Urea and creatinine
Physiology
Creatinine
- Creatine is a substance produced primarily by the liver
- Creatine is phosphorylated to creatine phosphate, which is used as an energy store for muscles
- To produce energy, creatine phosphate is broken down to creatine and phosphate, which allows ADP to be converted to ATP
- Creatine is metabolised to the waste product creatinine, which passes to the kidneys where it is excreted
- Changes in creatinine concentration are fairly specific for determining kidney injury, but baseline level depends on muscle mass
Urea
- Ammonia is a toxic waste product produced during amino acid catabolism
- Ammonia is converted to urea in the liver by the ‘urea cycle’
- Urea then passes to the kidneys where it is excreted
- Serum urea concentration also rises in kidney injury but it is not specific for this. Other causes of high/low urea include:
- ↑urea = dehydration, GI bleeding, increased protein breakdown (trauma, infection, malignancy), high protein intake
- ↓urea = malnutrition, liver disease, pregnancy
Acute kidney injury
Acute kidney injury (AKI) = rise in serum creatinine >50% from baseline, or urine output <0.5ml/kg/hour for 6 hours.
Determine if AKI is pre-renal, renal, or post-renal.
ALL patients need:
- Urine dipstick (interpreted in context of history)
- Bloods: FBC ± haematinics, U&Es, CRP, Ca2+, PO43-, PTH
- VBG: check for: metabolic acidosis/low bicarbonate (may need weak bicarbonate infusion); and hyperkalaemia
- Accurate fluid balance chart (requires catheterisation)
- Stop nephrotoxic drugs and stop/dose-reduce renal excreted drugs
Pre-renal AKI (70%) – caused by renal hypoperfusion
- Causes: hypovolaemia/sepsis (most common AKI cause), renovascular disease, cardiorenal failure (increased venous pressure reduces renal perfusion pressure)
- Suggested by: history, dehydration, hypotension, rise in urea greater than rise in creatinine
- Investigation:
- Treatment: treat cause (IV fluids in hypovolaemia)
- Complications: acute tubular necrosis
Intrinsic AKI (20%) – caused by renal damage
- Causes
- Acute tubular necrosis (ischaemic or nephrotoxic): suggested by renal hypoperfusion or tubular nephrotoxin
- Acute interstitial nephritis: suggested by causative drugs, sometimes with eosinophillia or rash
- Glomerulonephritis: suggested by haematuria/proteinuria on dip and other glomerulonephritis/vasculitic symptoms
- Thrombotic microangiopathy (e.g. microangiopathic haemolytic anaemia, hypertensive emergency, scleroderma renal crisis): suggested by anaemia, thrombocytopaenia ± haemolysis evidence (e.g. hyperbilirubinaemia, fragments on film)
- Investigation:
- Urine dipstick: blood +++ protein +++ in glomerulonephritis; in acute tubular necrosis, urine is usually bland
- Urine protein:creatinine ratio (to quantify and monitor proteinuria if dipstick is positive for protein; <15mg/mmol = normal; >300mg/mmol = nephrotic)
- NB: urine protein:creatinine ratio (mg/mmol) X 10 ≈ 24 hour protein loss (mg)
- Possible further tests
- Nephritic screen (if suspect glomerulonephritis): antinuclear antibodies, anti-neutrophil cytoplasmic antibodies, anti-glomerular basement membrane antibody, complement, rheumatoid factor, anti-streptolysin O titre, anti-DNase B, hepatitis B/C serology, HIV serology, antiphospholipid antibodies
- Myeloma screen: immunoglobulins/protein electrophoresis and serum free light chains
- If thrombocytopenia/suspicion of haemolysis: blood film, lactate dehydrogenase, haptoglobin, bilirubin
- Creatinine kinase (if rhabdomyolysis suspected)
- Renal biopsy indications: unexplained AKI, suspected glomerulonephritis, positive nephritic screen, persistent acute tubular necrosis, or suspected interstitial nephritis
- Urgent renal biopsy if rapidly progressive glomerulonephritis suspected (suggested by rapid loss of kidney function, worsening severe proteinuria/haematuria, and nephritic syndrome)
- Treat cause, for example:
- Stop causative agent for acute interstitial nephritis
- Corticosteroids, diuretics and ACE inhibitor may be required for glomerulonephritis
Post-renal AKI (10%) – caused by obstruction of the urinary tract
- Cause: urinary tract obstruction
