Association of Circulating 25-Hydroxyvitamin D and Recurrence of Glomerulonephritis in Kidney Transplant Recipients: The Wisconsin Allograft Recipient Database (WisARD).

Background: Recurrence of glomerulonephritis (GN) is a significant contributor to long-term allograft failure among kidney transplant recipients (KTRs) with kidney failure because of GN. Accumulating evidence has revealed the role of vitamin D in both innate and adaptive immunity. Although vitamin D deficiency is common among KTRs, the association between 25-hydroxyvitamin D (25[OH]D) and GN recurrence in KTRs remains unclear. Methods: We analyzed data from KTRs with kidney failure caused by GN who received a transplant at our center from 2000 to 2019 and had at least 1 valid posttransplant serum 25(OH)D measurement. Survival analyses were performed using a competing risk regression model considering other causes of allograft failure, including death, as competing risk events. Results: A total of 67 cases of GN recurrence were identified in 947 recipients with GN followed for a median of 7.0 y after transplant. Each 1 ng/mL lower serum 25(OH)D was associated with a 4% higher hazard of recurrence (subdistribution hazard ratio [HR]: 1.04; 95% confidence interval [CI], 1.01-1.06). Vitamin D deficiency (≤20 ng/mL) was associated with a 2.99-fold (subdistribution HR: 2.99; 95% CI, 1.56-5.73) higher hazard of recurrence compared with vitamin D sufficiency (≥30 ng/mL). Results were similar after further adjusting for concurrent urine protein-creatinine ratio, serum albumin, and estimated glomerular filtration rate (eGFR). Conclusions: Posttransplant vitamin D deficiency is associated with a higher hazard of GN recurrence in KTRs. Further prospective observational studies and clinical trials are needed to determine any causal role of vitamin D in the recurrence of GN after kidney transplantation. More in vitro and in vivo experiments would be helpful to understand its effects on autoimmune and inflammation processes.

Associations between collagen X biomarker and linear growth velocity in a pediatric chronic kidney disease cohort.

BACKGROUND: Collagen X biomarker (CXM) is a novel biomarker of linear growth velocity. We investigated whether CXM correlated with measured growth velocity in children with impaired kidney function. METHODS: We used data from children aged 2 through 16 years old enrolled in the Chronic Kidney Disease in Children (CKiD) study. We assessed the association between CXM level and growth velocity based on height measurements obtained at study visits using linear regression models constructed separately by sex, with and without adjustment for CKD covariates. Linear mixed-effects models were used to capture the between-individual and within-individual CXM changes over time associated with concomitant changes in growth velocity from baseline through follow-up. RESULTS: A total of 967 serum samples from 209 participants were assayed for CXM. CXM correlated more strongly in females compared to male participants. After adjustment for growth velocity and CKD covariates, only proteinuria in male participants affected CXM levels. Finally, we quantified the between- and within-participant associations between CXM level and growth velocity. A between-participant increase of 24% and 15% in CXM level in females and males, respectively, correlated with a 1 cm/year higher growth velocity. Within an individual participant, on average, 28% and 13% increases in CXM values in females and males, respectively, correlated with a 1 cm/year change in measured growth. CONCLUSIONS: CXM measurement is potentially a valuable aid for monitoring growth in pediatric CKD. However, future research, including studies of CXM metabolism, is needed to clarify whether CXM can be a surrogate of growth in children with CKD. A higher resolution version of the Graphical abstract is available as Supplementary information.

Food Insecurity Is Associated With Urge Urinary Incontinence: An Analysis of the 2005-2010 National Health and Nutrition Examination Survey.

PURPOSE: Urge urinary incontinence is the involuntary leakage of urine associated with a sudden compelling urge to void. A previous study found an association between urge urinary incontinence and household income, indicating that social determinants of health may influence urge urinary incontinence. Food insecurity is a relevant social determinant of health, as a diet with bladder irritants may worsen urge urinary incontinence symptoms. This study aimed to investigate the association between urge urinary incontinence and food insecurity. MATERIALS AND METHODS: We collected data from the 2005-2010 cycles of the National Health and Nutrition Examination Survey, a nationally representative health survey administered by the Centers for Disease Control and Prevention. The association between urge urinary incontinence and food insecurity was analyzed using survey-weighed logistic regression with adjustments for demographic, socioeconomic status, behavioral, and medical comorbidities covariates. RESULTS: We included 14,847 participants with mean age 50.4±17.9 years; 22.4% of participants reported at least 1 episode of urge urinary incontinence. We found that participants who reported food insecurity had 55% greater odds of experiencing urge urinary incontinence compared to those who have not (OR=1.55, 95% CI=1.33-1.82, P < .001). When comparing diets, food-insecure participants reported significantly less intake of bladder irritants (caffeine and alcohol) compared to food-secure participants. When the sample was stratified by food insecurity status (yes vs no), consumption of caffeine did not differ by urge urinary incontinence status and consumption of alcohol was lower among participants with vs without urge urinary incontinence. CONCLUSIONS: Adults reporting food insecurity in the past year are significantly more likely to experience urge urinary incontinence than those who did not. Consumption of bladder irritants including caffeine and alcohol was significantly less in food-insecure compared to food-secure participants. When the sample was stratified by food insecurity status (yes vs no), consumption of caffeine did not differ by urge urinary incontinence status and consumption of alcohol was lower among participants with vs without urge urinary incontinence. These data indicate that diet alone does not drive the association between urge urinary incontinence and food insecurity. Instead, food insecurity may be a proxy for social inequity, perhaps the greatest driver of disease.

