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Saudi Journal of Kidney Diseases and Transplantation
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ORIGINAL ARTICLE  
Year : 2021  |  Volume : 32  |  Issue : 6  |  Page : 1600-1614
Practice of Childhood Nephrotic Syndrome Management amongPediatric Nephrologists in the GCC Countries


1 Division of Pediatric Nephrology, Mubarak Al-Kabeer Hospital, Al-Jabriya, Kuwait; Division of Nephrology, Hamid Al-Essa Organ Transplant Center, Shuwaikh, Kuwait
2 Division of Pediatric Nephrology and Kidney Transplant, King Fahad Specialist Hospital, Dammam, Saudi Arabia, Kuwait
3 Division of Pediatric Nephrology, Dubai Hospital, Dubai, United Arab of Emirates

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Date of Web Publication27-Jul-2022
 

   Abstract 


Childhood nephrotic syndrome (NS) management is greatly variable among pediatric nephrologists worldwide. We aimed to evaluate if this variability exists among pediatric nephrologists in the gulf countries and whether certain training programs influence this variability. A web-based multiple-choice survey of 35 NS management questions distributed to certified pediatric nephrologists working in the Gulf countries. Amongst 92 invitees, the response rate was 67%. The majority (73%) were older than 50 years and male (58%). Sixty percent trained in North America and 41% had >10 years of experience. Sixty-three percent use a 12- week corticosteroids regimen for the initial treatment of childhood NS and only 10% never consider long-term small alternate dose corticosteroids therapy to sustain remission before commencing a corticosteroids-sparing agent for frequently relapsing or corticosteroids-dependent NS. Mycophenolate mofetil was the drug of choice for frequently relapsing and corticosteroids dependent NS in 51% and 58% of the participants, respectively, whereas calcineurin inhibitors were preferred by the vast majority (95%) of the participants for corticosteroids-resistant childhood NS. Regarding rituximab treatment, almost half of the participants (48%) give two doses of rituximab one to two weeks apart and 61% do not give another course of rituximab until the child relapse. Fellowship training site and the duration of the clinical experience did not seem to influence certain management of childhood NS. As shown in North American studies, great variability in the management of childhood NS does exist in the Gulf countries. The country of fellowship training and the experience did not seem to contribute to this variability.

How to cite this article:
Alkandari O, Alshami AA, Alhammadi EA. Practice of Childhood Nephrotic Syndrome Management amongPediatric Nephrologists in the GCC Countries. Saudi J Kidney Dis Transpl 2021;32:1600-14

How to cite this URL:
Alkandari O, Alshami AA, Alhammadi EA. Practice of Childhood Nephrotic Syndrome Management amongPediatric Nephrologists in the GCC Countries. Saudi J Kidney Dis Transpl [serial online] 2021 [cited 2022 Aug 14];32:1600-14. Available from: https://www.sjkdt.org/text.asp?2021/32/6/1600/352421

   Introduction Top


Childhood nephrotic syndrome (NS) is one of the most common diagnoses that pediatric nephrologists encounter in their career. Its incidence range between 1 and 17 per 100,000 children worldwide.[1],[2],[3] Since the establishment of the initial treatment protocol by the International Study of Kidney Disease in Children (ISKDC) more than the four decades ago, several different treatment strategies and drugs have evolved in the management of NS.[4] The majority of children with minimal change disease (90%) will respond to corticosteroids as shown by the ISKDC study; however, there is no agreement about the optimal duration for the corticosteroids therapy.[5],[6] The ISKDC proposed an eight-week regimen for the corticosteroids therapy; however, a subsequent meta-analysis of six trials has shown that the risk of relapse decreases with a 12 week or more regimen of corticosteroids therapy.[5],[7] Furthermore, another meta-analysis of four trials has shown that the risk of relapse is less with six months’ regimen of corticosteroids therapy in comparison to three months’ regimen.[6],[7] Based on these studies, Kidney Disease Improving Global Outcomes (KDIGO) guidelines recommended a total corticosteroid therapy (initially daily and then alternate-day/tapering dosing) of 3–6.5 months.[6]

