24-hour Excretion Research Articles

Independent and joint associations of urinary potassium excretion with cardiovascular death: a national population-based cohort study

Abstract Background Elevated potassium excretion is associated with lower blood pressure, as well as reduced risks of cardiovascular disease (CVD) death. However, the impact of varied sodium levels on this association remains a topic of debate, and the mediators of this association besides blood pressure remain uncertain. Purpose To examine the joint association of potassium and sodium with CVD mortality risk, and to identify potential mediating factors of this association. Methods Based on the ChinaHEART (China Health Evaluation And risk Reduction through nationwide Teamwork) project, participants aged 35-75 from 239 sites across all 31 provinces in the mainland of China were recruited from November 2014 to December 2022. We collected spot urine samples from participants and estimated 24-hour sodium and potassium excretion using the Kawasaki formula. Death records were captured through data linkage with the National Mortality Surveillance System and Vital Registration. Multiple regressions were used to analyze the association between potassium excretion and CVD death, as well as to examine the addictive interaction of potassium and sodium. Results This study included 270,991 participants with a mean age of 55.8±9.8 years, and 60.5% of them were female. The mean potassium excretion was 54.36±12.58 mmol/d , which was higher in males and people living in the north. Findings revealed a positive correlation between low urinary potassium levels and CVD death , and the lowest adjusted hazard rate for CVD mortality was 0.65 (95% CI: 0.58-0.73) in the group with the highest potassium excretion (i.e. ≥64.27 mmol/d) compared with the reference group (<43.79 mmol/d), after adjusting for sociodemographic characteristics, medical histories, and lifestyles. Age modified the association between potassium excretion and risk of CVD death (P for interaction=0.031). In addition to systolic blood pressure (16.6%), heart rate (2.2%) also served as the significant mediator between urinary potassium excretion and CVD death. The relative excess risk of interaction (RERI) of lower potassium excretion and lower sodium was significantly positive (RERI=0.22, 95% CI: 0.02-0.42), which implied the synergy effect. Conclusion Potassium intake in the Chinese population is evidently lower than the guideline recommendations, and increasing potassium intake, especially in the population aged <65 years, may reduce the risk and burden of cardiovascular and other diseases. Moreover, when sodium intake is insufficient, supplementation with both sodium and potassium salt can achieve greater health benefits.Graphic abstract

Efficacy and Safety of TransCon PTH in Adults with Hypoparathyroidism: 52-Week Results From the Phase 3 PaTHway Trial.

Conventional therapy for hypoparathyroidism aims to alleviate symptoms of hypocalcemia but does not address insufficient parathyroid hormone (PTH) levels. Assess the long-term efficacy and safety of TransCon PTH (palopegteriparatide) for hypoparathyroidism. Phase 3 trial with a 26-week double-blind, placebo-controlled period followed by a 156-week open-label extension (OLE). 21 sites across North America and Europe. 82 adults with hypoparathyroidism were randomized and received study drug and 78 completed week 52. All OLE participants received TransCon PTH administered once daily. Multi-component efficacy endpoint: proportion of participants at week 52 who achieved normal serum calcium (8.3-10.6 mg/dL) and independence from conventional therapy (≤600 mg/day of elemental calcium and no active vitamin D). Other efficacy endpoints included patient-reported outcomes (PROs) and bone mineral density (BMD). Safety was assessed by 24-hour urine calcium and treatment-emergent adverse events (TEAEs). At week 52, 81% (63/78) met the multi-component efficacy endpoint, 95% (74/78) achieved independence from conventional therapy, and none required active vitamin D. PROs showed sustained improvements in quality of life, physical functioning, and well-being. Mean BMD Z-scores decreased toward age- and sex-matched norms from baseline to week 52. Mean (SD) 24-hour urine calcium excretion decreased from 376 (168) mg/day at baseline to 195 (114) mg/day at week 52. Most TEAEs were mild or moderate and none led to trial discontinuation during the OLE. At week 52 of the PaTHway trial, TransCon PTH showed sustained efficacy, safety, and tolerability in adults with hypoparathyroidism.

