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1.  Evaluation of Genetic Association and Expression Reduction of TRPC1 in the Development of Diabetic Nephropathy 
American journal of nephrology  2008;29(3):244-251.
The TRPC1 gene on chromosome 3q22–24 resides within the linkage region for diabetic nephropa-thy (DN) in type 1 (T1D) and type 2 diabetes mellitus (T2D). A recent study has demonstrated that TRPC1 expression is reduced in the kidney of diabetic ZDF- and STZ-treated rats. The present study aimed to evaluate the genetic and functional role of TRPC1 in the development of DN.
Genetic association study was performed with two independent cohorts, including 1,177 T1D European Americans with or without DN from GoKinD population and 850 African-American subjects with T2D-associated end-stage renal disease (ESRD), or with hypertensive (non-diabetic) ESRD, and nondiabetic controls. Seven tag SNP markers derived from HapMap data (phase II) were genotyped. TRPC1 gene expression was examined using real time RT-PCR.
No significant association of TRPC1 DNA polymorphisms with DN or ERSD was found in GoKinD and African-American populations. TRPC1 gene mRNA expression in kidney was found to be trendily reduced in 12-week and significantly in 26-week-old db/db mice.
TRPC1 genetic polymorphism may not fundamentally contribute to the development of DN, while reduction of the gene expression in kidney may be a late phenomenon of DN as seen in diabetic animal models.
PMCID: PMC2698220  PMID: 18802326
TRPC1 gene; Single-nucleotide polymorphism; Diabetic nephropathy; End-stage renal disease; Diabetes types 1 and 2
2.  Tetracycline-Inducible Gene Expression in Conditionally Immortalized Mouse Podocytes 
American journal of nephrology  2008;29(3):153-163.
Conditionally immortalized podocytes are valuable research tools but are difficult to efficiently transfect and do not provide graded transgene expression.
Conditionally immortalized mouse podocyte cell lines were established employing a tetracycline-inducible system. Glomerular cells, isolated from transgenic mice bearing two transgenes, NPHS2-reverse tetracycline-controlled transactivator, rtTA (A transgene) and H2-Kb-thermosensitive SV40 T, ts58A (I transgene), were cloned. One clone (AI podocytes) expressing WT1 and synaptopodin was transfected with pBI-EGFP (enhanced green fluorescent protein, G transgene) and separately with ptTS-Neo (transcriptional suppressor, T transgene) to produce stable transformants, AIG podocytes and AIT podocytes.
AIG podocytes expressed EGFP at 33 and 37°C after doxycycline treatment, and retained podocin and rtTA mRNA expression and temperature-sensitive growth regulation. AIT podocytes, transiently transfected with luciferase-BI-EGFP (LG transgene), showed reduced background expression of EGFP and luciferase in the absence of doxycycline. In AITLG podocytes, generated by stable transfection of AIT podocytes with the LG transgene, luciferase expression was tightly regulated by doxycycline in a time- and concentration-dependent manner both at 33 and 37°C, although background expression was not entirely eliminated. These podocytes retained temperature-sensitive growth regulation and expression of podocyte differentiation markers.
Mouse podocytes expressed tetracycline-induced transgenes efficiently while retaining differentiation markers.
PMCID: PMC2698022  PMID: 18753740
Tetracycline-inducible system; Conditional immortalization; Transcription; Gene of interest
3.  Angiotensin II Infusion Induces Nephrin Expression Changes and Podocyte Apoptosis 
American journal of nephrology  2008;28(3):500-507.
In in vitro studies, angiotensin (Ang) II has been demonstrated to promote podocyte apoptosis. The present study evaluates the effects of Ang II infusion in rats on podocyte nephrin expression and apoptosis and the molecular mechanisms involved in Ang II-induced proteinuria and mesangial expansion.
Sprague-Dawley rats were randomly assigned to receive either normal saline or Ang II (400 ng·kg−1·min−1) by means of a mini-osmotic pump for variable time periods. Systolic blood pressure and urinary protein and albumin excretion rate measurements were carried out on days 7, 14, 21, and 28. The animals were sacrificed on days 14 and 28 and evaluated for serum creatinine, renal pathological changes, podocyte apoptosis, renal nephrin mRNA, and protein expression.
The Ang II-infused rats developed hypertension and proteinuria. On day 14, the Ang II-infused rats showed narrowing of the slit diaphragm, an increase in podocyte nephrin mRNA and protein expression, and alterations in its distribution along the foot processes. On day 28, the Ang II-infused rats demonstrated the presence of apoptotic podocytes and decreased nephrin mRNA and protein expression. There was a negative correlation between nephrin expression and the numbers of apoptotic podocytes (r = −0.63, p < 0.05).
These results suggest that changes in nephrin expression may play a role in the pathogenesis of Ang II-induced podocyte apoptosis.
PMCID: PMC2630486  PMID: 18204248
Angiotensin II; Proteinuria; Nephrin expression; Podocyte; Apoptosis
4.  Precision of Biomarkers to Define Chronic Inflammation in CKD 
American journal of nephrology  2008;28(5):808-812.
