High Dose Vitamin D3 Attenuates the Hypocalciuric Effect of Thiazide in Hypercalciuric Rats

Thiazide is known to decrease urinary calcium excretion. We hypothesized that thiazide shows different hypocalciuric effects depending on the stimuli causing hypercalciuria. The hypocalciuric effect of hydrochlorothiazide (HCTZ) and the expression of transient receptor potential vanilloid 5 (TRPV5), calbindin-D28K, and several sodium transporters were assessed in hypercalciuric rats induced by high calcium diet and vitamin D3. Urine calcium excretion and the expression of transporters were measured from 4 groups of Sprague-Dawley rats; control, HCTZ, high calcium-vitamin D, and high calcium-vitamin D with HCTZ groups. HCTZ decreased urinary calcium excretion by 51.4% in the HCTZ group and only 15% in the high calcium-vitamin D with HCTZ group. TRPV5 protein abundance was not changed by HCTZ in the high calcium-vitamin D with HCTZ group compared to the high calcium-vitamin D group. Protein abundance of NHE3, SGLT1, and NKCC2 decreased in the hypercalciuric rats, and only SGLT1 protein abundance was increased by HCTZ in the hypercalciuric rats. The hypocalciuric effect of HCTZ is attenuated in high calcium and vitamin D-induced hypercalciuric rats. This attenuation seems to have resulted from the lack of HCTZ's effect on protein abundance of TRPV5 in severe hypercalciuric condition induced by high calcium and vitamin D

Albuminuria, Cerebrovascular Disease and Cortical Atrophy: among Cognitively Normal Elderly Individuals

We tested the hypothesis that decreased glomerular filtration rate and albuminuria have different roles in brain structure alterations. We enrolled 1,215 cognitively normal individuals, all of whom underwent high-resolution T1-weighted volumetric magnetic resonance imaging scans. The cerebral small vessel disease burdens were assessed with white matter hyperintensities (WMH), lacunes, and microbleeds. Subjects were considered to have an abnormally elevated urine albumin creatinine ratio if the value was ≥17 mg/g for men and ≥25 mg/g for women. Albuminuria, but not estimated glomerular filtration rate (eGFR), was associated with increased WMH burdens (p = 0.002). The data was analyzed after adjusting for age, sex, education, history of hypertension, diabetes mellitus, hyperlipidemia, ischemic heart disease, stroke, total cholesterol level, body mass index, status of smoking and alcohol drinking, and intracranial volume. Albuminuria was also associated with cortical thinning, predominantly in the frontal and occipital regions (both p < 0.01) in multiple linear regression analysis. However, eGFR was not associated with cortical thickness. Furthermore, path analysis for cortical thickness showed that albuminuria was associated with frontal thinning partially mediated by WMH burdens. The assessment of albuminuria is needed to improve our ability to identify individuals with high risk for cognitive impairments, and further institute appropriate preventive measures

Effects of Thiazide on the Expression of TRPV5, Calbindin-D28K, and Sodium Transporters in Hypercalciuric Rats

TRPV5 is believed to play an important role in the regulation of urinary calcium excretion. We assessed the effects of hydrochlorothiazide (HCTZ) on the expression of TRPV5, calbindin-D28K, and several sodium transporters in hypercalciuric rats. Sprague-Dawley rats were divided into 4 groups; control, HCTZ, high salt, and high salt with HCTZ group in experiment 1; control, HCTZ, high calcium (Ca), and high Ca with HCTZ group in experiment 2. To quantitate the expression of TRPV5, calbindin-D28K, and sodium transporters, western blotting was performed. In both experiments, HCTZ significantly decreased urinary calcium excretion. TRPV5 protein abundance decreased in all hypercalciuric rats, and restored by HCTZ in both high salt with HCTZ and high Ca with HCTZ group. Calbindin-D28K protein abundance increased in the high salt and high salt with HCTZ groups, but did not differ among groups in experiment 2. Protein abundance of NHE3 and NKCC2 decreased in all hypercalciuric rats, and were restored by HCTZ in only high Ca-induced hypercalciuric rats. In summary, protein abundance of TRPV5, NHE3, and NKCC2 decreased in all hypercalciuric rats. The hypocalciuric effect of HCTZ is associated with increased protein abundance of TRPV5 in high salt or calcium diet-induced hypercalciuric rats

