Jeffrey J. Fadrowski

Mutations in Kelch-like 3 and Cullin 3 cause hypertension and electrolyte abnormalities

Hypertension affects one billion people and is a principal reversible risk factor for cardiovascular disease. Pseudohypoaldosteronism type II (PHAII), a rare Mendelian syndrome featuring hypertension, hyperkalaemia and metabolic acidosis, has revealed previously unrecognized physiology orchestrating the balance between renal salt reabsorption and K+ and H+ excretion. Here we used exome sequencing to identify mutations in kelch-like 3 (KLHL3) or cullin 3 (CUL3) in PHAII patients from 41 unrelated families. KLHL3 mutations are either recessive or dominant, whereas CUL3 mutations are dominant and predominantly de novo. CUL3 and BTB-domain-containing kelch proteins such as KLHL3 are components of cullin–RING E3 ligase complexes that ubiquitinate substrates bound to kelch propeller domains. Dominant KLHL3 mutations are clustered in short segments within the kelch propeller and BTB domains implicated in substrate and cullin binding, respectively. Diverse CUL3 mutations all result in skipping of exon 9, producing an in-frame deletion. Because dominant KLHL3 and CUL3 mutations both phenocopy recessive loss-of-function KLHL3 mutations, they may abrogate ubiquitination of KLHL3 substrates. Disease features are reversed by thiazide diuretics, which inhibit the Na–Cl cotransporter in the distal nephron of the kidney; KLHL3 and CUL3 are expressed in this location, suggesting a mechanistic link between KLHL3 and CUL3 mutations, increased Na–Cl reabsorption, and disease pathogenesis. These findings demonstrate the utility of exome sequencing in disease gene identification despite the combined complexities of locus heterogeneity, mixed models of transmission and frequent de novo mutation, and establish a fundamental role for KLHL3 and CUL3 in blood pressure, K+ and pH homeostasis.

Uric Acid Level and Elevated Blood Pressure in US Adolescents National Health and Nutrition Examination Survey, 1999–2006

Uric acid is associated with cardiovascular disease and cardiovascular disease risk factors in adults, including chronic kidney disease, coronary artery disease, stroke, diabetes mellitus, preeclampsia, and hypertension. We examined the association between uric acid and elevated blood pressure in a large, nationally representative cohort of US adolescents, a population with a relatively low prevalence of cardiovascular disease and cardiovascular disease risk factors. Among 6036 adolescents 12 to 17 years of age examined in the 1999–2006 National Health and Nutrition Examination Survey, the mean age was 14.5 years, 17% were obese (body mass index: ≥95th percentile), and 3.3% had elevated blood pressure. Mean serum uric acid level was 5.0 mg/dL, and 34% had a uric acid level ≥5.5 mg/dL. In analyses adjusted for age, sex, race/ethnicity, and body mass index percentile, the odds ratio of elevated blood pressure, defined as a systolic or diastolic blood pressure ≥95th percentile for age, sex, and height, for each 0.1-mg/dL increase in uric acid level was 1.38 (95% CI: 1.16–1.65). Compared with <5.5 mg/dL, participants with a uric acid level ≥5.5 mg/dL had a 2.03 times higher odds of having elevated blood pressure (95% CI: 1.38–3.00). In conclusion, increasing levels of serum uric acid are associated with elevated blood pressure in healthy US adolescents. Additional prospective studies and clinical trials are needed to determine whether uric acid is merely a marker in a complex metabolic pathway or causal of hypertension and, thus, a potential screening and therapeutic target.

Blood Lead Level and Kidney Function in US Adolescents The Third National Health and Nutrition Examination Survey

BACKGROUND Chronic, high-level lead exposure is a known risk factor for kidney disease. The effect of current low-level environmental lead exposure is less well known, particularly among children, a population generally free from kidney disease risk factors such as hypertension and diabetes mellitus. Therefore, in this study, we investigated the association between lead exposure and kidney function in a representative sample of US adolescents. METHODS Participants included 769 adolescents aged 12 to 20 years for whom whole blood lead and serum cystatin C were measured in the Third National Health and Nutrition Examination Survey, conducted from 1988-1994. The association between blood lead level and level of kidney function (glomerular filtration rate [GFR]), determined by cystatin C-based and creatinine-based estimating equations, was examined. RESULTS Median whole blood lead level was 1.5 microg/dL (to convert to micromoles per liter, multiply by 0.0483), and median cystatin C-estimated GFR was 112.9 mL/min/1.73 m(2). Participants with lead levels in the highest quartile (> or =3.0 microg/dL) had 6.6 mL/min/1.73 m(2)-lower estimated GFR (95% confidence interval, -0.7 to -12.6 mL/min/1.73 m(2)) compared with those in the first quartile (<1 microg/dL). A doubling of blood lead level was associated with a 2.9 mL/min/1.73 m(2)-lower estimated GFR (95% confidence interval, -0.7 to -5.0 mL/min/1.73 m(2)). Lead levels were also associated with lower creatinine-based estimated GFR levels, but the association was weaker than with cystatin C-based GFR and not statistically significant. CONCLUSIONS Higher blood lead levels in a range below the current Centers for Disease Control and Prevention-designated level of concern (10 microg/dL) were associated with lower estimated GFRs in a representative sample of US adolescents. This finding contributes to the increasing epidemiologic evidence indicating an adverse effect of low-level environmental lead exposure.

