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Familial Nephrotic Syndrome and FSGS

Welcome to the Familial Nephrotic Syndrome Study Homepage at Children's Hospital of Pittsburgh and the University of Pittsburgh. This project aims to identify the gene or genes responsible for familial nephrotic syndrome and focal segmental glomerulosclerosis. Click on the links below for information about the genetics of nephrotic syndrome, frequently asked questions about this condition and previous investigations into the genetic aspects of nephrotic syndrome. It is our hope that a new understanding of the genetic basis of nephrotic syndrome will provide insight into its treatment and contribute to early identification of individuals at risk.

Participation in the Study
Frequently Asked Questions about Nephrotic Syndrome
Genetics of Familial Nephrotic Syndrome and FSGS
Prior Investigations and References
Links to Related Genetics and Nephrotic Syndrome Web Pages
Update on Related Research at Children's Hospital

Participation in the Study

ONLY families with TWO or MORE individuals diagnosed with PRIMARY nephrotic syndrome are eligible to participate in this study. Participation is, of course, entirely voluntary. If a family elects to participate, individual family members may refuse to participate. Participants can withdraw from the study at any time. The study involves telephone interviews with several family members during which information about the family’s history would be collected. In addition, blood samples from family members both with and without nephrotic syndrome would be requested. You may contact us using the information below for details about the study and eligibility requirements.

If you and at least one other family member have been diagnosed with nephrotic syndrome, focal segmental glomerulosclerosis (FSGS) or minimal change disease (MCD) and you would like more information on how to become involved in this study, please contact:

Dr. Abhay Vats, the Division of Pediatric Nephrology, at the address or phone number below or Alice Nayak, family studies coordinator, at the email address listed below:

Familial Nephrotic Syndrome Study
Children's Hospital of Pittsburgh of UPMC
Division of Pediatric Nephrology
4401 Penn Avenue, Floor 3
Pittsburgh, PA 15224

Phone: 412-692-5182
Fax: 412-692-7443
Alice Nayak, anayak@yahoo.com
Abhay Vats, MD, Abhay.Vats@chp.edu

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Frequently Asked Questions about Nephrotic Syndrome

What is nephrotic syndrome?

Nephrotic syndrome is a condition in which kidneys lose a large amount of protein in the urine causing the blood levels of various proteins to fall. If left untreated, this generally leads to swelling, first, around the eyes and, later, all over the body.

What causes nephrotic syndrome?
The cause for nephrotic syndrome is not known, but there may be a genetic susceptibility to certain types of nephrotic syndromes. A number of kidney diseases may be associated with nephrotic syndrome. Although, nephrotic syndrome may be seen as a part of other more complex diseases like lupus, HSP, or IgA nephropathy, it usually occurs in isolation.

What are the complications of this disease?
Among the various proteins lost in the urine are certain proteins required to fight infections and proteins that prevent blood from clotting. Hence, two of the important complications of this disease are an increased risk of infections and of clot formation within the blood vessels, which may affect the blood supply to one or more organs such as the lungs or kidneys. You must inform your physician if your child comes in contact with any infectious disease, such as chicken pox, develops a fever or has sudden onset of difficulty breathing or blood in his or her urine.

How is nephrotic syndrome treated?
The standard treatment for nephrotic syndrome is a steroid (prednisone) trial. In most children with nephrotic syndrome, steroids cause a prompt improvement in the symptoms of the disease (which is called remission). The dose and duration of prednisone depends on the weight and size of the child, as well as his or her clinical condition and, if applicable, previous response to steroids. In general, steroids are taken for a few weeks, even after the symptoms have resolved, and then gradually tapered. It is important that you follow the exact directions of your physician and not discontinue or change the dose without discussing it first, otherwise your child may be at increased risk for recurrence or other complications.

Is the treatment of nephrotic syndrome a permanent cure?
Although steroids are effective in a majority of children with this disease, they do not cure the condition. Your child is likely to have further episodes of nephrotic syndrome (called relapses) especially following infections such as the common cold, even though a minority of children with this condition have only one episode. You will be required to assess the response of your child to treatment by checking urine protein levels periodically by special strips that are dipped in urine called dipsticks. A child is having a relapse if the urine protein is 3 + or more for three days in a row. Similarly, the child is in remission if the urine protein is trace or negative for three or more days.  It is important to record when your child's treatment is started or changes are made, the response to the treatment, and whenever your child goes into a remission or is having a relapse.

