Egyptian pediatric clinical practice adapted guidelines: evidence-based [2] steroid-resistant nephrotic syndrome (SRNS) 2022

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% (Mickinney et al. Pediatr Nephrol 16:1040-1044, 2001). While MCD is the most common histopathology in SS type, children with SRNS have MCD, mesangial proliferative glomerulonephritis, or focal and segmental glomerulosclerosis (FSGS) (International Study Kidney Disease in children, Kidney Int 20;765-771, 1981). SRNS is defined as those who do not show remission after 6 weeks and standard dose of oral steroids ± 3 IV MPD doses (Trautmann et al. Pediatr Nephrol 35:1529-1561, 2020). These national adapted guidelines aim to frame evidence-based recommendations adopted or adapted from the IPNA 2020, KDIGO 2021, and Japanese 2014 de novo guidelines for diagnosis and management of nephrotic children to be presented in two manuscripts: (1) steroid sensitive (SSNS) and (2) steroid-resistant nephrotic syndrome (SRNS). Formulation of key questions was followed with a review of literature guided by our appraised guidelines using AGREE plus appraisal tool. Virtual monthly meetings all through the year 2021 were activated for reviewing and validation of final adaptation evidence-based draft, considering all comments of external reviewers including KDIGO assigned reviewer. Rationale behind the selection of adopted statements and tailoring of others to suit our local facilities, expertise, and our local disease profile was discussed in the text with reasons. The provided guidelines aim to optimize patient care and outcome and suggest research areas lacking validated research recommendations.


Introduction
Most nephrotic children have steroid-sensitive nephrotic syndrome (SSNS), with only 20% of them having steroidresistant nephrotic syndrome (SRNS), depending on the geographic area [1]. MCD is the most common histopathology in SSNS, while children with SRNS have MCD, mesangial proliferative glomerulonephritis, or focal and segmental glomerulosclerosis (FSGS) [2]. In children, SRNS is defined as those who do not show remission after 6 weeks and standard dose of oral steroids ± 3 IV MPD doses [3].
Most nephrotic children (85-92%) show idiopathic type that affects only the kidney without extrarenal involvement and without identifiable cause. MCD pathology constitutes (75-85%) and FSGS (7-10%), while other histological types are rare [KDIGO 2021] [4]. The secondary type where the immune complex renal injury is mediated by a primary cause is less common and is related to drugs, infections, and autoimmune diseases such as lupus, IgAV, ANCA vasculitis, Wegner granulomatosis, AGBM, sarcoidosis, malignancies, and sickle cell disease.
Congenital and hereditary podocytopathies constitute two thirds of SRNS presenting in the first year of life and result from mutation in podocytes regulating genes [KDIGO 2021] [4]. Identification of a podocyte gene defect is fundamental to determine treatment response to steroids and calcineurin inhibitors. It is far superior to histopathology classification in predicting response to immune suppression, clinical course and progress to ESRD, and risk of post-transplant recurrence, thereby subsequent management of SRNS. To date, over sixty genes have been identified as causing monogenic forms of SRNS recessive or dominant with an onset before 25 years [5][6][7][8]. Family counseling, screening of at-risk family members, and prenatal diagnosis are major steps following genetic diagnosis.
Renal biopsy and antibody serology is also crucial. Light microscopy identifies histopathology as MCD, FSGS, DMS or MP, MN and grade tubular atrophy, interstitial fibrosis, and glomerulosclerosis as prognostic markers of chronicity [9]. Occasionally, SRNS is secondary to infectious disease, drugs, and autoimmune disease such as SLE, IgA vasculitis, and malignancy. Therefore, infection screen for viruses and bacteria as well as serology tests for antibodies (ASOT, ANA, ADNA, ANCA, PLA2R ab) are important. Renal biopsy with immunofluorescence reports immune complex/complement deposits with pauci or linear or granular pattern. This helps in the diagnosis of SLE, IgAV, ANCAV, C3 C4/DDD, and immune complement mediated with membranoproliferative changes [KDIGO 2021] [4]. Electron microscopy reports the ultrastructure of glomerular basement membrane (GBM) and podocytes that are helpful in many hereditary and syndromic types. Light microscopy without IF and EM is not enough as it would report only histopathology without referring to pathogenesis if immune complex mediated or genetic in origin [10].
SRNS without genetic mutation is expected to respond to immunosuppressive drugs with complete remission in up to 60% of cases and with partial remission in up to 19%. Those with no genetic mutation have a substantial advantage in terms of kidney survival over 10 years, with ESRD occurring in 71% of those with a genetic disease versus 29% in those without [11,12]. Genetic types need transplantation with less rate of disease recurrence. Early treatment of infections (bacterial, viral, parasitic) [13][14][15], and proper treatment of auto immune disease according to its therapy plan is mandatory to prevent progress of renal injury [16,17].
Current EPG/SRNS is an adaptation GL using both de novo IPNA 2020 and KDIGO 2021 guidelines customized to our community with high rate of infections, consanguinity, autoimmune diseases such as SLE, and with shortage of genetic testing as routine screening for all SRNS. Renal biopsy and lab immunology are more available and thereby were suggested for EPG based on immune suppressive drug therapy plans. However, exclusion of genetic and secondary types is mandatory, as this significantly determine therapy plan. Management recommendations for FSGS were mainly adopted/adapted from IPNA 2020. Other types (ANCA, IgA, LE, infection related, C3GN/DDD, and MN) were mainly adopted/ adapted from KDIGO 2021 considering patient evaluation for genetic and secondary types. This CPG adaptation project for nephrotic syndrome is part of a national CPG program by the Egyptian Pediatric Clinical Practice Guidelines Committee (EPG), which was formulated in June 2018 by an initiative in collaboration with the faculty staff of 15 Egyptian Universities' Pediatrics Departments and a National Research Centre. EPG was later affiliated with the Supreme Council of Egyptian University Hospitals, with the goal of defining the topics of pediatric evidence-based CPGs, assigning authors to them, and assisting in their adaption in accordance with a national strategic plan (http:// epg. edu. eg) [18]. The EPG follows the "Adapted ADAPTE" as a formal CPG adaption method [19].

