Acid-base disorders and renal tubular acidosis

• "Acidosis" names a process; "acidemia" names a low blood pH. A person can have severe acidosis with a normal pH once compensation takes effect, and the pH can hide two opposite processes at once. ^[1]
• Read any arterial blood gas in the same order: pH; which of bicarbonate or PaCO2 matches the pH; whether the other compensates as predicted; the anion gap; the osmolar and delta gaps. ^[1]
• A raised anion gap means unmeasured acids have appeared (ketoacids, lactate, toxins, renal failure); a normal anion gap means bicarbonate has been lost or chloride has taken its place. ^[2]
• Renal tubular acidosis (RTA) is a kidney-made normal anion gap acidosis. Type 4 is common; types 1 and 2 are rare but explain stones, rickets and growth failure. ^[6]
• Give intravenous sodium bicarbonate for severe acidemia, but the decision depends on the type of acidosis and on the pH. ^[2]

By the end of this page you should be able to:

1. Define acidemia, alkalemia, acidosis and alkalosis, and explain why compensation never fully corrects the pH. ^[1]
2. Calculate the anion gap, delta gap and osmolar gap, and apply the expected compensation formulas. ^[1][2]
3. List common causes of high and normal anion gap metabolic acidosis in plain language. ^[2]
4. Explain metabolic alkalosis and use urine chloride to separate chloride-responsive from chloride-resistant forms. ^[3]
5. State the acute and chronic compensations for respiratory acidosis and alkalosis and summarise management. ^[4][5]
6. Compare RTA types 1, 2 (including Fanconi syndrome) and 4 by urine pH, potassium and treatment. ^[6]
7. Recognise mixed acid-base disorders and work one through to the end. ^[1][2]
8. Outline management where laboratory tests are limited. ^[2]

Acid-base balance is a conversation between three partners: the lungs govern carbon dioxide, the kidneys govern bicarbonate, and buffers blunt sudden swings while the other two adjust. Every disorder declares itself through the same measurements: arterial pH, arterial partial pressure of carbon dioxide (PaCO2) and serum bicarbonate (HCO3-). Read those three numbers in the same order, identify the cause, then decide what to do. RTA is the kidney making its own normal anion gap acidosis, and it can be diagnosed at the bedside from a few rules. ^[1]

The Henderson-Hasselbalch relationship links the measured quantities: pH is about 6.1 plus the log of [HCO3-] divided by (0.03 times PaCO2). In words, pH rises when bicarbonate rises or carbon dioxide falls, and falls when bicarbonate falls or carbon dioxide rises. Bicarbonate is mainly set by the kidney and carbon dioxide by ventilation. Normal ranges used here are pH 7.35 to 7.45, PaCO2 35 to 45 mm Hg, serum HCO3- about 22 to 29 mmol/L, and an anion gap near 12 mmol/L (Merck Manual gives 10 to 12 mmol/L as usual). ^[1]

Compensatory mechanisms are negative feedback: they wane as pH nears normal, so they never fully correct the pH and never overshoot. If a calculated compensation predicts one pH and the actual pH is on the other side, a second, opposing process is in play. This is the key to mixed disorders. ^[1]

The anion gap is [Na+] minus ([Cl-] plus [HCO3-]). Other cations (potassium, calcium, magnesium, roughly 11 mmol/L of charge) and other anions (albumin, phosphate, sulphate, organic acids, roughly 23 to 24 mmol/L) are unmeasured. Merck Manual gives the typical value as 23 minus 11 equals 12 mmol/L; reference ranges differ between laboratories and sources (about 8 to 12 or 8 to 16 mmol/L), so use your own laboratory's range. Albumin is the main unmeasured anion, so in hypoalbuminaemia adjust the expected gap downward by 2.5 mmol/L for every 10 g/L (1 g/dL) fall in albumin. A raised gap means new unmeasured acids have appeared; a low gap is not an acidosis. ^[1]

For every 1 mmol/L the anion gap rises, bicarbonate should fall by about 1 mmol/L if buffering is the only process. Adding the delta gap to the measured bicarbonate (the corrected bicarbonate) should land in the normal range. If it is above normal, a metabolic alkalosis hides behind the acidosis. Classic example: sodium 137, chloride 90, bicarbonate 22, anion gap 25, delta gap 15, corrected bicarbonate 37, indicating mixed metabolic acidosis and metabolic alkalosis. ^{[1][2] [3]}

