Clinical trial NCT01209000: Nephrotic Syndrome Study Network
Official title: Nephrotic Syndrome Study Network Under the Rare Diseases Clinical Research Network
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Minimal Change Disease (MCD)
Membranous Nephropathy
Glomerulosclerosis, Focal Segmental
Keywords: Focal and Segmental Glomerulosclerosis
Focal & Segmental Glomerulosclerosis
Focal Segmental Glomerulosclerosis
FSGS
Minimal change disease
MCD
Membranous Nephropathy
MN
Nephrotic Syndrome
Neph Syndrome
NEPTUNE
NephCure
Halpin
Lead sponsor: University of Michigan
Sponsor class: OTHER
Collaborators: name: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
name: The NephCure Foundation
First posted: 2010-09-24
Enrollment: 1200
Sex: ALL
Maximum age (years): 80
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Patients with signs and symptoms of kidney disease consistent with FSGS, MCD, MN or proteinuric renal disease or pediatric participants not previously biopsied, who present for patient care at participating clinical centers will be eligible for Cohort A (biopsy cohort) study population targeted for enrollment into the NEPTUNE study.

To establish a cohort of pediatric participants with incident nephrotic syndrome, Cohort B, a non-biopsy cohort has been initiated for Protocol V4.0. This population, \<19 years of age, presenting for nephrotic syndrome and less than 30 days of immunosuppression therapy exposure, will also be targeted for enrollment into the cNEPTUNE study.

Potential participants willing to receive their initial care and subsequent follow-up study visits at one of these sites are welcome to participate.

Brief summary: Minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS), and Membranous nephropathy (MN), generate an enormous individual and societal financial burden, accounting for approximately 12% of prevalent end stage renal disease (ESRD) cases (2005) at an annual cost in the US of more than $3 billion. However, the clinical classification of these diseases is widely believed to be inadequate by the scientific community. Given the poor understanding of MCD/FSGS and MN biology, it is not surprising that the available therapies are imperfect. The therapies lack a clear biological basis, and as many families have experienced, they are often not beneficial, and in fact may be significantly toxic. Given these observations, it is essential that research be conducted that address these serious obstacles to effectively caring for patients.

In response to a request for applications by the National Institutes of Health, Office of Rare Diseases (NIH, ORD) for the creation of Rare Disease Clinical Research Consortia, a number of affiliated universities joined together with The NephCure Foundation the NIDDK, the ORDR, and the University of Michigan in collaboration towards the establishment of a Nephrotic Syndrome (NS) Rare Diseases Clinical Research Consortium.

Through this consortium the investigators hope to understand the fundamental biology of these rare diseases and aim to bank long-term observational data and corresponding biological specimens for researchers to access and further enrich.

Detailed description: 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.

Eligibility criteria: 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)