Methodology [20-28]
We followed the "Adapted ADAPTE" CPG formal adaptation methodology that consists of three phases and 24 steps and tools [20] (EPG methodology figures from 1 to 9 and Table A in Additional file 1). The target users include physicians (viz. pediatrics, primary healthcare, family medicine, pediatric nephrology), nurses, and clinical pharmacists. The work group was divided into two panels assigned to cover each type of SS and SR with continuous communication at monthly virtual meeting with attendance of all working groups members. This manuscript article will be devoted to (2) SRNS to be associated with another article (1) SSNS.

Adaptation phase (SRNS)
In phase 2, we identified 12 health questions, using the PIPOH model, including 6 questions for diagnosis and 6 for treatment. The PIPOH model included the target patient population (P), intervention(s) (I), professionals and clinical specialties (P), outcomes (O), and healthcare setting or context (H). The literature search was conducted using MEDLINE/PubMed and Google Scholar portals. Eligible source CPGs were evaluated using the Appraisal of Guidelines for Research and Evaluation (AGREE II) Instrument. AGREE II is a valid and reliable instrument with 23 items organized into six domains and is considered the gold standard for quality assessment of CPGs [21][22][23][24][25][26][27][28] (refer to the Additional file 1 including appraisal for source CPGs [24-28], health questions, PIPOH model). The first draft of the adapted CPG marks the last step of this phase, where RIGHT-AD patient checklist reporting evidence-based SRNS guideline was used (see Additional file 1: Table A).

