The global incidence of chronic kidney disease (CKD) is increasing among individuals of all ages. Despite advances in proteomics, genomics and metabolomics, there remains a lack of safe and effective ...drugs to reverse or stabilize renal function in patients with glomerular or tubulointerstitial causes of CKD. Consequently, modifiable risk factors that are associated with a progressive decline in kidney function need to be identified. Numerous reports have documented the adverse effects that occur in response to graded exposure to a wide range of environmental chemicals. This Review summarizes the effects of such chemicals on four aspects of cardiorenal function: albuminuria, glomerular filtration rate, blood pressure and serum uric acid concentration. We focus on compounds that individuals are likely to be exposed to as a consequence of normal consumer activities or medical treatment, namely phthalates, bisphenol A, polyfluorinated alkyl acids, dioxins and furans, polycyclic aromatic hydrocarbons and polychlorinated biphenyls. Environmental exposure to these chemicals during everyday life could have adverse consequences on renal function and might contribute to progressive cumulative renal injury over a lifetime. Regulatory efforts should be made to limit individual exposure to environmental chemicals in an attempt to reduce the incidence of cardiorenal disease.
Research imperative Trachtman, Howard
Contemporary clinical trials communications,
06/2019, Volume:
14
Journal Article
Peer reviewed
Open access
Abstract There is a note of caution expressed when clinical care providers enroll their own patients into investigational trials, a concern expressed in the called dual-role consent. There is concern ...that this circumstance may create a conflict of interest for the physician-investigator, lead to loss of patient voluntarism, and promote the therapeutic misconceptions. In this opinion paper, I review the circumstances surrounding participation in clinical research and the conduct of standard patient care. I propose that when a patient is eligible for an institutional review board-approved clinical trial, instead of representing a potential ethical lapse, soliciting enrollment by the clinician-researcher may represent optimal care for the patient.
Glomerulonephritis (GN) is an important cause of morbidity and mortality in patients of all ages throughout the world. Because these disorders are relatively rare, it is difficult to perform ...randomized clinical trials to define optimal treatment for many of the specific glomerulopathies. In the absence of high-grade evidence to guide the care of glomerular diseases, in June 2012, KDIGO (Kidney Disease: Improving Global Outcomes) published an international clinical guideline for GN. The Work Group report represents an important review of the literature in this area and offers valid and useful guidelines for the most common situations that arise in the management of patients with glomerular disease. This commentary, developed by a panel of clinical experts convened by the National Kidney Foundation, attempts to put the GN guideline into the context of the US health care system. Overall, we support the vast majority of the recommendations and highlight select areas in which epidemiological factors and medical practice patterns in this country justify modifications and adjustments in order to achieve favorable outcomes. There remain large gaps in our knowledge of the best approaches to treat glomerular disease and we strongly endorse an expanded clinical research effort to improve the health and long-term outcomes of children and adults with GN.
Relatively high plasma levels of soluble urokinase-type plasminogen activator receptor (suPAR) have been associated with focal segmental glomerulosclerosis and poor clinical outcomes in patients with ...various conditions. It is unknown whether elevated suPAR levels in patients with normal kidney function are associated with future decline in the estimated glomerular filtration rate (eGFR) and with incident chronic kidney disease.
We measured plasma suPAR levels in 3683 persons enrolled in the Emory Cardiovascular Biobank (mean age, 63 years; 65% men; median suPAR level, 3040 pg per milliliter) and determined renal function at enrollment and at subsequent visits in 2292 persons. The relationship between suPAR levels and the eGFR at baseline, the change in the eGFR over time, and the development of chronic kidney disease (eGFR <60 ml per minute per 1.73 m(2) of body-surface area) were analyzed with the use of linear mixed models and Cox regression after adjustment for demographic and clinical variables.
A higher suPAR level at baseline was associated with a greater decline in the eGFR during follow-up; the annual change in the eGFR was -0.9 ml per minute per 1.73 m(2) among participants in the lowest quartile of suPAR levels as compared with -4.2 ml per minute per 1.73 m(2) among participants in the highest quartile (P<0.001). The 921 participants with a normal eGFR (≥ 90 ml per minute per 1.73 m(2)) at baseline had the largest suPAR-related decline in the eGFR. In 1335 participants with a baseline eGFR of at least 60 ml per minute per 1.73 m(2), the risk of progression to chronic kidney disease in the highest quartile of suPAR levels was 3.13 times as high (95% confidence interval, 2.11 to 4.65) as that in the lowest quartile.
