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1.  Trophoblast Glycoprotein: Possible Candidate Mediating Podocyte Injuries in Glomerulonephritis 
American Journal of Nephrology  2010;32(6):505-521.
Trophoblast glycoprotein (Tpbg), a 72-kDa transmembrane glycoprotein, is known to regulate the phenotypes of epithelial cells by modifying actin organization and cell motility. Recently, a microarray study showed that Tpbg is upregulated in Thy1 glomerulonephritis (Thy1 GN). We hypothesized that Tpbg regulates cytoskeletal rearrangement and modulates phenotypic alteration in podocytes under pathological conditions.
We examined Tpbg expression in Thy1 GN and Tpbg function in mouse podocytes.
We demonstrated that Tpbg is upregulated in the injured podocytes of Thy1 GN. In vitro, immunofluorescence studies revealed that Tpbg colocalized with the focal adhesion protein, vinculin, in parallel with stress fiber formation. This colocalization was observed even when actin filaments were depolymerized with cytochalasin D. Tpbg localization at focal adhesions was induced by dominant-active RhoA and suppressed by the ROCK1 inhibitor Y-26732. In addition, transforming growth factor-β increased Tpbg expression at focal adhesions concurrently with rearrangement of stress fibers. Stress fiber formation was suppressed in differentiated podocytes transfected with full-length Tpbg. Furthermore, knockdown of Tpbg using small interfering RNA decreased podocyte motility.
Our findings suggest a novel role of Tpbg in the phenotypic alteration of injured podocytes, and we accordingly propose a new mechanism of glomerular injury in glomerulonephritis.
PMCID: PMC2992649  PMID: 20980737
Trophoblast glycoprotein; Podocyte; Thy1 glomerulonephritis; Transforming growth factor-β; Cell motility; Stress fiber
2.  Salt-Induced Renal Injury in Spontaneously Hypertensive Rats: Effects of Nebivolol 
American Journal of Nephrology  2010;32(6):557-566.
We investigated renal effects of nebivolol, a selective β1-receptor blocker with additional antioxidative ability, in spontaneously hypertensive rats (SHR) where increased salt intake induces oxidative stress and worsens renal function as a result of further activation of the renin-angiotensin and sympathetic nervous systems.
Male SHR were given an 8% salt diet (HS; n = 22) for 5 weeks; their age-matched controls (n = 9) received standard chow. Nebivolol was given at a dose of 10 mg/kg/day for 5 weeks in 11 HS rats.
HS increased blood pressure, plasma renin concentration, urinary protein excretion, and renal nitroxidative stress while decreasing renal blood flow and angiotensin 1–7 receptor (mas) protein expression. There was no change in angiotensin II type 1 receptor expression among the experimental groups. Nebivolol did not alter the salt-induced increase in blood pressure but reduced urinary protein excretion, plasma renin concentration, and nitroxidative stress. Nebivolol also increased neuronal NOS expression while preventing the salt-induced decrease in renal blood flow and mas protein expression.
Nebivolol prevented salt-induced kidney injury and associated proteinuria in SHR through a blood pressure-independent mechanism. Its protective effects may be related to reduction in oxidative stress, increases in neuronal NOS and restoration of angiotensin II type 1/mas receptor balance.
PMCID: PMC2992650  PMID: 21042014
Salt; Hypertension; Kidney; Oxidative stress; Nitric oxide; β1-Receptor antagonism
3.  Chronic Nitric Oxide Deficiency and Progression of Kidney Disease after Renal Mass Reduction in the C57Bl6 Mouse 
American Journal of Nephrology  2010;32(6):575-580.
The C57Bl6 mouse is resistant to chronic kidney disease (CKD) induced by reduction of renal mass (RRM). Nitric oxide (NO) deficiency exacerbates CKD progression so this study investigated whether combination of RRM and NO deficiency would render the C57Bl6 mouse vulnerable to CKD.
We used wild-type (WT) mice with RRM, chronic NO synthase (NOS) inhibition and a combination. Also, endothelial NOS (eNOS) knockout (KO) C57Bl6 mice were studied with and without RRM. Primary endpoints were albuminuria and structural damage.
Both nonselective (+l-NAME) and neuronal NOS ‘selective’ (+7NI) NOS inhibition greatly exacerbated the albuminuria and structural damage seen with RRM in the WT mice; NOS inhibition alone had little effect. The eNOS KO mice showed marked structural damage and significant albuminuria in the shams and RRM produced minimal exacerbation of structural damage although the albuminuria was massively amplified.
These studies demonstrate that the C57Bl6 mouse is rendered vulnerable to RRM-induced CKD when concomitant NO deficiency is produced. This observation supports previous work in CKD-resistant rats and suggests that NO deficiency is required for progression of CKD.
PMCID: PMC2992651  PMID: 21071934
Nitric oxide synthase inhibition; Endothelial NOS knockout; Albuminuria; Creatinine clearance; Renal pathology
4.  Association of Cumulatively Low or High Serum Calcium Levels with Mortality in Long-Term Hemodialysis Patients 
American Journal of Nephrology  2010;32(5):403-413.
