Coding Variants in Nephrin (NPHS1) and Susceptibility to Nephropathy in African Americans

Background and objectives

Presumed genetic risk for diabetic and nondiabetic end stage renal disease is strong in African Americans.

Design, setting, participants, & measurements

Exome sequencing data from African Americans with type 2 diabetic end stage renal disease and nondiabetic, non-nephropathy controls in the T2D-GENES study (Discovery, n=529 patients and n=535 controls) were evaluated, focusing on missense variants in NPHS1. Associated variants were then evaluated in independent type 2 diabetic end stage renal disease (Replication, n=1305 patients and n=760 controls), nondiabetic end stage renal disease (n=1705), and type 2 diabetes-only, non-nephropathy samples (n=503). All participants were recruited from dialysis facilities and internal medicine clinics across the southeastern United States from 1991 to present. Additional NPHS1 missense variants were identified from exome sequencing resources, genotyped, and sequence kernel association testing was then performed.

Results

Initial analysis identified rs35238405 (T233A; minor allele frequency=0.0096) as associated with type 2 diabetic end stage renal disease (adjustment for admixture P=0.042; adjustment for admixture+APOL1 P=0.080; odds ratio, 2.89 and 2.36, respectively); with replication in independent type 2 diabetic end stage renal disease samples (P=0.018; odds ratio, 4.30) and nondiabetic end stage renal disease samples (P=0.016; odds ratio, 4.48). In a combined analysis (all patients with end stage renal disease versus all controls), T233A was associated with all-cause end stage renal disease (P=0.0038; odds ratio, 2.82; n=3270 patients and n=1187 controls). A P-value of <0.001 was obtained after adjustment for admixture and APOL1 in sequence kernel association testing. Two additional variants (H800R and Y1174H) were nominally associated with protection from end stage renal disease (P=0.036; odds ratio, 0.44; P=0.0084; odds ratio, 0.040, respectively) in the locus-wide single-variant association tests.

Conclusions

Coding variants in NPHS1 are associated with both risk for and protection from common forms of nephropathy in African Americans.     

Association of APOL1 Genotype with Renal Histology among Black HIV-Positive Patients Undergoing Kidney Biopsy

Background and objectives

Prior studies have shown that the APOL1 risk alleles are associated with a greater risk of HIV-associated nephropathy and FSGS among blacks who are HIV positive. We sought to determine whether the APOL1 high–risk genotype incrementally improved the prediction of these underlying lesions beyond conventional clinical factors.

Design, setting, participants, & measurements

In a cross-sectional study, we analyzed data from 203 blacks who are HIV positive, underwent kidney biopsies between 1996 and 2011, and were genotyped for the APOL1 G1 and G2 alleles. Predictive logistic regression models with conventional clinical factors were compared with those that also included APOL1 genotype using receiver-operating curves and bootstrapping analyses with crossvalidation.

Results

The addition of APOL1 genotype to HIV–related risk factors for kidney disease in a predictive model improved the prediction of non–HIV–associated nephropathy FSGS, specifically, increasing the c statistic from 0.65 to 0.74 (P=0.04). Although two risk alleles were significantly associated with higher odds of HIV-associated nephropathy, APOL1 genotype did not add incrementally to the prediction of this specific histopathology.

Conclusions

APOL1 genotype may provide additional diagnostic information to traditional clinical variables in predicting underlying FSGS spectrum lesions in blacks who are HIV positive. In contrast, although APOL1 risk genotype predicts HIV-associated nephropathy, it lacked a high c statistic sufficient for discrimination to eliminate the role of kidney biopsy in the clinical care of blacks who are HIV positive with nephrotic proteinuria or unexplained kidney disease.     

Urinary Biomarkers and Risk of ESRD in the Atherosclerosis Risk in Communities Study

Background and objectives

Liver fatty acid binding protein (L-FABP), kidney injury molecule 1 (KIM-1), N-acetyl-β-d-glucosaminidase (NAG), and neutrophil gelatinase–associated lipocalin (NGAL) are urinary markers of tubular injury that may also be markers of chronic kidney damage. We evaluated the association of these markers with incident ESRD in a community-based sample from the Atherosclerosis Risk in Communities Study.

Design, setting, participants, & measurements

This was a matched case-control study of 135 patients with ESRD and 186 controls who were matched on sex, race, kidney function, and diabetes status at baseline (Atherosclerosis Risk in Communities Study visit 4, 1996–1998). Urinary KIM-1 indexed to creatinine (Cr), NAG/Cr, NGAL/Cr, and L-FABP/Cr were measured in stored spot urine samples from the baseline examination. Associations of KIM-1/Cr, NAG/Cr, and NGAL/Cr with patients with incident ESRD through 2008 were modeled continuously and categorically (quartiles) using conditional logistic regression. L-FABP/Cr was modeled only categorically because of a large number of measurements below the lower limit of detection for the assay (2.4 ng/ml).

