Effects of sex hormones on fluid and solute transport in Madin-Darby canine kidney cells

Effects of sex hormones on fluid and solute transport in Madin-Darby canine kidney cells. Polycystic kidney disease progresses more rapidly in men than in women. To investigate the basis for this sexual dimorphism, we exposed Madin-Darby canine kidney (MDCK) cells grown on collagen-coated cell culture inserts to control media, or to estradiol or testosterone (1 nM-1 µM). Compared to control and estradiol-treated cells, testosterone stimulated fluid secretion in a dose-dependent manner, enhancing fluid secretion 4.8-fold at 1nM and 19.7-fold at 1 µM (0.59 ± 0.18 vs. 0.03 ± 0.01 µ1/cm2/hr, P < 0.001). Chloride transport paralleled fluid secretion. Testosterone increased cellular cyclic AMP levels 3.2-fold at 1 µM and 12.3-fold at 1 µM (81.3 ± 30.7 vs. 6.6 ± 3.3 pmol/mg protein, P < 0.001). GDPβS (500 µM), an inhibitor of Gs, and 2′,3′-dideoxyadenosine (10 µM), an inhibitor of the catalytic subunit of adenylate cyclase, suppressed testosterone-induced fluid and solute secretion. Neither testosterone nor estradiol had any effect on microsomal Na,K-ATPase activity, cellular proliferation or cellular total protein content. Our studies show that testosterone stimulates fluid secretion and solute transport by MDCK cells by increasing cAMP generation. In vivo, testosterone may contribute to cyst expansion by enhancing fluid secretion. This observation may help explain the worse prognosis of polycystic kidney disease observed in men

Raloxifene, a selective estrogen receptor modulator, is renoprotective: a post-hoc analysis

Estrogens have a protective effect on kidney fibrosis in several animal models. Here, we tested the effect of raloxifene, an estrogen receptor modulator, on the change in serum creatinine or estimated glomerular filtration rate (eGFR) and incident kidney-related adverse events. We performed a post-hoc analysis of the multiple outcomes of raloxifene evaluation trial, a double-masked, placebo-controlled randomized clinical trial encompassing 7705 post-menopausal women (aged 31–80 years) with osteoporosis. Participants were randomized to either of two doses of raloxifene, 60 or 120 mg/day, or placebo. Serum creatinine was measured at a central laboratory at baseline and annually. Adverse events were assessed every 6 months and uniformly categorized. Compared with those in the placebo group, participants on raloxifene had a slower yearly rate of increase in creatinine (significant at the low dose) and a significantly slower yearly rate of decrease in eGFR for both doses over 3 years of follow-up. Raloxifene was associated with significantly fewer kidney-related adverse events compared with placebo. Thus, treatment with raloxifene was safe and renoprotective. Clinical trials of raloxifene in post-menopausal women with kidney disease designed to look at kidney outcomes are needed to confirm these findings

Female sex reduces the risk of hospital-associated acute kidney injury: a meta-analysis

Abstract Background Female sex has been included as a risk factor in models developed to predict the development of AKI. In addition, the commentary to the Kidney Disease Improving Global Outcomes Clinical Practice Guideline for AKI concludes that female sex is a risk factor for hospital-acquired AKI. In contrast, a protective effect of female sex has been demonstrated in animal models of ischemic AKI. Methods To further explore this issue, we performed a meta-analysis of AKI studies published between January, 1978 and April, 2018 and identified 83 studies reporting sex-stratified data on the incidence of hospital-associated AKI among nearly 240,000,000 patients. Results Twenty-eight studies (6,758,124 patients) utilized multivariate analysis to assess risk factors for hospital-associated AKI and provided sex-stratified ORs. Meta-analysis of this cohort showed that the risk of developing hospital-associated AKI was significantly greater in men than in women (OR 1.23 (1.11,1.36). Since AKI is not a single disease but instead represents a heterogeneous group of disorders characterized by an acute reduction in renal function, we performed subgroup meta-analyses. The association of male sex with AKI was strongest among studies of patients who underwent non-cardiac surgery. Male sex was also associated with AKI in studies which included unselected hospitalized patients and in studies of critically ill patients who received care in an intensive care unit. In contrast, cardiac surgery-associated AKI and radiocontrast-induced AKI showed no sexual dimorphism. Conclusions Our meta-analysis contradicts the established belief that female sex confers a greater risk of AKI and instead suggests a protective role

Sex differences in acute kidney injury requiring dialysis

Abstract Background Female sex has been included as a risk factor in models developed to predict the risk of acute kidney injury (AKI) associated with cardiac surgery, aminoglycoside nephrotoxicity and contrast-induced nephropathy. The commentary acompanying the Kidney Disease Improving Global Outcomes Clinical Practice Guideline for Acute Kidney Injury concludes that female sex is a shared susceptibility factor for acute kidney injury based on observations that female sex is associated with the development of hospital-acquired acute kidney injury. In contrast, female sex is reno-protective in animal models. In this context, we sought to examine the role of sex in hospital-associated acute kidney injury in greater detail. Methods We utilized the Hospital Episode Statistics database to calculate the sex-stratified incidence of AKI requiring renal replacement therapy (AKI-D) among 194,157,726 hospital discharges reported for the years 1998–2013. In addition, we conducted a systematic review of the English literature to evaluate dialysis practices among men versus women with AKI. Results Hospitalized men were more likely to develop AKI-D than hospitalized women (OR 2.19 (2.15, 2.22) p < 0.0001). We found no evidence in the published literature that dialysis practices differ between men and women with AKI. Conclusions Based on a population of hospitalized patients which is more than 3 times larger than all previously published cohorts reporting sex-stratified AKI data combined, we conclude that male sex is associated with an increased incidence of hospital-associated AKI-D. Our study is among the first reports to highlight the protective role of female gender in AKI

Avoidable visits to the emergency department(ED) and their association with sex, age and race in a cohort of low socio-economic status patients on hemodialysis in the Bronx.

