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Aims: Sodium excretion is a well-defined marker used to assess diuretic response in acute heart failure (AHF). Despite a strong pathophysiological background, the role of urine chloride excretion has not been described and established yet. We aimed to evaluate chloride trajectory during intensive diuretic treatment in AHF patients and examine its potential role in predicting poor diuretic response., Methods: The study was conducted on 50 AHF patients. Participants were included within the first 36 h of hospitalization. They received furosemide dose adjusted for body weight (half in bolus, half in 2 h infusion). Post-diuretic hourly urine collection with biochemical analysis was performed., Results: In general, the concentrations of urine chloride (uCl - ) and sodium (uNa + ) at the baseline samples exhibited a comparable level (71 ± 39 vs. 70 ± 44 mmol/L, respectively; P = 0.99), but across all post-furosemide study timepoints, uCl - remained significantly higher than uNa + since 1 to 6 h of the study. In this course, both ions (uCl - and uNa + ) reached peak values in 2 h (114 ± 28 vs. 97 ± 34 mmol/L, respectively; P < 0.01). The pattern of uCl - dominance over uNa + concentration was also observed in separate analyses of patients naïve to furosemide and those chronically exposed to furosemide. Regardless of these patterns, naïve to furosemide individuals excreted more ions (both uCl - and uNa + ) than chronically exposed patients at all timepoints. Additionally, a strong, linear correlation between uCl - and uNa + was observed in each post-furosemide timepoint (the strongest in 1 h r = 0.87; P < 0.001). Both interdependent ions concentration was almost parallel when analysed in chronic furosemide users and those naïve to furosemide separately [uCl -  = 0.85 * uNa +  + 28.82, P < 0.001, R 2  = 0.83 for chronic furosemide users, and uCl -  = 0.72 * uNa +  + 41.55, P < 0.001, R 2  = 0.65 for naïves to furosemide (linear regression model)]. Moreover, uCl - (with cutoff point: 72 mmol/L) was a satisfactory predictive factor for poor diuretic response (<100 mL/h in 6 h since the beginning of furosemide infusion) [odds ratio (OR) 95% confidence interval (CI): 39.0 (3.8-405.00)]. It presented those properties also after adjusting for urine creatinine [cutoff point: 0.296 mmol/mg-OR (95% CI): 81.0 (8.0-816.0)]., Conclusions: Urine chloride and sodium are highly interrelated during decongestion of AHF patients. The uCl - (cutoff 72 mmol/L) exhibits better prognostic abilities to identify poor diuretic response than uNa + ., (© 2024 The Author(s). ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Renal chloride metabolism is currently poorly understood but may serve as both a diagnostic and a treatment approach for acute kidney injury. We investigated whether plasma chloride, ammonia and glutamine as well as urinary chloride, ammonium and glutamine concentrations may serve as markers for acute kidney injury in paediatric patients. We conducted a prospective observational trial in a tertiary care paediatric intensive care unit. Ninety-one patients after cardiopulmonary bypass surgery were enrolled. Plasma glutamine, creatinine, (serum) albumin, urinary electrolytes and glutamine were collected pre-cardiopulmonary bypass surgery, at paediatric intensive care unit admission, and at 6, 12, 24, 48 and 72 h after paediatric intensive care unit admission. The urinary strong ion difference was calculated. The median urinary chloride excretion decreased from 51 mmol/L pre-cardiopulmonary bypass to 25 mmol/L at paediatric intensive care unit admission, and increased from 24 h onwards. Patients with acute kidney injury had lower urinary chloride excretion than those without. The median urinary strong ion difference was 59 mmol/L pre-cardiopulmonary bypass, rose to 131 mmol/L at 24 h and fell to 20 mmol/L at 72 h. The plasma chloride rose from 105 mmol/L pre-cardiopulmonary bypass to a maximum of 109 mmol/L at 24 h. At 24 h the plasma chloride concentration was associated with the presence of acute kidney injury. There was no association between plasma or urinary amino acids and chloride excretion or kidney injury. In conclusion, renal chloride excretion decreased in all patients, although this decrease was more pronounced in patients with acute kidney injury. Our findings may reflect a response of the kidneys to critical illness, and acute kidney injury may make these changes more pronounced. Targeting chloride metabolism may offer treatment approaches to acute kidney injury., Competing Interests: Declaration of conflicting interestsThe author(s) have no financial or non-financial interests or benefits related to the work published in this article to declare.

In our retrospective study, we aimed to investigate the relationship between urinary chloride (uCl - ) and selected clinical and laboratory biomarkers, renal function, and patient outcomes in the acute heart failure (AHF) population. We divided 248 adult patients (≥ 18 years) with AHF into two groups: low uCl - (< 115 mmol/L) and high uCl - . The mean age of the patient group was 70.2 ± 12.6, and 182 patients were male (73.4%). Clinical endpoints included in-hospital mortality, one-year mortality, and a composite endpoint of one-year mortality and rehospitalization for heart failure. Patients were followed up for at least one year. Relevant clinical and baseline biomarker data were collected, including markers concerning inflammation, liver and kidney function, perfusion and congestion, iron status, cardiac remodeling, gasometry, renin and aldosterone. Low uCl - was associated with worse in-hospital outcomes, including higher in-hospital mortality (7.7% vs. 1.4%, p = 0.014), the need for inotropic support (20.19% vs. 2.08%, p ≤ 0.001), worsening of HF during therapy (17.31% vs. 4.86%, p ≤ 0.001), and the need for treatment in an intensive cardiac care unit (33.65% vs. 15.28%, p ≤ 0.001). Low uCl - was a significant predictor of one-year mortality (40.4% vs. 16.7%, p < 0.05) and the composite outcome (HR 2.42, 95% CI 1.43-4.08, p < 0.001). In the multivariable analysis, uCl - was independently associated with the risk of one-year mortality (HR 0.92, 95% CI 0.87-0.98, p < 0.05) and the composite outcome (HR 0.95, 95% CI 0.92-0.99, p < 0.05). Our findings suggest that low uCl - is a marker of more advanced heart failure, activation of the renin-angiotensin-aldosterone system and is related to worse one-year outcomes., (© 2024. The Author(s).)

Patients with primary aldosteronism have an increased risk of developing cardiovascular disease. The response to mineralocorticoid receptor antagonists varies among individuals, indicating diverse mineralocorticoid receptor activities in these patients. This study explored the factors linked to the efficacy of blood pressure reduction through mineralocorticoid receptor antagonists in patients with primary aldosteronism. We examined the relationship between the reduction in blood pressure and patient characteristics in a group of 41 patients with primary aldosteronism (24 males, mean age 55 ± 13 years, including 34 patients diagnosed with bilateral primary aldosteronism) before and after undergoing treatment with mineralocorticoid receptor antagonists. Significant reductions in office blood pressure were observed 3 and 6 months after treatment initiation. Single correlation analyses showed that the urinary chloride-to-potassium ratio displayed the strongest positive association with blood pressure reduction, surpassing plasma aldosterone concentration, plasma renin activity, and urinary sodium-to-potassium ratio, at 3 and 6 months. Multiple correlation analyses revealed a consistent and independent positive correlation between the urinary chloride-to-potassium ratio and blood pressure reduction at 3 and 6 months. The optimal threshold for the urinary chloride-to-potassium ratio with respect to its ability to lower blood pressure, was determined as 3.18. These results imply that the urinary chloride-to-potassium ratio may be independently associated with the effectiveness of blood pressure reduction facilitated by mineralocorticoid receptor antagonists. Moreover, it could potentially serve as a valuable predictor of the effectiveness of these agents and function as an indicator of endogenous mineralocorticoid receptor activity in patients with primary aldosteronism., (© 2024. The Author(s), under exclusive licence to The Japanese Society of Hypertension.)

