Every enzyme in the human body functions optimally at a narrow pH range. The body maintains arterial pH at 7.35–7.45 (corresponding to [H⁺] of ~35–45 nmol/L). When pH deviates beyond this range, protein structures denature, enzyme kinetics fail, and cellular functions collapse.

Normal pH: 7.4 (range 7.35–7.45); pH 7.4 = [H⁺] 40 nmol/L. Lethal: pH < 7.1 or > 7.7 ^[1]

$pH = 6.1 + \log \frac{[HCO_3^-]}{0.03 \times pCO_2}$

This equation tells us pH is determined by the ratio of HCO₃⁻ (metabolic component, controlled by kidneys) to pCO₂ (respiratory component, controlled by lungs). If HCO₃⁻ drops or pCO₂ rises, pH falls (acidosis). If HCO₃⁻ rises or pCO₂ drops, pH rises (alkalosis) ^[2][3].

Mnemonic: Acidity = Bicarb / Carbon Dioxide (A = B/CD) ^[3].

Acidosis = a process leading to increase in plasma [H⁺]. Alkalosis = a process leading to removal of plasma [H⁺]. Acidaemia = [H⁺] > normal. Alkalaemia = [H⁺] < normal. ^[1]

The body never overcompensates—compensation brings pH toward normal but does not fully correct it (with one exception: chronic respiratory alkalosis may fully compensate).

Lungs compensate immediately; Kidneys take several days. ^[1]

^[1]

Expected Compensation Formulas (from senior notes, useful for data interpretation) ^[4]:

If compensation is outside expected ranges → mixed acid-base disorder.

Characterized by ↓HCO₃⁻ (Normal: 22–28 mmol/L; < 22 = metabolic acidosis). Compensated with hyperventilation → reduced pCO₂. ^[1]

Steps: (1) Confirm it is metabolic acidosis. (2) Determine the Anion Gap. (3) If normal AG → determine urine AG. (4) Look for any osmolar gap. (5) Check for mixed disorders (ΔAG vs ΔHCO₃⁻). ^[1]

(The lecturer explicitly notes steps 3 and 5 are "advanced/too advanced for MBBS" but step 2—the anion gap—is absolutely core.)

Why does it exist? Plasma must be electrically neutral—total cations = total anions. We routinely measure Na⁺, Cl⁻, and HCO₃⁻, but there are unmeasured anions (albumin, phosphate, sulphate, organic acids) that make up the "gap."

AG = Na⁺ − Cl⁻ − HCO₃⁻. Example: 140 − 105 − 25 = 10. Normal AG ≈ 8–14 ^[1]

Why the AG matters in metabolic acidosis:

When an acid (HA) is added to blood, it dissociates into H⁺ + A⁻. The H⁺ consumes HCO₃⁻ (buffering), so HCO₃⁻ drops. Meanwhile, A⁻ (the conjugate base anion) accumulates. If A⁻ is a "measured" anion like Cl⁻, Cl⁻ replaces HCO₃⁻ and the AG stays normal. If A⁻ is "unmeasured" (like lactate, ketoacids), the AG rises because HCO₃⁻ drops without a compensatory Cl⁻ rise.

In normal AG acidosis, ↓HCO₃⁻ is compensated by ↑Cl⁻ (hyperchloraemic acidosis). In high AG acidosis, ↓HCO₃⁻ is due to accumulation of unmeasured anions. ^[1]

Causes of ↑AG: ^[1]

• DKA, alcoholic ketoacidosis
• Lactic acidosis
• Ingestion: salicylate, formic acid (methanol), glycolate (ethylene glycol)
• Renal failure: sulphate, phosphate, hippurate
• Rhabdomyolysis: release of organic acids
• Remarks: altered AG in paraproteinaemia (e.g., ↓ in IgG gammopathy; ↑ in IgA gammopathy)

Paraproteinaemia and AG: IgG carries a net negative charge (raises AG); IgA carries a net positive charge (lowers AG). This is a subtle point the lecturer specifically includes—it can confound AG interpretation in myeloma patients ^[1].

