Ignite Creation Date:
2024-05-06 @ 10:40 AM
Last Modification Date:
2024-10-26 @ 12:34 PM
Study NCT ID:
NCT03326037
Status:
UNKNOWN
Last Update Posted:
2019-01-10
First Post:
2017-10-22
Brief Title:
Study of The Association of Mutations in The NPHS2 Gene and Nephrotic Syndrome in Children and Adults in Middle East
Sponsor:
AHMED ABDULQADER HAMMOUDA ABOU SHALL
Organization:
Assiut University
Study Overview
Official Title:
Study of The Association of Mutations in The NPHS2 Gene and Nephrotic Syndrome in Children and Adults in Middle East
Status:
UNKNOWN
Status Verified Date:
2019-01
Last Known Status:
ACTIVE_NOT_RECRUITING
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
Nephrotic syndrome NS represents one of the most common diagnoses in pediatric and adult nephrology with a prevalence of 16 per 100000 children and 3 per 100000 adults in Western countries
In most cases the pathogenesis of NS remains elusive and the clinical phenotype of patients does not allow discrimination among different causes Thus children with NS are usually treated with corticosteroids before a biopsy is taken and approximately 80 of them respond to such a treatment According to this observation pediatric NS has been separated into two broad categories Steroid-Sensitive Nephrotic Syndrome SSNS and Steroid-Resistant Nephrotic Syndrome SRNS In both these categories the biopsy result is usually Minimal Change Disease MCD while a few may show Focal and Segmental Glomerulosclerosis FSGS Although children affected by SSNS have good long-term prognosis most patients with SRNS progress to End Stage Renal Disease ESRD within 2-10 years of diagnosis
In adults a biopsy diagnosis of FSGS is more common than in children and more patients will not respond to corticosteroids alone and will need additional immunosuppressant medication About 40 will progress to ESRD within 10 years
Currently at least 19 genes have been clearly identified with association to SRNS harboring 300 independent mutations conferring a considerable genetic heterogeneity to the disorder
Genetic testing is emerging as a useful diagnostic tool in SRNS as it has implications for clinical course treatment response risk for posttransplant proteinuria and prenatal diagnosis An approach for genetic testing based on the current evidence seems cost-effective and may help in the best possible management of SRNS
The NPHS2 gene is located on chromosome 1 and is also known as the Podocin gene It encodes the podocin protein Podocin is a 383-amino acid lipid-raft-associated protein localized at the slit diaphragm where it is required for the structural organization and regulation of the glomerular filtration barrier Its interaction with other slit diaphragm proteins eg nephrin NEPH1 CD2AP and TRPC6 is important in mechanosensation signaling podocyte survival cell polarity and cytoskeletal organization
It has been reported that variants in the NPHS2 gene are associated with NS
The commonly studied rs61747728 NPHS2 gene polymorphism also known as pR229Q has been reported to be associated with NS and SRNS
However others have failed to report an association which might be due to population differences
The rs61747728 is a non-synonymous variant found on exon 5 which is suggested to be involved in in altering the functional properties of podocin in vitro and possibly in vivo
The investigators will therefore investigate the frequency of the pR229Q variant in Middle East patients with NS
Genetic analysis will have important implications in several aspects-
1 Understanding the biology of the disease in this part of the world
2 Counselling patients about their clinical course and what medication they will respond to
3 Counselling patients about the possibility of a kidney transplant sooner in their disease course
In most cases the pathogenesis of NS remains elusive and the clinical phenotype of patients does not allow discrimination among different causes Thus children with NS are usually treated with corticosteroids before a biopsy is taken and approximately 80 of them respond to such a treatment According to this observation pediatric NS has been separated into two broad categories Steroid-Sensitive Nephrotic Syndrome SSNS and Steroid-Resistant Nephrotic Syndrome SRNS In both these categories the biopsy result is usually Minimal Change Disease MCD while a few may show Focal and Segmental Glomerulosclerosis FSGS Although children affected by SSNS have good long-term prognosis most patients with SRNS progress to End Stage Renal Disease ESRD within 2-10 years of diagnosis
In adults a biopsy diagnosis of FSGS is more common than in children and more patients will not respond to corticosteroids alone and will need additional immunosuppressant medication About 40 will progress to ESRD within 10 years
Currently at least 19 genes have been clearly identified with association to SRNS harboring 300 independent mutations conferring a considerable genetic heterogeneity to the disorder
Genetic testing is emerging as a useful diagnostic tool in SRNS as it has implications for clinical course treatment response risk for posttransplant proteinuria and prenatal diagnosis An approach for genetic testing based on the current evidence seems cost-effective and may help in the best possible management of SRNS
The NPHS2 gene is located on chromosome 1 and is also known as the Podocin gene It encodes the podocin protein Podocin is a 383-amino acid lipid-raft-associated protein localized at the slit diaphragm where it is required for the structural organization and regulation of the glomerular filtration barrier Its interaction with other slit diaphragm proteins eg nephrin NEPH1 CD2AP and TRPC6 is important in mechanosensation signaling podocyte survival cell polarity and cytoskeletal organization
It has been reported that variants in the NPHS2 gene are associated with NS
The commonly studied rs61747728 NPHS2 gene polymorphism also known as pR229Q has been reported to be associated with NS and SRNS
However others have failed to report an association which might be due to population differences
The rs61747728 is a non-synonymous variant found on exon 5 which is suggested to be involved in in altering the functional properties of podocin in vitro and possibly in vivo
The investigators will therefore investigate the frequency of the pR229Q variant in Middle East patients with NS
