Haemolytic Uraemic Syndrome

Cite this article as:
Jennifer Watt. Haemolytic Uraemic Syndrome, Don't Forget the Bubbles, 2020. Available at:
https://doi.org/10.31440/DFTB.26233

What is HUS?

Haemolytic Uraemic Syndrome is a combination of findings which involves the triad of:

  • Microangiopathic haemolytic anaemia with red blood cell fragmentation on blood film
  • Acute renal failure
  • Thrombocytopenia

 What causes HUS?

About 90% of cases follow an infection, most commonly with entero-haemorrhagic E. Coli (EHEC). Other infective causes to be considered include Shigella and Streptococcus pneumoniae.

These infections are commonly contracted by the ingestion of contaminated food or water sources. In the US and UK, E. Coli 0.157 forms part of the natural intestinal microflora of cattle and sheep, therefore infection can be caused by direct contact with animal faeces. This can take place at farms or petting zoos, or via undercooked contaminated meat or dairy products.

The other 10-15% of cases represent atypical HUS and are due to a variety of causes, which will not be discussed here.

How do children present?

In children infected with EHEC about 10-15% of them will go on to develop HUS.

The common presentation includes bloody diarrhoea +/- cramping abdominal pain, fever and/or vomiting. The average onset of HUS after development of diarrhoea is about 7-10 days, with children under the age of 5 at highest risk.

Dependent on the extent of HUS progression, children may present with pallor, oedema, lethargy, or reduced urine output.

How to approach the examination

As with any unwell child, an A to E assessment is critical to rule out any immediate, life threatening complications.

Specific attention should be paid to assessing their fluid status, especially for evidence of dehydration.

*Although they may be oedematous, it is important to assess if they are intra-vascularly dry.

Things to examine for:

  • Prolonged capillary refill time
  • Observations: Tachycardia; hypotension or hypertension
  • Are they are cool peripherally?
  • Assess fontanelle tension (if applicable)
  • Dry mucus membranes/reduced skin turgor
  • Oedema (common locations in children include lower limbs, sacral and peri-orbital)

Is there evidence of neurological sequelae?

  • Irritable/restlessness
  • Confusion
  • Reduced GCS

Key investigations to perform

A. Initial blood samples:

  • Full blood count with blood film to assess for RBC fragmentation
  • Coagulation
  • Group and Save +/- cross match if haemoglobin low
  • Biochemistry: U&Es, calcium, phosphate, magnesium, bicarbonate
  • Glucose
  • CRP
  • Liver function including albumin
  • Amylase/Lipase (hospital dependent)
  • LDH
  • Blood gas
  • Blood cultures

B. Stool MC&S + E. Coli PCR

C. Urinalysis + MC&S

How to approach the management of HUS

Management should always be discussed with your local paediatric nephrologist in order to individualise/optimise management.

This is a generalised framework for the approach to management. Treatment involves supportive therapy to allow time for the infection to clear and the HUS process to cease.

1. Fluid Management:

  • IV access
  • Assess fluid status
  • Monitor for electrolyte disturbances and correct as per local guidelines
  • Daily weight, In/Out fluid balance, close monitoring of patient observations

*Fluid rehydration should be administered cautiously and in the setting of oliguria/anuria and oedema, fluids given should not exceed insensible loss + urine output.

*Evidence has shown that children presenting to hospital with dehydration in the prodromal phase of EHEC-induced HUS have a higher risk of developing an oliguric AKI and the requirement for dialysis. The administration of isotonic fluid in this phase has shown to be nephroprotective. 

2. Hypertension:

  • Can be secondary to fluid overload or as a result of the HUS process
  • Trial of diuretics or if receiving dialysis, fluid can be offloaded
  • If unresponsive to diuretics, consider a vasodilator (For example, amlodipine/ nifedipine *hospital dependent)

3. Anaemia:

  • Target Haemoglobin: 70-100g/L
  • Avoid excessive transfusion due to the associated risk of development of hyperkalaemia or fluid overload

4. Thrombocytopenia:

  • Consideration for platelet transfusion if platelets <10 x109
  • If undergoing surgery may require platelets > 50 x 109

5. Abdominal pain/vomiting:

  • Secondary to colitis
  • Regular paracetamol for pain relief
  • Avoid opiates if possible due to constipating side effects

*NSAIDS like Ibuprofen should not be prescribed*

6. Nutrition:

  • All patients should be reviewed by a dietician
  • NG tube and feeding regime

7. Dialysis (Peritoneal Dialysis or Haemodialysis) Indications:

  • Intractable acidosis
  • Diuretic resistant fluid overload
  • Electrolyte abnormalities Hyperkalaemia
  • Symptoms of uraemia

In children with HUS, peritoneal dialysis is the preferred treatment option as it is a gentler form of dialysis.

