L6 Renal Physiology 6 (and stuff from 5

Acid–Base Balance — Lectures 5 & 6 (combined)

Overview

These two lectures together build the full logic of whole-body pH control. The body faces a large daily acid load and defends a very narrow pH window using two distinct processes: buffering (which only hides H⁺) and excretion (which actually removes it). The work is split between the lungs (volatile CO₂) and the kidneys (non-volatile acid plus bicarbonate). The material runs from the chemistry of the CO₂/HCO₃⁻ system, through renal bicarbonate reabsorption and the generation of “new” bicarbonate (titratable acid and ammonia), to the Henderson–Hasselbalch framework. It then classifies the four primary disturbances, explains compensation as restoration of a 20:1 ratio, introduces the anion gap to subclassify metabolic acidosis, works five clinical cases, and finishes with potassium homeostasis, which is tightly coupled to acid–base status.

Lectures 5 and 6 overlap heavily in their first half. This note keeps the shared foundations once and adds Lecture 6’s unique material (compensation, anion gap, the Douglas and Frankie cases, and K homeostasis).

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Why pH must be controlled

• Know the normal values: ECF pH 7.4 (range 7.36–7.45); intracellular pH nearer 7.
  • Acidosis is pH < 7.35; alkalosis is 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 system exists to defend this window.
• Know why pH matters: it sets enzyme activity (each has an optimum pH), regulates ion transport, 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.
• Understand the scale of the problem (Pitts, 1953): injecting a dog with 150 mL of 1 mol/L HCl dropped blood pH only 7.44 to 7.14, whereas adding the same acid to an equal volume of water dropped pH 7.44 to 1.84. This demonstrates buffering of greater than 99.99 percent.

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The daily acid challenge

Understand that the body faces two separate acid problems each day, handled by different organs.

• Volatile acid (CO₂): cells produce ~13,000 mmol/day (≈10 mmol/min). Through the central reaction it is potentially a huge acid load, but the lungs remove it, so it is “not normally a problem.”

• Non-volatile (fixed) acids: metabolism produces 50–80 mmol/day. This is the NEAP (net endogenous acid production).

• The central reaction underlying everything:

  CO₂ + H₂O ⇌ H₂CO₃ ⇌ H⁺ + HCO₃⁻

• Know the sources of non-volatile acid (predicts where acidosis arises):

  • H₂SO₄ from sulphur-containing amino acids
  • H₃PO₄ from phosphoproteins and phospholipids
  • Organic acids (lactate, pyruvate) from anaerobic exercise
  • Ketoacids from fat metabolism

• H⁺ from fixed acids has two separate fates: it must be buffered and then excreted.

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Handling CO₂ (the volatile acid)

• Even though CO₂ is exhaled, two things still have to work:
  1. CO₂ is produced in tissues, not the lungs, so it must be buffered in transit in the blood.
  2. Alveolar ventilation must continuously match metabolic production.
• Understand the in-transit buffering: CO₂ is mostly buffered in blood by haemoglobin.
  • In cells: CO₂ + H₂O → H₂CO₃ → H⁺ + HCO₃⁻, then H⁺ + O₂Hb⁻ → HHb + O₂. HHb buffers the H⁺, so CO₂ production causes very little pH change.
  • In lungs: the reactions reverse, H⁺ + HCO₃⁻ → H₂CO₃ → CO₂ + H₂O, and CO₂ is removed.
• Understand how ventilation shifts the equilibrium:
  • Hypoventilation: CO₂ accumulates, equation shifts right, excess H⁺ → respiratory acidosis.
  • Hyperventilation: excess CO₂ removed, equation shifts left, decreased H⁺ → respiratory alkalosis.

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Buffering vs excretion: the two-stage logic

Central insight

Buffering only hides H⁺; it does not remove it. The body must still excrete the H⁺ and regenerate the bicarbonate that buffering consumed. This is why the kidney is essential even though buffers and the lungs act first.

• Know the three main buffers: bicarbonate, protein, phosphate (plus dilution and exchange with bone minerals). Collectively “whole body buffering,” which prevents pH falling to dangerous levels.

• Understand the disposal step: buffered H⁺ reacts with bicarbonate,

  H⁺ + HCO₃⁻ → H₂CO₃ → CO₂ + H₂O

  CO₂ is exhaled and the H⁺ is now part of a water molecule, so it is no longer an acid threat.

• The cost: this process consumes an HCO₃⁻, which the kidney must replace.

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Renal handling of bicarbonate

The kidney does two distinct bicarbonate jobs.