Results

No significant associations were observed for NAG/Cr, NGAL/Cr, or L-FABP/Cr with ESRD. Those in the highest category for KIM-1/Cr had a higher risk of ESRD compared with those with undetectable biomarker levels (reference group) in unadjusted models (odds ratio, 2.24; 95% confidence interval, 1.97 to 4.69; P=0.03) or adjustment for age (odds ratio, 2.23; 95% confidence interval, 1.06 to 4.67; P=0.03). This association was attenuated with additional adjustment for baseline kidney function (odds ratio, 2.02; 95% confidence interval, 0.95 to 4.31; P=0.07 after additional adjustment for eGFR and natural log of the urinary albumin-to-creatinine ratio). No association between KIM-1/Cr and ESRD was found when KIM-1/Cr was analyzed as a continuous variable.

Conclusions

Elevated urinary KIM-1/Cr may be associated with a higher risk of incident ESRD, but it does not add to risk prediction after accounting for traditional markers of kidney function in this population.     

Examination of Potential Modifiers of the Association of APOL1 Alleles with CKD Progression

Background and objectives

Common apolipoprotein L1 (APOL1) variants are associated with increased risk of progressive CKD; however, not all individuals with high–risk APOL1 variants experience CKD progression. Identification of factors contributing to heterogeneity has important scientific and clinical implications.

Design, setting, participants, & measurements

Using multivariable Cox models, we analyzed data from 693 participants in the African American Study of Kidney Disease and Hypertension to identify factors that modify the association between APOL1 genotypes and CKD progression (doubling of serum creatinine or incident ESRD).

Results

Participant mean age was 54 years old, median GFR was 49 ml/min per 1.73 m², and 23% had the APOL1 high–risk genotype (two copies of the high-risk allele). Over a mean follow-up of 7.8 years, 288 (42%) participants experienced CKD progression. As previously reported, the high-risk genotype was associated with higher risk of CKD progression compared with the low-risk genotype (hazard ratio [HR], 1.88; 95% confidence interval [95% CI], 1.46 to 2.41). Although we found some suggestion that obesity (HR, 1.48; 95% CI, 1.05 to 2.08 and HR, 2.44; 95% CI, 1.66 to 3.57 for body mass index ≥30 versus <30 kg/m²; P interaction =0.04) and increased urinary excretion of urea nitrogen (HR, 1.43; 95% CI, 0.98 to 2.09 versus HR, 2.33; 95% CI, 1.65 to 3.30 for urine urea nitrogen ≥8 versus <8 g/d; P interaction =0.04) were associated with lower APOL1–associated risk for CKD progression, these findings were not robust in sensitivity analyses with alternative cut points. No other sociodemographic (e.g., education and income), clinical (e.g., systolic BP and smoking), or laboratory (e.g., net endogenous acid production, urinary sodium and potassium excretions, 25-hydroxy vitamin D, intact parathyroid hormone, or fibroblast growth factor 23) variables modified the association between APOL1 and CKD progression (P interaction >0.05 for each).

Conclusions

Sociodemographic factors and common risk factors for CKD progression do not seem to alter APOL1–related CKD progression. Additional investigation is needed to identify nontraditional factors that may affect the association between APOL1 and progressive CKD.     

Asymmetric Dimethylarginine,Race, and Mortality in Hemodialysis Patients

Background and objectives

Levels of asymmetric dimethylarginine, an inhibitor of nitric oxide synthase, are elevated in kidney disease and associated with mortality in white European hemodialysis populations. Nitric oxide production and degradation are partially genetically determined and differ by racial background. No studies have measured asymmetric dimethylarginine in African Americans on dialysis and assessed whether differences exist in its association with mortality by race.

Design, setting, participants, & measurements

Asymmetric dimethylarginine was measured in 259 patients on maintenance hemodialysis assembled from 2004 to 2012 in Boston area outpatient centers. Cox proportional hazards models were used to determine the association between asymmetric dimethylarginine and all-cause mortality, and an interaction with race was tested.

