Nephrotic Syndrome

Clinician Information

Idiopathic Nephrotic Syndrome can broadly be classified as Steroid Sensitive (SSNS) or Steroid Resistant (SRNS) and is rare in children and adults. Many of these cases, especially in early childhood, are genetic. The Nephroptic Syndrome Rare Disease Group has been based from the start around a research study. It therefore collects not just information, but also some extra samples from patients recruited into RaDaR, and it therefore requires extra consent from participants.

The research group is based in Bristol. The aim is to correlate the epidemiological and clinical features of SSNS and SRNS including FSGS (Focal Segmental GlomeruloSclerosis) and to develop biomarkers of disease activity post transplantation. Initially the project was designed to focus exclusively on FSGS, however, in order to be more inclusive and with the advent of a European Registry of Nephrotic Syndrome it seemed prudent to encompass all Idiopathic Nephrotic Syndromes which might allow for easier collaboration at a later date. Rather than a leading hypothesis, the central aims of this study are: To identify and develop a cohort of adults and children in the UK with SSNS/SRNS and to perform whole genome sequencing analysis. To provide a comprehensive genotype/phenotype correlation of the disease, in a substantial cohort of patients. The results of the genetic analysis will be returned to the patient’s clinician. To answer the question of whether and to what degree post-transplant recurrence of Nephrotic Syndrome is a heterogeneous disease, seen at the level of the cellular response. To provide the basis for a predictive in vitro test for patients who will suffer recurrence of the disease post-transplantation. The project will utilise data collected by RaDaR on every adult and child in the UK with Nephrotic Syndrome and analyse it for patterns, particularly clinical parameters on diagnosis that may predict future outcome. Each patient consented will be offered whole genome sequencing as part of the BioResource study (see below) to look for the gene mutations currently associated with Nephrotic Syndrome. Patients will have blood samples taken at baseline, at times of relapse and remission and (if applicable), pre- and post- operatively (immediately after, -6, -12 and -18 months after) to look for biomarkers of disease and their correlation to disease recurrence post transplantation. Finally, for those patients who suffer disease recurrence post transplantation and undergo plasma exchange, samples of plasma will be taken whilst in disease recurrence and then again in remission to compare for the presence of biomarkers of disease. The following resources are designed to help with recruitment to NephroS: NephroS Study background information NephroS Study data entry guidelines NephroS Study consent forms and information sheets

Seven genes had been identified when the research proposal was first written in 2009 but this is increasing all the time – as of April 2016 there are over 50 genes associated with SRNS. The NephroS Study consent has been specifically written so that the samples can be utilised at a later date to test for any new genes. It is expected that approximately 20-25% of sporadic cases of childhood FSGS will have an identifiable gene mutation. However in Nephrotic Syndrome as a whole it is expected that this number may be less in those above the age of two at onset. However this is an exciting opportunity to test a large cohort of patients to tell us more about prevalence of these gene abnormalities in the UK population. It also affords the opportunity to look for heterozygous sequence variants, digenic inheritance (2 separate genes affected) in greater detail as well as to discover new genes and gene variants that cause the disease or predict response to particular treatments Any genetic abnormalities found within genes known to cause Nephrotic Syndrome will be fed back to the patients via their nephrologist as soon as results become available. However, if the outcome of genetic results is urgent – please contact the North Bristol Genetics Lab who can provide an SRNS gene panel service (see here for details).

The NIHR BioResource – Rare diseases has been established to identify genetic causes of rare diseases. Upon further consent from patients/their parents, DNA from NephroS samples will be shared with BioResource. This will allow whole genome sequencing using next generation sequencing techniques. Results are accessible to the NephroS study team and any mutations found will be confirmed. Reports will be sent out to the Nephrologist to discuss with the patient. For more information about the BioResource please click here

In 1974 Robert Shalhoub was the first to postulate the theory of a circulating factor inducing nephrosis in Nephrotic Syndrome. He postulated that abnormal T-cell function resulted in the secretion of a ‘circulating chemical mediator’, which was toxic to the Glomerular Basement Membrane (GBM) (Shalhoub. 1974. Lancet. 2(7880); 556-60.). The circulating theory is reinforced clinically by the high risk of disease recurrence post-transplant, the reduction in proteinuria following plasma exchange in post-transplant recurrence and the in-vitro finding that disease plasma induces nephrotic changes in cultured podocytes. A large part of the research effort is in order to discover the ‘factors’ in circulating blood plasma that are responsible for causing a large proportion of Nephrotic Syndrome cases. The main aspects of the work are: Establish the components in circulating blood plasma that cause damage to the podocyte cell. We have identified a group of proteins that cause specific effects on the podocyte, and are actively seeking and collecting plasma samples from patients with active disease in order to extend and validate these findings. We are simultaneously looking at the effect of these plasma proteins on specific ‘pathways’ within the podocyte that become active in disease states. This would allow targeted therapies to be tried that can block the activity of these pathways, and thereby reverse the damage to the podocyte. We have developed an active academic collaboration with an Industrial partner company, which allows us to test candidate compounds in a high throughput fashion, which can reverse the pathological effects we discover in podocytes.


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