24-h Urine Research Articles

THU208 Predicting Treatment Quality Assessment Of Children With Congenital Adrenal Hyperplasia Using 24h Urine Metabolomics Profiling And A Machine Learning-assisted Approach

Abstract Disclosure: O. Abawi: None. G. Sommer: None. M. Groessl: None. U. Halbsguth: None. S.E. Hannema: None. C. de Bruin: None. E. Charmandari: None. E.L. van den Akker: None. A.B. Leichtle: None. C.E. Flueck: None. Introduction: Current treatment monitoring of children with congenital adrenal hyperplasia (CAH) relies on specialist’s interpretation of clinical and biochemical parameters, but remains dissatisfactory. Comprehensive 24h urine steroid profiling provides detailed insight into adrenal steroid pathways, but its merit in routine treatment monitoring of CAH is not yet established. Aim: To investigate whether 24h urine steroid profiling can predict treatment quality assessment in children with CAH using machine learning (ML). Methods: This prospective observational cohort study included children with genetically confirmed 21-hydroxylase deficiency. Children collected 24h urine at 2 outpatient clinic visits (mean 4.1 ± 0.7 months apart). Using gas chromatography-mass spectrometry, 40 adrenal steroids and metabolites from the classic, backdoor and 11-oxygenated pathways were analysed. Patients were classified as undertreated, optimally treated or overtreated by the pediatric endocrinologist based on detailed clinical and endocrinological evaluation including serum 17-hydroxyprogesterone and androstenedione. We used sparse partial least-squares discriminant analysis (sPLS-DA) to investigate optimal prediction of treatment quality assessment. This ML method computes components (combinations of all input variables) and selects the most discriminative parameters to classify samples (in our case optimally treated vs undertreated) by maximizing between-class variance. We computed area under the ROC-curve (AUC) of two sPLS-DA models: 1. using only 24h urine metabolites; 2. adding also clinical variables age, sex, pubertal status, CAH subtype (classic vs non-classic), medication (hydrocortisone [HC] vs prednisolone), daily HC-equivalent dose, Δbone age minus chronological age, ΔBMI-z, and Δheight-z. Results: We included 112 visits (68 [61%] optimally treated, 44 [39%] undertreated) of 59 patients: 27 (46%) girls, 46 (78%) classic CAH, 19 (32%) prepubertal. Mean age at first visit was 11.9 ± 4.0 years and mean BMI SDS 0.6 ± 1.1. SPLS-DA using 24h urine metabolites showed clear clustering of optimally treated patients on two components, while undertreated patients were more heterogenous (AUC 0.88; 95% CI 0.81-0.94). The model selected pregnanetriol and hydroxypregnanolon contributing to excluding undertreatment and 7 metabolites contributing to excluding optimal treatment: estradiol, cortison, tetrahydroaldosterone, androstenetriol, etiocholanolone, androstenediol, and α-dihydrocortison. Addition of clinical variables did not improve classification (AUC 0.90, 95% CI 0.84-0.96, P=0.59). Discussion: Using ML on 24h urine steroid profiling predicted treatment quality assessment in children with CAH even in absence of clinical data, suggesting that comprehensive 24h urine steroid profiling could improve treatment monitoring in children with CAH. Presentation: Thursday, June 15, 2023

FRI203 A Case Of Pseudoadrenal Tumor Mimicking Left Adrenal Pheochromocytoma

Abstract Disclosure: A. Tanabe: None. E. Sugito: None. H. Kajio: None. Approximately 50% of adrenal incidentalomas are non-functional cortical adenomas, and 25% are adrenocortical hormone-secreting adenomas and pheochromocytomas. Adrenocortical carcinomas, and pheochromocytomas which have malignant potential, need to be differentiated and removed even if the tumors are hormonally inactive. In addition to these adrenal origin tumors, anatomic structures and tumors that develop in tissues neighboring the adrenal glands (pseudoadrenal tumors) may be confused with primary adrenal tumors. The larger the tumor, the more difficult it is to determine continuity with the adrenal glands. Herein we report a patient with gastrointestinal stromal tumor (GIST) that mimicked a left adrenal pheochromocytoma. A 47-year-old man was diagnosed with a left adrenal incidentaloma at 40 years of age. The tumor had irregular margins and grew from 18 mm to 30 mm in maximum diameter over 7 years. The mass appeared to be in the tip of the lateral limb of the left adrenal gland and was located between the left adrenal gland and the posterior wall of the stomach. The patient had no abnormal findings other than general obesity. The blood pressure was 106/72 mmHg with antihypertensive agents. The plasma corticotropin and cortisol concentrations were normal and suppressed normally after a 1-mg overnight dexamethasone suppression test. The plasma aldosterone concentration and renin activity were increased with angiotensin receptor blocker and diuretic therapy. The 24-h urine fractionated metanephrines levels were at the upper limit of the reference range. Because the tumor showed unenhanced computed tomography (CT) attenuation of 40-50 Hounsfield units, hormonally-inactive adrenocortical carcinoma or pheochromocytoma had to be differentiated. I-123-metaiodobenylguanidine (I-123-MIBG) scintigraphy showed tumor avidity consistent with a pheochromocytoma. A laparoscopic left adrenalectomy was performed; however, no tumor was present in the resected specimen. Abdominal CT postoperatively showed that the tumor remained intact and appeared to connect to the posterior wall of the stomach. A laparotomy was performed and the tumor was removed. The tumor was localized to the intraperitoneal space and isolated from the posterior wall of the stomach. The pathological diagnosis was a GIST. Although it has been reported that I-123-MIBG may accumulate in tumors other than neuroendocrine tumors, reports on GISTs are rare. Lessons learned from our case include the importance of clinicians need to be aware of the limitations of diagnostic imaging studies in diagnosing non-functioning adrenal incidentalomas, which require a pathologic analysis for the final diagnosis. Moreover, clinicians need to provide patients with sufficient informed consent when deciding on treatment strategies. Presentation: Friday, June 16, 2023