Results

Mean (SD) age was 63 (17) years, 46% were women, and 22% were African American. Mean asymmetric dimethylarginine in non–African Americans was 0.79 µmol/L (0.16) versus 0.70 µmol/L (0.11) in African Americans (P<0.001); 130 patients died over a median follow-up of 2.3 years. African Americans had lower mortality risk than non–African Americans (hazard ratio, 0.27; 95% confidence interval, 0.15 to 0.50) that was robust to adjustment for age, comorbidity, and asymmetric dimethylarginine (hazard ratio, 0.35; 95% confidence interval, 0.17 to 0.69). An interaction was noted between race and asymmetric dimethylarginine (P=0.03), such that asymmetric dimethylarginine was associated with higher mortality in non–African Americans (adjusted hazard ratio, 1.29; 95% confidence interval, 1.06 to 1.57 per 1 SD higher asymmetric dimethylarginine) but not in African Americans (adjusted hazard ratio, 0.57; 95% confidence interval, 0.28 to 1.18). Additional adjustment for fibroblast growth factor 23 partially attenuated the association for non–African Americans (adjusted hazard ratio, 1.22; 95% confidence interval, 0.98 to 1.50).

Conclusions

African Americans have lower asymmetric dimethylarginine levels and lower hazard for mortality compared with non–African Americans. Levels of asymmetric dimethylarginine did not explain lower hazard for mortality in non–African American patients. High asymmetric dimethylarginine was a risk factor for mortality exclusively in non–African Americans. Mechanisms explaining these relationships need to be evaluated.     

Long-Term Risk of Cancer in Survivors of Pediatric ESRD

Background and objectives

ESRD is associated with an increased risk of malignancies. We analyzed the incidence of cancer in patients with pediatric ESRD after long–term follow-up.

Design, setting, participants, & measurements

All Dutch patients born before 1979 who were transplanted at age <15 years old in 1972–1992 were followed until 2010. We explored type and incidence of malignancies in patients compared with the general population using the National Cancer Registry.

Results

After a median of 25.3 years (1.3–37.8) of transplantation and at a median age of 33.5 years old (11.0–49.0), 105 primary malignancies had occurred in 54 of 249 patients. Among them, cutaneous squamous cell carcinoma was most frequent. Patients ages 25–30 years old had developed 16.5 times (95% confidence interval, 7.9 to 34.6) as many de novo tumors and 991 times (95% confidence interval, 313 to 3137) as many de novo cutaneous squamous cell carcinomas as their general population counterparts; in survivors ages 45–50 years old, these numbers were 81.5 (95% confidence interval, 50.7 to 131.1) and 2610 (95% confidence interval, 1596 to 4267), respectively. Cumulative incidence competing risk analysis showed that, after 30 years of transplantation, 41% of the survivors had developed cancer; 31% had developed a second de novo cancer <1 year after initial cancer diagnosis.

Conclusions

Cancer is highly prevalent among patients with pediatric ESRD after 25.3 years of transplantation, with a high rate of recurrence.     

Adiposity Patterns and the Risk for ESRD in Postmenopausal Women

Background and objectives

Body mass index and waist circumference associate with adverse health outcomes, including CKD. Studies of the association of body mass index and ESRD have been inconsistent; these adiposity measures have not been previously assessed together for ESRD risk or among postmenopausal women.

Design, settings, participants, & measurements

This was prospective cohort study of 20,117 postmenopausal women enrolled in the multiethnic cohort of the Women’s Health Initiative. Body mass index and waist circumference were obtained at baseline, incident ESRD was obtained from the US Renal Data System, and all-cause death was obtained from surveillance data. A competing-risk framework was used to account for the effect of mortality before ESRD while adjusting for significant predictors and baseline kidney function. Associations of adiposity with mortality were also studied.

Results

Events included 212 patients with incident ESRD and 3104 deaths for a mean follow-up of 11.6 years. Increased waist circumference and body mass index were associated with 2.59- (95% confidence interval, 1.89 to 3.53) and 1.97-fold (95% confidence interval, 1.30 to 2.98) higher hazards of ESRD as well as 1.42- (95% confidence interval, 1.32 to 1.53) and 1.21-fold (95% confidence interval, 1.11 to 1.33) higher hazards of death, respectively, compared with the lower categories in adjusted analyses. The associations of waist circumference with ESRD varied by baseline renal function (P for interaction=0.01) and were significant only among women without baseline eGFR-defined CKD (hazard ratio, 1.93; 95% confidence interval, 1.23 to 3.03).

Conclusions

Central obesity was associated with an increased risk of ESRD in postmenopausal women, even among women with normal body mass index but not among women with reduced baseline kidney function, and an increased risk of death. Body mass index was associated with ESRD, and the association is likely mediated through hypertension and diabetes.     

Risk of Stroke in Patients with ESRD

Background and objectives

This study aimed to determine absolute and excess stroke risks in people with ESRD compared with the general population.

