mammalian target of rapamycin (mTOR)/S6 kinase 1 (S6K1) signaling in tubulointerstitial fibrosis; however, the mechanisms remain unclear. Thereby, we investigated the role of Ang II on mTOR/S6K1-dependent proximal tubule (PT) injury, remodeling, and fibrosis.
We utilized young transgenic Ren2 rats (R2-T) and Sprague-Dawley rats (SD-T) treated with the Ang type 1 receptor (AT1R) blocker telmisartan (2 mg · kg−1 · day−1) or vehicle (R2-C; SD-C) for 3 weeks to examine PT structure and function.
Ren2 rats displayed increased systolic blood pressure, proteinuria and increased PT oxidant stress and remodeling. There were parallel increases in kidney injury molecule-1 and reductions in neprilysin and megalin with associated ultrastructural findings of decreased clathrin-coated pits, endosomes, and vacuoles. Ren2 rats displayed increased Serine2448 phosphorylation of mTOR and downstream S6K1, in concert with ultrastructural basement membrane thickening, tubulointerstitial fibrosis and loss of the adhesion molecule N-cadherin. Telmisartan treatment attenuated proteinuria as well as the biochemical and tubulointerstitial structural abnormalities seen in the Ren2 rats.
Our observations suggest that Ang II activation of the AT1R contributes to PT brush border injury and remodeling, in part, due to enhanced mTOR/S6K1 signaling which promotes tubulointerstitial fibrosis through loss of N-cadherin.
PMCID: PMC3130895  PMID: 21720156
Angiotensin II; mTOR; N-Cadherin; Proximal tubule; Tubulointerstitial fibrosis
20.  Relationship between Stage of Kidney Disease and Incident Heart Failure in Older Adults 
American Journal of Nephrology  2011;34(2):135-141.
The relationship between stage of chronic kidney disease (CKD) and incident heart failure (HF) remains unclear.
Of the 5,795 community-dwelling adults ≥65 years in the Cardiovascular Health Study, 5,450 were free of prevalent HF and had baseline estimated glomerular filtration rate (eGFR: ml/min/1.73 m2) data. Of these, 898 (16%) had CKD 3A (eGFR 45–59 ml/min/1.73 m2) and 242 (4%) had CKD stage ≥3B (eGFR <45 ml/min/1.73 m2). Data on baseline proteinuria were not available and 4,310 (79%) individuals with eGFR ≥60 ml/min/1.73 m2 were considered to have no CKD. Propensity scores estimated separately for CKD 3A and ≥3B were used to assemble two cohorts of 1,714 (857 pairs with CKD 3A and no CKD) and 557 participants (148 CKD ≥3B and 409 no CKD), respectively, balanced on 50 baseline characteristics.
During 13 years of follow-up, centrally-adjudicated incident HF occurred in 19, 24 and 38% of pre-match participants without CKD (reference), with CKD 3A [unadjusted hazard ratio (HR) 1.40; 95% confidence interval (CI) 1.20–1.63; p < 0.001] and with CKD ≥3B (HR 3.37; 95% CI 2.71–4.18; p < 0.001), respectively. In contrast, among matched participants, incident HF occurred in 23 and 23% of those with CKD 3A and no CKD, respectively (HR 1.03; 95% CI 0.85–1.26; p = 0.746), and 36 and 28% of those with CKD ≥3B and no CKD, respectively (HR 1.44; 95% CI 1.04–2.00; p = 0.027).
Among community-dwelling older adults, CKD is a marker of incident HF regardless of stage; however, CKD ≥3B, not CKD 3A, has a modest independent association with incident HF.
PMCID: PMC3136373  PMID: 21734366
Chronic kidney disease; Heart failure
21.  Relationship between Uric Acid and Subtle Cognitive Dysfunction in Chronic Kidney Disease 
American Journal of Nephrology  2011;34(1):49-54.
Elevated serum uric acid has been associated with cognitive dysfunction and vascular cognitive impairment in the elderly. Serum uric acid is also commonly elevated in chronic kidney disease (CKD), but its relationship with cognitive function in these patients has not been addressed.
Subjects with CKD (defined as eGFR <60/ml/min/1.73 m2) were evaluated for cognitive dysfunction using the validated Standardized Mini-Mental State Examination (SMMSE). Individuals with dementia, depression or other psychiatric disorders were excluded, as were subjects on uric acid-lowering therapy or with serious illnesses such as severe anemia or active or ongoing cardiovascular or cerebrovascular disease.
247 subjects were enrolled. SMMSE scores showed stepwise deterioration with increasing quartile of serum uric acid (26.4; 26.1; 25.5; 25.3, score range 20–30, p = 0.019). Post-hoc analysis demonstrated that there was no linear trend and only groups 1 and 4 were different with respect to SMMSE scores (p = 0.025). Stepwise multivariate linear regression revealed that age, educational status, presence of cerebrovascular disease, and serum uric acid were independently related to SMMSE scores.
Serum uric acid levels are independently and inversely associated with mild cognitive dysfunction in subjects with CKD.
PMCID: PMC3121541  PMID: 21659739
Cognitive function; Chronic kidney disease; Uric acid
22.  Outpatient versus Inpatient Observation after Percutaneous Native Kidney Biopsy: A Cost Minimization Study 
American Journal of Nephrology  2011;34(1):64-70.
Percutaneous kidney biopsy (PKB) is the primary diagnostic tool for kidney disease. Outpatient ‘day surgery’ (ODS) following PKB in low-risk patients has previously been described as a safe alternative to inpatient observation (IO). This study aims to determine if ODS is less costly compared to IO while accounting for all institutional costs (IC) associated with post-PKB complications, including death.