Several inflammatory biomarkers have been found to be associated with cardiovascular disease or all-cause mortality in dialysis patients, but their usefulness in clinical practice or as surrogate endpoints is not certain. The purpose of the present study was to determine the intrapatient variation of C-reactive protein, IL-6, fetuin-A and albumin in a population of dialysis patients.
Apparently healthy dialysis patients with either a tunneled dialysis catheter or fistula had monthly assessments of these biomarkers for a total of four determinations, and the intraclass correlation coefficients were calculated as measures of intersubject variance.
Our results showed large within-subject variation relative to the total variation in the measurements (31-46%). Having a tunneled catheter as opposed to a fistula was not significantly associated with mean levels, suggesting that chronic subclinical catheter infection does not explain the variation seen in the biomarkers. In contrast, there was a rapid change in these biomarkers with a clinically apparent acute infection.
These results suggest that these biomarkers have limitations for use as surrogate endpoints in clinical trials due to wide fluctuations, even in apparently clinically healthy individuals.
PMCID: PMC2574778  PMID: 18506106
Biomarkers, precision; Chronic inflammation; Chronic kidney disease; CKD stage 5D; Inflammatory biomarkers, intrapatient variance; Tunneled dialysis catheter
5.  Novel Methodology to Evaluate Renal Cysts in Polycystic Kidney Disease 
American journal of nephrology  2014;39(3):210-217.
To develop and assess a semi-automated method for segmenting and counting individual renal cysts from mid-slice MR images in patients with autosomal dominant polycystic kidney disease (ADPKD)
Materials and Methods
A semi-automated method was developed to segment and count individual renal cysts from mid-slice MR images in 241 participants with ADPKD from the Consortium for Radiologic Imaging Studies of ADPKD (CRISP). For each subject, a mid-slice MR image was selected from each set of coronal T2-weighted MR images covering the entire kidney. The selected mid-slice image was processed with the semi-automated method to segment and count individual renal cysts. The number of cysts from the mid-slice image of each kidney was also measured by manual counting. The level of agreement between the semi-automated and manual cyst counts was compared using intra-class correlation (ICC) and a Bland-Altman plot.
Individual renal cysts were successfully segmented using the semi-automated method in all 241 cases. The number of cysts in each kidney measured with the semi-automated and manual counting methods correlated well (ICC=0.96 for the right or left kidney), with a small average difference (-0.52, with higher semi-automated counts, for the right and 0.13, with higher manual counts, for the left) in the semi-automated method. There was, however, substantial variation in a small number of subjects: 6 of 241 (2.5%) participants had a difference in the total cyst count of more than 15.
We have developed a semi-automated method to segment individual renal cysts from mid-slice of MR images in ADPKD kidneys for a quantitative indicator of characterization and disease progression of ADPKD.
PMCID: PMC4020571  PMID: 24576800
kidney; polycystic kidney disease; renal cysts; magnetic resonance imaging; segmentation
6.  Acute Kidney Injury and Mortality following Ventricular Assist Device Implantation 
American journal of nephrology  2014;39(3):195-203.
Ventricular assist devices (VADs) are increasingly common and their surgical implantation predisposes patients to an increased risk of acute kidney injury (AKI). We sought to evaluate the incidence, risk factors, short and long term all cause mortality of patients with AKI following VAD implantation.
We identified all patients who underwent VAD implantation at the University of Chicago from January 1, 2008 to January 31, 2012. We evaluated the incidence of AKI, defined as a ≥50% increase in serum creatinine over the first 7 post-operative days (RIFLE Risk-Creatinine). A logistic regression model was used to identify risk factors for development of AKI and a cox proportional hazards model was used to examine factors associated with 30-day and 365-day all cause mortality.
157 eligible patients had VAD implantations with 44 (28%) developing post-implantation AKI. In a multivariate analysis only diabetes mellitus [OR=2.25 (1.03-4.94), P=0.04] was identified as a significant predictor of postoperative AKI. Using a multivariable model censored for heart transplantation, only AKI [HR= 3.01(1.15-7.92), P=0.03] and cardiopulmonary bypass time [HR =1.01(1.001-1.02), P= 0.02] were independent predictors of 30-day mortality. Pre-operative Body Mass Index [HR=0.95(0.90-0.99), P=0.03], pre-operative diabetes mellitus [HR=1.89 (1.07-3.35), P=0.03] and post-implantation AKI [HR=1.85 (1.06-3.21); P=0.03] independently predicted 365-day mortality.
AKI is common following VAD implantation and is an independent predictor of 30-day and 1-year all cause mortality.
PMCID: PMC4000722  PMID: 24556808
Acute Kidney Injury; Cardiac Surgery; Mortality; Ventricular Assist Device; RIFLE
7.  Impact of Age, Race and Ethnicity on Dialysis Patient Survival and Kidney Transplantation Disparities 
American journal of nephrology  2014;39(3):183-194.
Prior studies show that African-American and Hispanic dialysis patients have lower mortality risk than whites. Recent age-stratified analyses suggest this survival advantage may be limited to younger age groups, but did not concurrently compare Hispanic, African-American, and white patients, nor account for differences in nutritional and inflammatory status as potential confounders. Minorities experience inequities in kidney transplantation access, but it is unknown whether these racial/ethnic disparities differ across age groups.