12609 Navigating The Therapeutic Challenge Of Post-surgical Hypoparathyroidism And Refractory Hypocalcemia

Abstract Disclosure: D. Fawcett: None. A. Domingo: None. Introduction: Post-surgical hypoparathyroidism poses a challenge due to calcium metabolism disturbances, ranging from mild to life-threatening complications. Despite advancements, vigilant monitoring and tailored interventions are vital for optimizing outcomes. Refractory hypocalcemia, resistant to standard therapies, underscores the need for specialized care to prevent prolonged hospitalization and morbidity. Case description: A 68-year-old woman with a history of Graves' disease and parathyroid carcinoma underwent total thyroidectomy and parathyroidectomy in January 2024. She presented to the emergency department for the second time with a recurrence of bilateral hand and perioral paresthesias, along with numbness, tingling, and weakness throughout her body. Notably, she had a prior hospital admission with similar symptoms and was discharged on calcium carbonate, magnesium, calcitriol, and vitamin D3. Vital signs were not provided. Initial laboratory workup revealed a calcium level of 4.3, with corrected calcium at 5.8, and magnesium levels at 1.8, supplemented with magnesium oxide. A 24-hour urine calcium test, vitamin D, and malabsorptive workup for celiac disease were unremarkable. Immunoglobulin A was low; however, tissue transglutaminase IgA and anti-gliadin antibodies were negative. An electrocardiogram showed a normal sinus rhythm with QT prolongation to 570 ms. Despite resuming her home regimen, her calcium level remained low, prompting initiation of calcium infusion. Consultations with endocrinology and nephrology were made, necessitating close monitoring and uptitration of calcium and vitamin D supplements for achievement and maintenance of low normal calcium levels. High doses of 3g TID of calcium and calcitriol 2mcg PO TID allowed for symptom control and discharge with outpatient follow-up with endocrinology and nephrology. Conclusion: Supplemental therapy with calcium and vitamin D analogues is standard for managing post-surgical hypoparathyroidism. Early identification and adequate management prevent hypocalcemia-related complications, including tetany, seizures, and cardiovascular anomalies such as QTc prolongation, as seen in our patient, which can result in torsade de pointes. Multidisciplinary care alongside nephrology was paramount. Serum calcium should be maintained in the low normal range, and 24-hour urine calcium excretion should also be closely monitored. Daily hydrochlorothiazide can be used to prevent hypercalciuria. In recurrent cases, as in our patient, titration of calcium and vitamin D analogues is imperative. Long-term consequences, including renal dysfunction, osteoporosis, and increased cardiovascular risk, underscore the necessity for timely diagnosis and management. Presentation: 6/2/2024

Placenta may exert fetal protection against maternal high salt diet intake via renin-angiotensin-aldosterone system

ObjectiveThis study investigated the effects of high compared to normal dietary salt intake on fetoplacental vascular function, activity of renin-angiotensin-aldosterone system (RAAS), placental pro- and anti-angiogenic factors and biomarkers of placental remodeling and oxidative stress during healthy uncomplicated pregnancy. Materials and MethodsBased on their 24-hour sodium excretion pregnant women (37–40 weeks’ gestation) were categorized into three groups: normal salt (NS, <5.75 g/day, N=12), high salt (HS, 5.75–10.25 g/day, N=36), and very high salt (VHS, >10.25 g/day, N=17). Pulsatility (PI) and resistive index of middle cerebral artery (MCA) and umbilical artery, plasma renin activity (PRA), serum aldosterone, soluble fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF) concentrations, as well as placental vascular endothelial growth factor C (VEGF-C), oxidative/antioxidative stress markers (TBARS/FRAP) and matrix metalloproteinase 9 (MMP-9) concentration were measured. ResultsPI MCA was significantly decreased in HS/VHS groups compared to NS group. HS/VHS intake did not suppress PRA and aldosterone concentration. Serum PlGF concentration was significantly increased while sFlt-1 concentration and sFlt-1/PlGF ratio were significantly decreased in VHS group compared to NS group. MMP-9, VEGF-C concentration, TBARS and FRAP in placental tissue were similar between study groups. ConclusionsHS/VHS diet does not suppress RAAS during pregnancy; however, it is associated with decreased PI MCA, a significantly decreased sFlt-1/PlGF ratio and unchanged biomarkers of placental remodeling or oxidative stress in healthy pregnant women, suggesting the presence of a possible protective or compensatory mechanism aimed at preserving placental function and pregnancy outcome itself in terms of maternal HS intake.

Abstract P331: Simple Instruction and Provision of Literature on Low Salt Diet Ineffective in Reducing Salt Intake in Patients with Hypertension

Objective: Hypertension remains poorly controlled at the population level. Reduction of salt intake via the DASH diet is effective in reducing blood pressure (BP). We enrolled a cohort of patients with hypertension to assess molecular factors that influence BP control over a follow up period of 6 months. Here we report dietary sodium intake and BP control. Methods: 80 non-diabetic patients aged &gt;40 with hypertension were enrolled in the study. Subjects reccieved brief instruction and a handout on the DASH diet from a study coordinator. Medications were titrated to a BP of &lt;130/80 at enrollment, months 1, 2,3 and 6. BP was measured at each visit using an automated cuff following clinical trial methodology. 24-hour urine sodium excretion was collected at enrollment, months 3 and 6. Descriptive variables were summarized and paired t-tests were used to compare sodium excretion and BP. Results: Cohort characteristics are in Table 1. 73 subjects provided 24-hour urine samples and BP at enrollment and month 3 while 67 had samples at enrollment and month 6. Mean BP at enrollment was 129.9/75.3 (SD 16.6/12.5) which reduced 123/71.8 (SD 12.9/10) at month 3, p &lt;0.001and 125.4/73.4 (SD 15.2/10.5), p=0.02. 24-hour sodium excretion was 152 mmol (SD 73.6) at enrollment. There was no difference in sodium excretion at 3- (154 mmol, SD 86.2, p=0.8) or 6 months (139 mmol, SD 60,, p=0.18). Conclusions: According to 24-hour urine collection, participants consumed roughly 3.5 g of sodium per day. Simple instruction and provision of literature regarding a DASH diet was ineffective in reducing sodium intake. Further study is required to determine a more effective educational delivery method and understand any social factors that may inhibit diet implementation in this urban hypertensive cohort.

Elevated Cystatin C Predicts Higher Mortality in Chronic Heart Failure Independently of Renal Function.