Design, setting, participants, & measurements

This cohort study used data linkage between the Australia and New Zealand Dialysis and Transplant Registry and hospital and death records for 10,745 people with ESRD in New South Wales from 2000 to 2010. For the general population, Australian Institute of Health and Welfare hospital usage records and Australian Bureau of Statistics census data were used. Rates and standardized incidence rate ratios of hospitalization with a stroke were calculated.

Results

People with ESRD had 640 hospitalizations with stroke in 49,472 person-years of follow-up (1294 per 100,000 person-years), and people in the general population had 338,392 hospitalizations with stroke (212 per 100,000 person-years), an incidence rate ratio of 3.32 (95% confidence interval, 3.31 to 3.33). Excess risk was greater for women (incidence rate ratio, 5.14; 95% confidence interval, 5.11 to 5.18) than men (incidence rate ratio, 2.52; 95% confidence interval, 2.51 to 2.54; P for interaction <0.001) and decreased with age. People ages 35–39 years old with ESRD had an 11 times increased risk of stroke (incidence rate ratio, 11.08; 95% confidence interval, 9.41 to 13.05), and risk in people ages ≥85 years old increased 2-fold (incidence rate ratio, 2.04; 95% confidence interval, 1.87 to 2.23; P for interaction <0.001). Excess risk was greater for intracerebral hemorrhage (incidence rate ratio, 4.18; 95% confidence interval, 4.11 to 4.26) than ischemic stroke (incidence rate ratio, 3.43; 95% confidence interval, 3.40 to 3.45; P for interaction <0.01).

Conclusions

People with ESRD have a substantially higher risk of stroke, particularly women and young people, and hemorrhagic stroke. Future work could investigate effective and safe interventions for primary and secondary prevention of stroke in people with ESRD.     

Genetic African Ancestry and Markers of Mineral Metabolism in CKD

Background and objectives

Disorders of mineral metabolism are more common in African Americans with CKD than in European Americans with CKD. Previous studies have focused on the differences in mineral metabolism by self-reported race, making it difficult to delineate the importance of environmental compared with biologic factors.

Design, setting, participants, & measurements

In a cross-sectional analysis of 3013 participants of the Chronic Renal Insufficiency Cohort study with complete data, we compared markers of mineral metabolism (phosphorus, calcium, alkaline phosphatase, parathyroid hormone, fibroblast growth factor 23, and urine calcium and phosphorus excretion) in European Americans versus African Americans and separately, across quartiles of genetic African ancestry in African Americans (n=1490).

Results

Compared with European Americans, African Americans had higher blood concentrations of phosphorus, alkaline phosphatase, fibroblast growth factor 23, and parathyroid hormone, lower 24-hour urinary excretion of calcium and phosphorus, and lower urinary fractional excretion of calcium and phosphorus at baseline (P<0.001 for all). Among African Americans, a higher percentage of African ancestry was associated with lower 24-hour urinary excretion of phosphorus (P_trend<0.01) in unadjusted analyses. In linear regression models adjusted for socio-demographic characteristics, kidney function, serum phosphorus, and dietary phosphorus intake, higher percentage of African ancestry was significantly associated with lower 24-hour urinary phosphorus excretion (each 10% higher African ancestry was associated with 39.6 mg lower 24-hour urinary phosphorus, P<0.001) and fractional excretion of phosphorus (each 10% higher African ancestry was associated with an absolute 1.1% lower fractional excretion of phosphorus, P=0.01).

Conclusions

A higher percentage of African ancestry was independently associated with lower 24-hour urinary phosphorus excretion and lower fractional excretion of phosphorus among African Americans with CKD. These findings suggest that genetic variability might contribute to racial differences in urinary phosphorus excretion in CKD.     

Identification of Strategies to Facilitate Organ Donation among African Americans using the Nominal Group Technique

Background and objectives

African Americans are disproportionately affected by ESRD, but few receive a living donor kidney transplant. Surveys assessing attitudes toward donation have shown that African Americans are less likely to express a willingness to donate their own organs. Studies aimed at understanding factors that may facilitate the willingness of African Americans to become organ donors are needed.

Design, setting, participants, & measurements

A novel formative research method was used (the nominal group technique) to identify and prioritize strategies for facilitating increases in organ donation among church-attending African Americans. Four nominal group technique panel interviews were convened (three community and one clergy). Each community panel represented a distinct local church; the clergy panel represented five distinct faith-based denominations. Before nominal group technique interviews, participants completed a questionnaire that assessed willingness to become a donor; 28 African-American adults (≥19 years old) participated in the study.