Feasibility of a Peer Mentor Training Program for Patients Receiving Hemodialysis: An Educational Program Evaluation.

Rationale and Objective: The 'PEER-HD' multicenter study tests the effectiveness of peer mentorship to reduce hospitalizations in patients receiving maintenance hemodialysis. In this study, we describe the feasibility, efficacy, and acceptability of the mentor training program. Study Design: Educational program evaluation including the following aspects: (1) description of training content, (2) quantitative analysis of feasibility and acceptability of the program, and (3) quantitative pre-post analysis of efficacy of the training to impart knowledge and self-efficacy. Setting and Participants: Data were collected using baseline clinical and sociodemographic questionnaires from mentor participants enrolled in Bronx, NY, and Nashville, TN, themselves receiving maintenance hemodialysis. Analytical Approach: The outcome variables were the following: (1) feasibility measured by training module attendance and completion, (2) efficacy of the program to impart knowledge and self-efficacy measured by kidney knowledge and self-efficacy surveys, and (3) acceptability as measured by an 11-item survey of trainer performance and module content. Results: The PEER-HD training program included 4 2-hour modules that covered topics including dialysis-specific knowledge and mentorship skills. Of the 16 mentor participants, 14 completed the training program. There was complete attendance to all training modules, though some patients required flexibility in scheduling and format. Performance on posttraining quizzes was consistent with high knowledge (mean scores ranged from 82.0%-90.0% correct). Mean dialysis-specific knowledge scores trended higher post training than at baseline though this difference was not statistically significant (90.0% vs 78.1%; P = 0.1). No change in mean self-efficacy scores was demonstrated from before to after training, among mentor participants (P = 0.2). Program evaluation assessments of acceptability were favorable [mean of all patient scores (0-4) within each module ranged from 3.43-3.93]. Limitations: Small sample size. Conclusions: The PEER-HD mentor training program required accommodation to patients' schedules but was feasible. Participants rated the program favorably, and although the comparison of performance on knowledge assessments post- and pre-program showed uptake of knowledge, this was not statistically significant.

Reduced kidney function and hypertension in adolescents with low birth weight, NHANES 1999-2016.

BACKGROUND: Chronic kidney disease (CKD) is a major health problem, and the risk of CKD and hypertension in children born low birth weight (LBW) is under-recognized. We hypothesized that children born with LBW would have a higher prevalence of reduced kidney function and hypertension. METHODS: Using the National Health and Nutrition Examination Survey (NHANES), we conducted a cross-sectional study to evaluate whether LBW (< 2500 g), very low birth weight (VLBW < 1500 g), and large birth weight (BW) (> 4000 g) were associated with kidney disease using 4 different estimating equations. We used the Counahan-Barratt, updated Schwartz, CKiD-U25, and full age spectrum creatinine-based GFR estimating equations to evaluate associations between a history of LBW/VLBW/large BW and reduced kidney function (eGFR < 90 mL/min/1.73 m2) in children. We also assessed blood pressure (BP) using the old and new pediatric hypertension guidelines. RESULTS: Our analysis included 6336 children (age 12-15 years) in NHANES representing over 13 million US individuals. Using the updated Schwartz, the prevalence of reduced kidney function was 30.1% (25.2-35.6) for children born with LBW compared to 22.4% (20.5-24.3) in children with normal BW. Equations yielded different estimates of prevalence of reduced kidney function in LBW from 21.5% for Counahan-Barratt to 35.4% for CKiD-U25. Compared to those with normal BW, participants with LBW and VLBW had a 7.2 and 10.3% higher prevalence of elevated BP and a 2.4 and 14.6% higher prevalence of hypertension, respectively. CONCLUSIONS: Children born with LBW are at higher risk of reduced kidney function and hypertension than previously described. A higher resolution version of the Graphical abstract is available as Supplementary information.

Urinary Ammonium in Clinical Medicine: Direct Measurement and the Urine Anion Gap as a Surrogate Marker During Metabolic Acidosis.

