Organophosphate esters (OPEs) have been widely used in building materials and consumer products as flame retardants and plasticizers. In vitro studies have suggested adverse effects of OPEs on the kidney. Despite accumulating evidence indicating widespread exposure to OPEs, their association with renal function in humans has not been evaluated. This study aims to investigate the association between OPEs exposure and chronic kidney disease (CKD) among the general US adult population by employing data from the US National Health and Nutrition Examination Survey (NHANES) 2013-2014. Among 1578 adults who were not currently pregnant, the associations of the urinary OPE metabolites with two CKD-related parameters, i.e., estimated glomerular filtration rate (eGFR) and albumin-to-creatinine ratio (ACR), and CKD were assessed. To account for urine dilution, in addition to conventional creatinine-adjustment, covariate-adjusted creatinine standardization, which controls for potential confounding by kidney function, was employed. Multi-pollutant models were also constructed to verify the associations observed in the models on individual OPE metabolites. The urinary bis(2-chloroethyl) phosphate (BCEP) level was negatively associated with eGFR only with the covariate-adjusted standardization method, but not with the conventional creatinine adjustment. In addition, both bis(1,3-dichloro-2-propyl) phosphate (BDCIPP) and di-n-butyl phosphate (DNBP) were positively associated with the ACR, regardless of methods of urine dilution adjustment. These three compounds were also associated with CKD. Following adjusting urine dilution with the covariate-adjusted standardization method, the association became more evident. Moreover, similar results were observed in the secondary analysis with the multi-pollutant models. Among the US general population, several OPEs were identified as potential chemical determinants of CKD. Experimental studies are warranted to understand the potential mechanisms underlying this observation.

Chronic kidney disease (CKD) is a global health threat of growing concern. Recently, exposure to endocrine disrupting compounds (EDCs) such as phthalates and bisphenol A has been suggested as a risk factor for CKD. However, most epidemiological studies have focused on a limited number of urinary chemicals. This study aimed to identify chemical determinants of the urinary albumin-to-creatinine ratio (ACR), which is a kidney function marker, among multiple major EDCs including phthalate metabolites, bisphenols, and benzophenones in a Korean female population (20-45 years old, n = 441). First, the creatinine-adjusted urinary concentration of each urinary chemical was associated with ACR in a linear regression model (single-pollutant model). Then, compounds with a significant association with ACR in the single-pollutant model were added in a multi-pollutant model and evaluated for their association with ACR. Moreover, to prevent potential reverse causality due to impaired kidney function, quartile analyses were performed for the subjects with healthy renal function (ACR < 9.71 mg/g). In addition to creatinine adjustment, the statistical analysis was also conducted with specific gravity-adjusted concentrations of urinary chemicals, and the results were compared. Several compounds measured in the urine showed a significant association with ACR in the single-pollutant model. In the multi-pollutant model, however, only monobutyl phthalate and benzophenone-1, which are metabolites of dibutyl phthalate and benzophenone-3, respectively, showed significant positive associations. The association of these chemicals remained significant in a couple of the sensitivity analyses with a different adjustment of urine dilution and in a subpopulation with normal ACR. In conclusion, among dozens of urinary chemicals, monobutyl phthalate and benzophenone-1 consistently showed a strong association with urinary ACR. Confirmation of our observation in other human populations and experimental studies is warranted.

In hemodialysis patients, fluid overload and malnutrition are accompanied by extracellular fluid (ECF) expansion and intracellular fluid (ICF) depletion, respectively. We investigated the relationship between ECF/ICF ratio (as an integrated marker reflecting both fluid overload and malnutrition) and survival and cardiovascular disease (CVD) in the context of malnutrition-inflammation-arteriosclerosis (MIA) complex. Seventy-seven patients from a single hemodialysis unit were prospectively enrolled. The ECF/ICF volume was measured by segmental multi-frequency bioimpedance analysis. MIA and volume status were measured by serum albumin, C-reactive protein (CRP), pulse wave velocity (PWV) and plasma B-type natriuretic peptide (BNP), respectively. The mean ECF/ICF ratio was 0.56±0.06 and the cut-off value for maximum discrimination of survival was 0.57. Compared with the low ECF/ICF group, the high ECF/ICF group (ratio≥0.57, 42%) had higher all-cause mortality, CVD, CRP, PWV, and BNP, but lower serum albumin. During the 5-year follow-up, 24 all-cause mortality and 38 CVD occurred (18 and 24, respectively, in the high ECF/ICF group versus 6 and 14 respectively in the low ECF/ICF group, P<0.001). In the adjusted Cox analysis, the ECF/ICF ratio nullifies the effects of the MIA and volume status on survival and CVD and was an independent predictor of all-cause mortality and CVD: hazard ratio (95% confidence interval); 1.12 (1.01–1.25) and 1.09 (1.01–1.18) for a 0.01 increase in the ECF/ICF ratio. The degree of malnutrition (albumin), inflammation (CRP), arteriosclerosis (PWV), and fluid overload (BNP) were correlated well with the ECF/ICF ratio. Hemodialysis patients with high ECF/ICF ratio are not only fluid overloaded, but malnourished and have stiff artery with more inflammation. The ECF/ICF ratio is highly related to the MIA complex, and is a major risk indicator for all-cause mortality and CVD.

