Androgen exposure impairs neutrophil maturation and function within the infected kidney.

Urinary tract infections (UTIs) in men are uncommon yet carry an increased risk for severe pyelonephritis and other complications. In models of Escherichia coli UTI, C3H/HeN mice develop high-titer pyelonephritis (most with renal abscesses) in a testosterone-dependent manner, but the mechanisms underlying this phenotype are unknown. Here, using female mouse models, we show that androgen exposure impairs neutrophil maturation in the upper and lower urinary tract, compounded by a reduction of neutrophil function within the infected kidney, enabling persistent high-titer infection and promoting abscess formation. Following intravesical inoculation with uropathogenic E. coli (UPEC), kidneys of androgen-exposed C3H mice showed delayed local pro-inflammatory cytokine responses while robustly recruiting neutrophils. These were enriched for an end-organ-specific population of aged but immature neutrophils (CD49d+, CD101-). Compared to their mature counterparts, these aged immature kidney neutrophils exhibited reduced function in vitro, including impaired degranulation and diminished phagocytic activity, while splenic, bone marrow, and bladder neutrophils did not display these alterations. Furthermore, aged immature neutrophils manifested little phagocytic activity within intratubular UPEC communities in vivo. Experiments with B6 conditional androgen receptor (AR)-deficient mice indicated rescue of the maturation defect when AR was deleted in myeloid cells. We conclude that the recognized enhancement of UTI severity by androgens is attributable, at least in part, to local impairment of neutrophil maturation in the urinary tract (largely via cell-intrinsic AR signaling) and a kidney-specific reduction in neutrophil antimicrobial capacity.IMPORTANCEAlthough urinary tract infections (UTIs) predominantly occur in women, male UTIs carry an increased risk of morbidity and mortality. Pyelonephritis in androgen-exposed mice features robust neutrophil recruitment and abscess formation, while bacterial load remains consistently high. Here, we demonstrate that during UTI, neutrophils infiltrating the urinary tract of androgen-exposed mice exhibit reduced maturation, and those that have infiltrated the kidney have reduced phagocytic and degranulation functions, limiting their ability to effectively control infection. This work helps to elucidate mechanisms by which androgens enhance UTI susceptibility and severity, illuminating why male patients may be predisposed to severe outcomes of pyelonephritis.

Urogenital urobiome of healthy children does not differ from that of children with bladder and bowel dysfunction.

INTRODUCTION: The pediatric urinary microbiome (urobiome) has been studied in the context of healthy children and children with genitourinary pathologies including neuropathic bladder, urinary tract infection (UTI) and nephrolithiasis. Little is known about the urobiome of children with bladder and bowel dysfunction (BBD), a condition that is an established risk factor of UTI. We hypothesized that the symptoms of a child with BBD may be related to urobiome composition. OBJECTIVE: To evaluate the urogenital urobiome's role in BBD, we compared the urogenital urobiomes of children with and without BBD. STUDY DESIGN: We performed a prospective case-control pilot study at a single large, academic children's hospital. Cases included toilet trained prepubertal females over 2 years of age with BBD established through a validated scoring system and controls included asymptomatic, presumably healthy, children. Children were excluded if they had symptoms or lab work consistent with a concurrent UTI or antibiotic course for any reason within the prior 14 days. We performed 16 S ribosomal RNA gene sequencing and expanded quantitative urine culture on clean catch urine samples. To compare within sample (alpha) diversity, we used the Kruskal-Wallis test. To compare between sample (beta) diversity, we calculated the Bray-Curtis distance and performed the PERMANOVA test. RESULTS: Data from 25 children with BBD and 8 asymptomatic controls were analyzed. The demographic and clinical characteristics of the two comparison groups were similar, though a higher proportion of Black children were included in the asymptomatic control group. Neither alpha diversity nor beta diversity was significantly different between the two groups. The core microbiome of the BBD group included all the genera in the core urogenital urobiome of the controls, plus additional genera associated with opportunistic infection and/or UTI, including Escherichia, Campylobacter and Streptococcus. DISCUSSION: The results of both the 16 S sequencing and expanded quantitative urine culture in this small study suggest that the urogenital urobiomes of children with BBD do not differ significantly from those of asymptomatic children. However, the core urogenital urobiome of children with BBD included genera associated with opportunistic infection and/or UTI. This study was limited by the sample collection method ("clean catch" midstream voided urine samples, which introduce the possibility of vulvovaginal contamination), small sample size, and unequal balance of patient characteristics between the two study groups. CONCLUSION: The urogenital urobiomes of children with and without BBD do not appear to significantly differ. Larger studies are needed to confirm these findings.