Results

In total, 66.7% of participants identified knowledge- or education-related strategies as most important strategies in facilitating willingness to become an organ donor, a view that was even more pronounced among clergy. Three of four nominal group technique panels rated a knowledge-based strategy as the most important and included strategies, such as information on donor involvement and donation-related risks; 29.6% of participants indicated that they disagreed with deceased donation, and 37% of participants disagreed with living donation. Community participants’ reservations about becoming an organ donor were similar for living (38.1%) and deceased (33.4%) donation; in contrast, clergy participants were more likely to express reservations about living donation (33.3% versus 16.7%).

Conclusions

These data indicate a greater opposition to living donation compared with donation after one’s death among African Americans and suggest that improving knowledge about organ donation, particularly with regard to donor involvement and donation-related risks, may facilitate increases in organ donation. Existing educational campaigns may fall short of meeting information needs of African Americans.     

Urinary Creatinine Excretion,Bioelectrical Impedance Analysis,and Clinical Outcomes in Patients with CKD: The CRIC Study

Background and objectives

Previous studies in chronic disease states have demonstrated an association between lower urinary creatinine excretion (UCr) and increased mortality, a finding presumed to reflect the effect of low muscle mass on clinical outcomes. Little is known about the relationship between UCr and other measures of body composition in terms of the ability to predict outcomes of interest.

Design, setting, participants, & measurements

Using data from the Chronic Renal Insufficiency Cohort (CRIC), the relationship between UCr, fat free mass (FFM) as estimated by bioelectrical impedance analysis, and (in a subpopulation) whole-body dual-energy x-ray absorptiometry assessment of appendicular lean mass were characterized. The associations of UCr and FFM with mortality and ESRD were compared using Cox proportional hazards models.

Results

A total of 3604 CRIC participants (91% of the full CRIC cohort) with both a baseline UCr and FFM measurement were included; of these, 232 had contemporaneous dual-energy x-ray absorptiometry measurements. Participants were recruited between July 2003 and March 2007. UCr and FFM were modestly correlated (rho=0.50; P<0.001), while FFM and appendicular lean mass were highly correlated (rho=0.91; P<0.001). Higher urinary urea nitrogen, black race, younger age, and lower serum cystatin C level were all significantly associated with higher UCr. Over a median (interquartile range) of 4.2 (3.1–5.0) years of follow-up, 336 (9.3%) participants died and 510 (14.2%) reached ESRD. Lower UCr was associated with death and ESRD even after adjustment for FFM (adjusted hazard ratio for death per 1 SD higher level of UCr, 0.63 [95% confidence interval, 0.56 to 0.72]; adjusted hazard ratio for ESRD per 1 SD higher level of UCr, 0.70 [95% confidence interval, 0.63 to 0.75]).

Conclusions

Among a cohort of individuals with CKD, lower UCr is associated with death and ESRD independent of FFM as assessed by bioelectrical impedance analysis.     

Menopause,complement, and hemostatic markers in women at midlife: The Study of Women's Health Across the Nation

Objective

To evaluate whether higher circulating levels of complement proteins C3 and C4 are associated with menopausal status and with hemostatic/thrombus formation markers (circulating factor VII (factor VIIc), fibrinogen, plasminogen activator inhibitor-1 (PAI-1) and tissue plasminogen activator antigen (tPA-ag)) in a sample of midlife women.

Methods and results

A total of 100 women (50 late peri-/postmenopausal and 50 pre-/early peri- menopausal women) from the Study of Women's Health Across the Nation (SWAN) Pittsburgh site were included in the present analysis. Factor VIIc and PAI-1 were log transformed. Linear regression was used for analysis. The mean age of the study participants was 50.5 ± 2.6 years with 73% were Caucasian and 27% were African American. C3 but not C4 was significantly higher in postmenopausal women compared to premenopausal women (P value = 0.03), adjusting for age, race and BMI. In final model (adjusting for age, race, BMI and menopausal status), C3 was associated with higher levels of log PAI-1 (P value = 0.0009) and tPA-ag (P value = 0.0003), while C4 was associated with higher levels of log factor VIIc (P value = 0.04) and fibrinogen (P value = 0.005).

Conclusions

These data suggest that C3 and C4 may be related to blood clots via their associations with hemostatic markers and that C3 is related to menopausal status. Complement proteins C3 and C4 could be possible pathways by which postmenopausal women are at higher risk of atherosclerosis and cardiovascular related events. It is important to replicate these findings in a larger sample size.     

Retinopathy and Progression of CKD: The CRIC Study

Background and objectives

Retinal abnormalities may be associated with changes in the renal vasculature. This study assessed the association between retinopathy and progression of kidney disease in participants of the Chronic Renal Insufficiency Cohort (CRIC) study.

