Nephrotic Syndrome Management

Disclaimer These guidelines have been produced to guide clinical decision making for the medical, nursing and allied health staff of Perth Children’s Hospital. They are not strict protocols, and they do not replace the judgement of a senior clinician. Clinical common sense should be applied at all times. These clinical guidelines should never be relied on as a substitute for proper assessment with respect to the particular circumstances of each case and the needs of each patient. Clinicians should also consider the local skill level available and their local area policies before following any guideline.  Read the full PCH Emergency Department disclaimer.

Aim

To present a standardised treatment regimen and management plan for children with idiopathic (typical) nephrotic syndrome (NS) at first presentation and for subsequent relapses.

Definitions ^1-4

Nephrotic Syndrome (NS)	A clinical disorder that affects permeability of the glomerular membrane; typical clinical findings in NS are: Oedema: typically periorbital, abdominal and lower limbs Proteinuria:  ≥ 3+ protein on urine dipstick, or a urine protein / creatinine ratio (uPCR) >200 mg/mmol Hypoalbuminemia: serum albumin <25 g/l
Complete remission	<1+ protein on urine dipstick, or uPCR <200 mg/mmol for 3 consecutive days 80-90% of children with NS will see improvement within 2-4 weeks of corticosteroid treatment and achieve complete remission with 8 weeks
Relapse	≥3+ protein on urine dipstick or uPCR ≥200 mg/mmol for 3 consecutive days 80-90% of children with NS will experience one or more relapses; approximately half of these will have frequent relapses

Risks

Delays in recognition and initiation of treatment can place children at increased risk of developing a life-threatening infection which remains the leading cause of mortality in children with NS, currently at around 3%.¹

The effects of treatment itself can place children at risk for adverse outcomes if not appropriately and carefully managed. Prolonged use of high dose corticosteroids has well known side effects^4,5 including immunosuppression, increasing the risk of infection; cataracts; and osteoporosis.⁵  A standardised approach and rationalised corticosteroid regimen aims to minimise these risks. 

Key points

• Children presenting to hospital with first episode of NS should be either admitted to an inpatient ward for initiation of treatment and stabilisation, or if clinically well can be managed in an outpatient setting.
• Children < 1 year or >12 years, and children presenting with non-typical features of nephrotic syndrome (see Nephrologist Referral) should be referred to a specialist paediatric nephrologist for further investigation and management. 
• Acute presenting complications of nephrotic syndrome (hypovolaemia, infection and thrombosis) should be managed in consultation with the relevant specialty teams.
• Standard treatment regimen at first presentation is an 8 week course of corticosteroids (prednisolone), prophylactic oral antibiotics and vaccination.⁵
  • A Cochrane review demonstrated no benefit of extending prednisolone treatment beyond 2-3 months.¹ 
• Children, who are planned for or on significant immunosuppressive doses of corticosteroids (≥2 mg/kg/day of the prednisolone equivalent dose for greater than 1 week), require additional pneumococcal vaccines and annual influenza vaccination. Refer to the Asplenia, Hyposplenia and Complement Deficiency Vaccination and Prophylaxis and medically at-risk WA Immunisation schedule.¹
• Due to the likelihood of relapse³, it is important during the first admission to initiate a child / carer education plan that includes recognising the signs / symptoms of relapse and home monitoring of proteinuria.
• All children being treated in the inpatient wards or in DTU should be referred to the Renal Clinical Nurse Specialist (CNS) so that education can be coordinated and an individualised home relapse treatment plan formulated.

Assessment

Once Nephrotic syndrome is suspected as the presenting diagnosis, follow the assessment below:

• Oedema - principal presenting feature:
  • Mild to moderate periorbital, scrotal or labial swelling
  • Severe / symptomatic: gross scrotal / labial or limb swelling, ascites, increased respiratory effort / distress can indicate pleural effusion.
  • Weight gain – measure weight and height
• Vital signs, including blood pressure (BP)
• Neurological assessment
• Assess for acute complications and seek advice from specialty team/s if signs and symptoms present:
  • Intravascular volume depletion: 
    • poor peripheral perfusion, tachycardia, dizziness and abdominal cramps, low urinary sodium
  • Infection (at increased risk during nephrotic state): ⁶
    • Cellulitis, peritonitis 
    • Fever / sepsis (refer to Emergency Department Sepsis Management guideline and Children's Antimicrobial Management Program (ChAMP) Sepsis and Bacteraemia Guideline.
  • Thrombosis (at increased risk during nephrotic state): ^7,8  
    • Deep vein thrombosis - pulmonary embolus
    • Renal vein thrombosis - palpable kidney, hypertension, loin tenderness
    • Cerebral vein thrombosis (CVT) – neurological signs and symptoms
• Immunisation status and history of recent exposure to vaccine preventable diseases, in particular Streptococcus pneumoniae and varicella exposure. 