THU615 Rhabdomyolysis: A Rare Presentation Of Extra-adrenal Neuroendocrine Tumor

Abstract Disclosure: M. Saleem: None. S.M. Harman: None. J. Targovnik: None. Introduction:Paraganglioma is a rare neuroendocrine tumor (NET) arising from neural crest progenitors located outside of the adrenal gland and predominantly produce norepinephrine if functional. Here, we present a case of epinephrine producing extra-adrenal sympathetic neuroendocrine tumor. Case: A 66-year-old male with history of resistant hypertension (on amlodipine, lisinopril & metoprolol), hyperlipidemia & obesity presented for evaluation of possible pheochromocytoma/paraganglioma. He reported paroxysmal episodes of muscle spasm & paresthesia accompanied by hypertension (up to 200 mm Hg), palpitation, sweating & tremor lasting about 30-60 minutes. His CPK was elevated up to 428 U/L (NR 30-170 U/L) during those episodes. He reported 7 "major episodes" beginning ∼15 years prior to diagnosis, of which 3 occurred after major surgery with "small episodes" occurring monthly, exacerbated by sun & heat. Family history was remarkable for sister with recurrent rhabdomyolysis. Labs showed elevated epinephrine 181 pg/ml (normal <57), Dopamin 67 pg/ml (normal <10) and normal norepinephrine, significantly elevated 24h urine metanephrine 855 mcg/24h (normal 90-315), normal normetanephrine & dopamine levels. CT showed a 2.2 x 2.2 x 2.1 cm retroperitoneal mass with 84% absolute concerning for possible paraganglioma. FDG-PET and DOTATATE showed hypermetabolic activity (SUV max 6.63) and DOTATATE avid left retroperitoneal mass respectively. After discontinuing beta blocker and optimizing alpha blockage with doxazosin, the patient was referred to endocrine surgery and had a successful resection of this mass and left adrenalectomy. Pathology was consistent with chromaffin cell neoplasm and normal left adrenal gland. Patient had clinical and biochemical resolution of his symptoms post-op. Genetic counseling was done with pending results. Discussion: Pheochromocytomas & paragangliomas (PPGLs) are rare NET arising from chromaffin cells of the adrenal medulla or neural crest progenitors located outside of the adrenal gland, and predominantly produce epinephrine and norepinephrine respectively. Adrenal medullary tissue secretes epinephrine due to the activity of PNMT, induced by high local levels of cortisol from the adrenal cortex, which attaches a methyl radical to the catechol amino group. Extramedullary sympathetic secretory cells normally lack this enzyme and secrete norepinephrine. Thus, it is likely that the neoplasm we report had ectopic expression of this enzyme. PPGLs have variable signs and symptoms which mainly reflect the hemodynamic and metabolic actions of the catecholamines produced and secreted by the tumors with hypertension being the most common sign. Rhabdomyolysis is an unusual manifestation. This case is unique in that it presented as an extra-adrenal NET predominantly produced epinephrine and presented with rhabdomyolysis. Presentation: Thursday, June 15, 2023

THU016 Hiding In Plain Sight: Florid Cushing’s Disease Presenting As A Severe Extremity Cellulitis

Abstract Disclosure: C.M. Godar: None. E.B. Noble: None. N.O. Vietor: None. T.S. Knee: None. Background: Cushing’s syndrome may rarely present as an emergency known as Florid Cushing’s Syndrome. Patients can exhibit severe hyperglycemia, hypertension, hypokalemia, infections, and hypercoagulability. Cushing’s syndrome is a rare disease, and the constellation of clinical features can be overlooked if clinicians are not aware of the manifestations of hypercortisolism. We present the case of a patient with Cushing’s syndrome that went unrecognized with life-threatening sequelae. Case presentation: A 52-year-old woman with well-controlled type 2 diabetes and hypertension was admitted to the hospital for severe left lower extremity cellulitis. Prior to hospitalization she had noted rapid weight gain, fatigue, weakness, mental clouding, and moodiness. She was admitted for antibiotics and surgical debridement. The infection persisted despite broad spectrum antibiotics, multiple surgical debridements, and skin grafting. She became bacteremic, and extremity amputation was considered. She additionally developed hypertensive emergency, refractory hypokalemia, and hyperglycemia to 396 mg/dL. Exam was notable for facial plethora, supraclavicular fullness, dorsocervical fat pad, and violaceous abdominal striae. Cushing’s Syndrome was suspected, and labs revealed a significantly elevated random serum cortisol of 60.5mcg/dL (Ref 6.2-19.4), significantly elevated 24H urine cortisol of 2157mcg/24H (Ref 0-50), and ACTH elevated to 81.8pg/mL (Ref 7.2-63.3) that confirmed Cushing’s Disease. MRI sella and octreotide scans did not localize a lesion. Inpatient therapy included multiple antihypertensive agents, insulin drip, aggressive potassium repletion, and initiation of ketoconazole to reduce cortisol levels. Ketoconazole was maximally dosed and she underwent surgical exploration and removal of a small pituitary microadenoma. Following surgery, she developed transient adrenal insufficiency requiring hydrocortisone and she no longer required antihypertensives, insulin, or potassium therapy. Follow up 7 years later has revealed no recurrence of Cushing’s Disease. Discussion: Cushing’s Syndrome may present with a variety of clinical features and rarely may present as a medical emergency. Delay in diagnosis can lead to Florid Cushing’s Syndrome which carries high risk for morbidity and mortality. This case illustrates the need for clinician awareness of the features of Cushing’s Syndrome: hypertension, hyperglycemia, rapid weight gain, cushingoid exam features, hypokalemia, hirsutism, virilization, infection, and/or hypercoagulable state. Severe hypercortisolism was responsible for this patient’s refractory infection, and if not controlled, she likely would have endured a lower extremity amputation. Rapid detection with elevated random serum and/or urine cortisol and treatment with a cortisol-lowering agent is critical and lifesaving. Presentation: Thursday, June 15, 2023

