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1.  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
2.  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
3.  Relationship of Copeptin, a Surrogate Marker for Arginine Vasopressin, With Change in Total Kidney Volume and GFR Decline in Autosomal Dominant Polycystic Kidney Disease: Results From the CRISP Cohort 
Experimental studies indicate that arginine vasopressin (AVP) may have deleterious effects in the pathogenesis of ADPKD. The significance of AVP in human ADPKD, however, is yet unclear.
Study design
Longitudinal, observational study with 8.5 (IQR, 7.7-9.0) years follow-up (CRISP; Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease).
Setting & Participants
241 ADPKD patients with creatinine clearance >70 mL/min.
Plasma copeptin concentration, a surrogate marker for vasopressin.
Change in measured glomerular filtration rate (mGFR, assessed by iothalamate clearance), and total kidney volume (TKV, measured by MRI).
Baseline copeptin, plasma and urinary osmolality, and measurements of TKV and mGFR during follow-up.
In these patients (median age, 34; [IQR, 25-40] years; 38% male; median mGFR, 94 [IQR, 79-145] mL/min/1.73 m2; median total kidney volume, 859 [IQR, 577-1299] mL) median copeptin level was 2.9 (IQR, 1.8-5.1) pmol/L. Copeptin was not associated with plasma osmolality (p=0.3), the physiologic stimulus for AVP release, but was significantly associated with change in TKV during follow-up (p<0.001). This association remained significant after adjusting for gender, age, cardiovascular risk factors and diuretic use (p=0.03). Copeptin level was borderline significantly associated with change in mGFR after adjusting for these variables (p=0.09).
No standardization of hydration status at time of copeptin measurement.
These data show that in ADPKD copeptin levels, as a marker for AVP, are not correlated with plasma osmolality. Most importantly, high copeptin levels are independently associated with disease progression in early ADPKD. This is in line with experimental studies that indicate a disease-promoting role for AVP.
PMCID: PMC3574620  PMID: 23089511
4.  Prevalence and Awareness of CKD Among African Americans: The Jackson Heart Study 
Chronic kidney disease (CKD) leads to End Stage Renal Disease (ESRD) and is a growing epidemic throughout the world. In the United States, African Americans have an incidence of ESRD four times that of Whites.
Study Design
Cross Sectional to examine the prevalence and awareness of CKD in African Americans
Setting & Participants
Observational Cohort in the Jackson Heart Study (JHS)
CKD was defined as estimated glomerular filtration rate < 60 ml/min/1.73 m2, presence of albuminuria, or being on dialysis
Outcomes and Measurements
Data from the Jackson Heart Study (JHS) were analyzed. Medical history including disease awareness and drug therapy, anthropometric measurements, serum, and urine samples were obtained from JHS participants at the baseline visit. Associations between CKD prevalence and awareness and selected demographic, socioeconomic, healthcare access, and disease status parameters were assessed utilizing logistic regression models.
The prevalence of CKD in the JHS was 20%; CKD awareness was only 15.8%. Older participants had higher prevalence but were also more aware of CKD. Hypertension, diabetes, cardiovascular disease (CVD), hypercholesterolemia, hypertriglyceridemia, increasing age and waist circumference as well as being single or less physically active were associated with CKD. Only advancing of CKD stage was associated with awareness.
Cross-sectional assessment, single urine measurement
The JHS has a high prevalence and low awareness of CKD, especially those with less severe disease status. This emphasizes the need for earlier diagnosis and increased education of health care providers and the general population.
PMCID: PMC2668959  PMID: 19166799
renal insufficiency; proteinuria; African American; chronic disease; epidemiology; population
5.  Sleep-Disordered Breathing Symptoms among African-Americans in the Jackson Heart Study 
Sleep medicine  2012;13(8):1039-1049.
Sleep-disordered breathing (SDB) is an increasingly recognized risk factor for cardiovascular disease (CVD). Limited data are available from large African American cohorts.
We examined the prevalence, burden, and correlates of sleep symptoms suggestive of SDB and risk for obstructive sleep apnea (OSA) in the Jackson Heart Study (JHS), an all-African-American cohort of 5,301 adults. Data on selected daytime and nighttime sleep symptoms were collected using a modified Berlin questionnaire during the baseline examination. Risk of OSA was calculated according to published prediction model. Age and multivariable-adjusted logistic regression models were used to examine the associations between potential risk factors and measures of sleep.
