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Saudi Journal of Kidney Diseases and Transplantation
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Table of Contents   
ORIGINAL ARTICLE  
Year : 2020  |  Volume : 31  |  Issue : 1  |  Page : 79-89
Evaluation of the children with C3 glomerulopathy


1 Department of Pediatrics, Division of Pediatric Nephrology, Erciyes University Faculty of Medicine, Kayseri, Turkey
2 Department of Pathology, Erciyes University Faculty of Medicine, Kayseri, Turkey
3 Department of Pediatrics, Nevsehir State Hospital, Nevsehir, Turkey

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Date of Submission25-Sep-2018
Date of Acceptance04-Nov-2018
Date of Web Publication3-Mar-2020
 

   Abstract 


C3 glomerulopathy (C3G) is a clinical spectrum that presents with a variety of symptoms, ranging from a mild disease with asymptomatic microhematuria and/or proteinuria to severe disease with nephritic or nephrotic syndrome and renal impairment. Herein, we aim to document the clinical and laboratory findings, response to immunosuppressive and supportive treatment and prognosis of the children with C3G. We retrospectively reviewed the medical records of patients diagnosed with membranoproliferative glomerulonephritis (MPGN). Kidney biopsy materials were reexamined for the diagnosis of C3G. The inclusion criteria for C3G are the dominant C3 staining with or without scanty immunoglobulins (Ig) deposition on immuno- fluorescence (IF) and MPGN patterns on light microscope. Twelve of 69 patients with MPGN were included in the study based on the definition criteria of C3G. Ten of them had only C3 staining and the rest of the patients had both C3 staining and a small amount of IgG/M staining on IF microscopy. One patient was on remission with only ACEI. The rest of the patients used immunosuppressive treatment and two of them needed eculizumab therapy. One of them did not respond to the treatment of eculizumab and progressed to end-stage renal failure. C3G is a disease characterized by a heterogeneous clinical presentation and outcome. Because of this broad spectrum of disease, treatment may vary widely. We think that complement-targeting therapy with eculizumab should be an alternative option for refractory cases, especially in the early stage of disease, if they did not respond to immunosuppressive treatment.

How to cite this article:
Pinarbasi AS, Dursun I, Poyrazoglu MH, Akgun H, Bozpolat A, Dusunsel R. Evaluation of the children with C3 glomerulopathy. Saudi J Kidney Dis Transpl 2020;31:79-89

How to cite this URL:
Pinarbasi AS, Dursun I, Poyrazoglu MH, Akgun H, Bozpolat A, Dusunsel R. Evaluation of the children with C3 glomerulopathy. Saudi J Kidney Dis Transpl [serial online] 2020 [cited 2020 Apr 4];31:79-89. Available from: http://www.sjkdt.org/text.asp?2020/31/1/79/279964



   Introduction Top


Membranoproliferative glomerulonephritis (MPGN) is a description based on light microscopy (LM) findings as mesangial hyper- cellularity and endocapillary proliferation. Two types are defined as immune-complex mediated and complement-mediated depending on the subendothelial, subepithelial and/or mesangial deposition of pathogenic immunecomplexes. Those with deposits containing immunoglo- bulins (Ig) and classical complement pathway components called as immune-complex mediated MPGN or MPGN type I which shows positive Ig and/or C3 staining in immuno- fluorescence (IF) staining and those with deposits containing complement C3 and terminal complement complex (C5b-C9) called as MPGN Type II or dense deposit disease (DDD) which shows positive C3 staining and negative Ig staining.[1],[2],[3] This entity was redefined by Servais in 2007 as C3 glome- rulopathy [C3 glomerulopathy (C3G)].[1] This classification was accepted with the 2013 consensus report.[4] With this report, C3G is defined as glomerular pathology including DDD and C3 glomerulonephritis (C3GN) and characterized by C3 accumulation with absent or scanty Ig deposition.[4],[5],[6],[7]

