PURPOSE OF REVIEW:Initiation of hemodialysis treatment with a thrice-weekly prescription is currently the standard of care irrespective of patients' residual kidney function (RKF), comorbidities, and preferences. RECENT FINDINGS:Each year ∼12 000 Veterans with advanced kidney disease progress to end-stage kidney disease (ESKD) requiring dialysis and comprise greater than 10% of the US incident ESKD population. Dialysis is costly and is associated with impaired health-related quality of life (HRQOL) and high mortality risk, especially in the first year of treatment. Evidence suggests an incremental dialysis transition using twice-weekly hemodialysis provides various benefits, including more dialysis-free time, longer RKF preservation, less vascular access damage, and lower patient burden. Pragmatic studies are needed to inform the efficacy and safety of incremental hemodialysis as a personalized dialysis regimen, and could inform its consideration as a conservation strategy during times of supply shortages. Broadly implementing twice-weekly hemodialysis could also potentially allow more Veterans to receive care within VA-based dialysis units. The VA IncHVets Trial is a pragmatic, multicenter, randomized controlled trial comparing the efficacy and safety of twice-weekly incremental vs. thrice-weekly hemodialysis among Veterans transitioning to ESKD. SUMMARY:Further research is needed to determine whether incremental hemodialysis is well tolerated, effective, and facilitates a more favorable transition to dialysis.

The prevalence of pediatric obesity has increased exponentially over the past four decades. The American Academy of Pediatrics recently released updated clinical practice guidelines highlighting the importance of identifying pediatric obesity as a chronic disease. The guidelines support consideration of concurrent treatment with intensive lifestyle interventions, obesity pharmacotherapy, and bariatric surgery. The dramatic rise in pediatric obesity has spurred interest in utilizing obesity pharmacotherapy to support sustained weight reduction in pediatric cohorts, in the hopes of preventing the emergence of later-appearing, significant co-morbidities. Despite the enormous demand, the obstacles posed by performance of needed clinical trials in the pediatric population markedly limits available pharmacotherapy for the treatment of obesity in pediatrics. Currently, there are five medications approved by the Food and Drug Administration for use in youth with obesity. In 2022, the phentermine/topiramate (PHEN/TPM), once-daily, controlled-release, combination product received FDA approval, for the indication of chronic weight management, in youth with obesity, ages 12 years and older. The objectives of this narrative review are to: (1) Review the mechanism of action of phentermine and topiramate, (2) Summarize the safety and efficacy data of topiramate and phentermine use as both monotherapies and in combination, and (3) Discuss clinical practice guidelines and clinical implications, for the use of these agents in youths with obesity.

Familial hyperaldosteronism (FH) is a group of rare autosomal dominant disorders associated with primary aldosteronism (PA) with variable penetrance causing monogenic hypertension. Of these, FH-I or glucocorticoid-remediable aldosteronism is the most common form of monogenic hypertension; it features ACTH (adrenocorticotropin)-dependent mineralocorticoid overproduction which can be suppressed by oral glucocorticoid therapy. Other familial forms of hyperaldosteronism are FH-II, FH-III, FH-IV, and PA, seizures, and neurological abnormalities syndrome. Prompt clinical work up with biochemical testing followed by appropriate molecular genetic analysis helps the diagnosis of these groups of diseases. The genetic landscape of these rare disorders is now well characterized in the recent years, and new genes associated with both familial and sporadic PA are currently being discovered. Proper understanding of the pathobiological aspects of these disorders is important for diagnostic evaluation and management which is the purpose of this chapter.

