Cause of Focal Segmental Glomerulosclerosis

This study is currently recruiting participants. (see Contacts and Locations)
Verified May 2013 by National Institutes of Health Clinical Center (CC)
Sponsor:
Information provided by:
National Institutes of Health Clinical Center (CC)
ClinicalTrials.gov Identifier:
NCT00001392
First received: November 3, 1999
Last updated: March 14, 2014
Last verified: May 2013
  Purpose

The present protocol seeks to advance our understanding of glomerular diseases characterized by progressive glomerulosclerosis in the absence of established immune-mediated renal injury. To this end, we will enroll patients with primary podocytopathies (minimal change nephropathy, focal segmental glomerulosclerosis, collapsing glomerulopathy) and diabetic nephropathy, as well as patients with the clinical diagnosis (prior to renal biopsy) with one of these conditions. The protocol has three modules, with two consents and two assents. There is no ceiling on patient recruitment for modules 1 and 2. We want to recruit 16 patients for module 3.

  1. EVALUATION AND TREATMENT OF GLOMERULOSCLEROSIS: This protocol will serve as a screening protocol for specific treatment protocols. It will also allow us to provide second opinions about selected glomerular diseases, to collect research samples (blood, urine, and archival kidney tissue) and treat selected patients with renal disease using standard therapy. These studies will allow us to test particular hypotheses and may provide the opportunity to generate new hypotheses that could be tested in other protocols.
  2. RESEARCH RENAL BIOPSY IN PATIENTS WITH GLOMERULOSCLEROSIS: We will carry out renal biopsy for research purposes (limited to previously-diagnosed collapsing glomerulopathy) or to obtain additional renal tissue for research from a biopsy performed for clinical indications (includes diagnosed or suspected minimal change nephropathy, focal segmental glomerulosclerosis, collapsing glomerulopathy, diffuse mesangial sclerosis, and diabetic nephropathy). This tissue will be used for studies of the podocyte transcriptome, and other glomerular and tubular processes, and for studies to identify viral causes of primary podocyte diseases.
  3. Obesity-Associated Kidney Disease. We will collaborate with Dr. Mona Khurana in studies of lean and obese young adults carried out at Children s National Medical Center. We will assist her in the measurements of iothalamate and para-aminnohippurate clearance, in order to determine glomerular filtration rate and renal plasma flow.

Condition
AIDS Associated Nephropathy
Focal Glomerulosclerosis
HIV Infections

Study Type: Observational
Official Title: Pathogenesis of Glomerulosclerosis

Resource links provided by NLM:


Further study details as provided by National Institutes of Health Clinical Center (CC):

Estimated Enrollment: 99999999
Study Start Date: April 1994
Detailed Description:

The present protocol seeks to advance our understanding of glomerular diseases characterized by progressive glomerulosclerosis in the absence of established immune-mediated renal injury. To this end, we will enroll patients with primary podocytopathies (minimal change nephropathy, focal segmental glomerulosclerosis, collapsing glomerulopathy) and diabetic nephropathy, as well as patients with the clinical diagnosis (prior to renal biopsy) with one of these conditions. The protocol has four modules, with four consents and four assents. There is no ceiling on patient recruitment for modules 1 and 2. We want to recruit 16 patients for module 3 and 20 patients for module 4.

  1. EVALUATION AND TREATMENT OF GLOMERULOSCLEROSIS: This protocol will serve as a screening protocol for specific treatment protocols. It will also allow us to provide second opinions about selected glomerular diseases, to collect research samples (blood, urine, and archival kidney tissue) and treat selected patients with renal disease using standard therapy. These studies will allow us to test particular hypotheses and may provide the opportunity to generate new hypotheses that could be tested in other protocols.
  2. RESEARCH RENAL BIOPSY IN PATIENTS WITH GLOMERULOSCLEROSIS: We will carry out renal biopsy for research purposes (limited to previously-diagnosed collapsing glomerulopathy) or to obtain additional renal tissue for research from a biopsy performed for clinical indications (includes diagnosed or suspected minimal change nephropathy, focal segmental glomerulosclerosis, collapsing glomerulopathy, diffuse mesangial sclerosis, and diabetic nephropathy). This tissue will be used for studies of the podocyte transcriptome, and other glomerular and tubular processes, and for studies to identify viral causes of primary podocyte diseases.
  3. OBESITY-ASSOCIATED KIDNEY DISEASE. We will collaborate with Dr. Mona Khurana in studies of lean and obese young adults carried out at Children s National Medical Center. We will assist her in the measurements of iothalamate and para-aminnohippurate clearance, in order to determine glomerular filtration rate and renal plasma flow.
  4. PILOT STUDY OF RITUXIMAB PLUS CYCLOSPORINE IN FSGS. We will test this combination therapy in an open label phase 2 study involving up to 20 subjects who have failed to maintain a sustained remission first-line therapy with glucocorticoids or who have a compelling contraindication to the use of glucocorticoids, including diabetes mellitus, morbid obesity, or patient choice; patients may also have failed one or more additional immunosuppressive therapies. Therapy will involve up to two courses of rituximab and approximately 48 weeks of cyclosporine, followed by a taper. If the second course of rituximab is delayed, then the duration of cyclosporine exposure will be longer.
  Eligibility