The pathophysiology of genetic hypokalemia is close to that of non-genetic hypokalemia. New molecular pathways physiologically involved in renal and extrarenal potassium homeostasis have been highlighted. A physiological approach to diagnosis is illustrated here, with 6 cases. Mechanisms generating and sustaining of hypokalemia are discussed. After excluding acute shift of extracellular potassium to the intracellular compartment, related to hypokalemic periodic paralysis, inappropriate kaliuresis (>40mmol/24h) concomitant to hypokalemia indicates renal potassium wasting. Clinical analysis distinguishes hypertension-associated hypokalemia, due to hypermineralocorticism or related disorders. Genetic hypertensive hypokalemia is rare. It includes familial hyperaldosteronism, Liddle syndrome, apparent mineralocorticoid excess,11beta hydroxylase deficiency and Geller syndrome. In case of normo- or hypo-tensive hypokalemia, two etiologies are to be considered: chloride depletion or salt-wasting tubulopathy. Diarrhea chlorea is a rare disease responsible for intestinal chloride depletion. Due to the severity of hypokalemic metabolic alkalosis, this disease can be misdiagnosed as pseudo-Bartter syndrome. Gitelman syndrome is the most frequent cause of genetic hypokalemia. It typically associates renal sodium and potassium wasting, hypomagnesemia, conserved chloride excretion (>40mmol/24h), and low-range calcium excretion (urinary Ca/creatinine ratio<0.20mmol/mmol). Systematic analysis of hydroelectrolytic disorder and dynamic hormonal investigation optimizes indications for and orientation of genotyping of hereditary salt-losing tubulopathy., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Intravenous magnesium sulfate (MgSO4) is used in equine practice to treat hypomagnesemia, dysrhythmias, neurological disorders, and calcium dysregulation. MgSO4 is also used as a calming agent in equestrian events. Hypercalcemia affects calcium-regulating hormones, as well as plasma and urinary electrolytes; however, the effect of hypermagnesemia on these variables is unknown. The goal of this study was to investigate the effect of hypermagnesemia on blood parathyroid hormone (PTH), calcitonin (CT), ionized calcium (Ca2+), ionized magnesium (Mg2+), sodium (Na+), potassium (K+), chloride (Cl-) and their urinary fractional excretion (F) after intravenous administration of MgSO4 in healthy horses. Twelve healthy female horses of 4-18 years of age and 432-600 kg of body weight received a single intravenous dose of MgSO4 (60 mg/kg) over 5 minutes, and blood and urine samples were collected at different time points over 360 minutes. Plasma Mg2+ concentrations increased 3.7-fold over baseline values at 5 minutes and remained elevated for 120 minutes (P < 0.05), Ca2+ concentrations decreased from 30-60 minutes (P < 0.05), but Na+, K+ and Cl- concentrations did not change. Serum PTH concentrations dropped initially to rebound and remain elevated from 30 to 60 minutes, while CT concentrations increased at 5 minutes to return to baseline by 10 minutes (P < 0.05). The FMg, FCa, FNa, FK, and FCl increased, while urine osmolality decreased from 30-60 minutes compared baseline (P < 0.05). Short-term experimental hypermagnesemia alters calcium-regulating hormones (PTH, CT), reduces plasma Ca2+ concentrations, and increases the urinary excretion of Mg2+, Ca2+, K+, Na+ and Cl- in healthy horses. This information has clinical implications for the short-term effects of hypermagnesemia on calcium-regulation, electrolytes, and neuromuscular activity, in particular with increasing use of Mg salts to treat horses with various acute and chronic conditions as well as a calming agent in equestrian events., Competing Interests: Dr. Stephen Schumacher is employed by the sponsor of the project (USEF). However, this affiliation does not alter our adherence to all PLOS ONE policies on sharing data and materials.

In humans, most renal functions, including urine volume and electrolyte excretions, have a circadian rhythm. Light is a strong circadian entrainment factor and daytime-light exposure is known to affect the circadian rhythm of rectal temperature (RT). The effects of daytime-light exposure on the diurnal rhythm of urinary excretion have yet to be clarified. The aim of this study was to clarify whether and how daytime exposure to bright-light affects urinary excretions. Twenty-one healthy men (21-27 years old) participated in a 4-day study involving daytime (08:00-18:00 h) exposure to two light conditions, Dim (< 50 lx) and Bright (~ 2500 lx), in a random order. During the experiment, RT was measured continuously. Urine samples were collected every 3 ~ 4 h. Compared to the Dim condition, under the Bright condition, the RT nadir time was 45 min earlier (p = 0.017) and sodium (Na), chloride (Cl), and uric acid (UA) excretion and urine volumes were greater (all p < 0.001), from 11:00 h to 13:00 h without a difference in total daily urine volume. The present results suggest that daytime bright light exposure can induce a phase shift advance in urine volume and urinary Na, Cl, and UA excretion rhythms.

Background: Urinary chloride is regulated by kidney transport channels, and high urinary chloride concentration in the distal tubules can trigger tubuloglomerular feedback. However, little attention has been paid to urinary chloride as a biomarker of clinical outcomes. Here, we studied the relationship between urinary chloride concentration and chronic kidney disease (CKD) progression., Methods: We included 2086 participants with CKD from the KoreaN cohort study for Outcomes in patients With Chronic Kidney Disease. Patients were categorized into three groups, according to baseline urinary chloride concentration tertiles. The study endpoint was a composite of ≥50% decrease in estimated glomerular filtration rate from baseline values, or end-stage kidney disease., Results: During a median follow-up period of 3.4 years (7452 person-years), 565 participants reached the primary endpoint. There was a higher rate of CKD progression events in the lowest and middle tertiles than in the highest tertile. Compared with the lowest tertile, the highest tertile was associated with 33% [95% confidence interval (CI) 0.49-0.90] lower risk for the primary outcome in a cause-specific hazard model after adjustment for confounding variables. In addition, for every 25 mEq/L increase in urinary chloride concentration, there was 11% (95% CI 0.83-0.96) lower risk for CKD progression. This association was consistent in a time-varying model. Urinary chloride concentration correlated well with tubule function and kidney injury markers, and its predictive performance for CKD progression was comparable to that of these markers., Conclusions: In this hypothesis-generating study, low urinary chloride concentration was associated with a higher risk for CKD progression., (© The Author(s) 2019. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

A system for sorbent-assisted peritoneal dialysis (SAPD) has been developed that continuously recirculates dialysate via a tidal mode using a single-lumen peritoneal catheter with the regeneration of spent dialysate by means of sorbents. SAPD treatment may improve plasma clearance by the maintenance of a high plasma-to-dialysate concentration gradient and by increasing the mass transfer area coefficient (MTAC) of solutes. The system is designed for daily 8-hr treatment (12 kg, nighttime system). A wearable system (2.3 kg, daytime system) may further enhance the clearance of phosphate and organic waste solutes during the day. Uremic pigs (n = 3) were treated with the day- (n = 3) and nighttime system (n = 15) for 4-8 hr per treatment. Plasma clearance (Cl), MTAC, and total mass transport (MT) of urea, creatinine, phosphate, and potassium were compared with a static dwell (n = 28). Cl, MTAC, and MT of urea, creatinine, phosphate, and potassium were low in the pig as compared to humans due to the pig's low peritoneal transport status and could be enhanced only to a limited extent by SAPD treatment compared with a static dwell (nighttime system: Cl urea: ×1.5 (p = .029), Cl creatinine: ×1.7 (p = .054), Cl phosphate: ×1.5 (p = .158), Cl potassium: ×1.6 (p = .011); daytime system: Cl creatinine: ×2.7 (p = .040), Cl phosphate: ×2.2 (p = .039)). Sorbent-assisted peritoneal dialysis treatment in a uremic pig model is safe and enhances small solute clearance as compared to a static dwell. Future studies in humans or animal species with higher peritoneal transport should elucidate whether our SAPD system enhances clearance to a clinically relevant extent as compared to conventional PD., (© 2020 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.)

Aim: Gitelman syndrome (GS) is a rare inherited salt-losing renal tubulopathy. Data on clinical features and the pregnancy outcome for female GS patients in a large cohort are lacking. The study was aimed to explore the phenotype and pregnant issue for female GS patients., Methods: GS cases from the National Rare Diseases Registry System of China (NRSC) were collected, and detailed clinical, laboratory and genetic data were analysed. Articles on pregnancy in GS were also systemically reviewed., Results: A total of 101 GS patients were included; among them, 42.6% were female and 79.2% showed hypomagnesaemia. A lower proportion of female patients presented before 18 years of age, with less frequently reported polyuria, higher serum potassium and less urine sodium and chloride excretions. There was no gender difference in the sodium-chloride cotransporter (NCC) dysfunction evaluated by hydrochlorothiazide test. Twelve of the 43 female GS patients delivered after disease symptom onset, and their pregnancies were generally uneventful. As a group, pregnant GS patients had lower potassium levels in the first-trimester (P = .002) requiring higher potassium supplementation. After delivery, serum potassium (P = .02) and magnesium (P = .03) increased significantly. Both caesarean section and vaginal delivery were safe., Conclusion: Female GS patients may have a less severe phenotype with generally favourable outcomes of pregnancy. Intensive monitoring and increased potassium supplementation are necessary during pregnancy, especially in the first-trimester., (© 2020 Asian Pacific Society of Nephrology.)