Abstract Disclosure: J.T. Nguyen: None. D.H. Geller: None. A. Ryabets-Lienhard: None. Introduction: Parathyroid carcinoma is a rare cause of primary hyperparathyroidism in the pediatric population, with only 20 previously reported cases. Variations in the CDC73 gene have been associated with sporadic parathyroid carcinoma, autosomal dominant hyperparathyroidism-jaw tumor syndrome (HPT-JT), and familial isolated hyperparathyroidism (FIHP). To our knowledge, only 3 cases of pediatric parathyroid carcinoma with confirmed variants of CDC73 have been reported. We present a case of severe hyperparathyroidism and nephrolithiasis due to parathyroid carcinoma caused by a pathogenic variant in CDC73 in a pediatric patient, highlighting the importance of early recognition and management. Clinical Case: An otherwise asymptomatic 14-year-old male presented with one year of recurrent nephrolithiasis. Initial tests demonstrated hypercalcemia (13.8 mg/dL, 8.4-10.2 mg/dL), normal phosphorous, elevated PTH (1,379 pg/mL, 7.5-53.5 pg/mL), and elevated alkaline phosphatase (514 U/L, 30-250 U/L). The hypercalcemia was treated with hyperhydration, furosemide, and pamidronate. Sestamibi scan revealed a focus of abnormal uptake suggestive of a left parathyroid mass, with ultrasonographic demonstration of a predominantly solid, hypoechoic, and vascular mass centered posterior to the inferior left thyroid lobe. Skeletal survey was notable for trabecular abnormalities and osteopenia. He underwent a left parathyroid mass excision. Final pathology confirmed the parathyroid carcinoma, with multiple foci of vascular invasion without evidence of capsular involvement. Immunohistochemistry demonstrated diffuse positivity for PTH and loss of parafibromin expression by the tumor cells. Genetic testing revealed a pathogenic germline heterozygous nonsense variant in CDC73 (c.376C>T(p.Arg126Ter)) resulting in protein truncation. Post-operative PTH was undetectable with normal calcium and phosphorous. Calcitriol, cholecalciferol, and calcium carbonate supplementation were implemented to prevent further hypocalcemia due to transient hypoparathyroidism and hungry bone syndrome. Calcium supplementation was discontinued within one year of his surgery. Serial thyroid ultrasounds and CT scans have been negative for recurrent or residual disease without evidence of metastasis. Mandibular x-ray showed no evidence of tumors or lesions involving the jaw. He has been noted to have small right renal cysts without other kidney abnormalities. Conclusion: Severe hyperparathyroidism due to parathyroid carcinoma can present as recurrent nephrolithiasis in an otherwise asymptomatic individual. Pediatric patients with a longstanding history of kidney stones should undergo screening for hypercalcemia and hyperparathyroidism even in the absence of other signs and symptoms of elevated calcium to ensure timely diagnosis and appropriate management. Presentation: Friday, June 16, 2023

Abstract Objective Adolescent polycystic ovary syndrome (PCOS) is a heterogenous clinical syndrome characterized by hyperandrogenism and irregular menses. Heterogeneous features of the syndrome include the presence/absence of obesity, degree of insulin resistance, and clinical and/or biochemical hyperandrogenism. In adult women with PCOS, discrete metabolic and reproductive subgroups can be identified. A recent study described distinct phenotypes using unsupervised hierarchical cluster analysis: a metabolic subgroup characterized by higher BMI, glucose, and insulin levels, and a reproductive subgroup demonstrating higher LH and SHBG levels. We hypothesized that non-obese and obese adolescent girls with PCOS would exhibit similar distinct phenotypes at the time of diagnosis. Methods Data were extracted from a multi-site PCOS registry including seven academic centers in the US with the following inclusion criteria: PCOS confirmed per 2018 international guidelines, diagnosis before age 18 years, and at least one follow-up visit. Data collected included demographics, medical and family history, physical characteristics including hirsutism, acanthosis nigricans, and laboratory measures such as HbA1c, ALT, lipid profiles and reproductive hormones (androgens, LH, FSH, SHBG). Hormone levels were normalized to the upper limit provided by the measuring laboratory. Patients were divided by obesity status, defined as obese (OB) with BMI ≥ 95th percentile for age and sex and non-obese (NO) < 85th percentile for age and sex. Differences in continuous variables were assessed with unpaired t-tests using GraphPad Prism. Results Complete diagnostic data from 390 patients from 7 different sites were included for analysis, with 284 OB (Age 15.3±1.5 years, BMI 36.1±5.6 kg/m2) and 68 NO (Age 15.8±1.3 years, BMI 22.6±3.4 kg/m2). OB presented with more severe acanthosis (p<0.0001) and higher HbA1c (OB 5.5±0.5, NO 5.2±0.3; %, p<0.0001), ALT (OB 35±30, NO 22±17; IU/L, p=0.0006), and triglycerides (OB 145±90, NO 110,±88; mg/dL, p=0.002). OB also presented with higher free testosterone (OB 219±188% vs NO 158±125% above upper limit of normal; p=0.003), while NO presented with higher total testosterone (OB 121±68%, NO 152±88% above upper limit of normal; p=0.003), androstenedione (OB 87±37%, NO 125±62 above upper limit of normal; p=0.002), and LH (OB 9.7±4.9, NO 15.2±10.4; mIU/mL, p=0.0001). No differences in Ferriman Gallwey score or number of menses in the 6 months prior to diagnosis were detected. Conclusions Metabolic and reproductive phenotypes differed in OB and NO adolescent girls at the time of PCOS diagnosis. The reproductive phenotype in NO was characterized by increased LH, total testosterone and androstenedione levels. In contrast, OB girls had a phenotype characterized by insulin resistance-driven hyperandrogenemia established by lower SHBG and higher free testosterone levels. Our data are consistent with findings reported for adult women with two divergent phenotypes: an insulin resistance-driven metabolic subtype and a primarily reproductive subtype, potentially driven by neuroendocrine mechanisms. Presentation: Sunday, June 12, 2022 11:45 a.m. - 12:00 p.m.