Finalization phase
Phase 3 involved finalizing the initial draft of the adapted CPG, as well as determining whether it was acceptable and suitable to the Egyptian healthcare system. After that, the document was sent out to a panel of four clinical (including one nominated by KDIGO) and one methodology external reviewers. Reviewers' comments were revised, and the updated draft was further reviewed within the Nephrotic Syndrome Guideline Adaptation Group (NS-GAG), considering the national context. The finalized version of the revised CPG contained useful tools and strategies for implementation.
For clarity, we will report the adapted CPG recommendations of the EPG NS CPG in two separate papers: (1) steroid-sensitive and (2) steroid-resistant NS.

R.1: Definitions we recommend.
All definitions are included in Table 1

a:
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 (A IPNA) (EPG-GPP).
• National guideline strongly recommends the availability of genetic testing in all its universityrelated pediatric nephrology centers and to be covered by medical insurance (EPG-GPP). • Dose, duration, efficacy, and complications for each drug have been summarized in

b:
We define our target population for referral to include:   Live vaccines should not be given to SR on immunosuppressive (X). 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 (ungraded).
We recommend VZIG (A) on exposure to chickenpox, treatment with acyclovir 10 mg/kg 7 days within 7-10 days of exposure, varicella vaccine in remission (C)  We recommend discussing with the family and dialysis team benefit risk of transplantation and post TX recurrence rate (A).

Results
This is a guideline, no reported results.

Discussion
Through this discussion, we will analyze the panel rational and background behind each of the following three policies: (1) which recommendations the panel decided to include as adopted or exclude from the retrieved guidelines, (2) added good practice points (EPG-GPP) with consensus approval related to our local community disease profile, and (3) adaptation and modification of some existing recommendations to suit our facilities and expertise.

[1] Adopted recommendations
• The panel has chosen the recommendations with clearly presented evidence that were common in the three source guidelines and those that represent the current acceptable and applicable practice addressed to our target users. • The panel also considered variation in facilities and expertise at our local different health care settings thus supported referral policy to advanced secondary and tertiary levels where specialized care is available. • All relevant methodology, additional evidence, and documents for the development of the source CPGs are available and freely downloadable from their official websites stated at the end of the guideline.

• The final version of the adapted CPG was thoroughly reviewed by local and international external reviewer's panel (KDIGO was presented in the board). Final draft was guided by their official recommendations.
Indeed, IPNA 2020, KDIGO 2021, and JAPANESE 2014, our three de novo, systematically developed evidence-based clinical practice guidelines, were very helpful to the panel for making most acceptable statements tailored to suit our local community distinctive pattern, with (1) high rate for consanguineous marriage and (2) where endemic infections are common in some focal hot spots. Facilities and expertise are affordable in many pediatric nephrology centers but are still lacking on the community average, mostly lagging in rural areas. Referral to expert centers is not routinely applied; patient reluctance and insistence of some families to keep their children followed by their practitioners or general pediatricians is a major limitation. All such challenges were considered while developing our recommendations.
IPNA 2020 used flexible recommendations fluctuating between ideal statements, as well those applicable for areas with limited resources lacking genetic testing, renal biopsy, and even cyclosporine. Their panel clinical practice as pediatric nephrologists dealing with children was very evident, especially when discussing genetic types.
KDIGO 2021 recommendations reflect major experience in the management of different types of glomerular diseases based on histopathological types. First and alternative treatment options of immunosuppressives were clear whenever patient intolerance or resistance is present.
Therefore, the National EPG used best statements as adopted from either for each topic. We also tailored unavailable recommendations to our highest priority target group and supported referral to secondary and tertiary PNCs with experts and facilities. The following paragraphs will show examples reflecting panel rationale and background behind the following: (1) inclusion and exclusion of recommendation statements, (2) addition of clinical practice points, and (3) modification areas Why and How.