The outcome-predictability of baseline and instantaneously changing serum calcium in hemodialysis patients has been examined. We investigated the mortality-predictability of time-averaged calcium values to reflect the ‘cumulative’ effect of calcium burden over time.
We employed a Cox model using up-to-5-year (7/2001–6/2006) time-averaged values to examine the mortality-predictability of cumulative serum calcium levels in 107,200 hemodialysis patients prior to the use of calcimimetics, but during the time where other calcium-lowering interventions, including lower dialysate calcium, were employed.
Both low (<9.0 mg/dl) and high (>10.0 mg/dl) calcium levels were associated with increased mortality (reference: 9.0 to <9.5 mg/dl). Whereas mortality of hypercalcemia was consistent, hypocalcemia mortality was most prominent with higher serum phosphorus (>3.5 mg/dl) and PTH levels (>150 pg/ml). Higher paricalcitol doses shifted the calcium range associated with the greatest survival to the right, i.e. from 9.0 to <9.5 to 9.5 to <10.0 mg/dl. African-Americans exhibited the highest death hazard ratio of hypocalcemia <8.5 mg/dl, being 1.35 (95% CI: 1.22–1.49). Both a rise and drop in serum calcium over 6 months were associated with increased mortality compared to the stable group.
Whereas in hemodialysis patients cumulatively high or low calcium levels are associated with higher death risk, subtle but meaningful interactions with phosphorus, PTH, paricalcitol dose and race exist.
PMCID: PMC2941140  PMID: 20814200
Hypocalcemia; Hypercalcemia; Phosphorus; Hyperparathyroidism; Racial disparities; Mineral and bone disorder; Chronic kidney disease; Paricalcitol
5.  Common Charge-Shift Mutation Glu65Lys in K+ Channel β1-Subunit KCNMB1: Pleiotropic Consequences for Glomerular Filtration Rate and Progressive Renal Disease 
American Journal of Nephrology  2010;32(5):414-424.
Glomerular filtration rate (GFR) is a heritable trait, and hyperfiltration (GFR increment in remnant nephrons) may accelerate renal functional decline in chronic kidney disease (CKD). Mesangial and vascular smooth myocytes control GFR by contraction, dependent on voltage-gated Ca2+ influx, which is controlled by the regulatory β1-subunit (KCNMB1) of large-conductance heteromeric K+ (‘BK’) channels. KCNMB1 gain-of-function variant Glu65Lys results in generalized vasorelaxation and thus protection against systemic hypertension. Here we asked whether the Glu65Lys variant influences GFR, in the basal state or during progressive renal decline.
We explored Glu65Lys effects on GFR in three populations spanning two ethnicities and two diseases (hypertension and nephrosclerosis). GFR was either estimated (eGFR from serum creatinine) or directly measured (iothalamate clearance).
The 65Lys variant was relatively common, occurring on ∼5−10% of chromosomes in different biogeographic ancestry groups, and 65Lys carriers exhibited higher eGFR in two primary care populations: extreme BP values in Kaiser clinics (p = 0.029, accounting for ∼0.2% of trait variance), or treated hypertensives in VA clinics (p = 0.017, accounting for ∼0.9% of trait variance). In blacks with progressive renal disease (NIDDK AASK), 65Lys carriers displayed a steeper slope in GFR chronic decline (p = 0.030, accounting for ∼0.4% of trait variance), and Glu65Lys genotype also predicted time of onset of renal failure (log rank p = 0.019).
Common KCNMB1 gain-of-function variant Glu65Lys influences GFR, and 65Lys carriers exhibit not only elevated baseline GFR, but also more rapid GFR decline (and consequent development of renal failure) in CKD. The results suggest that profiling patients at Glu65Lys can assist in gauging renal prognosis as well as selection of rational therapy in hypertension with progressive renal disease.
PMCID: PMC2975731  PMID: 20861615
Glomerular filtration rate; KCNMB1; Hypertensive nephrosclerosis; African-American Study of Kidney Disease and Hypertension
6.  Hepatitis C Increases the Risk of Progression of Chronic Kidney Disease in Patients with Glomerulonephritis 
American Journal of Nephrology  2010;32(4):311-316.
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.
We retrospectively identified patients with primary glomerulonephritis on biopsy over 4 years, evaluating the progression of CKD over time.
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.
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.
PMCID: PMC2969148  PMID: 20714136
Hepatitis C; Chronic kidney disease; Glomerulonephritis; Diabetic nephropathy; Dialysis; Focal segmental glomerulosclerosis
7.  Blockade of Osteopontin Inhibits Glomerular Fibrosis in a Model of Anti-Glomerular Basement Membrane Glomerulonephritis 
American Journal of Nephrology  2010;32(4):324-331.
In our rat model for anti-GBM GN, severe fibrosis follows glomerular inflammation. A potential role of extracellular matrix protein osteopontin (OPN) in glomerular fibrosis was investigated.