C3 glomerulopathy, which presents with a variety of symptoms, ranging from a mild disease with asymptomatic microhematuria and/or proteinuria to a severe disease with nephritic or nephrotic syndrome and renal impairment, is a rare disease which constitutes roughly 1.34% of the biopsies in nephrology clinics. The incidence is 1-2 per million populations per year.[8],[9],[10] The characteristic features of C3G on kidney biopsy are a membranoproliferative type of injury on LM, C3 dominant staining without IgG on mesangial and capillary wall on IF microscopy, and many mesangial and sub- endothelial deposits with or without a few intramembranous and subepithelial deposits.[11] Immunohistochemistry studies show the same predominance of C3 staining in both subtypes. To differentiate C3GN and DDD; electron microscopy (EM) is used. In C3GN, discrete C3 deposits are located in the mesangium and along the capillary walls, whereas in DDD, C3 deposits are more intense in the mesangium and within the glomerular basement membrane (GBM) forming a unique ribbon-shaped band.[7] C3 glomerulonephritis and DDD are results from dysregulation of the alternative complement pathway and terminal complement complex.[12] The normal level of complement C4 and low levels of complement C3 show alternative pathway abnormality, but normal level of C3 or low levels of C4 do not rule out the C3G. Hence, there is no pathognomonic test for C3G.[51314]

Beside the variety of the clinical symptoms and laboratory results, there is no consensus on the treatment of C3G. In recent years, complement targeting treatment strategy has been became mainstay of therapy.[15] Since C3G can resolve spontaneously in some of the patients, experts’ advice is to follow-up without giving any medication if there is normal renal function tests and only non-nephrotic proteinuria.[16]

To our knowledge, there are no many studies investigating the clinical and laboratory findings, treatment strategy and prognosis in children with C3G. This retrospective study aims to present the clinical and laboratory findings, response to immunosuppressive and supportive treatment and prognosis of the children with C3G.


   Materials and Methods Top


We retrospectively reviewed the medical records of patients diagnosed with MPGN who were followed up between 2007 and 2016 in the department of Pediatric Nephrology at Erciyes University Faculty of Medicine, Kayseri, Turkey. All patients were younger than 18 years of age at diagnosis. The local institutional Ethics Committee approved the study protocol (Erciyes University Ethics Committee - Decision number: 2017/209).

We reexamined kidney biopsy materials for the diagnosis of C3G. We basically studied light and IF microscopy which is the key to the classification of proliferative glomeruloneph- ritis into Ig/immune-complex mediated or complement mediated.[17] EM could not be used because of non-availability in our hospital and financial constraints.

The dominant C3 staining with or without scanty Ig deposition on IF microscope and MPGN patterns on the light microscope was the inclusion criteria as in the definition of the

C3G. The medical records of patients were reviewed in terms of demographic data, clinical presentation, laboratory findings, treatments, and outcomes of the patients with C3G.

Nephrotic syndrome was defined as edema, serum albumin level <2.5 g/dL and nephrotic range proteinuria [>40 mg/m2/h or micro- protein/creatinine (mp/Cr) ratio >2 mg/mg]. Nephritic syndrome was defined as macroscopic hematuria, edema, and hypertension. Clinical and laboratory findings of patients having nephrotic syndrome with a nephritic component was accepted as nephrotic-nephritic syndrome. Abnormal proteinuria was defined as non-nephrotic range proteinuria (4-40 mg/ m2/h or mp/Cr 0.2-2 mg/mg).[18]

Complete remission was defined as normal serum albumin and creatinine level without proteinuria (4 mg/m2/h or mp/Cr <0.2 mg/mg). Partial remission is defined as non-nephrotic proteinuria (4-40 mg/m2/h or mp/Cr 0.2-2 mg/mg) with improvement or normalization of albumin level and stabilized serum creatinine. Non-responder is defined as continuation of nephrotic range proteinuria (>40 mg/m2/h or mp/Cr >2 mg/mg). End-stage renal disease (ESRD) is defined as having estimated glome- rular filtration rate (eGFR) <15 mL/min/1.73 m2 and requiring renal replacement treatment.


   Statistical Analysis Top


All tests were performed using IBM SPSS Statistics version 22.0 (IBM Corp., Armonk, NY, USA). The parameters with normal distribution were expressed as mean ± standard deviation, and the parameters with abnormal distribution were expressed as median (minimum-maximum).