The associations between race/ethnicity with all-cause mortality and kidney transplantation were separately examined among 130,909 adult dialysis patients from a large national dialysis organization (entry period 2001-2006, follow-up through 2009) within 7 age categories using Cox proportional hazard models adjusted for case-mix and malnutrition and inflammatory surrogates.
African-Americans had similar mortality vs. whites in younger age groups (18-40 years), but decreased mortality in older age groups (>40 years). In contrast, Hispanics had lower mortality vs. whites across all ages. In sensitivity analyses using competing risk regression to account for differential kidney transplantation rates across racial/ethnic groups, the African-American survival advantage was limited to >60 year old age categories. African-Americans and Hispanics were less likely to undergo kidney transplantation from all donor types vs. whites across all ages, and these disparities were even more pronounced for living donor kidney transplantations (LDKT).
Hispanic dialysis patients have greater survival vs. whites across all ages; in African-Americans, this survival advantage is limited to patients >40 years old. Minorities are less likely to undergo kidney transplantation, particularly LDKT, across all ages.
PMCID: PMC4024458  PMID: 24556752
Race; Ethnicity; Disparities; Survival; Transplantation
8.  Gentamicin Pharmacokinetics and Pharmacodynamics during Short-daily Hemodialysis 
American journal of nephrology  2012;36(2):144-150.
Gentamicin pharmacokinetics have not been described in patients undergoing short-daily hemodialysis (SDHD). The aim of this study is to describe gentamicin pharmacokinetics and dialytic clearance (Cldial) in SDHD patients and simulate gentamicin exposure after six dosing regimens to help guide future dosing.
Six anuric patients undergoing SDHD were enrolled. Patients received IV infusion of 2 mg/kg gentamicin on day 1 after first HD session followed by HD sessions on days 2, 3, and 4. Blood samples for determination of gentamicin concentrations were serially collected. Gentamicin pharmacokinetic parameters and Cldial and inter-individual variability terms (IIV) were estimated using NONMEM VII. Influence of patient weight on systemic clearance (Cls) and central volume of distribution (Vc) and influence of urea removal estimates on Cldial were assessed. The model was used to simulate gentamicin concentrations after six dosing regimens including pre- and post-dialysis as well as daily and every other day dosing.
A two-compartment model with first-order elimination from central compartment described gentamicin pharmacokinetics. Population estimates for Cls and Cldial were 7.6 and 134 ml/min, respectively. Patient weight was statistically significantly associated with Cls and Vc
Pre-dialysis every other day regimens were as effective (Cmax ≥ 8 mg/L and AUC48 hrs ≥ 140 and less toxic (Cmin < 2 mg/L and AUC48 hrs < 240 than post-dialysis regimens.
Estimated gentamicin Cldial is higher than previous estimates with thrice-weekly regimens. Pre-dialysis every other day dosing may be recommended during SDHD.
PMCID: PMC4303467  PMID: 22813936
gentamicin; hemodialysis; pharmacokinetics; renal failure
9.  Cystatin C enhances GFR estimating Equations in Kidney Transplant Recipients 
American journal of nephrology  2014;39(1):59-65.
The glomerular filtration rate (GFR) estimating equation incorporating both cystatin C and creatinine perform better than those using creatinine or cystatin C alone in patients with reduced GFR. Whether this equation performs well in kidney transplant recipients cross-sectionally, and more importantly, over time has not been addressed.
We analyzed four GFR estimating equations in participants of the Angiotensin II Blockade for Chronic Allograft Nephropathy Trial (NCT 00067990): Chronic Kidney Disease Epidemiology Collaboration equations based on serum cystatin C and creatinine (eGFR (CKD-EPI-Creat+CysC)), cystatin C alone (eGFR (CKD-EPI-CysC)), creatinine alone (eGFR (CKD-EPI-Creat)) and the Modification of Diet in Renal Disease study equation (eGFR(MDRD)). Iothalamate GFR served as a standard (mGFR).
mGFR, serum creatinine, and cystatin C shortly after transplant were 56.1 ± 17.0 mL/min/1.73 m2, 1.2 ± 0.4 mg/dL, and 1.2 ± 0.3 mg/L respectively. eGFR (CKD-EPI-Creat+CysC) was most precise (R2=0.50) but slightly more biased than eGFR (MDRD); 9.0 ± 12.7 ml/min/1.73m2 vs. 6.4 ± 15.8 ml/min/1.73m2, respectively. This improved precision was most evident in recipients with mGFR >60 ml/min/1.73m2. For relative accuracy, eGFR (MDRD) and eGFR (CKD-EPI-Creat+CysC) had the highest percentage of estimates falling within 30% of mGFR; 75.8% and 68.9%, respectively. Longitudinally, equations incorporating cystatin C most closely paralleled the change in mGFR.
eGFR (CKD-EPI-Creat+CysC) is more precise and reflects GFR change over time reasonably well. eGFR (MDRD) had superior performance in recipients with mGFR between 30–60 ml/min/1.73m2.