Transient Hyperphosphatasemia Following Pediatric Kidney Transplant.

Introduction Transient hyperphosphatasemia (TH) is a rare benign condition of elevated serum alkaline phosphatase (AP) levels seen in healthy children. TH has been reported to occur in pediatric solid organ transplants, including kidney transplant patients. Little is known about TH in pediatric kidney transplant patients. Objective To evaluate the incidence and natural history of TH in pediatric kidney transplant patients. Methods A retrospective chart review of patients < 18 years of age who underwent kidney transplantation at the University of Pittsburgh Medical Center (UPMC) Children's Hospital of Pittsburgh between 2008 and 2019 was performed to identify patients with TH, defined as an AP level greater than 1,000 IU/L. Exclusion criteria included repeat kidney transplants or kidney transplant as part of a multiorgan transplant. Results One hundred seventy-six patients underwent a solitary kidney transplant, of which 87 were less than 12 years of age. Eleven patients (6.5%) were found to have TH, all of whom were < 12 years of age (12.8%) (median age: 5 years; range: 1 - 11 years). The median AP level prior to transplant was 183 IU/L (range: 104 - 309 IU/L) and the median peak AP was > 2,300 IU/L (range: 1,227 - 4,912 IU/L). The median time from a kidney transplant to the diagnosis of TH was 0.6 years (range: 0.3 to 7.7 years). The median length of time that TH persisted was 0.5 years (range: 0.2 to 0.9 years). The median estimated glomerular filtration rate (GFR) at the time of diagnosis of TH was 84 mL/min/1.73m2 per the bedside Schwartz equation (range: 45 to 152 mL/min/1.73m2). One patient had variable AP levels over nine months prior to resolution; the other 10 patients had a solitary peak of AP prior to resolution. No patient required treatment of elevated AP levels and the TH resolved spontaneously without intervention. No patients had significant abnormalities of markers of metabolic bone disease or were on active vitamin D, calcium, or phosphorus supplements. Two patients reported bone pain, and one patient was found to have avascular necrosis of the hip. Conclusions TH is a relatively common finding following a pediatric kidney transplant in pre-pubertal children less than 12 years of age. It primarily occurs in the first year following a kidney transplant and usually resolves without recurrence within one year of onset.

Frequency of Surveillance and Impact of Surveillance Colonoscopies in Patients With Ulcerative Colitis Who Developed Colorectal Cancer.

BACKGROUND: The risk of developing colorectal cancer (CRC) in patients with chronic ulcerative colitis (UC) is increased. The aim of this study was to evaluate if patients who developed CRC in the setting of UC were undergoing guideline-recommended surveillance colonoscopies and to determine the impact of surveillance on the staging of CRC. PATIENTS AND METHODS: Data was obtained from the Veterans Affairs healthcare system to identify patients with UC and CRC. Stage 0 and I were considered early-stage CRC, whereas stage ≥ II were considered advanced-stage CRC. Patients were considered to have adequate surveillance if they had a colonoscopy within 2 years before developing CRC. We conducted a case-case analysis using multivariable logistic regression to estimate the odds ratio for presenting with advanced-stage CRC associated with lack of adequate surveillance. RESULTS: Of the 48 patients, the majority were white (70.8%) and male (100%). Sixty-nine percent of patients had inadequate surveillance. In multivariable analysis, prior adherence to CRC surveillance was associated with a decreased risk of presenting with advanced-stage CRC (vs. early-stage CRC) (adjusted odds ratio, 0.20; 95% confidence interval, 0.05-0.85; P = .029). CONCLUSION: The majority of patients who developed CRC in the setting of UC underwent inadequate surveillance, and they were more likely to present with advanced-stage CRC.