Neutralizing OPN antiserum or control normal serum was injected into the experimental rats at late inflammatory/early fibrotic stage. Glomerular inflammation and fibrosis were determined.
OPN antiserum treatment had little effect on glomerular inflammation. However, the antiserum treatment resulted in a significant reduction in number of fibrotic glomeruli (50% of the controls). Histology observation showed that fibrotic tissue in glomeruli of the antiserum treated rats was mild and poorly developed. OPN antiserum treatment resulted in downregulated glomerular expression of collagen 1α1; collagen deposition in the antiserum treated rats reduced to <30% of that for normal serum controls.
Neutralization of OPN inhibited progression of fibrosis in vivo when given at early fibrotic stage. Thus, OPN may be a therapeutic target for glomerular fibrosis.
PMCID: PMC2969149  PMID: 20720406
Fibrosis; Extracellular matrix; Glomerulonephritis; Animal models
8.  Effects of a High-Salt Diet on TRPV-1-Dependent Renal Nerve Activity in Dahl Salt-Sensitive Rats 
American Journal of Nephrology  2010;32(3):194-200.
To test the hypothesis that transient receptor potential vanilloid type 1 channel (TRPV1)-mediated increases in afferent renal nerve activity (ARNA) and release of substance P (SP) and calcitonin gene-related peptide (CGRP) from the renal pelvis are suppressed in Dahl salt-sensitive (DS), but not -resistant (DR), rats fed a high-salt (HS) diet.
Methods and Results
Male DS and DR rats were given a HS or low-salt (LS) diet for 3 weeks. Perfusion of capsaicin (CAP, 10−6M), a selective TRPV1 agonist, into the left renal pelvis increased ipsilateral ARNA in all groups, but with a smaller magnitude in DS-HS compared to other groups. CAP increased contralateral urine flow in all groups except DS-HS rats. CAP-induced release of SP and CGRP from the renal pelvis was less in DS-HS compared to other groups. Western blot showed that TRPV1 expression in the kidney decreased while expression of neurokinin 1 receptors increased in DS-HS compared to other groups.
TRPV1-mediated increases in ARNA and release of SP and CGRP in the renal pelvis are impaired in DS rats fed a HS diet, which can likely be attributed to suppressed TRPV1 expression in the kidney and contributes to increased salt sensitivity.
PMCID: PMC2980518  PMID: 20639627
Transient receptor potential vanilloid type 1; Afferent renal nerve activity; Dahl rats; Salt sensitivity; Substance P; Calcitonin gene-related peptide
9.  Impact of Reduced Kidney Function on Cardiopulmonary Fitness in Patients with Systolic Heart Failure 
American Journal of Nephrology  2010;32(3):226-233.
Decreased renal function has been consistently associated with increased mortality among patients with systolic heart failure. The relationship between estimated glomerular filtration rate (eGFR) and other high-risk features including reduced cardiorespiratory fitness has not been previously reported in this patient population.
The HF-ACTION trial was a prospective, randomized trial of exercise therapy versus usual care in patients with systolic heart failure. Patients with class 2–4 heart failure and a left ventricular ejection fraction of ≤35% were recruited. Serum creatinine was measured up to 1 year prior to entry. The 4-variable modified Modification of Diet in Renal Disease equation was used to calculate eGFR. Peak oxygen consumption (peak VO2) was directly measured using gas exchange analysis during progressive exercise testing to volitional fatigue or adverse signs/symptoms.
Of 2,091 subjects (mean age 59 ± 13 years, with serum creatinine available at baseline), 72% were men, and 61, 33, and 5% were Caucasians, African Americans, and others, respectively. Older age, diabetes, and hypertension were all more frequent with declining eGFR. The Pearson correlation between eGFR and peak VO2 was 0.22 (p < 0.0001). Age was negatively correlated with both eGFR (r = −0.44, p < 0.0001) and peak VO2 (r = −0.27, p < 0.0001). The peak VO2 tended to decline across decreasing levels of eGFR. Individuals with an eGFR <30 ml/min/1.73 m2 had, on average, 2.1 high-risk features including peak VO2 <14 ml/kg/min, age >75 years, diabetes, and functional class 3–4 symptoms. Conversely, those with an eGFR >90 ml/min/1.73 m2 had relatively few (1.0) high-risk characteristics.
Reduced renal filtration is associated with impaired cardiorespiratory fitness and a clustering of high-risk features in systolic heart failure patients which portend a more complicated course and higher all-cause mortality.
PMCID: PMC2980519  PMID: 20664198
Heart failure; Chronic kidney disease; Cardiopulmonary fitness; Glomerular filtration rate; Renal insufficiency; Mortality risk
10.  Racial and Gender Differences in Arteriovenous Fistula Use among Incident Hemodialysis Patients 
American Journal of Nephrology  2010;32(3):234-241.
Arteriovenous fistula (AVF) use is reported to differ among racial and gender groups. We sought to identify risk factors associated with incident AVF and whether racial and gender differences in AVF use persist after controlling for these factors.