Ethylene glycol and methanol are osmotically active and raise measured osmolality beyond the calculated value. Calculated osmolarity is 2 times [Na+] plus glucose/18 plus BUN/2.8 plus ethanol/5 (conventional units). A difference above 10 mmol/kg suggests an exogenous osmole. In a high anion gap acidosis, an osmolar gap above 10 points strongly to methanol or ethylene glycol. Ethanol can produce a gap and mild acidosis, but it should never be considered the sole cause of a significant metabolic acidosis. ^[2]

Use this sequence for every gas.

1. Look at the pH: below 7.35 acidemia, above 7.45 alkalemia. ^[1]
2. Decide the primary process: low bicarbonate means metabolic acidosis, high PaCO2 respiratory acidosis, high bicarbonate metabolic alkalosis, low PaCO2 respiratory alkalosis. ^[1]
3. Check the other parameter against the compensation formulas. ^[1]
4. If metabolic acidosis, calculate the anion gap. ^[2]
5. Calculate delta gap and osmolar gap for a metabolic acidosis. ^[1][2]
6. For a normal anion gap acidosis, calculate the urine anion gap: [Na+] plus [K+] minus [Cl-] in urine. A strongly negative value (about -30 to -50 mmol/L) means renal response to gut loss; a positive value means renal bicarbonate loss, as in RTA. ^[2]
7. Recheck against the clinical picture. Numbers never diagnose a person. ^[1]

Compensation cannot bring the pH all the way back and never overshoots. Acute respiratory acidosis needs 3 to 5 days to become chronic; respiratory alkalosis shows full renal compensation after 2 to 3 days. ^[1][4][5]

The commonest causes are ketoacidosis, lactic acidosis, renal failure and toxic ingestions, and these four cover most cases. ^[2]

Ketoacidosis. The body switches from glucose to free fatty acid burning; the liver turns fatty acids into ketoacids (acetoacetate and beta-hydroxybutyrate, both unmeasured anions). Common settings: diabetes mellitus (diabetic ketoacidosis, insulin deficiency), alcohol use disorder (often after days of heavy drinking with vomiting and starvation), fasting and undernutrition (milder), and rare inherited amino acid disorders (isovaleric, methylmalonic acidemia). Alcoholic ketoacidosis often presents with normal or low glucose and prolonged vomiting. ^[2]

Lactic acidosis. Lactate accumulates when production outruns clearance, and it is the commonest metabolic acidosis in inpatients. Serious forms arise in shock (tissue hypoxia), severe hypoxia from lung disease, seizures, and hepatocellular failure. Drugs and toxins can impair mitochondrial oxidation (metformin and other biguanides, HIV nucleoside reverse transcriptase inhibitors, cyanide, carbon monoxide, iron, isoniazid, propofol). Bacterial overgrowth in short bowel syndrome can produce D-lactate, which standard lactate assays may not detect but which still causes an anion gap acidosis with encephalopathy. ^[2]

Renal failure raises the gap two ways: the failing kidney excretes less acid and reabsorbs less bicarbonate, and retained anions (sulphate, phosphate, urate, hippurate) are unmeasured. ^[2]

Toxins metabolised to acids. Methanol becomes formate and ethylene glycol becomes oxalate; both raise the anion gap and osmolar gap. Salicylates produce their own anions and stimulate respiration. Paraldehyde is a rare cause. If neither ketoacids nor lactate explains the picture, measure salicylates and look for an osmolar gap; ethylene glycol is often flagged by calcium oxalate crystals in the urine. Rhabdomyolysis is a rare acidosis attributed to proton and anion release. ^[2]

Many toxins add a second process, so recheck compensation. If the measured PaCO2 is lower than Winter's formula predicts, the patient is hyperventilating beyond compensation. ^[2]

Here bicarbonate is low but the anion gap is normal, so chloride rises. The commonest causes are gut or renal bicarbonate loss and impaired renal acid excretion. ^[2]

Gastrointestinal bicarbonate loss is most common: severe diarrhoea, drainage, fistulas, ileostomy or colostomy losses. These fluids are rich in bicarbonate. Some drugs (calcium chloride, magnesium sulphate, anion-exchange resins) and ureterosigmoidostomy convert chloride-rich urine into bicarbonate loss across bowel. ^[2]