FRI266 Medical Management Of Cushing’s Syndrome Caused By Primary Bilateral Macronodular Adrenal Hyperplasia (PBMA) With Low Dose Of Ketoconazole

Abstract Disclosure: J.S. Hatfield: None. C.M. Godar: None. N.O. Vietor: None. T.D. Hoang: None. M.K. Shakir: None. Introduction: Primary bilateral macronodular adrenal hyperplasia (PBMA) is an uncommon cause of endogenous Cushing's syndrome, defined as both adrenal glands with multiple nodules > 10mm in diameter. It often presents as incidentally found, bilateral, macronodular adrenal glands in patients between 40-60 years of age, frequently with only mild cortisol elevation. Although surgical treatment is recommended in these patients, we report the effectiveness of low-dose ketoconazole to control excessive cortisol secretion. Clinical Case: A 62 y/o woman with type 2 diabetes mellitus and hypertension was found to have bilateral adrenal nodules in 2010 while undergoing evaluation for abdominal pain. An adrenal CT scan confirmed bilateral adrenal nodules (largest left adrenal nodule 3.2cm x 2.9cm and right adrenal nodule 1.0cm x 1.0 cm). She was first referred for endocrine biochemical evaluation nearly 9 years later. Cortisol after 1mg dexamethasone suppression test was 17.3 mcg/dL, with corresponding ACTH of 3.1 pg/mL and dexamethasone of 310 ng/d, 24H urine cortisol 61 mcg/24 hr (6-42), 11 pm salivary cortisol 0.141, 0.133, 0.142 mcg/dL, and DHEA-S 11.4 mcg/dL (18.9-205.0). Biochemical evaluation for pheochromocytoma and primary hyperaldosteronism were negative. Serum 17-Hydroxyprogesterone 27 ng/dL was normal. Clinically, beyond her hypertension and diabetes she has no stigmata of hypercortisolism. Her type 2 diabetes with HbA1c of 7.8 is controlled with sitagliptin, insulin glargine and correctional lispro, and hypertension is treated with lisinopril. Due to the patient’s hesitancy for surgery, she was initiated on fluconazole which initially normalized urine cortisol levels (24H cortisol 20 mcg/24hr), though a rise to 70 mcg/24hr was noted after 6 months of treatment. She was transitioned to ketoconazole 200mg BID with resultant lowering of cortisol. Treatment was complicated by severe body aches that impaired ambulation, and symptoms resolved after decrease of ketoconazole to 100mg daily and rosuvastatin from 10mg to 5mg daily. Urine cortisol has remained in the normal range (15-22 mcg/24hr) for the last 2.5 years with no further side effects from ketoconazole. Discussion: Our patient’s clinical features suggest a diagnosis of PBMA. Most patients with PBMA have only mild elevation of cortisol levels and present with bilateral adrenal incidentalomas as seen in our patient. The classical features of Cushing's syndrome may be absent, and the nodular adrenals are frequently identified when abdominal imaging is performed for unrelated reasons. The amount of cortisol secretion is often sufficient to produce mild or overt Cushing’s syndrome. Although surgical treatment was considered, our patient was successfully treated with low-dose ketoconazole and thus, this may be an option in patients with mild PBMA-related Cushing’s syndrome. Presentation: Friday, June 16, 2023

