Acute kidney injury
Background, pathophysiology, and causes [link]
Assessment and investigations [link]
Nutrition in acute kidney injury [link]
Drug therapy [link]
Follow-up of acute kidney injury [link]
Haemolytic uraemic syndrome: definitions [link]
Typical (D+) haemolytic uraemic syndrome: epidemiology and notes [link]
Haemolytic uraemic syndrome: atypical [link]
Tumour lysis syndrome [link]
Background, pathophysiology, and causes
Acute renal failure (ARF) is a sudden, potentially reversible inability of the kidney to maintain normal body chemistry and fluid balance. It is usually accompanied by oliguria (urine output <0.5mL/kg/h or <1mL/kg/h in a neonate), but polyuric ARF can also occur.
The term ARF is now being replaced by acute kidney injury (AKI). However, pre-renal ARF without renal injury (e.g. hypovolaemia), does not fulfill the definition of AKI.
• Renal insult causes vasoconstriction, desquamation of tubular cells (forming casts), intraluminal tubular obstruction, and back leakage of glomerular filtrate.
• Neutrophils adhere to ischaemic endothelium and release substances that promote inflammation.
The primary event is usually tubular damage, which leads to an adaptive fall in glomerular filtration rate (GFR) due to renal vasoconstriction, to compensate for failure to reabsorb filtered solute. This vasoconstriction may then perpetuate renal damage. For this reason research has focused on vasoactive compounds, such as angiotensin, prostaglandins, adenosine, endothelin, and nitric oxide. The role of inflammatory mediators has also been explored. As yet, there have been no real advances in the prevention/treatment of AKI.
Paediatric RIFLE (pRIFLE) criteria
Used for the detection and classification of AKI and for correlation with clinical outcomes:
• R = risk for renal dysfunction (serum creatinine x1.5).
• I = injury to the kidney (serum creatinine x 2).
• F = failure of kidney function (serum creatinine x 3).
• L = loss of kidney function.
• E = end-stage renal disease.
Causes are pre-renal, renal (including acute on chronic kidney disease (CKD)) and post-renal. Pre-renal causes may lead to established renal AKI.
Pre-renal acute renal failure
• Hypovolaemia: gastrointestinal (GI) losses, burns, third space losses (sepsis and nephrotic syndrome) and excess renal losses (renal tubular disorders).
• Peripheral vasodilatation: sepsis.
• Circulatory failure: congestive cardiac failure (CCF), pericarditis, cardiac tamponade.
• Bilateral renal arterial or venous thrombosis.
• Drugs (diuretics, angiotensin-converting enzyme inhibitors (ACEI), non-steroidal anti-inflammatory drugs (NSAIDS)).
• Hepato-renal syndrome.
Renal acute kidney injury
• Arterial: embolic, arteritis, haemolytic uraemic syndrome (HUS).
• Venous: renal venous thrombosis.
• Glomerular: acute glomerulonephritis.
• Tubular: established acute tubular necrosis (ATN) due to prolonged pre-renal ARF, ischaemia, toxins or drugs; obstructive (crystals).
• Interstitial: tubulointerstitial nephritis, pyelonephritis.
• Acute on chronic: decompensation of CKD due to intercurrent illness.
Post-renal acute kidney injury
• Obstruction in a solitary kidney.
• Bilateral ureteric obstruction.
• Urethral obstruction.
• Neuropathic bladder.
Obstruction may be congenital (e.g. at the pelviureteric junction (PUJ), vesicoureteric junction (VUJ), ureterocoele or posterior urethral valve (PUV)), or acquired (e.g. calculi, external compression).
Acute kidney injury in neonates
• More common in neonates than in older children.
• Occurs in 4/1000 live births, 34.5/1000 in neonatal units.
• Occurs particularly following:
• birth asphyxia;
• low birth weight/prematurity;
• patent ductus arteriosus (PDA);
• mother received antibiotics, NSAIDs or ACEI;
• cardiac surgery.
Assessment and investigations
Important points in the history
The major differential diagnosis of AKI is the patient presenting for the first time with CKD, which may be either acute on CKD or just advanced CKD. The two may be difficult to distinguish from the biochemistry alone, so the history and US findings are particularly helpful (Table 17.1). This is important because, as well as different investigations and fluid management, patients with CKD may need plans for long term, more permanent dialysis access, while those with post-renal AKI need urgent urological review.
Table 17.1 Points in the history and examination that assist in the differential diagnosis of ARF/AKI
Acute or chronic
Diarrhoea and vomiting
Bloody diarrhoea (HUS)
Antenatally diagnosed anomaly
Antenatally diagnosed anomaly
Polydipsia and polyuria
Poor urinary stream
Recent throat or skin infection
Poor urinary stream
Acute weight loss
Palpable bladder or kidneys
Poor capillary refill
*It is possible for the BP to be paradoxically high if there is extreme vasoconstriction.
Initial assessment, examination, and resuscitation
• Attend to life-threatening features first i.e. volume status (see Table 17.2), oxygenation (colour, respiratory rate, oxygen saturation), and electrolyte derangements.
• Oedema may not be helpful in deciding fluid replacement as it can be present with both intravascular overload and hypovolaemia due to third spacing.
• BP should not be viewed in isolation—hypertension with cool peripheries suggests intravascular depletion, while hypertension with warm peripheries suggests fluid overload.
