The Nephrotic Syndrome Study Network (NEPTUNE)

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 (1). 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.

- INCLUSION CRITERIA

Inclusion Criteria for the FSGS/MCD Cohort

- A new diagnosis of FSGS or MCD according to characteristic light, electron (EM), and
immunofluorescence microscopy (IM), with presence of at least five glomeruli per
biopsy available for analysis. Biopsy slides will be reviewed and diagnosis confirmed
by 2 study pathologists according to standardized criteria developed by the pathology
committee;

- Documented urinary protein excretion greater than or equal to 500 mg/24 hours or spot
protein: creatinine ratio equivalent at the time of diagnosis or within 3 months of
the screening/eligibility visit.

Inclusion criteria for the MN Cohort

- A new diagnosis of MN according to characteristic light, electron (EM), and
immunofluorescence microscopy (IM), with presence of diagnostic changes in at least
one glomerulus per biopsy. Biopsy slides will be reviewed and diagnosis confirmed by
2 study pathologists according to standardized criteria developed by the pathology
committee

- Documented urinary protein excretion greater than or equal to 500 mg/24 hours or spot
protein: creatinine ratio equivalent at the time of diagnosis or within 3 months of
the screening/eligibility visit.

Inclusion criteria for the OG Cohort

- A new diagnosis of glomerulopathy according to characteristic light, electron (EM),
and immunofluorescence microscopy (IM), with presence of diagnostic changes in at
least one glomerulus per biopsy. Biopsy slides will be reviewed and diagnosis
confirmed by 2 study pathologists according to standardized criteria developed by the
pathology committee;

- Documented urinary protein excretion greater than or equal to 500 mg/24 hours or spot
protein:creatinine ratio equivalent at the time of diagnosis or within 3 months of
the screening/eligibility visit.

EXCLUSION CRITERIA

Exclusion criteria for the FSGS/MCD and MN Cohorts

- Prior solid organ transplant

- A clinical diagnosis of FSGS/MCD or MN 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

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

- Known systemic disease diagnosis at time of enrollment with 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)

- Laboratory information unavailable prior to consent and biopsy procedure subsequently
supporting exclusion criteria will deem a participant ineligible.

Exclusion Criteria for the Other Glomerulopathies

- 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

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

- Laboratory information unavailable prior to consent and biopsy procedure subsequently
supporting exclusion criteria will deem a participant ineligible.