PMCID: PMC4026030  PMID: 24457184
Glomerular filtration rate; Chronic Kidney Disease Epidemiology Collaboration; Modification of Diet in Renal Disease; cystatin C; kidney transplantation
10.  Pre-end-stage renal disease care not associated with dialysis facility neighborhood poverty in the United States 
American journal of nephrology  2014;39(1):50-58.
Receipt of nephrology care prior to end-stage renal disease (ESRD) is a strong predictor of decreased mortality and morbidity, and neighborhood poverty may influence access to care. Our objective was to examine whether neighborhood poverty is associated with lack of pre-ESRD care at dialysis facilities.
In a multi-level ecological study using geospatially linked 2007-2010 Dialysis Facility Report and 2006-2010 American Community Survey data, we examined whether high neighborhood poverty (≥20% of households in census tract living below poverty) was associated with dialysis facility-level lack of pre-ESRD care (percentage of patients with no nephrology care prior to dialysis start) in mixed-effects models, adjusting for facility and neighborhood confounders and allowing for neighborhood and regional random effects.
Among the 5184 facilities examined, 1778 (34.3%) were located in a high poverty area. Lack of pre-ESRD care was similar in poverty areas (30.8%) and other neighborhoods (29.6%). With adjustment, the absolute increase in percentage of patients at a facility with no pre-ESRD care associated with facility location in a poverty area vs. other neighborhood was only 0.08% (95% CI: -1.32%, 1.47%; P=0.9). Potential effect modification by race and income inequality was detected.
Despite previously reported detrimental effects of neighborhood poverty on health, facility neighborhood poverty was not associated with receipt of pre-ESRD care, suggesting no need to target interventions to increase access to pre-ESRD care at facilities in poorer geographic areas.
PMCID: PMC3958935  PMID: 24434854
neighborhood; poverty; end-stage renal disease; access to care
11.  Effect of Food Insecurity on Chronic Kidney Disease in Lower Income Americans 
American journal of nephrology  2014;39(1):27-35.
The relation of food insecurity (inability to acquire nutritionally adequate and safe foods) and chronic kidney disease (CKD) is unknown. We examined whether food insecurity is associated with prevalent CKD among lower income individuals in both the general U.S. adult population and an urban population.
We conducted cross-sectional analyses of lower income participants of the National Health and Nutrition Examination Survey (NHANES) 2003–2008 (n=9,126); and the Healthy Aging in Neighborhoods of Diversity across the Life Span (HANDLS) study (n=1,239). Food insecurity was defined based on questionnaires and CKD was defined by reduced estimated glomerular filtration rate or albuminuria; adjustment was performed with multivariable logistic regression.
In NHANES, the age-adjusted prevalence of CKD was 20.3%, 17.6% and 15.7% for the high, marginal and no food insecurity groups, respectively. Analyses adjusting for sociodemographics and smoking status revealed high food insecurity to be associated with greater odds of CKD only among participants with either diabetes [odds ratio (OR) 1.67, 95% confidence interval (CI) 1.14–2.45 comparing high to no food insecurity group] or hypertension (OR 1.37, 95% CI 1.03–1.82). In HANDLS, the age-adjusted CKD prevalence was 5.9% and 4.6% for those with and without food insecurity, respectively (P=0.33). Food insecurity was associated with a trend towards greater odds of CKD (OR 1.46, 95% CI 0.98–2.18) with no evidence of effect modification across diabetes, hypertension or obesity subgroups.
Food insecurity may contribute to disparities in kidney disease, especially among persons with diabetes or hypertension, and is worthy of further study.
PMCID: PMC3952065  PMID: 24434743
renal; socioeconomic status; disparity; nutrition
Identifying the best method to estimate the glomerular filtration rate (GFR) in bariatric surgery patients has important implications for the clinical care of obese patients and research into the impact of obesity and weight reduction on kidney health. We therefore performed such an analysis in patients before and after surgical weight loss.
Fasting measured GFR (mGFR) by plasma iohexol clearance before and after bariatric surgery was obtained in 36 severely obese individuals. Estimated GFR (eGFR) was calculated using the MDRD, CKD-EPIcreat, CKD-EPIcystC, and CKD-EPIcreat-cystC equations and then compared to mGFR.
Participants were primarily middle-aged white females with a mean baseline body mass index of 46 ± 9 kg/m2, serum creatinine of 0.81 ± 0.24 mg/dl, and mGFR of 117 ± 40 ml/min. mGFR had a stronger linear relationship with inverse cystatin C before (r=0.28, p=0.09) and after (r=0.38, p=0.02) surgery compared to the inverse of creatinine (before: r=0.26, p=0.13; after: r=0.11, p=0.51). mGFR fell by 17 ± 35 ml/min (p=0.007) post-surgery. The CKD-EPIcreat-cystC was unquestionably the best overall performing estimating equation before and after surgery, reflecting very little bias and a capacity to estimate mGFR within 30% of its true value over 80% of the time. This was true whether or not mGFR was indexed for body surface area.
In severely obese bariatric surgery patients with normal kidney function cystatin C is more strongly associated with mGFR than is serum creatinine. The CKD-EPIcreat-cystC equation best predicted mGFR both before and after surgery.