FRI206 A Rare Case Of Coexisting Acromegaly And Adrenal Cushing’s Syndrome

Abstract Disclosure: T. Chamakkala: None. T. Gallagher: None. Introduction: Acromegaly has been associated with higher risk of cancer morbidity and mortality. Acromegaly coexisting with adrenal Cushing’s disease has been rarely described in literature. We present a patient who was found to have acromegaly during evaluation for Cushing’s syndrome. Clinical Case: A 50-year-old woman presented to the office for endocrinology evaluation at the referral of PCP for elevated 24h urine cortisol level 176ug/24h. She had noticed facial plethora over several years, fatigue, and easy bruising. She had recently been diagnosed with hypertension, poorly controlled on two medications at the time of evaluation. Repeat 24h urine cortisol and midnight salivary cortisol levels were elevated; dexamethasone suppression test was positive. ACTH was <1.5pg/mL, consistent with ACTH independent hypercortisolemia. Adrenal CT showed 2.6x3cm left adrenal adenoma. She underwent left adrenalectomy and pathology showed adrenal cortical adenoma. During evaluation for Cushing’s disease and new onset hypertension, IGF1 was evaluated and found to be elevated at 354ng/mL. She additionally endorsed symptoms of worsening carpal tunnel syndrome and increasing ring size. After adrenalectomy, IGF1 was repeated and remained elevated at 429ng/mL. Growth hormone suppression test showed nadir of 0.56ng/mL which is higher than <0.3ng/mL expected of high sensitivity GH assays. Pituitary MRI showed three suspected pituitary microadenomas, 4mm and 5mm in left gland, 7mm in right gland. Given difficulty with surgical approach and higher risk of hypopituitarism, she was started on lanreotide for treatment without surgery. She underwent genetic counseling and was offered genetic testing. Conclusion: This case highlights the rare coexistence of acromegaly and adrenal Cushing’s disease in a 50 year old woman. Though the relationship between acromegaly and cancer has been historically controversial, more recent studies have shown an increased risk of both benign and malignant tumors with acromegaly. Untreated Cushing’s Disease has been associated with mildly elevated IGF1 which then decreases after remission; it is unclear if the same pathological process is involved in other etiologies of hypercortisolemia like adrenal Cushing’s syndrome, but re-evaluation of IGF1 after treatment of Cushing’s should be considered. As Cushing’s and acromegaly share similar consequences such as worsening HTN, changing facial appearance, and worsening diabetes, it is prudent to consider each as differential diagnoses when signs do not remit after treatment. Acromegaly has additionally been associated with other endocrinopathies in syndromes including MEN1 syndrome, McCune Albright Syndrome, and Carney Complex. Evaluation for these syndromes and consideration for genetic testing should be considered in the evaluation of a patient with acromegaly and additional associated endocrinopathies. Presentation: Friday, June 16, 2023

A Case Report of an Effective Treatment for Syndrome of Inappropriate Secretion of Antidiuretic Hormone with Integration of Western Medicine and Traditional Chinese Medicine

Background: Syndrome of Inappropriate secretion of Antidiuretic Hormone (SIADH) is a group of disorders in which free water excretion is impaired due to increased Arginine Vaso Pressin (AVP) secretion in the absence of renal or endocrine dysfunction, which in turn leads to hypotonic hyponatremia. In this case report, we describe the diagnostic process of a patient with SIADH and the treatment with integration of Western and Chinese medicine. Case Presentation: A 69-year-old man was admitted to our hospital for intermittent hand tremors. He was diagnosed with hyponatremia based on laboratory tests. However, after 2 weeks of sodium supplementation, his condition did not improve. Combined with Pituitary MRI, 24h urine sodium and other laboratory tests, he was diagnosed with SIADH. After taking oral tolvaptan and traditional Chinese medicine Rehmanniae Decoction of Six Ingredients granules, his symptoms were alleviated and the serum sodium normalized. Conclusion: SIADH could be as an etiology for hyponatremia that is difficult-to-correct, and traditional Chinese medicine may have some efficacy and advantages.

Sex-independent timing of the onset of central puberty revealed by nocturnal luteinizing hormone concentrations.

We designed a longitudinal study to investigate the association between the ages of central pubertal activation and the appearance of clinical signs of puberty and determined total luteinizing hormone (LH) immunoreactivity in daytime- and nocturnal sleeptime-excreted urine samples. Thirty healthy volunteers (17 boys and 13 girls, aged 3.4-15.2years and 4.3-14.3years, respectively, at the beginning of the study) were included. Male and female subjects were followed for an average of 15 visits during 5.5 and 5.8 years on average, respectively. At each visit, subjects provided 24-h urine samples divided into nocturnal sleeptime and waketime portions according to the participant's sleep-and-wake rhythm. Total urinary LH (U-LH) concentrations were measured in duplicate by Delfia® IFMA (Wallac), which has been designed specifically to detect intact LH as well as the beta subunit and its core fragment, but not the human chorionic gonadotropin. The initial increases in nocturnal sleeptime total U-LH concentrations over the cutoff value of 0.7 IU/L occurred at around the same time (around 9-10 years of age) in both sexes, which could not be detected in waketime urine samples. The mean first age for the nocturnal sleeptime total U-LH concentrations to reach or surpass the cutoff was 10.7 years (range: 10.2-11.6years) in boys and 11.8 years (range: 10.7-13.4years) in girls, showing no statistically significant difference between the sexes (p = .15). The mean time span from the age at which sleeptime total U-LH concentration first exceeded the 0.7 IU/L level to observing pubertal stage 2 was 1.5years in boys and 0.1years in girls. Findings in our population with a limited sample size suggest that the timing of central pubertal activation is a sex-independent phenomenon, which can be observed by monitoring the nocturnal sleeptime total LH concentrations in urine. The lag time from central pubertal activation of gonadotropin secretion to the clinical onset of puberty is significantly longer in boys.