Context First-degree relatives of women with polycystic ovary syndrome (PCOS) present hormonal and metabolic alterations compared to girls unrelated to PCOS. It is unknown whether glucose intolerance in the PCOS proband confers a more severe metabolic predisposition on their first-degree relatives. Objective To determine whether glucose tolerance status in women with PCOS is associated with worsened glucose metabolism and sex hormone levels in their peripubertal daughters or sisters. Design Cross-sectional study. Setting Seven academic centers in North America, South America, and Europe. Patients Sixty-four pairs of women with PCOS and their daughters or younger sisters aged between 8 and 14 years were recruited. Twenty-five mothers or older sisters with PCOS were glucose intolerant (GI) and 39 were normal glucose tolerant (NGT). Main Outcome Measures Beta-cell function estimated by the insulin secretion-sensitivity index-2 (ISSI-2) during an oral glucose tolerance test and by the disposition index during a frequently sampled IV glucose tolerance test. Free testosterone and 17-hydroxyprogesterone (17-OHP) levels. Results Being related to a GI PCOS proband was associated with a lower ISSI-2 (P-value = 0.032) after adjusting for ethnicity, body mass index z-score, and pubertal stage. They also had higher free testosterone (P-value = 0.011) and 17-OHP levels compared to girls with an NGT proband, the latter becoming significant after adjusting for confounders (P-value = 0.040). Conclusions Compared to first-degree female relatives of women with PCOS and NGT, first-degree relatives of women with PCOS and GI display lower beta-cell function and hyperandrogenemia, putting them at higher risk of GI and PCOS development.

Background: Familial Hyperinsulinism due to HNF4A deficiency (FHI-HNF4A) is a form of diazoxide-sensitive, diffuse hyperinsulinism, characterized by transient or persistent hyperinsulinemic hypoglycemia, and a propensity to develop Maturity-Onset Diabetes of the Young type 1 (MODY1). The association between FHI-HNF4A deficiency and benign premature adrenarche (BPA) is unknown. The Case: We report the case of a 5-year-old girl with FHI-HNF4A, controlled on diazoxide, who presented with BPA and Tanner stage III pubic hair associated with body odor and acne. Work-up revealed elevated dehydroepiandrosterone sulfate (DHEAS), elevated free testosterone, and advanced bone age. Insulin levels were elevated in the setting of normal fasting blood glucose. We discuss the possible hormonal underpinnings of hyperandrogenism. Conclusion: Though the underlying pathophysiology of this phenotype is unclear, a possible synergistic mechanism exists between insulin-induced hyperandrogenism and HNF4A deficiency leading to a transient decrease of SHBG and thus increased free testosterone levels. Further investigation is required to determine the association between HNF4A dysfunction and BPA.

BACKGROUND Bartter syndrome is a rare genetic disease characterized by hypokalemia, metabolic alkalosis, and hyperreninemic hyperaldosteronism. Five different subtypes have been described based on the genetic defect identified. Bartter syndrome type II is caused by homozygous or compound heterozygous loss-of-function mutations in the KCNJ1 gene encoding ROMK. This subtype is typically described as a severe antenatal form of the disease, often presenting with polyhydramnios before childbirth. CASE REPORT Here, we describe the case of a 26-year-old man who presented with generalized body weakness and hypokalemia and was ultimately diagnosed with Bartter syndrome type II based on his clinical features coupled with the identification of a homozygous missense mutation in KCNJ1. CONCLUSIONS To the best of our knowledge, this is the fifth case of late-onset Bartter syndrome type II. Interestingly, the mutation identified in our patient has been previously described in patients with antenatal Bartter's Syndrome. The late presentation in our patient suggests a surprising degree of phenotypic variability, even in patients carrying the identical disease-causing mutation.

