Rachael Kermond. Nephrotic syndrome, Don't Forget the Bubbles, 2021. Available at:
https://doi.org/10.31440/DFTB.31540
Who, when and what…
Nephrotic syndrome is the most common glomerular disorder of childhood, affecting 1-7 children in 100,000 per year. It most typically affects children aged 2- 12 years of age and is characterized by proteinuria, hypoalbuminaemia and oedema.
Why it happens…
The villain of nephrotic syndrome is the glomerular filtration barrier (GFB). If we peer back at our textbooks, we remember the GFB is composed of two cells, the capillary endothelial cells and the podocytes separated by the glomerular basement membrane. The GFB is responsible for the filtration of water and small solutes but the retention of albumin. Defects in this GFB result in increased permeability to albumin and the subsequent proteinuria that defines nephrotic syndrome.
Idiopathic nephrotic syndrome (INS) is the most common cause of nephrotic syndrome in children. The aetiology is unclear however it could be related to circulating factors that, via immune mechanisms, alter the podocyte function and thus the GFB. The underlying histopathology of INS is minimal change disease (MCD) and less frequently focal segmental glomerulosclerosis (FSGS) which carries a poorer prognosis.
Other, less common causes include genetic mutations (with up to 50 genes affecting various components of the GFB identified to date), membranous glomerulopathy and glomerulonephritis (such as systemic lupus erythematous).
How it presents…
Children often present with a history of intermittent periorbital or pedal oedema. It is not commonly diagnosed until the child develops gross oedema with scrotal or labial oedema, ascites and even pleural effusions which prompts presentation.
Other potential presenting features include sepsis, cellulitis related to oedema, spontaneous bacterial peritonitis and complications of a prothrombotic state such as venous sinus thromboses.
How we investigate it…
It’s important to confirm proteinuria with a urine protein:creatinine ratio. Other investigations include a full blood count to evaluate for evidence of haemoconcentration, biochemistry to assess for hyponatraemia, acute kidney injury and serum albumin levels and a urinary sodium to assist in determining the intravascular fluid status of the patient.
Consideration of an immunologic assessment (ANA, complements) should occur if a patient presents with other systemic symptoms or haematuria. Finally, the patient’s immune status to varicella-zoster is important as it will guide prophylaxis if future exposure occurs.
How we treat it…
There are two main arms to the treatment of nephrotic syndrome. Acutely, the management of severe oedema and chronically, the treatment of the disease for which the basis is corticosteroids.
Management of acute presentation:
When assessing oedema in a nephrotic patient, it’s important to evaluate the intravascular fluid status of the patient. Hypotension, cool peripheries, elevated creatinine and a low urinary sodium are all features consistent with intravascular depletion. Whereas those who are oedematous, well-perfused with hypertension and a urinary sodium > 10mmol/L are likely well hydrated.
Management includes a strict fluid balance with a daily weight, a diet low in salt, the introduction of a fluid restriction (unless there is evidence of intravascular depletion) and consideration of IV albumin with frusemide.
If indicated, 1g/kg (5ml/kg) of 20% albumin should be given over 4-6 hours with 1mg/kg IV frusemide dose either halfway through and/or on completion of the infusion (depending on the patient’s fluid status). Those who have evidence of hypervolaemia may be treated with IV frusemide alone. However, this is a short term strategy and they should be closely monitored for evidence of hypovolaemia.
Another component of the acute management is consideration and treatment of the potential complications including sepsis, cellulitis, spontaneous peritonitis and thrombotic sequelae.
Long term management:
Whilst oedema is being treated it is important to instigate the mainstay of nephrotic syndrome therapy, prednisolone. The initial dose is 60mg/m2 for 4-6 weeks followed by a weaning course (alternate daily dosing) for up to 2 months. Previously, this initial course had been as long as 6 months. There is consistent data in the literature that demonstrates that this shorter regime is non-inferior and leads to a reduction in the side effects of steroids, particularly on growth.
The initial presentation is an invaluable opportunity to provide support to these families who are now presented with a chronic medical illness. This is facilitated by intensive education, dietician review and social work (or equivalent) input.
Education:
- A dedicated consult explaining the diagnosis, management, ongoing monitoring requirements and prognosis.