Ages Eligible for Study:   4 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria
  • Module 1: EVALUATION AND TREATMENT OF GLOMERULOSCLEROSIS

INCLUSION CRITERIA:

Children of all ages and adults, including pregnant women, and impaired subjects, all with kidney disease. For pathogenetic studies, we will also include healthy volunteers, including children greater than 12 yrs of age and adults.

EXCLUSION CRITERIA:

None

Module 2: RESEARCH RENAL BIOPSY

  1. Clinically-indicated renal biopsy, with use of a portion of a second biopsy core for research.

    INCLUSION CRITERIA:

    All adults or children with past renal biopsy which demonstrated a glomerulosclerotic disease or in all adults or children without prior renal biopsy and clinical suspicion of glomerulosclerotic disease.

    EXCLUSION CRITERIA;

    Pregnant women.

  2. Clinically-indicated renal biopsy, obtaining a third biopsy core for research purposes.

    INCLUSION CRITERIA:

    All adults with past renal biopsy which demonstrated a glomerulosclerotic disease or in all adult patients without prior renal biopsy and high pre-test likelihood of a glomerulosclerotic disease.

    EXCLUSION CRITERIA:

    Pregnant women, patients with a single kidney, impaired subjects, and children less than 18 yr.

  3. Research renal biopsy, performed largely or exclusively for research purposes.

    INCLUSION CRITERIA:

    Adults with collapsing glomerulopathy.

    EXCLUSION CRITERIA:

    Pregnant women, patients with a single kidney, impaired subjects, and children less than 18 yr.

    Module 3: RENAL FUNCTION AND STRUCTURE IN LEAN, OVERWEIGHT, AND OBESE YOUNG ADULTS

    INCLUSION CRITERIA:

    Young adults aged 18 to 21, including lean young adults with BMI less than 25 kg/m2 and obese young adults with BMI greater than 30 kg/m2. Participants with a history of hyperlipidemias or high fasting glucose will still be eligible for the study as these co-morbidities are often consequence of being obese.

    EXCLUSION CRITERIA:

    Young adults with proteinuria (random urine protein to creatinine ratio greater than 0.2, microalbuminuria (spot urine albumin to cretinine ratio greater than 20 mg/g), creatinine clearance less than 80 mL/min/1.73m2, chronic kidney disease, high blood pressure (systolic blood pressure greater than 140 and diastolic blood pressure greater than 90 on 3 blood pressure readings obtained at least one week apart), diabetes, and pregnant women.

    Module 4: PILOT STUDY OF RITUXIMAB AND CYCLOSPORINE

    INCLUSION CRITERIA: (Up to 20 patients)

    Inclusion criteria for adult patients

    • Estimated average proteinuria greater than 3.5 g/d despite optimal use of an ACE inhibitor or ARB (or possibly both), last dose increase at least 4 weeks before qualifying proteinuria determination
    • Women must use reliable birth control method to avoid pregnancy while participating in the study.
    • Patients who have failed to respond with a complete remission or partial remission after at least 8 weeks of prednisone at a dose of at least 60 mg.
    • Patients who have compelling contraindications to the use of glucocorticoids, such as morbid obesity, defined as BMI greater than 35 or diabetes mellitus
    • Patients with idiopathic FSGS or collapsing glomerulopathy
    • Patients with MDRD eGFR greater than or equal to 50 mL/min/1.73 m(2) at screening or at some time in preceding 6 months.