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Exocrine pancreatic insufficiency (EPI), an important cause of maldigestion and malabsorption, results from primary pancreatic diseases or secondarily impaired exocrine pancreatic function. Besides cystic fibrosis and chronic pancreatitis, the most common etiologies of EPI, other causes of EPI include un-resectable pancreatic cancer, metabolic diseases (diabetes); impaired hormonal stimulation of exocrine pancreatic secretion by cholecystokinin (CCK); celiac or inflammatory bowel disease (IBD) due to loss of intestinal brush border proteins; and gastrointestinal surgery (asynchrony between motor and secretory functions, impaired enteropancreatic feedback, and inadequate mixing of pancreatic secretions with food). This paper reviews such conditions that have less straightforward associations with EPI and examines the role of pancreatic enzyme replacement therapy (PERT). Relevant literature was identified by database searches. Most patients with inoperable pancreatic cancer develop EPI (66%-92%). EPI occurs in patients with type 1 (26%-57%) or type 2 diabetes (20%-36%) and is typically mild to moderate; by definition, all patients with type 3c (pancreatogenic) diabetes have EPI. EPI occurs in untreated celiac disease (4%-80%), but typically resolves on a gluten-free diet. EPI manifests in patients with IBD (14%-74%) and up to 100% of gastrointestinal surgery patients (47%-100%; dependent on surgical site). With the paucity of published studies on PERT use for these conditions, recommendations for or against PERT use remain ambiguous. The authors conclude that there is an urgent need to conduct robust clinical studies to understand the validity and nature of associations between EPI and medical conditions beyond those with proven mechanisms, and examine the potential role for PERT.

We and others have observed that young girls predisposed to polycystic ovary syndrome (PCOS) display defective insulin sensitivity, beta-cell function and non-esterified fatty acids (NEFA) suppressibility during early pubertal years, compared to controls. Our objective is to assess whether these differences in glucose and NEFA metabolisms persist after 5 years in late/post-puberty.

AIMS/HYPOTHESIS:Endothelial cells (ECs) play an essential role in pancreatic organogenesis. We hypothesise that effective in vitro interactions between human microvascular endothelial cells (HMECs) and human pluripotent stem cells (hPSCs) results in the generation of functional pancreatic beta cells.METHODS:Embryoid bodies (EBs) derived from hPSCs were cultured alone (controls) or with ECs in collagen gels. Subsequently, cells were analysed for pancreatic beta cell markers, and then isolated and expanded. Insulin secretion in response to glucose was evaluated in vitro by static and dynamic (perifusion) assays, and in vivo by EB transplantation into immunodeficient mice.RESULTS:Co-cultured EBs had a higher expression of mature beta cells markers and enhanced insulin secretion in vitro, compared with controls. In mice, transplanted EBs had higher levels of human C-peptide secretion with a significant reduction in hyperglycaemia after the selective destruction of native pancreatic beta cells. In addition, there was significant in vitro upregulation of bone morphogenetic proteins 2 and 4 (BMP-2, 4) in co-cultured cells, compared with controls.CONCLUSIONS/INTERPRETATION:ECs provide essential signalling in vitro, such as activation of the BMP pathway, for derivation of functional insulin-producing beta cells from hPSCs.

Assess whether metabolic alterations observed during puberty in young girls at risk of developing polycystic ovary syndrome (PCOS) persist after five years when compared to healthy girls.

BackgroundInhaled antibiotics are standard of care for persons with cystic fibrosis (CF) and chronic Pseudomonas aeruginosa airway infection. APT-1026 (levofloxacin inhalation solution, LIS) is fluoroquinolone in development. We compared the safety and efficacy of LIS to tobramycin inhalation solution (TIS) in persons ≥12years old with CF and chronic P. aeruginosa infection.MethodsThis multinational, randomized (2:1), non-inferiority study compared LIS and TIS over three 28-day on/off cycles. Day 28 FEV1 % predicted relative change was the primary endpoint. Time to exacerbation and patient-reported quality of life were among secondary endpoints.ResultsBaseline demographics for 282 subjects were comparable. Non-inferiority was demonstrated (1.86% predicted mean FEV1 difference [95% CI −0.66 to 4.39%]). LIS was well-tolerated, with dysgeusia (taste distortion) as the most frequent adverse event.ConclusionsLIS is a safe and effective therapy for the management of CF patients with chronic P. aeruginosa infection.