Parenteral infusion of ammonium chloride, arginine or lysine, or rapid sodium chloride infusion can produce the same picture. ^[2]

Renal bicarbonate loss includes acetazolamide and other carbonic anhydrase inhibitors, hyperparathyroidism, tubulointerstitial disease, early chronic kidney disease and RTA. ^[2][6]

Urological procedures such as ureteroileal conduits and ureterosigmoidostomy allow chloride-rich urine to contact a mucosa that secretes bicarbonate. ^[2]

Toluene behaves like two acidoses: early it raises the anion gap, and later, as metabolites are excreted, leaves a normal gap. ^[2]

Urine anion gap. In a normal anion gap acidosis, calculate [Na+] plus [K+] minus [Cl-] in urine. A strongly negative value (about -30 to -50 mmol/L) means the kidneys are responding to extra-renal (usually gut) loss; a positive value means renal bicarbonate loss, most commonly RTA. ^[2]

RTA is a group of disorders in which the kidney excretes too little hydrogen ion or reabsorbs too little filtered bicarbonate, producing chronic metabolic acidosis with normal anion gap and usually hyperchloraemia. Presentation ranges from asymptomatic to stones, rickets or electrolyte crises. ^[6]

Type 3 RTA (carbonic anhydrase II deficiency) is extremely rare and behaves like a mixture of types 1 and 2. ^[6]

The distal tubule cannot secrete hydrogen ion, so urine stays inappropriately alkaline (pH above 5.5) during systemic acidosis. Plasma bicarbonate is frequently below 15 and sometimes below 10 mmol/L. Hypokalaemia is common, and hypercalciuria with low urine citrate produces nephrocalcinosis and calcium stones. Bone pain, osteomalacia or rickets can occur. ^[6]

Sporadic disease is commoner in adults and is often primary (almost always in women) or secondary; familial disease begins in childhood and is usually autosomal dominant. Secondary causes include autoimmune disease with hypergammaglobulinaemia (especially Sjogren disease and rheumatoid arthritis), kidney transplantation, medullary sponge kidney, chronic obstructive uropathy, nephrocalcinosis, cirrhosis, sickle cell anaemia, and drugs (amphotericin B, ifosfamide, lithium). Potassium can be high in chronic obstructive uropathy or sickle cell anaemia. Chronic kidney disease is common. ^[6]

Diagnosis is confirmed by a urine pH that stays above 5.5 during systemic acidosis, spontaneous or after an acid load test with ammonium chloride 100 mg/kg by mouth; healthy kidneys drop urine pH below about 5.3 within roughly 6 hours (sources quote 5.2 or 5.3). ^[6]

Treatment is alkali: adults receive sodium bicarbonate or sodium citrate 0.25 to 0.5 mmol/kg by mouth every 6 hours; children may need up to 2 mmol/kg per day divided every 8 hours. Potassium supplementation is usually unnecessary once dehydration and secondary hyperaldosteronism are corrected by bicarbonate. Potassium citrate is substituted when there is persistent hypokalaemia or calcium stones (sodium increases calcium excretion). Vitamin D and calcium address rickets or osteomalacia. ^[6]

The proximal tubule cannot reabsorb filtered bicarbonate, so bicarbonate spills into the urine: urine pH above 7 if plasma bicarbonate is normal, and below 5.5 once the plasma level is depleted. Plasma bicarbonate is usually 12 to 20 mmol/L, potassium is low and falls further when alkali is given. Volume depletion may give clinical clues. ^[6]

This syndrome is very rare. It most often occurs with Fanconi syndrome, light chain nephropathy from multiple myeloma, or drugs (acetazolamide, sulphonamides, ifosfamide, outdated tetracycline, streptozocin). It can accompany generalised proximal tubular dysfunction: glucose, uric acid, phosphate, amino acids, citrate, calcium, potassium and protein in the urine, with rickets or osteomalacia. Other causes include vitamin D deficiency, chronic hypocalcaemia with secondary hyperparathyroidism, kidney transplantation, heavy metal exposure, fructose intolerance, Wilson disease, Lowe syndrome and cystinosis. ^[6]