Design, setting, participants, & measurements

This was a prospective study in which patients with CKD enrolled in CRIC had nonmydriatic fundus photographs of both eyes. All CRIC participants in six clinical sites in which fundus cameras were deployed were offered participation. Photographs were reviewed at a reading center. The presence and severity of retinopathy and vessel calibers were assessed using standard protocols by graders masked to clinical information. The associations of retinal features with changes in eGFR and the need for RRT (ESRD) were assessed.

Results

Retinal images and renal progression outcomes were obtained from 1852 of the 2605 participants (71.1%) approached. During follow-up (median 2.3 years), 152 participants (8.2%) developed ESRD. Presence and severity of retinopathy at baseline were strongly associated with the risk of subsequent progression to ESRD and reductions in eGFR in unadjusted analyses. For example, participants with retinopathy were 4.4 times (95% confidence interval [95% CI], 3.12 to 6.31) more likely to develop ESRD than those without retinopathy (P<0.001). However, this association was not statistically significant after adjustment for initial eGFR and 24-hour proteinuria. Venular and arteriolar diameter calibers were not associated with ESRD or eGFR decline. The results showed a nonlinear relationship between mean ratio of arteriole/vein calibers and the risk of progression to ESRD; participants within the fourth arteriole/vein ratio quartile were 3.11 times (95% CI, 1.51 to 6.40) more likely to develop ESRD than those in the first quartile (P<0.001).

Conclusions

The presence and severity of retinopathy were not associated with ESRD and decline in eGFR after taking into account established risk factors.     

External Validation of the Kidney Failure Risk Equation and Re-Calibration with Addition of Ultrasound Parameters

Background and objectives

Progression of CKD toward ESRD is heterogeneous. The Kidney Failure Risk Equation (KFRE) was developed to identify CKD patients at high risk of ESRD. We aimed to externally validate KFRE and to test whether the addition of predefined Duplex ultrasound markers – renal resistive index (RRI) or difference of resistive indices in spleen and kidney (DI-RISK) – improved ESRD prediction.

Design, setting, participants, & measurements

The prospective Cardiovascular and Renal Outcome in CKD 2-4 Patients—The Fourth Homburg evaluation (CARE FOR HOMe) study recruits CKD stage G2–G4 patients referred to a tertiary referral center for nephrologic care. Four hundred three CARE FOR HOMe participants enrolled between 2008 and 2012 had available RRI measurements at study inclusion; they were subsequently followed for a mean of 4.4±1.6 years. This subcohort was used to validate KFRE and to assess the added value of the ultrasound markers (new models KFRE+RRI and KFRE+DI-RISK). Model performance was assessed by log-likelihood ratio test, c-statistic, integrated discrimination improvement metrics (for study participants without subsequent ESRD [IDI _{No ESRD}] and for patients with ESRD [IDI _ESRD]), and calibration plots. If either new model improved on KFRE, we determined to validate it in an independent cohort of 162 CKD patients.

Results

KFRE predicted ESRD in CARE FOR HOMe participants with a c-statistic of 0.91 (95% confidence interval, 0.83 to 0.99). Adding RRI improved the KFRE model (P<0.001), and the KFRE+RRI model was well calibrated; however, the c-statistic (0.91 [0.83–1.00]) was similar, and overall sensitivity (IDI _{No ESRD}=0.05 [0.00–0.10]) or overall specificity (IDI _ESRD=0.00 [0.00–0.01]) did not improve. Adding DI-RISK did not improve the KRFE model. In the external validation cohort, we confirmed that the KFRE+RRI model did not outperform KFRE.

Conclusions

Routine Duplex examinations among CKD patients did not improve risk prediction for progression to ESRD beyond a validated equation.     

Renal Parenchymal Area and Risk of ESRD in Boys with Posterior Urethral Valves

Background and objectives

Approximately 20% of boys with posterior urethral valves develop ESRD; however, few factors associated with the risk of ESRD have been identified. The objective of this study was to determine if renal parenchymal area, defined as the area of the kidney minus the area of the pelvicaliceal system on first postnatal ultrasound, is associated with the risk of ESRD in infants with posterior urethral valves.

Design, setting, participants, & measurements

A retrospective cohort of boys who were diagnosed with posterior urethral valves at less than 6 months of age between 1988 and 2011 and followed for at least 1 year at a free-standing children’s hospital was assembled. Cox proportional hazard regression and Kaplan–Meier analysis were used to estimate the association between renal parenchymal area and time to ESRD. Cox models were adjusted for age at presentation, minimum creatinine 1 month after bladder decompression, and vesicoureteral reflux.

