steroid‑resistant nephrotic syndrome (SRNS)

Term

Definitions

Nephrotic-range proteinuria

UPCR ≥ 200 mg/mmol (2 mg/mg) in first morning void or

 24 h urine sample ≥ 1000 mg/m2/day corresponding to 3+ or 4+

by urine dipstick.

Nephrotic syndrome                                                           

Nephrotic-range proteinuria and either hypoalbuminemia (serum albumin < 30 g/l) or edema when serum albumin level is not available.

Complete remission

UPCR (based on first morning void or 24 h urine sample) ≤ 20 mg/mmol (0.2 mg/mg) or negative or trace dipstick on three or more consecutive occasions.

Partial remission

UPCR (based on first morning void or 24 h urine sample) > 20 but < 200 mg/mmol and, if available, serum albumin ≥ 30 g/l.

Relapse

Relapse Recurrence of nephrotic-range proteinuria.

*   In children, relapse is commonly assessed by urine dipstick and is thus defined as dipstick ≥ 3+ on 3 consecutive days, or

UPCR ≥ 200 mg/mmol (2 mg/mg) on a first morning urine sample, with or without reappearance of edema in a child who had previously achieved partial or complete remission.

Confirmation Period

Time period between 4 and 6 weeks from PDN initiation during which response to further oral PDN and/or pulses of iv MPDN and RAASi are ascertained in patients achieving only partial remission at 4 weeks.

*   A patient achieving complete remission at 6 weeks is defined as a late responder.

*   A patient not achieving complete remission at 6 weeks although he had achieved partial remission at 4 weeks is defined as SRNS.

SSNS 

Complete remission within 4 weeks of prednisone or prednisolone (PDN) at standard dose (60 mg/m2/day or 2 mg/kg/day, maximum 60 mg/day).

Infrequent relapsing NS

˂ 2 relapses per 6 months or ˂ 4 relapses per 12 months.

Frequent relapsing  NS

≤ 2 relapses per 6 months or ≤ 4 relapses per 12 months.

Steroid dependent NS

Relapses during therapy with prednisone or prednisolone (either at full dose or during tapering) or within 15 days of prednisone or prednisolone discontinuation.

SRNS

Lack of complete remission within 4 weeks of treatment with PDN at standard dose.

Late Responder NS

Complete remission at 6 weeks.

CNI-resistant SRNS

Absence of at least partial remission after 6 months of treatment with a CNI at adequate doses and/or levels.

Multi-drug-resistant SRNS

Absence of complete remission after 12 months of treatment with 2 mechanistically distinct steroid-sparing agents at standard doses (see text).

Secondary steroid resistance

Children with initial steroid-sensitivity who in subsequent relapses develop SRNS.

Recurrent nephrotic syndrome

post-renal transplantation

A child with SRNS presenting post-renal transplantation with a relapse of nephrotic-range proteinuria in the absence of other apparent causes and/or podocyte foot process effacement on kidney biopsy.

*        This diagnosis should also be considered in case of persistent proteinuria (UPCR ≥ 100 mg/mmol (1 mg/mg) in a previously anuric patient, or

*        An increase of UPCR ≥ 100 mg/mmol (1 mg/mg) in a patient with prevalent proteinuria at the time of transplant in the absence of other apparent causes.

Table abbreviations

UPCR urine protein/creatinine ratio, SSNS steroid sensitive nephrotic syndrome,

SRNS steroid-resistant nephrotic syndrome, PDN prednisolone or prednisone,

MPDN methylprednisolone, RAASi renin-angiotensin-aldosterone system, CNI calcineurin inhibitor

Table 5. Recommendations

B. Diagnosis

N

Health questions

Source Guideline

Recommendations

Quality of evidence

Strength of Recommendation

B1

What are the Initial Diagnosis workup of a child with SRNS?