Table 17.2 Assessment and management of intravascular volume status
Tachycardia, cool hands, feet and nose (>2°C core-peripheral temperature gap), prolonged capillary refill time, low BP (late sign), dry mucous membranes, sunken eyes
Fluid resuscitation 10mL/kg normal saline over 30min, assess urine output and repeat if necessary
Fluid challenge 10–20mL/kg normal saline over 1h, with furosemide 2–4mg/kg IV, max 12mg/kg/day
Intravascular fluid overload
Tachycardia, gallop rhythm, raised JVP and BP, palpable liver
Furosemide 2–4mg/kg IV; max 12mg/kg/day. Dialysis if no response
An US of the urinary tract is essential at the earliest opportunity (Fig. 17.1):
• To exclude obstruction: the absence of hydronephrosis does not rule out significant high pressure obstruction, so any degree of dilatation should be considered significant, as dilatation will not occur if there is anuria and may be minimal with oliguria. Nephrostomy drainage may be necessary if there is no other clear diagnosis.
• To see if there are signs of CKD (small or cystic kidneys), although in some conditions, such as nephronophthisis, renal size may be preserved.
• In most cases of AKI the kidneys are enlarged and echobright.
• To look at vascular flow using Doppler studies if an abnormality of renal blood flow is suspected.
• Urine biochemistry is useful in distinguishing between pre-renal ARF and established ATN: urinary sodium (UNa) <10mmol/L (<20 in neonates), fractional excretion of sodium (see Appendix, [link]) (FeNa) <1% (<2.5% in neonates) and urine osmolality >500mOsm/kg (>400 in neonates) suggests pre-renal ARF.
• Urine for blood, protein, and casts.
• Urine microscopy, culture, and sensitivity (M,C&S).
• Urea and electrolytes (U&Es), creatinine, plasma bicarbonate, Ca, PO4, and Mg, alkaline phosphatase, albumin, liver function tests (LFTs), glucose.
• Full blood count (FBC) including blood film if low platelets.
• Coagulation screen.
• Blood culture and C-reactive protein (CRP).
• Chest X-ray (CXR) if respiratory or cardiac signs.
Further additional investigations depend on clinical presentation
For suspected HUS
See ‘Typical (D+) haemolytic uraemic syndrome: epidemiology and notes’, [link]:
• Blood film to look for fragmented cells, lactate dehydrogenase (LDH).
• Group and save or cross-match.
• Stool culture.
• Verotoxin producing Escherichia coli (VTEC) serology.
• Non-diarrhoea associated (D negative) HUS may be due to T antigen exposure by: Streptococcus pneumoniae; systemic lupus erythematosus (SLE); abnormalities of complement regulation—factor H, autoantibodies to factor H, factors I and B, membrane cofactor protein and thrombomodulin; and Von Willebrand factor (vWF) protease deficiency.
For acute nephritis
• Throat or infected skin swab.
• Anti-Streptolysin O titre (ASOT), anti-DNAse B.
• Complement (C3, C4, C3 nephritic factor if C3 low).
• Immunoglobulins including IgA.
• Antinuclear antibodies (ANA), ds-DNA, anti-glomerular basement membrane (GBM), anti-neutrophil cytoplasmic antibody (ANCA), extractable nuclear antibodies (ENA), anti-cardiolipin antibodies.
Infections and acute kidney injury
• Meningococcal septicaemia.
• Hepatitis B, C, human immunodeficiency virus (HIV).
For suspected rhabdomyolysis
e.g. prolonged convulsions; see ‘Rhabdomyolysis’, [link]:
• Creatine kinase.
• Urine myoglobin.
For tumour lysis
See ‘Tumour lysis syndrome’, [link]: Urate.
For renal hypouricaemia (a rare cause of AKI)
• History of loin pain and AKI post-exercise.
• Low plasma urate and high urine urate.
Is indicated as soon as possible when:
• Renal function is deteriorating and the aetiology is not certain.
• Nephritic/nephrotic presentation.
Ongoing management, the first 24h
• Weigh twice daily.
• Hourly input-output recording.
• Hourly observations including BP and monitoring of toe-core temperature gradient.
• 6-hourly BMs if disease may affect blood sugar control (e.g. HUS).
• Neurological observations-hourly.
• U&Es, creatinine and plasma bicarbonate, Ca, PO4, FBC, frequency determined by clinical picture (may be appropriate to perform up to every 6h).
• Further boluses of crystalloid or colloid and/or furosemide as indicated by hydration and urine output.
• A furosemide infusion may be of benefit (max 12mg/kg/24h).
• If nephrotic, consider bolus of albumin (see ‘Nephrotic syndromes: definitions’, [link]).
• Give insensible losses (400mL/m2/day or 30mL/kg/day) plus urine output, and other ongoing fluid losses. This can be given as feed if tolerated (see ‘Ongoing management’, [link]) or IV normal saline (half normal if hypernatraemia).
• Replace 100% of urine output if euvolaemic.
• Restrict to 50–75% urine output if intravascularly overloaded to allow a negative fluid balance.
• There is no evidence to support the use of renal dose dopamine.
Ongoing management, the next 24–48h
After 24h an assessment can be made as to whether to proceed to dialysis or to continue to manage conservatively, although this decision needs to be reviewed on a daily basis.
• Frequency of measurements of weight, fluid balance, routine, and neurological observations as for the first 24h.
• U&Es, creatinine and plasma bicarbonate, Ca, PO4, Mg, albumin, FBC (usually daily but frequency is determined by the clinical picture).
• Urinalysis daily.
• With careful attention to diet and fluid restriction of the euvolaemic child to an intake of insensible fluid losses and urine output, even patients with oliguria can be managed without dialysis. However it is difficult to maintain an adequate nutritional intake if the fluid allowance is very low, as catabolism (which also causes a high urea and hyperkalaemia) culminates in malnutrition.