Cystatin C (CysC) is a known prognostic marker in cardiovascular diseases and its role in acute heart failure (HF) has been documented. We prospectively recruited HF patients followed in a HF clinic. Inclusion criteria: HF diagnosed ≥6 months, optimized evidence-based therapy, and ejection fraction <40% (Heart Failure with reduced ejection fraction). Exclusion criteria: renal replacement therapy and hospitalizations or therapeutic adjustments in the previous 2 months. A venous blood sample and 24-hour urine were collected. Follow-up: 5 years; endpoint: all-cause mortality. CysC was measured and creatinine clearance (CrCl) was calculated using 24-hour urine creatinine excretion. A Receiver operating characteristic curve was used to assess association of CysC with 5-year mortality. The prognostic role of CysC was determined using Cox-regression analysis. The multivariate model included CrCl (24-hour urine). We evaluated 215 chronic stable Heart Failure with reduced ejection fraction patients. Mean age was 68 years, 72.1% were male. Median CysC = 1.15 mg/L, creatinine = 1.20 mg/dL, and CrCl = 63.6 mL/min. During follow-up, 103 (47.9%) patients died. The area under the curve for CysC in predicting mortality was 0.77 (0.70-0.83). Best cut-off value for death prediction = 1.00 mg/L with a sensitivity = 83.5%, specificity = 56.2%, positive predictive value = 63.7%, and negative predictive value = 78.7%. Multivariate-adjusted (age-, B-type natriuretic peptide-, evidence-based therapy, New York Heart Association class, and CrCl) 5-year mortality Hazard ratio = 2.40 (95% Confidence interval, 1.25-4.61), P value = 0.008 when CysC ≥1.00 mg/L. Patients with CysC <1.00 mg/L have almost 80% probability of being alive at 5 years; If CysC ≥1.00 mg/L, there is almost 2.5-fold higher death risk independently of B-type natriuretic peptide and CrCl.

Reliability of the spot urine protein/creatinine ratio for assessing proteinuria in patients with renal disease.

This study aimed to assess the reliability of the spot urine protein/creatinine (sP/Cr) ratio for evaluating proteinuria across different ranges and renal functions. In this retrospective study, we analyzed 24-hour urine protein excretion (24 h UP) and sP/Cr measurements in 216 patients with renal disease. Pearson correlation and Bland-Altman analyses were performed to evaluate the correlation and agreement between 24 h UP and the sP/Cr. The patients were categorized into the following three 24 h UP groups: 150 to 299 mg/24 hours, 300 to 3499 mg/24 hours, and >3500 mg/24 hours. Significant positive correlations were found between the sP/Cr and the first two 24 h UP groups (r = 0.9104 and r = 0.9721, respectively) but not between the third group (r = 0.3110). Bland-Altman analysis confirmed good agreement in the group with <3500 mg/day proteinuria. Estimated glomerular filtration rates ≥60 mL/minute and <60 mL/minute were significantly correlated with the sP/Cr (r = 0.8714 and r = 0.4516, respectively). The sP/Cr ratio is a reliable indicator for non-nephrotic proteinuria, irrespective of renal function, but is unreliable for nephrotic-range proteinuria.

O79 DAILY URINARY POTASSIUM EXCRETION IS NOT A FIXED PERCENTAGE OF DAILY POTASSIUM INTAKE

Background and Objective: High potassium intake is associated with a lower blood pressure and lower incidence of cardiovascular events. For estimation of potassium intake, the World Health Organization advices to multiply the 24-hour renal potassium excretion by 1.3, considering the substantial fecal potassium loss. We examined the variation in the required conversion factor in healthy volunteers and evaluated the effect of factors associated with tissue cation storage on the renal potassium excretion. Methods: We performed a post-hoc analysis of the Mars long-term sodium balance studies. Healthy male participants consumed a fixed amount of salt (6, 9 and 12 grams/day for &gt;29 days) and potassium (4 grams/day) for 105 (n=4) and 205 days (n=6). All urine was collected in 24-hour aliquots. We calculated the percentage of potassium intake that was excreted in the corresponding 24-hour urine collection during steady-state. A multivariable mixed-effects model was used to assess associations of this percentage with sodium intake, potassium intake, urinary aldosterone, urinary cortisol and urine volume. Results: The median renal potassium excretion was 80% of potassium intake (IQR 65-97%, range 24-304%), corresponding to a conversion factor of 1.25 (IQR 1.03-1.54). Within individual subjects we also observed a marked day-to-day variation in the percentage of renal potassium excretion: the average intraperson width of the IQR was 25%. Sodium intake (figure A), urinary aldosterone (figure B), urinary cortisol (figure C) and urine volume (figure D) were positively associated with the percentage of renal potassium excretion, whereas potassium intake showed a negative association (figure A). A significant positive interaction between the effects of sodium and potassium intake was present (P&lt;0.001). Conclusions: The percentage of dietary potassium that is excreted via urine varies considerably. During steady-state, this percentage is independently affected by sodium intake, potassium intake, urinary aldosterone, urinary cortisol, and urine volume. Our results suggest that the WHO's fixed 1.3 conversion factor may lead to inaccurate estimations of potassium intake.