Sleep symptoms, burden, and risk of OSA were high among men and women in the JHS and increased with age and obesity. Being married was positively associated with sleep symptoms among women. In men, poor to fair perceived health and increased levels of stress were associated with higher odds of sleep burden, whereas prevalent hypertension and CVD were associated with higher odds of OSA risk. Similar associations were observed among women with slight variations. Sleep duration <7 hours was associated with increased odds of sleep symptoms among women and increased sleep burden among men. Moderate to severe restless sleep was consistently and positively associated with odds of adverse sleep symptoms, sleep burden, and high risk OSA.
Sleep symptoms in JHS had a strong positive association with features of visceral obesity, stress, and poor perceived health. With increasing obesity among younger African Americans, these findings are likely to have broad public health implications.
PMCID: PMC3427405  PMID: 22841028
African-American; epidemiology; Jackson Heart study; health status; obesity; sleep; sleep apnea syndromes; sleep disordered breathing
6.  Association between Circulating Specific Leukocyte Types and Incident Chronic Kidney Disease: the Atherosclerosis Risk in Communities (ARIC) Study 
Progressive renal fibrosis is a characteristic of all the diseases that cause renal failure and is invariably accompanied by a prominent leukocyte infiltration in the kidney. The goal of this study was to determine the association between the circulating specific leukocyte types, and incident chronic kidney disease (CKD). In a cohort of 10,056 middle aged white and African-American adults, levels of circulating neutrophils, lymphocytes and monocytes were measured at baseline; Blood pressure (BP) and serum creatinine were measured and estimated glomerular filtration rate (eGFR) was calculated at baseline and 3 and 9 years later; and surveillance for first hospitalization or death with CKD was carried out over a mean follow-up of 7.4 years (maximum 11.9 years). Increased neutrophil levels and decreased lymphocyte levels were significantly associated with greater CKD incidence after adjustment for covariates. African-Americans tended to have similar but stronger patterns of association between circulating leukocytes and CKD incidence than whites, although the differences between race groups were not statistically significant. We also found that eGFR and BPs were higher at each visit in African-Americans than whites between age 45–65. These findings support a potential role for circulating specific leukocytes in the pathogenesis of kidney dysfunction, especially in African-Americans indicating the leukocyte-related renal mechanism of essential hypertension (HT).
PMCID: PMC3275659  PMID: 22054781
Neutrophil; Lymphocyte; Glomerular hyperfiltration; Kidney dysfunction
7.  Association of Filtered Sodium Load With Medullary Volumes and Medullary Hypoxia in Hypertensive African Americans as Compared With Whites 
African-Americans (AA) develop hypertension earlier with more target manifestations than Whites despite having higher GFR for any level of serum creatinine.
Study Design and Participants
This study tested the hypothesis that increased GFR and sodium reabsorption in AA is associated with increased metabolic work and medullary hypoxia in 49 non-diabetic, essential hypertensive subjects (29 Whites and 20 AAs) taking constant sodium diet (150 mEq/d) and renin-angiotensin system blockade.
Ethnicity, age, measured GFR, sodium excretion, and body mass index.
We examined cortical and medullary volumes and blood flows using multi-detector CT and intra-renal deoxyhemoglobin (R2*) using blood oxygen level dependent (BOLD) MR.
Blood pressure and sodium excretion were similar, while AA were more obese and had higher iothalamate GFR. Renal cortical volumes did not differ, but medullary volumes adjusted for body size and age were higher in AA (32.3 ± 11.2 vs 24.9±7.4 cc/m2 BSA, p<.001). Sodium reabsorption and blood flows were higher in AA. Basal cortical deoxyhemoglobin was similar between ethnic groups, while medullary R2* was higher in AA (39.7± 5.1 vs 36.3± 6.5 /sec, p=.02), but fell to levels similar to Whites after furosemide. The circulating isoprostane prostaglandin F2α was higher in AA and daily urinary prostaglandin F2α excretion in AAs correlated directly with renal blood flow (R=0.71, p<.01).