• A suggested dietary approach is described in ‘Nutrition in acute kidney injury’, [link].
Indications for dialysis
• Hyperkalaemia >6.5mmol/L.
• Severe fluid overload with pulmonary oedema, which is resistant to furosemide.
• Urea >40mmol/L (>30mmol/L in a neonate).
• Severe hypo- or hypernatraemia or acidosis.
• Multi-system failure.
• Anticipation of prolonged oliguria, e.g. HUS, so that space can be made for dietary intake.
Fluids for the patient on dialysis
• A fixed fluid intake can be prescribed when dialysis is established. A suggested starting volume would be half the normal maintenance fluid allowance (see Table 17.3), which can be increased depending on efficiency of dialysis or the development of urine output.
Table 17.3 Maintenance water and electrolyte allowance for healthy children
1000mL plus 50mL/kg for each extra kg >10
1500mL plus 20mL/kg for each extra kg >20
Na, K, and Cl
Established acute kidney injury
• Monitoring of routine observations can be decreased to 4-hourly, and weight and U&Es, creatinine and plasma bicarbonate, Ca, PO4, FBC to daily.
• A fixed fluid intake can be introduced for conservatively managed patients as urine output increases, using a regimen similar to patients on dialysis (see ‘Fluids for the patient on dialysis’, [link], and Table 17.3).
The recovery phase
• Polyuria may develop in the recovery phase, so during this time it may be necessary to return for twice daily weighing, hourly input-output recording, and hourly observations, including BP and monitoring of the toe-core temperature gradient.
• Urine output and insensible losses should be replaced for 24h with normal saline, then a fixed fluid intake can be set. This can start at around two-thirds of the previous day's intake, if renal function continues to improve.
• Dialysis can be stopped when the urine output is sufficient to allow an adequate nutritional intake and the creatinine starts to decline.
Management of electrolyte abnormalities in acute kidney injury before dialysis
• K >6.5mmol/L is an indication for emergency treatment until dialysis or urine output has been established (Table 17.4).
• Toxicity of K is increased if there is hypocalcaemia.
• Only ion exchange resins remove potassium from the body, so it is important to check the serum K for rebound after 2–4h.
• Of all the ways to reduce K, the simplest is to use a salbutamol nebulizer, which is familiar to all paediatric nurses, quick to prepare and administer, and rapidly effective.
Table 17.4 Emergency management of hyperkalaemia
Effect on K
Reduces toxic effect of K by stabilizing the myocardium
10% calcium gluconate IV
0.5–1mL/kg over 5–10min
Shifts K into cells
2.5mg if<25kg, 5.0mg if>25kg, maximum 2-hourly
4micrograms/kg over 10min
Sodium bicarbonate 8.4% IV
1–2mmol (mL)/kg over 10–30 min
Hypernatraemia reduces ionized calcium
Glucose and insulin IV
0.5–1.0g/kg/h glucose (2.5–5.0mL/kg/h10% glucose) and insulin 0.1–0.2U/kg as a bolus or continuous infusion of 10% glucose at 5mL/kg/h(0.5g/kg/h) with insulin 0.1U/kg/h.
Hypoglycaemia, monitor blood glucose every 15min during bolus then at least hourly
Removal of K from the body
Calcium Resonium® orally or per rectum with oral lactulose
2.5mL<1 year; 5mL
1–5 years, 10mL >5 years
Effect is slow. Large doses can become impacted in the gut if given orally
Resonium A® as above
• Mild hyponatraemia is often dilutional secondary to prior prescription of hypotonic fluids.
• A plasma Na >118mmol/L will usually correct with fluid restriction ± dialysis and fluid replacement with normal saline.
• A plasma Na <118mmol/L risks central nervous system (CNS) damage so the Na should be raised to around 125mmol/L with hypertonic saline (3 %) according to formula:
Na dose (mmol) = (125 – measured PNa × weight in kg × 0.6) and given over 2–4h
(see ‘Disorders of sodium and water: hyponatraemia’, [link]).
• Severe hyponatraemia with oliguria is an indication for dialysis.
• Much less common than hyponatraemia.
• May be caused by sodium retention or water depletion so careful assessment of fluid status is mandatory.
• Give furosemide 3–4 mg/kg IV (max 12mg/kg/day) if salt and water retention is the cause.
• Replace insensible losses as 0.45 % saline.
• Severe hypernatraemia with oliguria is an indication for dialysis.
• Start treatment if plasma PO4 >1.7mmol/L (>2.0mmol/L in a neonate).
• Treatment is by dietary phosphorus restriction and phosphate binders, which are given with oral intake.
• Calcium carbonate 250mg tablets can be dissolved in feeds, starting dose:
• up to 2 years: 250mg qds;
• 2–5 years: 500mg tds;
• 5–10 years: 750mg tds;
• over 10s: 1000mg tds.
These doses may need to be increased considerably, depending on plasma PO4 levels.
• Hypocalcaemia, particularly in association with hyperkalaemia can lead to cardiac arrest; therefore, cardiac monitoring is necessary if hypocalcaemia is severe.
• Corrected calcium can be estimated from total calcium and albumin as follows:
• corrected calcium = total plasma calcium + (36 – plasma albumin)/40
• If the corrected calcium is <1.9mmol/L or if bicarbonate therapy is required, treat with IV 10% calcium gluconate 0.1mg/kg (0.5mL/kg) over 30min to 1h.
• Hypocalcaemia will improve if hyperphosphataemia is treated.
• If acute on CKD, commence activated vitamin D (alfacalcidol or calcitriol) at a dose of 0.01micrograms/kg/day.