- Ureters: ureteric calculi, vesico-ureteric reflux, ureteric stricture, tumour (e.g. transitional cell carcinoma), extrinsic compression
- Bladder: neurogenic bladder, bladder calculi, tumour (e.g. bladder carcinoma)
- Urethra: benign prostatic hypertrophy, prostate cancer, stricture, blocked catheter
- Suggested by: history, urea and creatinine raised in equal proportion
- Investigation:
- Bladder scan
- Renal tract USS
- Treatment: relieve obstruction (catheter if urethral; nephrostomy/ureteric stent if ureteric) and treat cause
- Complications: hydronephrosis (can progress to irreversible renal damage)
Indications for renal replacement therapy in acute kidney injury
Refractory:
- Acidosis – pH<7.2
- Electrolyte abnormalities (hyperkalaemia, hyponatraemia, hypercalcaemia) – K+>6.5 or ECG changes
- Intoxicants (methanol, lithium, salicylates)
- Overload – acute pulmonary oedema
- Uraemia – urea >60, uraemic pericarditis or encephalopathy
NB: in chronic kidney disease, regular dialysis is required when the GFR is <15ml/minute, and there are symptoms or complications of kidney disease.
Chronic kidney disease
Chronic kidney disease = presence of marker of kidney damage (e.g. proteinuria) or decreased GFR for > 3 months
Commonest causes
- Diabetes (secondary glomerular disease)
- Chronic hypertension
- Chronic glomerulonephritis
- Polycystic kidney disease
Determining cause
- History
- Urine dipstick
- Renal USS
- Renal biopsy if required
Management
- Manage cause, e.g. diabetic control, antihypertensives, cardiovascular risk factor modification
- General measures: fluid restriction, dietary protein restriction, ACE inhibitor
- Treat complications:
- Hypertension → antihypertensives
- Oedema → fluid restriction ± furosemide
- Anaemia → iron supplementation ± erythropoietin
- Secondary hyperparathyroidism →
- Active vitamin D therapy, e.g. alfacalcidol, calcitriol
- Dietary phosphate restriction ± phosphate binders, e.g. calcium edetate/sevelamer
- PTH-control with parathyroidectomy or cinacalcet
- Acidosis → sodium bicarbonate
- Hyperlipidaemia → statin
- Hyperkalaemia → dietary potassium restriction
- Acidosis → sodium bicarbonate
- Dialysis (when GFR is <15ml/minute, and there are symptoms or complications of kidney disease)
Sodium
Physiology
- Na+ is an extracellular ion
- H2O follows solutes due to osmosis (e.g. Na+, albumin)
- Aldosterone increases Na+ reabsorption (in exchange for K+) from the distal convoluted tubule
- Antidiuretic hormone causes reabsorption of H2O (alone) from the collecting duct
Hyponatraemia
→ nausea/vomiting, headache, confusion, seizures, reduced consciousness
Causes
Hyponatraemia causes
Investigations
- Plasma osmolality (to confirm if true hyponatraemia) + glucose
- Low = true hyponatraemia
- Normal = false hyponatraemia (‘pseudohyponatraemia’ due to hyperlipidaemia or hyperproteinemia)
- High = dilutional (due to hyperglycaemia, e.g. in hyperosmolar hyperglycaemic state/DKA; alcohols; or mannitol)
- Urinary sodium and osmolality (to determine whether the problem is occurring in the kidneys or elsewhere)
- Specific tests to investigate for specific causes, for example:
- SIADH: low plasma osmolality (<275) with high urine osmolality (>100) and high urine sodium (>30); investigate cause
- Adrenal insufficiency: 9am cortisol screening test, Synacthen (synthetic ACTH) test
- Hypothyroidism: TFTs
Check TFTs and 9am cortisol in all euvolaemic patients |
Management
- Treat cause
- Sodium correction
- Severe symptoms (e.g. vomiting, seizures, low GCS), regardless of cause: consider 3% hypertonic saline (e.g. 150ml over 20 minutes, repeated if necessary), usually in ICU with close monitoring
- Hypovolaemic: replace lost fluid with 0.9% saline/Hartmann’s solution – slowly if chronic, e.g. 1L over 12 hours
- Euvolaemic: treat cause
- If SIADH or oedematous: fluid restrict to 1 litre/day (excess H2O causes dilutional hyponatraemia); consider demeclocycline (± tolvaptan) for fluid restriction-resistant SIADH; diuretics for heart failure
NB: chronic hyponatraemia (onset over 48 hours) must be corrected slowly, i.e. maximum 10mmol/L change in 24 hours (risk of osmotic change causing osmotic demyelination syndrome).