- Provide demonstration of urine dipsticks as this will be required daily for at least a year post-diagnosis and even longer if the patient frequently relapses.
- Supplement with written information and a diary for the family to record urine results, weights and steroid dose.
Dietetics:
- A dietetic consult to provide advice around a low salt diet and fluid restriction.
- These restrictions are required whilst the patient is nephrotic and are often reinstated during relapses.
- Education is also provided regarding a healthy balanced diet to avoid significant weight gain on high dose steroids.
Pastoral Care
- The diagnosis of nephrotic syndrome is often met with considerable anxiety and distress from families who now face a chronic disease for their child.
- A social worker or equivalent support structure is important to assist in acknowledging these concerns and anxieties.
- Provision of information regarding potential financial support is also considered.
- Preventative measures against complications of nephrotic syndrome are equally important.
Gastritis
- Gastritis is a common complication of high dose steroids and can present with epigastric pain or generalized abdominal pain.
- Acid suppression medications such as a proton pump inhibitor (PPI) are recommended whilst children are on high dose steroids.
- These can be ceased when the child moves to alternate-day steroid therapy.
Infection
- Penicillin V at 12.5mg/kg BD should be considered for those children who present with ascites as prophylaxis for spontaneous bacterial peritonitis. This therapy is continued until the patient remits (i.e. no longer proteinuric).
- If a child with nephrotic syndrome has contact with a known source of VZV, subcutaneous immunoglobulin should be administered
Immunisations
- Live vaccines are contraindicated whilst the child is nephrotic and/or on high dose steroids
- Ensure yearly influenza vaccine.
- Children who frequently relapse or have persistent nephrotic syndrome qualify for additional pneumococcal vaccine.
The use of aspirin and other anti-thrombotic agents have largely been abandoned given the risks of these therapies. The likelihood of thrombosis is significantly reduced once the child’s oedematous state is appropriately managed
What happens next…
90% of children respond to steroid therapy within 4-6 weeks (i.e. steroid-sensitive). Remission is defined as a negative/trace urine dipstick for three consecutive days. There are a small proportion of children who will not remit in this time period, referred to as steroid-resistant. These children require consideration of a renal biopsy and/or genetic testing (such as rapid genomic sequencing) thus warrant a referral to a paediatric nephrologist.
80% of children with nephrotic syndrome will relapse, often in the context of a concurrent illness. This is the basis for ongoing urine dipstick testing. This will detect a relapse prior to the child becoming oedematous and so may avoid further hospital admission.
Some children will demonstrate steroid-dependence or become frequent relapsers (i.e. ≥2 relapses in the first 6 months following diagnosis or ≥4 in any 12 month period). These patients, in addition to the steroid-resistant group, should be referred to a nephrologist for ongoing management.
Finally, approximately 10% of patients with nephrotic syndrome will continue to relapse in their adult life.
The bottom line…
- Nephrotic syndrome is the most common glomerular disorder of children
- Acute management involves the treatment of oedema and potential complications of the nephrotic state
- Long term management is with prednisolone
- Equally important at diagnosis is education, social support and dietetic review
- Referral to nephrology is required if a child demonstrates any of the following
- Steroid resistance
- Steroid dependence
- Frequent relapses
- Atypical presentation (e.g. microscopic haematuria, acute kidney injury etc…)
References
- Metz D, Kausman J. (2014) Childhood nephrotic syndrome in the 21st century: what’s new? Journal of Paediatric and Child Health, 51, 497-504.
- Hahn D, Samuel S, Willis N, Craig J, Hodson E. (2020). Corticosteroid therapy for nephrotic syndrome in children. Cochrane database of systematic reviews, accessed 11 October 2020, doi.org/10.1002/14651858.CD001533.pub6.
- Hodson E, Wong S, Willis N, Craig J. (2016) Interventions for idiopathic steroid-resistant nephrotic syndrome in children. Cochrane database of systemic reviews, accessed 11 October 2020, doi.org/10.1002/14651858.CD003594.pub5.
- Ding W, Moin S. (2012) Current concepts of the podocyte in nephrotic syndrome. Kidney research and clinical practice, 31, 87-93.
