Inclusion criteria:
Patients with nephrotic syndrome
(NS) and recurrence of nephrotic-
range proteinuria
Steroid sensitive nephrotic
syndrome: complete remission within
4-6 weeks of daily prednisone
Infrequent relapsing nephrotic
syndrome: steroid-sensitive nephrotic
syndrome with 0-1 relapses within 6
months, or ≤ 3 relapses within a 12-
month period
Steroid resistant nephrotic
syndrome: patient unable to obtain
remission after 6 weeks of prednisone
+/- IV methylprednisolone pulses
Remission /
Infrequent
Relapses
When in remission, wean
prednisone to 1.5 mg/kg/
dose (max of 40 mg) every
other day for 6 weeks then
stop the medication.
Long Term Management
Nephrotic Syndrome Relapse
Inpatient
Urine protein ≥ 3+ on urine
dipstick x 3 days or ≥ 1+ for 7
No Off Pathway Frequently relapsing nephrotic
days or edema with any
degree of proteinuria? syndrome: steroid-sensitive nephrotic
syndrome with 2 or more relapses
Yes within 6 months, or 4 or more
relapses within a 12-month period.
 Start prednisone 2 mg/kg (max 60 mg) by mouth
QAM
 Nursing team to advise patient and family to Steroid-dependent nephrotic
check urine for protein daily. Call nephrology office syndrome: steroid-sensitive nephrotic
syndrome with 2 or more consecutive
when urine protein is negative or trace for three
consecutive days. This means the patient is in relapses during tapering or within 14
days of stopping steroids.
remission.
Remission / Frequent No remission after 4
Relapses weeks of daily
Steroid-Dependent prednisone
 IV methylprednisolone pulses
500 mg/m² x 3 doses (max of 1
gram per dose) during weeks 5-
Wean prednisone: 6
 1.5 mg/kg (max 40 mg) QOD for 2 wks
 Lisinopril 0.1 mg/kg PO daily
 1.25 mg/kg (max 30 mg) QOD for 2 wks  Continue oral prednisone 2
 1 mg/kg (max 20 mg) QOD for 2 wks
mg/kg (max 60 mg/day) on non-
 0.75 mg/kg (max 10 mg) QOD for 2 wks
pulses days
 0.5 mg/kg (max 5 mg) QOD for 2 wks then off
Start Mycophenolic Acid (first line option) Remission
 400 mg/m2 per dose PO BID Yes at end of 6
 Increase to 600 mg /m2 per dose PO BID in 2-4 wks if well weeks?
tolerated (max dose is 1500 mg/dose)
If concerns for compliance, consider second line options: No
 Rituximab
 Tacrolimus: starting dose 0.05 mg/kg PO Q 12 hours, titrate to
goal level 5-8 Steroid resistant
protocol
 Rituximab
Treatment Guidelines:
 Appropriate to extend Prednisone until getting Rituximab
 Start Rituximab while in remission if possible

Premedication: Before initial dose check:

 Cetirizine:  Hep B surface antigen
• Infants ≥6 months and  Hep B surface antibodies
Children <2 years: 2.5 mg  Hep B core antibodies Black box warning
PO daily  IgG of Hepatitis B reactivation
• Children 2 to 5 years: 5 mg PO  Renal Function Panel
daily  Complete Blood Count with If hepatitis titer negative, give
• Children >5 years and Differential Hepatitis B booster ≥ 6 months
Adolescents: 10 mg  Urinalysis post Rituximab treatment
daily  Urine Protein/Creatinine ratio
 Acetaminophen: Energix-B ≤ 18 years
15 mg/kg PO once prior to Heplisav B > 18 years
infusion (max 1000 mg/dose) Rituximab Dosing:
 Methylprednisolone 375 mg/m2 IV (max 1 gram /dose)
1 mg/kg IV (max 60mg) Give 2 doses 10-14 days apart

Check CD 19 count and IgG

levels every 6 months for 2 Total B Cell (CD 19, CD 20)
years Quantitation by Flow, Blood (aka CD
19) at time of second dose
Lab Monitoring (Q 3-6 months):
 Renal Function Panel
 Complete Blood Count with
Differential Is CD 19
 Urine Protein/Creatinine count / B cell count Yes
Ratio < 5 B cells/mm3?
 Vitamin D 25 OH
Successful Rituximab

No  Continue Tacrolimus/
Failed Rituximab: Mycophenolate Mofetil
Relapse or persistent proteinuria (MMF) for a minimum 12- 24
< 6 months after Rituximab months then consider
Rituximab:
course weaning over 3-6 months
375 mg/m2 IV (max of 1 gm/ dose)
 Wean prednisone off per
algorithm

 Check CD count and IgG

Failed Rituximab levels every 3-6 months
Relapse
 No further rituximab No > 6 months post Yes
 Consider other options (see LT Rituximab?
management)
Consider:
 Repeat Rituximab per protocol above
 Max of 6 Rituximab doses
 Or consider other options (see LT
management)

Algorithm
 Long Term Management
(for Frequently Relapsing or Steroid Dependent Nephrotic Syndrome)

Once started with steroid sparing agent/

Goal achieved?
mycophenolate mofetil, target is 0-2 relapse / year

No

Select one:

Rituximab Change Mycophenolic Acid to

Tacrolimus

Tacrolimus Dosing:
Starting dose 0.05 mg/kg PO Q 12 hours
(target troughs 5-8 in first 6 months, 3-5
after that if no relapses)

Yes

Still relapsing?