PMCID: PMC3945154  PMID: 24356416
Obesity; bariatric surgery; glomerular filtration rate; creatinine; cystatin C; weight loss; estimating equation
13.  BK Virus Replication in Patients with ANCA Associated Vasculitis 
American journal of nephrology  2013;39(1):20-26.
BK virus (BKV) is an important cause of renal dysfunction in kidney transplant (KTX) recipients. Immunosuppression intensity is a major risk factor for BKV replication in these patients. The prevalence of BKV replication in immunosuppressed patients with granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) without transplant is not known.
Consecutive patients (N=37) with a diagnosis of GPA (N=25) or MPA (N=12) without history of KTX were evaluated for plasma BKV replication by quantitative PCR (Group A). Descriptive data were collected. BKV replication in this non-transplant immunosuppressed vasculitis cohort was compared to a historical cohort of vasculitis KTX recipients (Group B). Results: Group A patients had mean disease duration of 75 months. Mean age was 57yrs and 54% female. Mean time from vasculitis onset to BKV testing was 36 months and 19/37 patients were tested within 24 months of induction therapy. At the time of BKV testing, 73% were on prednisone (P) with azathioprine, mycophenolate mofetil (MMF), methotrexate or leflunomide. None of the non-transplanted vasculitis patients had detectable plasma BKV. Among 35 patients in group B, 16 were tested for BKV; 5/16 (31%) had detectable virus in plasma at a mean of 6 months post TX (P=0.002). Most (94%) were on maintenance therapy with MMF, P and tacrolimus.
Immunosuppressed patients with GPA/MPA without KTX had no evidence of plasma BKV. However, BKV was common in GPA/MPA patients after KTX suggesting that replication may be related to differences in immunosuppression, alloimmune activation or differences in host defense mechanisms.
PMCID: PMC4142761  PMID: 24401699
ANCA vasculitis; BK virus réplication; Granulomatosis with Polyangiitis; Microscopic Polyangiitis; immunosuppression
14.  The association of prevalent kidney stone disease with mortality in U.S. adults: the National Health and Nutrition Examination Survey III, 1988–1994 
American journal of nephrology  2013;37(5):501-506.
Kidney stone disease is associated with hypertension, diabetes, metabolic syndrome, kidney function decline and increased cardiovascular (CV) events. However, its association with all-cause and CV mortality is unclear.
We used The Third National Health and Nutrition Examination Survey, a large US population-based study with mortality data through 2006 determined via linkage to the National Death Index to examine kidney stone disease in relation to all-cause and CV mortality risks.
Among 14,879 men and women over 18 years of age who were eligible for analysis, 683 participants reported a history of kidney stones. There was a total of 3,590 all-cause and 1,608 CV deaths occurred during a median follow up of 14.9 years. Stone formers had a significantly higher risk for all-cause mortality (HR 1.95, 95% CI 1.64–2.33, p<0.0001), and CV mortality (HR 2.05, 95% CI 1.60–2.62, p<0.0001) in unadjusted analyses. However, after multivariate adjustment for age, gender, race and poverty, stone formers no longer had increased risk for all-cause mortality (HR 1.08, 95% CI 0.93–1.26, p=0.3) and CV mortality (HR 1.07, 95% CI 0.84–1.36, p=0.6). Results remain unchanged after further adjustment for other clinical variables including history of hypertension, diabetes, and CV disease.
The increased risk of all-cause and CV mortality in kidney stone formers is likely a reflection of unique demographics and associated co-morbidities. There is no independent association of prevalent kidney stone disease with all-cause and CV mortality.
PMCID: PMC4278430  PMID: 23635714
Mortality; Cardiovascular disease; Kidney stone disease
15.  Heart Rate Variability is a Predictor of Mortality in CKD - A Report from the CRIC Study 
American journal of nephrology  2013;38(6):517-528.
Low heart rate variability (HRV) is a risk factor for adverse outcomes in the general population. We aimed to determine the factors associated with HRV and evaluate the association between low HRV and clinical outcomes in patients with chronic kidney disease (CKD).
A 10 second electrocardiogram was obtained at baseline in the Chronic Renal Insufficiency Cohort (CRIC) Study. HRV was measured by the standard deviation of all R-R intervals (SDNN) and the root mean square of successive differences between R-R intervals (RMSSD).
In 3245 CRIC participants with available baseline SDNN and RMSSD, lower HRV was associated with older age, lack of exercise, heart failure, elevated phosphorus and hemoglobin A1c, and low estimated glomerular filtration rate. After a median follow-up of 4.2 years, in fully adjusted models, lower HRV was not associated with renal (SDNN: HR=0.96 (95% CI 0.88–1.05); RMSSD: HR=0.97 (95% CI 0.88–1.07)) or cardiovascular outcomes (SDNN: HR=1.02 (95% CI 0.92–1.13); RMSSD: HR=1.00 (95% CI 0.90–1.10)). There was a non-linear relationship between RMSSD and all-cause mortality with increased risk with both low and high RMSSD (P=0.04).
In a large cohort of participants with CKD, multiple risk factors for renal and cardiovascular disease were associated with lower HRV. Lower HRV was not associated with increased risk for renal or cardiovascular outcomes, but both low and high RMSSD were associated with increased risk for all-cause mortality. In conclusion, HRV as measured by RMSSD may be a novel and independent risk factor for mortality in CKD patients.