1. Reabsorption (replacing filtered HCO₃⁻)

• Distribution of reabsorption: PT 80% (via NHE-3), TAL 10%, DT/CD 10%.
  • DT/CD intercalated cells use H/K ATPase and H ATPase; some intercalated cells instead secrete HCO₃⁻ (Cl exchange).
• Understand the PT mechanism: filtered Na⁺ and HCO₃⁻ arrive in the lumen. H⁺ is secreted in exchange for Na⁺ via NHE-3. In the lumen HCO₃⁻ + H⁺ → H₂CO₃ → (carbonic anhydrase) H₂O + CO₂. CO₂ diffuses into the cell, where CO₂ + H₂O → H₂CO₃ → H⁺ + HCO₃⁻; the HCO₃⁻ is reabsorbed to blood. Basolateral Na/K ATPase drives the process. The reabsorbed bicarbonate is effectively “new” bicarbonate synthesised by PT cells to replace the filtered ions.

2. Generating “new” HCO₃⁻ (renal net acid excretion, RNAE)

• Understand the principle: when a tubule cell makes H⁺ for secretion, it simultaneously makes an HCO₃⁻ that is returned to plasma, replacing the HCO₃⁻ consumed in buffering non-volatile acid. The secreted H⁺ must be carried out of the body bound to a urinary buffer.

• Two mechanisms:

  Titratable acid (distal tubule): the urinary buffer is HPO₄²⁻. HPO₄²⁻ + H⁺ → H₂PO₄⁻, which is excreted.

  Ammonia (PT → medulla → CD): glutamine → NH₃ → NH₄⁺. Glutaminase in the PT generates NH₃/NH₄⁺ (and bicarbonate, ~2 HCO₃⁻ per glutamine); NH₄⁺ traffics via the loop of Henle into the medulla and is secreted by the collecting duct (glycoproteins). In the lumen NH₃ + H⁺ → NH₄⁺, which is excreted.

The whole sequence in one line

New fixed acid HA → A⁻ + H⁺ (buffered). The H⁺ reacts with HCO₃⁻ → CO₂ + H₂O (HCO₃⁻ consumed). A⁻ is filtered. The kidney secretes H⁺ and makes new HCO₃⁻; HA is excreted in the urine bound to buffer.

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The Henderson–Hasselbalch framework

• Know the equation:

  pH = 6.1 + log( [HCO₃⁻] / (0.03 × pCO₂) )

• Understand the division of labour: respiratory control of CO₂ (the denominator) and renal control of HCO₃⁻ (the numerator).

• For balance to hold you need: appropriate respiratory function (maintain CO₂) and appropriate renal function, which itself requires the kidney to be (a) able to function, (b) handling HCO₃⁻ appropriately, and (c) secreting acid appropriately. These three renal failure points map onto the clinical cases below.

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Classifying the four disturbances

• Respiratory acidosis — too much CO₂: hypoventilation (e.g. chronic bronchitis), high inspired CO₂.
• Respiratory alkalosis — too little CO₂: hyperventilation (e.g. anxiety, altitude, hypoxia).
• Metabolic alkalosis — too much HCO₃⁻ / acid deficit: excess bicarbonate (ingestion or renal overproduction), loss of acid secretions (gastric contents).
• Metabolic acidosis — too little HCO₃⁻ / acid excess: loss of bicarbonate (gut), inadequate renal bicarbonate production, addition or excessive production of (organic) acids.

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Compensation (Lecture 6)

The 20:1 ratio

Normally [HCO₃⁻] : (0.03 × pCO₂) is 20 : 1. Because pH depends on the ratio, if one variable changes, adjusting the other to restore 20:1 pulls pH back towards normal. That adjustment is compensation.

• Understand the integrated response: lungs and kidneys cover for each other.
  • Respiratory compensation of metabolic acidosis/alkalosis (fast, via ventilation changing CO₂).
  • Renal compensation of respiratory acidosis/alkalosis (slow, via changing HCO₃⁻).
• Worked example — respiratory acidosis (e.g. hypoventilation, excess CO₂ → excess H⁺): kidneys compensate by excreting more H⁺ and synthesising more HCO₃⁻.
• Know how the kidney varies HCO₃⁻ production to need:
  • If it needs to lose HCO₃⁻ (alkalosis): don’t reabsorb all filtered HCO₃⁻; secrete HCO₃⁻ (DT/CD); reduce acid secretion (which makes less new HCO₃⁻).
  • If it needs more HCO₃⁻ (acidosis): maximise reabsorption of filtered HCO₃⁻; excrete more titratable acid and ammonium, making more new HCO₃⁻.
• Understand the quantitative table (Table 2, mmol/day) — same machinery dialled up or down. The bottom row (total titratable acid + NH₄⁺ excreted) equals the additional HCO₃⁻ synthesised and added to plasma:

Parameter	Metabolic alkalosis	Normal	Metabolic acidosis
Plasma [HCO₃⁻]	33	25	17
HCO₃⁻ filtered	6000	4500	3000
HCO₃⁻ replaced	5600	4500	3000
HCO₃⁻ excreted	400	0	0
Total H⁺ secreted	5600	4580	3400
Titratable acid excreted	0	30	100
NH₄⁺ excreted	0	50	300
Total TA + NH₄⁺ (= new HCO₃⁻)	0	80	400

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The anion gap (Lecture 6)

• Know the formula and cut-offs:

  AG = ([Na⁺] + [K⁺]) − ([HCO₃⁻] + [Cl⁻])

  Normal up to ~15 mmol/L (lecture also quotes ~8–15); abnormally high is > 16 mmol/L.