Consider:

 Cyclophosphamide oral 2 mg/kg/day

x 8-12 weeks, max 168 mg/kg based Yes
on ideal body weight

 ACTHar  Rituximab
Fixed dosing (> 2 years and  Continue Tacrolimus and add
adolescents) 40-80 units/dose Mycophenolic Acid
IM or SubQ every 24-72 hours

Weight based dosing (> 2 years

and adolescents) 0.8 units/kg/
day or 25 units/m2/day divided Q
12-24 hours
Yes Still relapsing? No
 Pheresis course (9-12 treatments)

 Ofatumumab 300 mg/1.73 m2 of BSA

on the first week followed by 2000 mg/
1.73 m2 of BSA weekly x 5 infusions

 Consider changing tacrolimus to Continue Mycophenolic Acid /

cyclosporin A: 3-5 mg/kg/day divided Tacrolimus for a minimum 12- 24
Q 12 hours (trough target 100-250 for months then consider weaning off
the first 6 months then 50-15 once in gradually over 3-6 months.
remission)

 Enrollment inf NS drug/clinical trial Labs at least every 3-6 months:

Algorithm
RFP, CBC, UPC, UA and vit D25
 Steroid-Resistant Nephrotic Syndrome Protocol
Definition:
Proteinuria despite 6 weeks of Prednisone 2mg/kg/day max of 60 mg/day, +/- IV Methylprednisolone
pulses

General guidance:
 Get Genetic testing (Prevention NEPHROTIC SYNDROME- FSGS PANEL, test code: 10417)
 Get a renal biopsy within 2 -4 weeks of diagnosis
 Start calcineurin inhibitor (CNI):
Tacrolimus 0.1 mg/kg/dose Q 12 hours (target troughs 5-8 for first 6 months and then 3-5 once in remission)
or
Cyclosporin A 3-5 mg/kg/day divided Q 12hrs (trough target: 100-250 for first 6 months then 50-150 once in
remission)
 Consider keeping on a low dose of Prednisone for the first 6 months. (2.5-5 mg PO QAM or QOD), especially if
had some steroid sensitivity initially (late SRNS)
 Start ace inhibitor (ACEi) vs ARB in all patients, especially if hypertensive, target BP ≤ 50-75% as tolerated.
 Check RFP, CBC, CNI trough level, lipid panel (preferred fasting) and vit D 25 level at least every 3 months and
manage them accordingly.
 CNI trial: at least 3-6 months. Target of NS control: Full remission then partial remission.

Determine remission status

Partial remission No remission Full remission

UPC 0.2-2 mg/mg with Alb > 3 g/dl UPC < 0.2 mg/mg

Or  Consider continuing calcineurin

inhibitor +/- Prednisone/ ACEi for at
UPC reduction by at least 40- 50% with least 2 yrs
UPC < 1.5-2 mg/mg
 Consider a repeated renal Biopsy in
 Consider a trial of higher CNI trough 2-3 years of CNI
(Tacro level 7-10, Cyclosporin A level
100-250) + low dose prednisone +  Relapse? Consider an oral
ACEi for at least 3-6 months Prednisone course with a slow taper.
See Management of Nephrotic
 Or add Ritux as below Syndrome Relapse)

 If only achieving partial remission:

continue calcineurin inhibitor +ACEi
for > 2 years
(Partial remission prognosis is better than
no control)
 Steroid-Resistant Nephrotic Syndrome Protocol: No Remission

No Remission:

 Rituximab

 Continue CNI and low dose Prednisone and ACEi (as tolerated)

 Re-evaluate in 3-6 months

Remission?

No

Compliance
Yes
concerns?
Yes

No

Option A Option B
(especially if late SRNS-
Consider CNI + MMF
compliance concerns)
(400 mg / m2/dose) BID +
 IV Methylprednisolone 10- low dose Prednisone +
max tolerated dose of
15 mg/kg/dose (max of 500
ACEi/ ARBs.
mg per dose) 3 times per
week up to 4 weeks, then Full remission
start Prednisone 60 mg QD
and wean slowly UPC < 0.2 mg/mg

 Continue CNI and low dose  Consider continuing CNI +/-

Prednisone plus max Prednisone/ ACEi for at least 2
tolerated dose of ACEi/ yrs
ARBs. Remission in
Yes
3-6 months?  Consider a repeat renal biopsy
 Check fasting glucose in 4-8 in 2-3 yrs of CNI
weeks of IVMP, and HbA1c
at least every 6-12 months  Relapse? Consider a
Prednisone course with a slow
taper.
No

 Consider the other option (A vs B)

 Consider pheresis (9-12 treatments) vs

Ofatumumab vs SGLT 2 I vs enrollment in
a clinical trials
 Clinical Updates for Nurses
Nurses to use dot phrase: .nephroticsyndrome when calling the family / patient.