    Inclusion criteria for minors (between ages 4 and 18 years)

    • Estimated average protein to creatinine ratio greater than to 2.0 g/g despite use of an ACE inhibitor or ARB. At least one-first void urine will be obtained and must have a urine protein/creatinine ratio greater than to 2.0 g/g to exclude the diagnosis of orthostatic proteinuria
    • Girls who are going through puberty and/or have menstrual periods must use reliable birth control method to avoid pregnancy while participating in the study
    • Failed to respond with a complete remission or partial remission after at least 8 weeks of prednisone at a dose of at least 1 mg/kg
    • Compelling contraindications to the use of glucocorticoids, such as morbid obesity, defined as 99th percentile for age and sex or diabetes mellitus
    • Patients with idiopathic FSGS or collapsing glomerulopathy
    • Patients with Schwartz eGFR equal to or greater than or equal to50 mL/min/1.73 m2 at screening or at some time in preceding 6 months.

    EXCLUSION CRITERIA:

    • Age less than 4 years.
    • Prior intolerance of rituximab or other monoclonal antibody therapy, including severe infusion reaction or hypersensitivity to murine proteins.
    • History of cardiac arrhythmias, unless cardiology consult approves the use of rituximab.
    • Prior total lifetime rituximab dose exceeding 1500 mg/m2.
    • Prior intolerance of cyclosporine.
    • Patients with post-adaptive FSGS (including obesity-associated FSGS, reflux nephropathy, reduced nephron mass). There is not a strong rationale for the use of immunologic therapy in this population.
    • Patients with genetic FSGS due to a high penetrance mutation, e.g. NPHS2 mutation. There is not a strong rational for the use of immunologic therapy in this population.
    • Medication-associated FSGS.
    • Recurrent FSGS following renal transplant
    • Chronic viral infection, such as HIV-1, hepatitis B, and hepatitis C. The safety of aggressive immunologic therapy in these diseases is in question.
    • Chronic bacterial infection. At baseline, if the patient gives a history of BCG vaccination or prior positive PPD, we will consult with an infectious disease clinician before enrolling the patient.
    • Active malignancy
    • Poorly controlled hypertension, defined as home BP measurements greater than140/90 or controlled blood pressure requiring 4 or more medications. The rationale is that blood pressure elevation is common on cyclosporine therapy.
    • Women and girls who are pregnant or trying to become pregnant or are unwilling to practice birth control. Rituximab is in pregnancy class C: no systematic evidence of safety. In humans, cyclosporine crosses the placenta. Cyclosporine lacks genotoxic effects in human and animal studies. However, growth restriction and prematurity occur in up to 40% of neonates born to mothers with organ transplants who are treated with cyclosporine, but no congenital abnormalities have been documented.
    • Women and girls who are breastfeeding (possible immune suppression in infants as well as the unknown effects on growth or association with carcinogenesis.)
    • Predicted requirement for live vaccines over the 24 months following enrollment.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00001392

Contacts
Contact: Lilian V Howard, C.R.N.P. (301) 594-0298 lh357n@nih.gov
Contact: Jeffrey B Kopp, M.D. (301) 594-3403 jeffreyk@mail.nih.gov

Locations
United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike Recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact Patient Recruitment and Public Liaison Office (PRPL)    800-411-1222 ext TTY8664111010    prpl@mail.cc.nih.gov   
Sponsors and Collaborators
Investigators
Principal Investigator: Jeffrey B Kopp, M.D. National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
  More Information

Additional Information:
Publications:
ClinicalTrials.gov Identifier: NCT00001392     History of Changes
Other Study ID Numbers: 940127, 94-DK-0127
Study First Received: November 3, 1999
Last Updated: March 14, 2014
Health Authority: United States: Federal Government

Keywords provided by National Institutes of Health Clinical Center (CC):
Retrovirus
PCR
Renal Failure
HIV
Rituximab

Additional relevant MeSH terms:
HIV Infections
Acquired Immunodeficiency Syndrome
Glomerulosclerosis, Focal Segmental
Kidney Diseases
AIDS-Associated Nephropathy
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Virus Diseases
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Immunologic Deficiency Syndromes
Immune System Diseases
Slow Virus Diseases
Glomerulonephritis
Nephritis
Urologic Diseases

ClinicalTrials.gov processed this record on August 01, 2014