L5 Renal Physiology 5

Renal Physiology 5 — Acid–Base Balance

Overview

This lecture explains how body pH is kept within a very narrow range despite a large daily acid load. It covers the two arms of pH defence — buffering (hiding H⁺) and excretion (getting rid of it) — and how these are split between the lungs (handling volatile CO₂) and the kidneys (handling non-volatile acid and bicarbonate). It builds from the chemistry of the CO₂/HCO₃⁻ system, through renal bicarbonate reabsorption and the generation of “new” bicarbonate via titratable acid and ammonia, to the Henderson–Hasselbalch framework. It finishes by classifying the four acid–base disturbances (respiratory/metabolic × acidosis/alkalosis) and illustrating renal causes with clinical vignettes (Annabel, Beryl, Camilla → renal tubular acidosis).

---

Why pH Must Be Controlled

• Know the normal pH values: ECF pH 7.4 (range 7.36–7.45); intracellular pH nearer 7.
  • Acidosis is defined as pH < 7.35; alkalosis as pH > 7.45.
  • Plasma pH below 7 or above 7.8 is usually fatal.
• Understand: pH is held within an extremely tight band, equivalent to [H⁺] of roughly 36–44 nmol/L. The whole regulatory system exists to defend this narrow window.
• Know why pH matters (consequences of disturbance): it influences enzyme activity (each enzyme has an optimum pH), regulates ion transport mechanisms, affects hormone function, and affects cellular metabolism, DNA synthesis and growth, plus CNS function.
• Know the clinical features of each direction:
  • Alkalosis → headache, drowsiness, tetany, convulsions.
  • Acidosis → impaired respiratory control, drowsiness progressing to coma.

The Scale of the Problem

• Understand: regulation is challenging because the amount of free H⁺ is tiny (~0.004 mmol at pH 7) yet must be kept stable to within ±0.0004 mmol, while the body generates ~13,000 mmol of “acid” per day.
• Know the two sources of acid load:
  • CO₂ from metabolism (volatile acid).
  • Non-volatile acids from metabolism (e.g. phosphoric, sulfuric, lactic acid, ketone bodies).
• Know the two regulatory strategies: pH is controlled by (1) buffering and (2) excretion.
• Understand (Pitts 1953 dog experiment): injecting 150 mL of 1 mol/L HCl dropped blood pH only from 7.44 → 7.14, whereas the same acid in an equal volume of water would drop pH from 7.44 → 1.84. This demonstrates that body buffering neutralises >99.99% of an acid load.

---

The Central Equation

The reaction that ties everything together

$C{O}_2+H_{2}O\leftrightarrow H_{2}C{O}_3\leftrightarrow H^{+}+HC{O}_3^{-}$

• Understand: this single equilibrium links respiratory and renal control. Shifting it right generates H⁺ (acidosis); shifting it left removes H⁺ (alkalosis). Respiration controls the CO₂ end; the kidney controls the HCO₃⁻ end.

---

Handling CO₂ (the volatile acid)

• Understand: ~13,000 mmol CO₂ is produced per day (~10 mmol/min). Because it can be exhaled by the lungs, CO₂ is “not normally a problem” — but two issues remain.
• Know the two CO₂ problems:
  1. CO₂ is produced in tissues, not in the lungs → the resulting H⁺ must be buffered in transit in the blood.
  2. Ventilation must continue at a rate matching metabolic production.

Buffering H⁺ in transit

• Understand: most of the H⁺ generated from CO₂ in the blood is buffered by haemoglobin.
  • In tissues: CO₂ + H₂O → H₂CO₃ → H⁺ + HCO₃⁻; the H⁺ is taken up as H⁺ + O₂Hb⁻ → HHb + O₂. Because HHb buffers the H⁺, there is very little pH change despite large CO₂ production.
  • In lungs: the reaction reverses — HHb + O₂ → H⁺ + O₂Hb; H⁺ + HCO₃⁻ → H₂CO₃ → CO₂ + H₂O, and the CO₂ is exhaled.

Ventilation and respiratory disturbances

• Understand: alveolar ventilation must continuously exhale CO₂ at the rate it is produced.
• Know the two respiratory disturbances (apply the central equation):
  • Hypoventilation → CO₂ accumulates → equation shifts right → excess H⁺ → respiratory acidosis.
  • Hyperventilation → excess CO₂ removed → equation shifts left → decreased H⁺ → respiratory alkalosis.

Annabel — clinical vignette

Anxious presentation after a “panic attack”, with numbness/tingling in hands and feet, then cramps and spasms. Bloods: Na 137, Cl 112, K 4.2, PCO₂ 29 mmHg, pH 7.52, HCO₃⁻ 23.