- Bensimhon A, Williams A, Gbadegesin R. (2018) Treatment of steroid-resistant nephrotic syndrome in the genomic era. Paediatric Nephrology, 34, 2279-2293. https://doi.org/10.1007/s00467-018-4093-1
- McCaffrey J, Lennon R, Webb N. (2016) The non-immunosuppressive management of childhood nephrotic syndrome. Paediatric Nephrology, 31, 1383-1402 doi: 10.1007/s00467-015-3241-0
UTI whizzdom – the next steps
Felicity Beal. UTI whizzdom – the next steps, Don't Forget the Bubbles, 2021. Available at:
https://doi.org/10.31440/DFTB.32306
A 4-month-old baby presents with a temperature and urine microscopy suggestive of a urinary tract infection. He appears well and your plan is to discharge home on an oral antibiotic, whilst awaiting culture results. His mother asks you, “Does he need any other tests?”
Why does it matter?
Urinary tract infections (UTIs) are very common in children. Studies suggest that 6-8% of febrile, unwell children presenting to their GP have a UTI. Therefore it is important to carefully select which of these children need further investigations in order to identify those with underlying renal tract problems. It is estimated that up to 15% of children with a first UTI have evidence of scarring on follow up scans. If they are missed, these children may go on to develop hypertension and possible chronic kidney disease later in life.
Which children are more likely to get a UTI?
Before the age of 6 months, UTIs are more prevalent in boys. This is partly due to the increased chance of structural abnormalities within the urinary tract. Uncircumcised boys are particularly at risk, as bacteria on the foreskin are a reservoir for infection.
However, after 6 months of age, girls are at increased risk due to their shorter urethra and its proximity to the anus. This risk is increased again in females when they become sexually active.
Risk factors for UTIs
There are several other risk factors that increase the risk of developing a urinary tract infection. The main risk factor is something we see and manage on a daily basis, another really common presentation…constipation! If you haven’t yet read Chris Dadnam’s Conversations about Constipation post, now would be a great time to have a refresher as these two conditions go hand in hand.
As the colon and rectum fill with stool, the mass effect results in incomplete bladder emptying. This results in stasis of urine. Always ask about, and treat, constipation… If this is left unmanaged UTIs will continue to be a problem.
After taking a good constipation history and examining the abdomen, it’s important you assess the spine looking for dimples, swellings, birthmarks or hairy patch lesions that can be associated with a neuropathic bladder. This should be followed by a lower limb neurological assessment. I think of this as running a bath after a hard day at work. You are unable to fully empty the tub afterwards but continue to add more bathwater to the tub every time… this will encourage infection to harbour. Recurrent UTIs may be the main presenting complaint in young children and should always prompt a review of the spine.
Foreign bodies such as intermittent or indwelling catheters also pose a risk. But it is essential to remember the last risk factor, not visible to the eye … namely urinary reflux.
Is this the same as vesico-ureteric reflux?
Yes. This is simply a term describing where, anatomically, the reflux occurs – from the bladder (vesico) to the ureters (ureteric). Urine flows back up from the bladder to the ureters causing a bidirectional flow of urine.
VUR can be primary, i.e. within a normal renal tract, or secondary, due to an abnormal renal tract – such as a neuropathic bladder. It is graded from 1 (mild) to 5 (severe.) Most mild to moderate reflux resolves by 5 years of age. However, surgery may be indicated if severe reflux is present, with worsening renal impairment or frequent pyelonephritis.
History and examination
As part of the history taking and examination, it is key to think about whether there could be underlying constipation, VUR or a neuropathic bladder. Asking about a family history of renal problems as well as considering antenatal renal scans is important to risk stratify for structural problems.
Ask about
Examine for
What do we need to consider when further investigating UTIs?
NICE (the National Institute for Health and Care Excellence) ask the following three questions when considering a child’s risk of reflux and scarring:
How old is the child? Age is important. This may be a neonate or infant presenting with an infection as the first indicator of a possible underlying structural abnormality such as posterior urethral valves or VUR.