A cost minimization study was performed using decision analysis methodology which models relative costs in relation to outcome probabilities yielding an optimum decision. The potential outcomes included major complications (bleeding requiring blood transfusion or advanced intervention), minor complications (bleeding or pain requiring additional observation), and death. Probabilities were obtained from the published literature and a base case was selected. IC were obtained for all complications from institutional activity-based cost estimates. The base case assumed a complication rate of 10% with major bleeding occurring in 2.5% of patients (for both arms) and death in 0.1 and 0.15% of IO and ODS patients, respectively.
ODS costs USD 1,394 per biopsy compared to USD 1,800 for IO inclusive of all complications. IC for ODS remain less when overall complications <20%, major complications <5.5%, and IC per death
Outpatient management after PKB for low-risk patients costs less from the institutional perspective compared to IO, inclusive of complications and death. ODS should be considered for low-risk patients undergoing native kidney biopsy.
PMCID: PMC3123742  PMID: 21677428
Kidney biopsy; Decision analysis; Institutional costs
American Journal of Nephrology  2011;33(6):477-484.
Metabolic syndrome may increase the risk for incident cardiovascular disease (CVD) and all-cause mortality in the general population. It is unclear whether, and to what degree, metabolic syndrome is associated with CVD in chronic kidney disease (CKD). We determined metabolic syndrome prevalence among individuals with a broad spectrum of kidney dysfunction, examining the role of the individual elements of metabolic syndrome and their relationship to prevalent CVD.
We evaluated four models to compare metabolic syndrome or its components to predict prevalent CVD using prevalence ratios in the Chronic Renal Insufficiency Cohort (CRIC) Study.
Among 3,939 CKD participants, the prevalence of metabolic syndrome was 65% and there was a significant association with prevalent CVD. Metabolic syndrome was more common in diabetics (87.5%) compared with non-diabetics (44.3%). Hypertension was the most prevalent component, and increased triglycerides the least prevalent. Using the bayesian information criterion, we found that the factors defining metabolic syndrome, considered as a single interval-scaled variable, was the best of four models of metabolic syndrome, both for CKD participants overall and for diabetics and non-diabetics separately.
The predictive value of this model for future CVD outcomes will subsequently be validated in longitudinal analyses.
PMCID: PMC3095834  PMID: 21525746
Cardiovascular disease; Chronic kidney disease; Chronic Renal Insufficiency Cohort (CRIC) Study; Metabolic syndrome
American Journal of Nephrology  2011;33(5):381-389.
Diabetic nephropathy (DN) is a leading cause of mortality and morbidity in patients with type 1 and type 2 diabetes. The multicenter FIND consortium aims to identify genes for DN and its associated quantitative traits, e.g. the urine albumin:creatinine ratio (ACR). Herein, the results of whole-genome linkage analysis and a sparse association scan for ACR and a dichotomous DN phenotype are reported in diabetic individuals.
A genomewide scan comprising more than 5,500 autosomal single nucleotide polymorphism markers (average spacing of 0.6 cM) was performed on 1,235 nuclear and extended pedigrees (3,972 diabetic participants) ascertained for DN from African-American (AA), American-Indian (AI), European-American (EA) and Mexican-American (MA) populations.
Strong evidence for linkage to DN was detected on chromosome 6p (p = 8.0 × 10−5, LOD = 3.09) in EA families as well as suggestive evidence for linkage to chromosome 7p in AI families. Regions on chromosomes 3p in AA, 7q in EA, 16q in AA and 22q in MA displayed suggestive evidence of linkage for urine ACR. The linkage peak on chromosome 22q overlaps the MYH9/APOL1 gene region, previously implicated in AA diabetic and nondiabetic nephropathies.
These results strengthen the evidence for previously identified genomic regions and implicate several novel loci potentially involved in the pathogenesis of DN.
PMCID: PMC3078269  PMID: 21454968
Albuminuria; Diabetes mellitus; Renal failure; End-stage renal disease; Linkage; Allelic association
American Journal of Nephrology  2011;33(5):398-406.
Poor sleep quality is a common, persistent, and important problem to patients with end-stage renal disease (ESRD). This report examines whether sleep quality is associated with dialysis treatment factors and other modifiable clinical factors in a large group of hemodialysis (HD) patients.
Cross-sectional analyses were conducted on baseline data collected from participants in the Frequent Hemodialysis Network trials. Sleep quality was measured using the Medical Outcomes Study Sleep Problems Index II (SPI II), a 9-item measure of sleep quality with higher scores reflecting poorer sleep quality.
The participants had an age of 51.2 ± 13.6 years, 61% were male, 38% were black, and 42% had diabetes. Higher pre-dialysis serum phosphorus (per 0.5 mg/ml) (OR 0.91; 95% CI 0.85, 0.96) and depression (OR 0.16; 95% CI 0.10, 0.25) were independently associated with decrements in sleep quality. There was also a difference in time to recovery from dialysis for the fourth versus the first SPI II quartile (5.1 h; p < 0.0001).
These findings underscore the link between sleep and daytime function and suggest that improving sleep may provide an opportunity to improve outcomes in ESRD. Whether sleep problems may be improved by reduction of serum phosphorus or treatment of depression in the HD population merits further investigation.
PMCID: PMC3080580  PMID: 21474924
Hemodialysis; Sleep; Quality of life; Cognitive function; Cardiac magnetic resonance imaging

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