Are there any side effects of steroids?
Long term steroid treatment can be associated with various side effects which include: excessive weight gain especially on the cheeks, upper back and abdomen, mood swings, acne, facial hair, thinning of skin and appearance of stretch marks, abdominal pain, vomiting and high blood pressure. Sometimes an antacid or a blood pressure lowering medicine may be required. In the long term, steroids can also cause growth retardation and cataracts.

Are there any other medicines besides steroids that can be tried?
In certain instances, medicines other than steroids may be given (usually in addition to steroids) if your child is not responding to steroids or is requiring high dose steroids on a prolonged basis. The alternative medications that have been used in this disease include cyclosporine, FK 506, levamisole, and cyclophosphamide (Cytoxan) among others. A kidney biopsy is usually performed before any of these alternative medications are tried.

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Genetics of Familial Nephrotic Syndrome and FSGS

Nephrotic syndrome affects millions of individuals worldwide. Although nephrotic syndrome is usually sporadic, familial cases have been described with both autosomal dominant and recessive forms of inheritance. Thus, identification of the gene or genes involved in primary idiopathic nephrotic syndrome could provide insight into the cause of the disease, as well as new treatment strategies.

Genes and Nephrotic Syndrome
Although the cause of primary nephrotic syndrome is not understood, it is generally thought to be due to an abnormality of the filtering units of the kidney called glomerulus. The incidence of primary nephrotic syndrome is variable and depends upon the ethnic background, which suggests a genetic tendency. The African-American population is especially susceptible to a particularly severe form of nephrotic syndrome called focal segmental glomerulosclerosis (FSGS). A particular type of nephrotic syndrome called congenital nephrotic syndrome of Finnish type (CNF) is especially common in the Finnish population and is a distinct entity. Since age of onset is variable, primary nephrotic syndrome can be categorized according to this criterion as well as the underlying kidney pathology. Primary nephrotic syndrome symptoms can begin at birth (congenital), in childhood, or in adulthood.

Isolated familial nephrotic syndrome can exhibit dominant or recessive inheritance. The dominantly inherited primary nephrotic syndrome usually involves older persons and progresses slowly. Recessive forms of nephrotic syndrome have also been described and are usually more severe.

Dominant and Recessive Inheritance
Except for genes on the sex-determining chromosomes, both men and women have two copies of each gene. If only one changed copy of a gene causes a condition, the condition will be inherited in what is called a dominant pattern. Dominant disorders are ones that run from generation to generation. If an individual has a dominant condition, the chance of transmitting the gene to a child is 1 in 2 or 50% with each pregnancy. These odds are the same as getting “heads” in a coin toss. However, not everyone with the gene for this form of nephrotic syndrome may actually develop symptoms. Therefore, even if a child does not inherit nephrotic syndrome from a parent, he or she may still have inherited the gene and pass the gene and nephrotic syndrome on to his or her child.

Not every individual with primary nephrotic syndrome has other family members with the same condition. If neither of an individual’s parents has nephrotic syndrome, there are several explanations for why the condition has occurred. The first possibility is that one parent may have the changed gene, but for some reason shows no symptoms. This is called reduced penetrance because the gene has no effect on one individual, but a noticeable affect on another. The second explanation for the presence of a condition in an individual, but not in his or her parents, is that a new change, called a mutation, has occurred in that individual (in the single sperm or egg) which caused the condition. There would then still be a 1 in 2 or 50% chance for that person to pass the new change on to his or her own children. A third explanation could be that the disease is being transmitted as a recessive condition.

A recessive inheritance pattern requires that each parent have a defective copy of the gene. If an individual with this type of inheritance pattern has one defective copy, they do not have symptoms of the disease. However, if two individuals with one defective copy each pass the defective copy to their child, the child has two defective copies of the gene and will exhibit symptoms of the disease. When both parents carry the defective gene, each child has about 25% chance of being affected by the disease.

We hope a new understanding of the genetic basis of inherited nephrotic syndrome will provide insight into its treatment and contribute to early identification of individuals at risk.