Pediatric GFR Estimating Equations Applied to Adolescents in the General Population

BACKGROUND AND OBJECTIVES We examined the distribution of estimated GFR (eGFR) in a healthy cohort of adolescents to inform clinical and research use. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Various creatinine-based (n = 3256) and/or cystatin C-based (n = 811) equations, including the recently developed complete and bedside equations from the Chronic Kidney Disease in Children (CKiD) study, were applied to U.S. adolescents 12 to 17 years of age participating in the 1999-2002 National Health and Nutrition Examination Survey (NHANES). RESULTS The median serum creatinine and cystatin C were 0.7 mg/dl and 0.83 mg/L, respectively. The distribution of eGFR varied widely, with the median GFR ranging from a low of 96.6 ml/min per 1.73 m(2) (CKiD) to a high of 140.0 ml/min per 1.73 m(2) (original Schwartz). The proportions of participants with eGFRs <75 ml/min per 1.73 m(2) are as follows: bedside CKiD 8.9%, Counahan 6.3%, Leger 0.4%, original Schwartz 0%, Filler 1.3%, Grubb 3.1%, Bouvet 2.5%, CKiD 1.8%, and Zappitelli 5.6%. By any equation examined, no group of participants with eGFR ≤10th percentile had an increased prevalence of comorbid conditions consistent with a low measured GFR. CONCLUSIONS Most pediatric-specific GFR estimating equations resulted in 25% to 50% of the participants having an eGFR <100 ml/min per 1.73 m(2). However, participants with eGFR in the lower ranges did not have an increased prevalence of morbidities associated with chronic kidney disease. Clinical validation of creatinine- or cystatin C-based estimated GFRs in healthy children is needed before it is possible to screen the general population for chronic kidney disease.

Secondhand Tobacco Smoke: A Source of Lead Exposure in US Children and Adolescents

OBJECTIVES We evaluated the relationship between secondhand tobacco smoke (SHS) exposure and blood lead levels in US children and adolescents. METHODS We analyzed data from 6830 participants aged 3-19 years in the National Health and Nutrition Examination Survey (1999-2004) who were not active smokers and for whom SHS exposure information and blood lead measurements were available. RESULTS After multivariable adjustment, participants in the highest quartile of serum cotinine (≥ 0.44 μg/L) had 28% (95% confidence interval = 21%, 36%) higher blood lead levels than had those in the lowest quartile (< 0.03 μg/L). Similarly, blood lead levels were 14% and 24% higher in children who lived with 1 or with 2 or more smokers, respectively, than they were in children living with no smokers. Among participants for whom lead dust information was available, the associations between SHS and blood lead levels were similar before and after adjustment for lead dust concentrations. CONCLUSIONS SHS may contribute to increased blood lead levels in US children. Lead dust does not appear to mediate this association, suggesting inhalation as a major pathway of exposure. Eliminating SHS exposure could reduce lead exposure in children.

Changes in physical and psychosocial functioning among adolescents with chronic kidney disease

Little research has been published assessing changes in the functional health status of children and adolescents with chronic kidney disease (CKD). We know little about which clinical parameters influence functional status or health-related quality of life in these young people. In a prospective study using data from semi-annual visits over a 4-year period from 78 adolescents with CKD aged 11 years to 18 years, we detail the impact of several clinical measures (i.e., kidney function, albumin, hematocrit, height) on short-term changes in health-related quality of life. The 50-item Child Health Questionnaire Parent Form, a validated health-related quality of life measure in children, was used to obtain physical and psychosocial functioning summary scores at each visit. After adjustment for the variables mentioned above, the physical summary score on the Child Health Questionnaire (CHQ) declined as glomerular filtration rate declined. Increasing height was associated with a positive change in physical and psychosocial summary scores. We conclude that decline in kidney function is associated with a subsequent decline in health-related quality of life, particularly in terms of physical activity.

Arsenic and Chronic Kidney Disease: A Systematic Review.

