Physiology and pathophysiology of the renal Na-K-2Cl cotransporter (NKCC2)

Castrop, Hayo; Schießl, Ina Maria

doi:10.1152/ajprenal.00432.2014

Cited by 91 publications

(61 citation statements)

References 165 publications

(251 reference statements)

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“…However, this cotransporter also functions to deliver chloride to the cells of the macula densa, allowing the kidney to sense tubular delivery of sodium chloride. 38 When this channel is blocked, the kidney perceives reduced salt delivery, and increases renin secretion and sympathetic nervous system activity accordingly. 38 These effects have been demonstrated to have clinically measurable effects on hemodynamics in humans with decompensated heart failure, resulting in a decrease in stroke volume, increase in wedge pressure, and increase in systemic vascular resistance, all of which occur prior to meaningful natriuresis.…”

Section: Discussionmentioning

confidence: 99%

An exploratory analysis of the competing effects of aggressive decongestion and high-dose loop diuretic therapy in the DOSE trial

Hanberg

Tang

Wilson

et al. 2017

International Journal of Cardiology

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Structured Abstract Background Effective decongestion of heart failure patients predicts improved outcomes, but high dose loop diuretics (HDLD) used to achieve diuresis predict adverse outcomes. In the DOSE trial, randomization to a HDLD intensification strategy (HDLD-strategy) improved diuresis but not outcomes. Our objective was to determine if potential beneficial effects of more aggressive decongestion may have been offset by adverse effects of the HDLD used to achieve diuresis. Methods and Results A post hoc analysis of the DOSE trial (n=308) was conducted to determine the influence of post-randomization diuretic dose and fluid output on the rate of death, rehospitalization or emergency department visitation associated with the HDLD-strategy. Net fluid output was used as a surrogate for beneficial decongestive effects and cumulative loop diuretic dose for the dose-related adverse effects of the HDLD-strategy. Randomization to the HDLD-strategy resulted in increased fluid output, even after adjusting for cumulative diuretic dose (p=0.006). Unadjusted, the HDLD-strategy did not improve outcomes (p=0.28). However, following adjustment for cumulative diuretic dose, significant benefit emerged (HR=0.64, 95% CI 0.43–0.95, p=0.028). Adjusting for net fluid balance eliminated the benefit (HR=0.95, 95% CI 0.67–1.4, p=0.79). Conclusions A clinically meaningful benefit from a randomized aggressive decongestion strategy became apparent after accounting for the quantity of loop diuretic administered. Adjusting for the diuresis resulting from this strategy eliminated the benefit. These hypothesis-generating observations may suggest a role for aggressive decongestion in improved outcomes.

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Section: Discussionmentioning

confidence: 99%

An exploratory analysis of the competing effects of aggressive decongestion and high-dose loop diuretic therapy in the DOSE trial

Hanberg

Tang

Wilson

et al. 2017

International Journal of Cardiology

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“…ROMK, ClC-Kb, and barttin cross the boundary of TAL and are expressed in the distal convoluted tubule (DCT). They have been described in detail in the context of salt-losing nephropathy ( Table 1 ) [24][25][26][27][28][29] .…”

Section: Calcium-sensing Receptormentioning

confidence: 99%

Genetics of Magnesium Disorders

Sun

Chen

et al. 2017

Kidney Dis

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Background: Magnesium (Mg²⁺), the second most abundant cation in the cell, is woven into a multitude of cellular functions. Dysmagnesemia is associated with multiple diseases and, when severe, can be life-threatening. Summary: This review discusses Mg²⁺ homeostasis and function with specific focus on renal Mg²⁺ handling. Intrarenal channels and transporters related to Mg²⁺ absorption are discussed. Unraveling the rare genetic diseases with manifestations of dysmagnesemia has greatly increased our understanding of the complex and intricate regulatory network in the kidney, specifically, functions of tight junction proteins including claudin-14, -16, -19, and -10; apical ion channels including: TRPM6, K_v1.1, and ROMK; small regulatory proteins including AC3 and ANK3; and basolateral proteins including EGF receptor, γ-subunit (FXYD2) of Na-K-ATPase, K_ir4.1, CaSR, CNNM2, and SLC41A. Although our understanding of Mg²⁺ handling of the kidney has expanded considerably in the last two decades, many questions remain. Future studies are needed to elucidate a multitude of unknown aspects of Mg²⁺ handling in the kidney. Key Message: Understanding rare and genetic diseases of Mg²⁺ dysregulation has expanded our knowledge and furthers the development of strategies for preventing and managing dysmagnesemia.

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“…Gs-alpha may participate in the vasopressin-induced cyclic AMP-signaling cascade and thereby stimulate the activity of NKCC2 and NCC by promoting their insertion into the plasma membrane. 7,8 The transient nature of the salt-wasting phenotype is intriguing but unexplained. Laghmani et al speculate that higher sensitivity of adenylate cyclase activity to vasopressin during development or increasing levels of oxygenation in the kidney during gestation might underlie this transience.…”

Section: Mage-d2 and The Regulation Of Renal Salt Transportersmentioning

confidence: 99%