Background: Previous animal studies have shown that intragastric administration of water can accelerate mesenteric lymph flow. Similarly, human studies have shown that abdominal breathing can induce thoracic lymph drainage. In these studies, lymph flow was measured by hemodilution and a corresponding reduction in blood anti-diuretic hormone (ADH) levels, the latter being linked to urine osmolarity. Hence, we questioned if induction of lymph flow through water administration and supine positioning could be measured by monitoring urine osmolarity. Methods and Results: Volunteers were given 250 mL of distilled water and then made to rest for either 10 or 30 minutes in a supine position. Blood samples were taken pre and postrest to monitor changes in plasma ADH, total protein, plasma albumin, red blood cell, and hemoglobin concentrations. Urine was collected to monitor [Na + ], [Cl - ], and osmolarity. Intake of 250 mL distilled water with 10-minute rest caused a significant reduction in plasma ADH concentration, with decreases in urine [Na + ], [Cl - ], and osmolarity. We found a linear relationship between the ratio of plasma ADH concentrations after/before rest (between 1.1 and 3.0 pg·mL) and the ratio of urine osmolarity after/before rest (between 180 and 601 mOsm·L). Conclusions: Intake of 250 mL distilled water with 10-minute rest in a supine position caused hemodilution and a reduction in urine osmolarity consistent with thoracic lymph drainage. Urine osmolarity is a simple, safe clinical measure for monitoring lymph flow that could be used to evaluate the technique of lymph edema therapists.

Aim: Associations have been reported among serum chloride concentration, mortality and incidence of acute kidney injury (AKI) in intensive care units (ICU). This study aimed to examine associations among urinary chloride, mortality, and AKI incidence in ICU patients., Methods: A retrospective observational study was conducted among medical-surgical ICU in a tertiary hospital wherein 170 consecutive ICU patients were evaluated from October 2015 to March 2016 and 116 patients were enrolled. Serial data of serum and urine electrolytes from day 1 to day 4 of ICU admission were examined. The primary and secondary outcomes were ICU mortality and incidence of AKI in the ICU, respectively., Results: Among the 116 enrolled patients, 15 (13%) died during their ICU stay. Although serum and urinary sodium and potassium on day 1 did not significantly differ between ICU survivors and non-survivors, urinary chloride concentration on day 1 was significantly lower in non-survivors. Receiver operating characteristic analysis showed that the cutoff value of day 1 urinary chloride concentration for prediction of ICU mortality was 53 mEq/L. The lower urinary chloride concentration group on day 1 showed a significantly lower survival rate, even in long-term follow-up, compared with the higher urinary chloride group. Addition of day 1 urinary chloride concentration improved prediction of AKI incidence in the ICU by Sequential Organ Failure Assessment score alone., Conclusion: Lower urinary chloride concentration was associated with increased mortality and incidence of AKI in the ICU. Further investigation is necessary to clarify the mechanism of urinary chloride regulation., (© 2019 Asian Pacific Society of Nephrology.)

Objective: Research into dietary factors associated with hypertension has focused on the sodium component of salt. However, chloride has distinct physiological effects that may surpass the effect of sodium on blood pressure. This study aims to separate the specific effects of chloride and sodium intake on blood pressure., Methods: We studied 5673 participants from the Prevention of Renal and Vascular End-Stage Disease(PREVEND) study. Urinary chloride(uCl) and sodium(uNa) were measured in two 24-hour collections. We used generalized-linear-regression to evaluate the relation of uCl and uNa with baseline blood pressure and Cox-proportional-hazards-analysis to assess the association with hypertension. Multicollinearity was assessed with Ridge regression., Results: Baseline 24-hour uCl was 135±39mmol and uNa was 144±54mmol. The correlation between uCl and uNa was high (Pearson's r = 0.96). UCl and uNa had similar non-significant positive and linear associations with blood pressure. In 3515 normotensive patients, 1021 patients developed hypertension during a median follow-up of 7.4 years. UCl and uNa had a comparable but non-significant J-shaped effect on the risk of hypertension. Adding both uCl and uNa to the same model produced instability, demonstrated by Ridge coefficients that converged or changed sign. The single index of uNa minus uCl showed a non-significant higher risk of hypertension of 2% per 10mmol/24-hour difference (HR1.02, 95%CI 0.98-1.06)., Conclusion: UCl and uNa had similar positive but non-significant associations with blood pressure and risk of hypertension and their effects could not be disentangled. Hence, the alleged adverse effects of high salt intake could be due to sodium, chloride or both. This encourages further study into the effect of chloride in order to complement dietary recommendations currently focused on sodium alone., Competing Interests: This work was supported by a research grant from Astellas to JvdL and MBR. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

A 21-year-old man presented with hyperthyroidism and hypokalemia and was treated for thyrotoxic hypokalemic periodic paralysis caused by Graves' disease. Thyroid function soon normalized but hypokalemia persisted. Laboratory data revealed hyperreninemic hyperaldosteronism and metabolic alkalosis consistent with Gitelman Syndrome. The patient was found to have a previously unreported compound heterozygous mutation of T180K and L858H in the SLC12A3 gene, and Gitelman Syndrome was diagnosed. He was started on eplerenone to control serum potassium level. Alternative diagnoses should be considered when electrolyte imbalances persist after disease resolution.

Gain-of-function mutations in the chloride channel ClC-2 were recently described as a cause of familial hyperaldosteronism type II (FH-II). Here, we report the generation of a mouse model carrying a missense mutation homologous to the most common FH-II-associated CLCN2 mutation. In these Clcn2 R180Q/+ mice, adrenal morphology is normal, but Cyp11b2 expression and plasma aldosterone levels are elevated. Male Clcn2 R180Q/+ mice have increased aldosterone:renin ratios as well as elevated blood pressure levels. The counterpart knockout model (Clcn2 -/- ), in contrast, requires elevated renin levels to maintain normal aldosterone levels. Adrenal slices of Clcn2 R180Q/+ mice show increased calcium oscillatory activity. Together, our work provides a knockin mouse model with a mild form of primary aldosteronism, likely due to increased chloride efflux and depolarization. We demonstrate a role of ClC-2 in normal aldosterone production beyond the observed pathophysiology.

Chloride widely exists in the environment and will cause serious interference for arsenic speciation analysis. The determination of four arsenic species including arsenite (As(III)), arsenate (As(V)), monomethylarsenate (MMA), and dimethylarsonate (DMA) in samples containing high concentrations of Cl - was carried out in this work by coupling of liquid chromatography (LC) with hydride generation atomic fluorescence spectrometry (HG-AFS). The interference of Cl - was successfully eliminated by coupling two anion-exchange chromatographic columns in series and eluting with 35.0 mmol L -1 (NH 4 ) 2 HPO 4 (pH = 6.00). A novel pre-treatment system was subsequently developed to realize on-line column switch and pre-reduction of As(V). The analysis time was shortened by an isocratic elution but programmed flow rate method, and the sensitivity of As(V) was also enhanced by the introduction of pre-reduction using the developed system. The proposed method can resist at least 10 g L -1  Cl - without any pre-treatment operations. Since LC-HG-AFS is low-cost and can be afforded or self-assembled by most labs, the developed method can be adopted as a routine analysis method for arsenic species in chloride-bearing samples, such as urine and seawater. Graphical abstract.

The former perception of the urothelium as an impermeable barrier has been revised during the last decade, as increasing evidence of changes in urine composition during its passage of the urinary tract has been presented. Since differences in urothelial permeability between upper and lower urinary tract have been found, our aim is to demonstrate whether changes in urine composition occur during passage through the ureter. We studied consecutive urine samples from both renal pelvises in six pigs and compared them to samples from the bladder and distal ureter. We further sampled urine during storage in the bladder at a fixed volume. All samples were analysed by measuring osmolality and pH, along with the concentration of the following parameters: Na(+), K(+), Cl(-), creatinine, urea. Urine alkalinity increased significantly during passage of the ureter. Creatinine concentration, pH and K(+) increased significantly during the passage from pelvis to the bladder. All other parameters increased non-significantly during the passage to the bladder. The increase in concentration was more pronounced at low concentrations in the pelvis. During storage in the bladder, there was a significant increase in urea concentration. Changes in the composition of urine occur during its passage from the renal pelvis to the bladder and during storage in the bladder. Despite the brief transit time, significant changes in alkalinity were found already during passage through the ureter.