Adherence and efficacy of screening for low bone mineral density among ulcerative colitis patients treated with corticosteroids.

OBJECTIVES: Ulcerative colitis (UC) is associated with an increased risk of metabolic bone disease and fragility fractures. The aim of this study was to assess the adherence to the guidelines issued by the American Gastroenterology Association (AGA) for the screening for low bone density in UC patients and to assess the benefits of dual-energy X-ray absorptiometry (DXA) screening among corticosteroid (CS)-treated UC patients. METHODS: Nationwide Veterans Affairs system (VA) data were obtained. UC patients followed up in the VA between 2001 and 2011 and the occurrence of fragility fractures were identified using International Classification of Diseases, Ninth Revision codes. Exposure to CSs was assessed using pharmacy data. DXA screening was assessed using the VA procedure database. Post DXA screening, medication use was also assessed from the pharmacy database. Cox regression analysis was performed to calculate the hazard ratio (HR) of fragility fractures among those patients who received DXA compared with those who did not. RESULTS: We included 5,736 patients. Among them, 80 (1.4%) patients suffered from fragility fractures during the follow-up period. Overall adherence rate to AGA guidelines was 23%. Adherence rate was highest among postmenopausal women (48%) and lowest among men above 50 years of age (20%). UC patients who received DXA screening were more likely to be started on bisfosfonates (P<0.001), calcitonin (P<0.001), vitamin D, and calcium (P<0.001) compared with those who did not receive screening. Those who received DXA screening were half as likely (HR=0.5, 0.3-0.9, P=0.03) to develop fragility fractures as compared with those who did not receive screening. The benefits were more prominent among those with higher CS exposure. CONCLUSIONS: Rates of DXA screening were low among CS-treated UC patients. Those who received DXA screening were more likely to be started on antiresorptive therapy and supplemental medications and had a 50% reduction in the risk of fragility fractures. More efforts should be directed toward raising the adherence to AGA guidelines and the awareness of DXA benefits.

Aspirin protects against Barrett's esophagus in a multivariate logistic regression analysis.

BACKGROUND & AIMS: Better criteria are needed to identify patients who should be screened for Barrett's esophagus (BE) to reduce overtesting and improve the cost effectiveness. There is evidence that chemopreventive agents such as nonsteroidal anti-inflammatory drugs, particularly aspirin, reduce the risk of esophageal adenocarcinoma (EAC), but little is known about their effects on BE. We analyzed characteristics of patients with BE for factors that might be used in screening and management. METHODS: In this case-controlled study, we identified 434 patients with BE diagnosed at the first endoscopy (incident cases) at a single institution (1997-2010). BE cases were matched with controls on the basis of indication for endoscopy, year of endoscopy, and endoscopist. Risk factors analyzed included age, sex, body mass index, medical and social history, and medications. We performed a multivariate logistic regression analysis to identify clinical risk factors for BE. RESULTS: In a multivariate regression model, men had a greater risk for developing BE (odds ratio, 3.2; 95% confidence interval, 2.3-4.4), whereas current aspirin users had a lower risk than nonusers (odds ratio, 0.56; 95% confidence interval, 0.39-0.80). A subset analysis, limited to patients who had endoscopies for symptoms of gastroesophageal reflux disease, yielded similar findings. No interactions were found between aspirin use and smoking or use of acid-suppressive medications. CONCLUSIONS: In a case-controlled study of 434 patients with BE, current aspirin use appeared to reduce the risk of BE; previous studies associated aspirin use with a reduced risk of EAC. Although efforts were made to minimize biases in our analysis, the possibility of residual confounding remains.

Barriers to enrollment in inflammatory bowel disease randomized controlled trials: an investigation of patient perspectives.