Ammonium is the most important component of urinary acid excretion, normally accounting for about two-third of net acid excretion. In this article, we discuss urine ammonium not only in the evaluation of metabolic acidosis but also in other clinical conditions such as chronic kidney disease. Different methods to measure urine NH4+ that have been employed over the years are discussed. The enzymatic method used by clinical laboratories in the United States to measure plasma ammonia via the glutamate dehydrogenase can be used for urine ammonium. The urine anion gap calculation can be used as a rough marker of urine ammonium in the initial bedside evaluation of metabolic acidosis such as in distal renal tubular acidosis. Urine ammonium measurements, however, should be made more available in clinical medicine for a precise evaluation of this important component of urinary acid excretion.

Comprehensive Associations between Acidosis and the Skeleton in Patients with Kidney Disease.

SIGNIFICANCE STATEMENT: Renal osteodystrophy (ROD) contributes substantially to morbidity in CKD, including increased fracture risk. Metabolic acidosis (MA) contributes to the development of ROD, but an up-to-date skeletal phenotype in CKD-associated acidosis has not been described. We comprehensively studied associations between acidosis and bone in patients with CKD using advanced methods to image the skeleton and analyze bone-tissue, along with biochemical testing. Cross-sectionally, acidosis was associated with higher markers of bone remodeling and female-specific impairments in cortical and trabecular bone quality. Prospectively, acidosis was associated with cortical expansion and trabecular microarchitectural deterioration. At the bone-tissue level, acidosis was associated with deficits in bone mineral content. Future work investigating acidosis correction on bone quality is warranted. BACKGROUND: Renal osteodystrophy is a state of impaired bone quality and strength. Metabolic acidosis (MA) is associated with alterations in bone quality including remodeling, microarchitecture, and mineralization. No studies in patients with CKD have provided a comprehensive multimodal skeletal phenotype of MA. We aim to describe the structure and makeup of bone in patients with MA in the setting of CKD using biochemistry, noninvasive imaging, and histomorphometry. METHODS: The retrospective cross-sectional analyses included 180 patients with CKD. MA was defined as bicarbonate ≤22 mEq/L. We evaluated circulating bone turnover markers and skeletal imaging with dual energy x-ray absorptiometry and high-resolution peripheral computed tomography. A subset of 54 participants had follow-up. We assessed associations between baseline and change in bicarbonate with change in bone outcomes. Histomorphometry, microCT, and quantitative backscatter electron microscopy assessed bone biopsy outcomes in 22 participants. RESULTS: The mean age was 68±10 years, 54% of participants were male, and 55% were White. At baseline, acidotic subjects had higher markers of bone turnover, lower areal bone mineral density at the radius by dual energy x-ray absorptiometry, and lower cortical and trabecular volumetric bone mineral density and impaired trabecular microarchitecture. Over time, acidosis was associated with opposing cortical and trabecular effects: cortical expansion but trabecular deterioration. Bone-tissue analyses showed reduced tissue mineral density with increased heterogeneity of calcium distribution in acidotic participants. CONCLUSIONS: MA is associated with multiple impairments in bone quality. Future work should examine whether correction of acidosis improves bone quality and strength in patients with CKD.

The relationship between fecal incontinence and food insecurity in United States women: an analysis of 2005-2010 National Health and Nutrition Examination Survey.

BACKGROUND: Fecal incontinence is a prevalent debilitating pelvic floor disorder characterized by the involuntary loss of stool. Fecal incontinence is known to be associated with constipation and loose stool, advancing age, chronic comorbidities, and previous anorectal trauma, among other biologic risk factors. The relationship between social determinants of health, such as food insecurity, and fecal incontinence is not well elucidated. OBJECTIVE: This study aimed to investigate the association between fecal incontinence and food insecurity using a nationally representative sample of US adult women. Our secondary aim was to examine the role of diet by assessing dietary differences between participants with and without fecal incontinence and between food-insecure women with and without fecal incontinence. STUDY DESIGN: This study analyzed data from the National Health and Nutrition Examination Survey, a nationally representative series of cross-sectional health surveys. Fecal incontinence was defined as accidental leakage of stool within the last 30 days. Food insecurity was assessed using the household food security measure created by the US Department of Agriculture. Dietary data from the National Health and Nutrition Examination Survey dietary interviews titled "Individual Foods, First Day" and "Individual Foods, Second Day," which estimate the foods and drinks consumed in the preceding 24 hours, were pooled. The association between fecal incontinence and food insecurity was analyzed using logistic regression after controlling for patient characteristics. RESULTS: Overall, 3216 women were included, representing nearly 130 million US women. Of these women, 10.9% had fecal incontinence. There was no significant difference in diet between women with and without fecal incontinence (p>0.05). Food-insecure women in the overall sample reported higher carbohydrate and sugar intake and lower fiber and alcohol intake (all P<.05). Among food-insecure women, those with fecal incontinence had higher calorie and total fats intake than those without fecal incontinence; there was no significant difference in other dietary components (p>0.05). There was a significant association between food insecurity and fecal incontinence, such that women with food insecurity had higher odds of fecal incontinence after adjusting for patient characteristics and diet (odds ratio, 1.76; 95% confidence interval, 1.17-2.66; P=.008). CONCLUSION: Food insecurity was associated with fecal incontinence even after accounting for diet. Understanding the role of social determinants of health in fecal incontinence symptomatology and treatment is important to potentially alleviate symptom burden and improve the quality of life in at-risk populations.