Investigations 

• Urine: 
  • Urinalysis
  • Urine protein: creatinine ratio (uPCR), ideally first morning urine
  • Microculture and sensitivity (MCS) if febrile 
  • ±Urine sodium, (intravascular volume depletion)
• Bloods: 
  • Full Blood Picture (FBP), Urea Electrolytes & Creatinine (UEC), Liver Function Tests (LFTs), calcium, phosphate, magnesium
  • Initial presentation only: Streptococcal serology, complement levels (C3, C4) and antinuclear antibody (ANA)
  • Blood Cultures if febrile / septic
  • Please note: lipid profile (including cholesterol) and 25 - OH vitamin D are not required
• ± Imaging; if concerned about thromboembolism, in consultation with renal and haematology specialists.

Management

• Discussion with the accepting team - General Paediatrics or Nephrology.
• Most children would need admission to an inpatient ward for their initial presentation. 
  • Frequent DTU reviews may be an option at the discretion of the treating Consultant and if the child’s clinical condition allows. 

General Ward Management

• Daily weight 
• Daily urinalysis and / or uPCR
• Strict fluid balance and fluid restriction – only in nephrotic state:

• No added salt (NAS) diet - only in nephrotic state:
  • Select NAS option in ADA (Allergy and Diet Application)
  • Refer to renal dietician for patient/family education.

Corticosteroid and Prophylactic Antibiotics

Refer to the First Presentation Treatment and Relapse Treatment Protocols below.

Vaccination 

All children are recommended to receive the pneumococcal vaccine as part of the WA Immunisation Schedule at 2, 4 and 12 months of age with Prevenar13. Children with nephrotic syndrome require additional pneumococcal vaccines (given ideally at diagnosis) with the following: 

1st

Prevenar 13^® (PCV13) at:  

• 6 months of age OR on commencement of immunosuppressive therapy if older than 12 months. 
• NB Prevenar^®13 (PCV13) is to be given at least ≥8 weeks after the last Prevenar^®13 dose.

2nd

Pneumovax 23^® (PPV23) at: 

• 4 years of age (if persisting or relapsing nephrotic syndrome) OR on commencement of immunosuppressive therapy if older than 4 years. 
• NB Pneumovax23^® (PPV23) is to be given at least ≥8 weeks after the last Prevenar^®13 dose.

• Annual influenza vaccination from 6 months of age is recommended.
  • Refer to the medically at-risk WA Immunisation schedule and the online Australian Immunisation Handbook Influenza chapter for further information.
• Note: No live vaccines (i.e. MMR, Varicella) are to be given whilst on corticosteroids or within 1 month of completing steroids. Refer to PCH Immunosuppressive Therapy and Vaccination Guideline (internal WA Health access only) for further information.

Nephrotic Syndrome Treatment Protocol

First presentation Treatment Protocol
	First 4 weeks	Next 4 weeks
Oral corticosteroids	Once Daily Prednisolone^ (9-11) Dose*: 60 mg/m2 (to nearest 5 mg) <12 years up to max 60 mg / dose  ≥12 years up to max 80 mg / dose	Alternate day Prednisolone^  Dose: 40 mg/m2 <12 years up to max 40 mg / dose ≥12 years up to max 60 mg / dose
Oral antibiotics	Once daily Amoxicillin≠ All ages: 20 mg/kg/ dose (max 250 mg)	Cease antibiotics
Vaccination (Refer to Pneumococcal Disease chapter in the Australian Immunisation Handbook)	As per WA Immunisation schedule  plus additional pneumococcal vaccines at commencement of steroids: If ≥6months to 4 years – give an extra dose of Prevenar®13 If  ≥4years – give Prevenar®13 (followed 8 weeks later by Pneumovax23®)

* If oedematous, an estimated IBW should be used to calculate Body Surface Area.