   Results Top


A total of 69 patients with MPGN were found on database between 2007 and 2016. Twelve of them were included in the study based on the definition of C3G. In our cohort, 11 of them were females. The mean age at the diagnosis was 10.1 ± 2.8 years and follow-up duration 43.7 ± 34.5 months. Consanguinity was present in 25% of the patients. On admission, five children had a history of upper respiratory tract infection (URTI) (41%). None of the patients had drusen or lipodystrophy. At the time of diagnosis, seven children presented with edema and hypertension. None of the patients had serious symptoms such as pulmonary edema, heart failure, or convulsions. Gross hematuria was the leading symptom on admission. Six patients had nephritic/nephrotic features, three patients had nephrotic syndrome, two patients had nephritic syndrome, and one had abnormal proteinuria [Table 1]. One among the five children with a history of URTI had increased ASO level. The mean urinary protein excretion and the number of erythrocytes were 74.7 mg/m2/h and 173 ± 39 at the time of diagnosis, respectively. The median value of blood urea nitrogen, creatinine and albumin was 19 (9-73) mg/dL, 0.84 (0.42.6) mg/dL, and the 2.8 (1.7-4.1) g/dL, respectively. At the onset of disease, 83% of the patients had low C3 level and half of them still had low C3 level at the time of the study. C4 level was decreased in three patients at the beginning and no one had a low C4 level at the last follow-up [Table 1].
Table 1: Clinical status and complement levels of the patients.

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When patients were evaluated in terms of kidney biopsy findings, 10 patients had only C3 staining and the rest of the patients had both C3 staining and a small amount of IgG or M staining on IF microscopy. With LM, mesangial cell proliferation was detected in all patients. Four patients had basal membrane thickening and eight patients had endocapil- lary cell proliferation in addition to mesangial cell proliferation. While a small number of crescents was detected in two patients, severe crescentic glomerulonephritis, in which >50% of glomeruli have crescent formation was found only in one child. Glomerular sclerosis was detected in one of the children. There were no interstitial fibrosis and arteriolar sclerosis in kidney biopsy [Table 2].
Table 2: The light microscopy and immunofluorescence results of patients.

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All medications used are listed in [Table 3]. Ten patients used angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers (ACEI/ARB) for their antiproteinuric effect. All patients except patient #1 needed steroids. Of these, five were treated with only steroid ± ACEI/ARB. Remission was not achieved in the rest of the patients and additional immunosuppressive treatment was required. Azathioprine (AZA) was started in five patients; then it was switched to Myco- phenolate mofetil (MMF) in three of them. There is total of five patients receiving MMF therapy. Three of them did not reach remission and complement targeting treatment. Therefore, eculizumab, was given two of them and is being planned for the other patient.
Table 3: Follow-up of the patients.

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Only patient who did not need steroids was patient number 1. Non-nephrotic range protei- nuria was detected shortly after she was diagnosed with type 1 diabetes mellitus. Because of persistent hypocomplementemia and proteinuria, kidney biopsy was performed, and she was diagnosed with C3G. Non- nephrotic range proteinuria with normal serum albumin level and hypocomplementemia continued during the follow-up. She is still stable with normal serum creatinine under the ACEI/ ARB treatment.

Patient number 2 had complained of recurrent bloody urine for one year and was admitted with upper eyelid swelling and macroscopic hematuria after URTI. A kidney biopsy was performed due to decreased complement level and history of recurrent cola- colored urine. It was compatible with MPGN. Monthly pulses of intravenous methylpredni- solone (PMP) (30 mg/kg), along with tapering doses of oral prednisolone, were given and cyclosporine (CsA) was started. However, CsA was replaced by AZA because of side effects. With these treatments, complete remission was achieved at six months. Immuno- suppressive therapies were stopped at 18th months of follow-up. She experienced a relapse two years later. MMF and oral predni- solone were started. Due to poor response to treatment, kidney biopsy was repeated, and histopathologic findings showed C3G. Monthly PMP was resumed and given for three more months. She is currently on partial remission with MMF and ACEI.

Monthly PMP, oral prednisolone and CsA were started in patient number 3 who was diagnosed with MPGN at another nephrology center at the age of 11 years. Since no remission was achieved, CsA was replaced with AZA/MMF. Because of poor response, a repeat kidney biopsy revealed C3G. C3 nephritic factor was negative and she was given eculizumab based on a HUS standard treatment protocol. At last follow-up, she was on remission with the 15th dose of eculizumab, along with CsA and ACEI.