Studies were limited to treated, volunteer subjects with normal kidney function without knowledge of prior nutrient intake.
These data demonstrate for the first time that increased sodium reabsorption in obese, hypertensive AA patients was associated with enlarged medullary volumes, functional hypoxia related to solute reabsorption, and a direct relationship between blood flows and urinary isoprostanes. Our results support a model of increased oxygen consumption and oxidative stress in AA that may accelerate hypertension and target-organ injury compared to white essential hypertensive patients.
PMCID: PMC3259240  PMID: 22130642
Hypertension; ethnicity; GFR; oxidative stress; BOLD MR; hemodynamics
8.  Genome-wide association study for serum urate concentrations and gout among African Americans identifies genomic risk loci and a novel URAT1 loss-of-function allele 
Human Molecular Genetics  2011;20(20):4056-4068.
Serum urate concentrations are highly heritable and elevated serum urate is a key risk factor for gout. Genome-wide association studies (GWAS) of serum urate in African American (AA) populations are lacking. We conducted a meta-analysis of GWAS of serum urate levels and gout among 5820 AA and a large candidate gene study among 6890 AA and 21 708 participants of European ancestry (EA) within the Candidate Gene Association Resource Consortium. Findings were tested for replication among 1996 independent AA individuals, and evaluated for their association among 28 283 EA participants of the CHARGE Consortium. Functional studies were conducted using 14C-urate transport assays in mammalian Chinese hamster ovary cells. In the discovery GWAS of serum urate, three loci achieved genome-wide significance (P< 5.0 × 10−8): a novel locus near SGK1/SLC2A12 on chromosome 6 (rs9321453, P= 1.0 × 10−9), and two loci previously identified in EA participants, SLC2A9 (P= 3.8 × 10−32) and SLC22A12 (P= 2.1 × 10−10). A novel rare non-synonymous variant of large effect size in SLC22A12, rs12800450 (minor allele frequency 0.01, G65W), was identified and replicated (beta −1.19 mg/dl, P= 2.7 × 10−16). 14C-urate transport assays showed reduced urate transport for the G65W URAT1 mutant. Finally, in analyses of 11 loci previously associated with serum urate in EA individuals, 10 of 11 lead single-nucleotide polymorphisms showed direction-consistent association with urate among AA. In summary, we identified and replicated one novel locus in association with serum urate levels and experimentally characterize the novel G65W variant in URAT1 as a functional allele. Our data support the importance of multi-ethnic GWAS in the identification of novel risk loci as well as functional variants.
PMCID: PMC3177647  PMID: 21768215
Although total white blood cell (WBC) count has been associated with hypertension, the association between specific WBC types and blood pressure (BP) levels has not been studied.
In a cohort of 5,746 middle-aged African-American and white adults free of clinical cardiovascular disease and cancer and not taking hypertension or anti-inflammatory medications, BP was measured at baseline and 3, 6, and 9 years later. Levels of circulating neutrophils, lymphocytes, and monocytes were measured at baseline.
In African-Americans, but much less so in whites, increased neutrophil levels and decreased lymphocyte levels were significantly associated with elevation of BP but did not influence the rate of change of BP over time. The mean BP difference between the highest and lowest quartiles of neutrophils was approximately 8 mmHg for systolic BP (SBP), 4 mmHg for mean arterial pressure (MAP), and 5 mmHg for pulse pressure (PP). The mean BP difference between the lowest and highest quartiles of lymphocytes was approximately 6 mmHg for SBP, 2 mmHg for diastolic BP (DBP), 3 mmHg for MAP, and 4 mmHg for PP.
Increased neutrophils and decreased lymphocytes are significantly correlated with the regulation of BP and the development of hypertension, especially in African-Americans.
PMCID: PMC3014578  PMID: 20980213
Inflammation; Hypertension; Neutrophil; Lymphocyte
10.  Genetic Association for Renal Traits among Participants of African Ancestry Reveals New Loci for Renal Function 
PLoS Genetics  2011;7(9):e1002264.