IPNA 2020

IPNA

2020

IPNA 2020

We recommend clinical assessment to include family history for renal and extra-renal manifestations, consanguinity, patient age at onset of the disease, pattern of response to steroid therapy if already initiated

We recommend careful physical examination of the patient including search for extra-renal manifestations, primary causes drugs, infections, autoimmune diseases. Identify high-Risk patients with severe edema, hypertension, low GFR.   

Extended laboratory investigations

We suggest performing Initial Basic Laboratory testing for blood, serum, and   urine: Quantification of proteinuria, GFR.   Screening for infections (hepatitis B, C, TB, syphilis, HIV and Covid-Sars to rule out secondary types of NS before   immunosuppression, especially rituximab. Referral to secondary and tertiary PN centers with genetic facilities as indicated.

We recommend Extended and follow-up investigations   to   include :

Urine: Spot urine (first morning void) protein/creatinine or proteinuria 24 H. Urine analysis including hematuria.

Blood-Complete blood count (CBC): C-reactive protein, creatinine, BUN, or urea, electrolytes, serum albumin, total protein. Estimated GFR

Lipid profile: (LDL- and HDL-cholesterol, triglycerides)

Glucose/fasting glucose: HbA1c. -C3, antinuclear antibodies, ds-DNA, ANA, ANCA, APLA2R.

Infection screen: (bacterial, viral, parasitic). TB, Malaria Schistosomiasis in endemic areas. HBs-Ag, anti-HCV-IgG, syphilis, and HIV test, Immunoglobulin G

Thyroid function: (T3, T4, TSH), Base line coagulation tests prothrombin time (INR), a PTT, fibrinogen, AT (111), ALP, PTH, 25(OH) vitamin D, Blood gas analysis (HCO3). 

Drug-specific monitoring: as appropriate. 

Imaging: Renal ultrasound, chest X ray, echocardiography, X-ray wrist for bone age for children < 5 y old should be evaluated for selected cases 

Assessment for extra-renal involvement:

Depending on underlying disease and clinically evident extra-renal features:

*Brain MRI * Ophthalmology *Cardiology *Endocrinology *Dermatology *Orthopedics

*Immunology *Hematology

High

High

Low

Strong

Strong

conditional

Good practice statement

Table 6. Recommendations

C. Genetic testing

N

Health questions

Source Guideline

Recommendations

Quality of evidence

Strength of Recommendation

C1

C2

C3

When we recommend genetic testing?

What are the target population for referral?

Which tests and why recommended?

IPNA 2020

IPNA 2020

IPNA 2020

IPNA 2020

IPNA 2020

IPNA 2020

Ozaltin 2014

IPNA 2020

We recommend genetic testing with high suspicious

index for genetic types at any stage of disease

presentation

(1) Early if familial, syndromic, < less than 1 year age at

disease onset.

(2) After 4–6 weeks of steroid therapy for all steroid resistant if possible or those with target priority

including (previously mentioned if not done),

as well as all SR (FSGS, DMS) and CNI resistant,

C3GN/DDD with suspected complement mutation,

and pretransplant.

We suggest Referral

to the pediatric nephrology center with genetic

experts and facilities being crucial for early diagnosis

and proper management of these cases.

We strongly recommends the

availability of genetic testing in all its university related

pediatric nephrology centers and to be

covered by medical insurance.

• Familial, syndromic, congenital/infantile onset.

All SRNS at confirmation period, if possible.

• All SRNS biopsy proven as FSGS/DMS to identify

genetic types.

All SRNS/CNIs resistant after 6 m cyclosporine trial.

All C3GN/DDD with suspected complement mutation,

resistant to plasma exchange and MMF. Such

cases need treatment with complement blockade

even after transplant to avoid recurrence.

All pretransplant donor and recipients as we follow

live related donor transplant in a community with

high rate of consanguinity.

We recommend Gene Panel SGS unless

mutation is likely known where single gene analysis is

recommended.

We recommend referral to centers with

genetic experts to:

• Avoid use of steroids and immunosuppressive, renal biopsy, pre- and posttransplant

aggressive protocols of PE, and rituximab

that are recommended for idiopathic nonhereditary

FSGS.