We evaluated 28,712 incident adult hemodialysis patients (age ≥18) from five ESRD networks starting dialysis between June 1, 2005 and May 31, 2006. Data were obtained from the Center for Medicaid and Medicare Services 2728 form.
Incident AVF use was reported for 11% of black and 12% of white patients [OR = 0.89 (95% CI: 0.83, 0.96)], and for 9% of females and 13% of males [OR = 0.66 (0.62–0.71)]. After adjusting for facility clustering, blacks were as likely as whites to use an AVF [OR = 1.00 (0.92–1.09)], while gender differences persisted [OR = 0.64 (0.59–0.69)]. Compared to patients with no renal care prior to dialysis initiation, incident AVF use was 16-fold greater among those with ≥12 months of nephrology care [OR = 15.99 (13.25–19.29)], 9-fold greater among those with 6–12 months of care [OR = 9.00 (7.45–10.88)] and 7-fold greater among those with at least 6 months of care [OR = 7.13 (5.73–8.88)].
Racial, but not gender, differences in incident AVF use were eliminated after accounting for clustering within facilities.
PMCID: PMC2980520  PMID: 20664254
Adequacy of care; Chronic kidney disease; Vascular access
11.  Osteopontin Overproduction Is Associated with Progression of Glomerular Fibrosis in a Rat Model of Anti-Glomerular Basement Membrane Glomerulonephritis 
American Journal of Nephrology  2010;32(3):262-271.
Glomerular fibrosis is the common end result of glomerulonephritis (GN) regardless of etiology. In our rat model for anti-glomerular basement membrane GN, severe fibrosis follows glomerular inflammation. We investigated the association between expression of extracellular matrix (ECM) proteins and progression of glomerular fibrosis.
Expression of ECM genes in glomeruli was determined at RNA and protein levels. Immunofluorescence was applied to identify cell sources for the molecules.
DNA microarray for ECM genes, quantitative RT-PCR and Western blot revealed significant upregulation of osteopontin (OPN), a multifunctional molecule, in the glomeruli only after onset of glomerular fibrosis. Two-dimensional electrophoresis showed that the expressed OPN was in three major isoforms. Immunofluorescence showed that fibrotic tissues in glomeruli accumulated massive deposits of extracellular OPN. Both in vivo and in vitro experiments showed that a novel population of multinucleated α-smooth muscle actin+CD90– myofibroblast-like cells, which surrounded fibrotic tissue, was the main source of OPN during progression of fibrosis. Since senescence-associated β-galactosidase activity was detected in those cells both in vitro and in vivo, these cells probably were terminally differentiated senescent myofibroblasts.
OPN has been implicated in fibrosis in several organs. Our results suggest potential roles of OPN and its main source, the senescent myofibroblasts, in glomerular fibrosis.
PMCID: PMC2980521  PMID: 20714131
Fibrosis; Anti-glomerular basement membrane disease; Fibroblast; Extracellular matrix; Inflammation
12.  Associations between Genetic Variants in the ACE, AGT, AGTR1 and AGTR2 Genes and Renal Function in the Multi-Ethnic Study of Atherosclerosis 
American Journal of Nephrology  2010;32(2):156-162.
Some studies suggest that polymorphisms in angiotensin-converting enzyme (ACE), angiotensinogen (AGT), angiotensin II type I receptor (AGTR1) and angiotensin II type II receptor (AGTR2) genes may contribute to renal function variation.
Genotyping for single nucleotide polymorphisms (SNPs) in these candidate genes was performed in 2,847 participants from four racial/ethnic groups (African American, Chinese, White and Hispanic) without known cardiovascular disease in the Multi-Ethnic Study of Atherosclerosis. SNP and haplotype analyses were performed to determine associations between genotypes and cross-sectional renal function measurements, including urine albumin excretion (UAE) and estimated glomerular filtration rate (eGFR) using serum creatinine and cystatin C.
Twenty-four ACE SNPs, 10 AGT SNPs, 15 AGTR1 SNPs and 6 AGTR2 SNPs were typed successfully. After adjusting for ancestry, age and gender, 3 SNPs (AGT M235T, AGT rs2148582 and AGTR1 rs2131127) showed associations with an empiric p value <0.05 with the same phenotype in multiple racial/ethnic groups, suggesting replication. The AGT M235T SNP has been shown previously to be associated with diabetic and hypertensive nephropathy. Conclusions: These data suggest that genetic polymorphisms in the renin-angiotensin system are associated with renal phenotypes in the general population, but that many associations differ across racial/ethnic groups.
PMCID: PMC2941827  PMID: 20606419
Renin-angiotensin; ACE; AGT; AGTR1; AGTR2; Albuminuria; Creatinine clearance epidemiology; Genetics
13.  Podocyte Number in the Maturing Rat Kidney 
American Journal of Nephrology  2010;33(1):91-96.
The podocyte is an important cell for maintaining the normal structure and function of the glomerulus. In recent years much attention has been given to the number of podocytes in glomeruli. During this time there has been a debate as to whether podocytes can divide after the capillary-loop stage of development. The aim of this study was to use an unbiased counting method to determine if podocyte number increases after the capillary-loop stage of development.