Characterised by ↑Cl⁻. Causes: ^[1]

• GI loss of HCO₃⁻: diarrhoea
• Renal loss of HCO₃⁻: proximal RTA (type II), carbonic anhydrase inhibitors
• Failure to excrete H⁺: distal RTA (type I), type IV RTA
• Ingestion of excessive Cl⁻: NH₄Cl
• Increased reabsorption of Cl⁻: ureterosigmoidostomy

Why ureterosigmoidostomy? The sigmoid colon actively absorbs Cl⁻ and secretes HCO₃⁻. When urine drains into it, the colon exchanges Cl⁻ for HCO₃⁻ → patient loses HCO₃⁻ and gains Cl⁻ → hyperchloraemic metabolic acidosis.

Calculated osmolality = 2×[Na⁺] + urea + glucose. Osmolar gap = Measured osmolality − Calculated osmolality. ↑Osmolar gap = presence of an unmeasured osmotically active substance (e.g., ingestion of alcohol-related compounds). ^[1]

This is clinically vital when you suspect toxic alcohol ingestion (methanol, ethylene glycol). A patient with HAGMA + ↑osmolar gap → think toxic alcohol ingestion as the primary diagnosis.

Lactate is produced when pyruvate is reduced under anaerobic conditions (glycolysis without oxidative phosphorylation). Normal lactate < 2 mmol/L.

Type A (O₂ deficiency—overproduction): ^[1]

• Circulatory: hypotension
• Respiratory: hypoxia
• Haemoglobin: CO poisoning
• Increased metabolic demand: grand mal seizure, severe exercise

Type B (without hypoxaemia—reduced metabolism): ^[1]

• Liver disease
• Alcoholism
• Thiamine deficiency
• Phenformin, metformin

Rate of production up to 72 mmol/min with total hypoxia. Diagnosis: High AG metabolic acidosis + measure plasma lactate (normal < 2 mmol/L). ^[1]

Treatment of Type A L-lactic acidosis: Most effective = improve O₂ delivery to tissue (correct hypotension, hypoxaemia). NaHCO₃ therapy ineffective unless lactate production is controlled—its use may buy time. Na⁺ load limits massive use. Haemodialysis with bicarbonate dialysis is an option. ^[1]

Determine cause and treat the underlying cause. Some causes have independent threat to life (e.g., methanol poisoning). There may be specific treatment (e.g., fomepizole/ethanol for methanol poisoning). Correction of HCO₃⁻ by NaHCO₃. ^[1]

This is a favourite exam topic because it tests understanding of physiology:

1. Induces hypokalaemia — NaHCO₃ raises pH → alkalosis shifts K⁺ into cells. Dangerous if patient already has low K⁺ (e.g., DKA where total body K⁺ is depleted but serum K⁺ appears normal due to acidotic shift out of cells) ^[1].

2. Decreases ionic calcium — raising pH increases the proportion of calcium bound to albumin → ↓free/ionized Ca²⁺. Problematic in CRF patients who already have hypocalcaemia ^[1].

3. Volume expansion from Na⁺ load — 1 mmol HCO₃⁻ carries 1 mmol Na⁺. If 200 mmol NaHCO₃ given, that's 200 mmol Na⁺ = more than 1 litre of normal saline (which has 154 mmol Na⁺) ^[1].

4. Too rapid correction → paradoxical cerebral acidosis ^[1].

When NaHCO₃ is given IV, it reacts with H⁺ to form CO₂ and H₂O in the plasma. CO₂ crosses the blood-brain barrier (BBB) freely, but HCO₃⁻ does NOT cross the BBB easily. In the CSF, CO₂ is converted back to H⁺ + HCO₃⁻ by carbonic anhydrase → CSF pH drops (becomes more acidotic) even as blood pH is being corrected. ^[1]

This is why rapid NaHCO₃ infusion can paradoxically worsen neurological status.