• May be severe if the respiratory system is unable to compensate. Maximum respiratory compensation may take over 24h. Correct with sodium bicarbonate if HCO3– <18mmol/L. If the child is unwell use IV bicarbonate.
• Calculate IV dose as: mmol NaHCO3 = (18 - measured HCO3) × 0.5 × weight in kg.
• Give over 1h.
• Oral dose is 1–2mmol/kg/day for infants and 70mmol/m2/day for older children, to be divided into 2–4 doses.
• The ionized calcium must be checked and corrected before treatment since correction of acidosis further lowers ionized calcium.
• Usually due to fluid overload, although it is important to be sure that it is not due to intense vasoconstriction because of hypovolaemia.
• First treatment is furosemide, and failure to respond is an indication for dialysis, although it is usual to consider other first line agents (e.g. calcium channel blockers, labetalol if severe hypertension with signs of encephalopathy) in addition, particularly since it usually takes several hours to establish emergency dialysis.
• If dialysis is adequate but hypertension persists, nifedipine is the first choice; the starting dose is 250micrograms/kg tds. Maximal daily dose is 3mg/kg/day.
Nutrition in acute kidney injury
• Adequate nutrition will help (see Table 17.5):
• prevent catabolism;
• control metabolic abnormalities (particularly potassium and phosphate);
• it may delay or prevent the need for dialysis.
• The fluid restriction will limit the nutritional prescription. Dialysis allows a higher fluid intake and, therefore, better nutritional intake.
• Consider nasogastric feeding if the child is unable to meet the nutritional goals orally, e.g. due to nausea or neurological impairment.
• Parenteral nutrition should only be considered if enteral nutrition is not tolerated.
• If on prolonged peritoneal dialysis a higher protein intake may be required.
Table 17.5 Nutritional guidelines for the child with AKI
Boys and girls
EAR = Estimated average requirement.
RNI = Reference Nutrient Intake i.e. amount of protein needed for maintenance and growth.
• High energy protein-free fluids using a glucose polymer, e.g. Maxijul® solution.
• Concentration depends on degree of nausea, vomiting, diarrhoea:
• infants: 15% Maxijul®;
• 1–2 years: 20% Maxijul®;
• >2 years: 25% Maxijul®.
• Full energy requirements will not be met if fluid restricted.
• Potassium and phosphate intakes may need adjusting.
• Consider introduction of protein depending on degree of uraemia.
• If urea 30–40mmol/L start 0.5g protein/kg dry weight/day:
• infants—diluted whey based infant formula e.g. Cow & Gate® 1 or SMA® 1 + Maxijul®;
• children—diluted paediatric enteral feed, e.g. Nutrini® (paediatric sip feed, e.g. Paediasure® if feeding orally) + Maxijul®.
• If urea >40mmol/L continue protein-free high energy fluids for a further 24h.
Increase/introduce protein depending on degree of uraemia:
• If urea 20–30mmol/L increase protein to 1g/kg dry weight/day.
• If urea 30–40mmol/L start 0.5g protein/kg dry weight/day (see ‘Day 2’, [link]).
• Maximize energy intake using Maxijul® and fat emulsion, e.g. Calogen® as tolerated.
• Correct drug doses according to GFR. The calculation for estimated GFR (see Appendix, [link]) needs to be interpreted with caution as the formula assumes a stable situation.
• Change of GFR will necessitate regular revision of drug dosages.
• Many drugs require decreased doses or a prolonged dosage interval in renal failure.
• It is preferable to avoid known nephrotoxic drugs in AKI when an alternative is available.
Choice of dialysis
Options Peritoneal dialysis, haemodialysis or haemofiltration (Table 17.6).
• Most children requiring intensive care are managed with CRRT; see ‘Continuous renal replacement therapy’ (CRRT), [link].
• Haemodialysis is the preferred option if vascular access is needed for plasma exchange. If the urea is very high, a short session (2h) with mannitol will be necessary as intracerebral disequilibrium is most likely with the first session. Thereafter, daily haemodialysis (HD) will be needed until the biochemistry improves, when it then can be weaned.
• Peritoneal dialysis can be started immediately in the child with AKI.
• flush the catheter until the effluent is clear of blood and debris;
• use continuous, 24h cycling, initially with 20–30-min cycles (10 min fill, 10 min dwell, 10 min drain) then varying according to response;
• start with 10mL/kg fill volumes. This can be built up promptly if there is no leakage and the child tolerates it, to 40mL/kg;
• it is usual to start with 1.36% dialysate, but this can be increased if fluid removal is inadequate.
Table 17.6 Advantages and disadvantages of the different types of renal replacement therapy
Easy to set up
Can be carried out by ward nurses
Ease of access
May be continued indefinitely with Tenckhoff catheter
Risk of peritonitis/leakage/drainage problems
Rapid removal of a large volume of fluid is difficult so not recommended if pulmonary oedema present
Gold standard solute clearance
Bicarbonate is standard
Can be used to rapidly remove large volumes of fluid, e.g. with pulmonary oedema
Requires haemodynamically stable patient
Vascular access may be difficult
Solute clearance may be improved with addition of dialysis (CVVHD)
Does not cause major fluid shifts and disturbances to BP and cardiac output
Requires continuous anticoagulation
Vascular access may be difficult
Follow-up of acute kidney injury
Survival and renal recovery depends on the cause of the AKI. Long-term follow-up is necessary, with the exception of children with pre-renal ARF, in order to detect the development of proteinuria, hypertension and CKD.