Hypernatraemia
→ thirst, confusion, muscle twitching/spasms
Causes
- Euvolaemic = iatrogenic (e.g. excess IV sodium-containing fluids, sodium-containing drugs)
- Hypovolaemic
- Producing small volumes of concentrated urine (normal response to hypovolaemia) = dehydration
- Not producing small volumes of concentrated urine (abnormal response to hypovolaemia)
- Diabetes insipidus = urine osmolality <750 + serum osmolality >300 (kidneys not reabsorbing sufficient H2O)
- Osmotic diuresis, e.g. due to hyperglycaemia or osmotic diuretics (kidneys losing H20 and solutes)
Investigation
- Urine and serum osmolality
- Fluid deprivation test to confirm diabetes insipidus
Management
- Treat cause
- Sodium correction
- Hypovolaemic (signs include hypotension, tachycardia, orthostatic hypotension): replace deficit with 0.9% saline/Hartmann’s solution
- Euvolaemic: 5% dextrose – slowly if chronic, e.g. 1L over 12 hours
NB: chronic hypernatraemia (onset over 48 hours) must be corrected slowly, i.e. maximum 10mmol/L change in 24 hours (risk of osmotic change causing osmotic demyelination syndrome).
Potassium
Physiology
- K+ is 90% intracellular
- Multiple pumps affect serum K+:
Hypokalaemia
→ arrhythmias, tremor, muscle weakness/cramps, constipation
Causes
- Increased renal loss
- Diuretics (except potassium-sparing diuretics)
- Endocrinological (steroids, Cushing’s syndrome, hyperaldosteronism)
- Renal tubular acidosis
- Hypomagnesaemia
- Systemic alkalosis
- Intestinal loss
- Intestinal fluid loss (vomiting/diarrhoea)
- Increased cellular uptake
- Salbutamol
- Insulin
- Systemic alkalosis
Management
- >2.5mmol/L: potassium supplements (e.g. Sando-K 2 tablets TDS x 3/7), or 20-40mmol potassium chloride in each litre IV fluids
- <2.5mmol/L: 40mmol/L potassium chloride in 1L 0.9% saline over 4-6 hours (NEVER give >10mmol/hour K+ outside ICU)
- Treat cause
Hyperkalaemia
→ arrhythmias, lethargy, muscle weakness
Causes
- Reduced renal excretion
- Acute/chronic kidney injury
- Drugs (potassium-sparing diuretics, ACE inhibitors, NSAIDs)
- Aldosterone deficiency (Addison’s disease/adrenal insufficiency) – ↓Na+ ↑K+
- Systemic acidosis
- Excess K+ load
- Iatrogenic
- Massive blood transfusion
- Release from intracellular fluid
- Systemic acidosis
- Tissue breakdown, e.g. rhabdomyolysis, haemolysis, tumour lysis syndrome, burns, crush injury
NB: may be due to pseudohyperkalaemia (haemolysis/EDTA-contaminated sample).