Urinary chemistries vary widely in both health and disease and are affected by diet, volume status, medications, and disease states. When properly examined, these tests provide important insight into the mechanism and therapy of various clinical disorders that are first detected by abnormalities in plasma chemistries. These tests cannot be interpreted in isolation, but instead require knowledge of key clinical information, such as medications, physical examination, and plasma chemistries, to include kidney function. When used appropriately and with knowledge of limitations, urine chemistries can provide important insight into the pathophysiology and treatment of a wide variety of disorders., (Copyright © 2019 by the American Society of Nephrology.)

Purpose: Coconut water has long been touted for its medicinal qualities including natural hydration. We sought to determine whether its consumption would induce changes to urinary lithogenic factors beyond changes in urine volume., Materials and Methods: After Institutional Review Board approval, volunteers with no prior history of nephrolithiasis were recruited. Each participant was randomized initially to either the coconut water or the water phase of the study. Participants kept meticulous food and fluid intake logs during the first phase of the study and were asked to replicate that diet for the second phase. For each phase the participant consumed 2L of either Taste of Nirvana® pure coconut water or tap water daily for four days. Participants were not restricted to consume additional fluid of their choice during their assigned study phase. During days 3 and 4 of each phase the participant collected a 24-hour urine specimen. Coconut water citrate and malate content were measured and were used along with the beverage pH to calculate the total alkali content of the coconut water. Supersaturation levels were calculated using Equil2. Nonparametric paired analysis using the Wilcoxon test was performed for statistical analysis., Results: There were 4 adult male and 4 adult female participants. Each individual's 24-hour urine collection had a creatinine excretion within 20% of the mean for each subject's four samples corroborating that all samples were collected properly. The two samples from each phase for each individual were averaged. The coconut water itself was also analyzed and it was calculated to have a total alkali content of 13.8 mEq/L. Consumption of coconut water significantly increased urinary citrate (29%, p=0.02), urinary potassium (130%, p=0.01), and urinary chloride (37%, p=0.03), without affecting urine pH (p=0.16) or volume beyond that of tap water (p=1.00)., Conclusions: Coconut water consumption increases urinary potassium, chloride, and citrate in nonstone forming individuals.

Objective: Because the literature on the predictive value of fetal urinalysis is controversial in fetuses with lower urinary tract obstruction, we determined the best model of fetal urine biochemical markers correlated with long-term postnatal renal function based on glomerular filtration rate (GFR)., Method: This retrospective study concerned 89 fetuses with lower urinary tract obstruction and their renal function after 10 years of age. We correlated fetal urine biochemical markers (total protein, β2-microglobulin, sodium, chloride, glucose, calcium, and phosphorus) with GFR at 10 to 30 years of age in 89 patients with posterior urethral valves. We defined five stages of chronic kidney disease (CKD)., Results: Of the 89 patients, 18 (20%) are 20 years old or over. Postnatal renal function was good in 67.4% (GFR > 60 mL/min/1.73 m 2 ) and poor in 17% (GFR < 30 mL/min/1.73 m 2 ). All fetal urine markers differed between CKD stage 1 + 2 and CKD stage 4 + 5 (P < 0.001). β2-microblobulin showed an 87% sensitivity for a 72% specificity. A combination of β2-microglobulin and chloride gave the best results (93% sensitivity and 71% specificity) versus amniotic fluid volume (80% sensitivity and 73% specificity)., Conclusion: Fetal urine biochemistry predicts long-term (10-30 years) postnatal renal function., (© 2018 John Wiley & Sons, Ltd.)

Purpose: Using urinary indices as a quick bedside test to assist management of oliguria and acute kidney injury (AKI) has long been sought. This study assessed whether urinary potassium excretion is related to simultaneously calculated creatinine clearance (CrCl) and can predict AKI in the critically ill., Materials and Methods: In this prospective cohort study, the correlation between 2-h urinary potassium excretion and simultaneously calculated CrCl of 61 critically ill patients was assessed by Pearson's correlation coefficient, and their ability to predict AKI (≥stage 1 KDIGO) in the subsequent 7 days was assessed by area under the receiver-operating-characteristic (AUROC) curve., Results: Urinary potassium excretion (median 6.2 mmol, range 0.8-24.3) correlated linearly with CrCl (correlation coefficient: 0.58, 95% confidence interval [CI] 0.38-0.72; p = 0.001), and had a moderate ability to predict subsequent AKI (n = 19 [31%]; AUROC 0.747, 95%CI 0.620-0.850; p = 0.001), especially in patients without prior exposure to furosemide within 24-h (correlation coefficient 0.61, 95%CI 0.41-0.76; AUROC 0.789, 95%CI 0.654-0.890; p = 0.001, respectively)., Conclusions: Urinary potassium excretion correlates with CrCl and predicts AKI in the critically ill without recent furosemide exposure. Given 2-h urinary potassium excretion can be measured easily, its potential as a marker of renal function deserves further study., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Although present in the leaves of Mimosa bimucronata (DC.) and many other medicinal plants commonly used to augment urinary volume excretion, the effects of gallic acid as a diuretic agent remain to be studied. Wistar rats were orally treated with vehicle, hydrochlorothiazide, or gallic acid. The effects of gallic acid in the presence of hydrochlorothiazide, furosemide, amiloride, L-NAME, atropine, and indomethacin were also investigated. Diuretic index, pH, conductivity, and electrolyte excretion were evaluated at the end of the experiment (after 8 or 24 h). Gallic acid induced diuretic and saluretic (Na + and Cl - ) effects, without interfering with K + excretion, when orally given to female and male rats at a dose of 3 mg/kg. These effects were associated with increased creatinine and conductivity values while pH was unaffected by any of the treatments. Plasma Na + , K + , and Cl - levels were not affected by any of the acute treatments. The combination with hydrochlorothiazide or furosemide was unable to intensify the effects of gallic acid when compared with the response obtained with each drug alone. On the other hand, the treatment with amiloride plus gallic acid amplified both diuresis and saluresis, besides to a marked potassium-sparing effect. Its diuretic action was significantly prevented in the presence of indomethacin, a cyclooxygenase inhibitor, but not with the pretreatments with L-NAME or atropine. Although several biological activities have already been described for gallic acid, this is the first study demonstrating its potential as a diuretic agent.

Background: Phyllanthus amarus (Schum & Thonn), a plant belonging to the family of Euphorbiaceae is used in Ivorian traditional medicine to treat cardiovascular disorders such as hypertension. However, although this plant has been described as a diuretic agent, the underlying mechanism remains unclear. Therefore, the aim of the present study was to investigate the mechanism action of diuretic effects of an ethanolic fraction of Phyllanthus amarus (EFPA) in rats., Methods: Effects of EFPA on urinary excretion were carried out for doses ranging from 5 to 80 mg/kg given by intraperitoneal injection (i.p.) and compared with that induced by furosemide (5 mg/kg) after 8 h. Thereafter, the diuretic activity of EFPA was also evaluated in the presence of indomethacin (5 mg/kg, i.p.) in order to determine the involvement of prostaglandins, after 24 h., Results: Between 5 and 80 mg/kg, EFPA induced a significant urinary excretion. The profile of urinary excretion showed that after 2 h, the highest dose of 80 mg/kg induced a urinary volumetric excretion (UVE), which was similar to that induced by furosemide. After 24 h, EFPA at 10 mg/kg increased significantly UVE, Na + (43 mEq) and Cl ¯ (97 mEq) urinary excretions without promoting kaliuresis. In rats pretreated with indomethacin, the urinary excretion and the natriuretic response of EFPA were significantly reduced., Conclusion: Altogether, this study has shown that EFPA promotes a significant urinary excretion of water and Na + , confirming its diuretic activity. Moreover, the increased diuresis could be attributed, at least in part, to the involvement of prostaglandins.