HCO₃⁻ deficit = [HCO₃⁻ deficit per litre] × HCO₃⁻ space (= BW × 0.6). Usually only half the amount is given (i.e., BW × 0.3). Only replace to a safe level acutely (pH ~7.1), then slow correction. Give half the dose initially, recheck afterwards. Beware fluid overload in oliguric patients. ^[1]

Mechanism from first principles: The proximal convoluted tubule (PCT) normally reabsorbs ~85% of filtered HCO₃⁻. It does this via the Na⁺/H⁺ exchanger on the apical membrane: H⁺ is secreted into the lumen → combines with HCO₃⁻ → forms CO₂ + H₂O (via carbonic anhydrase IV on the brush border) → CO₂ diffuses into the cell → reformed into HCO₃⁻ + H⁺ (via intracellular carbonic anhydrase II) → HCO₃⁻ exits basolaterally.

In proximal RTA, the reabsorption threshold for HCO₃⁻ is lowered (normally ~25 mmol/L). So when plasma HCO₃⁻ is above this lowered threshold, massive HCO₃⁻ is lost in the urine. Once plasma HCO₃⁻ falls to the new (lower) threshold, reabsorption "catches up" and a new steady state is reached at a lower plasma HCO₃⁻.

Characterised by ↓HCO₃⁻ reabsorption threshold → loss of HCO₃⁻ in urine → low plasma HCO₃⁻ → normal AG metabolic acidosis with compensatory hyperchloraemia → alkaline urine (pH usually > 6). ^[1]

Loss of Na⁺ coupling with loss of HCO₃⁻ → hypovolaemia → secondary hyperaldosteronism → hypoK⁺. ^[1]

Associated with hyperphosphaturia, hypercitraturia (which prevents nephrocalcinosis/stones), hyperuricuria. Hyperphosphaturia → rickets, osteomalacia. ^[1]

Fanconi's syndrome = pan-dysfunction of proximal tubules with aminoaciduria, glycosuria on top of RTA and hyperphosphataemia. ^[1]

Mechanism from first principles: The α-intercalated cells of the collecting duct secrete H⁺ via the H⁺-ATPase pump on the apical membrane. This creates a steep H⁺ gradient (urine pH can go as low as 4.5). In distal RTA, either the pump is defective or H⁺ leaks back through a permeable membrane.

Due to inability to excrete H⁺: (a) H⁺-ATPase pump defect, or (b) H⁺ back-leak (increased permeability). Urine pH always > 6 because of failure to maintain a steep plasma-urine H⁺ gradient. ^[1]

↓H⁺ excretion → ↑K⁺ excretion for exchange of Na⁺ reabsorption in distal tubule → hypoK⁺. ^[1]

Why hypoK⁺ in distal RTA? Normally, both H⁺ and K⁺ can be secreted in exchange for Na⁺ reabsorption at the collecting duct. When H⁺ secretion fails, K⁺ secretion increases to compensate for Na⁺ reabsorption → renal K⁺ wasting → hypoK⁺.

Acidosis → ↑Ca²⁺ resorption from bone AND ↓tubular Ca²⁺ and PO₄ reabsorption → hypercalciuria → nephrocalcinosis/kidney stones. ^[1]

Proximal RTA causes: Hereditary (cystinosis, galactosaemia, Wilson's disease, Lowe's syndrome); Acquired (dysparaproteinaemia, heavy metal poisoning, carbonic anhydrase inhibitors, amyloidosis, renal transplant rejection, Sjögren's). ^[1]

Distal RTA causes: Hereditary (primary hypercalciuria, Marfan's, Ehlers-Danlos); Acquired (autoimmune: Sjögren's, RA, SLE, PBC; Drugs: amphotericin B, lithium, analgesic nephropathy; Renal: CRF, obstruction, interstitial nephritis, medullary sponge disease; Paraproteinaemia; HyperPTH, hyperCa²⁺, hypervitamin D). ^[1]

Clinical suspicion: Normal AG acidosis + hypoK⁺ (Hint: ↑Cl⁻ with normal Na⁺) + Urine pH > 5.5 in the presence of acidaemia. ^[1]

Confirmatory tests: ^[1]

• FEHCO₃⁻ (Fractional Excretion of Bicarbonate): Proximal RTA > 15% (sensitivity increases after NaHCO₃ infusion). Distal RTA < 5%.
• NH₄Cl acid loading test: Normal urine pH < 5.5. Distal RTA: urine pH remains > 6.0. Proximal RTA: variable.