PMCID: PMC3920657  PMID: 24356377
electrocardiography; autonomic nervous system; chronic renal insufficiency; cardiovascular diseases; mortality
16.  Prevalence and Correlates of Fatigue in CKD and ESRD: Are Sleep Disorders a Key to Understanding Fatigue? 
American journal of nephrology  2013;38(6):489-495.
Fatigue is an important symptom to patients with advanced CKD. The aim of this study is to examine the prevalence and severity of fatigue among non-dialysis dependent CKD and ESRD patients; examine association of fatigue with subjective and objective sleep quality; identify other modifiable factors associated with fatigue.
Cross-sectional survey of 87 non-dialysis dependent CKD (eGFR ≤45 ml/min/1.73 m2) and 86 ESRD patients was done using Functional Assessment of Chronic Illness Therapy – Fatigue (FACIT-F) and SF-36 vitality scale. Higher FACIT-F score denoted less fatigue. Objective sleep was assessed using in-home polysomnography. Predictors of fatigue were determined using linear regression model.
Mean FACIT-F score among all participants was 34.5±11.0. Mean scores were similar among CKD and ESRD groups (34.25±11.28 versus 34.73±10.86; p=0.73). On univariate analyses, patients with higher levels of fatigue were more likely to have cardiovascular disease, benzodiazepine use, depressive symptoms, slightly lower hemoglobin and serum albumin levels. There was no significant association between severity of sleep apnea and level of fatigue (Apnea Hypopnea Index 20.1±27.6 versus 20.3±22.0; p=0.69). Presence of cardiovascular disease, low serum albumin, depressive symptoms, poor subjective sleep quality, excessive daytime sleepiness and restless legs syndrome (RLS) were independently associated with greater fatigue in multivariable regression models. The FACIT-F score correlated closely with the SF-36 vitality score (r =0.81, p<0.0001).
Patients with advanced CKD and ESRD experience profound fatigue. Depressive symptoms, RLS, excessive daytime sleepiness, and low albumin levels may provide targets for interventions to improve fatigue in patients with advanced CKD.
PMCID: PMC3925636  PMID: 24335380
End stage renal disease (ESRD); fatigue; sleep; chronic kidney disease; FACIT-F scale
17.  Adverse mandibular bone effects associated with kidney disease are only partially corrected with bisphosphonate and/or calcium treatment 
American journal of nephrology  2013;38(6):458-464.
Patients with chronic kidney disease (CKD) have high prevalence of periodontal disease that may predispose to tooth loss and inflammation. The goal of this study was to test the hypotheses that a genetic rat model of progressive CKD would exhibit altered oral bone properties and that treatment with either bisphosphonates or calcium could attenuate these adverse changes.
At 25 weeks of age, rats were treated with zoledronate, calcium gluconate, or their combination for 5 or 10 weeks. Mandible bone properties were assessed using micro-computed tomography to determine bone volume (BV/TV) and cement-enamel junction to alveolar crest distance (CEJ-AC).
Untreated CKD animals had significantly lower BV/TV at both 30 (−5%) and 35 (−14%) weeks of age and higher CEJ-AC (+27 and 29%) compared to normal animals. CKD animals had significantly higher PTH compared to normal animals yet similar levels of C-reactive protein. Zoledronate-treatment normalized BV/TV over the first 5 weeks but this benefit was lost by 10 weeks. Calcium treatment, alone or in combination with zoledronate, was effective in normalizing BV/TV at both time points. Neither zoledronate nor calcium was able to correct the higher CEJ-AC caused by CKD. Calcium, but not zoledronate, significantly reduced serum parathyroid hormone (PTH) while neither treatment affected C-reactive protein.
1) this progressive animal model of chronic kidney disease shows a clear mandibular skeletal phenotype consistent with periodontitis, 2) the periodontitis is not associated with systemic inflammation as measured by C-reactive protein, and 3) reducing PTH has positive effects on the mandible phenotype.
PMCID: PMC3904105  PMID: 24280830
zoledronate; c-reactive protein; parathyroid hormone; oral bone; anti-remodeling
18.  Perceptions regarding genetic testing in populations at risk for nephropathy 
American journal of nephrology  2013;38(6):453-457.
Population ancestry-based differences exist in genetic risk for many kidney diseases. Substantial debate remains regarding returning genetic test results to participants. African Americans (AAs) and European Americans (EAs) at risk for ESKD were queried for views on the value and use of genetic testing in research.
A standardized survey regarding attitudes toward genetic testing was administered to 130 individuals (64 AA; 66 EA) with first-degree relatives on dialysis. Fisher’s Exact Test was used to assess differences in participant attitudes between population groups.
Mean(SD) age of surveyed AAs and EAs was 45.5(12.8) and 50.5(14.4) years, respectively (p=0.04), with similar familial relationships (p=0.22). AAs and EAs wished to know their test results if risk could be: (1) reduced by diet or exercise (100% and 98%, p=0.99); (2) reduced by medical treatment (100% and 98%, p=0.99); or (3) if no treatments were available (90% and 82%, p=0.21). If informed they lacked a disease susceptibility variant, 87% of AAs and 88% of EAs would be extremely or pretty likely to inform family members (p=0.84). If informed they had a disease susceptibility variant, 92% of AAs and 89% of EAs would be extremely or pretty likely to inform their family (p=0.43).