Chronic kidney disease (CKD) is an increasing global public health concern, particularly among populations of African ancestry. We performed an interrogation of known renal loci, genome-wide association (GWA), and IBC candidate-gene SNP association analyses in African Americans from the CARe Renal Consortium. In up to 8,110 participants, we performed meta-analyses of GWA and IBC array data for estimated glomerular filtration rate (eGFR), CKD (eGFR <60 mL/min/1.73 m2), urinary albumin-to-creatinine ratio (UACR), and microalbuminuria (UACR >30 mg/g) and interrogated the 250 kb flanking region around 24 SNPs previously identified in European Ancestry renal GWAS analyses. Findings were replicated in up to 4,358 African Americans. To assess function, individually identified genes were knocked down in zebrafish embryos by morpholino antisense oligonucleotides. Expression of kidney-specific genes was assessed by in situ hybridization, and glomerular filtration was evaluated by dextran clearance. Overall, 23 of 24 previously identified SNPs had direction-consistent associations with eGFR in African Americans, 2 of which achieved nominal significance (UMOD, PIP5K1B). Interrogation of the flanking regions uncovered 24 new index SNPs in African Americans, 12 of which were replicated (UMOD, ANXA9, GCKR, TFDP2, DAB2, VEGFA, ATXN2, GATM, SLC22A2, TMEM60, SLC6A13, and BCAS3). In addition, we identified 3 suggestive loci at DOK6 (p-value = 5.3×10−7) and FNDC1 (p-value = 3.0×10−7) for UACR, and KCNQ1 with eGFR (p = 3.6×10−6). Morpholino knockdown of kcnq1 in the zebrafish resulted in abnormal kidney development and filtration capacity. We identified several SNPs in association with eGFR in African Ancestry individuals, as well as 3 suggestive loci for UACR and eGFR. Functional genetic studies support a role for kcnq1 in glomerular development in zebrafish.
Author Summary
Chronic kidney disease (CKD) is an increasing global public health problem and disproportionately affects populations of African ancestry. Many studies have shown that genetic variants are associated with the development of CKD; however, similar studies are lacking in African ancestry populations. The CARe consortium consists of more than 8,000 individuals of African ancestry; genome-wide association analysis for renal-related phenotypes was conducted. In cross-ethnicity analyses, we found that 23 of 24 previously identified SNPs in European ancestry populations have the same effect direction in our samples of African ancestry. We also identified 3 suggestive genetic variants associated with measurement of kidney function. We then tested these genes in zebrafish knockdown models and demonstrated that kcnq1 is involved in kidney development in zebrafish. These results highlight the similarity of genetic variants across ethnicities and show that cross-species modeling in zebrafish is feasible for genes associated with chronic human disease.
PMCID: PMC3169523  PMID: 21931561
11.  Association of Socioeconomic Status and CKD among African Americans: The Jackson Heart Study 
Socioeconomic status (SES) is recognized as a key social environmental factor because it has implications for access to resources that help individuals care for themselves and others. Few studies have examined the association of SES with CKD in high-risk populations.
Study Design
Single-site longitudinal population-based cohort
Setting and Participants
The data for this study were drawn from the baseline examination of the Jackson Heart Study. The analytic cohort consisted of 3,430 African American men and women living in the tri-county area of the Jackson, Mississippi metropolitan areas with complete data to determine CKD status.
High SES (defined as having a family income at least 3.5 times the poverty level or having at least one undergraduate degree)
Outcomes and Measurements
CKD (defined as the presence of albuminuria or reduced estimated glomerular filtration rate (eGFR) <60 ml/min/1.73m2). Associations were explored through bivariable analyses and multivariable logistic regression analyses adjusting for CKD and cardiovascular disease risk factors as well as demographic factors.
The prevalence of CKD in the Jackson Heart Study was 20% (865/3430 participants). The proportion of the Jackson Heart Study cohort with albuminuria and decreased eGFR was 12.5% (429/3430 participants) and 10.1% (347/3430 participants) respectively. High SES was inversely associated with CKD. The odds of having CKD were 41% lower for affluent participants than their less affluent counterparts. There were no statistically significant interactions between sex and education or income although subgroup analysis showed that high income was associated with CKD among male (OR 0.47, CI 0.23–0.97) but not female (OR 0.64, CI 0.40–1.03) participants.