Management
- Acute management
- ECG and 3-lead cardiac monitoring
- Changes: flat wide P waves, wide bizarre QRS, tall tented T waves
- Calcium gluconate 30ml 10% IV over 15 minutes
- Protects myocytes (required if there are ECG changes; also consider if severe, i.e. ≥6.5mmol/L, without ECG changes)
- Works in minutes – check ECG changes resolved; repeat dose if no effect within 10 minutes
- Lasts 30-60 minutes
- Actrapid insulin 10 units in 125ml 20% dextrose IV over 30 minutes + 10mg salbutamol neb
- Temporarily shifts potassium into cells
- There is a risk of hypoglycaemia: monitor capillary glucose before, during and regularly after. Consider giving 10% glucose infusion at 50ml/h for 5 hours after, if the pre-treatment capillary glucose is <7mmol/L.
- Gradually decreases potassium and lasts 1-2 hours, after which there is usually a slow rebound
- Check K+ has normalised after 2 hours (dose can be repeated if not) and check again a few hours later
- Nebulised salbutamol may be used in addition for similar but lesser effect – lasts 2 hours
- Sodium zirconium cyclosilicate 10g PO TDS for up to 72 hours
- Works slowly
- Only treatment that actually removes potassium from body
- May start with this if only moderate hyperkalaemia, i.e. K+ ≤ 5.9mmol/L
- Consider renal replacement therapy if above fails (also consider sodium bicarbonate in severe acidosis)
- Treat cause
Reference: The Renal Association ‘Treatment of acute hyperkalaemia in adults’ 2020
Calcium
Physiology
- Arrows indicate movement of calcium under influence of vitamin D and PTH:
- PTH should increase in response to hypocalcaemia due to hormonal feedback
- Always look at the corrected calcium value, which is adjusted for albumin
Hypocalcaemia
→ CATs go numb: Convulsions, Arrhythmias, Tetany, numbness (periorbital, hands, feet)
Causes
- PTH deficiency (↑PO43-, ↓PTH)
- Hypoparathyroidism
- Hypomagnesaemia (magnesium is required for PTH secretion)
Cinacalcet
- Vitamin D deficiency (↓PO43-, ↑PTH)
- Increased deposition in bones
- Other causes (↑PO43-, ↑PTH)
- Chronic kidney disease (inability to hydroxylate 25-OH vitamin D and calcium binding to retained phosphate)
- Pseudohypoparathyroidism (resistance to PTH)
- Rhabdomyolysis/tumour lysis syndrome (calcium binds to high phosphate)
Investigation
- Initial tests
- Renal function
- PTH
- Phosphate, magnesium
Management
- Severe (<1.9mmol/L or symptomatic): calcium gluconate 10-20ml 10% in 50-100ml 5% dextrose IV over 10 minutes with cardiac monitoring – may be repeated until asymptomatic and can be followed by an infusion if required (50ml 10% calcium gluconate in 500ml 0.9% saline or 5% dextrose at 50-100ml/hour)
- Mild (>1.9mmol/L and asymptomatic): calcium supplements (e.g. Sandocal 1000 2 tablets BD)
- Treat cause: in severe vitamin D deficiency, load with 50,000 units colecalciferol once weekly for 6 weeks; in mild vitamin D deficiency, give 800 units once daily long-term; or, if calcium and vitamin D deficient, give Adcal-D3 long-term; in end-stage CKD-associated vitamin D deficiency, use alfacalcidol (1-α hydroxycholecalciferol) instead because the kidney disease impairs the terminal hydroxylation required for vitamin D synthesis.
Reference: Society for Endocrinology ‘Emergency management of acute hypocalcaemia in adult patients’ 2016
Hypercalcaemia
→ ‘painful bones, renal stones, abdominal groans, and psychic moans’
Causes
- PTH excess
- Primary hyperparathyroidism (↑PTH) or tertiary hyperparathyroidism (↑↑↑PTH)
- Ectopic PTH/PTH-related peptide secretion (e.g. squamous cell lung cancer)
- Vitamin D excess
- Excessive vitamin D intake
- Granulomatous diseases (e.g. sarcoidosis)
- Increased release from bones
- Bony metastasis (↑ALP)
- Myeloma (normal ALP)
- Thyrotoxicosis (mechanism unknown)
- Other causes
- Drugs that decrease renal excretion (e.g. thiazide diuretics)
NB: dehydration is also a common cause. (Urea and albumin also likely raised.)