• BP and urine albumin to creatinine ratio (Ua:Ucr, on the first urine of the morning taken on rising) should be monitored 12 months after AKI.
• Annual BP and Ua:Ucr for life.
• Check creatinine if previous measurement elevated or if proteinuria or raised BP develop.
S. (2009). Acute kidney injury in children. Pediatr Nephrol 24: 253–63.
Find This Resource
Haemolytic uraemic syndrome: definitions
• HUS is a triad of symptoms:
• haemolytic anaemia with fragmented erythrocytes;
• There are 3 broad categories of HUS (Box 17.1):
• typical, usually diarrhoea positive (D+) HUS;
• atypical, usually diarrhoea negative (D–) HUS;
• secondary HUS, secondary to drugs, malignancy, total body irradiation, transplantation, methylmalonic acidaemia (MMA) in neonates.
• VTEC: verotoxin producing Escherichia coli.
• STEC: shiga toxin producing Escherichia coli.
• MAHA: microangiopathic haemolytic anaemia.
• TMA: thrombotic microangiopathy. A microvascular occlusive disorder of capillaries, arterioles, and less frequently, arteries.
• TTP: thrombotic thrombocytopenic purpura. Microvascular aggregation of platelets causes ischaemic lesions mainly in the brain, and less frequently in the kidney and other organs.
The common event in HUS is endothelial injury resulting in MAHA, platelet aggregation, and local intravascular coagulation, particularly in the renal, mesenteric, and brain vasculature.
Notes on terminology
• The D+ HUS/D– HUS terminology, although simple, can mislead:
• the terms shiga toxin and verotoxin are equivalent;
• some patients with VTEC infection do not have diarrhoea;
• a diarrhoeal disease may trigger HUS in a patient with a genetic predisposition to HUS;
• thus, classifying patients only according the presence or absence of diarrhoea can lead to incorrect management.
Typical (D+) haemolytic uraemic syndrome: epidemiology and notes
• Typical (D+) HUS represents 90% of HUS in children.
• It occurs mainly in children <3 years, almost never in neonates.
• The average annual incidence of HUS for the United Kingdom and Ireland is 0.71/100,000. In Western Europe or North America, its annual incidence rate is 2–3 per 100,000 children <5 years of age.
• The incidence of exposure to VTEC has been demonstrated in many countries in about 85% of cases.
• Serotype Escherichia coli 0157:H7 is the most frequent (70 % of cases in the UK), but other serotypes (0111, 0103) are also associated.
• The risk of developing HUS in patients with intestinal Escherichia coli 0157:H7 infection is 10%.
• Cows are the main vectors of Escherichia coli 0157:H7, which can be present in their intestinal lumen and faeces.
• Humans are infected from contaminated undercooked ground beef, non-pasteurized raw milk, or milk products (cheese), contaminated water (well water or lake water swallowed during bathing), fruits, fruit juice, or vegetables.
• Person-to-person transmission is possible.
• Transit slowing agents and antibiotics (such as beta lactams or co-trimoxazole) increase the risk of HUS.
• D+ HUS may occur simultaneously or a few days or weeks apart in several members of a family, mainly siblings, because of contamination from the same environment.
• Epidemics are well described.
• HUS caused by Shigella dysenteriae is important on a worldwide basis, but is an uncommon cause of HUS in the UK.
Clinical features of typical infective haemolytic uraemic syndrome
• Diarrhoea (bloody) and vomiting (most, not all).
• Rectal prolapse, intussusception, toxic dilatation of colon, and bowel perforation.
• Hydration at the time of the diagnosis of HUS is variable—may be dehydrated or over hydrated (if anuric, but able to drink, or perhaps most commonly from inappropriate IV fluids).
• Hypovolaemic shock in 2%.
• Oligoanuria appears between 1 and 14 days after the onset of diarrhoea.
• MAHA and thrombocytopenia precede the AKI.
• Jaundice in 35%.
• Hypertension in one-third.
• The most common extra renal manifestation is central nervous system disturbance affecting up to 20%. Beware early signs such as lip-smacking:
• cranial nerve palsy;
• cerebral oedema;
• decerebrate posturing;
• hindbrain herniation—causing respiratory arrest.
• Diabetes mellitus (due to necrotizing pancreatitis) affects up to 5%.
• Renal cortical necrosis:
• due to acute cortical ischaemia;
• mainly observed in the most severe forms of D+ HUS;
• associated with prolonged anuria at the acute phase;
• high risk of CKD.
• FBC, platelets, blood film.
• Chemistry including renal and liver function, LDH, glucose, urate, lipase and amylase.
• Clotting screen.
• Group and save blood.
• Urine dipstick for blood and protein.
• Urine M,C&S.
• VTEC serology.
• Verotoxin polymerase chain reaction (VT PCR).
• Stool microscopy and culture.
• Direct Coomb's test (positive in T-antigen HUS–see ‘Haemolytic uraemic syndrome: atypical’, [link]).
• Erect CXR, abdominal X-ray (AXR).
• Renal and abdominal (to include biliary tree and pancreas) US: to exclude preceding structural renal abnormalities and other organ involvement.
• CT abdomen (if pancreatitis or suspect collection).
• ECG: if severe electrolyte disturbance or cardiac failure.
• Electroencephalogram (EEG): if seizures or altered conscious level.
• MRI brain (or CT): if seizures or altered conscious level.
• Renal biopsy very rarely required.
Early diagnosis and supportive care are of major importance. There is no specific therapy for D+ HUS.
• Packed red cell transfusion is indication for Hb <6g/dL, or if <7g/dL, but symptomatic (e.g. short of breath, shock). May worsen hyperkalaemia and volume overload.
