Urea and Electrolytes

The urea and electrolytes panel measures sodium, potassium, chloride, bicarbonate (total carbon dioxide), urea and creatinine, usually with a calculated eGFR and anion gap. Sodium, potassium and chloride are measured by ion selective electrodes, bicarbonate enzymatically, urea by the urease reaction, and creatinine by enzymatic or Jaffe methods. The panel assesses fluid and electrolyte balance, acid base status and kidney function, and is the commonest biochemistry request in hospital practice.

Abnormalities are frequent in inpatients. Hyponatraemia is the commonest electrolyte disorder, affecting up to a third of hospitalised patients on some measures, and potassium disorders and acute kidney injury follow in frequency.

Indications. Acute illness, vomiting, diarrhoea, dehydration, confusion, seizures, arrhythmia, hypertension, heart failure, diabetes, kidney disease, liver disease, adrenal and pituitary disease, monitoring of diuretics, ACE inhibitors, angiotensin receptor blockers, mineralocorticoid antagonists, lithium, digoxin and other nephrotoxic drugs, intravenous fluid therapy, and perioperative assessment.

Specimen. Serum or lithium heparin plasma, separated within 2 to 4 hours. Fasting is not needed, though a meal high in protein can raise urea and cooked meat raises creatinine. Sample from the arm not receiving an infusion, and without prolonged fist clenching or tourniquet time.

Adult reference ranges are given. Local ranges take precedence.

Sodium. The main extracellular cation, which determines plasma osmolality and reflects water balance more than sodium content. Range: 135 to 145 mmol/L. Raised: water loss (diabetes insipidus, osmotic diuresis, burns, insensible and gastrointestinal losses), inadequate water intake, and sodium gain (hypertonic saline, sodium bicarbonate, primary hyperaldosteronism).

Lowered: hypovolaemic causes (diuretics, vomiting, diarrhoea, adrenal insufficiency, cerebral salt wasting, third space losses), euvolaemic causes (SIADH, hypothyroidism, cortisol deficiency, primary polydipsia, low solute intake), and hypervolaemic causes (heart failure, cirrhosis, nephrotic syndrome, kidney failure).

Hyponatraemia is mild at 130 to 134 mmol/L, moderate at 125 to 129 and severe under 125. Always check serum osmolality, since hyperglycaemia and mannitol give hypertonic hyponatraemia, and severe hyperlipidaemia or paraproteinaemia give a false (pseudo) low value with indirect electrodes. Each 5.6 mmol/L (100 mg/dL) rise in glucose over normal lowers sodium by about 1.6 to 2.4 mmol/L. Rapid correction of chronic hyponatraemia risks osmotic demyelination, particularly with alcohol dependence, malnutrition, liver disease or hypokalaemia.

Potassium. The main intracellular cation, which sets the resting membrane potential of nerve and muscle. Range: 3.5 to 5.0 mmol/L in plasma, and up to about 0.4 mmol/L higher in serum.

Raised: reduced kidney excretion (acute kidney injury, chronic kidney disease), acidosis, adrenal insufficiency, type 4 renal tubular acidosis, rhabdomyolysis, tumour lysis, and drugs (ACE inhibitors, angiotensin receptor blockers, spironolactone, eplerenone, trimethoprim, non-steroidal anti-inflammatory drugs, heparin, ciclosporin, tacrolimus, potassium supplements, suxamethonium, beta blockers).

Lowered: gastrointestinal loss, loop and thiazide diuretics, hyperaldosteronism, Cushing syndrome, magnesium deficiency, insulin, beta agonists, alkalosis, periodic paralysis, renal tubular acidosis, amphotericin and refeeding.

Hyperkalaemia is mild at 5.5 to 5.9 mmol/L, moderate at 6.0 to 6.4 and severe at 6.5 or over. Hypokalaemia is mild at 3.0 to 3.4, moderate at 2.5 to 2.9 and severe under 2.5. ECG changes (peaked T waves, flat P waves, wide QRS in high values, and U waves, ST depression and arrhythmia in low values) matter more than the number. Acidosis raises potassium by about 0.6 mmol/L for each 0.1 fall in pH, though the relationship varies by cause.