Sestrin2 knockout exacerbates high-fat diet induced metabolic disorders and complications in female mice

BackgroundObesity and its associated complications raise significant public concern, revealing gender disparities in the susceptibility to metabolic disorders, with females often displaying greater resistance to obesity-related metabolic disorder than males. Sestrin2 is a crucial protein involved in metabolism and energy balance. This study seeks to explore whether Sesn2 knockout (KO) exacerbates high-fat diet (HFD) induced obesity in female mice.MethodsFemale mice with wild-type (WT) and Sesn2 KO were subjected to a 12-week regimen of normal diet or HFD. Using a Body Composition Analyzer, body composition was gauged. Biochemical assays encompassed glucose, lipid, and liver function measurements, alongside 24-hour urine albumin excretion. Echocardiographic evaluation assessed cardiac function. Histopathological analysis of key metabolic tissues (liver, kidney, and heart tissues) were conducted. Western blotting or qRT-PCR evaluated key proteins and genes linked to inflammation, mitochondrial, and lipid metabolism in adipose tissues.ResultsIn comparison to mice fed a regular diet, those on a HFD exhibited significant increases in body weight and fat mass. Notably, Sesn2 KO further aggravated obesity, showcasing the most pronounced metabolic anomalies: elevated body weight, fat mass, impaired glucose tolerance, and insulin sensitivity, alongside heightened levels of free fatty acids and triglycerides. Additionally, KO-HFD mice displayed exacerbated multi-tissue impairments, including elevated hepatic enzymes, increased urinary albumin excretion, compromised cardiac function, and accumulation of lipids in the liver, kidney, and heart. Moreover, adipose tissue showcased altered lipid dynamics and function, characterized by enhanced triglyceride breakdown and modified adipokine levels. Browning was diminished, along with decreased Pgc1α and Sirt1 in KO-HFD mice.ConclusionSesn2 KO exacerbates HFD-induced obesity and metabolic disorders in female mice. These findings underscore Sestrin2’s novel role as a regulator of obesity in female mice.

Association of urinary excretion rates of uric acid with biomarkers of kidney injury in patients with advanced chronic kidney disease.

The potential influence of hyperuricemia on the genesis and progression of chronic kidney disease (CKD) remains controversial. In general, the correlation between blood levels of uric acid (UA) and the rate of progression of CKD is considered to be modest, if any, and the results of relevant trials oriented to disclose the effect of urate-lowering therapies on this outcome have been disappointing. Urinary excretion rates of UA could reflect more accurately the potential consequences of urate-related kidney injury. Using a cross-sectional design, we investigated the correlation between different estimators of the rates of urinary excretion of UA (total 24-hour excretion, mean urinary concentration, renal clearance and fractional excretion)(main study variables), on one side, and urinary levels of selected biomarkers of kidney injury and CKD progression (DKK3, KIM1, NGAL, interleukin 1b and MCP)(main outcome variables), in 120 patients with advanced CKD (mean glomerular filtration rate 21.5 mL/minute). We took into consideration essential demographic, clinical and analytic variables with a potential confounding effect on the explored correlations (control variables). Spearman's rho correlation and nonlinear generalized additive regression models (GAM) with p-splines smoothers were used for statistical analysis. Multivariate analysis disclosed independent correlations between urinary UA concentrations, clearances and fractional excretion rates (but not plasma UA or total 24-hour excretion rates of UA), on one side, and the scrutinized markers. These correlations were more consistent for DKK3 and NGAL than for the other biomarkers. Glomerular filtration rate, proteinuria and treatment with statins or RAA axis antagonists were other independent correlates of the main outcome variables. Our results support the hypothesis that urinary excretion rates of UA may represent a more accurate marker of UA-related kidney injury than plasma levels of this metabolite, in patients with advanced stages of CKD. Further, longitudinal studies will be necessary, to disclose the clinical significance of these findings.

Sodium Intake and Atopic Dermatitis

The association of diet with atopic dermatitis (AD) remains poorly understood and could help explain heterogeneity in disease course. To determine the extent to which a higher level of dietary sodium intake, estimated using urine sodium as a biomarker, is associated with AD in a large, population-based cohort. This cross-sectional study of adult participants (aged 37-73 years) from the UK Biobank examined 24-hour urine sodium excretion, which was estimated using a single spot urine sample collected between March 31, 2006, and October 1, 2010, and calculations from the sex-specific International Cooperative Study on Salt, Other Factors, and Blood Pressure equation, incorporating body mass index; age; and urine concentrations of potassium, sodium, and creatinine. The data were analyzed between February 23, 2022, and March 20, 2024. The primary exposure was 24-hour urinary sodium excretion. The primary outcome was AD or active AD based on diagnostic and prescription codes from linked electronic medical records. Multivariable logistic regression models adjusted for age, sex, race and ethnicity, Townsend Deprivation Index, and education were used to measure the association. The analytic sample comprised 215 832 participants (mean [SD] age, 56.52 [8.06] years; 54.3% female). Mean (SD) estimated 24-hour urine sodium excretion was 3.01 (0.82) g per day, and 10 839 participants (5.0%) had a diagnosis of AD. Multivariable logistic regression revealed that a 1-g increase in estimated 24-hour urine sodium excretion was associated with increased odds of AD (adjusted odds ratio [AOR], 1.11; 95% CI, 1.07-1.14), increased odds of active AD (AOR, 1.16; 95% CI, 1.05-1.28), and increased odds of increasing severity of AD (AOR, 1.11; 95% CI, 1.07-1.15). In a validation cohort of 13 014 participants from the National Health and Nutrition Examination Survey, a 1 g per day higher dietary sodium intake estimated using dietary recall questionnaires was associated with a higher risk of current AD (AOR, 1.22; 95% CI, 1.01-1.47). These findings suggest that restriction of dietary sodium intake may be a cost-effective and low-risk intervention for AD.