Characterised by normal AG metabolic acidosis + hyperK⁺. Mechanism: aldosterone deficiency/resistance. Aldosterone promotes distal K⁺ and H⁺ secretion and Na⁺ reabsorption. Deficiency → retention of K⁺ (hyperkalaemia) + decreased H⁺ excretion (acidosis, usually mild). Urine pH variable. ^[1]

Causes: Drugs (ACEI, ARB, K⁺-sparing diuretics: spironolactone, amiloride, triamterene; Cyclosporin A, Tacrolimus), Hyporeninism (diabetic nephropathy), Renal failure, Mineralocorticoid deficiency, Kidney transplant rejection (tubulitis). ^[1]

Type I & II RTA: ^[1] 1. Correct acidosis with oral NaHCO₃ (very high dose required in proximal RTA because of urinary HCO₃⁻ loss). 2. Potassium citrate is a better alternative for distal RTA (citrate → converted to HCO₃⁻ by liver, also ↑urinary citrate to prevent stones). 3. K⁺ supplement for hypoK⁺. 4. Distal RTA due to Sjögren's: steroids.

Type IV RTA: ^[1] 1. Stop/reduce inciting drugs. 2. Loop diuretics + low K⁺ diet for hyperK⁺.

[Na⁺] does not reflect absolute content of Na⁺ in body, but the amount of solvent—water. Na⁺ is primarily an extracellular cation. In the absence of Na⁺ loss or retention: hypoNa⁺ = water retention; hyperNa⁺ = water depletion. Complicated when there is also Na⁺ loss or retention. ^[1]

This is the single most important concept in sodium disorders: serum [Na⁺] is a marker of water balance, not sodium balance. Volume status (assessed clinically) tells you about total body sodium ^[3].

↓Serum [Na⁺] but normal osmolality. Due to occupation of large amount of non-water (e.g., fat, paraprotein) in plasma → ↑plasma volume (denominator) while actual plasma water Na⁺ (numerator) is normal → [Na⁺] appears low. Clue: check serum osmolality—normal. Confirmation: check plasma water [Na⁺]. Causes: hyperglycaemia, ↑↑TG, paraproteinaemia, ↑↑WCC. ^[1]

Steps: ^[1] 1. Serum osmolarity? (↓ = true hyponatraemia) 2. Volume status? 3. Urine osmolarity? ( > 100 = ADH is working; appropriate?) 4. Urine Na⁺ level? ( > 20 = inappropriate, i.e., SIADH)

CNS: meningitis, encephalitis, brain abscess, head trauma, SAH, CVA, raised ICP. Respiratory: CA lung, chest infection, positive pressure breathing. Drugs: SSRIs, ecstasy. Hypothyroidism. ^[1]

Non-specific: malaise, lethargy, headache. Confusion, convulsion, coma. More serious with acute hyponatraemia. ^[1]

Acute ( < 48h): More serious symptoms, severe at [Na⁺] < 120, less complications if corrected rapidly. Chronic ( > 72h): Symptoms may not develop even at [Na⁺] < 110, more prone to CNS complications with rapid correction. ^[1]

Why the difference? In chronic hyponatraemia, brain cells adapt by extruding osmolytes (organic solutes like taurine, myoinositol) to match the low extracellular osmolality. If you rapidly correct the Na⁺, the extracellular osmolality rises faster than the brain can re-accumulate osmolytes → water rushes out of brain cells → oligodendrocyte damage → central pontine myelinolysis (osmotic demyelination syndrome).

Rate of correction: SLOW for chronic hyponatraemia ( > 2 days): < 0.5 mmol/L/hr, or < 12 mmol/L/day. Too rapid correction → central pontine myelinolysis. Treat according to ECF volume status. Hypertonic saline only in very experienced hands. Demeclocycline or V2 antagonist (tolvaptan) can be considered in SIADH. ^[1]

Volume depletion assessment: Mild (loss of skin turgor) = 5% BW loss. Moderate (postural hypotension) = 10%. Severe (shock) = 15%. Mild oedema = 5% excess. Replace volume with normal saline cautiously. Initial 1/3 in first 8 hours, reduce speed afterwards. Monitor [Na⁺] regularly. ^[1]