Patient number 4, who was referred with gross hematuria after URTI, had normal complement levels and impaired renal function. Initial kidney biopsy findings were compatible with MPGN. Kidney biopsy was repeated due to relapses despite oral predni- solone and indicated characteristic features of C3G. EM supported the diagnosis of C3G with electron-dense deposits in GBM and mesan- gium. She received monthly PMP, ACEI and MMF treatment. The patient is now on partial remission with MMF and ACEI.

The only male patient in our cohort, patient number 5, had nephrotic syndrome after URTI. He had low C3 level. He underwent kidney biopsy, which revealed C3G. Since he was non-responder for a six months course of PMP, oral prednisolone and ACEI, AZA was added. Six months later, kidney biopsy was repeated because of the poor response to treatment. Histopathologic findings were compatible with C3G, along with moderate chronic changes on both glomerular and tubulointers- titial regions. Complement factor H gene mutation was negative. He was lost to follow- up.

The patient number 6 presented with cola- colored urine and acute kidney injury without any history of infection and her serum complement levels (C3 and 4) were low. Because of her atypical clinical and laboratory pictures, kidney biopsy was performed, and it was reported as C3G. She was given a dose of PMP, tapering dose of oral prednisolone and ACEI. She is still on remission with low dose of oral prednisolone and ACEI.

At the age of 12, renal biopsy was performed to patient number 7 because of acute kidney injury accompanied by nephrotic syndrome after URTI. Kidney biopsy showed prolife- rative glomerulonephritis with crescent in 35% glomeruli, along with C3 staining on IF microscopy. Monthly PMP, oral prednisolone and pulse cyclophosphamide were started as an induction therapy, then tapering dose of oral prednisolone, AZA and ACEI were used. At last follow-up, she had partial remission with normal serum creatinine and non- nephrotic proteinuria (30 mg/m2/h).

A 13-year-old patient, patient number 8, with a nephrotic-nephritic syndrome had a low C3 level on admission. Pulse cyclophosphamide, PMP, and AZA were initiated upon the biopsy which was compatible with Class IV-V SLE nephritis. Due to the lack of remission, MMF and RTX were introduced into treatment. Since she was non-responder for this therapy, kidney biopsy was performed. It demonstrated classical findings of C3G. Her glomerular filtration rate (GFR) was 57 mL/min/1.73 m2 and proteinuria was 461 mg/m2/h. Plasma- pheresis was started as previously performed by Häffner et al.[19] Then, tacrolimus and eculizumab were started. During the follow- up, we were not able to use eculizumab according to the recommended dose schedule because of financial constraints. At the end of 15th dose of eculizumab, her GFR was <15 mL/min/1.73 m2. Therefore, we stopped immunosuppressive therapy and put her on regular intermittent hemodialysis. The genetic study showed that she only carried a heterozygous mutation in C3 gene (P314L).

Patient numbers 9 and 10 were treated with oral prednisolone and one dose of PMP (patient number 10) and reached remission. Prednisolone was ceased at the 6th month of follow-up.

A 12-year-old patient, patient number 11, had nephrotic syndrome, microscopic hematuria and low C3 level. Kidney biopsy revealed C3G. Initially, she was treated with monthly PMP, oral prednisolone and ACEI, and was started on MMF at the 3rd month of follow-up. Ten months later, since she had persistent low C3 level, nephrotic syndrome and positive C3 nephritic factor, we started plasmapheresis as previously described[19] and switched MMF to tacrolimus. At the last follow-up, she had active disease. Therefore, we have planned to give her complement targeting therapy with eculizumab.

The patient number 12 was admitted with a complaint of recurrent abdominal pain and was detected low C3 level and nephrotic range proteinuria. The serum albumin was in the lower limit of the normal range. Her kidney biopsy findings demonstrated C3G. With two doses of monthly PMP, tapering dose of oral prednisolone and ACEI, she reached partial remission.


   Discussion Top


In the present study, C3G was found to be a disease characterized by heterogeneous clinical presentation and outcome. It was described by Servais in 2007.[1] Since then, advances in our understanding of the physio- pathology of C3 glomerulopathy such as definition of the role of alternative complement pathway has resulted in opening new therapeutic windows.