Haemodialysis is indicated for children with severe colitis, severe electrolyte abnormalities and those with neurological complications.

 HUS Complications

  • AKI:  Oliguria/anuria; hyperkalaemia; hypertension
  • Neurological: Irritable, confusion, seizures
  • Bleeding Risk
  • Cardiac: Hypertensive cardiomyopathy/myocarditis
  • Gastrointestinal: Severe colitis with bleeding/perforation
  • Pancreatitis
  • Pulmonary oedema

Selected references

Mayer CL, Leibowitz CS, Kurosawa S and Stearns-Kurosawa DJ. Shiga Toxins and the Pathophysiology of Hemolytic Uremic Syndrome in Humans and Animals. Toxins (Basel). Nov 2012. [Cited June 2020]; 4 (11): 1261-1287. doi: 10.3390/toxins4111261

Kausman. J 517 Haemolytic uraemia syndrome. Royal Hospital for Children- Nephrology. Dec 2013. [Cited June 2020]; Available from:  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3509707/

Hughes D. Management and investigation of bloody diarrhoea and haemolytic uraemic syndrome [draft].  GG&C Paediatric Guidelines- Kidney Diseases. Oct 30 2019. [Cited June 2020]; Available from: https://www.clinicalguidelines.scot.nhs.uk/ggc-paediatric-guidelines/ggc-guidelines/kidney-diseases/management-and-investigation-of-bloody-diarrhoea-and-haemolytic-uraemic-syndrome-draft/

Balestracci A et al. Dehydration at admission increased the need for dialysis in hemolytic uremic syndrome children. Pediatr Nephrol. 2012. [ Cited June 2020];27: 1407-1410. Doi: 10.1007/s00467-012-2158-0

Scheiring J. Andreoli SP. Zimmerhackl LB. Treatment and outcome of Shiga-toxin-associated hemolytic uremic syndrome (HUS). Ped Neprhrol. 2008. [Cited June 2020]; 23: 1749-1760. Doi: 10.1007/s00467-008-0935-6

Grisaru Silviu. Management of hemolytic-uremic syndrome in children. Int J Nephrol Renovasc Dis. 2014 [Cited June 2020]; 7: 231-239. Doi: 10.2147/IJNRD.S41837.

COVID19 and ACE inhibitors

Cite this article as:
Cathy Quinlan. COVID19 and ACE inhibitors, Don't Forget the Bubbles, 2020. Available at:
https://doi.org/10.31440/DFTB.24225

Why do my patients keep asking me about ACE inhibitors and COVID-19?

Hypertension is a common problem affecting 3.5% of children and adolescents and correlating with increased cardiovascular risk in young adults. Common first-line therapies include angiotensin converting enzyme inhibitors (ACEi), such as ramipril, lisinopril and enalapril.

Over the last few weeks, a storm has erupted over the use of ACEi with the suggestion that they could be associated with severe COVID-19. A statement by the European Society of Cardiology, was quickly followed by most national hypertension societies, including the American Society of Pediatric Nephrology and the High Blood Pressure Research Council of Australia, recommending the continuation of ACEi in patients with COVID-19. 

 

How are ACEi linked with COVID-19?

The COVID-19 literature to date has suggested increased mortality for adults with hypertension and for those with diabetes, a patient cohort frequently treated with ACEi. Although medication use has not been reported in patients with COVID-19, a letter to the Lancet postulated that the use of ACEi could be implicated in the increased mortality rate described in patients with hypertension. 

Human coronoviruses, such as SARS-CoV-2, gain entry to the cell through ACE2 which is expressed by epithelial cells of the lung and kidney. Thus a treatment that increases the expression of ACE2 at the cell surface could increase the severity of COVID-19 infection. There is animal evidence that circulating ACE2 levels are increased by treatment with ACEi. But also conflicting evidence in humans showing no association between circulating ACE2 levels and the use of ACEi. 