The fractionator/disector method was used to count podocytes in glomeruli from rats aged 1 day, 5, 12, and 24 weeks. Glomerular volume was also measured with the unbiased Cavalieri principle and used to calculate the density of podocytes per glomerulus.
The number of podocytes did not increase from the capillary-loop stage of glomerular development to 24 weeks of age. Glomerular volume increased 3.6-fold during this time, which resulted in a decrease of podocyte density as the rats aged.
The study documents that the number of podocytes is stable after the capillary-loop stage of glomerular development. The data does not confirm but adds evidence that podocytes do not divide from the capillary-loop stage of glomerular development to 24 weeks of age in the normal rat.
PMCID: PMC3030545  PMID: 21196721
Fractionator/disector; Glomerular volume; Podocyte number; Rat; Stereology
14.  Cognitive Function and Dialysis Adequacy: No Clear Relationship 
American Journal of Nephrology  2010;33(1):33-38.
Cognitive impairment is common in hemodialysis patients and may be impacted by multiple patient and treatment characteristics. The impact of dialysis dose on cognitive function remains uncertain, particularly in the current era of increased dialysis dose and flux.
We explored the cross-sectional relationship between dialysis adequacy and cognitive function in a cohort of maintenance hemodialysis patients. Adequacy was defined as the average of the 3 most proximate single pool Kt/V assessments. A detailed neurocognitive battery was administered during the 1st hour of dialysis. Multivariable linear regression models were adjusted for age, sex, education, race and other clinical and demographic characteristics.
Among 273 patients who underwent cognitive testing, the mean (SD) age was 63 (17) years and the median dialysis duration was 13 months, 47% were woman, 22% were African American, and 48% had diabetes. The mean (SD) Kt/V was 1.51 (0.24). In univariate, parsimonious and multivariable models, there were no significant relationships between decreased cognitive function and lower Kt/V.
In contrast to several older studies, there is no association between lower Kt/V and worse cognitive performance in the current era of increased dialysis dose. Future studies should address the longitudinal relationship between adequacy of dialysis and cognitive function to confirm these findings.
PMCID: PMC3245831  PMID: 21150193
Cognitive function; Dialysis adequacy; Chronic kidney disease
15.  Heritability of Renal Function and Inflammatory Markers in Adult Male Twins 
American Journal of Nephrology  2010;32(4):317-323.
Loss of renal function is accompanied by a progressive increase in markers of inflammation; it is unknown whether they share common genetic pathways.
Study Design
We evaluated the shared heritability of estimated glomerular filtration rate (eGFR) and markers of inflammation and endothelial activation in 524 twin males from the Vietnam Era Twin Registry; 9 twins were excluded due to incomplete or incorrect data. Models were adjusted for age, race, body mass index, smoking, hypertension, diabetes mellitus, prior coronary artery disease and intercurrent medications.
The mean eGFR was 89 ± 13 ml/min/1.73 m2 (range 35–146); eGFR, intracellular adhesion molecule (ICAM) and TNF-α receptor (TNF-αR) were moderately heritable (all ∼50%), while IL-6 receptor (IL-6R) and P-selectin were highly heritable (68 and 76%, respectively). IL-6R and TNF-αR showed a significant inverse association with eGFR (p = 0.04 and p < 0.0001) while the association with ICAM and P-selectin was direct (p = 0.001 and p = 0.06). Bivariate structural equation models showed that the association between eGFR and biomarkers was due to unique environmental factors and there were no shared genetic pathways.
We found no shared genetic pathways between renal function and inflammation. Thus, increased inflammation represents a response to declining renal function rather than being a mechanism contributing to renal deterioration.
PMCID: PMC2980816  PMID: 20720405
Heritability; Renal function; Inflammation
16.  Progression of Chronic Kidney Disease: Adrenergic Genetic Influence on Glomerular Filtration Rate Decline in Hypertensive Nephrosclerosis 
American Journal of Nephrology  2010;32(1):23-30.
African-Americans are likely to develop hypertension and hypertensive nephrosclerosis. This grave prognosis, coupled with familial aggregation of end-stage renal disease (ESRD) in Blacks, prompts a search for genetic risk factors for ESRD. Recent evidence implicates a crucial role for the sympathetic nervous system in progressive renal disease.
We used the African-American Study of Kidney Disease to probe whether β2-adrenergic receptor (ADRB2) predicts glomerular filtration rate (GFR) decline rate. A total of 580 participants were included. Baseline GFR was 51.2 ± 0.5 ml/min/1.73 m2. Subjects were randomized in a 2 × 3 block design: to intensively lowered (MAP ≤92 mm Hg) versus ‘usual’ (MAP = 102–107 mm Hg) blood pressure goal groups, and also divided by three randomized antihypertensive drugs (ramipril, metoprolol, or amlodipine). We scored 4 SNPs at the ADRB2 locus.