Background & Aims: Urinary sodium concentration is a commonly used marker for extracellular fluid depletion which is often associated with dehydration. A point of care test for urinary sodium may reduce delays in clinical decision making by offering more timely guidance leading to improved salt and fluid management. We compared laboratory assessed urinary sodium with a potential point of care measure of urinary chloride in a variety of in- and outpatient specialities, to explore its use as an indicator of low urine sodium., Methods: Urinary chloride concentrations were estimated using a Quantab titrator stick in samples from patients that had been sent for urinary sodium assays. We validated the results of this titrator stick with laboratory-assessed sodium concentrations by deriving correlation coefficients between these methods and using limits of agreement testing. We determined the optimal titrator stick cut-point for identifying low urinary sodium (urinary sodium <20 mmol/L) by maximising the product of the sensitivity and specificity. This level of urinary sodium was used to mirror the British Society of Gastroenterology guidance on short bowel patients Nightingale and Woodward, 2006., Results: We obtained laboratory urinary sodium concentration and Quantab stick chloride measures on 127 samples. Twenty three percent had a urinary sodium below 20 mmol/L so were regarded as biochemically dehydrated. A threshold of <4.3 on the Quantab scale had a positive predictive value for low sodium of 56% (95%CI 40%-71%) and a negative predictive value of 94% (95%CI 87%-98%)., Conclusions: These data suggest that the Quantab stick could be used as a point of care test to aid fluid and salt management decisions in an outpatient setting. Further work to explore the use of the titrator stick in specific patient populations at risk of salt and water depletion is justified., (Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: To investigate the impact of green tea on urinary oxalate excretion in healthy male volunteers., Materials and Methods: The oxalate concentrations after different brewing times (2-60 min) of different qualities (2-8 g) of green tea were measured in in vitro experiment. In in vivo experiment, the effects on urine composition were assessed in 12 healthy men with an age of 24-29 years. Each subject was requested to collect two 24-h urine samples under normal dietary conditions. Green tea prepared from tea bags containing 2 g of tea leafs was consumed by the subjects for 7 consecutive days, and 24-h urine samples were collected and analyzed on days 6 and 7. After 3-week washout interval, all subjects consumed green tea containing 4 g of leaf tea for another 7 consecutive days. Two 24-h urine samples were collected on the last 2 days. Urine volume, pH, calcium, magnesium, sodium, phosphate, potassium, chloride, citrate, oxalate, urate and creatinine were measured., Results: In the in vitro experiments, oxalate in solution increased with brewing time (p < 0.05) and tea quality (p < 0.05). In the in vivo experiment, 24-h urinary oxalate increased significantly (0.24 ± 0.09 mmol to 0.32 ± 0.13 mmol, p = 0.045) when tea was prepared from 2-g bags of green leaf tea. Consumption of green tea containing 4 g of leaf tea resulted in 24-h urinary oxalate increase (0.25 ± 0.25 mmol to 0.34 ± 0.22 mmol, p = 0.041)., Conclusions: In vitro studies showed that there was a gradual increase in solution concentrations of oxalate that was associated with increased brewing time and increased quality of green tea. Studies in normal men showed that green tea consumption was associated with increased urinary exertion of oxalate.

Background/aims: Patients with cystic fibrosis (CF) are prone to the development of metabolic alkalosis; however, the pathogenesis of this life threatening derangement remains unknown. We hypothesized that altered acid base transport machinery in the kidney collecting duct underlies the mechanism of impaired bicarbonate elimination in the CF kidney., Methods: Balance studies in metabolic cages were performed in WT and CFTR knockout (CF) mice with the intestinal rescue in response to bicarbonate loading or salt restriction, and the expression levels and cellular distribution of acid base and electrolyte transporters in the proximal tubule, collecting duct and small intestine were examined by western blots, northern blots and/or immunofluorescence labeling., Results: Baseline parameters, including acid-base and systemic vascular volume status were comparable in WT and CF mice, as determined by blood gas, kidney renin expression and urine chloride excretion. Compared with WT animals, CF mice demonstrated a significantly higher serum HCO3- concentration (22.63 in WT vs. 26.83 mEq/l in CF mice; n=4, p=0.013) and serum pH (7.33 in WT vs. 7.42 in CF mice; n=4, p=0.00792) and exhibited impaired kidney HCO3- excretion (urine pH 8.10 in WT vs. 7.35 in CF mice; n=7, p=0.00990) following a 3-day oral bicarbonate load. When subjected to salt restriction, CF mice developed a significantly higher serum HCO3- concentration vs. WT animals (29.26 mEq/L in CF mice vs. 26.72 in WT; n=5, p=0.0291). Immunofluorescence labeling demonstrated a profound reduction in the apical expression of the Cl-/HCO3- exchanger pendrin in cortical collecting duct cells and western and northern blots indicated diminished plasma membrane abundance and mRNA expression of pendrin in CF kidneys., Conclusions: We propose that patients with cystic fibrosis are prone to the development of metabolic alkalosis secondary to the inactivation of the bicarbonate secreting transporter pendrin, specifically during volume depletion, which is a common occurrence in CF patients., (© 2018 The Author(s). Published by S. Karger AG, Basel.)

Gitelman syndrome is the most common inherited tubular disease resulting from mutations of the SLC12A3 gene that encodes the thiazide-sensitive sodium-chloride cotransporter in the early distal convoluted tubules. The review presents the underlying pathophysiologic mechanisms of acid-base and electrolyte abnormalities observed in patients with Gitelman syndrome. The syndrome is usually characterized by hypokalemic metabolic alkalosis in combination with hypomagnesemia and hypocalciuria. Additionally, increased chloride excretion and renin/aldosterone levels, hypophosphatemia (occasionally), hyponatremia (rarely) and glucose intolerance/insulin resistance have been reported. The knowledge of the pathophysiologic mechanisms is useful for the treatment of patients with Gitelman syndrome as well as for the understanding of other tubular diseases.

Background: Uncovering the correct diagnosis of chronic hypokalemia with potassium (K + ) wasting from the kidneys or gut can be fraught with challenges. We identified clinical and laboratory parameters helpful for differentiating the causes of chronic hypokalemia., Methods: Normotensive patients referred to our tertiary academic medical center for the evaluation of chronic hypokalemia were prospectively enrolled over 5 years. Clinical features, laboratory examinations-including blood and spot urine electrolytes, acid-base status, biochemistries, and hormones-as well as genetic analysis, were determined., Results: Ninety-nine patients with chronic normotensive hypokalemia (serum K + 2.8 ± 0.4 mmol/L, duration 4.1 ± 0.9 years) were enrolled. Neuromuscular symptoms were the most common complaints. Although Gitelman syndrome (n = 33), Bartter syndrome (n = 10), and distal renal tubular acidosis (n = 12) were the predominant renal tubular disorders, 44 patients (44%) were diagnosed with anorexia/bulimia nervosa (n = 21), surreptitious use of laxatives (n = 11), or diuretics (n = 12). Patients with gastrointestinal causes and surreptitious diuretics use exhibited a female predominance, lower body mass index, and less K + supplementation. High urine K + excretion (transtubular potassium gradient >3, urine K + /Cr >2 mmol/mmol) was universally present in patients with renal tubular disorders, but also found in >50% patients with gastrointestinal causes. Of interest, while urine sodium (Na + ) and chloride (Cl - ) excretions were high and coupled (urine Na + /Cl - ratio ∼1) in renal tubular disorders and "on" diuretics use, skewed or uncoupled urine Na + and Cl - excretions were found in anorexia/bulimia nervosa and laxatives abuse (urine Na + /Cl - ratio: 5.0 ± 2.2, 0.4 ± 0.2, respectively) and low urine Na + and Cl - excretions with fixed Na + /Cl - ratios (0.9 ± 0.2) when "off" diuretics., Conclusion: Besides body mass index, sex, and blood acid-base status, integrated interpretation of the urine Na + :Cl - excretion and their ratio is important to make an accurate diagnosis and treatment plan for patients with chronic normotensive hypokalemia., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Pendrin is a membrane transporter encoded by solute carrier family26A4 (SLC26A4). Mutations in this gene are known to cause hearing loss, and recent data from animal studies indicate a link between pendrin expression and hypertension; although, this association in humans is unclear. To clarify this issue, we investigated the influence of pendrin on blood pressure by analyzing demographic and biochemical data - including blood pressure and urinary electrolyte excretion - in patients with bi-allelic SLC26A4 mutations. Systolic and diastolic blood pressure and the left ventricular hypertrophy index were lower in subjects with pendrin mutations than in controls. In addition, fractional excretion of Na + and Cl - was increased and serum renin, angiotensin I and II levels were higher in subjects with pendrin mutations as compared to controls. Thus, patients with impaired pendrin function are likely to be resistant to high blood pressure due to enhanced urinary Na + /Cl - excretion. These results suggest that pendrin may regulate blood pressure through increased urinary salt excretion., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

An increase of total glucagon-like peptide-1 (GLP-1) concentration in the plasma in rats was revealed 5 min after oral, but not intraperitoneal administration of NaCl or Trizma HCl solutions. The increase in GLP-1 level was similar to that after oral glucose administration. After intraperitoneal administration of 2.5% NaCl, GLP-1 mimetic exenatide accelerated natriuresis and urinary chloride excretion. Under conditions of normonatriemia and hyperchloremia induced by injection of 6.7% Trizma HCl, exenatide stimulated chloride excretion and reabsorption of sodium ions in the kidneys. These findings suggest that GLP-1 participates in selective regulation of the balance of sodium and chloride ions.