#1964 Diagnosis performance of urine oxalate/creatinine ratio for hyperoxaluria screening

Abstract Background and Aims Primary and secondary hyperoxaluria is characterized by significantly elevated urinary oxalate levels, increased risk of kidney stones, nephrocalcinosis, and chronic kidney disease. Patients with enteric hyperoxaluria are especially at high-risk populations. However, identifying hyperoxaluric individuals within these populations remains challenging due to difficulties in obtaining complete urine collections. This study aims to evaluate the diagnostic performance of the urine oxalate/creatinine ratio to improve the screening of hyperoxaluria. Method We pooled data from an adult tertiary renal exploration center, including living donors, short bowel syndrome patients, bariatric surgery patients, and individuals with nephrolithiasis or other nephrological issues undergoing 24-hour urine analysis. We assessed the relationship between the urine oxalate/creatinine ratio and 24-hour oxalate excretion. The diagnostic performance of the ratio was analyzed using ROC curves, and an optimal diagnostic threshold was established. Results Of the 1485 initially included adult patients reported in Table 1, 37% lacked complete urine collections, resulting in a study population of 974 individuals (453 females, 521 males, median age 48 years, median renal function 97 ml/min/1.73 m²). Nineteen percent had hyperoxaluria, with a higher prevalence in females (25% vs. 13% in males). Median 24-hour oxaluria was 548 (432,740) µmol/d in the diseased group and 244 (188,309) µmol/d in the healthy group. A strong correlation (Spearman's rank correlation rho= 0.8, p &amp;lt; 0.001) was found between the urine oxalate/creatinine ratio and 24-hour oxalate excretion. ROC curves for both genders exhibited similar performance, with an optimal threshold for the entire population yielding an AUC of 0.97 (0.962-0.981). The diagnostic threshold for maximum sensitivity was an oxalate/creatinine ratio of 0.025 mmol/mmol (Sensitivity = 1, Specificity = 0.65, PPV = 0.4, NPV = 1), while for maximum specificity, it was an oxalate/creatinine 0.074 mmol/mmol (Sensitivity= 0.31, Specificity = 1, PPV = 1, NPV = 0.862). The optimal diagnostic threshold chosen by the minimum distance from the left-upper corner was an oxalate/creatinine 0.034 mmol/mmol (Sensitivity= 0.92, Specificity = 0.91, PPV = 0.69, NPV = 0.98) (Fig. 1). Conclusion The urine oxalate/creatinine ratio demonstrates excellent diagnostic performance and is efficient in screening hyperoxaluric patients within high-risk populations. However, the positive predictive value is insufficient to be a standalone reliable diagnostic test. Therefore, 24-hour urine oxalate measurement remains necessary for diagnosis.

#190 Long-term treatment with lumasiran: final results from the phase 2 open-label extension study