Haplotypes at ADRB2 predicted chronic GFR decline rate, GFR declined more slowely in individuals with haplotype-1 (−804G→173T→16Gly→27GIn), and faster in those who carried haplotype-3 (−804G→173T→16Arg→27Gln). ADRB2 genotype interacted with antihypertensive drug class to influence GFR slope (p = 0.001–0.037). We extended our findings to an independent case/control sample of Black hypertensive ESRD, in which we found that variant Gly16Arg that tagged the GFR slope-determining ADRB2 haplotype also conferred risk for the ESRD trait in Blacks.
The GFR decline/progression rate in hypertensive renal disease is controlled in part by genetic variation within the adrenergic pathway.
PMCID: PMC2914391  PMID: 20484896
Adrenergic genetic influence; African-American Study of Kidney Disease; Chronic kidney disease; End-stage renal disease; Glomerular filtration rate; Hypertensive nephrosclerosis
17.  Poverty and Racial Disparities in Kidney Disease: The REGARDS Study 
American Journal of Nephrology  2010;32(1):38-46.
There are pronounced disparities among black compared to white Americans for risk of end-stage renal disease. This study examines whether similar relationships exist between poverty and racial disparities in chronic kidney disease (CKD) prevalence.
We studied 22,538 participants in the REasons for Geographic And Racial Differences in Stroke (REGARDS) cohort study. We defined individual poverty as family income below USD 15,000 and a neighborhood as poor if 25% or more of the households were below the federal poverty level.
As the estimated glomerular filtration rate (GFR) declined from 50–59 to 10–19 ml/min/ 1.73 m2, the black:white odds ratio (OR) for impaired kidney function increased from 0.74 (95% CI 0.66, 0.84) to 2.96 (95% CI 1.96, 5.57). Controlling for individual income below poverty, community poverty, demographic and comorbid characteristics attenuated the black:white prevalence to an OR of 0.65 (95% CI 0.57, 0.74) among individuals with a GFR of 59–50 ml/min/1.73 m2 and an OR of 2.21 (95% CI 1.25, 3.93) among individuals with a GFR between 10 and 19 ml/min/ 1.73 m2.
Household, but not community poverty, was independently associated with CKD and attenuated but did not fully account for differences in CKD prevalence between whites and blacks.
PMCID: PMC2914392  PMID: 20516678
Chronic kidney disease; Poverty; Racial disparities
18.  The Non-Muscle Myosin Heavy Chain 9 Gene (MYH9) Is Not Associated with Lupus Nephritis in African Americans 
American Journal of Nephrology  2010;32(1):66-72.
African Americans (AA) disproportionately develop lupus nephritis (LN) relative to European Americans and familial clustering supports causative genes. Since MYH9 underlies approximately 40% of end-stage renal disease (ESRD) in AA, we tested for genetic association with LN.
Seven MYH9 single nucleotide polymorphisms (SNPs) and the E1 risk haplotype were tested for association with LN in three cohorts of AA.
A preliminary analysis revealed that the MYH9 E1 risk haplotype was associated with ESRD in 25 cases with presumed systemic lupus erythematosus (SLE)-associated ESRD, compared to 735 non-SLE controls (odds ratio 3.1; p = 0.010 recessive). Replication analyses were performed in 583 AA with SLE in the PROFILE cohort (318 with LN; 265 with SLE but without nephropathy) and 60 AA from the NIH (39 with LN; 21 with SLE but without nephropathy). Analysis of the NIH and larger PROFILE cohorts, as well as a combined analysis, did not support this association.
These results suggest that AA with ESRD and coincident SLE who were recruited from dialysis clinics more likely have kidney diseases in the MYH9-associated spectrum of focal segmental glomerulosclerosis. PROFILE and NIH participants, recruited from rheumatology practices, demonstrate that MYH9 does not contribute substantially to the development of LN in AA.
PMCID: PMC2914393  PMID: 20523037
African Americans; Genetics; Lupus nephritis; Kidney; MYH9; Systemic lupus erythematosus
19.  Renal Failure in Mice with Gsα Deletion in Juxtaglomerular Cells 
American Journal of Nephrology  2010;32(1):83-94.
Mice with deletion of Gsα in renin-producing cells (RC/FF mice) have been shown to have greatly reduced renin production and lack of responsiveness of renin secretion to acute stimuli. In addition, young RC/FF mice are hypotensive and have a vasopressin-resistant concentrating defect. In the present study we have determined the long-term effect on renal function, blood pressure, and renal pathology in this low renin and diuretic mouse model.
Methods and Results
Urine osmolarity of RC/FF mice was decreased in all age groups. GFR measured at 7, 14 and 20 weeks of age declined progressively. Single nephron GFR similarly declined while fractional proximal fluid absorption was maintained. Expression levels of extracellular matrix proteins (collagen I, IV and fibronectin) and α-smooth muscle actin were increased in kidneys of RC/FF mice at 20 weeks, and this was accompanied by focal segmental glomerulosclerosis and periglomerular interstitial fibrosis. RC/FF mice showed a progressive reduction of body weight, an increase in urine albumin excretion, and an increase of blood pressure with aging.