If patient in relapse or new onset- call weekly for updates

If patient is on taper- every 2 weeks for updates

Questions to ask:
 Urine protein levels
 Remission or relapse?
 Swelling: Y/N
 Weight recently
 Remind low salt diet
 Patient seen in ER – admitted since last visit / call?
 Any recent albumin/ Lasix infusions?
 Any fevers or new sick symptoms
 Current dose of steroids
 Any missed doses of steroids- if yes how many and the reason why
 Any side effects of steroids
 Total dose of prednisone for this relapse ?

When should a NS patient be evaluated by MD (PCP / Nephrologist):

 Has unexplained fever (no obvious source such as URI)
 Might have peritonitis (any combination of vomiting, pain, fever, etc.)
 Parent is not experienced enough to judge severity of edema
 Where appropriate, call the local MD to discuss specific concerns/issues

Should be admitted if:

 Peritonitis is suspected after evaluation by local MD (or if reported signs & symptoms are obvious)
 Edema is severe enough so that child is clearly uncomfortable
 Child has skin breakdown/cellulitis from their edema
 Child is having profuse vomiting / diarrhea, suggesting poor absorption of PO meds
 Any suggestion of respiratory distress/compromise

Algorithm
 References

 https://kdigo.org/wp-content/uploads/2017/02/KDIGO-Glomerular-Diseases-Guideline-2021-English.pdf
 Gipson DS, Massengill SF, Yao L, Nagaraj S. Smoyer WE, Mahan JD, Wigfall D, Miles P, Powell L, Lin
J, Trachtman H, Greenbaum LA. Management of childhood onset nephrotic syndrome. Pediatrics
2009;124:747-757.
 Sinha A, Bagga A. Clinical practice guidelines for nephrotic syndrome: consensus is emerging.
Pediatric Nephrology 2022;37:2975-2984.
 Bagga A, Sinha A. Individualizing treatment of steroid-resistant nephrotic syndrome. CJASN July
2020, 15 (7) 920-922; DOI: https://doi.org/10.2215/CJN.08080520
 Trautmann A, Vivarelli M, Samuel S, Gipson D, Sinha A, Schaefer F, Hui NK, Boyer O, Saleem MA,
Feltran L, Müller-Deile J, Becker JU, Cano F, Xu H, Lim YN, Smoyer W, Anochie I, Nakanishi K,
Hodson E, Haffner D; International Pediatric Nephrology Association. IPNA clinical practice
recommendations for the diagnosis and management of children with steroid-resistant nephrotic
syndrome. Pediatr Nephrol. 2020 Aug;35(8):1529-1561. doi: 10.1007/s00467-020-04519-1. Epub 2020
May 7. PMID: 32382828; PMCID: PMC7316686.

Algorithm
 Pathway Team & Process

Content Development Team: Clinical Pathway Program:

Leaders Berkeley Bennett MD, MS– Co-Medical Director

Mahmoud Kallash, MD – Nephrology
John David Spencer, MD – Nephrology
Members
Brian Becknell, MD, PhD – Nephrology
Ray Bignall, MD – Nephrology
Beth Faz, BSN, RN – Nephrology
Megan Lewis, PharmD – Nephrology
John Mahan, MD – Nephrology
Pamela Meiring, BSN, RN – Nephrology
Tahagod Mohamed, MD – Nephrology
Hiren Patel, MD – Nephrology
William E. Smoyer, MD – Nephrology
John David Spencer, MD – Nephrology
Emily Stonebrook, MD – Nephrology
Beth Vogt, MD – Nephrology
Diana Zepeda-Orozco, MD – Nephrology
Laura Rust MD, Co-Medical Director
Juan Chaparro MD – Physician Informaticist
Tahje Brown, MBA – Program Coordinator
Andrew Bethune MA, MFA, PMP – Business and
Development Manager
Pathway Approved
Rustin Morse, MD
Chief Medical Officer
Lee Ann Wallace, MBA, BSN, RN, NEA-BC.
Chief Nursing Officer
CPP Outpatient, UC, ED Advisory Committee
CPP Inpatient Advisory Committee
Published: February 2023
Next Revision Date: February 2026

Clinical Pathway Development

This clinical pathway was developed using the process described in the NCH Evidence
Based Practice Guideline Development Manual v4.1.
Clinical Pathways at Nationwide Children’s Hospital (NCH) provide general guidance to
clinicians. Patient choice and clinician judgment remain central to the selection of
diagnostic tests and therapy. The ordering provider is ultimately responsible for care
decisions. NCH’s pathways are reviewed periodically for consistency with new evidence;
however, new developments may not be represented.
Copyright © 2022. Nationwide Children’s Hospital. All rights reserved. No part of this
document may be reproduced, displayed, modified, or distributed in any form without the
express written permission of Nationwide Children’s Hospital.

Algorithm