Genetic analysis will have important implications in several aspects-
1 Understanding the biology of the disease in this part of the world
2 Counselling patients about their clinical course and what medication they will respond to
3 Counselling patients about the possibility of a kidney transplant sooner in their disease course
Detailed Description:
Aim of the work
The aim of this study is
1 To identify any relationship between NPHS2 gene mutations and NS in children and adults in Middle East
2 To study the relationship of mutations in this gene with the clinical presentation clinical coarse and response to treatment in these patients and compare it with patients without mutations in this gene
3 To compare our results with similar data from other World populationsethnic groups
4 To share our results with the treating clinicians so that counselling of the patients can be done in terms of treatment prognosis and family screening
Anticipated outcome and benefit
With the increasing number of patients with NS in Middle East and the higher number of consanguineous marriages as compared to other societies the investigators are sure that many gene mutations will be uncovered that may be the same as the previously reported genes or new novel genes
In either case the investigators would have studied the genetic predisposition in our patient population and helped the nephrologists in taking appropriate treatment decisions
The investigators expect a total of 150 patients with NS in both children and adults About 20 will be from the pediatric population with MCD while about 80 will be adults with predominantly FSGS
Patient Recruitment
This study will include patients referred to the nephrology departments in the major hospitals in Kuwait- MubarakAmiriFarwaniya Adan and Jahra Hospitals Both children and adults of all ages
This study will also include patients referred to the nephrology departments in Assuit university hospitals and all Upper Egypt hospitals Both children and adults of all ages
Procedures
Saliva and blood sampling and DNA extraction
After obtaining informed consent from parents of children and adults 3 ml of blood will be collected from children and in the event that the patients or their parents refuse then buccal swabs will be collected from children and 5 ml of blood will be collected from adultsAll patients will be fully informed about the methods of blood sampling or buccal swabs and A written consent will be obtained from adult patients and parents of childrens The buccal swabs will be processed to extract DNA and stored at -20 till time of genetic analysis Peripheral blood samples will be collected in EDTA anticoagulated tubes and DNA will be extracted according to standard methods using QIAGEN DNA blood mini kit QIAGEN and stored at 20 till time of analysis
Genotyping
Genotyping of the NPHS2 variant rs61747728 will be performed by Real-time TaqMan Allelic Discrimination Assay Life technologies CA USA according to standard manufacturer protocols Allelic discrimination analysis will be performed and analyzed using ABI 7500 Fast Real-time PCR system SDS software Life technologies CA USA
Statistical analysis
Basic statistical analysis will performed using SPSS software version 22 SPSS Inc Chicago IL USA The genetic analysis will be performed using the SNPassoc package from R software
The aim of this study is
1 To identify any relationship between NPHS2 gene mutations and NS in children and adults in Middle East
2 To study the relationship of mutations in this gene with the clinical presentation clinical coarse and response to treatment in these patients and compare it with patients without mutations in this gene
3 To compare our results with similar data from other World populationsethnic groups
4 To share our results with the treating clinicians so that counselling of the patients can be done in terms of treatment prognosis and family screening
Anticipated outcome and benefit
With the increasing number of patients with NS in Middle East and the higher number of consanguineous marriages as compared to other societies the investigators are sure that many gene mutations will be uncovered that may be the same as the previously reported genes or new novel genes
In either case the investigators would have studied the genetic predisposition in our patient population and helped the nephrologists in taking appropriate treatment decisions
The investigators expect a total of 150 patients with NS in both children and adults About 20 will be from the pediatric population with MCD while about 80 will be adults with predominantly FSGS
Patient Recruitment
This study will include patients referred to the nephrology departments in the major hospitals in Kuwait- MubarakAmiriFarwaniya Adan and Jahra Hospitals Both children and adults of all ages
This study will also include patients referred to the nephrology departments in Assuit university hospitals and all Upper Egypt hospitals Both children and adults of all ages
Procedures
Saliva and blood sampling and DNA extraction
After obtaining informed consent from parents of children and adults 3 ml of blood will be collected from children and in the event that the patients or their parents refuse then buccal swabs will be collected from children and 5 ml of blood will be collected from adultsAll patients will be fully informed about the methods of blood sampling or buccal swabs and A written consent will be obtained from adult patients and parents of childrens The buccal swabs will be processed to extract DNA and stored at -20 till time of genetic analysis Peripheral blood samples will be collected in EDTA anticoagulated tubes and DNA will be extracted according to standard methods using QIAGEN DNA blood mini kit QIAGEN and stored at 20 till time of analysis
Genotyping
Genotyping of the NPHS2 variant rs61747728 will be performed by Real-time TaqMan Allelic Discrimination Assay Life technologies CA USA according to standard manufacturer protocols Allelic discrimination analysis will be performed and analyzed using ABI 7500 Fast Real-time PCR system SDS software Life technologies CA USA
Statistical analysis
Basic statistical analysis will performed using SPSS software version 22 SPSS Inc Chicago IL USA The genetic analysis will be performed using the SNPassoc package from R software
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None