A-099 Assessment of Stability of Routine Clinical Biochemical Results in 24-h Urine Specimen Under Conditions Simulating Various Preanalytical Variables

Abstract Background The preanalytical phase has long been recognized as a source of substantial variability for 24-h urine samples. Hence, we examined the stability of analyte concentrations of 14 clinical biochemistry parameters commonly requested in a 24-h urine sample. The effects of various preanalytical variables simulating preexamination processes of the testing process were assessed. Methods We aimed to examine the effect of time delay in sample processing (up to 7 days), storage temperature (at 4 °C and room temperature), storage container (24-h urine bag, styrofoam box), and the effect of addition of toluene as preservative. The effect of the variables on clinical biochemistry parameters (uric acid, calcium, amylase, LDH, total protein, urea nitrogen, magnesium, phophorus, glucose, creatinine, sodium, potassium, chloride, and micro-albumin) in 24-h urine samples were assessed. Results Most of the analytes (uric acid, calcium, amylase, total protein, urea nitrogen, magnesium, creatinine, sodium, chloride, and micro-albumin) showed values not significantly different (≤± 5%) from baseline after 7 days of storage regardless of the storage temperature or addition of preservative. Three analytes were stable ≤24-h: phosphorus and glucose were stable up to 24-h and potassium up to 4-h. The addition of toluene had significant positive interference with LDH measurements. Conclusion According to our results, major analytes (uric acid, calcium, amylase, total protein, urea nitrogen, magnesium, creatinine, sodium, chloride, and micro-albumin) were stable up to 7 days in ambient storage conditions and toluene as a preservative was not necessary. However, a few analytes (phosphate, glucose, and potassium) were much more unstable and allowed ≤24-h or ≤4-h of storage in ambient or refrigerated conditions.

Clinical manifestations and outcomes in tubulointerstitial nephritis and uveitis syndrome: a case report and a systematic review in China

PurposeTubulointerstitial nephritis and uveitis (TINU) syndrome is an uncommon disease. We present a confirmed case of TINU syndrome, and a systematic review of epidemiological characteristics, clinical manifestations, management, and outcomes in Chinese patients.MethodsA systematic search was carried out using defined terms and updated up to September 2022, in PubMed, Web of Science, Wanfang, CNKI, and VIP, to identify reported cases of TINU in China, according to PRISMA guidelines.ResultsAn 18-year-old boy presented with elevated serum creatinine and 24-h urine protein level of > 2 g. Inspection result revealed acute tubulointerstitial nephritis, and bilateral uveitis. The patient was diagnosed with TINU syndrome and received treatment with methylprednisolone sodium succinate, which resulted in a significant decrease in creatinine and urinary protein levels. Systematic review identified 35 publications that met the inclusion criteria. A total of 71 cases were included in this article, of which 70 were from publications and 1 was from our hospital. The median age at onset was 42 years and was significantly lower in males than females (P < 0.05). The symptoms of uveitis often occurred after kidney injury (54%) and most uveitis was anterior (55%) and bilateral (75%). Among the 51 patients who were followed up for more than 6 months, 24 had recurrent ocular symptoms or progression to chronic uveitis. Twenty patients experienced chronic or progressive kidney disease.ConclusionTINU syndrome is prone to misdiagnosis because kidney damage may not occur simultaneously with uveitis. The incidence of kidney sequelae in children is lower than that in adults, and glucocorticoids are the preferred treatment.INPLASY registration number INPLASY202350050.

The intestinal microbiome of children with initial and recurrent nephrolithiasis: A pilot study and exploratory analysis

Kidney stone disease in children is rising disproportionate to the general population, representing a disease population with a distinct biological mechanism as compared to adults. Factors influencing recurrent kidney stone disease in children are poorly characterized and the associations of the intestinal microbiome within sub-populations of kidney stone formers, however, are not well described. We evaluated a pilot cohort of children with nephrolithiasis comparing patients based on recurrent kidney stone episodes and abnormal 24-h urinary parameters, with dual aims to compare the microbiome signal in children with initial and recurrent nephrolithiasis and to explore additional associations in microbiome composition and diversity within this population. Children aged 6-18 with a history of nephrolithiasis, without an active ureteral calculus or antibiotic exposure within 30 days of study entry were eligible to participate. All participants had a 24-h urine study within 6 months of study entry and provided a fecal sample. Microbiome samples were analyzed using 16S ribosomal DNA sequencing techniques for alpha and beta diversity comparing initial and recurrent stone formers as well as microbiome multivariate association (MaAsLin2) to determine differentially abundant taxa. Shotgun sequencing reads were aligned to custom oxidase degradation and butyrate production gene databases (5 databases total). Comparisons for MaAsLin2 and shotgun metagenomics, normalized to sequencing depth, were based on stone recurrence, sex, hypercalcuria (≤4mg/kg/day), hyperoxaluria (≥45 mg/1.73m2), and hypocitraturia (<310 mg/1.73 m2 [females] or<365 mg/1.73 m2 [males]). A total of 16 enrolled children provided samples sufficient for analyses, including 9 girls and 7 boys, of whom 5 had experienced recurrent kidney stone events. Three participants had hypercalcuria, 2 had hyperoxaluria, and 4 had hypocitraturia. Comparisons of Formyl-CoA transferase between index and recurrent urinary stone disease revealed a trend towards higher mean abundance of the gene in initial stone formers (0.166% vs 0.0343%, p=0.2847) (Summary Figure), while trends toward lower biodiversity were also noted in the recurrent stone cohort on both Faith (p=0.06) and Shannon (p=0.05) indices. Exploratory analyses found Eubacterium siraeum to be significantly greater in relative abundance in children with documented hypercalciuria (p=0.001). Our pilot study demonstrates possible signals in both microbial diversity and oxalate gene expression, both of which are lower in recurrent pediatric kidney stone patients. These findings warrant further investigation as a potential diagnostic marker for future kidney stone events.