Among the corticosteroids-sensitive children, 40%–45% will have infrequent relapses and a similar percentage will have either frequently relapsing or corticosteroids-dependent NS.[6] There is no universal agreement about when to start a corticosteroids-sparing agent and which drug to choose.[4],[6],[8],[9],[10],[11],[12] Several international practice guidelines were published in the last 12 years, which include guidelines from India, France, North America, and more recently KDIGO clinical practice guidelines for glomerulonephritis in 2012.[6],[8],[9],[13]

Childhood NS management variability was elicited in several studies in North America. Lande and Leonard reported significant variability in practice and perceptions amongst 105 pediatric nephrologists in North America (Canada and USA) in treating new-onset corticosteroids-sensitive NS.[4] Another two different web-based survey studies have shown great variability in the management of childhood NS amongst 70 pediatric nephrologists (30 from the USA and 40 from Canada) from different centers.[10],[11] Recently, the Canadian Childhood NS Project Team performed a longitudinal cohort study over ≥2.5 years of follow-up across 12 pediatric centers in Canada and including 48 pediatric nephrologists which again confirmed the practice variability in the management of childhood NS.[4]

The Gulf Cooperation Council (GCC) was founded in May of 1981 and it includes the countries of the Arab states along the Arabian Gulf which are Bahrain, Kingdom of Saudi Arabia (KSA), Kuwait, Oman, Qatar, and United Arab of Emirates (UAE). The total area of the GCC countries is 2,673,108 km2 with a population of around 54 million people.[14] Since the discovery of oil in the GCC countries in the 1930–1940s, they underwent large-scale modernization and development including the health care system. Currently, the Saudi Commission for Health Specialties is the only institution in the GCC countries that provide an accredited pediatric nephrology fellowship training program which was established in 2000.[15] Before the year 2000, all certified pediatric nephrologists in the GCC countries were trained at different parts of the world. Given the variability in the management of childhood NS among pediatric nephrologists elsewhere and that the majority of the certified pediatric nephrologists in the GCC countries trained at different centers/ countries, our aim was to evaluate the variability in the management of childhood NS in the GCC countries and whether certain fellowship training programs influence certain way of management.


   Subjects and methods Top


Study design and participants

This was a cross-sectional, web-based survey methodology that was conducted between June 25, 2019, and July 10, 2019, among pediatric nephrologists in the six GCC countries. Only pediatric nephrologists who had official training in pediatric nephrology (fellowship training or equivalent) were eligible. This study was approved by the research ethics board of the Ministry of Health of Kuwait and the research ethics board in Dubai health authority in UAE. Informed consent was taken by the participants electronically.

The questionnaire

Thirty-five multiple-choice questions about childhood NS management and practice among pediatric nephrologists in the GCC countries [Supplement Table 1 [Additional file 1]] were developed by the three investigators of this manuscript. The survey starts with an introduction which gives a brief background about the aim of the study and then followed by an informed consent statement for participation. The questions cover four main topics: (1) participants’ characteristics which include age, gender, postgraduate pediatric nephrology training (fellowship) country, current working place, duration of clinical practice in pediatric nephrology and whether participants’ current center accept uncomplicated first presentation NS patients; (2) corticosteroids-related questions; (3) corticosteroids-sparing agents-related questions; (4) miscellaneous which covers biopsy and genetic testing related questions. A web-based survey link (SurveyMonkey™) was sent to the invitee by a text message and/or email. A reminder text message and/or email was sent a week later.

Table 1. Participants' demographics.
USA: United States of America, UK: United Kingdom, KSA: Kingdom of Saudi Arabia, UAE: United Arab Emirates, NS: Nephrotic syndrome.


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   Statistical Analysis Top


Data were analyzed using the STATA statistical software package (STATA v.12, STATA Corporation, College Station, TX, USA). Categorical variables were expressed as numbers and percentages. An evaluation of the possible association between fellowship training site and duration of clinical experience versus certain practice among pediatric nephrologists (corticosteroids treatment dosing regimen, duration, weaning; choice of corticosteroids-sparing agent in frequently relapsing, corticosteroids dependent, corticosteroids-resistant NS; corticosteroids pulse therapy for corticosteroids-resistant NS; and biopsy indication) using Chi-square or Fisher’s exact test as appropriate. To limit the number of subgroups, the variable “fellowship training site” was modified into three groups, excluding two participants trained in two different other countries, as follows (total n = 58): (1) North America (Canada and USA, n = 36); (2) Europe (all European countries, n = 5); (3) KSA (n=17) and the variable “duration of clinical experience” was also modified into two groups as follows: (1) less than 10 years; (2) 10 years or more. Statistical significance was taken as a P-value of <0.05.