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Prior Investigations and References 

Prior Investigations
Massive proteinuria, hypoalbuminemia and edema characterize idiopathic nephrotic syndrome (NS). Renal biopsy in children who respond to steroids usually shows minimal change disease, which is usually associated with a favorable prognosis [1]. Conversely, steroid non-responsive NS has poorer prognosis and is more frequently associated with diseases such as focal segmental glomerulosclerosis (FSGS) and mesangioproliferative glomerulonephritis (GN) [1, 2]. Although minimal change disease is thought to be the most common cause of NS in children, there has recently been an increase in the incidence of FSGS among the pediatric NS population [3]. Progression from minimal change and mesangial proliferative GN to FSGS has been reported in both steroid responsive and non-responsive NS patients [2,4,5].

Idiopathic NS is generally regarded as a sporadic disease although congenital NS of the Finnish type (CNF) is a well-recognized heritable form of NS. Recently, both autosomal dominant and recessive forms of familial idiopathic NS have been identified [6-10]. The reported autosomal dominant forms of NS are generally less severe than the recessive forms. Although the histopathology of familial NS patients has primarily shown FSGS, the clinical features of these patients show a wide range of clinical features including age at presentation and progression to ESRD. Hence, elucidation of genetic factors associated with various heritable forms of NS will allow greater understanding of etiopathogenesis and possibly lead to a more robust classification and new therapeutic approaches.

Recently, linkage analysis has been reported in two large pedigrees with autosomal dominant NS where the primary pathology was FSGS. Mathis et al first reported a kindred from Oklahoma with linkage to a narrow region on chromosome 19q13 [7, 8]. This region also includes the gene for CNF [11]. However, Winn etal. excluded linkage to the same locus in a large family from New Zealand with similar disease and inheritance pattern [10] suggesting genetic heterogeneity. Recently, we have identified a family with autosomal dominant NS with significantly different clinical and histopathological features in which the trait maps to chromosome 19q13 confirming the findings of Mathis et al.

With the help of additional families we hope to further define the gene(s) responsible for NS, which would lead to a greater understanding of the pathologic mechanism causing nephrotic syndrome.

References
Many of these references may be found by using PubMed literature search:

1. Schnaper HW, Robson AM: Nephrotic syndrome:
Minimal change disease, focal glomerulosclerosis and related disorders, in Diseases of the Kidney: Fifth Edition, edited by Schrier RW, Gottschalk CW, Boston, Little, Brown and Company, 1993, p. 1731-1784

2. Korbet SM:
Primary focal segmental glomeruosclerosis. J Am Soc Nephrol 9:1333-1340, 1998

3. Bonilla-Felix M. Panca C, Dajani T, Ferris M, Swinford RD, Portman RJ, Verani R:
Changing patterns in the histopathology of idiopathic nephrotic syndrome in children. Kidney Int 55:1885-1889, 1999

4. Tejani A:
Morphologic transition in minimal change nephrotic syndrome. Nephron 39:157-159, 1985

5. Nash MA, Bakare MA, D'Agati V, Pirani CL:
Late development of chronic renal failure in steroid responsive nephrotic syndrome. J Pediatr 101:411-414, 1982

6. Fuchshuber A, Jean G, Gribouval O, Gubler MC, Broyer M, Beckmann JS, Niaudet P, Antignac C:
Mapping a gene (SRN1) to chromosome 1q25-31 in idiopathic nephrotic syndrome confirms a distinct entity of autosomal recessive nephrosis. Hum Mol Gen 4: 2155-2158, 1995

7. Mathis BJ, Calabrese KE, Slick GL:
Familial glomerular disease with asymptomatic proteinuria and nephrotic syndrome: A new clinical entity. J Am Osteopath Assoc 92: 875-884, 1992

8. Mathis BJ, Kim SH, Calabreses MH, Seidman JG, Seidman CE, Pollack MR:
A locus for inherited focal segmental glomerulosclerosis maps to chromosome 19q13. Kidney Inl 53: 282-286, 1998

9. Conlon PJ, Butterly D, Albers F, Rodby R, Gunnells JC, Howell DN:
Clinical and pathologic features of familial focal segmental glomerulosclerosis. Am. J. Kidney Dis. 26: 34-40.