Interestingly, there is clinical data to suggest that ACE inhibition may actually be a potential therapy for viral pneumonia. Though it should be noted that this is confined to retrospective, observational data, clinical trials are underway to examine the use of recombinant ACE2 and losartan in adults with COVID-19, highlighting that the use of ACEi in patients with COVID-19 is not clearcut. 

 

How does this impact our patients?

A growing body of evidence, summarised by the DFTB team here, shows that children are at much less risk of severe disease than adults. Indeed, only 1 of 731 patients with confirmed COVID-19 infection in the largest study to date, had clinically critical disease. The data on ACEi in COVID-19 is inconclusive and pending further data there is no evidence to change anti-hypertensive management in children at this point in time. 

 

The Bottom Line

There is currently no evidence, in children or adults, to support changing blood pressure medication due to the COVID-19 pandemic.

 

I want to know more!

If you want to read more about HTN then please review the 2017 Hypertension guidelines from the American Academy of Paediatrics.

If you’d like to know more about ACE2, hypertension, and COVID-19 then check out the dedicated ACE2 NephJC page.

For up to date reviews of the COVID-19 literature as it pertains to the kidney along with management guidelines check out the COVID-19 NephJC page

If you are aware of resources that you think would be useful to the nephrology community then please tag it with #CoronaKidney and they will be added to the page after they are reviewed. 

 

Renal Failure

Cite this article as:
Marc Anders. Renal Failure, Don't Forget the Bubbles, 2013. Available at:
https://doi.org/10.31440/DFTB.3719

Definition: acute kidney injury (AKI) is failure of the kidneys to regulate electrolyte, acid-base and fluid homeostasis adequately with concomitant reduction in glomerular filtration rate (GFR). pRIFLE (paediatric Risk, Injury, Failure, Loss, End-Stage Criteria).

Chronic renal failure: hyperfiltration, estimated creatinine clearance <75 ml/min/1.73m2 , hypertension, microalbuminuria.

Diabetes Insipidus

Cite this article as:
Tessa Davis. Diabetes Insipidus, Don't Forget the Bubbles, 2013. Available at:
https://doi.org/10.31440/DFTB.3030

A 5-year-old girl is on the ward following resection of a craniopharyngioma.  The nurses call you because her urine output has increased dramatically over the last few hours.  You check her sodium and it’s 150.

Is your brain hurting just thinking about it?

 

Bottom Line

  • Suspect diabetes insipidus if there is polyuria, polydipsia in the presence of a high serum Na and low urinary Na
  • Manage with vasopressin and appropriate hydration
  • Watch for hyponatraemia following the commencement of treatment
  • This can be a life-long condition and ease of management will depend on whether the patient has an intact thirst centre

 

What is DI?

In diabetes insipidus, the body produces no (or very little) anti-diuretic hormone.  This means that the patient cannot concentrate the urine and ends up with dehydration and electrolyte imbalance.

 

What causes it?

ADH is a hormone that regulated fluids and sodium retention.

In cranial DI the pituitary does not properly signal for the release of ADH when needed (i.e. when dehydrated) and so there is no ADH to instigate fluid retention.  Due to dehydration, the body then tries to retain sodium.

Cranial DI causes include: surgery (trans-sphenoidal); traumatic brain injury; idiopathic; autoimmune; tumours (suprasellar, lung, breast, lymphoma, leukaemia); hypoxic brain injury; brain stem death; profound hyponatraemia; radiotherapy; drugs – amiodarone, lithium; inflammatory conditions – sickle cell, sarcoid, Wegener’s, histiocytosis X; infections – TB, abscess, encephalitis, meningitis; vascular disease – CVA, SAH, Sheehan’s syndrome.

In nephrogenic DI, ADH is being produced but the kidneys are not responding to it.   This is a different condition and will not be dealt with in this post.

How can I recognise it?

The symptoms of DI can include polyuria, polydipsia and dehydration or weight loss.

In some patients, the thirst centre is not intact and so they will no have symptoms of polydipsia.