   Results Top


Participant ’s demographics

[Table 1] shows the details of the participants’ characteristics. Among 92 pediatric nephrologists invitees, 62 completed the questionnaire which gives a response rate of (67%). Two participants were excluded for not having an official pediatric nephrology fellowship training, so the final number of participants eligible for analysis was 60. Almost three quarters (73%) were <50 years old and male participants were slightly higher than females. More than half (60%) were trained in North America and most are currently working in the KSA (58%). The vast majority (80%) accept to follow and manage children with uncomplicated first presentation NS.

Corticosteroid therapy

Forty-two percent of participants would always use mg/m2 dosing whereas 30% would always use mg/kg dosing and the rest (28%) sometimes use mg/m2 and sometimes use mg/kg dosing. The majority (63%) use the 12- weeks (vs. 8 weeks) corticosteroids induction regimen (6 weeks of daily corticosteroids therapy and then another six weeks of alternate-day dosing) for first presentation of childhood NS. The vast majority (92%) wean and do not stop abruptly, the corticosteroids after the alternate-day dosing. [Figure 1] shows the weaning duration of corticosteroids after completion of the induction phase amongst nephrologists who tend to wean the corticosteroids. Only two participants (3%) check the cortisol level before stopping the corticosteroids and none have observed or diagnosed an adrenal insufficiency.

Figure 1. Duration of corticosteroids weaning postcorticosteroids induction phase for treating first presentation nephrotic syndrome.


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A minority of participants (10%) have never considered a long term, small dose, alternate-day corticosteroids therapy to sustain remission for frequently relapsing and corticosteroid dependent CNS before commencing a corticosteroids-sparing agent. Among participants who might use long-term corticosteroids to sustain remission, only three participants (5%) use a dose that is higher than 0.5 mg/kg for frequently relapsing NS, whereas the rest use a dose ranging between 0.1–0.5 mg/kg. For corticosteroid-dependent NS, five participants use a dose between 0.5–1 mg/kg to sustain remission and the rest use a dose that is ≤0.5 mg/kg. Almost half of the participants (48%) attempt to discontinue corticosteroid after introducing a corticosteroids-sparing agent for frequently relapsing or corticosteroids-dependent NS.

Corticosteroids-resistant NS was defined by participants as follows: no response to daily prednisone dosing of 2 mg/kg or 60 mg/m2 for four weeks in 35% of the participants, for four weeks and methylprednisolone pulse therapy in 39% of the participants, for six weeks in 5% of the participants, for six weeks and methylprednisolone pulse therapy in 2% of the participants, for eight weeks in 14% of the participants and for eight weeks and methylprednisolone pulse therapy in 5% of the participants. A slightly more than a quarter of participants (27%) would always give methylprednisolone pulse therapy before considering a corticosteroids-sparing agent, whereas 8% never give methylprednisolone pulse therapy, and the remaining (64%) sometimes give methylprednisolone pulse therapy. The methylprednisone pulse therapy dosing by participants was as follows: 10 mg/kg for three successive days (38%); 15-20 mg/kg for three successive days (12%); 30 mg/kg for three successive days (25%); and the rest have different dosing/frequency.

Corticosteroids-sparing agent therapy

A minority of participants (<9%) rarely or never use a corticosteroids-sparing agent until a patient develop corticosteroids related toxicity in frequently relapsing or corticosteroids dependent NS. Three quarters (75%) of the participants’ first choice of corticosteroids-sparing agent for frequently relapsing and corticosteroids dependent are the same, whereas the rest have a different first choice of corticosteroids-sparing agent for frequently relapsing and corticosteroids-dependent NS [Table 2]. The majority of participants (95%) prefer calcineurin inhibitors (CNI) (tacrolimus in 65% and cyclosporin in 30%) as the first choice for corticosteroids-resistant NS whereas cyclophosphamide, rituximab, and mycophenolate mofetil (MMF) were preferred by 1.5%, 1.5%, and 3% of the participants, respectively. [Figure 2] shows how the participants define CNI or MMF resistance.