Objective: A low-salt diet has been the main treatment modality for Ménière's disease (MD) since the 1930s, although the mechanisms behind this therapy have not yet been elucidated. Salt reduction is associated with a physiological increase in plasma aldosterone concentration. Several experimental reports have suggested that aldosterone may increase endolymph absorption in the inner ear, particularly in the endolymphatic sac. Therefore, aldosterone elevations due to a low-salt diet may increase endolymph absorption in the endolymphatic sac. In this study, urinary sodium excretion, plasma aldosterone, and other hormones were measured during low-salt diet therapy in patients with MD., Methods: We included 13 patients with unilateral definite MD diagnosed at the Kagawa University Hospital. A national registered dietitian provided nutritional guidance initially for 14 enrolled patients with MD and prescribed them a low-salt diet (2g Na/day). Twenty-four hour urine was sampled at baseline, at 2, 4, 6, and 8 weeks, and at 6, 12, 18, and 24 months after initiating the low-salt diet. Urine osmotic pressure, and Na, K, and Cl levels were measured, and 24-h urinary Na, K, and Cl excretion was estimated. Aldosterone, cortisol, hormones (including anti-diuretic hormone), Na, K, and Cl in the blood were measured, alongside plasma osmotic pressure. A total of 13 patients followed the low salt diet therapy for more than 2 years, while one patient dropped out., Results: Group 1 (n=7) included patients with a mean urinary sodium excretion amount lower than 3g/day and Group 2 (n=6) included those with more than 3g/day. Vertiginous states of all Group 1 patients comprised complete control (Class A, 100%), while Group 2 patients included Class A (four patients, 66%), Class C (one patient, 17%), and Class D (one patients, 17%). Plasma aldosterone concentrations significantly increased during the 2-year low-salt diet; concentrations in Group 1 tended to be higher than that in Group 2. Hearing improvements after 2 years in Group 1 were significantly better than that in Group 2. The plasma concentration of the hormones except aldosterone was not significantly changed during 2-year low-salt diet., Conclusion: A low-salt diet was an effective treatment for patients with Ménière's disease. This treatment will have a greater effect, when sodium intake is reduced to less than 3g/day. A low-salt diet may induce an increase in the plasma aldosterone concentration that can activate ion transport and absorbing endolymph in the endolymphatic sac., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Objective: To evaluate the association between ultrasonographic renal parameters and urine biochemistry in fetuses with lower urinary tract obstruction (LUTO)., Methods: Data were collected prospectively from 31 consecutive fetuses with LUTO that underwent vesicocentesis for fetal urinary biochemistry between April 2013 and September 2015. The following renal ultrasound markers were assessed immediately before the vesicocentesis: renal echogenicity, presence of cortical cysts, presence of findings suggestive of 'renal dysplasia' (hyperechogenic cystic kidneys with no cortical-medullary differentiation) and severe oligohydramnios (amniotic fluid < 5th percentile). The association of these parameters to the fetal urinary concentration of sodium, chloride, calcium, osmolality and beta2-microglobulin was investigated by logistic regression analysis., Results: There was no relationship between any of the ultrasonographic fetal renal characteristics and fetal urinary biochemistry., Conclusions: In LUTO, the ultrasound appearance of the fetal kidneys and urinary biochemistry are not correlated. It may be better to take both ultrasound and biochemistry into account when evaluating fetuses with fetal LUTO. © 2016 John Wiley & Sons, Ltd., (© 2016 John Wiley & Sons, Ltd.)

Introduction: The kidneys play a crucial role in the regulation of electrolytes and acid-base homeostasis. Urinary Strong Ion Difference (SIDu = NaU + KU-ClU) represents an important aspect of renal acid-base regulation. We evaluated the role of SIDu as a marker of renal dysfunction in critically ill patients., Materials and Methods: Patients admitted to the Medical Intensive Care Unit with a diagnosis of AKI for whom concomitant urinary samples available for SIDu calculation were retrospectively reviewed and staged according to KDIGO criteria for 3 days from inclusion. Patients were classified as Recovered (R-AKI) or Persistent-AKI (P-AKI) whether they exited KDIGO criteria within the 3-day observation period or not. A control group with normal renal function and normal serum acid-base and electrolytes was prospectively recruited in order to identify reference SIDu values., Results: One-hundred-and-forty-three patients with a diagnosis of AKI were included: 77 with R-AKI, and 66 with P-AKI. Thirty-six controls were recruited. Patients with P-AKI had more severe renal dysfunction and higher mortality than patients with R-AKI (SCr 2.23(IQR:1.68-3.45) and 1.81(IQR1.5-2.5) mg/dl respectively, p<0.001; 24-h UO 1297(950) and 2100(1094) ml respectively, p = 0.003); 30-d mortality, 39% and 13% respectively; p<0.001). SIDu significantly differed between groups, with rising values from controls to P-AKI groups (16.4(12), 30(24) and 47.3(21.5) mEq/l respectively, p<0.001)., Discussion: SIDu may be a simple and inexpensive tool in AKI patients' evaluation. Further research is needed to evaluate the ability of SIDu to identify patients with renal dysfunction before derangements in serum creatinine or urine output are observed.

Purpose: Phenotypic overlap exists among type III Bartter syndrome (BS), Gitelman syndrome (GS), and pseudo-BS/GS (p-BS/GS), which are clinically difficult to distinguish. We aimed to clarify the differences between these diseases, allowing accurate diagnosis based on their clinical features., Methods: A total of 163 patients with genetically defined type III BS (n = 30), GS (n = 90), and p-BS/GS (n = 43) were included. Age at diagnosis, sex, body mass index, estimated glomerular filtration rate, and serum and urine electrolyte concentrations were determined., Results: Patients with p-BS/GS were significantly older at diagnosis than those with type III BS and GS. Patients with p-BS/GS included a significantly higher percentage of women and had a lower body mass index and estimated glomerular filtration rate than did patients with GS. Although hypomagnesemia and hypocalciuria were predominant biochemical findings in patients with GS, 17 and 23% of patients with type III BS and p-BS/GS, respectively, also showed these abnormalities. Of patients with type III BS, GS, and p-BS/GS, 40, 12, and 63%, respectively, presented with chronic kidney disease., Conclusions: This study clarified the clinical differences between BS, GS, and p-BS/GS for the first time, which will help clinicians establish differential diagnoses for these three conditions.

Objective: In recent decades, the thiazide test has been introduced to aid the diagnosis of Gitelman syndrome (GS), but the effect of thiazide in normomagnesemic GS patients is currently unknown. This study was conducted to compare the thiazide test results of normomagnesemic and hypomagnesemic GS patients., Methods: Seventeen GS patients with SLC12A3 gene mutations were enrolled, five of whom did not have a history of hypomagnesemia. The clinical data were documented, and SLC12A3 gene screening was performed. The thiazide test was performed in all of the patients and 20 healthy controls. A receiver operating characteristic curve was used to evaluate the sensitivity and specificity of the thiazide test in the diagnosis of GS., Results: A 7-fold increase in sodium and chloride excretion was observed after thiazide application in healthy controls, and an approximately 2-fold increase was found in the 5 normomagnesemic GS patients; however, there was no change in the 12 hypomagnesemic GS patients. A weaker reaction to thiazide was observed in hypomagnesemic compared with normomagnesemic GS patients. The clearance of chloride in 1 patient was overestimated because of chronic renal function insufficiency (CRI). When a reasonable cutoff value for chloride fractional excretion was selected, the thiazide test was 95% sensitive and 94.1% specific for the diagnosis of GS., Conclusion: Hypomagnesemic GS patients exhibited greater sodium-chloride cotransporter dysfunction than normomagnesemic GS patients. When CRI occurs, the chloride and sodium clearance rates, rather than the fractional excretion, should be used in the evaluation of the thiazide test results.