• Interpretation: high pH + low PCO₂ = respiratory alkalosis from hyperventilation. The low ionised calcium effect of alkalosis explains the tetany/paraesthesia.

---

Handling Non-Volatile Acids

• Know the magnitude and sources: metabolism produces ~50–80 mmol/day (the net endogenous acid production, NEAP).
  • H₂SO₄ from sulfur-containing amino acids.
  • H₃PO₄ from phosphoproteins and phospholipids.
  • Organic acids (e.g. lactate, pyruvate) from anaerobic exercise.
  • Ketoacids from fat metabolism.
• Understand: H⁺ from these acids must be both buffered and excreted — buffering alone is not enough.

Whole-body buffering

• Know the three main buffers: bicarbonate, protein, phosphate (plus dilution and exchange with bone minerals).
• Understand: this “whole-body buffering” prevents pH from falling to dangerous levels — but it only hides the H⁺; it does not remove it.

Why buffering alone isn’t enough

• Understand the key logical step: buffered H⁺ reacts with HCO₃⁻ → H₂CO₃ → CO₂ + H₂O. The CO₂ is exhaled and the H⁺ is now locked in a water molecule, so it is no longer an acid threat — but a molecule of HCO₃⁻ has been consumed in the process. That bicarbonate must be replaced, and that is the kidney’s job.

---

Renal Handling of Bicarbonate

• Know the kidney’s two bicarbonate tasks:
  1. “Reabsorption” — replacing filtered HCO₃⁻ (PT cells synthesise “new” HCO₃⁻ to replace the filtered ions).
  2. Replacement of HCO₃⁻ consumed in buffering non-volatile acids (or excretion of excess bicarbonate when needed).

1. Bicarbonate “reabsorption”

• Know the segmental distribution:
  • PT ~80% — via NHE-3 (Na⁺/H⁺ exchanger).
  • TAL ~10%.
  • DT/CD ~10% — intercalated cells using H⁺/K⁺ ATPase and H⁺ ATPase; some intercalated cells instead secrete HCO₃⁻ (via Cl⁻ exchange).
• Understand the mechanism (why it is called “reabsorption” in quotes): filtered HCO₃⁻ combines with secreted H⁺ in the lumen → H₂CO₃ → (carbonic anhydrase) → CO₂ + H₂O. These diffuse into the cell, where CA reverses the reaction to regenerate H⁺ (re-secreted) and HCO₃⁻ (passed to blood). The bicarbonate entering blood is technically newly made, not the same molecule that was filtered — hence the quotation marks.

2. Replacement of HCO₃⁻ consumed in buffering (Renal Net Acid Excretion, RNAE)

• Understand the core coupling: when a tubule cell makes H⁺ for secretion, it simultaneously generates a HCO₃⁻ (from CO₂ + H₂O → H₂CO₃ → H⁺ + HCO₃⁻). The secreted H⁺ is buffered in the urine and excreted, while the “new” HCO₃⁻ is returned to plasma to replace what was consumed buffering non-volatile acid.
• Understand: secreted H⁺ cannot simply be left free in urine (urine pH cannot fall low enough to dump meaningful amounts of free H⁺), so it must be carried out bound to a urinary buffer. There are two such mechanisms.

Mechanism 1 — Titratable acid

• Know: the urinary buffer is phosphate (HPO₄²⁻), acting mainly in the distal tubule.
• Understand: filtered HPO₄²⁻ + secreted H⁺ → H₂PO₄⁻, which is excreted. For each H⁺ buffered and excreted this way, a “new” HCO₃⁻ is returned to blood.

Mechanism 2 — Ammonia

• Know the pathway: Glutamine → NH₃ → NH₄⁺.
  • Glutamine is metabolised in the PT (NHE-3 involved), generating NH₃/NH₄⁺ and HCO₃⁻.
  • NH₄⁺/NH₃ traffics through the loop of Henle and medulla, and is finally trapped in the collecting duct (glycoproteins).
• Understand: NH₃ combines with secreted H⁺ to form NH₄⁺, which is trapped in the lumen (“diffusion trapping”) and excreted, again returning a “new” HCO₃⁻ to plasma. Note the slide shows ~2 HCO₃⁻ generated per glutamine.

The whole non-volatile acid cycle in one line

New acid HA → A⁻ + H⁺ (buffered) → H⁺ + HCO₃⁻ → CO₂ + H₂O. The kidney excretes the H⁺ (as titratable acid or NH₄⁺), generates new HCO₃⁻ to replace what was consumed, and the conjugate base A⁻ is filtered out. This closes the loop and keeps pH stable.