Table 2. Number (n=57)/(percentage) of first choice of corticosteroid-sparing agent in frequently relapsing and corticosteroid-dependent nephrotic syndrome.
CNI: Calcineurin inhibitor, MMF: Mycophenolate mofetil.
Gray shaded areas represent the same first choice of corticosteroids-sparing agent for frequently relapsing and corticosteroid-dependent nephrotic syndrome.


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Almost three quarters (73%) of the participants never used rituximab as a first-line corticosteroids-sparing agent for frequently relapsing or corticosteroids-dependent NS, whereas the rest did sometimes. Regarding rituximab dose, all give 375 mg/m2 per dose except one participant who uses 500 mg/m2. For the rituximab frequency per one treatment course, about half of the participants (48%) give two doses one to two weeks apart, 26% give four doses weekly, 14% give only one dose, and 12% give one to four doses based on CD19/CD20 level. Eighty-two percent of the participants follow CD19/20 whereas the rest don’t. Sixty-one percent of the participants do not give further rituximab courses until the child relapse, 27% give it when the CD19/20 starts to repopulate before the relapse happens, 4% will give it six months after the initial course, 4% will give it one year after the initial course and the rest have different management. Post-rituximab treatment, 17% always stops corticosteroids and other corticosteroids-sparing agent(s) and 15% will keep at least one immunosuppression and the rest sometimes stop and sometimes keep other immunosuppression.

Miscellaneous

The vast majority (88%) of participants said renal biopsy is done by intervention radiology at their centers. [Table 3] shows the number/ percentage of participants who agree with some of the renal biopsy indications for children with NS. For children treated with CNI for few years and then started to relapse after stopping CNI, 27% of participants will always do a biopsy before recommencing CNI, only 10% will not do a biopsy, and the majority will do it sometimes. Regarding genetic testing indication, 92% will do it for children <1 year of age and 83% for corticosteroids resistant.

Table 3. Number/percentage of participants agrees with the following renal biopsy indication for children with nephrotic syndrome.
NS: Nephrotic syndrome, CNI: Calcineurin inhibitor GFR: Glomerular filtration rate


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Fellowship training site and duration of clinical experience as a factor for specific practice

We evaluated the association between the fellowship training site/country and the duration of clinical experience against the current practice of the participants. There was no significant association between the fellowship training site/country and the duration of clinical experience and different items in the NS management [Table 4].

Table 4. Association between fellowship training site and duration of clinical experience and NS management among participants.
1: North America versus Europe versus KSA, 2: <10 versus ≥10 years, 3: 4 versus 6 weeks, 4: mg/m2 versus mg/kg, 5: No versus Yes, 6: Cyclophosphamide versus CNI versus MMF versus rituximab versus levamisole, NS: Nephrotic syndrome, CNI: Calcineurin inhibitor GFR: Glomerular filtration rate.


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   Discussion Top


Despite the great effort put in by KDIGO guidelines for the treatment of children with NS, which was based on an explicit process of evidence review and expert appraisal, great variability in the management of CNS still exists among pediatric nephrologists in different parts of the world including the GCC countries.[10],[11],[12] These variabilities were not only in the minor areas of CNS management but include the main aspects of CNS management such as the dose and duration of corticosteroids therapy and the choice of second-line corticosteroids-sparing agent.

About 30% of the participants still use the eight-week regimen as per the ISKDC guidelines despite the more recent and stronger evidence that supports a 12-week regimen as per KDIGO guidelines.[6],[7] However, a recent well-designed phase III randomized controlled trial (RCT) have shown that there is no significant difference between an extended 16 week versus a standard eight week’ course of prednisolone for the treatment of a first episode of childhood NS in regard to time to first relapse, incidence of frequently relapsing or corticosteroids-dependent NS and requirement for corticosteroids-sparing agent.[4] Teeninga et al have shown in another RCT that 6 versus 3 months of prednisolone for the initial treatment of childhood NS did not benefit the clinical outcome of children with NS without increasing cumulative prednisolone dose.[16] Moreover, an Indian RCT has shown similar findings where an extending initial prednisolone treatment from three to six months did not influence the course of illness in children with NS.[17] The contradictory findings between old and recent RCTs attributed to some methodological flaws in the former such as incomplete blindness and biases as opposed to more recent, well-designed RCTs.[7],[18] About 92% of the participants prefer to wean and not to stop the corticosteroid abruptly after the alternate day phase of treatment. The majority will wean and then stop the corticosteroids within one to three months, whereas only 15% wean over four to six months. Regarding corticosteroids-resistant NS, about one third (35%) use four weeks of corticosteroids to label the patient as corticosteroids resistant and only 14% concur with KDIGO guidelines definition, which is after eight weeks of corticosteroids therapy. Interestingly, 46% of the participants require pulse methylprednisolone therapy after the initial oral corticosteroids treatment to label a child as corticosteroids resistant.

