Volume-independent reductions in glomerular filtration rate in acute chloride-depletion alkalosis in the rat. Evidence for mediation by tubuloglomerular feedback.

Abstract

Abstract. We have recently described reduced superficial nephron glomerular filtration rate (SNGFR) in chloride-depletion alkalosis (CDA) without volume depletion. To elucidate the mechanism of this phenomenon, we studied three degrees of increasing severity of CDA (groups CDA-1, 2, and 3) produced by one or two peritoneal dialyzes against 0.15 M NaHCO3 and electrolyte infusions of different Cl and HCO3 content in Sprague-Dawley rats; control rats (CON) were dialyzed against and infused with Ringers-HCO3. Extracellular fluid (ECF) volume was assessed by blood pressure, hematocrit, plasma protein concentration, and '251-albumin space; none of these variables differed among the four groups. Micropuncture of the latest proximal and earliest distal convolutions was carried out. As CDA intensified from CON to CDA-3 (plasma tCO2 25±1 to 43±1 meq/L; P < 0.01), distally determined SNGFR declined progressively (40.9±1.7 to 28.3±1.8 nl/min; P < 0.01), while in early distal tubule fluid, flow rate (8.6±0.7 to 3.4±0.6 nl/min) and Cl concentration (36±2 to 19±3 meq/L) decreased and osmolality (110±5 to 208±12 mosmol/kg) increased (P < 0.01), and, in the loop segment, Cl reabsorption decreased progressively (2,009±112 to 765±128 peq/min; P < 0.01). In early distal tubule fluid, Cl concentration correlated positively This study has been published in abstract form in Clin.

Perturbations in serum chloride homeostasis in heart failure with preserved ejection fraction: insights from TOPCAT

“…The mechanisms by which lower chloride leads to an increased risk of adverse events, however, remains unclear. Lower serum chloride levels may represent several downstream effects of maladaptive mechanisms in heart failure: increased arginine vasopressin release, the pleotropic effects of excess angiotensin II on renal sodium and water handling, and altered acid–base homeostasis …”

Implications of Serum Chloride Homeostasis in Acute Heart Failure (from ROSE-AHF)

“…In contrast to Na depletion, however, Cl depletion may be a more specific electrolyte marker for impaired diuretic response because this association was independent of both Na, bicarbonate, and cystatin C. Murine models have suggested that systemic Cl depletion is essential for mediating a contraction alkalosis and can effect tubuloglomerular feedback, independent of volume expansion. 19,20 As a result, Cl depletion may lead to diuretic resistance by fueling adaptive renal mechanisms to maintain volume status.…”

“…As Cl depletion evolves, lower levels of Cl signal a reduction in glomerular filtration rate, which is the normal homeostatic response to lower delivery of bicarbonate to the distal nephron, thus attenuating further Na and fluid losses. 20 Therefore, changing renal function during decongestive therapies may be mediated, at least in part, by Cl imbalance underscoring the complex interplay between hemodynamic and non-hemodynamic determinants of renal function during AHF. 21 …”

It Is Chloride Depletion Alkalosis, Not Contraction Alkalosis

“…First, GFR was inversely correlated with the degree of CDA by tubuloglomerular feedback. 12 Although intact function of the proximal tubule and the loop of Henle are essential to the renal response, these segments have no identifiable adaptive role in the corrective response to chloride repletion in that glomerulotubular balance is maintained whether CDA is being corrected. 8,9 Delivery of chloride and bicarbonate out of the loop of Henle was not different whether rats were maintaining or correcting CDA.…”