BACKGROUND: Despite a sizeable inflammatory bowel disease (IBD) population in the United States, large trials in IBD have difficulty recruiting patients. Reasons for low enrollment are uncertain. Our objective was to investigate specific barriers to enrollment in clinical trials by determining aspects of study design, disease state, demographics, and previous experiences with research that influence a patient's willingness to participate. METHODS: Patients with Crohn's disease (CD) and ulcerative colitis (UC) at the Massachusetts General Hospital Crohn's and Colitis Center were surveyed. RESULTS: Most participants (61%) had participated in some clinical research previously, although 50% of those were not interested in participating in a future study. Frequent doctor visits (69%), requirement of colonoscopy (55%), or sigmoidoscopy (49%), and blinding (46%) were the biggest deterrent study requirements. With each addition of one of these components, potential enrollment fell from 43.2% (86) to 14.6% (29) interested patients. Respondents were likely to participate in studies that were open label (60%), initially randomized then open label (57.6%), or saw the same doctor (52.5%). Among those disinclined to participate, strategies to boost enrollment included monetary compensation, an open-label component, or providing the same doctor at each visit. Men and patients who were currently flaring were more likely to participate. CONCLUSIONS: Elements of study design negatively and positively influence willingness to participate. Invasive procedures, randomization, and frequent visits negatively influenced willingness to participate and as each of these components are added, a significant additive percent of potential subjects are lost. Strategies to further identify barriers to enrollment within IBD study populations should be pursued.

When should ulcerative colitis patients undergo colectomy for dysplasia? Mismatch between patient preferences and physician recommendations.

BACKGROUND: If dysplasia is found on biopsies during surveillance colonoscopy for ulcerative colitis (UC), many experts recommend colectomy given the substantial risk of synchronous colon cancer. The objective was to learn if UC patients' perceptions of their colon cancer risk and if their preferences for elective colectomy match with physicians' recommendations if dysplasia was found. METHODS: A self-administered written survey included 199 patients with UC for at least 8 years (mean age 49 years, 52% female) who were recruited from Dartmouth-Hitchcock (n = 104) and the University of Chicago (n = 95). The main outcome was the proportion of patients who disagree with physicians' recommendations for colectomy because of dysplasia. RESULTS: Almost all respondents recognized that UC raised their chance of getting colon cancer. In all, 74% thought it was "unlikely" or "very unlikely" to get colon cancer within the next 10 years and they quantified this risk to be 23%; 60% of patients would refuse a physician's recommendation for elective colectomy if dysplasia was detected, despite being told that they had a 20% risk of having cancer now. On average, these patients would only agree to colectomy if their risk of colon cancer "right now" were at least 73%. CONCLUSIONS: UC patients recognize their increased risk of colon cancer and undergo frequent surveillance to reduce their risk. Nonetheless, few seem prepared to follow standard recommendations for elective colectomy if dysplasia is found. This may reflect the belief that surveillance alone is sufficient to reduce their colon cancer risk or genuine disagreement about when it is worth undergoing colectomy.

Identification and activity of a lower eukaryotic serine proteinase inhibitor (serpin) from Cyanea capillata: analysis of a jellyfish serpin, jellypin.

Delineating the phylogenetic relationships among members of a protein family can provide a high degree of insight into the evolution of domain structure and function relationships. To identify an early metazoan member of the high molecular weight serine proteinase inhibitor (serpin) superfamily, we initiated a cDNA library screen of the cnidarian, Cyanea capillata. We identified one serpin cDNA encoding for a full-length serpin, jellypin. Phylogenetic analysis using the deduced amino acid sequence showed that jellypin was most similar to the platyhelminthe Echinococcus multiocularis serpin and the clade P serpins, suggesting that this serpin evolved approximately 1000 million years ago (MYA). Modeling of jellypin showed that it contained all the functional elements of an inhibitory serpin. In vitro biochemical analysis confirmed that jellypin was an inhibitor of the S1 clan SA family of serine proteinases. Analysis of the interactions between the human serine proteinases, chymotrypsin, cathepsin G, and elastase, showed that jellypin inhibited these enzymes in the classical serpin manner, forming a SDS stable enzyme/inhibitor complex. These data suggest that the coevolution of serpin structure and inhibitory function date back to at least early metazoan evolution, approximately 1000 MYA.