Attitudes toward obtaining and using genetic test results for disease in research contexts were similar in AAs and EAs at risk for ESKD. A substantial majority would want information regardless of available treatments and would share information with family. These results have important implications for patient care, study design and the informed consent process.
PMCID: PMC3914164  PMID: 24280773
African Americans; bioethics; kidney disease; European Americans; genetic testing; risk prediction
19.  Dialysis dose and intra-dialytic hypotension – results from the HEMO Study 
American journal of nephrology  2013;38(5):388-396.
Intra-dialytic hypotension is common and is associated with increased morbidity and mortality in chronic hemodialysis patients. Higher dialysis ‘dose’ may generate transient intra-dialytic osmotic gradients, predisposing to intracellular fluid shifts and resulting in hypotension.
Study Design
We performed a post-hoc analysis of the HEMO Study, a multi-center trial that randomized chronic hemodialysis patients to high vs. standard Kt/V and higher vs. lower membrane flux. In order to achieve dose targets, per protocol, adjustments were made in membrane efficiency, blood flow, or dialysate flow before changing session length. Detailed hemodynamic and urea kinetic modeling data were abstracted from 1825 individuals. The primary outcome was the occurrence of hypotensive events necessitating clinical intervention (saline infusion, lowering of ultrafiltration rate or reduced blood flow).
Intra-dialytic hypotensive events occurred more frequently in the higher Kt/V group (18.3 vs. 16.8%; p<0.001). Participants randomized to higher target Kt/V had a greater adjusted risk of intra-dialytic hypotension than those randomized to standard Kt/V (OR 1.12; 95%CI 1.01–1.25). Higher KoA and rate of urea removal was associated with greater adjusted odds of intra-dialytic hypotension (OR 1.05; 95%CI 1.04–1.06 per mg/dL/hr).
Higher dialysis dose, over relatively constrained treatment times, may associate with an increased risk of intra-dialytic hypotension. These findings raise the possibility that rapidity of intra-dialytic reductions in plasma osmolality may have an important role in mediating hemodynamic instability.
PMCID: PMC3904183  PMID: 24192428
intra-dialytic hypotension; dose; urea reduction; osmolality; hemodialysis; HEMO Study
20.  Novel Approach to Estimate Kidney and Cyst Volumes using Mid-Slice Magnetic Resonance Images in Polycystic Kidney Disease 
American journal of nephrology  2013;38(4):10.1159/000355375.
To evaluate whether kidney and cyst volumes can be accurately estimated based on limited area measurements from MR images of patients with autosomal dominant polycystic kidney disease (ADPKD).
Materials and Methods
MR coronal images of 178 ADPKD participants from the Consortium for Radiologic Imaging Studies of ADPKD (CRISP) were analyzed. For each MR image slice, we measured kidney and renal cyst areas using stereology and region-based thresholding methods, respectively. The kidney and cyst ‘observed’ volumes were calculated by summing up the area measurements of all the slices covering the kidney. To estimate the volume, we selected a coronal mid-slice in each kidney and multiplied its area by the total number of slices (‘PANK2’ for kidney and ‘PANC2’ for cyst). We then compared the kidney and cyst volumes predicted from PANK2 and PANC2, respectively, to the corresponding observed volumes, using a linear regression analysis.
The kidney volume predicted from PANK2 correlated extremely well with the observed kidney volume: R2=0.994 for right and 0.991 for left kidney. The linear regression coefficient multiplier to PANK2 that best fit the kidney volume was 0.637 (95%CI: 0.629–0.644) for right and 0.624 (95%CI: 0.616–0.633) for left kidney. The correlation between the cyst volume predicted from PANC2 and the observed cyst volume was also very high: R2=0.984 for right and 0.967 for left kidney. The least squares linear regression coefficient for PANC2 was 0.637 (95%CI: 0.624–0.649) for right and 0.608 (95%CI: 0.591–0.625) for left kidney.
Kidney and cyst volumes can be closely approximated by multiplying the product of the mid-slice area measurement and the total number of slices in the coronal MR images of ADPKD kidneys by 0.61–0.64. This information will help save processing time needed to estimate total kidney and cyst volumes of ADPKD kidneys.
PMCID: PMC3863613  PMID: 24107679
kidney; polycystic kidney disease; kidney volume; renal cysts; magnetic resonance imaging
22.  Current Concepts in the Diagnosis and Classification of Renal Dysfunction in Cirrhosis 
American journal of nephrology  2013;38(4):345-354.
Renal dysfunction is one of the most common complications of cirrhosis with high morbidity and mortality.
In subjects with cirrhosis, renal dysfunction can present either as a direct consequence of cirrhosis (e.g. hepatorenal syndrome Type I and Type II) or secondary to etiologies other than cirrhosis (chronic kidney disease due to diabetic nephropathy, prerenal azotemia). Or, patients with cirrhosis may have renal dysfunction resulting directly from cirrhosis; and an underlying chronic kidney disease.