^ To be taken with food. Consider gastrointestinal protection (proton pump inhibitor) if signs / symptoms of gastric discomfort during corticosteroid therapy.

≠ Refer to Asplenia / Hyposplenia Vaccination and Prophylaxis protocol and consult Infectious Disease team for patients with penicillin allergy.

 

Relapse Treatment Protocol
	Until in remission for 3 consecutive days:	Next 4 weeks:
Oral corticosteroids	Once Daily Prednisolone^  Dose: 60 mg/m2  <12 years up to max 60 mg / dose  ≥12 years up to max 80 mg / dose	Alternate day Prednisolone^ Dose: 40 mg/m2 <12 years up to max 40 mg / dose ≥12 years up to max 60 mg / dose
Oral antibiotics	Once daily Amoxicillin≠ All ages: 20 mg/kg/dose (max 250 mg)	Cease antibiotics

Managing acute complications

Hypovolaemia / Severe Oedema:

• Note: oedematous patients can also have intravascular volume depletion
• Intravenous Albumin 20%: 
  • 1 g/kg (5mL/kg) administered over 4-6 hours
• IV Frusemide 0.5 - 1 mg/kg (maximum 80 mg)⁸ mid infusion; repeated at end of infusion if severe oedema or poor response.
• Caution: Patients with a raised serum creatinine may have difficulty excreting albumin 20% and are at risk of active pulmonary oedema. Volume repletion with sodium chloride 0.9% or albumin 4% may be required. Consult a nephrologist.
• The use of diuretics to treat intravascular volume overload should be approached with caution. Please discuss with a Nephrologist to avoid Acute Kidney Injury or intravascular depletion.

Hypertension

• Most patients with typical NS will be normotensive. Transient hypertension may be displayed in a small number of patients as a result of intravascular depletion.
• Persistent hypertension may be an indicator of an atypical presentation or alternative diagnosis and advice should be sought from a nephrology specialist.
  • Short-acting antihypertensive agent (e.g. isradipine - Medication Manual (internal WA Health only)⁹ may be considered for systolic BP >99th centile (centile charts – see RCH Resources).
  • Persistent hypertension >95th centile, may benefit from longer acting agents.

Nephrologist Referral

Referral to a paediatric nephrologist should be made should any of the following features be present at first presentation or at any time during the course of treatment: 

Age < 1 year or >12 years	At first presentation
Family history of Nephrotic Syndrome
Atypical signs and symptoms at presentation (or develops during the clinical course)	Macroscopic haematuria  Persistent hypertension Elevated serum creatinine
Failure to respond to treatment	Two or more relapses within six months of initial presentation  Four or more relapses within any 12 month period
Corticosteroid dependency	Two or more relapses while on corticosteroids  Two or more relapses within 14 days of ceasing corticosteroids
Extra-renal symptoms	Rash, arthralgia, aphthous ulcers, alopecia

Discharge planning and education

Patients and carers should commence education early in the admission and referrals made to the Renal Dietitian and the Renal CNS.  An education plan must include: 

• Dietary management advice on ‘no added salt diet’ and fluid restrictions. 
• How and when to perform urine dipstick and interpret the result.
• How to recognise signs and symptoms of relapse.
• Explanation of the child’s individualised ‘Nephrotic Syndrome Relapse Treatment Plan’ with the patient / carer.  
• When to present to the Emergency Department and / or seek urgent medical advice.
• Ensure Prevenar^®13 vaccination has been administered, and if ≥4years, a Pneumovax23^® is required 8 weeks after Prevenar^®13 dose. 

Outpatient schedule

• Patients with NS will be reviewed by the treating medical team for 12 months after first presentation at the following intervals:
  • 1 week post discharge
  • 4 weeks post discharge
  • 3 months, 6 months and 12 months.
• Follow-up will then continue with 6 monthly clinic reviews alternating between the Nephrotic CNS clinic and the child’s named Consultant.
• Should the child’s signs / symptoms become atypical in nature, clinic visits and follow up will be increased accordingly.

Ophthalmology 

• There is risk of developing cataracts with prolonged, repeat dosing of corticosteroids¹³
• Children who have two or more relapses in one year should be referred for an ophthalmology assessment.  