 

Biochemical abnormalities

  • Urine output >4ml/kg/hr for 2 hours
  • Serum Na>145
  • Osmolality: serum >295 mOsmol/kg H2O And urine <450 mOsmol/kg H2O
  • Weight loss of >5%

Additional studies such as plasma ADH, urine specific gravity and a water deprivation test can assist with diagnosis. Urine specific gravity is a particularly handy test as it can be done there and then without going to the lab.

 

  • Water deprivation test

  • This test aims to check if the kidneys can concentrate urine in the presence of ADH
  • The patient is fluid deprived for 8 hours or until 5% of body weight is lost
  • Measure plasma osmolality every 4 hours. and urine volume and osmolality every 2 hours.
  • After the 8 hours, the patient is given IM vasopressin unless there is a clear indication of DI prior to this
  • urine and serum osmolality are checked over the following 4 hours
  • In cranial DI the urine osmolality will initially be low (<300 mmol/kg) and after vasopressin it will rise to >800
  • In nephrogenic DI giving the vasopressin will not make any difference to the osmolality

 

What is the treatment?

Management in ICU

If the patient has a high serum Na, high urine output and low urine osmolality in the post-op period, treatment should be considered (usually in discussion with the endocrine team).

Treatment is based around a combination of rehydration and vasopressin.

Vasopressin can be given IN, orally or IV.

The aim is to keep the Na at 135-140.  If the Na>150 the amount of vasopressin should be increased.

The other aim is to maintain hydration and a normal urine output (target 2-3 mls/kg/hr).

Be careful of hyponatraemia from over-treatment and also of bringing the sodium down too fast (this can cause cerebral oedema).

If the Na<135 then either stop the vasopressin or give some hypertonic saline.  Consider fluid restriction or frusemide if the Na continues to fall and is <130.  These patients can have seizures due to hyponatraemia post commencement of vasopressin if it’s not tightly monitored.

 

Calculating sodium replacement

(Target sodium – current sodium) x 0.6 x weight = mmol Na required to reach target

 

Sodium content of fluids

[wpsm_comparison_table id=”9″ class=”center-table-align”]

Ongoing DI management

Daily serum electrolytes and osmolality, and daily urine osmolality are required until stable.

Make sure sodium is above 145 mmol/L prior to administration of vasopressin.

Should have 1-2 hrs of diuresis (greater than 4ml/kg/hour) prior to administration of next dose to avoid hyponatraemia.

Patients should be weighed daily and keep a strict fluid balance chart.

 

What is cerebral salt wasting (CSW)?

This is rare but can occur following cranial surgery.

It causes polyuria and dehydration but with high urinary sodium (i.e. hyponatraemic dehydration).

The urine:serum osmolality ratio will be greater than 1.

CSW is managed with fluid replacement and salt replacement of urinary sodium losses (as guided by the serum sodium).

What’s the prognosis?

DI can be transient or permanent.

Pratheesh et al (2013) did a retrospective analysis of 102 children who were status post removal of craniopharyngioma (and compared them to adults)

  • DI was more common post-op in children than adults (80% v 63%)
  • Triphasic response (fluctuating serum sodium levels) was more common in children
  • Children had a higher incidence of permanent DI (55.6%)

 

Selected references

Diabetes insipidus, Royal Children’s Hospital (Melbourne)

Diabetes insipidus, Medscape

Pratheesh R, Swallow DM, Rajaratnam S, Jacob KS, Chacko G, Joseph M, et al. Incidence, predictors and early post-operative course of diabetes insipidus in paediatric craniopharygioma: a comparison with adults. Childs Nerv Syst. 2013;29(6):941-9.

How to do the water deprivation test

Microscopic haematuria

Cite this article as:
Ben Lawton. Microscopic haematuria, Don't Forget the Bubbles, 2013. Available at:
https://doi.org/10.31440/DFTB.2916

A previously well 3-year-old girl presented to your ED with a history of fever. You have confidently diagnosed otitis media and are just about to discharge the child when the nurse mentions a urine was requested at triage and has come back positive for blood.

The nurse asks you what it means if the girl has blood in her urine….