• Allow genetic counseling, prenatal diagnosis. Transplant carries low recurrence rate.

• In these centers, pre-transplant care is available

and well presented (nutritional support, CPD,

management of complications as infection and

thrombosis), proper selection of donors especially

when potential donors are family related and when

disease inheritance is unidentified.

• Special treatment is available for some types as Q.

 Early diagnosis and management control progress

of extra renal manifestations as well

Intermediate

Low

Good practice statement

Good practice statement

Good practice statement

Strong

conditional

Good practice statement

Good practice statement

Good practice statement

Table 7. Recommendations

D. Renal biopsy

N

Health questions

Source Guideline

Recommendations

Quality of evidence

Strength of Recommendation

D1

What are the indications of renal biopsy in the initial presentation of NS?

IPNA 2020

IPNA 2020

IPNA 2020

We recommend Renal Biopsy (LM, IF, EM) for

all SRNS

excluding genetic types especially

those known as CNIs resistant

and also secondary

NS related to drugs, infections, or malignancy.

In countries where genetic tests are not

available or limited to few tertiary centers or expensive

and not covered with medical insurance, renal

biopsy and lab immunology may be the gold standard

diagnostic workup for NS in children

test to put therapeutic plan and predict disease outcome

based on renal histopathology.

High

Intermediate

High

Intermediate

Strong

Strong

Strong

Strong

Table 8. Recommendations

E. treatment

N

Health questions

Source Guideline

Recommendations

Quality of evidence

Strength of Recommendation

E1

E2

E3

E4

E5

What is the first line treatment drug in first episode?

Should vitamin D & Calcium supplements be routinely given to FR&SD?

What are your (Diet, Fluids, Activity) recommendations?

What are the recommended vaccinations?

What information & instructions you like to share with the family during follow-up?

prevention of thrombosis

IPNA 2020

IPNA 2020

KDIGO 2021

KDIGO 2021

IPNA 2020

ACI or ARBS to start early at 4th week,

avoided in CKD, AKI, hyperkalemia, volume depletion,

and female adolescent.

Statin. We suggest statin in MDR, high LDL

cholesterol, control of BP if 95th,

calcium,

vitamin D,

levothyroxine T4 if hypothyroidism,

magnesium if hypomagnesaemia.

Diuretics to treat edema if severe, considering

the risk of hypovolemia and thrombosis in

under filled patients.

We recommend oral or IV

furosemide if severe edema.

In refractory edema, metolazone, thiazides, and amiloride potassium

sparing diuretic.

Albumin infusion 1 mg/

kg 20–25% albumin over 4 h with furosemides at the

middle and the end.

We recommend identification of the cause

of SRNS (1) secondary type need treatment of the

cause (infections, drugs, auto immune disease).

(2) Genetic types. Mostly need supportive care till

transplantation is available, showing low recurrence

rate.

(3) Idiopathic types (MCD, FSGS,

DMS) and (IMP, IMN) need immunosuppressive

therapy.

We recommend for treatment plan to be

based on cause, genetic testing, renal biopsy and lab

immunology findings, and clinical severity of disease

(GFR, presence of extrarenal manifestations) at

its presentation.

We suggest to avoid excess salt intake

2 mEq/kg/day, with balanced fluid intake.

We suggest statin in MDR, high LDL,

control of BP if > 95th percentile,

calcium,

vitamin D,

levothyroxine T4 if hypothyroidism,

magnesium if hypomagnesaemia

For prevention of infection, we suggest

IVIG for children with recurrent infections or low

IgG,

no routine antibiotics, cotrimoxazole

in patients on rituximab 5–10 mg/kg/day three

times weekly 3–6 m.

cotrimoxazole

in patients on rituximab 5–10 mg/kg/day three

times weekly 3–6 m.

Receiving all vaccinations

pneumococcal, meningococcal, influenza, and varicella.

Live vaccines should not be given to SR

on immunosuppressive. Family members can

get live vaccines to limit risk of transfer to immunocompromised

children but avoid exposure to

their urine, stool, and respiratory excreta for 3–6

weeks after vaccination.

