Bicarbonate Reabsorption and Kidney Physiology

We are a bit slappy at the beginning of the episode since we had just recorded our conversation with the Glaucomfleckens.

References

Chapter 18 Metabolic alkalosis! 

Part 1 February 23, 2023

It is chloride depletion alkalosis, not contraction alkalosis classic review by Galla and Luke, the metabolic alkalosis mavens who review the role of chloride.

On the mechanism by which chloride corrects metabolic alkalosis in man and this is the study when they induced a metabolic alkalosis and studied the effect of treating with KCl vs NaPhos and found the former (with chloride) reversed the alkalosis but not the sodium containing protocol. 

Some elegant reports on the increased proximal reabsorption of bicarbonate above normal stimulated by Ang II. 

Tubular transport responses to angiotensin | American Journal of Physiology-Renal Physiology

Crosstalk between the renal sympathetic nerve and intrarenal angiotensin II modulates proximal tubular sodium reabsorption - Pontes - 2015 - Experimental Physiology - Wiley Online Library

THE RENAL REGULATION OF ACID-BASE BALANCE IN MAN. III. THE REABSORPTION AND EXCRETION OF BICARBONATE 1949  this is the correct figure for 11.14 and shows what happens when filtered bicarb exceeds normal threshold in normal human (men) and appears in the urine. 

Masterful review Symposium on acid-base homeostasis. The generation and maintenance of metabolic alkalosis by Seldin and Rector 

And a modern review from Michael Emmet! Metabolic Alkalosis - PMC (so many favorite reviews on this exciting topic!) and this one from Soleimani Metabolic Alkalosis Pathogenesis, Diagnosis, and Treatment: Core Curriculum 2022 both of these elaborate on pendrin’s role. 

The effect of prolonged administration of large doses of sodium bicarbonate in man  (Clin Sci. 1954 Aug;13(3):383-401)

Kidney v Renal: KDIGO versus Don’t

Plus: We got a little off topic and discussed the Kidney Failure Risk Equation: https://kidneyfailurerisk.com/

Outline: Chapter 18Metabolic Alkalosis

Elevation of arterial pH, increased plasma HCO3, and compensatory hypoventilation

High HCO3 may be compensatory for respiratory acidosis

HCO3 > 40 indicates metabolic alkalosis

Pathophysiology: Two Key Questions

How do patients become alkalotic?

Why do they remain alkalotic?

Generation of Metabolic Alkalosis

Loss of H+ ions

GI loss: vomiting, GI suction, antacids

Renal loss: diuretics, mineralocorticoid excess, hypercalcemia, post-hypercapnia

Administration of bicarbonate

Transcellular shift

K+ loss → H+ shifts intracellularly

Intracellular acidosis

Refeeding syndrome

Contraction alkalosis

Same HCO3, smaller extracellular volume → increased [HCO3]

Seen in CF (sweating), illustrated in Fig 18-1

Common theme: hypochloremia is essential for maintenance

Maintenance of Metabolic Alkalosis

Kidneys normally excrete excess HCO3

Example: Normal subjects excrete 1000 mEq NaHCO3/day with minor pH change

Impaired HCO3 excretion required for maintenance

Table 18-2

Mechanisms of Maintenance

Decreased GFR (less important)

Increased tubular reabsorption

Proximal tubule (PT): reabsorbs 90% of filtered HCO3

TALH and distal nephron manage the rest

Contributing factors:

Effective circulating volume depletion

Enhances HCO3 reabsorption

Ang II increases Na-H exchange

Increased tubular [HCO3] enables more H+ secretion

Distal nephron HCO3 reabsorption

Stimulated by aldosterone (↑ H-ATPase, ↑ Na reabsorption)

Negative luminal charge impedes H+ back-diffusion

Chloride depletion

Reduces NaK2Cl activity → ↑ renin → ↑ aldosterone

Luminal H-ATPase co-secretes Cl → low Cl increases H+ secretion

Cl-HCO3 exchanger needs Cl gradient → low Cl impairs HCO3 secretion

Key conclusion: Cl depletion > volume depletion in perpetuating alkalosis

Albumin corrects volume but not alkalosis

Non-N Cl salts correct alkalosis without fixing volume

Hypokalemia

Stimulates H+ secretion and HCO3 reabsorption

Transcellular shift (H/K exchange) → intracellular acidosis

H-K ATPase reabsorbs K and secretes H

Severe hypokalemia reduces Cl reabsorption → ↑ H+ secretion

Important with mineralocorticoid excess

Respiratory Compensation

Hypoventilation: 0.7 mmHg PCO2 ↑ per 1 mEq/L HCO3 ↑

PCO2 can exceed 60

Rise in PCO2 increases acid excretion (limited effect on pH)

