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⁺, PO₄^3-, 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

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

1. Diabetes (secondary glomerular disease)
2. Chronic hypertension
3. Chronic glomerulonephritis
4. 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

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

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 (↑PO₄^3-, ↓PTH)
  • Hypoparathyroidism
  • Hypomagnesaemia (magnesium is required for PTH secretion)
  • Cinacalcet
• Vitamin D deficiency (↓PO₄^3-, ↑PTH)
• Increased deposition in bones          
  • Bisphosphonates
• Other causes (↑PO₄^3-, ↑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 10ml 10% IV over 10 minutes – may be repeated until asymptomatic and can be followed by an infusion if required (50ml 10% calcium gluconate in 500ml 0.9% saline over 12 hours)
• Mild (>1.9mmol/L and asymptomatic): calcium supplements (e.g. Sandocal or Calcichew 1000mg 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.

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. continuous 0.9% saline at 1L over 4-6 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

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.

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.

A patient with known prostate cancer with bony metastasis presents with confusion. A calcium level (corrected) is elevated at 3.6mmol/L.

Try some interpretation stations

1. Hyperkalaemia
2. Diabetic ketoacidosis
3. Find lots more interpretation stations here