Abstract Background and Aims Primary hyperoxaluria type 1 (PH1) is a rare genetic disorder in which hepatic oxalate overproduction can lead to kidney failure and life-threatening systemic disease. Lumasiran, an RNA interference (RNAi) therapeutic indicated for treatment of PH1 to lower urinary oxalate (UOx) and plasma oxalate (POx) levels, reduces hepatic oxalate production by degrading the mRNA encoding glycolate oxidase. Patients with PH1 who completed a Phase 1/2 study were eligible to enroll in a Phase 2 open-label extension (OLE) study (NCT03350451) within 12 months of completing the Phase 1/2 study. Method Patients enrolled in the 54-month Phase 2 OLE had previously met eligibility criteria for the Phase 1/2 study, including: age 6 to 64 years, PH1 confirmed by genetic criteria, 24-hour (24 h) UOx excretion &amp;gt;0.7 mmol/1.73 m2/day, estimated glomerular filtration rate (eGFR) &amp;gt;45 mL/min/1.73 m2, and a stable pyridoxine (vitamin B6) regimen for patients taking vitamin B6. In the Phase 2 OLE, patients were to initiate subcutaneous lumasiran 1.0 mg/kg once monthly (qM), 3.0 mg/kg qM, or 3.0 mg/kg every 3 months (q3M) based on their dose/regimen in the Phase 1/2 study. The primary endpoint was the incidence of adverse events (AEs). Secondary endpoints were change in 24 h UOx corrected for body surface area (BSA) over time, change in 24 h UOx:creatinine ratio (UOx:Cr) over time, and change in estimated glomerular filtration rate (eGFR) over time. Change over time in POx and plasma glycolate, incidence of anti-drug antibodies (ADAs), and rates of kidney stone AEs were also assessed. Results All 20 patients (median age 11.5 years; 65% female) who completed the Phase 1/2 study entered the Phase 2 OLE (Table 1). Most patients (65%) were taking vitamin B6 at baseline. All patients transitioned to the 3.0 mg/kg q3M dose/regimen by month (M) 21, and all patients completed the study. Six patients transitioned to commercially available lumasiran prior to M54 but on or after M45. The most common treatment-related AEs were injection-site reactions (ISRs) with 13 events in 8 patients (40%); all ISRs were graded mild. Of all lumasiran doses administered during the OLE, 3% (13 of 427 total doses of lumasiran) were associated with ISRs. Other than ISRs, the only treatment-related AEs affecting &amp;gt;1 patient were increases in bilirubin (N=3 patients; 15%); all events resolved without lumasiran dosing changes. Severe AEs were reported by 2 patients (10%); serious AEs were reported by 7 patients (35%). No deaths occurred. No severe or serious AEs were related to treatment, and no patients discontinued lumasiran or withdrew due to AEs. Lumasiran treatment led to a substantial reduction in 24 h UOx relative to the Phase 1/2 study-derived baseline (Fig. 1A). At M54, the mean absolute change from baseline in 24 h UOx was −1.5 mmol/24 h/1.73 m2 and the mean percent change was −68%. From M42 through M54, 24 h UOx was ≤1.5×ULN in ≥89% of patients. At M54, the mean percent change from baseline in 24 h UOx:Cr was −77%. Mean eGFR was generally stable over time (Fig. 1B). Mean absolute change from baseline in eGFR at M54 was −1.6 mL/min/1.73 m2. Lumasiran treatment also led to reductions in POx from baseline, and mean post-baseline POx values remained within the normal range through M54. Mean plasma glycolate levels were elevated at the start of the Phase 2 OLE due to persistence of the treatment effect from the Phase 1/2 study. After treatment resumed, levels increased and then plateaued. One patient (5%) had an ADA positive result at M6 but no ADA-related AEs; subsequent tests were negative through M48. Overall, the kidney stone AE rate was low during the Phase 2 OLE (0.17/person-year (PY]); by comparison, the rate of symptomatic kidney stones was 0.45/PY during the 12 months prior to the Phase 1/2 study and the kidney stone AE rate was 0.90/PY during the Phase 1/2 study. Conclusion In the longest follow-up reported to date, lumasiran treatment was well tolerated in patients with PH1 in the Phase 2 OLE. The most common treatment-related AEs were mild, transient ISRs; no severe or serious AEs were treatment related. Mean 24 h UOx reductions were sustained over more than 4.5 years of treatment. Mean eGFR was stable over time.

#1179 Early change of eGFR predicts long-term renal event in patients with hypertensive chronic kidney disease using a RAS blocker

Abstract Background and Aims The renin-angiotensin-aldosterone inhibitor (RASI) is one of the important medications for chronic kidney disease (CKD) with potential decrease of glomerular filtration rate (GFR) after initiation. There are few studies about the effect of GFR change by the RASI on variations of GFR and albuminuria. Method This observational cohort study was the extension of an open-label, case-controlled randomized clinical trial (NCT01552954) including adult hypertensive CKD patients with estimated GFR ≥30 ml/min/1.73 m2 and random urine albumin-to-creatinine ratio (UACR) ≥ 30 mg/g creatinine. In the trial phase, the angiotensin receptor blocker (ARB: Olmesartan 40 mg/day) was prescribed to participants after cessation of RASIs for 8 weeks of screening phase. (0-week). Participants had the second visit at 8 weeks after initiation of ARB (8-week) with randomization into the intensive education for low salt diet and the conventional education. Third visit was conducted at 16 weeks after 0-week (16-week). After 27 (19∼38) months later, we recruited participants for the cohort observation and finished at 38 (29∼48) months after 0-week visit. We grouped patients by tertiles of percent change of initial GFR during the first 8 weeks (from 0-week to 8-week) (pcGFRi) and compared the change of UACR from 24-hour urine and estimated GFR during trial and observational period. Results We analyzed data from 174 people finished 38-month observation among 235 participants enrolled for the trial phase. Initial GFR and 24-h urine UACR were 67 ± 24 ml/min/1.73 m2 and 829 ± 829 mg/g cr, respectively. There were −16.0 (−41.5∼−8.1) %, −2.8 (−7.3∼1.6) %, and 8.3 (1.8∼28.4) % pcGFRi in the first tertile group (group 1), the second tertile group (group 2), and the third tertile group (group 3), respectively. There were no differences in age, gender, GFR, 24-hour UACR, and 24-hour sodium excretion among the tertile groups at 0-week visit. The pcGFRi and the tertile group showed positive correlation with GFR change during 16 weeks of the trial, however, were not related to the percent change of 24-hour UACR during the trial phase. They were also positively correlated to the percent change of GFR during whole study period of 38 months (factor B = 8.180 and p-value&amp;lt; 0.001 for the group and factor B = 0.801 and p-value&amp;lt; 0.001 for pcGFRi), although, they did not show relationships with the percent change of 24-hour UACR during whole study period and UACR at last visit. The GFR slopes per year during 38 (29∼48) months were −2.9 (−4.0∼ −1.8), −1.3 (−2.4∼-0.3), and 0.1 (−1.0∼1.2) ml/min/1.73 m2/year in group 1, group 2, and group 3, respectively (p = 0.001 by the ANCOVA test). The relative risks to estimate GFR decrease ≥ 30% during whole study period were 0.237 (0.07∼0.798) (p = 0.020) and 0.035 (0.004∼0.302) (p = 0.035) in group 2 and group 3 compared to group 1, respectively. The AUC to estimate GFR decline ≥ 30% by the pcGFRi was 0.787 (0.685∼0.889, p&amp;lt; 0.001). The cut-off value 7.25% of pcGFRi estimates GFR decline ≥ 30% with 71.4% sensitivity and 70.9% specificity. Conclusion The decline of GFR by initiation of RASI predicts long-term renal event of GFR decline ≥ 30% in users of RASI, strongly. We need to compare the renal outcomes between RASI users with initial decrease of GFR and non-users to make guideline adjusting RASI usage according to initial change of GFR with RASI prescription.

