steroid‑resistant nephrotic syndrome (SRNS)

- Executive Summary

Nephrotic syndrome is one of the most common chronic kidney diseases in children. Steroid sensitive type (SSNS) constitutes about 85–90%, whereas steroid-resistant type (SRNS) only 15–20%. While MCD is the most common histopathology in SS type, children with SRNS have MCD, mesangial proliferative glomerulonephritis, or focal and segmental glomerulosclerosis (FSGS). SRNS is defined as those who do not show remission after 6 weeks and standard dose of oral steroids ± 3 IV MPD doses.

This guideline focuses on prevention and management of steroid-resistant nephrotic syndrome

(SRNS).

➡️Guideline development process and methods

After reviewing all the inclusion and exclusion criteria and quality appraisal results, the GDG/ GAG recommended using the following source original clinical practice guidelines (CPGs):

1-     IPNA clinical practice recommendations for the diagnosis and management of children with steroid-resistant nephrotic syndrome (2020).

2-     Clinical practice guideline for pediatric idiopathic nephrotic syndrome 2013: medical therapy. Japanese Society of Nephrology and The Japanese Society for Pediatric Nephrology (2015).

3-     KDIGO Clinical Practice Guideline on Glomerular Diseases (2012).

4-     Kidney Disease: Improving Global Outcomes (KDIGO) Glomerular Disease Work Group. KDIGO 2021.Clinical Practice Guideline for the management of  Glomerular Diseases.  KidneyInt. (2021).

We conducted Adolopment for these guidelines: (Adoption, Adaptation, and Development)

         -          Adoption for most of the guideline recommendations.

         -          Development of Good Practice Statements

 

Recommendations and Good Practice Statements (GPS)

This version of the CPG includes recommendations and good practice statements on the following four sub-sections:

A. Diagnosis of steroid-resistant nephrotic syndrome.

The guideline covers infants 3 months till children and adolescents 18 years of age, presenting with nephrotic syndrome in secondary and tertiary healthcare setting like clinics, emergency

rooms, dialysis, or transplant wards. Excluded population were infants with congenital NS presenting during the first 3 months of life.

 

B. Management of steroid-resistant nephrotic syndrome

This section includes recommendations and good practice statements on management of steroid-resistant nephrotic syndrome

 

 

We can summarize the guidelines’ recommendations for steroid‑resistant nephrotic syndrome in the following:

·       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 (strong recommendation).

·       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 (Strong recommendation).   

·       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 (conditional recommendation).

·       We suggest 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 (Good practice statement).

·       We suggest 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 (Good practice statement).

We strongly recommends the availability of genetic testing in all its university related pediatric nephrology centers and to be covered by medical insurance (Good practice statement).

·       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 (Good practice statement).

·       We recommend Gene Panel SGS unless mutation is likely known where single gene analysis is recommended (Strong recommendation).

·       We ssuggest 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 (conditional recommendation).

Allow genetic counseling, prenatal diagnosis. Transplant carries low recurrence rate (Good practice statement).

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 (Good practice statement).

·        Special treatment is available for some types as Q. Early diagnosis and management control progress of extra renal manifestations as well (Good practice statement).

·       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 (strong recommendation).

·       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 (strong resommendation).

·       We recommend ACI or ARBS to start early at 4th week (strong recommendation).

·       We suggest to avoided it in CKD, AKI, hyperkalemia, volume depletion, and female adolescent (Good practice statement).

·       We recommend statin in MDR, high LDL cholesterol, control of BP if 95th (strong recommendation). calcium, vitamin D (conditional recommendation) levothyroxine T4 if hypothyroidism (strong recommendation), magnesium if hypomagnesaemia (conditional recommendation). Diuretics to treat edema if severe, considering the risk of hypovolemia and thrombosis in under filled patients (Good practice statement).

·       We recommend oral or IV furosemide if severe edema. In refractory edema, metolazone, thiazides, and amiloride potassium sparing diuretic (conditional recommendation).

·       Albumin infusion 1 mg/kg 20–25% albumin over 4 h with furosemides at the middle and the end (Good practice statement).

·       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 (strong recommendation).

·       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 (Good practice statement).

·       We suggest to avoid excess salt intake 2 mEq/kg/day, with balanced fluid intake (conditional recommendation).

·       We suggest statin in MDR, high LDL (conditional recommendation), control of BP if > 95th percentile (strong recommendation), calcium, vitamin D, (conditional recommendation), levothyroxine T4 if hypothyroidism (strong recommendation) magnesium if hypomagnesaemia (conditional recommendation).

·       For prevention of infection, we suggest IVIG for children with recurrent infections or low IgG, (conditional recommendation).

·       no routine antibiotics, cotrimoxazole in patients on rituximab 5–10 mg/kg/day three times weekly 3–6 m (conditional recommendation).

·       Cotrimoxazole in patients on rituximab 5–10 mg/kg/day three times weekly 3–6 m (conditional recommendation).

·       Receiving all vaccinations pneumococcal, meningococcal, influenza, and varicella (strong recommendation).

·       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 (Good practice statement).

·       We recommend VZIG (Strong recommendation).

·       on exposure to chickenpox, treatment with acyclovir 10 mg/kg 7 days within 7–10 days of exposure, varicella vaccine in remission (conditional recommendation).

·       We suggest mobilization, avoid central lines (Good practice statement).

·       We suggest low molecular weight heparin in previous history of thrombosis, central lines, hereditary thrombophilia predisposition, infection, or dehydration (conditional recommendation).

·       We suggest thrombophilia screen in previous conditions for protein S, antithrombin, and factor V genes (conditional recommendation).

·       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 (Strong recommendation).

·       We recommend daily monitoring of proteinuria for assessment of native residual function (Strong recommendation).

·       We suggest nephrectomy if TX will be done before resolution of NS or if proteinuria is severe to minimize risk of thromboembolism (conditional recommendation).

·       We recommend genetic tests to recipients as hereditary types show low recurrence as compared to non-genetic types (Strong recommendation).

·       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 (Strong recommendation).

·       We recommend TX ESRD/SRNS regardless of genetic or non-genetic (Strong recommendation).

·       We recommend living related donor. Living related allograft donors should do GT as a part of evaluation in SRNS (Good practice statement).

·       Donors candidate with a pathogenic or likely pathogenic variant in a dominant gene with or without symptoms to be excluded as a potential donor (Good practice statement).

·       Carrier of recessive SRNS variant may be a potential donor after genetic counseling except in COL4A5, COL4A3, and COL4A4 (conditional recommendation).

·       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 (conditional recommendation).

·       We recommend discussing risk of recurrence or graft failure with the donor (Strong recommendation).

·       We ssuggest discouraging living related donation to recipients with previous recurrence in previous graft. Cadaveric graft always remains a better option than dialysis (conditional recommendation).

·       We suggest 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 (conditional recommendation).

·       We suggest for prevention or of recurrence in high-risk types, pre and post-transplant plasma exchange (conditional recommendation).

·       We suggest treating recurrence with pulse MPD, CNIs, rituximab, and plasma exchange (conditional recommendation).

·       We recommend on recurrence to start RASI re-transplant as the deceased donor is ethically acceptable and considered more appropriate than dialysis (conditional recommendation).

➡️Guideline Registration

PREPARE (Practice guideline REgistration for transPAREncy), WHO Collaborating Center for Guideline Implementation and Knowledge Translation, EBM Center, University of Lanzhou, Lanzhou, China. Registration Number: ((submitted and in process)). Link: http://www.guidelines-registry.org/