Renovascular hypertension is characterized by increased renal sympathetic activity, angiotensin II and by endothelial dysfunction. The purpose of this study was to determine the role of renal sympathetic nerve activity (RSNA) in mediating the anti-hypertensive effects of aliskiren (ALSK) and L-arginine (L-ARG) in a rat renovascular hypertension model. Hypertension was induced by clipping the right renal artery, and the following five groups were divided: SHAM operated; 2-kidney, 1-clip (2K1C); 2K1C plus ALSK; 2K1C plus L-ARG; and 2K1C plus ALSK+ L-ARG. The systolic blood pressure (SBP) of 2K1C rats increased from 114.4±5.2 to 204±12.7 mm Hg (P<0.05) and was only reduced by ALSK+L-ARG treatment (138.4±4.37 mm Hg). The 2K1C hypertension increased the baseline RSNA (SHAM: 62.4±6.39 vs. 2K1C: 97.4±8.43%). L-ARG or ALSK+L-ARG treatment significantly decreased baseline RSNA (2K1C L-ARG:70.7±2.39; 2K1C ALSK+L-ARG: 69.3±4.23%), but ALSK treatment alone did not (2K1C ALSK: 84.2±2.5%). Urinary water, Na(+), Cl(-) and urea excretion were similar in the 2K1C L-ARG, 2K1C ALSK+L-ARG and SHAM groups. The combination of ALSK+L-ARG restored urine flow and increased the glomerular filtration rate. The nNOS expression in the non clipped kidney was significantly increased in 2K1C ALSK+L-ARG rats. In conclusion, combined ALSK+L-ARG treatment normalizes SBP and prevents renal dysfunction in 2K1C hypertensive rats.

Thiazide diuretics are used to treat hypertension; however, compensatory processes in the kidney can limit antihypertensive responses to this class of drugs. Here, we evaluated compensatory pathways in SPAK kinase-deficient mice, which are unable to activate the thiazide-sensitive sodium chloride cotransporter NCC (encoded by Slc12a3). Global transcriptional profiling, combined with biochemical, cell biological, and physiological phenotyping, identified the gene expression signature of the response and revealed how it establishes an adaptive physiology. Salt reabsorption pathways were created by the coordinate induction of a multigene transport system, involving solute carriers (encoded by Slc26a4, Slc4a8, and Slc4a9), carbonic anhydrase isoforms, and V-type H⁺-ATPase subunits in pendrin-positive intercalated cells (PP-ICs) and ENaC subunits in principal cells (PCs). A distal nephron remodeling process and induction of jagged 1/NOTCH signaling, which expands the cortical connecting tubule with PCs and replaces acid-secreting α-ICs with PP-ICs, were partly responsible for the compensation. Salt reabsorption was also activated by induction of an α-ketoglutarate (α-KG) paracrine signaling system. Coordinate regulation of a multigene α-KG synthesis and transport pathway resulted in α-KG secretion into pro-urine, as the α-KG-activated GPCR (Oxgr1) increased on the PP-IC apical surface, allowing paracrine delivery of α-KG to stimulate salt transport. Identification of the integrated compensatory NaCl reabsorption mechanisms provides insight into thiazide diuretic efficacy.

Diuretics are commonly used to treat hypertension and extracellular fluid volume expansion. However, the development of compensatory responses in the kidney limits the benefit of this class of drugs. In this issue of the JCI, Grimm and colleagues use a systems biology approach in mice lacking the kinase SPAK and unravel a complex mechanism that explains thiazide diuretic resistance. The overall process involves interactions among six different cell types in the kidney.

Serelaxin, a recombinant form of the human relaxin-2 hormone, is currently under clinical investigation for treatment of acute heart failure. This double-blind, placebo-controlled, dose-ranging study investigated the effect of Japanese ethnicity on the pharmacokinetics (PK), pharmacodynamics (PD), and safety and tolerability of serelaxin. Japanese healthy subjects (n = 32) received 10, 30, or 100 µg/kg/day of serelaxin, or placebo, administered as a 48-hour intravenous infusion. A Caucasian cohort (n = 8) receiving 30 µg/kg/day open-label serelaxin was included for comparison. In all subjects, serum serelaxin concentrations increased rapidly after the start of infusion, approached steady state as early as 4 hours, and declined rapidly upon treatment cessation. Serum exposure to serelaxin increased with increasing doses. Statistical dose proportionality was shown for AUC(inf) over the entire dose range. A significant increase in estimated glomerular filtration rate from baseline to Day 2 (30 and 100 µg/kg/day) and to Day 3 (10 and 100 µg/kg/day) was observed compared with placebo. Serelaxin was well tolerated by all subjects. In conclusion, PK, PD, and safety profiles of serelaxin were generally comparable between Japanese and Caucasian subjects, suggesting that no dose adjustment will be required in Japanese subjects during routine clinical use of this agent., (© 2015, The American College of Clinical Pharmacology.)

We have previously demonstrated that estrogen (E2) downregulates phosphate transporter NaPi-IIa and causes phosphaturia and hypophosphatemia in ovariectomized rats. In the present study, we examined whether E2 directly targets NaPi-IIa in the proximal tubule (PT) and studied the respective roles of estrogen receptor isoforms (ERα and ERβ) in the downregulation of NaPi-IIa using both in vivo and an in vitro expression systems. We found that estrogen specifically downregulates NaPi-IIa but not NaPi-IIc or Pit2 in the kidney cortex. Proximal tubules incubated in a "shake" suspension with E2 for 24 h exhibited a dose-dependent decrease in NaPi-IIa protein abundance. Results from OVX rats treated with specific agonists for either ERα [4,4',4″;-(4-propyl-[1H]-pyrazole-1,3,5-triyl) trisphenol, PPT] or ERβ [4,4',4″-(4-propyl-[1H]-pyrazole-1,3,5-triyl) trisphenol, DPN] or both (PPT + DPN), indicated that only the latter caused a sharp downregulation of NaPi-IIa, along with significant phosphaturia and hypophosphatemia. Lastly, heterologous expression studies demonstrated that estrogen downregulated NaPi-IIa only in U20S cells expressing both ERα and ERβ, but not in cells expressing either receptor alone. In conclusion, these studies demonstrate that rat PT cells express both ERα and ERβ and that E2 induces phosphaturia by directly and specifically targeting NaPi-IIa in the PT cells. This effect is mediated via a mechanism involving coactivation of both ERα and ERβ, which likely form a functional heterodimer complex in the rat kidney proximal tubule., (Copyright © 2015 the American Physiological Society.)

This study examined the effect of electrolyte addition to drinks ingested after severe fluid and energy restriction (FER). Twelve subjects (6 male and 6 female) completed 3 trials consisting of 24-hour FER (energy intake: 21 kJ·kg body mass; water intake: 5 ml·kg body mass), followed by a 2-hour rehydration period and a 4-hour monitoring period. During rehydration, subjects ingested a volume of drink equal to 125% of the body mass lost during FER in 6 aliquots, once every 20 minutes. Drinks were a sugar-free lemon squash (P) or the P drink with the addition of 50 mmol·L sodium chloride (Na) or 30 mmol·L potassium chloride (K). Total void urine samples were given before and after FER and every hour during rehydration and monitoring. Over all trials, FER produced a 2.1% reduction in body mass and negative sodium (-67 mmol), potassium (-48 mmol), and chloride (-84 mmol) balances. Urine output after drinking was 1627 (540) ml (P), 1391 (388) ml (K), and 1150 (438) ml (Na), with a greater postdrinking urine output during P than Na (p ≤ 0.05). Ingestion of drink Na resulted in a more positive sodium balance compared with P or K (p < 0.001), whereas ingestion of drink K resulted in a more positive potassium balance compared with P or Na (p < 0.001). These results demonstrate that after 24-hour FER, ingestion of a high sodium drink results in an increased sodium balance that augments greater drink retention compared with a low electrolyte placebo drink.