#1429 Daily urinary potassium excretion is not a fixed percentage of daily potassium intake

Abstract Background and Aims High potassium intake is associated with a lower blood pressure and lower incidence of chronic kidney disease. Since a significant amount of potassium is lost via stool, the World Health Organization advices to multiply 24-hour renal potassium excretion by 1.3 for estimation of dietary intake. We analyzed whether this 1.3 factor for potassium intake varies in healthy volunteers and evaluated whether factors associated with tissue cation storage, namely sodium intake, aldosterone, cortisol and urine volume, affect the renal potassium excretion. Method We performed a post-hoc analysis of the long-term sodium balance studies Mars105 and Mars520. Ten healthy male participants consumed a fixed amount of salt (6, 9 and 12 grams/day for &amp;gt;29 days) and potassium (4 grams/day) for 105 (n = 4) and 205 days (n = 6). During the entire study period all urine was collected in 24-hour aliquots. We calculated the percentage of potassium intake that was excreted in the corresponding 24-hour urine collection during steady-state. We assessed whether this percentage was associated with sodium intake, potassium intake, urinary aldosterone, urinary cortisol and urine volume using a multivariable mixed-effects model. Results Overall, the median renal potassium excretion was 80% of potassium intake (IQR 65-97%; range 24-304%). This corresponds to a conversion factor of 1.25 (IQR 1.03-1.54). Within individual subjects we also observed a marked day-to-day variation in the percentage of renal potassium excretion: the average intraperson width of the IQR was 25%. A higher sodium intake was associated with an increased percentage of renal potassium excretion, whereas a higher potassium intake was associated with a decreased percentage of renal potassium excretion. A significant positive interaction between the effects of sodium and potassium intake was present (P &amp;lt; .001; Fig. A). Furthermore, urinary aldosterone (Fig. B), urinary cortisol (Fig. C) and urine volume (Fig. D) were positively associated with the percentage of renal potassium excretion. Conclusion The percentage of consumed potassium that is excreted via urine shows considerable intra- and inter-subject variability. During steady-state this percentage is independently affected by sodium intake, potassium intake, urinary aldosterone, urinary cortisol, and urine volume. Our results suggest that the WHO's fixed 1.3 conversion factor may lead to inaccurate estimations of potassium intake.

Prediction of 24-Hour Urinary Sodium Excretion Using Machine-Learning Algorithms.

Accurate quantification of sodium intake based on self-reported dietary assessments has been a persistent challenge. We aimed to apply machine-learning (ML) algorithms to predict 24-hour urinary sodium excretion from self-reported questionnaire information. We analyzed 3454 participants from the NHS (Nurses' Health Study), NHS-II (Nurses' Health Study II), and HPFS (Health Professionals Follow-Up Study), with repeated measures of 24-hour urinary sodium excretion over 1 year. We used an ensemble approach to predict averaged 24-hour urinary sodium excretion using 36 characteristics. The TOHP-I (Trial of Hypertension Prevention I) was used for the external validation. The final ML algorithms were applied to 167 920 nonhypertensive adults with 30-year follow-up to estimate confounder-adjusted hazard ratio (HR) of incident hypertension for predicted sodium. Averaged 24-hour urinary sodium excretion was better predicted and calibrated with ML compared with the food frequency questionnaire (Spearman correlation coefficient, 0.51 [95% CI, 0.49-0.54] with ML; 0.19 [95% CI, 0.16-0.23] with the food frequency questionnaire; 0.46 [95% CI, 0.42-0.50] in the TOHP-I). However, the prediction heavily depended on body size, and the prediction of energy-adjusted 24-hour sodium excretion was modestly better using ML. ML-predicted sodium was modestly more strongly associated than food frequency questionnaire-based sodium in the NHS-II (HR comparing Q5 versus Q1, 1.48 [95% CI, 1.40-1.56] with ML; 1.04 [95% CI, 0.99-1.08] with the food frequency questionnaire), but no material differences were observed in the NHS or HPFS. The present ML algorithm improved prediction of participants' absolute 24-hour urinary sodium excretion. The present algorithms may be a generalizable approach for predicting absolute sodium intake but do not substantially reduce the bias stemming from measurement error in disease associations.

Evaluation of Drug-Drug Interaction Between Henagliflozin and Hydrochlorothiazide in Healthy Chinese Volunteers.