Chloride. The main extracellular anion. Range: 98 to 106 mmol/L. Raised: non-anion gap metabolic acidosis (diarrhoea, renal tubular acidosis, saline loading), hypernatraemia, and compensation for respiratory alkalosis. Lowered: vomiting, nasogastric loss, loop and thiazide diuretics, metabolic alkalosis, SIADH, adrenal insufficiency, burns, and compensation for chronic respiratory acidosis.

It is read alongside sodium and bicarbonate. High chloride with low bicarbonate and a normal anion gap indicates non-gap acidosis, and low chloride with high bicarbonate indicates metabolic alkalosis. A urinary chloride under 20 mmol/L separates saline responsive alkalosis (vomiting, past diuretic use) from other causes. Bromide and iodide interfere with some chloride electrodes and give falsely high results.

Bicarbonate (total carbon dioxide). The main buffer of extracellular acid, which reflects metabolic acid base status. Range: 22 to 29 mmol/L. Raised: metabolic alkalosis (vomiting, diuretics, hyperaldosteronism, Cushing syndrome, milk alkali syndrome), compensation for chronic respiratory acidosis, and bicarbonate or acetate infusion. Lowered: metabolic acidosis (ketoacidosis, lactic acidosis, kidney failure, toxic alcohols, salicylates, diarrhoea, renal tubular acidosis), and compensation for respiratory alkalosis.

A value under 15 mmol/L suggests significant acidosis and under 10 is severe. Underfilled tubes and delay lower the result through loss of carbon dioxide. A venous value gives a good estimate, and a blood gas is needed when the pH or carbon dioxide tension matters.

Anion gap. Calculated as sodium minus (chloride plus bicarbonate), which estimates unmeasured anions. Range: about 8 to 16 mmol/L when potassium is not included, with laboratory specific limits. Raised: ketoacidosis (diabetic, alcoholic, starvation), lactic acidosis, uraemia, salicylate, methanol, ethylene glycol, propylene glycol, paracetamol toxicity (pyroglutamic acid), and D-lactic acidosis. Lowered: hypoalbuminaemia, paraproteinaemia (IgG myeloma), lithium, bromide, hypercalcaemia, hypermagnesaemia, and laboratory error.

Albumin lowers the gap by about 2.5 mmol/L for each 10 g/L fall below 40 g/L, so correct for albumin when it is low. The delta ratio (rise in anion gap divided by fall in bicarbonate) of 1 to 2 indicates a pure high gap acidosis, under 1 indicates an added non-gap acidosis, and over 2 indicates an added metabolic alkalosis. An osmolar gap over about 10 mOsm/kg suggests toxic alcohols.

Urea. Waste product of protein catabolism, filtered and partly reabsorbed in the tubule. Range: 2.5 to 7.8 mmol/L (blood urea nitrogen 7 to 21 mg/dL). Raised: reduced GFR, hypovolaemia, heart failure, high protein intake, upper gastrointestinal bleeding, catabolic states (sepsis, trauma, corticosteroids), tetracyclines and urinary tract obstruction. Lowered: liver failure, low protein intake, overhydration, SIADH, pregnancy, nephrotic syndrome, urea cycle disorders and infancy.

Urea rises more than creatinine in hypovolaemia, because volume depletion increases tubular reabsorption. A ratio of blood urea nitrogen to creatinine (both in mg/dL) over 20 to 1 suggests a pre-renal cause or upper gastrointestinal bleeding, and under 10 to 1 suggests intrinsic kidney disease or liver failure. Multiply mmol/L by 2.8 to give blood urea nitrogen in mg/dL.

Creatinine. Breakdown product of muscle creatine, filtered by the glomerulus with a small tubular secretion. Range: men 60 to 110 micromol/L (0.7 to 1.2 mg/dL), women 45 to 90 micromol/L (0.5 to 1.0 mg/dL).

Raised: reduced GFR (acute kidney injury, chronic kidney disease), large muscle mass, creatine supplements, cooked meat meal, rhabdomyolysis, drugs that block tubular secretion without lowering GFR (trimethoprim, cimetidine, dolutegravir, cobicistat, fenofibrate), and assay interference (Jaffe method with glucose, ketones, cephalosporins, bilirubin).