Almost three-quarters of the participants (74%) used the same corticosteroids-sparing agent for both frequently relapsing and corticosteroids-dependent NS. MMF was preferred as a first-line corticosteroids agent for frequently relapsing and corticosteroids-dependent NS in 58% and 51% of the participants, respectively. This first choice of corticosteroids-sparing agent is different than what was reported by MacHardy et al in 2009 among pediatric nephrologists in the USA and by Samuel et al in 2013 among Canadian nephrologists where oral cyclophosphamide was preferred by the majority of nephrologists in these two studies for non-biopsy patients or patients with minimal change disease.[10][11] However, the choice was different among children with focal segmental glomerulosclerosis (FSGS). This trend of using more of MMF among our participants is perhaps due to the personal experience in using MMF, fewer side effects including nephrotoxicity, and the presence of more studies in recent years.[19],[20] For corticosteroids-resistant NS, 95% of our participants prefer CNI over other immunosuppressions. Again, oral cyclophosphamide was preferred by North American nephrologists in patients with minimal change disease and having corticosteroids-resistant NS but not in patients with FSGS.[10],[11]

Rituximab use has become more popular amongst nephrologists for both corticosteroids sensitive and resistant NS.[4] Although almost all the participants in our study use the same dose of rituximab (375 mg/m2), there is a great variability among our participants in regard to the number of doses per each treatment course, the number of courses, when to give the subsequent course and whether to continue or stop other immunosuppressions. This variability is not a surprise since it is relatively a newer immunosuppression, in comparison to others, and the presence of over 100 publications with variable dosing, frequency, and outcomes.[4]

We hypothesize that the variability in the management of NS among our pediatric nephrologists is because of acquiring fellowship training at different centers/countries. However, we found no association between the country of training and the duration of clinical experience and the variability in CNS management. This practice variation is most probably due to the great variability existed in different NS guidelines, which was also elicited in three previous North American studies.[6],[8],[9],[10],[11],[12],[13]

This study has some limitations. First, the study design was a cross-sectional survey study in the form of multiple-choice questions which limits the explanation for certain practices by the participating nephrologists. Second, about one-third of the invitees did not participate in our survey; however, our sample was a good representative of all the GCC countries with different age groups and duration of clinical experience. On the other hand, this study was the first of its kind that addressed the existence of significant practice variation in the management of CNS in the GCC countries. A finding that necessitate the development of a local evidence-based clinical practice guidelines that dictate the management of CNS. Furthermore, we need a well-designed prospective studies tailored to our population to address the areas of knowledge gap in the management of CNS.

In summary, corticosteroids remain the main treatment for children with NS. Great practice variation exists in the corticosteroids dosing, duration and the choice of corticosteroids-sparing agents in our study, a finding that was similar to many other international studies. Future local studies are highly needed to improve the practice standards and quality of care for this population.


   Acknowledgment Top


We would like to thank our colleagues who participated in this study.

Conflict of interest: None declared.