Longitudinal Associations between Low Serum Bicarbonate and Linear Growth in Children with CKD.

Background: Poor linear growth is a consequence of chronic kidney disease (CKD) that has been linked to adverse outcomes. Metabolic acidosis (MA) has been identified as a risk factor for growth failure. We investigated the longitudinal relationship between MA and linear growth in children with CKD and examined whether treatment of MA modified linear growth. Methods: To describe longitudinal associations between MA and linear growth, we used serum bicarbonate levels, height measurements, and standard deviation (z scores) of children enrolled in the prospective cohort study Chronic Kidney Disease in Children. Analyses were adjusted for covariates recognized as correlating with poor growth, including demographic characteristics, glomerular filtration rate (GFR), proteinuria, calcium, phosphate, parathyroid hormone, and CKD duration. CKD diagnoses were analyzed by disease categories, nonglomerular or glomerular. Results: The study population included 1082 children with CKD: 808 with nonglomerular etiologies and 274 with glomerular etiologies. Baseline serum bicarbonate levels ≤22 mEq/L were associated with worse height z scores in all children. Longitudinally, serum bicarbonate levels ≤18 and 19-22 mEq/L were associated with worse height z scores in children with nonglomerular CKD causes, with adjusted mean values of -0.39 (95% CI, -0.58 to -0.2) and -0.17 (95% CI, -0.28 to -0.05), respectively. Children with nonglomerular disease and more severe GFR impairment had a higher risk for worse height z score. A significant association was not found in children with glomerular diseases. We also investigated the potential effect of treatment of MA on height in children with a history of alkali therapy use, finding that only persistent users had a significant positive association between their height z score and higher serum bicarbonate levels. Conclusions: We observed a longitudinal association between MA and lower height z score. Additionally, persistent alkali therapy use was associated with better height z scores. Future clinical trials of alkali therapy need to evaluate this relationship prospectively.

Interdisciplinary Care and Preparedness for Kidney Failure Management in a High-Risk Population.

Rationale & Objective: Interdisciplinary care may improve health outcomes in patients with chronic kidney disease (CKD). Few studies have evaluated this model of health care delivery in racial and ethnic minorities. Study Design: Retrospective cohort study. Setting & Participants: Incident end-stage kidney disease (ESKD) patients at Montefiore Medical Center from October 1, 2013, to October 31, 2019. Exposure: Pre-ESKD interdisciplinary care. Outcomes: Pre-ESKD transplant listing and optimal kidney replacement therapy (KRT) start (use of arteriovenous access at hemodialysis initiation, outpatient hemodialysis start, preemptive transplant, or peritoneal dialysis as the first modality). Analytical Approach: We constructed multivariable logistic regression models adjusted for sociodemographic and clinical factors to determine the odds of transplant listing and optimal KRT start between interdisciplinary versus the usual care group. Results: Of the 295 incident ESKD patients included in our study, 84 received interdisciplinary care and 211 received usual nephrology care. The mean age was 59.9 years (standard deviation, 13.9 years), 47% were women, and 87% were African American or Hispanic. Baseline characteristics were similar between the groups, except that the interdisciplinary care group had a lower prevalence of hypertension (60% vs 75%). Compared with usual care, a higher proportion of patients in the interdisciplinary care group were listed for kidney transplant (44% vs 16%) and had an optimal KRT start (53% vs 44%). Receipt of interdisciplinary care was associated with a higher odds (OR, 5.73; 95% CI, 2.78-11.80; P < 0.001) of transplant listing compared with usual care after adjusting for important sociodemographic and clinical factors. The odds of an optimal KRT start also favored interdisciplinary care (OR, 1.60; 95% CI, 0.88-2.89; P = 0.12) but did not achieve statistical significance. Limitations: The study was non-randomized and had a small sample size. Conclusions: Interdisciplinary care is associated with better ESKD preparedness compared with usual nephrology care alone in racial and ethnic minorities. Larger studies are needed to determine the effectiveness of interdisciplinary care in patients with advanced CKD.