Beside the variety of the clinical symptoms and laboratory results, the characteristics of the patients show alteration. Such as, patients with C3 glomerulopathy were predominantly male in the most of the studies;[9],[16],[20] our cohort mostly consisted of girls (91.6%) similar to the study performed by Zhang et al.[13] In our study, we could not explain this predominance among girls based on our current knowledge about C3G.

Although a small number of crescents may be present with any of the membranoproliferative, endocapillary proliferative, mesangial proliferative, or a sclerosing pattern of injury in patients with C3G, severe crescent formation is seen only rarely. Ravindran et al documented the clinical and laboratory findings of patients with C3G who had severe crescentic and necrotizing glomerulonephritis and showed some of the patients had a history of antecedent infection with positive ASO titers, normal complement level (50%) at diagnosis, and 75% of C3GN and 50% of DDD patients showed stable renal function at follow-up.[21] In our study, patient number 4 had severe crescentic glomerulonephritis with mesangial and endocapillary proliferation. She had normal C3 and C4 at diagnosis and was initially given three doses of pulse methylprednisolone monthly and oral steroids. Then, MMF and enalapril were added as a steroid- sparing agent and anti-proteinuric agent respectively. At the final follow-up, she still had abnormal proteinuria but with stable renal function and normal creatinine.

It is possible that some of the patients in our series may have atypical post-infectious glomerulonephritis (aPIGN) which is characterized by clinically persistent hematuria and proteinuria, with or without a history of preceding infection and characteristic histopatho- logic findings of post-infectious glomerulo- nephritis: (a) proliferative glomerulonephritis on LM, including diffuse or focal endo- capillary proliferation and exudative glome- rulonephritis, and mesangial proliferative glomerulonephritis; (b) mesangial and/or capillary wall C3 staining with or without Ig on IF microscopy; and (c) sub-epithelial “hump-like” deposits on EM.[9] Since aPIGN patients with C3GN may have few intra- membranous deposits and occasional sub- epithelial humps on EM,[11] it was accepted that the biopsy findings of patients with aPIGN and C3GN demonstrate striking similarity[12] possibly due to defect of alter-native pathway of complement both disease have.[11],[12] To distinguish one from other, the characteristic pattern of injury in both disease on LM and features of IF staining can be used. While patients with aPIGN usually have diffuse proliferative pattern of glomerulonephritis on LM and the possible presence of Ig staining on IF, patients with C3GN have MPGN on LM without Ig staining on IF.[11] In our study, most of the patients did not have IgG staining on IF, except patient 8 and 11, and kidney biopsy in 58% of patients showed basal membrane thickening, mesangial and endothelial cell proliferation [Table 2]. Atypical PIGN and C3GN may share similar abnormalities in the alternative pathway of complement.[11] Sethi et al detected abnormality (autoantibodies or mutations in complement genes) in the alternative pathway of complement in 91% of patients. They showed that seven patients were positive for C3Nefs, four patients had mutations of complement genes (CFH in 3 and CFHR5 in 1).[11] The screening of the C3Nef and autoantibodies for CFH, CFI and CFB, and genetic testing of CFH, CFI, MCP and CFHRP1-5 were recommended to differentiate autoimmune and genetic forms of C3G and optimize treatment strategy.[9] Unfortunately, we could not look at C3Nef and do genetic test for alternative pathways of complement in all patients because of retrospective nature of the study. In our cohort, only two patients had screening for C3Nef, which was negative and patient number 8 had heterozygous mutation on C3 gene (Pro314Leu). This variation was reported in patients with age-related macular degeneration.[22] However, its role in aHUS or C3G remains unclear. P314L is located in β chain of C3 contains six macroglobulin domains which are crucial elements for the correct orientation of the thioester-containing domain.[23] The amino acid changes may alter the structure of β chain in the C3 protein and enhance complement activation.[24]

There is no definitive test for C3G, which results from uncontrolled alternative pathway complement activation. Hence, the measurement of serological complement assays may be informative in these patients based on the etiopathogenetic mechanisms of the disease. The most common serologic abnormalities in the alternative pathway are reduced C3 and normal C4.[4] As the study by Zand et al,[25] patients in our cohort had low C3 (83%) and low C4 (25%) on admission.