Comparative analysis between the safety and efficacy of oral corticosteroids versus corticosteroids pulse therapies in IgA nephropathy

Objective This study retrospectively compared the safety and efficacy of oral corticosteroid therapy (OCT) and corticosteroid pulse therapy (CPT) in the treatment of IgA nephropathy. Methods One ninety-two patients were diagnosed with IgA nephropathy and had an estimated glomerular filtration rate > 15mL/min/1.73m2 and 24-h urine protein level of 0.75-3.5g. Patients were divided into CPT and OCT groups according to the treatment protocol. The differences in the efficacy and safety between the two groups were assessed by logistic regression analysis and propensity score matching. Results Significant differences at baseline, including 24-h urine protein level and eGFR, were observed between the two groups. Logistic regression analysis indicated that the remission rate increased significantly, while the incidences of total adverse events and infections decreased in CPT group compared with the OCT group after adjusting the potential confounding factors. Forty-seven pairs of subjects are matched by using propensity score matching with similar baseline data. The results indicate that the total remission rate and complete remission rate were significantly higher, while the incidences of total adverse events were lower (p = 0.008) in the CPT group than in the OCT group. The subgroup analysis showed that CPT group was more likely to achieve remission in patients with initial 24-h urine protein levels falling into the range of 2–3.5 g and Oxford Classification of S1 or C1/2 (p < 0.05). Conclusion Among patients with IgA nephropathy and 24-h urine protein levels of 0.75–3.5g, CPT may be more effective than OCT in reducing urinary protein levels and improving renal function with a lower incidence of adverse events.

Comparison of three spot proteinuria measurements for pediatric nephrotic syndrome: based on the International pediatric Nephrology Association 2022 Guidelines

Background Pediatric nephrotic syndrome (NS) requires routine proteinuria monitoring, which is costly and affects patients’ quality of life. The gold-standard 24-h urine protein (UP) measurement is challenging in children, and first-morning urine collection requires specific conditions, making it difficult in outpatient settings. Studies have reported comparability of second or random morning urine sample to the first-morning specimen. This study aimed to compare outcomes of random morning proteinuria measurements to 24-h UP and the roles of the urinary protein creatinine ratio (UPCR) and dipstick tests in pediatric NS, based on International Pediatric Nephrology Association (IPNA) 2022 Guidelines. Method Twenty-four-hour and morning urine samples were collected from 92 pediatric NS patients. These were subjected to automated analyses for 24-h UP, UPCR, and semi-automated dipstick analysis. A blinded doctor performed manual dipstick analysis. Results UPCR had a stronger correlation with 24-h UP than with automated and manual urine dipstick tests. UPCR had the highest sensitivity and specificity for predicting no remission/relapse and high sensitivity but low specificity for complete remission. The optimal UPCR cutoff for remission was 0.44 mg/mg and for no remission/relapse was 2.08 mg/mg. Automated and manual dipstick tests demonstrated limited sensitivity but high specificity and similar AUC values for remission/relapse. Conclusion UPCR was sensitive and specific for diagnosing no remission/relapse and sensitive but not specific for detecting remission. Manual and automated urine dipstick tests were comparable for remission and no remission/relapse detection. This study supports the IPNA 2022 Guidelines, as 2 mg/mg was the optimal UPCR cutoff for no remission/relapse, while for remission the optimal cutoff was 0.4 mg/mg.

Predictive Factors of Early 18F-Fluorodeoxyglucose-Positron Emission Tomography Response to [131I] Metaiodobenzylguanidine Treatment for Unresectable or Metastatic Pheochromocytomas and Paragangliomas

Introduction: Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumours that produce catecholamines. [131I] metaiodobenzylguanidine (MIBG)-avid unresectable or metastatic PPGLs are treated with [131I] MIBG radionuclide therapy. A high metabolic tumour volume (MTV) and total lesion glycolysis (TLG) can be poor prognostic factors. Therefore, we evaluated the metabolic responses to [131I] MIBG therapy with respect to other clinical factors. Methods: A retrospective study was performed on a series of 20 patients who underwent FDG-PET before and after [131I] MIBG therapy. We administered a single dose comprising 5.5 GBq of [131I] MIBG (usually three times; for some cases, the number was increased or decreased considering treatment efficacy and side effects). Semi-quantitative parameters (SUVmax, MTV, and TLG) were calculated using the liver SUV (mean + 3 × standard deviation) as a threshold on Metavol software. The semi-quantitative FDG-PET parameters for determining response were complete response (CR), partial remission (PR), stable disease (SD), and progressive disease (PD). We divided our study participants into the PD and non-PD groups (i.e., SD + PR + CR) and compared the overall survival (OS) between the two groups. Subsequently, we evaluated the relationships between metabolic response and age, sex, tumour type, metastatic site, chemotherapy or external radiation history, and 24-h urine catecholamine levels by univariate logistic regression analyses. Results: Both MTV-based and TLG-based criteria for PD versus non-PD were significant prognostic factors (p = 0.014). However, treatment response as evaluated based on the SUVmax was not a significant predictor. Higher urinary dopamine levels were associated with poor metabolic response as assessed by MTV and TLG (OR 1.002, p = 0.029). The other clinical parameters were non-significant. Conclusion: Poor metabolic response (measured with MTV and TLG) to [131I] MIBG therapy in unresectable or metastatic PPGLs was related to shorter OS. The poor metabolic response can be predicted using the urinary dopamine level.