A chronic reduction of renin production in mice may be a risk factor in its own right, and does not protect renal function against the profibrotic influence of a chronically elevated urine flow.
PMCID: PMC2914394  PMID: 20551626
Renin-angiotension system; Renal failure; Pathology
20.  Role of the Intrarenal Renin-Angiotensin-Aldosterone System in Chronic Kidney Disease 
American Journal of Nephrology  2010;31(6):541-550.
The existence of local or tissue-based renin-angiotensin-aldosterone systems (RAAS) is well documented and has been implicated as a key player in the pathogenesis of cardiovascular and renal diseases. The kidney contains all elements of the RAAS, and intrarenal formation of angiotensin II not only controls glomerular hemodynamics and tubule sodium transport, but also activates a number of inflammatory and fibrotic pathways. Experimental and clinical studies have shown that the intrarenal RAAS is activated early in diabetic nephropathy, the leading cause of chronic kidney disease (CKD). Although angiotensin-converting enzyme inhibitors and angiotensin receptor blockers decrease the rate of decline in kidney function in patients with diabetic and non-diabetic nephropathy, many patients still progress to end-stage renal disease or die from cardiovascular events. There is still a clear need for additional strategies to block the RAAS more effectively to reduce progression of CKD. The focus of this paper is to review the importance of the intrarenal RAAS in CKD and recent findings in renin-angiotensin biology pertinent to the kidney. We also discuss additional strategies to inhibit the RAAS more effectively and the potential impact of direct renin inhibition on the prevention and management of CKD.
PMCID: PMC3202956  PMID: 20484892
Angiotensin; Direct renin inhibition; Aliskiren; Kidney disease
21.  Prevention and Treatment of Acute Kidney Injury in Patients Undergoing Cardiac Surgery: A Systematic Review 
American Journal of Nephrology  2010;31(5):408-418.
Acute kidney injury (AKI) is common in patients undergoing cardiac surgery and is associated with a high rate of death, long-term sequelae and healthcare costs. We conducted a systematic review of randomized controlled trials for strategies to prevent or treat AKI in cardiac surgery.
We screened Medline, Scopus, Cochrane Renal Library, and Google Scholar for randomized controlled trails in cardiac surgery for prevention or treatment of AKI in adults.
We identified 70 studies that contained a total of 5,554 participants published until November 2008. Most studies were small in sample size, were single-center, focused on preventive strategies, and displayed wide variation in AKI definitions. Only 26% were assessed to be of high quality according to the Jadad criteria. The types of strategies with possible protective efficacy were dopaminergic agents, vasodilators, anti-inflammatory agents, and pump/perfusion strategies. When analyzed separately, dopamine and N-acetylcysteine did not reduce the risk for AKI.
This summary of all the literature on prevention and treatment strategies for AKI in cardiac surgery highlights the need for better information. The results advocate large, good-quality, multicenter studies to determine whether promising interventions reliably reduce rates of acute renal replacement therapy and mortality in the cardiac surgery setting.
PMCID: PMC2883845  PMID: 20375494
Acute kidney injury, prevention; Cardiac surgery; Healthcare costs
22.  Total and Individual Coronary Artery Calcium Scores as Independent Predictors of Mortality in Hemodialysis Patients 
American Journal of Nephrology  2010;31(5):419-425.
Many traditional and nontraditional risk factors contribute to vascular calcification among maintenance hemodialysis (MHD) patients. It is not clear whether coronary artery calcification (CAC) delineates a higher mortality risk independent of known risk factors. We examined 6-year (10/2001–9/2007) survival of 166 MHD patients, aged 53 ± 13 years, with baseline CAC scores. Patients were grouped into four CAC groups: 0, 1–100, 101–400, and 400+. The 101–400 and 400+ groups were associated with a significantly higher adjusted risk of death than CAC 0 with hazard ratios (HR) 8.5 (95% CI: 1.1–48.1, p = 0.02) and 13.3 (95% CI: 1.3–65.1, p = 0.01), respectively, independent of demographics, comorbidity, lipids and other cardiovascular risks, surrogates of bone disease, nutritional and inflammatory markers and dialysis dose. Total CAC [HR 6.7 (1.1–21.5, p = 0.03)] followed by the presence of CAC in the left main [4.6 (2.2–9.8, p = 0.001)] and left anterior descending artery [4.3 (2.1–14.2, p = 0.001)] were strong independent predictors of mortality even after adjusting for above covariates. Total and vessel-specific CAC predict mortality in MHD patients independent of traditional and nontraditional risk factors.
PMCID: PMC2883846  PMID: 20389057
Chronic kidney disease; Coronary artery calcium; Dialysis; Inflammation; Phosphorus binder; Sevelamer; Death risk
23.  Variability of Creatinine Measurements in Clinical Laboratories: Results from the CRIC Study 
American Journal of Nephrology  2010;31(5):426-434.