An elevated level of suPAR was independently associated with incident chronic kidney disease and an accelerated decline in the eGFR in the groups studied. (Funded by the Abraham J. and Phyllis Katz Foundation and others.).
Recent evidence has suggested that polycyclic aromatic hydrocarbons (PAHs) may contribute to cardiometabolic and kidney dysfunction by increasing oxidative stress, but little is known about impacts ...in childhood.
We performed cross-sectional analyses of 660 adolescents aged 12–19 years in the 2003–2008 National Health and Nutrition Examination Survey (NHANES), using levels of 10 monohydroxylated urinary PAH metabolites as our exposure. Our primary outcomes of interest were biomarkers of oxidative stress and renal function, including estimated glomerular filtration rate (eGFR), urinary albumin to creatinine ratio (ACR), insulin resistance, and serum uric acid, gamma glutamyl transferase (GGT) and C-reactive protein (CRP).
We observed statistically significant associations between PAH metabolites and levels of serum GGT, CRP, uric acid and eGFR. Each 100% increase in 2-hydroxyphenanthrene was related to a 3.36% increase in uric acid (95% CI: 0.338–6.372; p=0.032), a 3.86% increase in GGT (95% CI: 1.361–6.362; p=0.005) and a 16.78% increase in CRP (95% CI: 1.848–31.689; p=0.029). Each 100% increase in 4-hydroxyphenanthrene was associated with a 6.18% increase in GGT (95% CI: 4.064–8.301; p<0.001) and a 13.66% increase in CRP (95% CI: 2.764–24.564; p=0.017). Each 100% increase in 9-hydroxyfluorene was associated with a 2.58% increase in GGT (95% CI: 0.389–4776; p=0.024). Each 100% increase in 3-hydroxyphenanthrene was associated with a 2.66% decrease in eGFR (95% CI: −4.979 to −0.331; p=0.028).
Urinary PAH metabolites were associated with serum uric acid, GGT and CRP, suggesting possible impacts on cardiometabolic and kidney function in adolescents. Prospective work is needed to investigate the potential long-term health consequences of these findings.
•Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous environmental contaminants.•Younger populations may be more susceptible to the harmful effects of these exposures.•Little is known about how PAHs may impact health in childhood and adolescence.•PAH exposure was related to oxidative stress and renal function markers in adolescents.•PAH urinary metabolites were associated with serum GGT, CRP, uric acid and eGFR.
HUS and TTP in Children Trachtman, Howard
The Pediatric clinics of North America,
12/2013, Volume:
60, Issue:
6
Journal Article
Peer reviewed
Open access
This review describes the epidemiology, pathophysiology, presentation, clinical causes, treatment, and long-term prognosis of pediatric patients who present with thrombotic microangiopathy. The focus ...is on hemolytic uremic syndrome and thrombotic thrombocytopenic purpura, the most common phenotypes of thrombotic microangiopathy.
Low-grade albuminuria is an indicator of endothelial dysfunction and is associated with an increased risk of cardiovascular disease. A graded level of exposure to bisphenol A was recently identified ...to be associated with increased risk of low-grade albuminuria in children and adults. Because bisphenol A and phthalates coexist as dietary contaminants, this study investigated whether exposure to phthalates is also associated with low-grade albuminuria.
Data were examined from 667 children who participated in the 2009-2010 National Health and Nutrition Examination Survey and who had results for urinary phthalate metabolites and albumin excretion. Urinary albumin and creatinine concentrations were measured in a first morning specimen using a solid-phase fluorescent immunoassay and a Roche/Hitachi Modular P Chemistry Analyzer with an enzymatic method, respectively. Phthalate metabolites were analyzed in a separate spot urine sample from each participant, using high-performance liquid chromatography and tandem mass spectroscopy.
For each (roughly) 3-fold increase in metabolites of di-2-ethylhexylphthalate (a high molecular weight phthalate commonly found in foods), a 0.55 mg/g increase in albumin/creatinine ratio (ACR) was identified (P=0.02), whereas a 1.30-fold odds of a higher ACR quartile was also identified for each (roughly) 3-fold increase (P=0.02). Higher ACR was not identified in relationship to metabolites of lower molecular phthalates commonly found in lotions or shampoos, suggesting specificity.
Although reverse causation and unmeasured confounders represent alternative explanations, these findings, in conjunction with our earlier data on bisphenol A, indicate that a wide array of environmental toxins may adversely affect albuminuria and potentially increase the risk of cardiovascular disease. In view of the potential long-term health implications of ongoing exposure in this vulnerable subpopulation, our data support both further study and renewed regulatory efforts to limit exposure during childhood.