Key Messages
Given the challenges in the differential diagnosis of renal dysfunction and insufficient accuracy of serum creatinine and creatinine-based glomerular filtration rate estimating equations in cirrhosis, there is an urgent need for more accurate biomarkers of renal dysfunction in this population. This review will discuss novel concepts for the diagnosis and classification of renal dysfunction in cirrhosis to overcome at least some of the diagnostic and therapeutic challenges. Additionally, a new classification will be proposed for renal dysfunction in cirrhosis.
PMCID: PMC4072495  PMID: 24107793
Hepatorenal Syndrome; Cirrhosis; Creatinine; Cystatin C; Renal Dysfunction
23.  Physical Performance and Frailty in Chronic Kidney Disease 
American journal of nephrology  2013;38(4):307-315.
Poor physical performance and frailty are associated with elevated risks of death and disability. Chronic kidney disease (CKD) is also strongly associated with these outcomes. The risks of poor physical performance and frailty among CKD patients, however, are not well established.
We measured the Short Physical Performance Battery (SPPB, a summary test of gait speed, chair-raises and balance; range 0–12) and the five elements of frailty among 1111 Chronic Renal Insufficiency Cohort participants. Adjusting for demographics and multiple comorbidities, we fit a linear regression model for the outcome of SPPB score and an ordinal logistic regression model for frailty status.
Median (interquartile range [IQR]) age was 65 (57–71) years, median estimated glomerular filtration rate (eGFR) for non-dialysis patients was 49 (36–62) ml/min/1.73m2, and median SPPB score was 9 (7–10). Seven percent of participants were frail and 43% were pre-frail. Compared with the SPPB score for eGFR >60 ml/min/1.73m2, the SPPB was 0.51 points lower for eGFR 30 – 59; 0.61 points lower for eGFR 15 – 29; and 1.75 points lower for eGFR <15; (p<0.01 for all comparisons). eGFR 30 – 59 (OR 1.45; p=0.024), eGFR 15 – 29 (OR 2.02; p=0.002) and eGFR <15 (OR 4.83, p<0.001) were associated with worse frailty status compared with eGFR >60 ml/min/1.73m2.
CKD severity was associated with poor physical performance and frailty in a graded fashion. Future trials should determine if outcomes for CKD patients with frailty and poor physical performance are improved by targeted interventions.
PMCID: PMC4019506  PMID: 24107579
Physical performance; frailty; chronic kidney disease
24.  Differential diagnosis of glomerular disease: a systematic and inclusive approach 
American journal of nephrology  2013;38(3):10.1159/000354390.
Glomerular disease is a complex and evolving topic. In evaluating a specific case it is not unusual for the clinician to ask: Am I missing something? Should I biopsy? When? Should I treat first, then biopsy? This work, which is both evidence based and experience based, is intended to address each of these concerns, and many other issues relevant to the differential diagnosis of glomerular disease.
The central approach is the use of diagnostic algorithms that are based on quantitative measures routinely obtained early in the course of the diagnostic evaluation. The algorithms are designed to be easy to navigate, systematic, and inclusive. Also provided is a detailed and prioritized list of recommended diagnostic testing, and the rationale for each test.
Key message
This work is intended to facilitate accurate diagnosis in the individual patient presenting with evidence of glomerular disease.
PMCID: PMC3842189  PMID: 24052039
glomerular disease; proteinuria; glomerulonephritis
25.  Endothelial dysfunction occurs prior to clinical evidence of Polycystic Kidney Disease 
American journal of nephrology  2013;38(3):10.1159/000354236.
Polycystic kidney disease (PKD), a monogenic disease with an autosomal dominant or an autosomal recessive form of inheritance (ARPKD), is the most common genetic cause of renal dysfunction and end stage renal failure. In addition to the development of cysts, the autosomal form of PKD is associated with vascular endothelial dysfunction, a marker of vascular disease. Whether vascular endothelial dysfunction is also present in ARPKD, and the relationship with renal dysfunction remains to be determined.
ARPKD rats (PCK model) and controls were studied at 6 and 10 weeks of age, and mean arterial pressure (MAP) and renal function were measured. Aortic endothelial function was assessed using organ chamber techniques. Aortic endothelial cells (ECs) were isolated, characterized and their function studied.
Compared to controls, ARPKD animals had a decrease in the vasorelaxation to endothelium-dependent vasodilators, even prior to changes in MAP or renal function. The abnormal vasoreactivity was corrected with L-arginine (precursor to nitric oxide), while the expression of endothelial nitric oxide synthase (eNOS) was unchanged. Furthermore, isolated ECs from 6 week-old ARPKD animals showed increased oxidative stress, with preserved eNOS expression and abnormal patterns of migration and angiogenic capacity (measured by the scratch and tube formation assays, respectively).
ARPKD leads to impaired aortic vascular function and ECs at an early stage, which can have significant functional consequences, potentially representing a novel therapeutic target in this disease.
PMCID: PMC3835344  PMID: 24008943
polycystic kidney disease; cardiovascular; kidney; endothelial dysfunction; acetylcholine

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