Association of Urinary Sodium and Potassium Excretion with Blood Pressure

Mente, Andrew; Rangarajan, Sumathy; McQueen, Matthew; Poirier, Paul; Wielgosz, Andreas; Morrison, Howard; Li, Wei; Wang, Xingyu; Chen, Di; Mony, Prem; Devanath, Anitha; Rosengren, Annika; Oğuz, Aytekin; Zatońska, Katarzyna; Yusufali, Afzalhussein; López‐Jaramillo, Patricio; Avezum, Álvaro; Ismail, Noorhassim; Lanas, Fernando; Puoane, Thandi; Dı́az, Rafael; Kelishadi, Roya; Iqbal, Romaina; Yusuf, Rita; Chifamba, Jephat; Khatib, Rasha; Teo, Koon; Yusuf, Salim

doi:10.1056/nejmoa1311989

Cited by 712 publications

(669 citation statements)

References 25 publications

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“…High urinary potassium excretion is reported to be associated with low BP (22,23). In this study, the higher quartile subgroups showed lower Table 3.…”

Section: Discussionsupporting

confidence: 47%

Urinary Potassium Excretion and Renal and Cardiovascular Complications in Patients with Type 2 Diabetes and Normal Renal Function

Araki¹,

Haneda

Koya

et al. 2015

Clinical Journal of the American Society of Nephrology

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Background and objectives We investigated the association of urinary potassium and sodium excretion with the incidence of renal failure and cardiovascular disease in patients with type 2 diabetes.Design, setting, participants, & measurements A total of 623 Japanese type 2 diabetic patients with eGFR$60 ml/min per 1.73 m 2 were enrolled in this observational follow-up study between 1996 and 2003 and followed-up until 2013. At baseline, a 24-hour urine sample was collected to estimate urinary potassium and sodium excretion. The primary end point was renal and cardiovascular events (RRT, myocardial infarction, angina pectoris, stroke, and peripheral vascular disease). The secondary renal end points were the incidence of a 50% decline in eGFR, progression to CKD stage 4 (eGFR,30 ml/min per 1.73 m 2 ), and the annual decline rate in eGFR.Results During the 11-year median follow-up period, 134 primary end points occurred. Higher urinary potassium excretion was associated with lower risk of the primary end point, whereas urinary sodium excretion was not. The adjusted hazard ratios for the primary end point in Cox proportional hazards analysis were 0.56 (95% confidence interval [95% CI], 0.33 to 0.95) in the third quartile of urinary potassium excretion (2.33-2.90 g/d) and 0.33 (95% CI, 0.18 to 0.62) in the fourth quartile (.2.90 g/d) compared with the lowest quartile (,1.72 g/d). Similar associations were observed for the secondary renal end points. The annual decline rate in eGFR in the fourth quartile of urinary potassium excretion (-1.3 ml/min per 1.73 m 2 /y; 95% CI, -1.5 to -1.0) was significantly slower than those in the first quartile (-2.2; 95% CI, -2.4 to -1.8).Conclusions Higher urinary potassium excretion was associated with the slower decline of renal function and the lower incidence of cardiovascular complications in type 2 diabetic patients with normal renal function. Interventional trials are necessary to determine whether increasing dietary potassium is beneficial.

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“…High urinary potassium excretion is reported to be associated with low BP (22,23). In this study, the higher quartile subgroups showed lower Table 3.…”

Section: Discussionsupporting

confidence: 47%

Urinary Potassium Excretion and Renal and Cardiovascular Complications in Patients with Type 2 Diabetes and Normal Renal Function

Araki¹,

Haneda

Koya

et al. 2015

Clinical Journal of the American Society of Nephrology

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“…It is well recognized that higher levels of sodium intake are associated with elevated blood pressure (1)(2)(3). Importantly, the effect of dietary sodium on blood pressure is dependent on other components of the diet and, specifically, its potassium content (2,4).…”

Section: Introductionmentioning

confidence: 99%

Essential role of Kir5.1 channels in renal salt handling and blood pressure control