Gitelman's syndrome is a rare autosomal recessive tubulopathy caused by a defect of the thiazide-sensitive sodium chloride co-transporter at the distal tubule, leading to hypokalemia, metabolic alkalosis, hypomagnesemia, hypocalciuria and low-to-normal blood pressure. Clinical features include transient periods of muscle weakness and tetany, dizziness, abdominal pains and constipation. Patients can also present with convulsions due to severe metabolic alkalosis or hypomagnesemia. Therefore, early recognition and treatment are important. Diagnosis of Gitelman's syndrome is usually made incidentally during adolescence or early adulthood based on clinical and biochemical findings. In this paper we present the case of a 23-year-old female patient referred to our nephrology department for severe hypokalemia. Complementary evaluation revealed hypokalemia, hypomagnesemia, metabolic alkalosis, increased chloride and sodium urinary excretion and reduced urinary calcium excretion with normal renal function. A diagnosis of Gitelman syndrome was established. Treatment included magnesium and potassium salts and potassium saving diuretics. In general, the long-term prognosis of Gitelman's syndrome is good if the patient adhere with the treatment.

Aim: The evaluation of sodium and potassium intake is part of the optimal management of hypertension, metabolic syndrome, renal stones, and other conditions. To date, no convenient method for its evaluation exists, as the gold standard method of 24-hour urine collection is cumbersome and often incorrectly performed, and methods that use spot or shorter collections are not accurate enough to replace the gold standard. The aim of this study was to evaluate the correlation and agreement between a new method that uses multiple-scheduled spot urine collection and the gold standard method of 24-hour urine collection., Methods: The urine sodium or potassium to creatinine ratios were determined for four scheduled spot urine samples. The mean ratios of the four spot samples and the ratios of each of the single spot samples were corrected for estimated creatinine excretion and compared to the gold standard., Results: A significant linear correlation was demonstrated between the 24-hour urinary solute excretions and estimated excretion evaluated by any of the scheduled spot urine samples. The correlation of the mean of the four spots was better than for any of the single spots. Bland-Altman plots showed that the differences between these measurements were within the limits of agreement., Conclusion: Four scheduled spot urine samples can be used as a convenient method for estimation of 24-hour sodium or potassium excretion., (© 2015 S. Karger AG, Basel.)

Background: The urinary composition, including sodium (Na(+)) and chloride (Cl(-)) concentrations, might provide useful information in addition to urine output during decongestive treatment in heart failure., Methods and Results: Consecutive patients with heart failure (n=61), ejection fraction ≤45%, worsening symptoms, and scheduled treatment with intravenous loop diuretics were included. Patients received protocol-driven therapy until complete decongestion, assessed clinically and by echocardiography. Three consecutive 24-hour urinary collections were performed. With 2 mg (1-4 mg), 1 mg (0-2 mg), and 1 mg (0-1 mg) bumetanide administered in bolus during consecutive 24-hour intervals, in addition to combinational diuretic therapy in ≈70% and both oral spironolactone and vasodilators in ≈90%, euvolemia was reached, often within 24 hours. Urine output was higher during the first when compared with the second or third 24-hour interval (2700 versus 1550 or 1375 mL, respectively; P<0.001), but this was no longer significant after correction for diuretic dose (P=0.263), indicating preserved diuretic efficiency during the study. In contrast, urinary Na(+) and Cl(-) excretion both decreased significantly, even after correction for diuretic dose (P=0.040 and 0.004, respectively), leading to decreasing urinary concentrations with progressive decongestion. After reaching euvolemia, lower urinary Na(+)/Cr and Cl(-)/Cr ratios were both associated with urine output ≤1500 mL (area under the curve, 0.830 and 0.826, respectively; P<0.001 for both), in contrast to plasma N-terminal pro-B-type natriuretic peptide levels that were not (area under the curve, 0.515; P=0.735) CONCLUSIONS: The urinary composition during progressive decongestion in heart failure with reduced ejection fraction is characterized by a drop in urinary Na(+) and Cl(-) concentrations. The urinary Na(+)/Cr or Cl(-)/Cr ratio might provide insightful information to titrate diuretic therapy., (© 2014 American Heart Association, Inc.)

Recent data suggest possible net transport of urinary constituents across mammalian urinary tract epithelia (urothelia). To evaluate the effect of animal hydration status on such transport, we instilled urine collected during 2-day water deprivation, water loading, or ad libitum water intake into isolated in situ bladder(s) of groups of rats undergoing one of the same three hydration states. After 1-h bladder dwell, we retrieved the urine and measured differences in volume and solute concentrations between instilled and retrieved urine. We previously reported results regarding changes in urine volume and net urea and creatinine transport and herein report the results of net urinary sodium, potassium, and chloride transport in the same animals. During water-loading conditions, urinary concentrations of Na, K, and Cl rose 4.9 (30.7%), 2.6 (16.5%), and 6.0 meq/l (26.8%), respectively, indicating urothelial secretion into urine. During ad libitum water intake, urinary K and Cl concentrations fell 33.6 (14.8%) and 28.4 meq/l (12%), respectively (Na did not change), and during water deprivation urine Na, K, and Cl concentrations fell dramatically by 53.2 (18.6%), 159.4 (34.6%) and 133.7 meq/l (33.8%), respectively, reflecting urothelial reabsorption of each ion. For each ionic species, two factors independently influenced transport: instilled urinary ion concentration and animal hydration state. These results demonstrate significant regulated ion transport across mammalian urothelia, support the notion that lower urinary tract modifies final urine, and suggest that the lower urinary tract may play a role in local and whole animal solute homeostasis.

The clinical and laboratory findings in 78 patients with various forms of urolithiasis depending on the presence of primary hyperparathyroidism (PHPT) were analyzed. PHPT was diagnosed in 17 patients. Group "without PHPT" and group "with PHPT" differed significantly in terms of parathyroid hormone (PTH) level, serum calcium, phosphorus, chloride, alkaline phosphatase, calciuria and kaliuria. In patients with staghorn calculi, PHPT was diagnosed in 12.5%, and staghorn calculi in the presence of PHPT were identified in 17.7% of cases. Hypercalciuria in the group "with PHPT" was detected in 82.4% of patients (all 3 patients with staghorn calculi), and in the group "without PHPT"--in 18% of patients (2 of 21 patients with staghorn calculi). Hyperoxaluria was observed in 42.3% of patients "without PHPT" and in 35.3% of patients "with PHPT", in 36.8% of patients with simple stones and in 57.2%--with staghorn calculi. In 39% of patients "without PHPT", secondary hyperparathyroidism (SHPT) was diagnosed. SHPT prevalence was 28% in patients with staghorn calculi, and 45% in patients with simple stones. In 87.5% of patients with hypomagnesemia, staghorn calculi were observed. Significant relationship between magnesium and triglycerides (r(s) = -0.296; P = 0.041), and magnesium and high-density lipoproteins (r(s) = 0.339; P = 0.032) in all patients with urolithiasis were revealed. Thus, the study found no association between staghorn nephrolithiasis and PHPT. Elevated PTH levels usually indicate SHPT rather than PHPT. In hypocalcemia, there was more strong association between PTH and calcium, in normocalcaemia--between PTH and magnesium.

Objective: The control of hypertension is often suboptimal, and it is frequently due to excessive sodium intake. Monitoring sodium intake is cumbersome and involves 24-hour collection of urine. We hypothesize that a spot urine test can accurately predict 24-hour urine sodium excretion in an Asian population., Design: This is a prospective, observational study. We used stored urine specimens (n = 333) from the Asian Kidney Disease Study and Singapore Kidney Function Study Phase I. We measured spot urine tests and correlated these variables to the previously measured 24-hour urine sodium measurements., Results: Age, gender, ethnicity, diastolic blood pressure, height, weight, body mass index, serum creatinine, spot urine sodium, spot urine chloride, and spot urine osmolality were associated with 24-hour urine sodium excretion. The final model for predicting 24-hour urine sodium less than 100 mmol included age, gender, ethnicity, weight, and spot urine sodium., Conclusion: Spot urine sodium can help monitor a patient's sodium intake when used in the derived 5-variable equation., (Copyright © 2013 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)