Fanconi syndrome is the clinical face of type 2 RTA: generalised proximal tubular dysfunction with bicarbonate, phosphate, glucose and amino acid wasting. Treat each deficiency, not just the acidosis. ^[6]

Diagnosis uses a bicarbonate infusion (sodium bicarbonate 0.5 to 1.0 mmol/kg/hour intravenously); in type 2 the urine pH rises above 7.5 and fractional bicarbonate excretion exceeds 15 percent. Potassium supplements are given before infusion because IV bicarbonate can worsen hypokalaemia. ^[6]

Management differs from type 1: plasma bicarbonate cannot be restored all the way to normal, so replacement only needs to exceed the daily acid load and hold serum bicarbonate at 22 to 24 mmol/L. Sodium bicarbonate or sodium citrate 10 to 15 mmol/kg/day in up to four divided doses is typical; lower levels risk growth disturbance, higher ones worsen potassium loss. Potassium supplements or potassium citrate are added if hypokalaemia develops. In difficult cases, low-dose hydrochlorothiazide 25 mg by mouth twice daily can stimulate proximal reabsorption. Hypophosphataemia and bone disease are treated with phosphate and vitamin D. ^[6]

Type 4 is by far the commonest RTA. It results from too little aldosterone or from distal tubular resistance. Aldosterone drives sodium reabsorption in exchange for potassium and hydrogen, so without it potassium and acid accumulate. Urine pH is usually below 5.5 (distal acidification remains intact), plasma bicarbonate usually above 17 mmol/L, and hyperkalaemia can suppress ammonia excretion, deepening the acidosis. ^[6]

The classic setting is hyporeninaemic hypoaldosteronism in diabetic nephropathy or chronic interstitial nephritis, but the list is long: chronic kidney disease of any cause, ACE inhibitors, angiotensin receptor blockers, potassium-sparing diuretics (amiloride, spironolactone, eplerenone, triamterene), NSAIDs, cyclosporine, heparin and low molecular weight heparins, pentamidine, trimethoprim, congenital adrenal hyperplasia (especially 21-hydroxylase deficiency), primary adrenal insufficiency, pseudohypoaldosteronism, volume expansion, obstructive nephropathy, sickle cell disease, systemic lupus erythematosus, HIV nephropathy, critical illness and aldosterone synthase deficiency. ^[6]

Type 4 is suspected in anyone with persistent hyperkalaemia without obvious cause (potassium supplements, potassium-sparing diuretics, chronic kidney disease) plus a normal or mildly reduced bicarbonate. Plasma renin activity is low, aldosterone low, cortisol normal in most cases. ^[6]

Treatment centres on the potassium, not the acid: volume expansion, dietary potassium restriction and potassium-wasting diuretics such as furosemide 20 to 40 mg by mouth once or twice daily titrated to effect. Alkalinisation is often unnecessary. A few patients need mineralocorticoid replacement (fludrocortisone 0.05 to 0.2 mg by mouth once daily, often higher in hyporeninaemic hypoaldosteronism), used cautiously because it can worsen hypertension, heart failure and oedema. ^[6]

Metabolic alkalosis is a primary rise in bicarbonate. Bicarbonate accumulation persists only when the kidney is told to retain it. Volume depletion and hypokalaemia are the commonest stimuli; anything raising aldosterone or mineralocorticoid activity (heart failure, cirrhosis, nephrotic syndrome, renal artery stenosis, Cushing syndrome, primary or secondary hyperaldosteronism) does the same. Hypokalaemia is both a cause and a consequence. ^[3]

The commonest causes are diuretic use and volume loss with loss of gastric acid and chloride (recurrent vomiting, nasogastric suction). Other causes include bicarbonate excess (milk-alkali syndrome, overzealous sodium bicarbonate, contraction and post-hypercapnic alkalosis), gastrointestinal acid loss (congenital chloridorrhea, villous adenoma, laxative abuse) and renal acid loss (Bartter and Gitelman syndromes, hypokalaemia and hypomagnesaemia, carbonic anhydrase inhibitors, some antibiotics such as carbenicillin, ticarcillin and penicillin, licorice and chewing tobacco via glycyrrhizin, and primary hyperaldosteronism). ^[3]