Results

Sixty patients were followed for 393 person-years. Eight patients developed ESRD. Median renal parenchymal area was 15.9 cm² (interquartile range=13.0–21.6 cm²). Each 1-cm² increase in renal parenchymal area was associated with a lower risk of ESRD (hazard ratio, 0.64; 95% confidence interval, 0.42 to 0.98). The rate of time to ESRD was 10 times higher in boys with renal parenchymal area<12.4 cm² than boys with renal parenchymal area≥12.4 cm² (P<0.001). Renal parenchymal area could best discriminate children at risk for ESRD when the minimum creatinine in the first 1 month after bladder decompression was between 0.8 and 1.1 mg/dl.

Conclusion

In boys with posterior urethral valves presenting during the first 6 months of life, lower renal parenchymal area is associated with an increased risk of ESRD during childhood. The predictive ability of renal parenchymal area, which is available at time of diagnosis, should be validated in a larger, prospectively-enrolled cohort.     

Nephron Hypertrophy and Glomerulosclerosis and Their Association with Kidney Function and Risk Factors among Living Kidney Donors

Background and objectives

The relationship of kidney function and CKD risk factors to structural changes in the renal parenchyma of normal adults is unclear. This study assessed whether nephron hypertrophy and nephrosclerosis had similar or different associations with kidney function and risk factors.

Design, setting, participants, & measurements

From 1999 to 2009, 1395 living kidney donors had a core needle biopsy of their donated kidney during transplant surgery. The mean nonsclerotic glomerular volume and glomerular density (globally sclerotic and nonsclerotic) were estimated using the Weibel and Gomez stereologic methods. All tubules were counted in 1 cm² of cortex to determine a mean profile tubular area. Nephron hypertrophy was identified by larger glomerular volume, larger profile tubular area, and lower nonsclerotic glomerular density. Nephrosclerosis was identified by higher globally sclerotic glomerular density.

Results

The mean (±SD) age was 44±12 years, 24-hour urine albumin excretion was 5±7 mg, measured GFR was 103±17 ml/min per 1.73 m², uric acid was 5.2±1.4 mg/dl, and body mass index was 28±5 kg/m². Of the study participants, 43% were men, 11% had hypertension, and 52% had a family history of ESRD. Larger glomerular volume, larger profile tubular area, and lower nonsclerotic glomerular density were correlated. Male sex, higher 24-hour urine albumin excretion, family history of ESRD, and higher body mass index were independently associated with each of these measures of nephron hypertrophy. Higher uric acid, higher GFR, and older age were also independently associated with some of these measures of nephron hypertrophy. Hypertension was not independently associated with measures of nephron hypertrophy. However, hypertension and older age were independently associated with higher globally sclerotic glomerular density.

Conclusions

Nephron hypertrophy and nephrosclerosis are structural characteristics in normal adults that relate differently to clinical characteristics and may reflect kidney function and risk factors via separate but inter-related pathways.     

Abdominal adiposity depots are correlates of adverse cardiometabolic risk factors in Caucasian and African-American adults

Objective:

Accumulation of adipose tissue is associated with cardiometabolic risks. Although visceral adipose tissue (VAT) has been strongly implicated in this relationship, there is still some debate regarding the contribution of abdominal subcutaneous adipose tissue (SAT). The purpose of this study was to determine the contribution of abdominal SAT to cardiometabolic risk factors, independent of total and visceral adiposity. These relationships were assessed in Caucasian and African Americans.

Design:

It is a cross-sectional analysis of the Pennington Center Longitudinal Study.

Subjects:

Data were extracted from 1246 participants. Total body fat mass (FM) was measured by dual-energy X-ray absorptiometry, whereas abdominal VAT and SAT areas (cm²) were measured with computed tomography. The cardiometabolic risk factors included resting blood pressure (BP), fasting blood glucose and triglyceride concentrations and high-density lipoprotein cholesterol (HDL-C).

Results:

Positive relationships across tertiles of VAT were seen for the participants with high glucose, high BP and low HDL-C (P<0.043). There was also a significant increase in the percentage of participants with two or more cardiometabolic risk factors across most tertiles of abdominal SAT (P<0.042). Logistic regression analysis showed that in univariate models, all adiposity measures were significantly associated with increased odds of having all risk factors in men and women. In multivariate models, VAT was significantly associated with most risk factors across gender. Abdominal SAT and FM (odds ratios (ORs) 1.3–2.1; all P<0.05) were associated with fewer risk factors after accounting for VAT. VAT (OR=5.9 and 5.3) and SAT (OR=2.0 and 1.8) were both associated with higher odds of the presence of two or more cardiometabolic risk factors in both males and females (P<0.001).

Conclusion:

The data suggest that abdominal SAT is not protective against unfavorable cardiometabolic risk profiles. These conclusions were consistent across ethnic groups.     