Peer mentorship to improve outcomes in patients on hemodialysis (PEER-HD): a randomized controlled trial protocol.

BACKGROUND: Patients receiving in-center hemodialysis experience disproportionate morbidity and incur high healthcare-related costs. Much of this cost stems from potentially avoidable hospitalizations. Peer mentorship has been used effectively to improve outcomes for patients with complex chronic diseases. We propose testing the efficacy of peer mentorship on hospitalization rates among patients receiving hemodialysis. METHODS: This is a multicenter parallel group randomized controlled pragmatic trial of patients treated at hemodialysis facilities in Bronx, NY and Nashville, TN. The study has two phases. Phase 1 will enroll and train 16 hemodialysis patients (10 in Bronx, NY and 6 in Nashville TN) to be mentors using a program focused on enhancing self-efficacy, dialysis self-management and autonomy-supportive communication skills. Phase 2 will enroll 200 high risk adults receiving hemodialysis (140 in Bronx, NY and 60 in Nashville, TN), half of whom will be randomized to intervention and half to usual care. Intervention participants are assigned to weekly telephone calls with trained mentors (see Phase 1) for a 3-month period. The primary outcome of Phase 1 will be engagement of mentors with training and change in knowledge scores and autonomy skills from pre- to post-training. The primary outcome of Phase 2 will be the composite count of ED visits and hospitalizations at the end of study follow-up in patient participants assigned to intervention as compared to those assigned to usual care. Secondary outcomes for Phase 2 include the change over the trial period in validated survey scores measuring perception of social support and self-efficacy, and dialysis adherence metrics, among intervention participants as compared to usual care participants. DISCUSSION: The PEER-HD study will test the feasibility and efficacy of a pragmatic peer-mentorship program designed for patients receiving hemodialysis on ED visit and hospitalization rates. If effective, peer-mentorship holds promise as a scalable patient-centered intervention to decrease hospital resource utilization, and by extension morbidity and cost, for patients receiving maintenance in-center hemodialysis. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT03595748 ; 7/23/2018. TRIAL SPONSOR: National Institutes of Diabetes, Digestive and Kidney Disease (NIDDK) 5R18DK118471. FUNDING: Funding for this study was provided by the National Institutes of Diabetes, Digestive and Kidney Disease: R18DK118471. STUDY STATUS: This is an ongoing study and not complete. We are still collecting data for observational follow-up on participants. RELATED ARTICLES: No related articles for this study have been submitted to any journal. The study sponsor and funders had no role in the design, analysis or interpretation of this data. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Effects of Vitamin D3 Supplementation on Cardiovascular and Cancer Outcomes by eGFR in VITAL.

Background: Reduced 25-hydroxyvitamin D (25[OH]D) metabolism and secondary hyperparathyroidism are common with lower estimated glomerular filtration rate (eGFR) and may contribute to cardiovascular disease and cancer risk. Methods: We assessed for heterogeneity by baseline eGFR of the effects of vitamin D3 on cardiovascular and cancer outcomes in the Vitamin D and Omega-3 Trial (VITAL). Participants were randomized to 2000 IU vitamin D3 and/or 1 g Ω-3 fatty acids daily using a placebo-controlled, two-by-two factorial design (5.3 years follow-up). Primary study end points were incident major cardiovascular events and invasive cancer. Changes in serum 25(OH)D and parathyroid hormone (PTH) were examined. Results: Baseline eGFR was available for 15,917 participants. Participants' mean age was 68 years, and 51% were women. Vitamin D3 resulted in higher serum 25(OH)D compared with placebo (difference in change 12.5 ng/ml; 95% CI, 12 to 13.1 ng/ml), without heterogeneity by eGFR (P interaction, continuous eGFR=0.2). Difference in change in PTH between vitamin D3 and placebo was larger with lower eGFR (P interaction=0.05): -6.9 (95% CI, -10.5 to -3.4), -5.8 (95% CI, -8.3 to -3.4), -4 (95% CI, -5.9 to -2.2), and -3.8 (95% CI, -5.6 to -2) pg/ml for eGFR <60, 60-74, 75-89, and ≥90 ml/min per 1.73 m2, respectively. Effects of vitamin D3 supplementation on cardiovascular events (P interaction=0.61) and cancer (P interaction=0.89) did not differ by eGFR: HR=1.14 (95% CI, 0.73 to 1.79), HR=1.06 (95% CI, 0.75 to 1.5), HR=0.92 (95% CI, 0.67 to 1.25), and HR=0.92 (95% CI, 0.66 to 1.27) across eGFR categories for cardiovascular events and HR=1.63 (95% CI, 1.03 to 2.58), HR=0.85 (95% CI, 0.64 to 1.11), HR=0.84 (95% CI, 0.68 to 1.03), and 1.11 (95% CI, 0.92 to 1.35) for cancer, respectively. Conclusions: We observed no significant heterogeneity by baseline eGFR in the effects of vitamin D3 supplementation versus placebo on cardiovascular or cancer outcomes, despite effects on 25(OH)D and PTH concentrations.