• Platelet transfusion is rarely indicated unless invasive surgery is planned or there is intracranial haemorrhage. If given, platelets are rapidly consumed in the haemolytic process.
It is generally accepted that antibiotics are not part of the routine management of typical D+ HUS caused by VTEC. Some suggest that antibiotics may make HUS worse, although this remains controversial.
Prevention of haemolytic uraemic syndrome
• Ground beef must be cooked until the inside is no longer pink.
• Non-pasteurized products must not be given to young children.
• Children who touch cows or goats must wash their hands afterwards.
• Strict rules governing cattle slaughter to prevent contamination of meat by intestinal content.
• When Escherichia coli 0157:H7 infection is suspected, information and surveillance of siblings and family is necessary. Handwashing is the most effective means of preventing person-to-person spread.
• Confirmed VTEC HUS is a notifiable disease.
• Acute mortality rate is currently 5–10%.
• 5–10% develop CKD 5.
• After 15 years or more of follow-up, 20–60% of patients have proteinuria and/or hypertension, with up to 20% having CKD. These problems may appear after several years of apparent recovery.
Poor renal prognostic factors
• Neutrophilia >20 × 109/L.
• Shock during the acute phase.
• Anuria >2 weeks.
• Central nervous system involvement.
• Severe colitis and/or rectal prolapse.
• Atypical HUS.
• Cortical necrosis.
• 50% glomeruli with TMA lesions (best predictor, but biopsy is very rarely performed).
Outcome following renal transplantation for typical haemolytic uraemic syndrome
• In most retrospective series, no recurrence of HUS was observed.
• Occasional case reports of HUS recurrence in the graft are described, putting the risk at around 1%.
• Calcineurin inhibitors are not contraindicated in this setting.
Haemolytic uraemic syndrome: atypical
Atypical HUS is due to several different aetiologies. The commonest is pneumococcal HUS, the incidence of which is increasing so that in some countries it is overtaking D+ HUS as the commonest cause.
Pneumococcal haemolytic uraemic syndrome
• Streptococcus pneumoniae produces neuraminidase, which cleaves N-acetylneuraminic acid from the glycoproteins on the cell membranes of red cells, platelets and glomeruli. Current thinking is that this exposes the Thomsen-Friedenreich antigen (T antigen). The exposed antigen then reacts with anti-T antibody resulting in thrombotic microangiopathy (TMA).
• The antigen-antibody reaction is called T activation and occurs more commonly in infants and young children.
• Diagnosis is by testing for red cell T-activation; and the direct Coomb's test will be positive.
• Although all Streptococcus pneumoniae produce neuraminidase, not all cause T cell activation. Variation is likely to be due to different strains producing different quantities of neuraminidase with different enzymatic activity, and to individual patient variation in their amount of anti-T antibody.
• Anti-T antibody may be present in transfusions and plasma so red cells and platelets should be washed before transfusion (to remove anti-T antibody) and the use of plasma avoided as far as possible. Early diagnosis may prevent ongoing activation by the use of non-washed cells.
• HUS is typically associated with severe pneumococcal infections, such as empyema or meningitis.
• Activation clears when the infection is controlled so antibiotic therapy is needed.
• Initial reports suggested increased mortality and worse renal outcome than for D+ HUS. However, much of the morbidity is due to the Pneumococcal infection (e.g. meningitis) and, more recently, it appears that renal outcome is no worse.
Other causes of atypical haemolytic uraemic syndrome
• Represent less than 10% of HUS in children.
• Any age can be affected, including newborns.
• There is usually no prodromal diarrhoea, nor seasonal predominance, although infections (including viral or bacterial gastroenteritis) may trigger an episode of atypical HUS in a susceptible individual.
• Onset may be sudden, and is relapsing and remitting over weeks or months.
• Arterial hypertension is frequent.
• Deterioration in renal function of varying severity leads to CKD in most cases (and CKD 5 in some cases), after weeks, months, or years.
• Some children have relapses of HUS, often triggered by infectious diseases, which can occur even when there is CKD 5, i.e. extrarenal disease can continue, e.g. haemolytic episodes, pancreatitis, etc.
• Some have a presentation like TTP, with predominance of central nervous system symptoms, which is the main clinical feature that differentiates TTP from HUS (although HUS can have central nervous system involvement, so this differentiation is not clear-cut).
• Atypical HUS is often familial, with autosomal recessive or autosomal dominant inheritance (see ‘Genetics of haemolytic uraemic syndrome’, [link]).
• Histological lesions are arteriolar TMA, with intimal cell proliferation, thickening of the vessel wall and narrowed lumens of arterioles.
• Renal biopsy can be useful when diagnosis is uncertain.
Genetics of haemolytic uraemic syndrome
Central to the pathogenesis of atypical HUS is over-activation of the alternative pathway of complement (AP), and mutations have been detected in the following complement regulatory proteins:
• Complement factor H (CFH, the most important regulator of the AP), the commonest abnormality. Mutations may not result in a decrease in CFH levels.
• Complement factor I (CFI, up to 12% of cases). Again measured levels may be normal.
• Membrane cofactor protein (MCP, CD46), which protects cells from damage from complement and is present on podocytes.
• Thrombomodulin (THBD), an anticoagulant glycoprotein that plays a role in the inactivation of C3a and C5a.
• Autoantibodies to factor H (up to 10%).
• Deletions of CFHR1-5, CFH-related proteins, which are related to autoantibodies to CFH.
• Gain of function mutations of C3 and complement factor B (CFB).
