Clinical Significance of Spot Urinary Chloride Concentration Measurements in Patients with Acute Heart Failure: Investigation on the Basis of the ‘TubuloGlomerular Feedback’ Mechanism

Urinary chloride (Cl) is the key electrolyte for regulating renin secretion at the macula densa under the ‘tubulo-glomerular feedback’. Whether or not Cl filtrated into the urinary tubules actually associates with plasma renin activity (PRA) in clinical heart failure (HF) remains unclear. Data from 29 patients with acute worsening HF (48% men; 80.3±12 years) were analyzed. Blood and urine samples were immediately obtained before decongestive therapy after the patients rested in a supine position for 20-min. Clinical tests included peripheral blood tests, serum and spot urinary electrolytes, b-type natriuretic peptide (BNP), plasma neurohormones, and fractional urinary electrolyte excretion. In the 29 patients, urinary Cl concentrations inversely correlated with logarithmically transformed PRA (R2 =0.41, p=0.0002). The correlation was weaker in worsening chronic HF patients (R2 =0.32, p=0.01) compared with de novo HF patients (R2 =0.70, p=0.0026). Patients were divided into 2 groups according to the median urinary Cl concentration, a low group and a high group. Compared with the high group (100~184 mEq/L; n=14), the low group (4~95 mEq/L; n=15) exhibited more renal (serum creatinine; 1.45±0.63 vs 1.00±0.38 mg/d, p=0.029) and cardiac (log BNP; 2.99±0.3 vs 2.66±0.32 pg/mL, p=0.008 p=0.008) impairment, and higher PRA (3.42±4.7 vs 0.73±0.46 ng/mL/h, p=0.049), and lower fractional excretion of urinary Cl (1.34±1.3 vs 5.33±4.1%, p<0.0001). The present study provides clinical data on the possible functioning of urinary Cl involved in the mechanism of ‘tubulo-glomerular feedback’, and thus advances our understanding of the clinical meanings of the significance of urinary Cl concentration measurement.

Reducing salt intake by urine chloride self-measurement in non-compliant patients with chronic kidney disease followed in nephrology clinics: a randomized trial

Background Adherence to low salt diets and control of hypertension remain unmet clinical needs in chronic kidney disease (CKD) patients. Methods We performed a 6-month multicentre randomized trial in non-compliant patients with CKD followed in nephrology clinics testing the effect of self-measurement of urinary chloride (69 patients) as compared with standard care (69 patients) on two primary outcome measures, adherence to a low sodium (Na) diet (&lt;100 mmol/day) as measured by 24-h urine Na (UNa) excretion and 24-h ambulatory blood pressure (ABPM) monitoring. Results In the whole sample (N = 138), baseline UNa and 24-h ABPM were143 ± 64 mmol/24 h and 131 ± 18/72 ± 10 mmHg, respectively, and did not differ between the two study arms. Patients in the active arm of the trial used &gt;80% of the chloride strips provided to them at the baseline visit and at follow-up visits. At the third month, UNa was 35 mmol/24 h (95% CI 10.8–58.8 mmol/24 h; P = 0.005) lower in the active arm than the control arm, whereas at 6 months the between-arms difference in UNa decreased and was no longer significant [23 mmol/24 h (95% CI −5.6–50.7); P = 0.11]. The 24-h ABPM changes as well as daytime and night-time BP changes at 3 and 6 months were similar in the two study arms (Month 3, P = 0.69–0.99; Month 6, P = 0.73–0.91). Office BP, the use of antihypertensive drugs, estimated Glomerular Filtration Rate (eGFR) and proteinuria remained unchanged across the trial. Conclusions The application of self-measurement of urinary chloride to guide adherence to a low salt diet had a modest effect on 24-h UNa and no significant effect on 24-h ABPM.

Dietary Chloride Deficiency Syndrome: Pathophysiology, History, and Systematic Literature Review

Metabolic alkalosis may develop as a consequence of urinary chloride (and sodium) wasting, excessive loss of salt in the sweat, or intestinal chloride wasting, among other causes. There is also a likely underrecognized association between poor salt intake and the mentioned electrolyte and acid–base abnormality. In patients with excessive loss of salt in the sweat or poor salt intake, the maintenance of metabolic alkalosis is crucially modulated by the chloride–bicarbonate exchanger pendrin located on the renal tubular membrane of type B intercalated cells. In the late 1970s, recommendations were made to decrease the salt content of foods as part of an effort to minimize the tendency towards systemic hypertension. Hence, the baby food industry decided to remove added salt from formula milk. Some weeks later, approximately 200 infants (fed exclusively with formula milks with a chloride content of only 2–4 mmol/L), were admitted with failure to thrive, constipation, food refusal, muscular weakness, and delayed psychomotor development. The laboratory work-up disclosed metabolic alkalosis, hypokalemia, hypochloremia, and a reduced urinary chloride excretion. In all cases, both the clinical and the laboratory features remitted in ≤7 days when the infants were fed on formula milk with a normal chloride content. Since 1982, 13 further publications reported additional cases of dietary chloride depletion. It is therefore concluded that the dietary intake of chloride, which was previously considered a “mendicant” ion, plays a crucial role in acid–base and salt balance.

Differential diagnosis of perinatal Bartter, Bartter and Gitelman syndromes

The common finding of hypokalemic alkalosis in several unrelated disorders may confound the early diagnosis of salt-losing tubulopathy (SLT). Antenatal Bartter syndrome (BS) must be considered in idiopathic early-onset polyhydramnios. Fetal megabladder in BS may allow its distinction from third-trimester polyhydramnios that occurs in congenital chloride diarrhea (CCD). Fetal megacolon occurs in CCD while fecal chloride &gt;90 mEq/L in infants is diagnostic. Failure-to-thrive, polydipsia and polyuria in early childhood are the hallmarks of classic BS. Unlike BS, there is low urinary chloride in hypokalemic alkalosis of intractable emesis and cystic fibrosis. Rarely, renal salt wasting may result from cystinosis, Dent disease, disorders of paracellular claudin-10b and Kir4.1 potassium-channel deficiency. Acquired BS may result from calcimimetic up-regulation of a calcium-sensing receptor or autoantibody inactivation of sodium chloride co-transporters in Sjögren syndrome. A relatively common event of heterozygous gene mutations for Gitelman syndrome increases the likelihood of its random occurrence in certain diseases of adult onset. Finally, diuretic abuse is the most common differential diagnosis of SLT. Unlike the persistent elevation in BS, urinary chloride concentration losses waxes and wanes on day-to-day assessment in patients with diuretic misuse.

Urinary chloride concentration and progression of chronic kidney disease: results from the KoreaN cohort study for Outcomes in patients With Chronic Kidney Disease

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.