Female Sexual Dysfunction as Measured by Low Sexual Frequency is Associated With Lower Socioeconomic Status: An Analysis of the National Health and Nutrition Examination Survey (NHANES), 2007-2016.

BACKGROUND: Female sexual dysfunction (FSD) is a complex disorder of biopsychosocial etiology, and FSD symptoms affect more than 40% of adult women worldwide. AIM: In this cross-sectional study, we sought to investigate the association between FSD and socioeconomic status (SES) in a nationally representative female adult population. METHODS: Economic and sexual data for women aged 20-59 from the 2007-2016 National Health and Nutrition Examination Survey, a United States nationwide representative database, was analyzed. Poverty income ratio (PIR), a ratio of family income to poverty threshold, was used as a measure of SES, and low sexual frequency was used as a measure of FSD. The association between FSD and SES was analyzed using survey-weighted logistic regression after adjusting for relevant social and gynecologic covariates, such as marital status and history of pregnancy, as well as significant medical comorbidities. OUTCOMES: We found that FSD, as measured by low sexual frequency, was associated with lower SES. RESULTS: Among the 7,348 women of mean age 38.4 (IQR 29-47) included in the final analysis, 26.3% of participants reported sexual frequency of 0-11 times/year and 73.7% participants reported sexual frequency >11 times/year. Participants of PIR <2 were 92% more likely to report sexual frequency ≤11 times/year than those of PIR ≥2 after adjusting for demographics, social history, gynecologic history and significant medical conditions (OR = 1.92; 95% CI = 1.21-3.05; P < .006). CLINICAL IMPLICATIONS: The evaluation and treatment of FSD may benefit from a comprehensive approach that takes SES into account. STRENGTHS & LIMITATIONS: This study is limited by its cross-sectional design, but it is strengthened by a large, nationally representative sample with extensive, standardized data ascertainment. CONCLUSION: Lower SES and lower sexual frequency are directly correlated among female adults in the United States; future studies should focus on social determinants of health as risk factors for FSD. Kim JI, Zhu D, Davila J, et al. Female Sexual Dysfunction as Measured by Low Sexual Frequency is Associated With Lower Socioeconomic Status: An Analysis of the National Health and Nutrition Examination Survey (NHANES), 2007-2016. J Sex Med 2022;19:90-97.

Association of GSTM1 Deletion With Progression of CKD in Children: Findings From the Chronic Kidney Disease in Children (CKiD) Study.

RATIONALE & OBJECTIVE: Loss of function of the product of the GSTM1 gene has been implicated in rapid progression of adult chronic kidney disease (CKD). Its role in pediatric CKD has not been previously described. STUDY DESIGN: Secondary analysis of a prospective observational cohort examining the association between deletions in GSTM1 and progression of CKD. SETTING & PARTICIPANTS: We used data and samples from the prospective Chronic Kidney Disease in Children (CKiD) cohort aged 1-16 years at enrollment with CKD. EXPOSURE: We defined the exposure as fewer than 2 GSTM1 alleles on real-time polymerase chain reaction amplification. OUTCOME: The primary outcome was a composite of 50% decrease in estimated glomerular filtration rate (eGFR) or start of kidney replacement therapy. Secondary outcomes included remission of proteinuria in children with glomerular disease and cardiovascular complications. ANALYTICAL APPROACH: The primary analysis was by Cox proportional hazards model. Analysis was adjusted for age, sex, race, ethnicity, body mass index category, diagnosis category, and eGFR. RESULTS: The analysis included 674 children. Their mean age at most recent visit was 11.9 years; 61% were male, and 20% were Black. There were 241 occurrences of the primary outcome at the time of analysis. After adjustment for baseline characteristics, the risk of progression of CKD for exposed children was 1.94 (95% CI, 1.27-2.97). The effect size was similar with either 1 or 2 deletions (autosomal dominant inheritance). The relationships between number of functional GSTM1 alleles and prespecified secondary outcomes were not statistically significant after adjustment. LIMITATIONS: Missing data, especially for secondary outcomes, and relatively small sample size compared to genetic studies in adults. CONCLUSIONS: GSTM1 deletion is associated with more rapid progression of pediatric CKD after adjustment in this large prospective cohort. No statistically significant associations were seen with secondary outcomes. If replicated, these findings may inform development of interventions for CKD in children.

Sex-related differences in mortality, acute kidney injury, and respiratory failure among critically ill patients with COVID-19.