Is this an atypical UTI? 80% of paediatric UTIs are secondary to E.coli infection. An infection caused by an organism other than E.coli, or not responding within 48 hours of antibiotic therapy, is more unusual. Equally, if a child with a UTI looks unwell, has a palpable bladder, renal impairment or poor urine flow, your index of suspicion should be raised. These are uncharacteristic signs of a urinary tract infection.
Is this child having recurrent infections? Over 30% of children with UTIs will suffer from recurrent infections. Recurrent infections are defined as children who have either 2 or more upper UTIs (affecting the kidneys or ureters), 3 lower urinary tract infections (affecting the bladder or urethra) or 1 upper and 1 lower infection at any point up until the age of 16.
Investigations? Clear as M.U.D.
MCUG
An MCUG is a Micturating Cystourethrogram, which assesses for urinary reflux or obstruction. A catheter is inserted and radio-opaque contrast is administered via the catheter to fill up the bladder. X-rays are then taken during urination to see if urine is refluxing back towards the kidney.
DMSA
A DMSA scan is used to assess the function and location of the kidneys. An isotope that emits gamma rays is attached to ‘Dimercaptosuccinic acid’. This is administered via an intravenous cannula and is taken up by the kidneys a few hours later. If performed acutely it can show altered function consistent with pyelonephritis. In the UK, a DMSA scan is undertaken 4-6 months post-infection to assess for scarring.
What does the guidance say?
In 2007, NICE published a guideline called “Urinary tract infection in the under 16s: diagnosis and management”, updated in 2018. When it comes to imaging, there are three main highlights.
1. Children under 6 months of age with a first typical UTI should have an ultrasound to assess for a structural cause. An MCUG is considered if this is abnormal.
2. All children with an atypical UTI, regardless of age, should have an ultrasound acutely. A DMSA is also performed if they are under 3 years of age to assess renal parenchyma. Children under 6 months are investigated more fully with an USS, DMSA and MCUG.
3. All recurrent UTIs require a DMSA scan within 4-6 months to assess for scarring.
This traditional approach for investigating children for reflux and scarring is safe yet adopts a different approach to imaging children with UTIs compared with other countries.
Controversial whizzarding….
The decision of who should be investigated further has caused great controversy. Different approaches are adopted around the world. This is due to conflicting evidence with clinicians balancing the risk of radiation, invasive imaging and cost with that of detecting children with an underlying congenital anomaly and preventing the development of chronic kidney disease.
There is conflicting data surrounding the risk factors for VUR in children with their first UTI. Ristola et al (2017) investigated risk factors for children with UTIs, finding the following 3 as the main risk factors for reflux: ultrasound abnormalities, recurrent infections and atypical infections. Interestingly, non-E. coli infections were the only statistically significant risk factor of infection recurrence.
Yılmaz et al (2016) were unable to identify risk factors associated with VUR, although did note that an abnormal renal scan at 6 months after the infection was closely related to the presence of VUR and recurrent UTIs.
In America, Canada, Poland and Italy, children up to 2 -3 years of age with their first UTI would be advised to have an ultrasound. The European Association of Urology advises every child presenting with a first UTI to be investigated with sonography. This is in comparison with the 6 month cut off advised by NICE, which is argued to be a more cost effective and risk stratified approach.
However, the American, Canadian and Italian guidelines do not investigate all children with recurrent UTIs as previously advised by the NICE guidance. Instead of all children with recurrent UTIs undergoing a DMSA scan, recent guidance suggests only performing a DMSA if there were concerns regarding an abnormal ultrasound or alternative diagnosis.
Therefore this makes me wonder, instead of investigating all children with recurrent UTIs, perhaps this decision should be made on an individual basis, using their ultrasound findings and considering risk factors.
How accurate are ultrasound scans in picking up VUR?
An ultrasound cannot exclude all cases of VUR as it is an observer-dependent investigation. Mahant et al (2002) reported low sensitivity of 40% and a specificity of 76% when diagnosing VUR, but the majority of these patients had lower grade reflux. There is now increasing awareness that low-grade reflux and mild scarring are unlikely to cause long term problems, therefore the argument presents itself: is there any benefit in investigating for them? Ultrasound scans are more likely to detect higher grade reflux and hence clinically significant cases, but further evidence is needed to support this approach.