• Understand what it represents: a crude estimate of the plasma concentration of “unmeasured” anions (phosphates, proteins, and in disease, organic anions).

• Normal anion gap metabolic acidosis (Pattern A): loss of bicarbonate (gut diarrhoea or kidney), inadequate renal bicarbonate production, or addition of HCl / HCl precursors (e.g. NH₄Cl). HCO₃⁻ falls and Cl⁻ rises to maintain electroneutrality, so the gap is unchanged.

• High anion gap metabolic acidosis (Pattern B): excess organic acid production (lactate, ketones) or ingestion (methanol, ethylene glycol). The acid dissociates into an organic anion plus H⁺; H⁺ is buffered by bicarbonate (HCO₃⁻ falls); Cl⁻ does not rise because the organic anion replaces the lost bicarbonate, so the gap widens.

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Worked cases

Example

Anxious, “panic attack,” numbness and tingling in hands and feet, then cramps and spasms in the hands. Na 137, Cl 112, K 4.2, PCO₂ 29, pH 7.52, HCO₃⁻ 23. Interpretation: high pH with low PCO₂ and near-normal HCO₃⁻ is acute respiratory alkalosis from hyperventilation. The tetanic symptoms (tingling, carpal spasm) fit the alkalosis feature list (reduced ionised calcium). This case sits directly after the respiratory alkalosis slides as the illustrative example; the deck does not provide a separate worked answer slide.

Example

Vertebral collapse, recurrent UTIs, alkaline urine, and glucose, phosphate and amino acids in the urine. PaCO₂ 33, pH 7.25, HCO₃⁻ 14. Interpretation: the urinary glucose, phosphate and amino acids point to a generalised proximal tubule defect. The PT fails to reabsorb HCO₃⁻, so HCO₃⁻ is lost and acidosis follows. This is the “inappropriate HCO₃⁻ handling” failure mode, i.e. proximal RTA (Fanconi syndrome).

Example

SLE treated 5 years, stopped medication, now diffuse lupus nephritis. PaCO₂ 22, pH 7.37, HCO₃⁻ 13, urine pH 7. Interpretation: a urine pH of 7 means she is not secreting non-volatile acid despite systemic acidosis. This is the “inappropriate acid secretion” failure mode, i.e. distal (“classic”) RTA, here from SLE tubulointerstitial inflammation impairing distal TA/NH₄⁺ secretion.

Example

Paralytic ileus after GI surgery; naso-gastric tube with high losses (>2 L/day). Initial blood: Na 135, K 3.5, Cl 100, HCO₃⁻ 30, pH 7.48; urine pH 7.0, Na 45, Cl 30. Mechanism: parietal cells synthesise H⁺ and in doing so add HCO₃⁻ to plasma. Normally that HCO₃⁻ is “used up” when gastric acid is later neutralised, but with continuous NG removal of gastric H⁺ the bicarbonate accumulates → metabolic alkalosis. Three days later (ongoing losses): Na 136, K 3.4, Cl 98, HCO₃⁻ 35, pH 7.5; urine pH 5.3, Na 10, Cl 10. Understand the paradoxical aciduria: persistent volume loss switches renal priorities to volume retention. Na⁺ retention is maximised (taking any anion, Cl⁻ or HCO₃⁻, or exchanging for H⁺ which adds HCO₃⁻ to plasma). Renal removal of excess HCO₃⁻ therefore falls, the alkalosis persists, and the urine reverts to an acid pH despite the alkalosis.

Example

Dehydration; months of fatigue, polyuria and polydipsia, 9 kg weight loss, nocturia; acetone breath, pulse 115, BP 95/55, RR 20. Na 138, Cl 98, K 7.6, glucose 35, PCO₂ 25, pH 7.22, HCO₃⁻ 10. Disturbance: pH down, CO₂ down, HCO₃⁻ down → metabolic acidosis with respiratory compensation; the picture is diabetic ketoacidosis. Anion gap: (138 + 7.6) − (10 + 98) = 37.6, a high gap from the extra ketoacid anions. The potassium paradox: plasma K is high (7.6) because H⁺ enters cells in exchange for K⁺, and insulin deficiency reduces K⁺ entry into cells. But he does not have a K excess: osmotic diuresis drives urinary K⁺ loss, so total body K is actually depleted. Management: rehydration, insulin, potassium.