Models were estimated using cross-sectional data.
CKD is associated with SES. Additional research is needed to elucidate the impact of wealth and social contexts in which individuals are embedded, and the mediating effects of sociocultural factors.
PMCID: PMC2876216  PMID: 20381223
12.  The relation of C - reactive protein to chronic kidney disease in African Americans: the Jackson Heart Study 
BMC Nephrology  2010;11:1.
African Americans have an increased incidence and worse prognosis with chronic kidney disease (CKD - estimated glomerular filtration rate [eGFR] <60 ml/min/1.73 m2) than their counterparts of European-descent. Inflammation has been related to renal disease in non-Hispanic whites, but there are limited data on the role of inflammation in renal dysfunction in African Americans in the community.
We examined the cross-sectional relation of log transformed C-reactive protein (CRP) to renal function (eGFR by Modification of Diet and Renal Disease equation) in African American participants of the community-based Jackson Heart Study's first examination (2000 to 2004). We conducted multivariable linear regression relating CRP to eGFR adjusting for age, sex, body mass index, systolic and diastolic blood pressure, diabetes, total/HDL cholesterol, triglycerides, smoking, antihypertensive therapy, lipid lowering therapy, hormone replacement therapy, and prevalent cardiovascular disease events. In a secondary analysis we assessed the association of CRP with albuminuria (defined as albumin-to-creatinine ratio > 30 mg/g).
Participants (n = 4320, 63.2% women) had a mean age ± SD of 54.0 ± 12.8 years. The prevalence of CKD was 5.2% (n = 228 cases). In multivariable regression, CRP concentrations were higher in those with CKD compared to those without CKD (mean CRP 3.2 ± 1.1 mg/L vs. 2.4 ± 1.0 mg/L, respectively p < 0.0001). CRP was significantly associated with albuminuria in sex and age adjusted model however not in the multivariable adjusted model (p > 0.05).
CRP was associated with CKD however not albuminuria in multivariable-adjusted analyses. The study of inflammation in the progression of renal disease in African Americans merits further investigation.
PMCID: PMC2826325  PMID: 20078870
13.  Hemorrhagic Shock and Resuscitation-Mediated Tissue Water Distribution is Normalized by Adjunctive Peritoneal Resuscitation 
Adjunctive direct peritoneal resuscitation (DPR) from hemorrhagic shock (HS) improves intestinal blood flow and abrogates postresuscitation edema. HS causes water shifts as a result of sodium redistribution and changes in transcapillary Starling forces. Conventional resuscitation (CR) with crystalloid aggravates water sequestration. We examined the compartment pattern of organ tissue water after HS and CR, and modulation of tissue edema by adjunctive DPR.
Rats were hemorrhaged (40% mean arterial pressure for 60 minutes) and assigned to four groups (n = 7): sham, no HS; HS no resuscitation; HS+CR (shed blood plus 2 volumes Ringer’s lactate); and HS+CR+DPR (20 mL clinical intraperitoneal (IP) dialysis fluid). Isotopic markers determined equilibrium distribution volumes [VD] in gut, liver, lung, and muscle by quantitative autoradiography (2-hour postresuscitation). Total tissue water (TTW) was determined by wet-dry weights. Extracellular water was measured from 14C-mannitol VD, and intravascular volume (IVV) from 131I-labeled IgG VD. Cellular and interstitial water volumes were calculated.
HS alone decreased IVV in all tissues and TTW in gut, lung, and muscle, but not liver, compared with shams. IVV remained decreased with all resuscitations despite restoration of central hemodynamics. CR caused interstitial edema in gut, liver, and muscle, and cellular edema in lung. DPR reduced (liver, muscle) or prevented (gut, lung) these volume shifts.
HS decreases IVV. HS-induced water shifts are organ-specific and prominent in gut, lung, and muscle. CR restores central hemodynamics, does not restore IVV, and alters organ-specific TTW distribution. Adjunctive DPR with IP dialysis fluid normalizes TTW and water compartment distribution and prevents edema. Combined effect of DPR and intravascular fluid replacement appears to prevent global tissue edema and improve outcomes from HS.
PMCID: PMC2533357  PMID: 18471737

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