Background and objectives: Exposure to environmental chemicals has been recognized as one of the possible contributors to CKD. We aimed to identify environmental chemicals that are associated with CKD. Design, setting, participants, & measurements: We analyzed the data obtained from a total of 46,748 adults who participated in the National Health and Nutrition Examination Survey (1999–2016). Associations of chemicals measured in urine or blood (n=262) with albuminuria (urine albumin-to-creatinine ratio ≥30 mg/g), reduced eGFR (<60 ml/min per 1.73 m²), and a composite of albuminuria or reduced eGFR were tested and validated using the environment-wide association study approach. Results: Among 262 environmental chemicals, seven (3%) chemicals showed significant associations with increased risk of albuminuria, reduced eGFR, or the composite outcome. These chemicals included metals and other chemicals that have not previously been associated with CKD. Serum and urine cotinines, blood 2,5-dimethylfuran (a volatile organic compound), and blood cadmium were associated with albuminuria. Blood lead and cadmium were associated with reduced eGFR. Blood cadmium and lead and three volatile compounds (blood 2,5-dimethylfuran, blood furan, and urinary phenylglyoxylic acid) were associated with the composite outcome. A total of 23 chemicals, including serum perfluorooctanoic acid, seven urinary metals, three urinary arsenics, urinary nitrate and thiocyanate, three urinary polycyclic aromatic hydrocarbons, and seven volatile organic compounds, were associated with lower risks of one or more manifestations of CKD. Conclusions: A number of chemicals were identified as potential risk factors for CKD among the general population.

The kidneys play a pivotal role in most drug-removal processes and are important when evaluating drug safety. Kidney dysfunction resulting from various drugs is an important issue in clinical practice and during the drug development process. Traditional in vivo animal experiments are limited with respect to evaluating drug efficacy and nephrotoxicity due to discrepancies in drug pharmacokinetics and pharmacodynamics between humans and animals, and static cell culture experiments cannot fully reflect the actual microphysiological environment in humans. A kidney-on-a-chip is a microfluidic device that allows the culture of living renal cells in 3-dimensional channels and mimics the human microphysiological environment, thus simulating the actual drug filtering, absorption, and secretion process.. In this review, we discuss recent developments in microfluidic culturing technique and describe current and future kidney-on-a-chip applications. We focus on pharmacological interactions and drug-induced nephrotoxicity, and additionally discuss the development of multi-organ chips and their possible applications.

Background: The inhibition of dipeptidyl peptidase (DPP) IV shows protective effects on tissue injury of the heart, lung, and kidney. Forkhead box O (FoxO) transcriptional factors regulate cellular differentiation, growth, survival, the cell cycle, metabolism, and oxidative stress. The aims of this study were to investigate whether the DPP IV inhibitor sitagliptin could attenuate kidney injury and to evaluate the status of FoxO3a signaling in the rat remnant kidney model. Methods: Rats were received two-step surgery of 5/6 renal mass reduction and fed on an oral dose of 200 mg/kg/day sitagliptin for 8 weeks. Before and after the administration of sitagliptin, physiologic parameters were measured. After 8 weeks of treatment, the kidneys were harvested. Results: The sitagliptin treatment attenuated renal dysfunction. A histological evaluation revealed that glomerulosclerosis and tubulointerstitial injury were significantly decreased by sitagliptin. Sitagliptin decreased DPP IV activity and increased the renal expression of glucagon-like peptide-1 receptor (GLP-1R). The subtotal nephrectomy led to the activation of phosphatidylinositol 3-kinase (PI3K)-Akt and FoxO3a phosphorylation, whereas sitagliptin treatment reversed these changes, resulting in PI3K-Akt pathway inactivation and FoxO3a dephosphorylation. The renal expression of catalase was increased and the phosphorylation of c-Jun N-terminal kinase (JNK) was decreased by sitagliptin. Sitagliptin treatment reduced apoptosis by decreasing cleaved caspase-3 and −9 and Bax levels and decreased macrophage infiltration. Conclusions: In rat remnant kidneys, DPP IV inhibitor attenuated renal dysfunction and structural damage. A reduction of apoptosis, inflammation and an increase of antioxidant could be suggested as a renoprotective mechanism together with the activation of FoxO3a signaling. Therefore, DPP IV inhibitors might provide a promising approach for treating CKD, but their application in clinical practice remains to be investigated.