The Relationship between Epicardial Adipose Tissue and Malnutrition,Inflammation, Atherosclerosis/Calcification Syndrome in ESRD Patients

Summary

Background and objectives

Malnutrition, inflammation, atherosclerosis/calcification (MIAC) and endothelial dysfunction are the most commonly encountered risk factors in the pathogenesis of cardiovascular disease in ESRD patients. Epicardial adipose tissue (EAT) is the true visceral fat depot of the heart. The relationship between CAD and EAT was shown in patients with high risk of coronary artery disease. In this study, we aimed to investigate the relationship between EAT and MIAC syndrome in ESRD patients.

Design, setting, participants, & measurements

Eighty ESRD patients and 27 healthy subjects enrolled in this cross-sectional study. EAT and coronary artery calcification score were measured by a multidetector computed tomography (MDCT) scanner. Patients with serum albumin <3.5 mg/dl were defined as patients with malnutrition; those with serum C-reactive protein level >10 ng/dl (normal range, 0–5 ng/dl) had inflammation; and those with CACS >10 had atheroscleosis/calcification.

Results

Total CACS and EAT measurements were significantly higher in ESRD patients when compared with healthy subjects. There was a statistically significant relationship between EAT and CACS in ESRD patients (r = 0.48). EAT measurements were higher in PD patients than HD patients. Twenty-four of the patients had no component, 31 had one component, 17 had two components, and nine had all of the MIAC components. EAT was found to be significantly increased when the presence of MIAC components increased. EAT was positively correlated with age, body mass index, and presence of MIAC. These parameters were also found as independent predictors of increased EAT.

Conclusions

We found a relationship between EAT and components of MIAC syndrome in ESRD patients.     

Nephrolithiasis as a Risk Factor for CKD: The Atherosclerosis Risk in Communities Study

Background and objectives

Previous studies demonstrated a higher risk of CKD in persons with a history of kidney stones, but these studies examined mostly white populations and did not evaluate important potential interactions such as race and plasma uric acid.

Design, setting, participants, & measurements

In 10,678 Atherosclerosis Risk in Communities (ARIC) study participants free of CKD at baseline (ARIC visit 4 in 1996–1998), we assessed the association between a history of nephrolithiasis (a time-varying variable, defined by a combination of self-report and diagnostic codes) and incident CKD (defined by diagnostic codes from linkage to hospitalizations and US Centers for Medicare and Medicaid Services’ records).

Results

At baseline, 856 participants had a history of nephrolithiasis; 322 developed nephrolithiasis during follow-up. Over a mean follow-up of 12 years, there were 1037 incident CKD events. Nephrolithiasis history was associated with a 29% (hazard ratio [HR], 1.29; 95% confidence interval [95% CI], 1.07 to 1.54) higher risk of CKD in demographic-adjusted analyses, but the association was no longer statistically significant after multivariable adjustment (HR, 1.09; 95% CI, 0.90 to 1.32). The multivariable-adjusted association was stronger among participants with plasma uric acid levels ≤6 mg/dl (HR, 1.34; 95% CI, 1.05 to 1.72) compared with those with levels >6 mg/dl (HR, 0.94; 95% CI, 0.70 to 1.28; P_interaction=0.05). There was no interaction of stone disease and race with incident CKD.

Conclusions

In this community-based cohort, nephrolithiasis was not an independent risk factor for incident CKD overall. However, risk of CKD was unexpectedly elevated in participants with stone disease and lower plasma uric acid levels.     

Hepatic and pancreatic resection in patients with end-stage renal disease: a propensity analysis

Background

Hepatic and pancreatic surgery is rarely performed in patients with end-stage renal disease (ESRD). The present authors used a national clinical database to characterize outcomes and perioperative risk in ESRD patients who require hepatic or pancreatic resection.

Methods

The 2005–2011 National Surgical Quality Improvement Program database was queried for all patients undergoing hepatic or pancreatic resection. Patients were classified by the presence or absence of ESRD. The independent effects of ESRD on outcomes were assessed after propensity score adjustment and multivariable logistic regression.

Results

Of the 27 376 patients submitted to hepatic or pancreatic procedures identified in the database, 101 patients were found to have preoperative ESRD. Patients with ESRD experienced perioperative mortality at a rate similar to that in those without ESRD (5.0% versus 2.3%; P = 0.08). After risk adjustment, the presence of ESRD was associated with three-fold higher odds of postoperative sepsis (adjusted odds ratio: 2.98, P = 0.014), but no significant differences in mortality or major complication rates.

Conclusions

Hepatic and pancreatic resections can be performed safely in selected patients with ESRD. These patients may have an increased risk for the development of postoperative sepsis. Further study is needed to characterize modifiable risk factors that impact outcomes in patients with ESRD who require hepatic or pancreatic resection.