---

Henderson–Hasselbalch and the Four Disturbances

Henderson–Hasselbalch equation

$pH=6.1+\log \frac{[HC{O}_3^{-}]}{0.03\times pC{O}_2}$

• Understand: pH depends on the ratio of [HCO₃⁻] (renal, the numerator) to pCO₂ (respiratory, the denominator). This frames every acid–base disturbance as a change in one of those two terms.
• Know what is required for normal balance:
  • Appropriate respiratory function to maintain CO₂.
  • Appropriate renal function — kidney able to function, appropriate HCO₃⁻ handling, and appropriate acid secretion.

Respiratory disturbances (primary pCO₂ change)

• Respiratory acidosis — too much CO₂: hypoventilation (e.g. chronic bronchitis) or high inspired CO₂.
• Respiratory alkalosis — too little CO₂: hyperventilation (e.g. anxiety, altitude, hypoxia).

Metabolic disturbances (primary HCO₃⁻ change)

• Metabolic alkalosis — too much HCO₃⁻ / acid deficit: excess bicarbonate (ingestion or renal overproduction), or loss of acid secretions (e.g. gastric contents).
• Metabolic acidosis — too little HCO₃⁻ / acid excess: loss of bicarbonate (gut), inadequate renal bicarbonate production, or addition/excessive production of (organic) acids.

---

Renal Causes of Acidosis — Clinical Application

Beryl — defective HCO₃⁻ handling (proximal)

Vertebral collapse, recurrent UTIs; urine is alkaline and contains abnormal glucose, phosphate and amino acids. ABG: PaCO₂ 33, pH 7.25, HCO₃⁻ 14.

• Interpretation: glucose + phosphate + amino acids in urine points to a proximal tubule defect. The PT fails to reabsorb HCO₃⁻ → HCO₃⁻ lost → metabolic acidosis. This is a generalised PT transport defect (Fanconi syndrome).

Camilla — defective acid secretion (distal)

Treated for SLE for 5 years, stopped medication, now with diffuse lupus nephritis. ABG: PaCO₂ 22, pH 7.37, HCO₃⁻ 13, urine pH = 7.

• Interpretation: an inappropriately high urine pH (7) shows the distal tubule is not secreting non-volatile acid → acidosis. SLE causes tubulointerstitial inflammation impairing distal H⁺ secretion (titratable acid / NH₄⁺).

Renal Tubular Acidosis (RTA) — summary

• Proximal RTA — defect in the mechanism for “reabsorbing” HCO₃⁻ → HCO₃⁻ lost → acidosis.
  • Causes: congenital, paraproteins (myeloma), PTH, drugs.
• Distal (“classic”) RTA — defect in non-volatile acid secretion → acid not excreted → acidosis.
  • Causes: congenital, inflammation (e.g. SLE), toxins (amphotericin), hyperkalaemia, Conn’s.

---

Self-Test Checklist

Can you explain…?

• The normal ECF pH and the values defining acidosis, alkalosis, and the fatal limits?
• Why such tight pH control matters (enzymes, transport, CNS, and the clinical features of each direction)?
• The scale of the daily acid challenge and the two strategies (buffering vs excretion) used to meet it?
• The central CO₂/H₂CO₃/H⁺/HCO₃⁻ equilibrium and how shifting it left or right changes pH?
• How haemoglobin buffers the H⁺ generated from CO₂ in transit between tissues and lungs?
• How hypo- and hyperventilation produce respiratory acidosis and alkalosis?
• The sources and approximate magnitude of non-volatile acid production (NEAP)?
• The three main whole-body buffers, and why buffering alone is insufficient?
• Why buffering non-volatile acid consumes HCO₃⁻ that the kidney must replace?
• The two renal bicarbonate tasks, and the segmental distribution/transporters of HCO₃⁻ reabsorption?
• Why bicarbonate reabsorption is described as making “new” HCO₃⁻ rather than recovering the filtered molecule?
• The titratable acid mechanism (phosphate buffer, DT) and how it generates new HCO₃⁻?
• The ammonia mechanism (glutamine → NH₃ → NH₄⁺; PT → medulla → CD) and how it generates new HCO₃⁻?
• The Henderson–Hasselbalch equation and how it frames the [HCO₃⁻]/pCO₂ ratio?
• The four acid–base disturbances and the primary change defining each?
• How to interpret Annabel (respiratory alkalosis), Beryl (proximal RTA / Fanconi), and Camilla (distal RTA / SLE)?
• The defining defect and causes of proximal vs distal RTA?