• There is incomplete penetrance such that first degree relatives carrying the same mutation are often asymptomatic. Presumably, for HUS to develop there must be a combination of genetic and environmental factors.
• HUS can also be associated with deficiency of ADAMTS13 (Von Willebrand factor cleaving protease). This is the enzyme deficient in adults with TTP. Deficiency in TTP is usually due to the presence of an inhibitor, although occasionally can be due to constitutional/familial deficiency of ADAMTS13. There are a few reports of ADAMTS deficiency in paediatric patients with atypical HUS.
Specific tests to be considered for the investigation of atypical haemolytic uraemic syndrome
• Culture for verotoxin-producing Escherichia coli (VTEC).
• Serology for VTEC both acute and convalescent.
• Polymerase chain reaction (PCR) for VTEC.
• Liver function tests.
• Direct Coomb's test (positive in ‘T antigen’ associated cases).
• Thomsen-Friedenreich antigen (‘T antigen’) (if available).
• C3, C4, CH100, C3 nephritic factor, CFH, CFI plasma levels.
• vWF multimeric analysis.
• ADAMTS-13 enzyme activity.
• Urine for methylmalonic acidaemia and homocysteine.
• ANA, ds-DNA antibodies, ENA, anticardiolipin antibodies, lupus anticoagulant.
• HIV test.
• Renal biopsy if diagnosis unsure.
• Genetics (if pneumococcal HUS excluded): CFH, CFI, CD46, C3, CFB, and THBD for mutations and genomic disorders. Serum for CFH autoantibodies (preferably before any plasma has been given to be sure the antibodies are primary and not secondary).
• Treatment of atypical HUS must depend on the suspected underlying cause. For example, HUS-associated with T antigen exposure in pneumococcal-associated HUS requires antibiotic therapy to treat the underlying infection. HUS associated with drugs requires removal of the offending agent.
• For idiopathic (presumed genetic) atypical HUS, therapy with plasmapheresis and/or fresh frozen plasma has been shown to be effective in some series, particularly if there is neurological involvement. Treatment is usually started daily and after 5–10 days the response assessed. Some children do not respond, whereas others become dependent on plasma therapy and need regular ongoing treatments to prevent relapse.
• Renal function may deteriorate despite plasma therapy. Preliminary trials of eculizumab, a humanized monoclonal antibody against C5, have shown it to have a high success rate, at least in the short term, even in patients who are resistant to plasma therapy, and it is likely that this will become part of the therapeutic armamentarium in the near future.
Overall the prognosis is poor, with 25% mortality during the initial episode. 50% of survivors need long-term dialysis. Outcome is affected by the genetic abnormalities, but even with known mutations outcome can be variable and affected by the presence of additional undefined genetic modifiers.
Overall patient outcome
• CFH mutations is the worst: 60–70% die or reach CKD 5 within 1 year.
• MCP mutations is good: with >80% remaining dialysis-independent although recurrent episodes are common.
• CFI mutations is intermediate: 50% die or develop CKD 5 within 2 years.
• CFH antibodies: <50% develop CKD 5.
(See ‘Recurrent and de novo renal disease following renal transplantation’, [link].)
• MCP is corrected by an allograft bearing wild-type MCP so the recurrence rate is low.
• Overall there is a 50% chance of transplant loss due to recurrent disease.
• CFH or CFI mutations are associated with graft loss of 80% by 2 years.
Goodship T. (2010). Genetics and complement in atypical HUS. Pediatr Nephrol 25: 2431–42.
Find This Resource
Waters AM, Licht C. (2011) aHUS caused by complement dysregulation: new therapies on
the horizon. Pediatr Nephrol 26: 41–57.
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Rhabdomyolysis is the breakdown of striated muscle resulting in the release of myoglobin, which is nephrotoxic. It accounts for up to 20% of AKI. Early recognition is important as aggressive hydration may prevent AKI.
• Approximately half present with the triad of diffuse myalgia, weakness, and dark urine.
• Calf pain or muscle swelling.
• There may be a history of trauma, loss of consciousness, and prolonged immobilization or grand mal seizures.
• Excess muscle activity in normal muscles: mechanical and thermal muscle injury and ATP depletion can occur with heat stroke, status epilepticus, status asthmaticus, myoclonus, and severe dystonia.
• Crush injury and other trauma: due to direct muscle injury and ischaemia reperfusion injury after prolonged ischaemia. Large numbers of cases have been reported following earthquakes.
• Drugs and toxins: many drugs have been reported to cause rhabdomyolysis, either via a direct toxic effect, or by inducing myositis or coma, or by excessive neuromuscular stimulation. Some toxins include snake venom and insect bites.
Disorders of muscle carbohydrate metabolism
• McArdle's disease: an AR disorder resulting in deficiency of myophosphorylase, and, as a result, defective generation of glucose from glycogen. Anaerobic type 2 muscle fibres are activated during vigorous exercise and are therefore particularly dependent on ATP. The rhabdomyolysis that results from ATP depletion causes muscle pain which is relieved by rest. Other inherited diseases affecting the glycolytic/ glycogenolytic pathways include phosphofructokinase deficiency (Tarui's disease), and phosphoglycerate mutase deficiency.
• Carnitine palmitoyltransferase deficiency: an AR disorder resulting in abnormal production of energy from long chain fatty acids. Aerobic type 1 muscle fibres are affected, so that muscle pain and rhabdomyolysis occur with prolonged exercise and inadequate energy intake. Frequent high carbohydrate meals may help.
• Malignant hyperthermia: an AD disorder of the calcium release channel of the sarcoplasmic reticulum resulting in high resting sarcoplasmic calcium concentrations. Exposure to halothane, succinyl choline and caffeine triggers further calcium release, resulting in muscle contraction, hyperthermia and rhabdomyolysis.