The bedside division is chloride responsiveness, using urine chloride. A chloride-responsive alkalosis involves chloride loss, so urine chloride is below 20 mmol/L; common in volume depletion (especially vomiting or nasogastric suction) and diuretic use, and it corrects with saline. A chloride-resistant alkalosis means aldosterone excess with volume expansion, urine chloride above 20 mmol/L; it does not correct with saline and commonly carries severe magnesium or potassium deficiency. ^[3]

Urine potassium sorts the resistant group: below 30 mmol/day points to hypokalaemia or laxative misuse; above 30 mmol/day without hypertension suggests diuretic abuse, Bartter or Gitelman; above 30 mmol/day with hypertension demands evaluation for hyperaldosteronism, mineralocorticoid excess and renovascular disease, with renin, aldosterone and cortisol measured. ^[3]

Treatment: saline infusion 50 to 100 mL/hour above losses corrects the chloride-responsive form until urine chloride rises above 25 mmol/L and urine pH normalises. The resistant form rarely responds to fluids alone and needs potassium and magnesium replacement or potassium-sparing diuretics. For severe alkalaemia above pH 7.6, hemofiltration or haemodialysis is an option; acetazolamide 250 to 375 mg orally or intravenously once or twice daily increases bicarbonate excretion. In kidney failure where dialysis is not an option, 0.1 to 0.2 normal hydrochloric acid intravenously through a central catheter at 0.1 to 0.2 mmol/kg/hour is effective with frequent blood gas and electrolyte checks. ^[3]

Respiratory acidosis is a primary rise in PaCO2 (hypercapnia), almost always from hypoventilation: central drive depression (stroke, opioids, alcohol, sedatives), neuromuscular failure (myasthenia, Guillain-Barre, critical illness weakness) or obstructive, restrictive or parenchymal lung disease. Hypoxia usually accompanies it. ^[4]

Acute hypoventilation raises carbon dioxide fast and pH falls before the kidneys buffer. Over 3 to 5 days the kidneys increase bicarbonate reabsorption and hydrogen excretion, moving pH most of the way back to normal and converting acute into chronic respiratory acidosis. Acute or worsening chronic disease presents with headache, confusion, anxiety, drowsiness and CO2 narcosis. Chronic compensated disease (for example COPD) may be surprisingly well tolerated. ^[4]

Diagnosis rests on arterial blood gas and serum electrolytes; a normal alveolar-arterial oxygen gradient nearly excludes lung disease as the cause of hypercapnia. ^[4]

Treatment is adequate ventilation by non-invasive positive pressure ventilation or intubation. Correct chronic hypercapnia slowly (over several hours) to avoid post-hypercapnic overshoot alkalosis with seizures and death. Replace potassium and chloride if depleted. Sodium bicarbonate is almost always contraindicated because of paradoxical central acidosis, except possibly in severe bronchospasm. ^[4]

Respiratory alkalosis is a primary fall in PaCO2 from hyperventilation, usually in response to hypoxia (high altitude, pulmonary embolism, severe asthma), metabolic acidosis, increased metabolic demand (fever), pain or anxiety; central causes (stroke, post-ictal states) also occur. ^[5]

Blood buffers soak up excess bicarbonate within minutes, but renal compensation (lower hydrogen ion excretion) takes 2 to 3 days. Acute disease causes light-headedness, confusion, peripheral and circumoral paraesthesia, cramps, syncope and carpopedal spasm from low ionised calcium. Chronic disease is usually asymptomatic. Hypokalaemia and hypophosphataemia can occur from intracellular shifts. ^[5]

Do not assume anxiety is the cause until serious disease is excluded; pulmonary embolism often causes respiratory alkalosis without hypoxia. Pseudorespiratory alkalosis is a trap in the ventilated patient with circulatory failure: the ventilator washes CO2 from arterial blood while tissues run acidotic. ^[5]

There is no treatment for the alkalosis itself. Find and treat the cause. Rebreathing into a paper bag can be dangerous with an unrecognised metabolic acidosis or hypoxia. ^[5]

A mixed disorder is two or more primary disturbances at once. It is diagnosed by failed compensation: PaCO2 or bicarbonate moves in a way the simple formulas do not predict, or corrected bicarbonate falls outside the normal range. Compensation cannot fully correct pH and never overshoots. ^[1]

Worked example 1. An ill patient with alcohol use disorder and recurrent vomiting has pH 7.40, PaCO2 41 mm Hg, HCO3- 22 mmol/L, sodium 137, chloride 90.