Primary outcomes:
measure: Event rate of change in urinary protein excretion and renal function.
timeFrame: 60 months
measure: Rate of change in renal function.
timeFrame: 60 months
Secondary outcomes:
measure: Quality of Life:
timeFrame: 60 months
measure: Malignancies
timeFrame: 60 months
measure: Infections, Serious and Systemic
timeFrame: 60 months
measure: Thromboembolic Events
timeFrame: 60 months
measure: Hospitalization
timeFrame: 60 months
measure: Emergency Department/ Observation Unit Visit
timeFrame: 60 months
measure: Acute Kidney Injury
timeFrame: 60 months
measure: Death
timeFrame: 60 months
measure: New Onset Diabetes
timeFrame: 60 months
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: University of Southern California-Children's Hospital
state: California
city: Palo Alto
country: United States
facility: Stanford University School of Medicine
state: California
city: San Francisco
country: United States
facility: University of California San Francisco Benioff Children's Hospitals
state: California
city: Torrance
country: United States
facility: Lundquist Biomedical Research Institute at Harbor UCLA Medical Center
state: California
city: Aurora
country: United States
facility: Children's Hospital Colorado
state: Colorado
city: Aurora
country: United States
facility: University of Colorado Anschutz School of Medicine
state: Colorado
city: Miami
country: United States
facility: University of Miami Miller School of Medicine
state: Florida
city: Atlanta
country: United States
facility: Emory University and Children's Healthcare of Atlanta
state: Georgia
city: Chicago
country: United States
facility: John Stroger Cook County Hospital
state: Illinois
city: Kansas City
country: United States
facility: University of Kansas Medical Center
state: Kansas
city: Baltimore
country: United States
facility: Johns Hopkins Medical Institute
state: Maryland
city: Bethesda
country: United States
facility: Kidney Disease Section, NIDDK, NIH
state: Maryland
city: Ann Arbor
country: United States
facility: CS Mott Children's Hospital, University of Michigan
state: Michigan
city: Ann Arbor
country: United States
facility: University of Michigan Medical Center
state: Michigan
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Kansas City
country: United States
facility: Children's Mercy Hospital
state: Missouri
city: Saint Louis
country: United States
facility: Washington University - St Louis
state: Missouri
city: Bronx
country: United States
facility: Montefiore Medical Center
state: New York
city: New Hyde Park
country: United States
facility: Cohen Children's Hospital
state: New York
city: New York
country: United States
facility: New York University Medical Center
state: New York
city: New York
country: United States
facility: Bellevue Hospital
state: New York
city: New York
country: United States
facility: New York University Veterans Administration
state: New York
city: New York
country: United States
facility: Columbia University Medical Center
state: New York
city: Chapel Hill
country: United States
facility: University of North Carolina at Chapel Hill
state: North Carolina
city: Charlotte
country: United States
facility: Atrium Health Levine Children's Hospital
state: North Carolina
city: Winston-Salem
country: United States
facility: Wake Forest School of Medicine
state: North Carolina
city: Cleveland
country: United States
facility: University Hospital Rainbow Babies & Children's Hospital
state: Ohio
city: Cleveland
country: United States
facility: MetroHealth Hospital at Case Western Medical Center
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
city: Columbus
country: United States
facility: The Ohio State University Wexner Medical Center
state: Ohio
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
city: Philadelphia
country: United States
facility: University of Pennsylvania
state: Pennsylvania
city: Philadelphia
country: United States
facility: Temple University
state: Pennsylvania
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: Dallas
country: United States
facility: University of Texas-Southwestern
state: Texas
city: Houston
country: United States
facility: Texas Children's Hospital - Baylor College of Medicine
state: Texas
city: Seattle
country: United States
facility: Seattle Children's Hospital
state: Washington
city: Seattle
country: United States
facility: University of Washington
state: Washington
city: Spokane
country: United States
facility: Providence Medical Research Center
state: Washington
city: Richmond Hill
country: Canada
facility: York Central Hospital
state: Ontario
city: Scarborough
country: Canada
facility: Scarborough Hospital
state: Ontario
city: Toronto
country: Canada
facility: Credit Valley Hospital
state: Ontario
city: Toronto
country: Canada
facility: Sunnybrook Hospital
state: Ontario
city: Toronto
country: Canada
facility: University Health Network
state: Ontario
Study officials:
affiliation: University of Michigan
name: Matthias Kretzler, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Wang CS, Troost JP, Wang Y, Greenbaum LA, Gibson K, Trachtman H, Srivastava T, Reidy K, Kaskel F, Sethna CB, Meyers K, Dell KM, Tran CL, Hingorani S, Lemley KV, Lin JJ, Gipson DS. Determinants of medication adherence in childhood nephrotic syndrome and associations of adherence with clinical outcomes. Pediatr Nephrol. 2022 Jul;37(7):1585-1595. doi: 10.1007/s00467-021-05176-8. Epub 2021 Nov 18.
citation: Solagna F, Tezze C, Lindenmeyer MT, Lu S, Wu G, Liu S, Zhao Y, Mitchell R, Meyer C, Omairi S, Kilic T, Paolini A, Ritvos O, Pasternack A, Matsakas A, Kylies D, Wiesch JSZ, Turner JE, Wanner N, Nair V, Eichinger F, Menon R, Martin IV, Klinkhammer BM, Hoxha E, Cohen CD, Tharaux PL, Boor P, Ostendorf T, Kretzler M, Sandri M, Kretz O, Puelles VG, Patel K, Huber TB. Pro-cachectic factors link experimental and human chronic kidney disease to skeletal muscle wasting programs. J Clin Invest. 2021 Jun 1;131(11):e135821. doi: 10.1172/JCI135821.
citation: Kang H, Kim DR, Jung YH, Baek CW, Park YH, In Oh J, Kim WJ, Choi GJ. Pre-warming the Streamlined Liner of the Pharynx Airway (SLIPA) improves fitting to the laryngeal structure: a randomized, double-blind study. BMC Anesthesiol. 2015 Nov 20;15:167. doi: 10.1186/s12871-015-0151-4.
citation: Hogan MC, Lieske JC, Lienczewski CC, Nesbitt LL, Wickman LT, Heyer CM, Harris PC, Ward CJ, Sundsbak JL, Manganelli L, Ju W, Kopp JB, Nelson PJ, Adler SG, Reich HN, Holzmann LB, Kretzler M, Bitzer M. Strategy and rationale for urine collection protocols employed in the NEPTUNE study. BMC Nephrol. 2015 Nov 17;16:190. doi: 10.1186/s12882-015-0185-3.