[2] Added practice points (GPPs) for local
address to our health care settings (R 2.5) 1. EPG-GPP. Since general practitioners and pediatricians in our local health settings are the first who diagnose NS among children they are following, therefore, we recommend, upon primary diagnosis of NS, referral to pediatric nephrologist for extended evaluation and management. Primary diagnosis is based on the following: nephrotic proteinuria > 1 g/ m 2 /day in 24 h urine sample or first morning UCPR > 200 mg/mmol corresponding to 3-4 + by urine dip stick, edema, and serum albumin < 3 g/dl). 2. EPG-G PP. Since some pediatricians are interested to manage these cases, and some parents prefer to keep their children under their pediatrician care, we recommend the following red flags for referral to pediatric nephrologists: infants or young children, positive family history, presence of extra-renal manifestations, hematuria, hypertension, impaired GFR, frequently relapsing, steroid dependent, steroid resistant, progressive decline in renal function, complicated cases with severe edema, infection, and thrombosis. 3. EPG-GPP. Since pediatric nephrology centers are the well-equipped areas for proper management, we recommend sustained support of PNC centers with all needed facilities: genetic testing, laboratory tests for immunology, infection screen, drug monitoring, renal biopsy, and immunosuppressive drugs, with medical insurance cover.  Tables 1 and 2) of pediatric SRNS Genetic testing (R2.3): SRNS as recommended by IPNA 2020 were customized to suit our community since they are not affordable for all SRNS. IPNA 2020 recommends genetic testing to all SRNS if possible (A), at 4-6 weeks steroid therapy (B), and before biopsy (D).

[3] Adapted recommendations, rationale and background for adaptation
EPG prioritized timing of GT and frame our target group as: In late testing for SR after 4 weeks steroid therapy since GT for all SR is not possible, we suggest GT for: EPG-GPP SRNS with FSGS OR DMS, before starting cyclosporine therapy. FSGS is the most prevalent histopathology in genetic types [54][55][56][57]. There is correlation between histopathology and age onset of disease; DMS is common at infantile onset, FSGS at 7-25 years of age [5]. EPG-GPP cyclosporine resistant (6months) after standard dose. Those with monogenic etiology have fourfold risk of non-response to CNI [53] and should be excluded from further clinical trials, referred to PNC with genetic experts for TX after WES and pathogenicity tests that confirm genetic variant, and discussed with the family benefit risk of further immunosuppression. IPNA 2020 (A). Certain mutations respond to targeted therapy as coenzyme Q10 [59]. EPG-GPP complement genetic testing for mutations in cases of C3/DDD diagnosed with IFM. Mutant protein indicates complement blockade drugs rather than PE and MMF, even after TX. KDIGO 2021 [49,50]. EPG-GPP pretransplant GT: All IPNA transplant recommendations for ESRF are adopted since we represent a hot zone of consanguinity applying only live related donor allograft. Inherited kidney diseases (IKD) reported 43% of total kidney transplants in Egyptian children registry 2009-2017 [51]. R 2.4: Renal biopsy for SRNS was more implemented in national CGL as supported by KDIGO recommendations, being more available than GT in our area. When used with laboratory immunology (complement, antibodies, viral serology, infection screen [41][42][43][44]), as well as urine and blood biochemistry reflecting renal function, we can identify idiopathic, secondary types and predict genetic types for confirmation with genetic tests [41][42][43][44]. Thus, we can put therapy plan and predict disease course and outcome (EPG biopsy and serology of SRNS (Table B) adapted from KDIGO 2021). This was clearly explained while reporting our EPG recommendations in (Figs. 2, 3, 4, 5, 6 and 7) adapted from KDIGO 2021 and EPG diagnosis workup Fig. 8 adapted from IPNA 2020, KDIGO 021{refer to EPG recommendations guidelines}. R.3.Treatment modifications for SRNS after patient evaluation with clinical and lab assessments EPG modified IPNA 2020. Treatment recommendations for SRNS to be mainly based on histopathology, as well as genetic testing whenever possible after exclusion of infections, drugs, malignancy, and systemic autoimmune diseases (lupus, ANCA vasculitis, IgA) [ (Fig. (1.6) adapted from KDIGO 2021, Fig. 8 national CGL adapted from IPNA2020 and KDIGO2021].