To the best of our best knowledge, there is no guideline to pilot treatment of C3G in children. Current treatment strategies based on adult studies consist of reno-protective and anti-proteinuric therapy as well as immuno- suppressive and complement targeting therapy.[10] In the present study, various treatment strategies were followed as shown in Table 3. Although a partial or complete remission was achieved with MMF in 50% to 70% of the patients with MPGN, there is no study about the effect of MMF in children with C3G.[26],[27] Recently, it has been shown that the treatment of C3 glomerulonephritis with corticosteroid plus MMF in adults resulted in better renal survival as compared to patients treated with other immunosuppressive regimens and untreated patients. [8] In our cohort, MMF was given to five patients (patient 2, 3, 4, 8 and 11). Patient numbers 3, 8 and 11 did not give response and patient number 8 reached ESRD. Patient numbers 2 and 4 were partial respon- ders to MMF with microscopic hematuria and non-nephrotic range proteinuria at last follow- up.

Plasma therapy [plasma exchange (PE) or plasma infusions] may be effective in some cases, especially in patients with CFH mutations.[29],[30] Häffner et al demonstrated that four patients with positive for C3Nef and negative for CFH mutation were responder to the therapeutic regimen with plasma therapy, initial prednisone and MMF maintenance therapy.[19] We did plasmapheresis only in patient 8, who had low GFR on admission and experienced ESRD and in patient 11, who had steroid-resistant nephrotic syndrome with persistent low C3 level and positive C3 nephritic factor, and failed to show any response.

Although the efficacy of those attempts is controversial, complement targeting therapy looks reasonable since the data showed confirming the central role of abnormalities in the alternate pathway of complement in C3G.[31] Eculizumab, which is a humanized monoclonal antibody that interferes with membrane attack complex (MAC) assembly,[32] has become a rescue therapy for C3G.[33],[34] Bomback et al reported six C3G patients treated with eculizumab. While four of them had a high C5-9 level and responded to eculizumab, two patients with normal C5-9 levels did not respond to eculizumab treatment.[35] Therefore, it is suggested to give eculizumab therapy as early as in the patients with a high level of C5- 9.[31] In the present study, we gave eculizumab to two patients (patient #3 and #8). Patient #3 has been on eculizumab for 18 months and her urine protein to creatinine ratio, serum crea- tinine and albumin are within the normal range. Eculizumab was given to Patient #8 as a rescue treatment at five years of follow-up when she was non-responder to conventional immunosuppressive (cyclophosphamide, AZA, MMF, tacrolimus) and her kidney biopsy showed cellular crescent formation and endo- capillary proliferation in nine, total sclerosis in 22 of 46 glomeruli and diffuse thickening of the glomerular capillary basement membrane. There may be two reasons to explain the differences between two patients in terms of the response to eculizumab treatment. First, we speculate soluble C5b-9 may be different between patient #3 and #8 although we did not measure it.[32] It was shown that all patients who showed clinical benefit from treatment had elevated or borderline soluble C5b-9 compared to patients who showed no change in their disease course following treatment.[32] Second, eculizumab was given to patient 8 at the late course of disease. Recently, according to experts opinions, eculizumab should be started the patients who have had a relatively short duration of disease, have active inflammatory renal lesions and limited interstitial and glomerular fibrosis, and have had a recent increase in serum creatinine level and/or proteinuria.[31]

We are aware of the limitations of this study. It was a retrospective study and contained a few number of children with C3G. We could not perform genetic and serologic testing for inherited and acquired abnormalities of the alternative complement pathway. We were not able to use EM to differentiate DDD, aPIGN and C3GN because of non-availability in our hospital and financial constraints. This methodological variability may limit the reliability of our results.

In conclusion, C3G is a disease characterized by a heterogeneous clinical presentation and outcome. Most of the children are good responders for conventional treatment and we think that complement-targeting therapy with eculizumab should be an alternative option for refractory cases, especially in the early stage of disease.

Ethical Approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This Study Protocol was approved by the local ethics committee (Erciyes University Ethics Committee no. 2017/209).

Conflict of interest: None declared.



 
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Correspondence Address:
Ismail Dursun
Department of Pediatrics, Division of Pediatric Nephrology, Erciyes University Faculty of Medicine, Kayseri
Turkey
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DOI: 10.4103/1319-2442.279964

PMID: 32129200

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  [Table 1], [Table 2], [Table 3]



 

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