ABSTRACT: Although the number of deaths due to coronavirus disease 2019 (COVID-19) is higher in men than women, prior studies have provided limited sex-stratified clinical data.We evaluated sex-related differences in clinical outcomes among critically ill adults with COVID-19.Multicenter cohort study of adults with laboratory-confirmed COVID-19 admitted to intensive care units at 67 U.S. hospitals from March 4 to May 9, 2020. Multilevel logistic regression was used to evaluate 28-day in-hospital mortality, severe acute kidney injury (AKI requiring kidney replacement therapy), and respiratory failure occurring within 14 days of intensive care unit admission.A total of 4407 patients were included (median age, 62 years; 2793 [63.4%] men; 1159 [26.3%] non-Hispanic White; 1220 [27.7%] non-Hispanic Black; 994 [22.6%] Hispanic). Compared with women, men were younger (median age, 61 vs 64 years, less likely to be non-Hispanic Black (684 [24.5%] vs 536 [33.2%]), and more likely to smoke (877 [31.4%] vs 422 [26.2%]). During median follow-up of 14 days, 1072 men (38.4%) and 553 women (34.3%) died. Severe AKI occurred in 590 men (21.8%), and 239 women (15.5%), while respiratory failure occurred in 2255 men (80.7%) and 1234 women (76.5%). After adjusting for age, race/ethnicity and clinical variables, compared with women, men had a higher risk of death (OR, 1.50, 95% CI, 1.26-1.77), severe AKI (OR, 1.92; 95% CI 1.57-2.36), and respiratory failure (OR, 1.42; 95% CI, 1.11-1.80).In this multicenter cohort of critically ill adults with COVID-19, men were more likely to have adverse outcomes compared with women.

Muscle fibrosis and maladaptation occur progressively in CKD and are rescued by dialysis.

BACKGROUNDSkeletal muscle maladaptation accompanies chronic kidney disease (CKD) and negatively affects physical function. Emphasis in CKD has historically been placed on muscle fiber-intrinsic deficits, such as altered protein metabolism and atrophy. However, targeted treatment of fiber-intrinsic dysfunction has produced limited improvement, whereas alterations within the fiber-extrinsic environment have scarcely been examined.METHODSWe investigated alterations to the skeletal muscle interstitial environment with deep cellular phenotyping of biopsies from patients with CKD and age-matched controls and performed transcriptome profiling to define the molecular underpinnings of CKD-associated muscle impairments. We examined changes in muscle maladaptation following initiation of dialysis therapy for kidney failure.RESULTSPatients with CKD exhibited a progressive fibrotic muscle phenotype, which was associated with impaired regenerative capacity and lower vascular density. The severity of these deficits was strongly associated with the degree of kidney dysfunction. Consistent with these profound deficits, CKD was associated with broad alterations to the muscle transcriptome, including altered ECM organization, downregulated angiogenesis, and altered expression of pathways related to stem cell self-renewal. Remarkably, despite the seemingly advanced nature of this fibrotic transformation, dialysis treatment rescued these deficits, restoring a healthier muscle phenotype. Furthermore, after accounting for muscle atrophy, strength and endurance improved after dialysis initiation.CONCLUSIONThese data identify a dialysis-responsive muscle fibrotic phenotype in CKD and suggest the early dialysis window presents a unique opportunity of improved muscle regenerative capacity during which targeted interventions may achieve maximal impact.TRIAL REGISTRATIONNCT01452412FUNDINGNIH, NIH Clinical and Translational Science Awards (CTSA), and Einstein-Mount Sinai Diabetes Research Center.

Machine Learning Prediction of Death in Critically Ill Patients With Coronavirus Disease 2019.

OBJECTIVES: Critically ill patients with coronavirus disease 2019 have variable mortality. Risk scores could improve care and be used for prognostic enrichment in trials. We aimed to compare machine learning algorithms and develop a simple tool for predicting 28-day mortality in ICU patients with coronavirus disease 2019. DESIGN: This was an observational study of adult patients with coronavirus disease 2019. The primary outcome was 28-day inhospital mortality. Machine learning models and a simple tool were derived using variables from the first 48 hours of ICU admission and validated externally in independent sites and temporally with more recent admissions. Models were compared with a modified Sequential Organ Failure Assessment score, National Early Warning Score, and CURB-65 using the area under the receiver operating characteristic curve and calibration. SETTING: Sixty-eight U.S. ICUs. PATIENTS: Adults with coronavirus disease 2019 admitted to 68 ICUs in the United States between March 4, 2020, and June 29, 2020. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The study included 5,075 patients, 1,846 (36.4%) of whom died by day 28. eXtreme Gradient Boosting had the highest area under the receiver operating characteristic curve in external validation (0.81) and was well-calibrated, while k-nearest neighbors were the lowest performing machine learning algorithm (area under the receiver operating characteristic curve 0.69). Findings were similar with temporal validation. The simple tool, which was created using the most important features from the eXtreme Gradient Boosting model, had a significantly higher area under the receiver operating characteristic curve in external validation (0.78) than the Sequential Organ Failure Assessment score (0.69), National Early Warning Score (0.60), and CURB-65 (0.65; p < 0.05 for all comparisons). Age, number of ICU beds, creatinine, lactate, arterial pH, and Pao2/Fio2 ratio were the most important predictors in the eXtreme Gradient Boosting model. CONCLUSIONS: eXtreme Gradient Boosting had the highest discrimination overall, and our simple tool had higher discrimination than a modified Sequential Organ Failure Assessment score, National Early Warning Score, and CURB-65 on external validation. These models could be used to improve triage decisions and clinical trial enrichment.