Epidemiology

GI Hydrogen Loss

Gastric juice: high HCl, low KCl

Stomach H+ generation → blood HCO3

Normally recombine in duodenum

Vomiting/antacids prevent recombination → alkalosis

Antacids (e.g., MgOH)

Mg binds fats, leaves HCO3 unbound → alkalosis

Renal failure impairs excretion

Cation exchange resins (SPS, MgCO3) → same effect

Congenital chloridorrhea

High fecal Cl-, low pH → metabolic alkalosis

PPI may help by reducing gastric Cl load

Renal Hydrogen Loss

Mineralocorticoid excess & hypokalemia

Aldosterone → H+ ATPase stimulation, Na+ reabsorption → negative lumen → ↑ H+ secretion

Diuretics (loop/thiazide)

Volume contraction

Secondary hyperaldosteronism

Increased distal flow and H+ loss

Posthypercapnic alkalosis

Chronic respiratory acidosis → ↑ HCO3

Rapid correction (ventilation) → unopposed HCO3 → alkalosis

Gradual CO2 correction needed

Maintenance: hypoxemia, Cl loss

Low chloride intake (infants)

Na+ reabsorption must exchange with H+/K+

H+ co-secretion with Cl impaired if Cl is low

High dose carbenicillin

High Na+ load without Cl

Nonresorbable anion → hypokalemia, alkalosis

Hypercalcemia

↑ Renal H+ secretion & HCO3 reabsorption

Can contribute to milk-alkali syndrome

Rarely causes acidosis via reduced proximal HCO3 reabsorption

Intracellular H+ Shift

Hypokalemia

Common cause and effect of metabolic alkalosis

H+/K+ exchange → intracellular acidosis → ↑ H+ excretion

Refeeding Syndrome

Rapid carb reintroduction → cellular shift

No volume contraction or acid excretion increase

Retention of Bicarbonate

Requires impaired excretion to become significant

Organic anions (lactate, acetate, citrate, ketoacids)

Metabolism → CO2 + H2O + HCO3

Citrate in blood transfusion (16.8 mEq/500 mL)

8 units → alkalosis risk

CRRT + citrate anticoagulant

Sodium bicarbonate therapy

Rebound alkalosis possible with acid reversal (e.g., ketoacidosis)

Extreme cases: pH up to 7.9, HCO3 up to 70

Contraction Alkalosis

NaCl and water loss without HCO3

Seen in vomiting, diuretics, CF sweat

Mild losses neutralized by intracellular buffers

Symptoms

Often asymptomatic

From volume depletion: dizziness, weakness, cramps

From hypokalemia: polyuria, polydipsia, weakness

From alkalosis (rare): paresthesias, carpopedal spasm, lightheadedness

More common in respiratory alkalosis due to rapid pH shift across BBB

Physical exam not usually helpful

Clues: signs of vomiting

Diagnosis

History is key

If unclear, suspect:

Surreptitious vomiting

CF

Secret diuretic use

Mineralocorticoid excess

Use urine chloride

Table 18-3: urine Na is misleading in alkalosis

Table 18-4: urine chemistry changes with complete HCO3 reabsorption

Vomiting: low urine Na, K, Cl + acidic urine

Sufficient NaCl intake prevents this stage

Exceptions to low urine Cl:

Severe hypokalemia

Tubular defects

CKD

Distinguishing from respiratory acidosis

Use pH as guide

Caution with typo (duplicate pCO2)

A-a gradient might help

Treatment

Correct K+ and Cl− deficiency → kidneys self-correct

Upper GI losses: add H2 blockers

Saline-responsive alkalosis

Treat with NaCl

Mechanisms:

Reverse contraction component

Reduce Na+ retention → promote NaHCO3 excretion

↑ distal Cl delivery → enable HCO3 secretion via pendrin

Monitor urine pH: from 5.5 → 7–8 with therapy

Give K+ with Cl, not phosphate, acetate, or bicarbonate

Saline-resistant alkalosis

Seen in edematous states or K+ depletion

Edema (CHF, cirrhosis): use acetazolamide, HCl, dialysis

Acetazolamide: may ↑ CO2 via RBC carbonic anhydrase inhibition

Mineralocorticoid excess: K+ + K-sparing diuretic (use caution)

Severe hypokalemia:

eNaC Na+ reabsorption must be countered by H+ if no K+

Corrects rapidly with K+ replacement

Restores saline responsiveness

Renal failure: requires dialysis