Calcineurin inhibitors or cyclophosphamide in the treatment of membranous nephropathy superimposed with FSGS lesions: a retrospective study from China

Background Cyclophosphamide (CTX) and calcineurin inhibitors (CNIs) based regimens are recommended as immunosuppressive therapies for patients with idiopathic membranous nephropathy (IMN). Focal and segmental glomerular sclerosis (FSGS) lesions, which are common in membranous nephropathy (MN), are poor predictors of outcome. This study compared the differences of prognosis between two regimens in patients with IMN combined with FSGS lesions. Methods This retrospective study enrolled 108 patients with biopsy-proven IMN, accompanied with FSGS lesions, nephrotic syndrome and an estimated glomerular filtration rate (eGFR)≥60 mL/min/1.73 m2 who were treated with CTX or CNIs. We used propensity score matching (PSM) for balancing the confounding variables. Results During follow-up, 10 patients (10/55 [18.2%]; nine males) in the CNIs group showed a 50% decline in eGFR; eight had a not otherwise specified variant. Patients initially treated with CNIs had a significantly higher risk of progression to the primary outcome and a lower probability of complete or total remission. The relapse rate was higher in patients who initially received CNIs- than in those who received CTX-based treatment. Before PSM, age and 24-h urine protein level differed significantly between the groups. The PSM model included data from 72 patients. Worse outcomes were also noted among patients who initially received CNIs than those who received CTX-based treatments after matching. Conclusions Patients with MN combined with FSGS lesions have a higher risk of renal functional decline and a higher rate of relapse after CNIs than after CTX therapy.

Dietary sodium restriction reduces blood pressure in patients with treatment resistant hypertension

PurposePatients with treatment resistant hypertension (TRH) are at particular risk of cardiovascular disease. Life style modification, including sodium restriction, is an important part of the treatment of these patients. We aimed to analyse if self-performed dietary sodium restriction could be implemented in patients with TRH and to evaluate the effect of this intervention on blood pressure (BP). Moreover, we aimed to examine if mechanisms involving nitric oxide, body water content and BNP, renal function and handling of sodium were involved in the effect on nocturnal and 24-h BP. Also, measurement of erythrocyte sodium sensitivity was included as a possible predictor for the effect of sodium restriction on BP levels.Patients and methodsTRH patients were included for this interventional four week study: two weeks on usual diet and two weeks on self-performed sodium restricted diet with supplementary handed out sodium-free bread. At the end of each period, 24-h BP and 24-h urine collections (sodium, potassium, ENaC) were performed, blood samples (BNP, NOx, salt blood test) were drawn, and bio impedance measurements were made.ResultsFifteen patients, 11 males, with a mean age of 59 years were included. After sodium restriction, urinary sodium excretion decreased from 186 (70) to 91 [51] mmol/24-h, and all but one reduced sodium excretion. Nocturnal and 24-h systolic BP were significantly reduced (− 8 and − 10 mmHg, respectively, p < 0.05). NOx increased, BNP and extracellular water content decreased, all significantly. Change in NOx correlated to the change in 24-h systolic BP. BP response after sodium restriction was not related to sodium sensitivity examined by salt blood test.ConclusionSelf-performed dietary sodium restriction was feasible in a population of patients with TRH, and BP was significantly reduced. Increased NOx synthesis may be involved in the BP lowering effect of sodium restriction.Trial registrationThe study was registered in Clinical trials with ID: NCT06022133.

A novel web-based calculator to predict 30-day all-cause in-hospital mortality for 7,202 elderly patients with heart failure in ICUs: a multicenter retrospective cohort study in the United States.

Heart failure (HF) is a significant cause of in-hospital mortality, especially for the elderly admitted to intensive care units (ICUs). This study aimed to develop a web-based calculator to predict 30-day in-hospital mortality for elderly patients with HF in the ICU and found a relationship between risk factors and the predicted probability of death. Data (N = 4450) from the MIMIC-III/IV database were used for model training and internal testing. Data (N = 2,752) from the eICU-CRD database were used for external validation. The Brier score and area under the curve (AUC) were employed for the assessment of the proposed nomogram. Restrictive cubic splines (RCSs) found the cutoff values of variables. The smooth curve showed the relationship between the variables and the predicted probability of death. A total of 7,202 elderly patients with HF were included in the study, of which 1,212 died. Multivariate logistic regression analysis showed that 30-day mortality of HF patients in ICU was significantly associated with heart rate (HR), 24-h urine output (24h UOP), serum calcium, blood urea nitrogen (BUN), NT-proBNP, SpO2, systolic blood pressure (SBP), and temperature (P < 0.01). The AUC and Brier score of the nomogram were 0.71 (0.67, 0.75) and 0.12 (0.11, 0.15) in the testing set and 0.73 (0.70, 0.75), 0.13 (0.12, 0.15), 0.65 (0.62, 0.68), and 0.13 (0.12, 0.13) in the external validation set, respectively. The RCS plot showed that the cutoff values of variables were HR of 96 bmp, 24h UOP of 1.2 L, serum calcium of 8.7 mg/dL, BUN of 30 mg/dL, NT-pro-BNP of 5121 pg/mL, SpO2 of 93%, SBP of 137 mmHg, and a temperature of 36.4°C. Decreased temperature, decreased SpO2, decreased 24h UOP, increased NT-proBNP, increased serum BUN, increased or decreased SBP, fast HR, and increased or decreased serum calcium increase the predicted probability of death. The web-based nomogram developed in this study showed good performance in predicting 30-day in-hospital mortality for elderly HF patients in the ICU.