In epidemiologic studies, high arsenic exposure has been associated with adverse kidney disease outcomes. We performed a systematic review of the epidemiologic evidence of the association between arsenic and various kidney disease outcomes. The search period was January 1966 through January 2014. Twenty-five papers (comprising 24 studies) meeting the search criteria were identified and included in this review. In most studies, arsenic exposure was assessed by measurement of urine concentrations or with an ecological indicator. There was a generally positive association between arsenic and albuminuria and proteinuria outcomes. There was mixed evidence of an association between arsenic exposure and chronic kidney disease (CKD), β-2-microglobulin (β2MG), and N-acetyl-β-D-glucosaminidase (NAG) outcomes. There was evidence of a positive association between arsenic exposure and kidney disease mortality. Assessment of a small number of studies with three or more categories showed a clear dose-response association between arsenic and prevalent albuminuria and proteinuria, but not with CKD outcomes. Eight studies lacked adjustment for possible confounders, and two had small study populations. The evaluation of the causality of the association between arsenic exposure and kidney disease outcomes is limited by the small number of studies, lack of study quality, and limited prospective evidence. Because of the high prevalence of arsenic exposure worldwide, there is a need for additional well-designed epidemiologic and mechanistic studies of arsenic and kidney disease outcomes.

Vitamin D, Race, and Risk for Anemia in Children

OBJECTIVE To examine the association between 25-hydroxyvitamin D [25(OH)D] deficiency and anemia in a cohort of otherwise-healthy children and to determine whether race modifies the association between 25(OH)D status and hemoglobin (Hgb). STUDY DESIGN Cross-sectional study of 10,410 children and adolescents ages 1-21 years from the 2001-2006 National Health and Nutrition Examination Survey. Anemia was defined as Hgb less than the 5th percentile for age and sex based on National Health and Nutrition Examination Survey III (1988-1994) data. RESULTS Lower 25(OH)D levels were associated with increased risk for anemia; <30 ng/mL, adjusted OR 1.93, 95% CI 1.21-3.08, P = .006, and <20 ng/mL, OR 1.47, 95% CI 1.14-1.89, P = .004. In linear regression, small but significant increases in Hgb were noted in the upper quartiles of 25(OH)D compared with the lowest quartile (<20 ng/mL) in the full cohort. Results of race-stratified linear regression by 25(OH)D quartile in white children were similar to those observed in the full cohort, but in black children, an increase in Hgb in the upper 25(OH)D quartiles was only apparent compared with the lowest black race-specific quartile (<12 ng/mL). CONCLUSION 25(OH)D deficiency is associated with increased risk of anemia in healthy US children, but the 25(OH)D threshold levels for lower Hgb are lower in black children in comparison with white children.

Hemoglobin Decline in Children with Chronic Kidney Disease: Baseline Results from the Chronic Kidney Disease in Children Prospective Cohort Study

BACKGROUND AND OBJECTIVES The level of glomerular filtration rate at which hemoglobin declines in chronic kidney disease is poorly described in the pediatric population. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS This cross-sectional study of North American children with chronic kidney disease examined the association of glomerular filtration rate, determined by the plasma disappearance of iohexol, and hemoglobin concentration. RESULTS Of the 340 patients studied, the mean age was 11 +/- 4 yr, the mean glomerular filtration rate was 42 +/- 14 ml/min per 1.73 m(2), and the mean hemoglobin was 12.5 +/- 1.5. Below a glomerular filtration rate of 43, the hemoglobin declined by 0.3 g/dl (95% confidence interval -0.2 to -0.5) for every 5-ml/min per 1.73 m(2) decrease in glomerular filtration rate. Above a glomerular filtration rate of 43 ml/min per 1.73 m(2), the hemoglobin showed a nonsignificant decline of 0.1 g/dl for every 5-ml/min per 1.73 m(2) decrease in glomerular filtration rate. CONCLUSIONS In pediatric patients with chronic kidney disease, hemoglobin declines as an iohexol-determined glomerular filtration rate decreases below 43 ml/min per 1.73 m(2). Because serum creatinine-based estimated glomerular filtration rates may overestimate measured glomerular filtration rate in this population, clinicians need to be mindful of the potential for hemoglobin decline and anemia even at early stages of chronic kidney disease, as determined by current Schwartz formula estimates. Future longitudinal analyses will further characterize the relationship between glomerular filtration rate and hemoglobin, including elucidation of reasons for the heterogeneity of this association among individuals.

Global dimensions of chronic kidney disease of unknown etiology (CKDu): a modern era environmental and/or occupational nephropathy?

Diabetes and hypertension are the predominant risk factors for chronic kidney disease (CKD) globally. Infectious diseases resulting in glomerulonephritis are also important in low-income countries [1, 2]. However, in the past two decades, a severe form of CKD has been reported in individuals without these risk factors. CKD of unknown etiology (CKDu) affects adults in their third to fifth decade and is often fatal due to disease progression and lack of dialysis or transplant options in the involved geographic areas. CKDu has been reported in Sri Lanka, several Central American countries, the state of Andhra Prakesh in India and the El-Minia Governorate in Egypt.