BACKGROUND:In national samples drawn from the USRDS, female patients utilize the hospital ED and inpatient services at a higher rate than their male counterparts and have a higher rate of re-hospitalization. We wanted to explore the association of sex with avoidable ED visits made by a cohort of patients on hemodialysis in a mostly minority, lower socioeconomic status (SES), population in the Bronx to test the applicability of the USRDS findings. METHODS:We used Montefiore's clinical database to build a cohort of patients on hemodialysis with a first ED visit between 2013 and 2017. All ED visits after the index ED visit and those within one year prior to the index visit were recorded. None of the ED visits resulted in a hospitalization and were thus labeled "avoidable". Bivariate analysis tested the association of demographic and clinical variables with sex. We used negative binomial regression to test the association of each variable with avoidable ED visit count. The multivariate model used negative binomial regression with avoidable ED visit count as outcome and sex as the exposure variable and included ancestral variables age and race. Potential mediators were added to the model to measure their effects on the association of sex with avoidable ED visits. RESULTS:Four thousand six hundred and seventy three subjects on hemodialysis were identified as having at least one avoidable ED visit, in the period of 2013-2017 at one of four ED sites affiliated with Montefiore Medical Center in the Bronx. Over 5 years (2012-2017), the median number of ED visits made by the study sample was 4 (25-75% IQR: 2-8). Female patients on hemodialysis in our cohort were older, more commonly black, had lower SES scores, less commonly had commercial insurance and were less commonly married than their male counterparts. Female sex was not significantly associated with a higher rate of avoidable ED visits in the total cohort.(1.053(0.99-1.12) Female sex was significantly associated with outcome in non-Hispanic whites only and in those subjects younger than 44 years old.(IRR 1.30(1.06-1.69), 1.17(1.00-1.38) in non-Hispanic White and younger age group, respectively.) Marital status, SES and hemoglobin levels possibly mediated the association of sex and outcome in our population. (>25% change in the coefficient for sex with respect to outcome when variable added to the model). CONCLUSION:In this single center study of a lower-socioeconomic status, mostly minority dialysis population, the association of female sex with avoidable ED visits was not significant. These results suggest the association of sex with hospitalization outcomes, described by national datasets that determine quality indicators, are not consistent across different types of populations with some mediation possible by SES and marital status in poorer neighborhoods

Does comorbidity burden explain the higher COVID-19 mortality risk among men? A retrospective cross-sectional analysis of a well-defined cohort of patients in Bronx, New York

OBJECTIVES: Men have a higher mortality rate and more severe COVID-19 infection than women. The mechanism for this is unclear. We hypothesise that innate sex differences, rather than comorbidity burden, drive higher male mortality. DESIGN: Retrospective cohort. SETTING: Montefiore Health System (MHS) in Bronx, New York, USA. PARTICIPANTS: A cohort population of 364 992 patients at MHS between 1 January 2018 and 1 January 2020 was defined, from which individuals hospitalised during the pre-COVID period (1 January 2020–15 February 2020) (n=5856) and individuals hospitalised during the COVID-19 surge (1 March 2020–15 April 2020) (n=4793) were examined for outcomes. A subcohort with confirmed COVID-19+ hospitalisation was also examined (n=1742). PRIMARY AND SECONDARY OUTCOME MEASURES: Hospitalisation and in-hospital mortality. RESULTS: Men were older, had more comorbidities, lower body mass index and were more likely to smoke. Unadjusted logistic regression showed a higher odds of death in hospitalised men than women during both the pre-COVID-19 and COVID-19 periods (pre-COVID-19, OR: 1.66 vs COVID-19 OR: 1.98). After adjustment for relevant clinical and demographic factors, the higher risk of male death attenuated towards the null in the pre-COVID-19 period (OR 1.36, 95% CI 1.05 to 1.76) but remained significantly higher in the COVID-19 period (OR 2.02; 95% CI 1.73 to 2.34). In the subcohort of COVID-19+ hospitalised patients, men had 1.37 higher odds of in-hospital death (95% CI 1.09 to 1.72), which was not altered by adjustment for comorbidity (OR remained at 1.38 (95% CI 1.08 to 1.76)) but was attenuated with addition of initial pulse oximetry on presentation (OR 1.26, 95% CI 0.99 to 1.62). CONCLUSIONS: Higher male mortality risk during the COVID-19 period despite adjustment for comorbidity supports the role of innate physiological susceptibility to COVID-19 death. Attenuation of higher male risk towards the null after adjustment for severity of lung disease in hospitalised COVID-19+ patients further supports the role of higher severity of COVID-19 pneumonia in men