10. Winn MP, Conlon PJ, Lynn KL, Howell DN, Gross DA:
Clinical and Genetic heterogeneity in familial focal segmental glomerulosclerosis. Kidney Int 55: 1241-1246, 1998

11. Kestila M, Lenkkeri U, Manniko M, Lamerdin J, McCready P, Putaala H, routsalainen V, Morita T, Nissinen M, Herva R, Kashtan CE, Peltonen L, Holmberg C, Olsen A, Tryggvason K:
Positionally cloned gene for a novel glomerular protein - nephrin - is mutated in congenital nephrotic syndrome. Molecular Cell 1:575-582, 1998

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Links to Related Genetics and Nephrotic Syndrome Web Pages

National Institutes of Health
PubMed: A Medical Literature search engine
Internet Nephrology Resources – A comprehensive kidney information resource

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Update on Related Research at Children's Hospital

Abhay Vats, MD, Pediatric Nephrology, is working in conjunction with Demetrius Ellis, MD, Pediatric Nephrology, David N. Finegold, MD, Endocrinology and Human Genetics, and Robert E. Ferrell, PhD, Human Genetics at the University of Pittsburgh, to determine the genetic basis of primary inherited nephrotic syndrome. Alice Nayak is the Family Studies Coordinator for this project. The purpose of this study is to investigate the genetics of familial nephrotic syndrome using several families in which multiple members have been diagnosed with nephrotic syndrome.

The Familial Nephrotic Syndrome Study aims to determine how nephrotic syndrome is inherited in families. Our hope is that identification of the genes responsible for familial nephrotic syndrome will provide a better understanding of its cause, and aid in the development of new and better methods for diagnosing and treating nephrotic syndrome. The Familial Nephrotic Syndrome Study is a linkage study. Linkage analysis involves a comparison of genetic material between family members with and without nephrotic syndrome. This allows the identification of markers on a chromosome that is associated with a gene responsible for nephrotic syndrome. These markers indicate the chromosomal location of that gene.

We are currently examining the various inheritance patterns of familial nephrotic syndrome. At this time we are recruiting families with at least two or more affected members with both autosomal dominant and autosomal recessive inheritance [Link to Genetics of Familial Nephrotic Syndrome and FSGS] patterns. Family participation in the study is voluntary and includes answering questions regarding their medical and family history and supplying a blood sample (~ 10 cc) for DNA extraction.

We have recently ascertained a large family with autosomal dominant nephrotic syndrome in which the trait maps to chromosome 19q13. The affected family members presented with pathologic features ranging from minimal change disease to focal segmental glomerulosclerosis (FSGS).

We are continuing to collect blood samples from families participating in the study as well as new families. For both affected and non-affected family members unable to visit Children's Hospital of Pittsburgh, we mail a blood collection kit to your home so you may have your blood drawn locally. Therefore, those individuals interested in participation are encouraged to send in their kits if they already have them, call to request new ones if necessary, or contact Alice Nayak or Dr. Abhay Vats if your family is not yet participating, but would like to. Some family members will be invited to have additional blood and urine tests preformed. These tests will be used to determine the severity of nephrotic syndrome in affected individuals and to determine if any family members without obvious nephrotic syndrome have any other kidney disorders. If you are invited to participate in this testing, the Familial Nephrotic Syndrome Study will cover the expenses involved with testing.

We would like to remind you that this is a research study, and therefore, we cannot guarantee that any information will be available to individual families or participants. This study does not provide diagnosis or treatment of nephrotic syndrome, and may not result in any direct benefit to the participants. However, it is our hope that it will benefit nephrotic syndrome patients in the future. Also, as genes are identified and proven to be responsible for causing familial nephrotic syndrome in specific families, we will contact the participating family members to inform them of this finding and discuss the impact of this information on them and their family. In addition, the participation of families and family members is voluntary and confidential. Advances in understanding the underlying cause of familial nephrotic syndrome are critically dependent on the participation of individuals and families in our research. Should you have any questions or concerns about this information or the study in general, please don’t hesitate to call or contact Alice Nayak or Dr. Abhay Vats using the information listed on the Familial Nephrotic Syndrome Study home page.

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Last Update
July 30, 2011
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Last Update
July 30, 2011
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