Our reasons
(1) Being an endemic country for some infectious diseases such as hepatitis and currently few focal rural areas for tuberculosis and schistosomiasis, therefore, we suggest our NCGL to support early diagnosis and treatment of infections commonly related to SRNS. EPG ( Fig. 1 diagnosis workup) [13][14][15]. (2) Since exclusion of secondary types depends on efficient lab for diagnosis of autoimmune diseases, therefore, referral recommendations to pediatric nephrologists are supported in our local format. (3) Genetic labs are only available in few pediatric nephrology centers. Therefore, identifying our priority group and supporting their referral to centers with genetic expert will be of help in challenging genetic testing limitations in our low resource area [54][55][56][57][58], which is also ranked as hot zone for IKD that is only permitted for life related TX programs [51]. (4) Renal biopsy (LM, IF, EM) is available in all PNCs. Light microscopy confirms diagnosis of FSGS, MCD, and DMS podocytopathies for further differentiation between primary, genetic, and secondary. It also diagnoses crescentic types for aggressive immunosuppressives and PE and identifies ESRD for replacement therapy. Immune fluorescent microscopy differentiates secondary FSGS from idiopathic and genetic. Pattern of biopsy deposits with serology findings will identify ANCAV (pauci D), AGBM (linear D), granular deposits in post infectious, LE, IgA, MP, and membranous. Complement D in excess identifies C3/DDD. Electron M can further differentiate between all types of FSGS and report GBM changes related to some hereditary diseases such as Alport [39][40][41][42]. Class 1 and class II are KDIGO adopted. Class III, 1V (proliferative), and V (mixed proliferative and membranous) EPG adaptation: We adopt KDIGO suggesting IV methyl prednisolone 0.25-0.5 g/day for 3 days, and then oral CS 1 mg/kg/ day tapered over 6-12 months. However, we prefer IV monthly CYC 0.5-1 gm/m 2 for 6 months as initial therapy than oral CYC or MPA to ensure patient adherence provided not to exceed toxic cumulative dose and good leucocytic count.
MMF is suggested in resistant or recurrent flares in children with high cumulative dose and risk of infertility (EPG-GPP). Resistant cases not responding to initial therapy at 3 months should be evaluated, and renal biopsy may be considered before shift to any other treatment as switch from CYC to MPA or triple CNI, steroids, and MPA-based initial therapy or RTX KDIGO 2021.
We prefer use of triple therapy with CNIs, MPA, and glucocorticoids for those intolerants to MPA or CYC contraindicated or refractory to them EPG-GPP.
RTX is suggested in persistent or repeated flares considering its side effects and precautions.
Azathioprine is suggested for intolerance, high cost, or unavailability of other drugs. EPG-GPP. Maintenance therapy with MPA or AZA for 1-3 years is suggested for all patients as adopted from KDIGO 2021.
Class V (pure MN): We adopt KDIGO 2021 for patients with nephrotic range of proteinuria and or extra renal manifestations. KDIGO2021 suggests glucocorticoids with one other agent (e.g., MPA, CNI, CYC, RTX, and AZA). KDIGO 2012 previously graded CYC, CNI (2C), and MMF and AZA as (2D). EPG prefer MMF in class V, being effective and tolerant in most of our cases. CNI is suggested for resistant cases or those contraindicated for CYC. RTX is limited to resistant cases being expensive, unavailable of high risk in the presence of infection EPG-GPP.
• IgA N and IgAV KDIGO adopted, C3G/DDD KDIGO adopted • Idiopathic MN: We prefer CYC and steroids in severe cases provided no toxic load and suggest CsA in less severe and to be supported with 2 pulses RTX if resistant unless slowing GFR indicating switch to RTX or CYC (EPG-GPP).