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Renal tubular acidosis — summary

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

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Potassium homeostasis (Lecture 6)

• Know why K⁺ matters: it is the main cell cation; it maintains the cell environment and enzyme function, contributes to volume regulation and acid-base balance, and sets the resting membrane potential through the K_in/K_out ratio for nerve, muscle and heart.
• Three things must be kept appropriate simultaneously: plasma [K⁺], the plasma/cell ratio, and total body K.
• Know the distribution: 98% of K⁺ is intracellular (140–150 mmol/L; 80% of body K is in muscle); 2% is extracellular (3.5–5 mmol/L). Both hyper- and hypokalaemia are dangerous (nerve, muscle, cardiac, death).
• Know the turnover: intake ~100 mmol/day; output ~100 mmol/day (~10% faeces, ~90% urine). The kidney is the major organ for long-term K balance.

Internal balance (short term)

• Short-term plasma [K⁺] regulation is by shifting K⁺ into and out of cells.
• Understand the worked example: a 40 mmol K⁺ meal entering 14 L of ECF would raise [K⁺] by ~3 mmol/L (4.5 → 7.5) if it were not buffered into cells; cellular uptake prevents this.
• Factors that move K⁺ into cells (lower plasma K⁺): increased Na/K ATPase activity, insulin, adrenaline, aldosterone.
• pH coupling: acidosis drives H⁺ into cells and K⁺ out (raises plasma K⁺); alkalosis drives K⁺ in and H⁺ out (lowers plasma K⁺).
• Increased ECF osmolarity moves K⁺ out of cells; exercise moves K⁺ out of cells into ECF.

External balance (long term, kidney)

• ~700 mmol/day filtered: 66% reabsorbed in the PT, 20% in the LoH.
• In the DT/CD the kidney chooses: secrete K⁺ if in excess (principal cells) or reabsorb K⁺ if deficient (intercalated cells), so roughly 14% of filtered K⁺ reaches the urine.
• The kidney can secrete large amounts of K⁺ when needed, so GFR is rarely the limiting factor in K⁺ excretion; that requires substantial glomerular and/or tubular damage.

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Self-test checklist

Run through these and check you can explain each without notes.

• Can you state the normal ECF pH, the acidosis/alkalosis thresholds, and the fatal limits?
• Can you list the consequences of acidosis and of alkalosis?
• Can you contrast the volatile and non-volatile acid loads and name the organ that handles each?
• Can you name the four sources of non-volatile acid?
• Can you write the central CO₂/HCO₃⁻ reaction and explain how Hb buffers CO₂ in transit?
• Can you explain why hypoventilation causes acidosis and hyperventilation causes alkalosis using the equation?
• Can you name the three main buffers and explain why buffering alone is insufficient?
• Can you explain how buffered H⁺ is ultimately disposed of, and why this consumes a bicarbonate?
• Can you give the segmental distribution of HCO₃⁻ reabsorption (PT 80% / TAL 10% / DT/CD 10%) and the PT mechanism (NHE-3, carbonic anhydrase)?
• Can you distinguish reabsorption of filtered HCO₃⁻ from generation of “new” HCO₃⁻?
• Can you explain titratable acid (HPO₄²⁻, DT) and the ammonia mechanism (glutamine → NH₃/NH₄⁺; PT → medulla → CD)?
• Can you reproduce the Henderson–Hasselbalch equation and say which organ controls each term?
• Can you classify all four disturbances and give a cause of each?
• Can you explain compensation in terms of the 20:1 ratio, and say which organ compensates for which disturbance?
• Can you describe how the kidney varies HCO₃⁻ production in acidosis versus alkalosis?
• Can you calculate an anion gap and distinguish normal-gap from high-gap metabolic acidosis by mechanism?
• Can you interpret Annabel (respiratory alkalosis) and explain her tetany?
• Can you distinguish Beryl (proximal RTA / Fanconi) from Camilla (distal RTA) by the lab and urine findings?
• Can you explain Douglas’s metabolic alkalosis and the mechanism of paradoxical aciduria?
• Can you work Frankie’s case end to end: disturbance, anion gap, the high-K-but-total-body-deficit paradox, and management?
• Can you list the causes of proximal versus distal RTA?
• Can you state the K⁺ distribution in the fluid of the body and the roles of K⁺?
• Can you list the factors that shift K⁺ into cells, and explain the acidosis/alkalosis–K⁺ relationship?
• Can you describe renal K⁺ handling (filtered load, PT/LoH reabsorption, DT/CD secretion vs reabsorption) and why GFR rarely limits K⁺ excretion?