Calpain Inhibition Restores Autophagy and Prevents Mitochondrial Fragmentation in a Human iPSC Model of Diabetic Endotheliopathy

The relationship between diabetes and endothelial dysfunction remains unclear, particularly the association with pathological activation of calpain, an intracellular cysteine protease. Here, we used human induced pluripotent stem cells-derived endothelial cells (iPSC-ECs) to investigate the effects of diabetes on vascular health. Our results indicate that iPSC-ECs exposed to hyperglycemia had impaired autophagy, increased mitochondria fragmentation, and was associated with increased calpain activity. In addition, hyperglycemic iPSC-ECs had increased susceptibility to cell death when subjected to a secondary insult-simulated ischemia-reperfusion injury (sIRI). Importantly, calpain inhibition restored autophagy and reduced mitochondrial fragmentation, concurrent with maintenance of ATP production, normalized reactive oxygen species levels and reduced susceptibility to sIRI. Using a human iPSC model of diabetic endotheliopathy, we demonstrated that restoration of autophagy and prevention of mitochondrial fragmentation via calpain inhibition improves vascular integrity. Our human iPSC-EC model thus represents a valuable platform to explore biological mechanisms and new treatments for diabetes-induced endothelial dysfunction.Singapore Ministry of Health's National Medical Research Council Open Fund-Young Individual Research Grant [NMRC/OFYIRG/0021/2016]; Khoo Postdoctoral Fellowship Award [Duke-NUS-KPFA/2016/0010]; Hitachi Scholarship Research Support Grant from the Hitachi Global Foundation, Japan [RS-13, H-1]; American Heart Association Scientist Development Grant [16SDG27560003]; Stanford Diabetes Research Center under NIH [P30DK116074]; Frontier Research Grant 2017 from the Frontier Science Research Cluster (FSRC), Universiti Malaya, Malaysia [FG021-17AFR]; NIH [R01HL126516, R00HL130416]; Samsung Biomedical Research Institute [OTC 1180261]; National Research Foundation of Korea [NRF-2016R1A2B4008235]Open access journalThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Using additional pressure control lines when connecting a continuous renal replacement therapy device to an extracorporeal membrane oxygenation circuit

Abstract Background The introduction of a continuous renal replacement therapy (CRRT) device into the extracorporeal membrane oxygenation (ECMO) circuit is widely used. However, excessive pressure transmitted to the CRRT device is a major disadvantage. We investigated the effects of using additional pressure control lines on the pressure and the lifespan of the CRRT circuit connected to the ECMO. Methods This is an observational study using prospectively collected data from consecutive patients receiving CRRT connected into the ECMO circuit at a university-affiliated, tertiary hospital from January 2013 to December 2016. The CRRT circuit was connected into the ECMO circuit through the Luer Lock connection without an additional pressure control line in 16 patients (9%, no line group), an additional pressure control line on the inlet line in 36 patients (23%, single line group), and additional pressure control lines on both the inlet and outlet lines in 118 patients (77%, double line group). The outcome measures of interest were compared among the three groups. Results The median access pressure was higher in the no line group compared to the groups. However, median filter pressure, effluent pressure, and return pressure were higher in the double line group compared to the other groups. There were no significant differences in platelets, lactate dehydrogenase, and plasma hemoglobin among the 3 groups over the time period studied. Median lifespan of the CRRT circuits in the double line group was 45.0 (29.0–63.7) hours, which was higher compared to 21.8 (11.6–31.8) hours in the no line group and 23.0 (15.0–34.6) hours in the single line group, respectively. In addition, in-hospital mortality was lower in the double line group (48.3%) compared to the no line group (68.8%) and the single line group (75.0%). Conclusions Additional tubing can be considered a simple and safe method for pressure control and lengthening circuit survival when connecting the CRRT device to the ECMO circuit