The take homes
Some evidence suggests that children with ultrasound abnormalities or recurrent UTIS are at increased risk of complications from UTIs, regardless of their age or sex. There is no clear consensus on when to request a DMSA or MCUG but the latest evidence suggests that DMSA scans may not be necessary in all children with recurrent infections and a normal ultrasound scan. Clinicians should be aware of this existing controversy, weighing up the benefits and risks in order to make informed clinical decisions.
References
Craig J. Urinary tract infection: new perspectives on a common disease. Curr Opin Infect Dis 2001; 14 (3): 309–313.
Davis A, Obi B, Ingram M. Investigating Urinary tract infections in children BMJ 2013; 346 : e8654
Edlin RS, Shapiro DJ, Hersh AL, et al Antibiotic resistance patterns of outpatient pediatric urinary tract infections. J Urol2013;190:222–7.doi:10.1016/j.juro.2013.01.069
Kaufman J, Temple-Smith M, Sanci LUrinary tract infections in children: an overview of diagnosis and management BMJ Paediatrics Open 2019;3:e000487. doi: 10.1136/bmjpo-2019-000487
Mahant S, Friedman J, MacArthur C. Renal ultrasound findings and vesicoureteral reflux in children hospitalised with urinary tract infection. Arch Dis Child. 2002 Jun;86(6):419-20. doi: 10.1136/adc.86.6.419. PMID: 12023172; PMCID: PMC1762998.
Mori R, Lakhanpaul M, Verrier-Kones K. Diagnosis and management of urinary tract infection in children: summary of NICE guidance. Br Med J 2007; 335 (7616): 395–397.G
National Institute for Health and Care Excellence. Urinary tract infection in children: diagnosis, treatment and long-term management. Clinical guideline 54. London: NICE, 2007.
Newman DH, Shreves AE, Runde DP Pediatric urinary tract infection: does the evidence support aggressively pursuing the diagnosis?Ann Emerg Med2013;61:559–65.doi:10.1016/j.annemergmed.2012.10.034
O’Brien K, Edwards A, Hood K, et al Prevalence of urinary tract infection in acutely unwell children in general practice: a prospective study with systematic urine sampling. Br J Gen Pract2013;63:e156–64. doi:10.3399/bjgp13X663127
Okarska-Napierała M, Wasilewska A, Kuchar E Urinary tract infection in children: Diagnosis, treatment, imaging – Comparison of current guidelines. J Pediatr Urol2017;13:567–73.doi:10.1016/j.jpurol.2017.07.018
Ristola MT, Löyttyniemi E, Hurme T. Factors Associated with Abnormal Imaging and Infection Recurrence after a First Febrile Urinary Tract Infection in Children. Eur J Pediatr Surg. 2017 Apr;27(2):142-149. doi: 10.1055/s-0036-1572418. Epub 2016 Feb 8. PMID: 26855368.
Shaikh N, Craig JC, Rovers MM, et al. Identification of children and adolescents at risk for renal scarring after a first urinary tract infection: a meta-analysis with individual patient data. JAMA Pediatr2014;168:893–900.doi:10.1001/jamapediatrics.2014.637
Shaw KN, McGowan KL, Gorelick MH, Schwartz JS. Screening for Urinary Tract Infection in Infants in the Emergency Department: Which Test Is Best? Pediatrics. 1998;
Stein R, Dogan HS, Hoebeke P, et al Urinary tract infections in children: EAU/ESPU guidelines. Eur Urol2015;67:546–58.doi:10.1016/j.eururo.2014.11.007
Subcommittee on Urinary Tract Infection Reaffirmation of AAP clinical practice guideline: the diagnosis and management of the initial urinary tract infection in febrile infants and young children 2-24 months of age. Pediatrics 2016;138:e20163026.doi:10.1542/peds.2016-3026
Yılmaz S, Özçakar ZB, Kurt Şükür ED, Bulum B, Kavaz A, Elhan AH, Yalçınkaya F. Vesicoureteral Reflux and Renal Scarring Risk in Children after the First Febrile Urinary Tract Infection. Nephron. 2016;132(3):175-80. doi: 10.1159/000443536. Epub 2016 Feb 23. PMID: 26901769.