Trypanolytic variants in APOL1, which encodes apolipoprotein L1, associate with kidney disease in African Americans, but whether APOL1-associated glomerular disease has a distinct clinical phenotype ...is unknown. Here we determined APOL1 genotypes for 271 African American cases, 168 European American cases, and 939 control subjects. In a recessive model, APOL1 variants conferred seventeenfold higher odds (95% CI 11 to 26) for focal segmental glomerulosclerosis (FSGS) and twenty-nine-fold higher odds (95% CI 13 to 68) for HIV-associated nephropathy (HIVAN). FSGS associated with two APOL1 risk alleles associated with earlier age of onset (P = 0.01) and faster progression to ESRD (P < 0.01) but similar sensitivity to steroids compared with other subjects. Individuals with two APOL1 risk alleles have an estimated 4% lifetime risk for developing FSGS, and untreated HIV-infected individuals have a 50% risk for developing HIVAN. The effect of carrying two APOL1 risk alleles explains 18% of FSGS and 35% of HIVAN; alternatively, eliminating this effect would reduce FSGS and HIVAN by 67%. A survey of world populations indicated that the APOL1 kidney risk alleles are present only on African chromosomes. In summary, African Americans carrying two APOL1 risk alleles have a greatly increased risk for glomerular disease, and APOL1-associated FSGS occurs earlier and progresses to ESRD more rapidly. These data add to the evidence base required to determine whether genetic testing for APOL1 has a use in clinical practice.
•Longitudinally measured organophosphate pesticide metabolites and renal function.•Serially measured dialkyl phosphate metabolites were associated with tubular injury.•The association was strongest ...for diethyl metabolites.•Dialkyl phosphate metabolites were associated with higher oxidant stress biomarkers.•Organophosphate pesticides are potentially modifiable risk factors for renal damage.
Growing evidence suggests that exposure to environmental chemicals, such as pesticides, impacts renal function and chronic kidney disease (CKD). However, it is not clear if pesticides may affect CKD progression and no studies exist in children.
The objective of this study was to examine associations between serially measured urinary OP pesticide metabolites and clinical and laboratory measures of kidney function over time among children with CKD.
This study used data on 618 participants enrolled in the CKD in Children study (CKiD), a cohort study of pediatric CKD patients from the US and Canada. Children were followed over an average of 3.0 years (standard deviation (SD) = 1.6) between 2005 and 2015. In serially collected urine samples over time, six nonspecific dialkyl phosphate (DAP) metabolites of OP pesticides were measured. Biomarkers of tubular injury (kidney injury molecule-1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL)) and oxidant stress (8-hydroxy-2′-deoxyguanosine (8-OHdG) and F2-isoprostane) were determined in the same specimens. Estimated glomerular filtration rate (eGFR), proteinuria, and blood pressure were assessed annually.
DAPs were associated with increased KIM-1 and 8-OHdG throughout follow-up. A standard deviation increase in ∑diethyl metabolites was associated with increases of 11.9% (95% Confidence Interval (CI): 4.8%, 19.4%) and 13.2% (95% CI: 9.3%, 17.2%) in KIM-1 and 8-OHdG over time, respectively. DAPs were associated with lower eGFR at baseline and higher eGFR over subsequent years.
These findings provide preliminary evidence suggesting that urinary DAP metabolites are associated with subclinical kidney injury among children with CKD, which may signal the potential for clinical events to manifest in the future. The results from this study are significant from both a clinical and public health perspective, given that OP pesticide exposure is a modifiable risk factor.
Many Mendelian traits are likely unrecognized owing to absence of traditional segregation patterns in families due to causation by de novo mutations, incomplete penetrance, and/or variable ...expressivity. Genome-level sequencing can overcome these complications. Extreme childhood phenotypes are promising candidates for new Mendelian traits. One example is early onset hypertension, a rare form of a global cause of morbidity and mortality. We performed exome sequencing of 40 unrelated subjects with hypertension due to primary aldosteronism by age 10. Five subjects (12.5%) shared the identical, previously unidentified, heterozygous CACNA1H(M1549V) mutation. Two mutations were demonstrated to be de novo events, and all mutations occurred independently. CACNA1H encodes a voltage-gated calcium channel (CaV3.2) expressed in adrenal glomerulosa. CACNA1H(M1549V) showed drastically impaired channel inactivation and activation at more hyperpolarized potentials, producing increased intracellular Ca(2+), the signal for aldosterone production. This mutation explains disease pathogenesis and provides new insight into mechanisms mediating aldosterone production and hypertension.
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