MTADV 5-MER peptide suppresses chronic inflammations as well as autoimmune pathologies and unveils a new potential target-Serum Amyloid A.

Despite the existence of potent anti-inflammatory biological drugs e.g., anti-TNF and anti IL-6 receptor antibodies, for treating chronic inflammatory and autoimmune diseases, these are costly and not specific. Cheaper oral available drugs remain an unmet need. Expression of the acute phase protein Serum Amyloid A (SAA) is dependent on release of pro-inflammatory cytokines IL-1, IL-6 and TNF-α during inflammation. Conversely, SAA induces pro-inflammatory cytokine secretion, including Th17, leading to a pathogenic vicious cycle and chronic inflammation. 5- MER peptide (5-MP) MTADV (methionine-threonine-alanine-aspartic acid-valine), also called Amilo-5MER, was originally derived from a sequence of a pro-inflammatory CD44 variant isolated from synovial fluid of a Rheumatoid Arthritis (RA) patient. This human peptide displays an efficient anti-inflammatory effects to ameliorate pathology and clinical symptoms in mouse models of RA, Inflammatory Bowel Disease (IBD) and Multiple Sclerosis (MS). Bioinformatics and qRT-PCR revealed that 5-MP, administrated to encephalomyelytic mice, up-regulates genes contributing to chronic inflammation resistance. Mass spectrometry of proteins that were pulled down from an RA synovial cell extract with biotinylated 5-MP, showed that it binds SAA. 5-MP disrupted SAA assembly, which is correlated with its pro-inflammatory activity. The peptide MTADV (but not scrambled TMVAD) significantly inhibited the release of pro-inflammatory cytokines IL-6 and IL-1ß from SAA-activated human fibroblasts, THP-1 monocytes and peripheral blood mononuclear cells. 5-MP suppresses the pro-inflammatory IL-6 release from SAA-activated cells, but not from non-activated cells. 5-MP could not display therapeutic activity in rats, which are SAA deficient, but does inhibit inflammations in animal models of IBD and MS, both are SAA-dependent, as shown by others in SAA knockout mice. In conclusion, 5-MP suppresses chronic inflammation in animal models of RA, IBD and MS, which are SAA-dependent, but not in animal models, which are SAA-independent.

Comparison of the tissue distribution and metabolism of AN1284, a potent anti-inflammatory agent, after subcutaneous and oral administration in mice.

This study is to compare the tissue distribution and metabolism of AN1284 after subcutaneous and oral administration at doses causing maximal reductions in IL-6 in plasma and tissues of mice. Anti-inflammatory activity of AN1284 and its metabolites was detected in lipopolysaccharide (LPS) activated RAW 264.7 macrophages. Mice were given AN1284 by injection or gavage, 15 min before LPS. IL-6 protein levels were measured after 4 h. Using a liquid chromatography/mass spectrometry method we developed, we showed that AN1284 is rapidly metabolized to the indole (AN1422), a 7-OH derivative (AN1280) and its glucuronide. AN1422 has weaker anti-inflammatory activity than AN1284 in LPS-activated macrophages and in mice. AN1284 (0.5 mg/kg) caused maximal reductions in IL-6 in the plasma, brain, and liver when injected subcutaneously and after gavage only in the liver. Similar reductions in the plasma and brain required a dose of 2.5 mg/kg, which resulted in 5.5-fold higher hepatic levels than after injection of 0.5 mg/kg, but 7, 11, and 19-fold lower ones in the plasma, brain, and kidneys, respectively. Hepatic concentrations produced by AN1284 were 2.5 mg/kg/day given by subcutaneously implanted mini-pumps that were only 12% of the peak levels seen after acute injection of 0.5 mg/kg. Similar hepatic concentrations were obtained by (1 mg/kg/day), administered in the drinking fluid. These were sufficient to decrease hepatocellular damage and liver triglycerides in previous experiments in diabetic mice. AN1284 can be given orally by a method of continuous release to treat chronic liver disease, and its preferential concentration in the liver should limit any adverse effects.