Palygin¹,

Levchenko²,

Ilatovskaya³

et al. 2017

JCI Insight

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“…The study of Mendelian forms of hypertension has demonstrated the key role of increased renal salt reabsorption in disease pathogenesis (1)(2)(3)(4). Observational and intervention trials (5,6) also indicate that increased dietary K + lowers blood pressure; however, the mechanism of this effect has been unclear.…”

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confidence: 99%

Angiotensin II signaling via protein kinase C phosphorylates Kelch-like 3, preventing WNK4 degradation

Shibata

Arroyo

Castañeda‐Bueno

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

102

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Hypertension contributes to the global burden of cardiovascular disease. Increased dietary K + reduces blood pressure; however, the mechanism has been obscure. Human genetic studies have suggested that the mechanism is an obligatory inverse relationship between renal salt reabsorption and K + secretion. Mutations in the kinases with-no-lysine 4 (WNK4) or WNK1, or in either Cullin 3 (CUL3) or Kelch-like 3 (KLHL3)-components of an E3 ubiquitin ligase complex that targets WNKs for degradation-cause constitutively increased renal salt reabsorption and impaired K + secretion, resulting in hypertension and hyperkalemia. The normal mechanisms that regulate the activity of this ubiquitin ligase and levels of WNKs have been unknown. We posited that missense mutations in KLHL3 that impair binding of WNK4 might represent a phenocopy of the normal physiologic response to volume depletion in which salt reabsorption is maximized. We show that KLHL3 is phosphorylated at serine 433 in the Kelch domain (a site frequently mutated in hypertension with hyperkalemia) by protein kinase C in cultured cells and that this phosphorylation prevents WNK4 binding and degradation. This phosphorylation can be induced by angiotensin II (AII) signaling. Consistent with these in vitro observations, AII administration to mice, even in the absence of volume depletion, induces renal KLHL3 S433 phosphorylation and increased levels of both WNK4 and the NaCl cotransporter. Thus, AII, which is selectively induced in volume depletion, provides the signal that prevents CUL3/KLHL3-mediated degradation of WNK4, directing the kidney to maximize renal salt reabsorption while inhibiting K + secretion in the setting of volume depletion.renin-angiotensin-aldosterone system | distal tubule | hypertension | posttranslational modification | PHAII H ypertension affects 1 billion people worldwide and is a major risk factor for death from stroke, myocardial infarction, and congestive heart failure. The study of Mendelian forms of hypertension has demonstrated the key role of increased renal salt reabsorption in disease pathogenesis (1-4). Observational and intervention trials (5, 6) also indicate that increased dietary K + lowers blood pressure; however, the mechanism of this effect has been unclear.Pseudohypoaldosteronism type II (PHAII; Online Mendelian Inheritance in Man no. 145260), featuring hypertension and hyperkalemia, has revealed a previously unrecognized mechanism that regulates the balance between renal salt reabsorption and K + secretion in response to aldosterone (7). Aldosterone is produced by the adrenal glomerulosa in volume depletion, in response to angiotensin II (AII), and in hyperkalemia via membrane depolarization (8). In volume depletion, aldosterone maximizes renal salt reabsorption, whereas in hyperkalemia, aldosterone promotes maximal renal K + secretion. Volume depletion increases both the NaCl cotransporter (NCC) (9) and electrogenic Na + reabsorption via the epithelial Na + channel (ENaC) (10). The lumen-negative potential produced by ENa...

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Association of Urinary Sodium and Potassium Excretion with Blood Pressure

Cited by 712 publications

References 25 publications

Urinary Potassium Excretion and Renal and Cardiovascular Complications in Patients with Type 2 Diabetes and Normal Renal Function

Urinary Potassium Excretion and Renal and Cardiovascular Complications in Patients with Type 2 Diabetes and Normal Renal Function

Essential role of Kir5.1 channels in renal salt handling and blood pressure control

Angiotensin II signaling via protein kinase C phosphorylates Kelch-like 3, preventing WNK4 degradation

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