Immunisation

• Consider referral to the Specialist Immunisation clinic for ongoing advice and management, email  internal referrals to PCH.ImmunisationCentre@health.wa.gov.au

Nephrotic Syndrome Relapse Treatment Plan 

• Each child will have an individualised Nephrotic Syndrome Relapse Treatment Plan that will outline the steroid and antibiotic dosing regimen and fluid restriction (plus medication for gastrointestinal protection if warranted). 
  • The plan must be reviewed and signed by the treating Consultant and Clinical Pharmacist.  
• If the child remains clinically well, the treatment plan can be initiated at home after confirmation of relapse by a telephone call to the Renal CNS or treating medical team.

Renal CNS role:

The Renal CNS will maintain regular telephone contact with the family to keep updated with the child’s progress.

• The Renal CNS will be the first point of contact for the family to keep updated with the child's progress. 
• In the event of suspected relapse, the Renal CNS will be the first point of contact for the family (business hours: Monday-Friday, 0800-1600). Outside of business hours, families can contact the Nephrologist on-call via the PCH switchboard.
• With the parent / carers consent the school will be sent written notification of the child’s condition and treatment plan. A school visit can be arranged in cases where a letter is not sufficient.
• Referrals from PCH staff to the Nephrotic CNS Clinic can be made using e-Referrals.

References

1. Hahn D, Hodson EM, Willis NS, Craig JC. Corticosteroid therapy for nephrotic syndrome in children. Cochrane Database of Systematic Reviews. 2015 (3). PubMed PMID: CD001533. [Level I ]
2. Larkins N, Kim S, Craig J and Hodson E.  Steroid-sensitive nephrotic syndrome: an evidence-based update of immunosuppressive treatment in children.  Arch Dis Child. 2015 Aug 19; 0:1-5. Available from http://dx.doi.org.pklibresources.health.wa.gov.au/10.1136/archdischild-2015-308924
3. Niaudet P, Mattoo TK and Sim, MS. Treatment of idiopathic nephrotic syndrome in children. Up To Date. 2018 [updated May 2018]. Topic 6130, Version 40.0
4. Hodson, E, Evaluation and management of steroid-sensitive nephrotic syndrome. Current Opinion in Pediatrics.  Issue: Volume 20(2), April 2008, p 145–150
5. Saag KG & Furst DE Major side effects of systemic glucocorticoids. Up To Date. March 12, 2018. [reviewed Aug 2018] Topic 7988 Version 18.0
6. Torres RA, Torres BR, de Castilho ASR, Honorato R. Venous sinus thrombosis in a child with nephrotic syndrome: a case report and literature review. Revista Brasileira de Terapia Intensiva. 2014;26(4):430-4. PubMed PMID: PMC4304474.
7. Radhakrishnan J. Renal vein thrombosis and hypercoagulable state in nephrotic syndrome. Up To Date; 2017.
8. Niaudet P, Mattoo TK, and, Kim MS. Complications of nephrotic syndrome in children: Up To Date; 2018 [updated May 2018]. Topic 6102, Version 14.0
9. Australian Medicines Handbook Pty Ltd.  Last modified July 2018.  https://amhonline.amh.net.au/
10. Schijvens AM, ter Heine R, de Wildt SN and Schreuder MF. Pharmacology and pharmacogenetics of prednisone and prednisolone in patients with nephrotic syndrome.  Pediatric Nephrology. 2018. Retrieved from:https://doi.org/10.1007/s00467-018-3929-z
11. Teeninga N, Kist-van Holthe J, van Rijskwijk N, de Mos N, Wetzels JF, Nauta J: Extending prednisolone therapy does not reduce relapse in childhood nephrotic syndrome. J Am Soc Nephrol 24: 149–159, 2012
12. Australian Technical Advisory Group on Immunisation (ATAGI). The Australian Immunisation Handbook . Australian Government Department of Health, Canberra: 2018
13. Junping L,  Tripathi RC and Tripathi BJ. Drug-Induced Ocular Disorders.  Drug Safety (2008) 31 (2): 127-141 

Approved by:	CAHS Medication Safety Committee	Date:	Sept 2024
Endorsed by:	CAHS Drug and Therapeutic Committee	Date:	Oct 2024
		Review date:	July 2027

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