Estimating equations using serum creatinine (SCr) are often used to assess glomerular filtration rate (GFR). Such creatinine (Cr)-based formulae may produce biased estimates of GFR when using Cr measurements that have not been calibrated to reference laboratories. In this paper, we sought to examine the degree of this variation in Cr assays in several laboratories associated with academic medical centers affiliated with the Chronic Renal Insufficiency Cohort (CRIC) Study; to consider how best to correct for this variation, and to quantify the impact of such corrections on eligibility for participation in CRIC. Variability of Cr is of particular concern in the conduct of CRIC, a large multicenter study of subjects with chronic renal disease, because eligibility for the study depends on Cr-based assessment of GFR.
A library of 5 large volume plasma specimens from apheresis patients was assembled, representing levels of plasma Cr from 0.8 to 2.4 mg/dl. Samples from this library were used for measurement of Cr at each of the 14 CRIC laboratories repetitively over time. We used graphical displays and linear regression methods to examine the variability in Cr, and used linear regression to develop calibration equations. We also examined the impact of the various calibration equations on the proportion of subjects screened as potential participants who were actually eligible for the study.
There was substantial variability in Cr assays across laboratories and over time. We developed calibration equations for each laboratory; these equations varied substantially among laboratories and somewhat over time in some laboratories. The laboratory site contributed the most to variability (51% of the variance unexplained by the specimen) and variation with time accounted for another 15%. In some laboratories, calibration equations resulted in differences in eligibility for CRIC of as much as 20%.
The substantial variability in SCr assays across laboratories necessitates calibration of SCr measures to a common standard. Failing to do so may substantially affect study eligibility and clinical interpretations when they are determined by Cr-based estimates of GFR.
PMCID: PMC2883847  PMID: 20389058
Chronic renal disease; Creatinine measurements, variability; Chronic Renal Insufficiency Cohort (CRIC) Study; Glomerular filtration rate
24.  Hydrogen Sulfide Regulates Homocysteine-Mediated Glomerulosclerosis 
American Journal of Nephrology  2010;31(5):442-455.
In this study we tested the hypothesis that H2S regulates collagen deposition, matrix metalloproteinases (MMP) and inflammatory molecules during hyperhomocysteinemia (HHcy) resulting in attenuation of glomerulosclerosis and improved renal function.
Materials and Methods
A genetic model of HHcy, cystathionine β-synthase heterozygous (CBS+/−) and wild-type (WT) 2-kidney (2K) mice were used in this study and supplemented with or without NaHS (30 μmol/l, H2S donor) in drinking water for 8 weeks. To expedite the renal damage associated with HHcy, uninephrectomized (1K) mice of similar groups were also used.
Results demonstrated that NAD(P)H oxidase (p47phox subunit) and blood pressure were upregulated in WT 1K, CBS+/− 2K and CBS+/− 1K mice with downregulation of H2S production and reduced glomerular filtration rate. These changes were normalized with H2S supplementation. Both pro- and active MMP-2 and -9 and collagen protein expressions and glomerular depositions were also upregulated in WT 1K, CBS+/− 2K and CBS+/− 1K mice. Increased expressions of inflammatory molecules, intercellular cell adhesion molecule-1 and vascular cell adhesion molecule-1, as well as increased macrophage infiltration, were detected in WT 1K, CBS+/− 2K and CBS+/− 1K mice. These changes were ameliorated with H2S supplementation.
Together, these results suggest that increased oxidative stress and decreased H2S in HHcy causes matrix remodeling and inflammation resulting in glomerulosclerosis and reduced renal function.
PMCID: PMC2883848  PMID: 20395677
Collagen; Matrix metalloproteinase; Inflammation; Fibrosis; Hypertension; Renal dysfunction
25.  Physical and Psychological Burden of Chronic Kidney Disease among Older Adults 
American Journal of Nephrology  2010;31(4):309-317.
The purpose of the study is to determine if functional status and quality of life (QoL) vary with glomerular filtration rate (GFR) among older adults.
We studied adults aged 45 years and older participating in the REasons for Geographic And Racial Differences in Stroke (REGARDS) cohort study. Data included demographic and health information, serum creatinine and hemoglobin, the 4-item Center for Epidemiologic Studies Depression Scale (CES-D-4), the 4-item Cohen's Perceived Stress Scale (PSS-4), reported health status and inactivity and the Medical Outcomes Study Short Form-12 (SF-12) QoL scores.
CKD (GFR <60 ml/min/1.73 m2) was present in 11.6% of the subjects. As GFR declined, the SF-12 physical component score, adjusted for other participant attributes, declined from 38.9 to 35.9 (p = 0.0001). After adjustment for other risk factors, poorer personal health scores (p < 0.0001) and decreased physical activity (p < 0.0001) were reported as GFR declined. In contrast, after adjusting for other participant characteristics, depression scores and stress scores and the mental component score of the SF-12 were not associated with kidney function.
Older individuals with CKD in the US population experience an increased prevalence of impaired QoL that cannot be fully explained by other individual characteristics.
PMCID: PMC2859227  PMID: 20164652
Functional status; Quality of life; Chronic kidney disease; End-stage renal disease; Glomerular filtration rate; REGARDS cohort study; Medical Outcomes Study Short Form-12

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