Henagliflozin is an original, selective sodium-glucose cotransporter 2 (SGLT2) inhibitor. Hydrochlorothiazide (HCTZ) is a common anti-hypertensive drug. This study aimed to evaluate the potential interaction between henagliflozin and HCTZ. This was a single-arm, open-label, multi-dose, three-period study that was conducted in healthy Chinese volunteers. Twelve subjects were treated in three periods, period 1: 25 mg HCTZ for four days, period 2: 10 mg henagliflozin for four days and period 3: 25 mg HCTZ + 10 mg henagliflozin for four days. Blood samples and urine samples were collected before and up to 24 hours after drug administrations on day 4, day 10 and day 14. The plasma concentrations of henagliflozin and HCTZ were analyzed using LC-MS/MS. The urine samples were collected for pharmacodynamic glucose and electrolyte analyses. Tolerability was also evaluated. The 90% CI of the ratio of geometric means (combination: monotherapy) for AUCτ,ss of henagliflozin and HCTZ was within the bioequivalence interval of 0.80-1.25. For henagliflozin, co-administration increased Css, max by 24.32% and the 90% CI of the GMR was (108.34%, 142.65%), and the 24-hour urine volume and glucose excretion decreased by 0.43% and 19.6%, respectively. For HCTZ, co-administration decreased Css, max by 19.41% and the 90% CI of the GMR was (71.60%, 90.72%), and the 24-hour urine volume and urinary calcium, potassium, phosphorus, chloride, and sodium excretion decreased by 11.7%, 20.8%, 11.8%, 11.9%, 22.0% and 15.5%, respectively. All subjects (12/12) reported adverse events (AEs), but the majority of theses AEs were mild and no serious AEs were reported. Although Css,max was affected by the combination of henagliflozin and HCTZ, there was no clinically meaningful safety interaction between them. Given these results, coadministration of HCTZ should not require any adaptation of henagliflozin dosing. ClinicalTrials.gov NCT06083116.

Efficacy and Safety of Lumasiran in Patients With Primary Hyperoxaluria Type 1: Results from a Phase III Clinical Trial

Patients with primary hyperoxaluria type 1 (PH1), a genetic disorder associated with hepatic oxalate overproduction, frequently experience recurrent kidney stones and worsening kidney function. Lumasiran is indicated for the treatment of PH1 to lower urinary and plasma oxalate (POx). ILLUMINATE-A (NCT03681184) is a phase III trial in patients aged≥6 years with PH1 and estimated glomerular filtration rate (eGFR)≥30 ml/min per 1.73 m2. A 6-month double-blind placebo-controlled period is followed by an extension period (≤54 months; all patients receive lumasiran). We report interim data through month36. Of 39 patients enrolled, 24 of 26 (lumasiran/lumasiran group) and 13 of 13 (placebo/lumasiran group) entered and continue in the extension period. At month 36, in the lumasiran/lumasiran group (36 months of lumasiran treatment) and placebo/lumasiran group (30 months of lumasiran treatment), mean 24-hour urinary oxalate (UOx) reductions from baseline were 63% and 58%, respectively; 76% and 92% of patients reached a 24-hour UOx excretion≤1.5× the upper limit of normal (ULN). eGFR remained stable. Kidney stone event rates decreased from 2.31 (95% confidence interval: 1.88-2.84) per person-year (PY) during the 12 months before consent to 0.60 (0.46-0.77) per PY during lumasiran treatment. Medullary nephrocalcinosis generally remained stable or improved; approximately one-third of patients (both groups) improved to complete resolution. The most common lumasiran-related adverse events (AEs) were mild, transient injection-site reactions. In patients with PH1, longer-term lumasiran treatment led to sustained reduction in UOx excretion, with an acceptable safety profile and encouraging clinical outcomes.See for Video Abstract.

Impact of commonly used drugs on 24-hour urine metanephrine excretion.

Impact of commonly used drugs on 24-hour urine metanephrine excretion.

Sex-Specific Association of Ambient Temperature With Urine Biomarkers in Southwest Coastal Bangladesh

IntroductionMen are vulnerable to ambient heat-related kidney disease burden, but limited evidence exists on how vulnerable women are when exposed to high ambient heat. We evaluated the sex-specific association between ambient temperature and urine electrolytes (concentration and 24-hour excretion), and 24-hour urine total protein, and volume. MethodsWe pooled a longitudinal data of 1,175 participants' concentration and 24-hour excretion of urine electrolytes and other biomarkers (24-hour urine total protein and volume) (5624 person-visits) collected in southwest coastal Bangladesh (Khulna, Satkhira, and Mongla districts) during November 2016 - April 2017. We then spatiotemporally linked ambient temperature data from local weather stations to participants' health outcomes. For evaluating the relationships between average ambient temperature and urine electrolytes and other biomarkers, we plotted confounder-adjusted restricted cubic spline (RCS) plots using participant-, household-, and community-level random intercepts. We then used piece-wise linear mixed-effects models for different ambient temperature segments determined by inflection points in RCS plots and reported the maximum likelihood estimates and cluster robust standard errors. By applying interaction terms for sex and ambient temperature, we determined the overall significance using the Wald test. Bonferroni correction was used for multiple comparisons. ResultsThe RCS plots demonstrated non-linear associations between ambient heat and urine biomarkers for males and females. Piecewise linear mixed-effects models suggested sex did not modify the relationship of ambient temperature with any of the urine parameters after Bonferroni correction (p-value <0.004). ConclusionOur findings suggest that women are as susceptible to the effects of high ambient temperature exposure as men.