In pure water loss: Water deficit = TBW × ([Na⁺]/140 − 1). Rate: 1/3 rule (1/3 in first 8h, 1/3 in next 16h, 1/3 in third 24h). Replace ongoing losses. Max decrease 12 mmol/24h unless seriously symptomatic. Too rapid → cerebral oedema (rapidly reduced plasma osmolality → water influx into cells). ^[1]

K⁺ is an intracellular cation (ICF: 150 mmol/L; ECF/serum: 3.5–5.0 mmol/L). Na-K-ATPase pumps K⁺ into cells. Highly influenced by acid-base status: acidosis → K⁺ moves out of cells (and vice versa). Severe hypoK⁺ and hyperK⁺ are life-threatening → cardiac arrhythmia. ^[1]

TTKG = (Urine [K⁺] × Serum Osm) / (Serum [K⁺] × Urine Osm). In hypoK⁺: TTKG > 4 indicates renal K⁺ loss. In hyperK⁺: TTKG < 6 indicates inappropriate renal response (should be high if kidney is working properly). ^[1]

Why TTKG? Raw urine K⁺ concentration is misleading because urine is concentrated/diluted in the collecting duct. The TTKG corrects for this by estimating K⁺ concentration at the cortical collecting duct (before concentration changes).

DKA presents with high AG metabolic acidosis (ketoacids). Serum K⁺ may appear normal on admission due to acidotic shift, but total body K⁺ is depleted from osmotic diuresis. Giving insulin shifts K⁺ back into cells → risk of lethal hypokalaemia if not supplemented ^[7].

Relevant to distal RTA (hyperCa²⁺ damages the collecting duct → failure to acidify urine). Also connects to the 2025 MCQ Q13: chronic smoker with haemoptysis, bone pain, and lung mass → likely hypercalcaemia from PTHrP-secreting squamous cell lung cancer ^[5].

Both cause metabolic alkalosis + hypoK⁺. Bartter's mimics furosemide effect (thick ascending limb defect → hypokalaemia, metabolic alkalosis, hypercalciuria). Gitelman's mimics thiazide effect (distal tubule defect → hypokalaemia, metabolic alkalosis, hypocalciuria, hypomagnesaemia) ^[8].

Advanced CKD → accumulation of phosphate, sulphate → high AG metabolic acidosis. Also common to develop hyperK⁺ (↓GFR → ↓K⁺ excretion). Type IV RTA is common in diabetic nephropathy ^[1].

1. A patient on losartan with CKD develops K⁺ 6.8 and mild metabolic acidosis with normal AG. What type of RTA? → Type IV RTA (aldosterone antagonism from ARB + CKD).

2. Which treatment for hyperkalaemia does NOT lower serum [K⁺]? → IV calcium gluconate (it stabilises the myocardium but K⁺ remains elevated).

3. SSRI-induced hyponatraemia mechanism? → SIADH.

4. Complication of too-rapid correction of chronic hyponatraemia? → Central pontine myelinolysis (osmotic demyelination syndrome).

5. In DKA, why does K⁺ drop after insulin administration? → Insulin activates Na⁺/K⁺-ATPase → K⁺ shifts into cells. Total body K⁺ already depleted by osmotic diuresis.

Stem (modelled on 2024 SAQ Q11): A 65-year-old male with pH 7.28, pCO₂ 55 mmHg, HCO₃⁻ 22, lactate 4.5 mmol/L.

(a) Primary acid-base disturbance? → Mixed respiratory acidosis (↑pCO₂) AND metabolic acidosis (elevated lactate, base excess −4). HCO₃⁻ appears "normal" but is inappropriately low for the degree of respiratory acidosis (should be higher as compensation) → the lactate elevation confirms a concurrent metabolic acidosis process.

(b) Two investigations within 1 hour? → Blood cultures, CXR (or sputum culture, procalcitonin).

(c) Five management steps? → (1) O₂ supplementation / airway management, (2) IV fluid resuscitation, (3) Empirical IV antibiotics (within 1 hour of sepsis recognition), (4) Blood cultures before antibiotics, (5) Monitor electrolytes / ABG / urine output.