• Neuroleptic malignant syndrome (NMS): a central defect causing a gradual development of hyperthermia, muscle rigidity, fluctuating consciousness, autonomic instability and rhabdomyolysis. Drugs which can cause NMS include phenothiazines, butyrophenones, and other antipsychotics.
• Plasma myoglobin levels rapidly rise during injury, then fall within 6h, although plasma levels are not routinely measured.
• Plasma creatine phosphokinase (CPK) levels rise 2–12h after injury, and peak 24–72h later.
• urinalysis—stick test strongly positive for blood but no or few red cells on urine microscopy;
• urine myoglobin positive.
• Elevated plasma CPK (MM band).
• Other plasma electrolyte disturbances:
Manage the patient on the basis of urine output and plasma electrolytes and not the plasma CPK.
• If urine output is reasonable (>0.5mL/kg/h): high fluid input = 3L/m2/day (0.45% saline/2.5% glucose, may need adjustment: follow electrolytes regularly).
• If oligoanuric:
• consider first a fluid challenge (5–10mL/kg);
• possibly with furosemide to establish urine output.
• if unsuccessful =>
• dialyse for severe electrolyte disturbance;
• continuous veno-venous haemofiltration (CVVH) clears myoglobin reasonably well.
• Determine underlying condition. Muscle biopsy may be necessary for congenital enzyme defects.
• Outcome depends on cause, but full recovery is usual.
Tumour lysis syndrome
Tumour lysis syndrome (TLS) occurs in haematological malignancies and lymphoproliferative conditions. Rapid cell breakdown leads to hyperuricaemia (pre-TLS). The development of urate nephropathy, with AKI, hyperphosphataemia, hyperkalaemia, and hypocalcaemia indicates established TLS. Prevention is the aim of management, using high fluid intake and allopurinol or rasburicase. TLS can occur prior to chemotherapy because of autolysis of tumour cells but usually starts after induction of treatment. Duration depends on severity and supportive measures in place, but on average lasts for approximately 48h.
Factors that predispose to tumour lysis syndrome
• High cell count leukaemia (total white cell count usually in excess of 100 × 109/L).
• Burkitt's type lymphoma.
• Large tumour bulk.
• Bulky T cell lymphoma.
• Bulky lymphoproliferative disease (LPD) or post-transplant lymphoproliferative disease (PTLD).
• Evidence of renal infiltration with tumour (e.g. on US).
• Evidence of renal impairment.
• Insertion of a haemodialysis catheter at the time of anaesthetic for Hickman line or bone marrow.
• Patients already in established TLS at time of admission need urgent haemodialysis.
• Disturbances of calcium and magnesium homeostasis can also occur (as a result of the hyperphosphataemia, renal impairment, changes in acid-base balance or due to the diuresis), and can lead to tetany or seizures.
• It is important that K is not added to hydration fluids.
• Hydrate with 3L/m2/day of 0.45% NaCl/2.5% glucose. This can be increased to 4L/m2/day if there is no evidence of fluid overload (tachycardia, tachypnoea, gallop rhythm, desaturation, or oxygen requirement; see Fig. 17.2).
• Give allopurinol 100mg/m2, 8-hourly by mouth if no high risk features; or rasburicase 200micrograms/kg once per day if high risk or if poor response to allopurinol, starting 12h prior to chemotherapy if possible.
• For high risk patients with rapid tumour lysis and high plasma concentration of uric acid despite receiving IV rasburicase 200micrograms/kg every 24h, consider increasing the frequency of rasburicase (e.g. once every 18-hourly) up to maximum of once every 12h for 2–3 days.
• Review the patient clinically as appropriate (but at least every 4–6h). Check for oliguria or fluid overload. Calculate the fluid balance and measure plasma biochemistry (Na, K, Ca, PO4, TCO2, urate, urea, and creatinine) every 4–6h. (If very high risk, monitor biochemistry 2–3-hourly). Give furosemide 1–2mg/kg if there are signs of fluid overload. Use a cardiac monitor to look for evidence of peaked T waves and dysrhythmias secondary to hyperkalaemia.
• Alkalinization of the urine is not recommended. This is because although bicarbonate may render the urate more soluble, an alkaline urine is very difficult to achieve without a dangerously high blood pH. This, along with the arrival of rasburicase, has made bicarbonate therapy unnecessary.
Treatment of established tumour lysis syndrome
HD is the preferred treatment for established TLS; haemofiltration or haemodiafiltration are less efficient in the acute phase.
Absolute indications for HD include:
• Plasma potassium >5mmol/L.
• Plasma phosphate >4mmol/L.
• Pulmonary oedema (give oxygen and consider ventilation as immediate measures).
Relative indications for HD include:
• Rapid rise in potassium, phosphate, or urate.
• Oliguria unresponsive to furosemide (1–2mg/kg, but may need up to 5mg/kg).
• Urea >15mmol/L or creatinine >150µmol/L.
The rate of rise of these markers is very important—act before the patient reaches a critical state.
Management after haemodialysis
• Nearly all patients require two HD sessions; some need three or more.
• After HD there will be a rebound in biochemistry, therefore continue to review the patient every 2–4h both clinically (for oliguria and fluid overload) and biochemically (Na, K, Ca, PO4, TCO2, urate, urea, and creatinine).
• The indications for further HD are as previously listed.
• Some patients may benefit from going onto haemofiltration after the first HD session in an attempt to prevent the biochemical rebound. This therapy is unproven.