Study of The Association of Mutations in The NPHS2 Gene and Nephrotic Syndrome in Children and Adults in Middle East

January 9, 2019 updated by: AHMED ABDULQADER HAMMOUDA ABOU SHALL

Nephrotic syndrome (NS) represents one of the most common diagnoses in pediatric and adult nephrology, with a prevalence of 16 per 100,000 children and 3 per 100,000 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 .

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It has been reported that variants in the NPHS2 gene are associated with NS .

The commonly studied rs61747728 NPHS2 gene polymorphism also known as p.R229Q 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 p.R229Q 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

Study Overview

Status

Unknown

Conditions

Intervention / Treatment

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 populations/ethnic 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- Mubarak,Amiri,Farwaniya, 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 adults.All 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 Type

Observational

Enrollment (Anticipated)

150

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Kuwait
      • Ḩawallī, Kuwait, 24923Safat13110
        • Faculty of Medicine-Pathology Department

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

2 years to 50 years (Child, Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Sampling Method

Non-Probability Sample

Study Population

This study will include patients referred to the nephrology departments in the major hospitals in Kuwait- Mubarak,Amiri,Farwaniya, 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

Description

Inclusion Criteria:

  • Inclusions criteria in children:

All children who presented with acute onset of heavy proteinuria (>3 g/24hrs).

If a biopsy was performed then only a diagnosis of MCD or FSGS will be included after performing light microscopy, immunofluorescence or immunoperoxidase testing and electron microscopy. These studies will be reviewed by the primary investigator.

If a biopsy is not performed as is the case with many children, then the clinical and serological parameters should be consistent with MCD or FSGS as evidenced by the negativity of autoimmune and infectious markers.. The cut off age used in referring patients to adult nephrologists is 16 years.

Inclusions criteria in adults :

All patients with proteinuria of acute or gradual onset but has to be more than 1g/24hrs. A biopsy must have been performed and reviewed by the primary investigator and the results should be MCD/FSGS after applying all the aforementioned pathological studies.

Exclusion Criteria:

  • 1) All patients diagnosed as MCD secondary to:-

    1. Drugs:NSAIDs (most common), antimicrobials, lithium, bisphosphonates, and penicillamine (many others).
    2. Cancer:haematological malignancies (most common), solid organ malignancies (rarely associated with MCD).
    3. Infections:(rarely):esp.TB,syphilis,HIV, HCV, mycoplasma.
    4. Atopy:30% of MCD patients.

    5. Immunizations.

      2) All patients diagnosed as FSGS secondary to:-

    1. Infection (podocyte invasion): HIV-associated nephropathy (HIVAN) , Parvovirus B19.
    2. Drugs (podocyte toxicity): Pmidronate, lithium, interferon, and heroin.
    3. Congenital or acquired nephron mass reduction: Renal dyplasia, reflux nephropathy, renovascular disease, partial or unilateral nephrectomy.
    4. Hyperfiltration as part of disease process: Morbid obesity, diabetic nephropathy, pre-eclampsia, sickle cell disease.
    5. Any cause of glomerular disease with progressive scarring: Eg. Membranous GN, IgAN, Alport syndrome, thrombotic microangiopathy, vasculitis.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Observational Models: Cohort
  • Time Perspectives: Prospective

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Number of participants achieving NPHS2 gene mutations (frequency of p.R229Q polymorphic site) in patients with steroid-resistant nephrotic syndrome in comparison with steroid - sensitive nephrotic syndrome
Time Frame: Baseline to 2 years

participants will be monitored for up to 2 years and classified as steroid -sensitive nephrotic syndrome or steroid - resistant nephrotic syndrome according to clinical response to steroid therapy ( 1 mg prednisolone /kg) for total 6 weeks.

Renal biopsy will be done for all patients above 5 years of age (MCD and FSGS) were included.

Blood sample or buccal swab will be collected from all patients and genotyping of the NPHS2 gene variant will be performed to report number of participants with NPHS2 gene mutations to share our results with the treating clinicians so that counselling of the patients can be done in terms of advising for kidney transplant sooner in their clinical course, prognosis and family screening.
Baseline to 2 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

AHMED ABDULQADER HAMMOUDA ABOU SHALL

Collaborators

Assiut University
Kuwait University

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

October 1, 2016

Primary Completion (Anticipated)

October 1, 2019

Study Completion (Anticipated)

June 1, 2020

Study Registration Dates

First Submitted

October 22, 2017

First Submitted That Met QC Criteria

October 27, 2017

First Posted (Actual)

October 30, 2017

Study Record Updates

Last Update Posted (Actual)

January 10, 2019

Last Update Submitted That Met QC Criteria

January 9, 2019

Last Verified

January 1, 2019

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • MG03/15

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

Undecided

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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