Investigation
Investigate for cause if not clear:
- Initial tests: renal function, ALP, PTH, phosphate, vitamin D
- Myeloma screen
- CT chest, abdomen and pelvis and/or isotope bone scan (if malignancy/bony metastasis suspected)
Management
- IV fluids: replace fluid deficit and keep patient well hydrated (e.g. . 0.9% saline 4-6L in 24 hours)
- IV bisphosphonate (e.g. zoledronic acid 4mg IV): may be used in severe hypercalcaemia (>3.5mmol/L or symptomatic) if calcium stops falling with IV fluids alone. One-off dose; generally takes a few days to work. Dose may be reduced for poor renal function.
- Treat cause
Reference: Society for Endocrinology ‘Emergency management of acute hypercalcaemia in adult patients’ 2016
Magnesium
Hypomagnesaemia
→ lethargy, muscle weakness/cramps, tremors, arrhythmias, seizures
Causes
- Reduced intake
- Poor nutritional intake
- Malabsorption
- Alcoholism
- Excess loss
- GI loss, e.g. severe diarrhoea, vomiting, NG losses, proton pump inhibitors
- Renal loss, e.g. ketoacidosis, renal tubular diseases, hyperaldosteronism, diuretics, aminoglycosides
NB: hypomagnesaemia can cause hypokalaemia (magnesium normally inhibits renal potassium excretion) and hypocalcaemia (magnesium is required for PTH secretion and sensitivity)
Management
- PO: magnesium aspartate 1 sachet (10mmol) BD x 3/7
- IV: 5grams (20mmol) magnesium in 500ml 0.9% saline over 5 hours
- Correct hypomagnesaemia before concurrent hypokalaemia and hypocalcaemia if possible
Phosphate
Hypophosphataemia
→ lethargy, muscle weakness (skeletal, cardiac and diaphragmatic), change in mental state
Causes
- Reduced intake/absorption
- Vitamin D deficiency
- Poor nutrition
- Malabsorption (including due to alcoholism and drugs, e.g. antacids)
- Increased use (phosphate shifts into cells to produce ATP from ADP for energy stores)
- Refeeding syndrome
- Insulin therapy
- Alkalosis
- Excess renal loss
- Primary hyperparathyroidism
- Renal tubular diseases
Management
- PO: Phosphate-Sandoz 2 tablets TDS x 3/7
- IV: Phosphate Polyfusor (50mmol in 500ml), 100-300ml over 12-24 hours depending on severity and patient weight or sodium glycerophosphate 10mmol in 500ml 0.9% saline over 12 hours – must give through different cannula to other electrolytes if co-administering
- Do not give if hypercalcaemic or oliguric
Try some scenarios
Find the normal lab values here.
A patient presents with worsening right heart failure with extensive peripheral oedema. She normally takes bumetanide 1mg BD, eplerenone 25mg OD and ramipril 2.5mg OD. Blood tests are taken: Na+ 120, K+ 4, Ur 14, Cr 288. Her kidney function and sodium were normal when last checked 6 months ago.
What abnormalities have you identified on the blood test and what is the likely reason for them?
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How would you manage the patient?
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You are on an acute medical unit shift. You are reviewing a patient referred in by their GP. The patient is a 42 year old with a history of recurrent UTIs, for which she takes prophylactic nitrofurantoin. She had a blood test because she was feeling tired. She was referred in due to the results, which showed: Na+ 144, K+ 6.9, Ur 25, Cr 780. The patient is systemically well and observations are normal. She appears euvolaemic.
Which initial investigations would you consider?
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What are your priorities in management? Include doses if you would give any medications.
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What are the indications for acute renal replacement therapy and does this patient require it?
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The patient has a normal urine dipstick and a normal ultrasound KUB. Her FBC shows a mild eosinophillia. What is the most likely diagnosis?
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A patient with known prostate cancer with bony metastasis presents with confusion. A calcium level (corrected) is elevated at 3.6mmol/L.
How would you treat the hypercalcaemia?
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Which ECG changes may be observed?
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Try some interpretation stations
- Hyperkalaemia
- Diabetic ketoacidosis
- Find lots more interpretation stations here