The Bottom Line

  • With a urine dipstick that is positive for blood, the first thing to do is establish whether the finding is real (by microscopy).
  • Remember to look for UTI, hypertension, proteinuria and concerning family history
  • In the absence of red flags on history and examination, no investigations beyond microscopy are required until the microscopic haematuria has proved to be persistent.

What does this finding represent?

Microscopic haematuria is a common finding in the setting of febrile illness. It can be caused by many benign phenomena including adenovirus, ibuprofen, antibiotics including penicillin and indeed by fever itself.

There is always a concern that haematuria represents significant underlying renal pathology but in this circumstance, the risk is extremely small.

What further assessment should you perform and what are you looking for?

Clinical examination and urine microscopy are sufficient at this stage. The following table outlines the major things you should be looking for. There are more sensitive and specific ways of searching for all these findings but in this context, underlying renal disease is pretty unlikely so clinical assessment alone is good enough for now.

The key things to remember are to check for hypertension, proteinuria, UTI and a family history of renal failure.

FindingSuggestive of
Failure to thrivechronic disease process
WTU for proteinglomerulonephritis
WTU for leucs/nitriteUTI
FH renal failureany hereditary nephropathy
FH deafnessAlport syndrome
FH renal stonesfamilial hypercalciuria
Hx infection (2 weeks ago)post strep GN
Hx infection (1-2 days ago)TBMN/IgA nephropathy
bruises/bleedingbleeding diathesis
loin massesWilm’s tumour
oedemanephrotic syndrome
hypertensionnephritis

If this is all normal the only investigation required at this stage is urine microscopy and culture to confirm and quantify the presence of blood and determine if the cells are dysmorphic (suggesting a glomerular source of bleeding), This is also the definitive test for a UTI.

Any positive findings from the list above should prompt more sensitive/specific investigation.

 

So the history, exam and urine microscopy was normal, can I forget about the haematuria?

No, although significant renal disease is unlikely the child should be referred back to their GP for a repeat urinalysis in 2-4 weeks when they are well. If the haematuria has resolved at that time then no further action is required. Persistent haematuria will require further investigation.

 

So what proportion of kids with microscopic haematuria actually have significant renal disease?

A large study where urinalysis was performed in asymptomatic school children to evaluate its suitability as a screening tool for occult renal disease found the following:

  • Children screened – 7 million
  • Abnormal UA – 1044
  • Isolated haematuria – 719 (of 1044)
  • Biopsy performed (indications for biopsy = severe proteinuria, hypertension, abnormal renal function of a family history of renal disease) – 52
  • Thin glomerular basement membrane nephropathy (benign condition) on biopsy – 33
  • Other defined pathology on biopsy – 16

In other words of 719 children with isolated haematuria, 16 went on to have proven renal disease that warranted further management.

This was a population of well children and you can imagine that in a population of febrile kids, with the benign reasons for having haematuria outlined above, the proportion of kids with significant renal disease as a cause of their microscopic haematuria would be even smaller.

 

Does a positive dipstick mean there is definitely blood in the urine?

No, false positives on a dipstick can result from haemoglobinuria (e.g secondary to haemolysis) or myoglobinuria. It is also worth remembering that blood in the urine may originate from the vagina or rectum and some causes (e.g. anal fissure) may not be immediately evident on exam). Several things have been reported to cause a red tinge to the urine that may be mistaken for blood.

The following can all cause the appearance of gross haematuria but they should not cause a dipstick to read positive:

  • Drugs – chloroquine, ibuprofen, iron, sorbitol, nitrofurantoin, phenazopyridine, phenolphthalein
    Foods – beets, blackberries, food colouring metabolites
    Other – bile pigments, homogentisic acid, melanin, methemoglobin, porphyrin, tyrosine, urates

Microscopy should be able to confirm that the blood is for real.

 

References

McTaggart S. Childhood Urinary Conditions. Aust Fam Phys 2005; 34:937-41.

Park YH, Choi JY, Chung HS, et al. Hematuria and proteinuria in a mass school urine screening test. Pediatr Nephrol 2005; 20:1126–1130.

Quigley R. Evaluation of hematuria and proteinuria: how should a pediatrician proceed? Current Opinion in Pediatrics 2008, 20:140–144.

Rees L, et al. Oxford Specialist Handbooks in Paediatrics: Paediatric Nephrology, Oxford University Press. 2007. p18-19.