 
   References Top

1.
McKinney PA, Feltbower RG, Brocklebank JT, Fitzpatrick MM. Time trends and ethnic patterns of childhood nephrotic syndrome in Yorkshire, UK. Pediatr Nephrol 2001 ;16:1040- 4.  Back to cited text no. 1
    
2.
Eddy AA, Symons JM. Nephrotic syndrome in childhood. Lancet 2003;362:629-39.  Back to cited text no. 2
    
3.
Banh TH, Hussain-Shamsy N, Patel V, et al. Ethnic differences in incidence and outcomes of childhood nephrotic syndrome. Clin J Am Soc Nephrol 2016;11:1760-8.  Back to cited text no. 3
    
4.
Lande MB, Leonard MB. Variability among pediatric nephrologists in the initial therapy of nephrotic syndrome. Pediatr Nephrol 2000;14: 766-9.  Back to cited text no. 4
    
5.
Nephrotic syndrome in children: Prediction of histopathology from clinical and laboratory characteristics at time of diagnosis. A report of the International Study of Kidney Disease in Children.Kidney Int1978;13:159-65.  Back to cited text no. 5
    
6.
KDIGO clinical practice guideline for glomerulonephritis. Kidney Int Suppl 2012;2: 139-274.  Back to cited text no. 6
    
7.
Hodson EM, Knight JF, Wilis NS, Craig JC. Corticosteroid therapy for nephrotic syndrome in children. Cochrane Database Syst Rev 2005;(1):CD001533.  Back to cited text no. 7
    
8.
Bagga A. Revised guidelines for management of steroid-sensitive nephrotic syndrome. Indian J Nephrol 2008;18:31-9.  Back to cited text no. 8
[PUBMED]  [Full text]  
9.
Gipson DS, Massengill SF, Yao L, et al. Management of childhood onset nephrotic syndrome. Pediatrics 2009;124:747-57.  Back to cited text no. 9
    
10.
MacHardy N, Miles PV, Massengill SF, Smoyer WE, Mahan JD, Greenbaum L, et al. Management patterns of childhood-onset nephrotic syndrome. Pediatr Nephrol 2009;24: 2193-201.  Back to cited text no. 10
    
11.
Samuel S, Morgan CJ, Bitzan M, et al. Substantial practice variation exists in the management of childhood nephrotic syndrome. Pediatr Nephrol 2013;28:2289-98.  Back to cited text no. 11
    
12.
Samuel SM, Dart A, Filler G, et al. The Canadian childhood nephrotic syndrome (CHILDNEPH) study: Report on mid-study feasibility, recruitment and main measures. BMC Nephrol 2019;20:159.  Back to cited text no. 12
    
13.
Childhood Idiopathic Nephrotic Syndrome. National Protocol for Diagnosis and Care for a Rare Disease. Saint-Denis La Plaine: High Authority for Health; 2008. p. 1-22.  Back to cited text no. 13
    
14.
The Statistical Centre for the Cooperation Council for the Arab Countries of the Gulf. Available from: https://gccstat.org/. [Last accessed on 8 May 2022].  Back to cited text no. 14
    
15.
Saudi Comission for Health Specialties. Available from: https://www.scfhs.org.sa/. [Last accessed on 8 May 2022].  Back to cited text no. 15
    
16.
Teeninga N, Kist-Van Holthe JE, Van Rijswijk N, et al. Extending prednisolone treatment does not reduce relapses in childhood nephrotic syndrome. J Am Soc Nephrol 2013; 24:149-59.  Back to cited text no. 16
    
17.
Sinha A, Saha A, Kumar M, et al. Extending initial prednisolone treatment in a randomized control trial from 3 to 6 months did not significantly influence the course of illness in children with steroid-sensitive nephrotic syndrome. Kidney Int 2015;87:217-24.  Back to cited text no. 17
    
18.
Webb NJ, Woolley RL, Lambe T, et al. Long term tapering versus standard prednisolone treatment for first episode of childhood nephrotic syndrome: Phase III randomised controlled trial and economic evaluation. BMJ 2019;365:l1800.  Back to cited text no. 18
    
19.
Li S, Yang H, Guo P, et al. Efficacy and safety of immunosuppressive medications for steroid-resistant nephrotic syndrome in children: A systematic review and network meta-analysis. Oncotarget 2017;8:73050-62.  Back to cited text no. 19
    
20.
Querfeld U, Weber LT. Mycophenolate mofetil for sustained remission in nephrotic syndrome. Pediatr Nephrol 2018;33:2253-65.  Back to cited text no. 20
    

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Correspondence Address:
Omar Alkandari
Division of Pediatric Nephrology, Mubarak Al-Kabeer Hospital, Al-Jabriya, Kuwait.
Kuwait
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/1319-2442.352421

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