Lowered: low muscle mass (older age, malnutrition, amputation, paraplegia, sarcopenia, cachexia), pregnancy, liver disease, and overhydration.

Creatinine rises only after GFR has fallen by about half, and lags behind acute change, so a normal value does not exclude early or acute kidney injury. Acute kidney injury is defined by a rise of 26.5 micromol/L (0.3 mg/dL) or more within 48 hours, a rise to 1.5 times baseline or more within 7 days, or urine output under 0.5 mL/kg/h for 6 hours. Stage 1 is 1.5 to 1.9 times baseline, stage 2 is 2.0 to 2.9 times, and stage 3 is 3.0 times or more, a value of 354 micromol/L (4 mg/dL) or more, or need for kidney replacement.

eGFR. Estimated glomerular filtration rate, calculated from creatinine, age and sex using a race free equation, and reported in mL/min/1.73 m². Range: over 90 in young adults, declining by about 1 each year from the fourth decade. Chronic kidney disease stages are G1 90 or over, G2 60 to 89, G3a 45 to 59, G3b 30 to 44, G4 15 to 29 and G5 under 15, and diagnosis needs persistence for over 3 months or markers of kidney damage.

It is not valid in acute kidney injury or any unsteady state, in pregnancy, in extremes of muscle mass or body size, with amputation, high meat intake, or on dialysis. Cystatin C improves accuracy when creatinine is unreliable. For drug dosing at extremes of body size, use the value de-indexed to body surface area, or measured clearance.

Critical values and findings needing immediate action. Triggers vary by laboratory.

• Sodium under 120 mmol/L or over 160 mmol/L, or any symptomatic change in sodium.
• Potassium under 2.5 mmol/L or over 6.5 mmol/L, or over 6.0 with ECG change.
• Bicarbonate under 10 mmol/L or over 40 mmol/L, with a high anion gap needing a cause urgently.
• Creatinine rising to 1.5 times baseline or more, or an eGFR under 15.
• Urea over 40 mmol/L, or any rapid rise with oliguria.
• Anion gap over 20 mmol/L with an unexplained osmolar gap (suspect toxic alcohols).

Interferences and pitfalls.

• Haemolysis, delayed separation, cold storage, fist clenching and thrombocytosis (over 600 x10⁹/L) or leucocytosis (over 100 x10⁹/L) raise serum potassium. A repeat in a heparinised sample confirms pseudohyperkalaemia.
• EDTA contamination gives high potassium with low calcium, magnesium and ALP.
• Sampling from an arm with an infusion dilutes the sample, or adds sodium, potassium or glucose.
• Severe hyperlipidaemia or paraproteinaemia causes pseudohyponatraemia with indirect electrodes.
• Delay and underfilled tubes lower bicarbonate.
• Jaffe creatinine is raised by glucose, ketones, bilirubin and some cephalosporins, and enzymatic methods are more specific.
• Creatinine and eGFR are unreliable in unsteady states, and a normal value does not exclude early kidney injury.
• Drugs that block tubular creatinine secretion raise creatinine without lowering GFR.

Special groups.

• Neonates: potassium up to about 6.0 mmol/L is common in the first days, creatinine at birth reflects maternal values, and age specific ranges apply.
• Children: creatinine is lower and rises with age. A bedside paediatric equation using height and creatinine estimates GFR.
• Pregnancy: creatinine falls to about 40 to 75 micromol/L and urea falls, sodium is about 4 to 5 mmol/L lower, and bicarbonate about 18 to 22 mmol/L from compensated respiratory alkalosis. A creatinine in the usual adult range can indicate renal impairment.
• Older adults: lower muscle mass overestimates GFR, and SIADH, diuretics and other drugs make hyponatraemia common.
• Liver disease: urea is low, and creatinine overestimates GFR.
• Athletes, those with large muscle mass and creatine users: creatinine is higher without kidney disease. Vegetarians have lower values.

Follow up tests. Serum and urine osmolality, urine sodium, potassium and chloride, glucose, calcium, magnesium and phosphate, cystatin C, urine albumin-to-creatinine ratio, urinalysis, cortisol, thyroid function tests, arterial or venous blood gas, lactate, blood ketones, creatine kinase, urate, aldosterone and renin, ECG, renal tract ultrasound.