The prevalence, hospitalization outcomes and risk factors of euthyroid sick syndrome in patients with diabetic ketosis/ketoacidosis

BackgroundTo investigate the prevalence of euthyroid sick syndrome (ESS) and to evaluate the outcomes and risk factors associated with ESS among hospitalized patients with diabetic ketosis (DK) or diabetic ketoacidosis (DKA).MethodsLaboratory and clinical data of 396 adult hospitalized DK/DKA patients with or without ESS were collected and analyzed. Spearman linear analysis and multivariable logistic regression analyses were used to evaluate correlated factors of thyroid hormones and risk factors of ESS.ResultsMost of the individuals were diagnosed with type 2 diabetes (359/396, 90.7%). The prevalence of ESS was 57.8% (229/396). Patients in ESS group were older and had a longer course of diabetes. Levels of thyroid hormones, serum lipids, and parameters reflecting acidosis were significantly decreased in ESS group. The proportion of patients with infection, acute renal injury and DKA was significantly higher in ESS group than in control group, accompanied by longer hospitalization stay and higher hospitalization costs. Free triiodothyronine positively correlates with albumin, eGFR, parameters reflecting acidosis and lipid profiles (All P < 0.001), and negatively correlates with age, onset age, 24-h urine albumin, hsCRP and WBC count (All P < 0.001). Hypoalbuminemia, low level of carbon dioxide combining power, high level of HbA1c and WBC, and co-infection are shown to be risk factors for ESS (OR = 0.866, 0.933, 1.112, 1.146, 1.929, respectively; All P < 0.05).ConclusionsThe prevalence of ESS was high in adult DK/DKA patients. Patients with ESS had inferior clinical and socioeconomic outcomes. Early recognition and management of patients with ESS may be necessary to improve outcome.

Novel low-sodium salt formulations combined with Chinese modified DASH diet for reducing blood pressure in patients with hypertension and type 2 diabetes: a clinical trial.

In this study, we aimed to explore the antihypertensive effect of 23 and 52% concentrations of low-sodium salt combined with the Chinese Modified Dietary Approaches to Stop Hypertension (CM-DASH) diet in patients with hypertension and type 2 diabetes. We conducted a randomized controlled single-blind trial with a semi-open design. One hundred and thirty-two participants were randomly assigned into Group A (control group), Group B (52% low-sodium salt group), Group C (23% low-sodium salt group), and Group D (meal pack group) for 8 weeks of dietary intervention. All participants were followed weekly to collect data on blood pressure, salt use, and adverse events. Blood and 24-h urine samples were analyzed at baseline, 4 weeks, and the end of the intervention. At the end of the intervention, the mean blood pressure decreased significantly by 10.81/5.03 mmHg, 14.32/6.32 mmHg, 14.20/6.59 mmHg, and 19.06/7.82 mmHg in Groups A-D, respectively, compared with baseline (p < 0.001). Comparison between groups showed that the systolic blood pressure was lower in Groups C and D than in Groups A (-6.54 mmHg, -8.70 mmHg, p < 0.05) and B (-6.60 mmHg, -8.76 mmHg, p < 0.05), and the diastolic blood pressure was lower in Group D than in Group A (-5.17 mmHg, p = 0.006). The 24-h urinary Na+ and Na+/K+ values were significantly decreased in participants using low-sodium salt (p < 0.001). No serious adverse events occurred during the trial. Our preliminary results suggest that 23 and 52% concentrations of low-sodium salt combined with the CM-DASH diet can effectively reduce sodium intake and increase potassium intake in patients with hypertension and type 2 diabetes mellitus, thus achieving "salt reduction" and attaining standard, smooth, comprehensive management of patients with hypertension and type 2 diabetes. http://www.chictr.org.cn/, ChiCTR2000029017.

Circadian Urinary Excretion of Water, and Not Salt, Is Affected by the White Coat Effect.

Hypertension is an important morbidity factor. The prognostic consequences of the white-coat effect have been studied extensively. The repercussion on the circadian rhythm of urinary water and salt excretion in the same subgroup remain, conversely, among the open topics. Postulating an impaired diurnal sodium and volume excretion we decided to investigate both, in subjects with or without a white-coat effect, in the general population. A sample of 1023 subjects, has been considered. We collected 24-h urine samples, divided in day and night, and we measured the blood pressure with an Ambulatory Blood Pressure Monitoring (ABPM). ABPM values were then compared with physician collected in-office values to assign subjects to the group with or without the white-coat effect. Concerning the circadian pattern of urinary sodium excretion, we found no significant differences between the groups. There was instead in the white-coat effect group a higher night/day ratio of urinary water excretion. The white-coat effect, has been considered a potential hypertension precursor, and its consequent handling could be prospectively relevant in hypertension prevention. The absence of repercussions on the urinary circadian sodium excretion pattern and on the potentially related risk factors in subjects with a white coat effect is reassuring. The clinical significance of the impact on the night/day ratio of water excretion needs to be further investigated.