• Anion gap = 137 - (90 + 22) = 25, raised: metabolic acidosis (alcoholic ketoacidosis). ^[1]
• Winter's formula gives expected PaCO2 about 41, so respiratory compensation is appropriate. ^[2]
• Delta gap 15, corrected bicarbonate 37, above normal: hidden metabolic alkalosis from vomiting. ^[1][2]
• Conclusion: mixed metabolic acidosis and metabolic alkalosis, both needing treatment.

Worked example 2. A ventilated patient with severe asthma: pH 7.15, PaCO2 70 mm Hg, HCO3- 24 mmol/L. pH low with high PaCO2 is respiratory acidosis; bicarbonate unchanged means acute disease without renal compensation, needing ventilatory support. ^[4]

Worked example 3. A patient with diabetic ketoacidosis also becomes septic and develops vomiting: high anion gap metabolic acidosis (DKA) plus hidden metabolic alkalosis (vomiting/volume depletion), with sepsis adding lactic acidosis or hyperventilation. Use the delta gap. ^[2]

Bedside evaluation rests on arterial blood gas and serum electrolytes plus anion, osmolar and urine anion gaps. In metabolic acidosis, further workup is guided as follows. ^[2]

• Elevated anion gap: blood urea nitrogen, creatinine, glucose, lactate, possible toxins; salicylate levels where available; methanol and ethylene glycol (often unavailable, so rely on osmolar gap and calcium oxalate crystals for ethylene glycol). ^[2]
• Normal anion gap: urinary electrolytes and a full assessment for RTA. ^[2][6]

For severe metabolic acidosis below pH 7.0, most experts recommend intravenous sodium bicarbonate because of cardiovascular instability at lower pH, with a target pH of at least 7.10. Dose calculation: desired HCO3- = 0.30 x PaCO2; then (desired HCO3- - observed HCO3-) x 0.4 x body weight in kg. Example: 70 kg man, pH 6.92, PaCO2 40 mm Hg, HCO3- 8 mmol/L needs target 12, a rise of 4, giving 112 mmol over several hours; recheck pH and bicarbonate 30 to 60 minutes later. Bicarbonate is generally appropriate in normal anion gap acidosis (replacing lost base). In high anion gap acidosis it is controversial because organic acids are metabolised back to bicarbonate when the cause is treated, risking overshoot alkalosis, sodium and volume overload, hypokalaemia, paradoxical intracellular acidosis from CO2 generation, and increased minute ventilation. Give cautiously with monitoring; alternatives exist but offer no proven advantage. ^{[2] [1][3]}

Potassium depletion is common in metabolic acidosis; check frequently and replace with potassium chloride. ^[2]

Acid-base disorders can be suspected and much managed with little: clinical picture, electrolytes and, where possible, an arterial (or venous) blood gas. ^[2]

• Calculate the anion gap from sodium, chloride and bicarbonate; even one bicarbonate value separates dangerous from tolerated acidosis.
• Volume depletion and diarrhoea are much commoner than poisoning; rehydrate first with oral rehydration solution while looking for more.
• If arterial blood gas machines are unavailable, venous pH and PaCO2 usually track arterial values well enough; direction matters more than the exact number.
• Osmolar gap needs an osmometer. If unavailable, suspect toxic alcohol from history and crystals (calcium oxalate for ethylene glycol), and arrange transfer and dialysis early.
• RTA follow-up works with urine dipstick pH, electrolytes, creatinine and plain films for stones or nephrocalcinosis. Cheap oral alkali in divided doses is the basis of treatment for types 1 and 2.
• For type 4, review the drug list first and stop unnecessary ACE inhibitors, angiotensin receptor blockers, potassium-sparing diuretics, NSAIDs and trimethoprim where the clinical situation allows.
• Severe acidosis below pH 7.0 without renal replacement often needs early referral; bicarbonate and transfer plans should start together.
• Do not correct chronic hypercapnia abruptly where monitoring is limited.

Acute kidney injury; chronic kidney disease; hypokalaemia; hyperkalaemia; hypocalcaemia; hyponatraemia; hypernatraemia; hypomagnesaemia; urinalysis.