We recommend VZIG.

on exposure to chickenpox,

treatment with acyclovir 10 mg/kg 7 days within 7–10

days of exposure,

varicella vaccine in remission.

We recommend mobilization, avoid central lines.

• We suggest low molecular weight heparin in previous

history of thrombosis, central lines, hereditary

thrombophilia predisposition, infection, or

dehydration.

• We recommend thrombophilia screen in previous

conditions for protein S, antithrombin,

and factor V genes.

Intermediate

High

Low

High

Very low

Low

Intermediate

Low

Low

High

Low

High

Very low

Very low

Low

Low

High

High

Low

Low

Low

Strong

Good practice statement

Strong

Conditional

Strong

conditional

Good practice statement

 conditional

Good practice statement

Strong

Good practice statement

 Conditional

 Conditional

Strong

 Conditional

Strong

 Conditional

Conditional

Conditional

 Conditional

Strong

Good practice statement

Strong

 Conditional

Good practice statement

Conditional

 Conditional

Table 9. Recommendations

F. Management of SRNS/ESRD

N

Health questions

Source Guideline

Recommendations

Quality of evidence

Strength of Recommendation

F1

What information & instructions you like to share with the family considering transplantation?

IPNA 2020

While on dialysis and or waiting for kidney

Transplant we recommend discussing with the family and

dialysis team benefit risk of transplantation and

post TX recurrence rate.

We recommend daily monitoring of proteinuria

for assessment of native residual function.

We recommend nephrectomy if TX will

be done before resolution of NS or if proteinuria is

severe to minimize risk of thromboembolism.

We recommend genetic tests to recipients

as hereditary types show low recurrence as

compared to non-genetic types.

Discuss benefit risks for genetic and non- genetic. 43% of total

kidney transplants in Egyptian children through

2009/2017 registry were identified as hereditary

ESRD.

High

High

Very low

Intermediate

High

Strong

Strong

 conditional

Strong

Strong

Table 10. Recommendations

G. Proper donor selection

N

Health questions

Source Guideline

Recommendations

Quality of evidence

Strength of Recommendation

G1

What information & instructions you like to share with the family considering transplantation & donor?

We recommend TX ESRD/SRNS regardless

of genetic or non-genetic.

We recommend living related donor. Living related allograft donors should do

GT as a part of evaluation in SRNS.

Donors candidate with a pathogenic or

likely pathogenic variant in a dominant gene with

or without symptoms to be excluded as a potential

donor.

Carrier of recessive SRNS variant may be a potential

donor after genetic counseling except in

COL4A5, COL4A3, and COL4A4.

Asymptomatic carriers of a variant with

unknown significance may be considered a TX

donor following extensive evaluation and counseling

where other organ donation options are

not available.

Intermediate

Low

Low

Strong

Good practice statement

Good practice statement

 conditional

 conditional

Table 11. Recommendations

H. Recurrence risk

N

Health questions

Source Guideline

Recommendations

Quality of evidence

Strength of Recommendation

H1

What information & instructions you like to share with the family considering recurrence?

We recommend discussing risk of recurrence

or graft failure with the donor.

We recommend discouraging living related

donation to recipients with previous recurrence in

previous graft. Cadaveric graft always remains a better

option than dialysis.

We recommend for early diagnosis of recurrence,

post TX monitoring of proteinuria daily for

4 months, weekly for 4 months, and monthly for 4

months for 1 year as a predictor of recurrence

after exclusion of other causes; however, renal

biopsy is conclusive

We suggest for prevention or of recurrence

in high-risk types, pre and post-transplant plasma

exchange.

We recommend treating recurrence with

pulse MPD, CNIs, rituximab, and plasma exchange.

We recommend on recurrence to start RASI

re-transplant as the deceased donor is ethically

acceptable and considered more appropriate than

dialysis.

High

Low

Low

Low

Low

Low

Strong

conditional

conditional

conditional

conditional

conditional