Nephrotic Syndrome Study Network

Idiopathic Nephrotic Syndrome (NS) is a rare disease syndrome responsible for approximately
12% of all causes of end-stage kidney disease (ESRD) and up to 20% of ESRD in children.
Treatment strategies for Focal and Segmental Glomerulosclerosis (FSGS), Minimal Change
Disease (MCD) and Membranous Nephropathy (MN), the major causes of NS, include high dose
prolonged steroid therapy, cyclophosphamide, cyclosporine A, tacrolimus, mycophenolate
mofetil and other immunosuppressive agents, which all carry significant side effects. Failure
to obtain remission using the current treatment approaches frequently results in progression
to ESRD with its associated costs, morbidities, and mortality. In the North American
Pediatric Renal Trials and Collaborative Studies (NAPRTCS) registry, half of the pediatric
patients with Steroid Resistant Nephrotic Syndrome required renal replacement therapy within
two years of being enrolled in the disease registry. FSGS also has a high recurrence rate
following kidney transplantation (30-40%) and is the most common recurrent disease leading to
allograft loss.

The prevailing classification of Nephrotic Syndrome categorizes patients into FSGS, MCD, and
MN, if in the absence of other underlying causes, glomerular histology shows a specific
histological pattern. This classification does not adequately predict the heterogeneous
natural history of patients with FSGS, MCD, and MN. Major advances in understanding the
pathogenesis of FSGS and MCD have come over the last ten years from the identification of
several mutated genes responsible for causing Steroid Resistant Nephrotic Syndrome (SRNS)
presenting with FSGS or MCD histopathology in humans and model organisms. These functionally
distinct genetic disorders can present with indistinguishable FSGS lesions on histology
confirming the presence of heterogeneous pathogenic mechanisms under the current histological
diagnoses.

The limited understanding of FSGS, MCD, and MN biology in humans has necessitated a
descriptive classification system in which heterogeneous disorders are grouped together. This
invariably consigns these heterogeneous patients to the same therapeutic approaches, which
use blunt immunosuppressive drugs that lack a clear biological basis, are often not
beneficial, and are complicated by significant toxicity. The foregoing shortcomings make a
strong case that concerted and innovative investigational strategies combining basic science,
translational, and clinical methods should be employed to study FSGS, MCD, and MN. It is for
these reasons that the Nephrotic Syndrome Study Network is established to conduct clinical
and translational research in patients with FSGS/MCD and MN.

Cohort A (biopsy cohort) Inclusion Criteria:

Patients presenting with an incipient clinical diagnosis for FSGS/MCD or MN or pediatric
participants not previously biopsied, with a clinical diagnosis for FSGS/MCD or MN meeting
the following inclusion criteria:

- Documented urinary protein excretion ≥1500 mg/24 hours or spot protein: creatinine
ratio equivalent at the time of diagnosis or within 3 months of the
screening/eligibility visit.

- Scheduled renal biopsy

Cohort B (non-biopsy, cNEPTUNE) Inclusion Criteria:

- Age <19 years of age

- Initial presentation with <30 days immunosuppression therapy

- Proteinuria/nephrotic

- UA>2+ and edema OR

- UA>2+ and serum albumin <3 OR

- UPC > 2g/g and serum albumin <3

Exclusion Criteria (Cohort A&B):

- Prior solid organ transplant

- A clinical diagnosis of glomerulopathy without diagnostic renal biopsy

- Clinical, serological or histological evidence of systemic lupus erythematosus (SLE)
as defined by the ARA criteria. Patients with membranous in combination with SLE will
be excluded because this entity is well defined within the International Society of
Nephrology/Renal Pathology Society categories of lupus nephritis, and frequently
overlaps with other classification categories of SLE nephritis (68)

- Clinical or histological evidence of other renal diseases (Alport, Nail Patella,
Diabetic Nephropathy, IgA-nephritis, monoclonal gammopathy (multiple myelomas),
genito-urinary malformations with vesico-urethral reflux or renal dysplasia)

- Known systemic disease diagnosis at time of enrollment with a life expectancy less
than 6 months

- Unwillingness or inability to give a comprehensive informed consent

- Unwillingness to comply with study procedures and visit schedule

- Institutionalized individuals (e.g., prisoners)