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Pathogenesis of Glomerulosclerosis

This study is currently recruiting participants.
Verified September 22, 2017 by National Institutes of Health Clinical Center (CC) ( National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) )
Sponsor:
ClinicalTrials.gov Identifier:
NCT00001392
First Posted: November 4, 1999
Last Update Posted: October 6, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) )
  Purpose

The present protocol seeks to advance our understanding of sclerosing glomerular and tubulointerstitial kidney diseases, including but not limited to variants of focal segmental glomerulosclerosis (FSGS) and chronic kidney disease of unknown etiology (CKDu). This protocol will encompass studies of the natural history, pathogenesis and treatment of these chronic kidney disorders. It will also allow us to: (1) provide second opinions to referring physicians about management of subjects with these relatively rare kidney diseases; (2) collect research samples (e.g., blood), urine, and kidney tissue obtained from clinically-indicated or from research renal biopsies); (3) and treat these subjects with standard or other approved therapies; or (4) invite selected subjects patients to participate in limited pilot studies of novel combinations of standard therapeutic agents, such as rituximab and cyclosporine. (5) Agricultural worker chronic kidney disease of undetermined etiology (CKDu) is a growing problem in tropical countries in the Americas and Asia, including Sri Lanka where collaborators are located. We will receive kidney tissue from 25 CKDu cases for pathologic examination and transcriptional profiling and blood, plasma, serum, urine for metabolomic and genetic analysis from 50 cases and controls. Subjects were consented and samples were collected under a protocol approved by the University of Colombo IRB. These studies may provide the opportunity to generate new hypotheses regarding pathogenesis and treatment that would be candidates for testing in other research protocols.

Subjects with known or suspected forms of sclerosing glomerular or chronic, fibrosing tubulointerstitial kidney diseases will undergo routine medical evaluation, laboratory testing, imaging procedures and kidney biopsies as medically indicated. Selected subjects will be invited to provide informed consent to undergo a kidney biopsy for research purposes. Blood, urine, and tissue samples will be evaluated both for standard diagnostic purposes and for research purposes using specialized molecular methods that may provide insights into specific disease pathogenesis. Subjects may elect to receive the results of their kidney disease evaluation, NIH treatment recommendations, and return to the care of their referring physicians. Other subjects may be treated with either conventional or approved agents, or (with separate consent) with a novel combination of conventional therapies (rituximab and cyclosporine) as part of pilot studies that would involve long-term follow-up care at the NIH.


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) ( National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) ):

Estimated Enrollment: 99999999
Study Start Date: April 7, 1994
Detailed Description:

The present protocol seeks to advance our understanding of sclerosing glomerular and tubulointerstitial kidney diseases, including but not limited to variants of focal segmental glomerulosclerosis (FSGS) and chronic kidney disease of unknown etiology (CKDu). This protocol will encompass studies of the natural history, pathogenesis and treatment of these chronic kidney disorders. It will also allow us to: (1) provide second opinions to referring physicians about management of subjects with these relatively rare kidney diseases; (2) collect research samples (e.g., blood), urine, and kidney tissue obtained from clinically-indicated or from research renal biopsies); (3) and treat these subjects with standard or other approved therapies; or (4) invite selected subjects patients to participate in limited pilot studies of novel combinations of standard therapeutic agents, such as rituximab and cyclosporine. (5) Agricultural worker chronic kidney disease of undetermined etiology (CKDu) is a growing problem in tropical countries in the Americas and Asia, including Sri Lanka where collaborators are located. We will receive kidney tissue from 25 CKDu cases for pathologic examination and transcriptional profiling and blood, plasma, serum, urine for metabolomic and genetic analysis from 50 cases and controls. Subjects were consented and samples were collected under a protocol approved by the University of Colombo IRB. These studies may provide the opportunity to generate new hypotheses regarding pathogenesis and treatment that would be candidates for testing in other research protocols.

Subjects with known or suspected forms of sclerosing glomerular or chronic, fibrosing tubulointerstitial kidney diseases will undergo routine medical evaluation, laboratory testing, imaging procedures and kidney biopsies as medically indicated. Selected subjects will be invited to provide informed consent to undergo a kidney biopsy for research purposes. Blood, urine, and tissue samples will be evaluated both for standard diagnostic purposes and for research purposes using specialized molecular methods that may provide insights into specific disease pathogenesis. Subjects may elect to receive the results of their kidney disease evaluation, NIH treatment recommendations, and return to the care of their referring physicians. Other subjects may be treated with either conventional or approved agents, or (with separate consent) with a novel combination of conventional therapies (rituximab and cyclosporine) as part of pilot studies that would involve long-term follow-up care at the NIH.

  Eligibility

Information from the National Library of Medicine

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Ages Eligible for Study:   4 Years and older   (Child, Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria
  • EVALUATION AND TREATMENT OF GLOMERULOSCLEROSIS
  • INCLUSION CRITERIA

    ---An unlimited number of subjects with known or suspected glomerular or tubulointerstitial disease will be eligible for study. No sex, race or ethnic selection will be applied. It is anticipated the African-Americans will predominate, given the increased risk of FSGS (focal segmental glomerulosclerosis) in this population.

  • EXCLUSION CRITERIA

    -RITUXIMAB AND CYCLOSPORINE. (CLOSED FOR SUBJECT RECRUITMENT.)

  • INCLUSION CRITERIA FOR ADULT PATIENTS PARTICIPATING IN PILOT STUDY OF COMBINATION RITUXIMAB AND CYCLOSPORINE

    • First void urine protein to creatinine ratio > 2g/g 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.
    • Subjects 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 or are steroid dependent or relapse off steroids.
    • Subjects who have compelling contraindications to the use of glucocorticoids, such as morbid obesity, defined as BMI >35 or diabetes mellitus
    • Subjects with idiopathic FSGS or collapsing glomerulopathy
    • Subjects with 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 >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 >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 or are steroid dependent or relapse off steroids.
    • Compelling contraindications to the use of glucocorticoids, such as morbid obesity, defined as 99th percentile for age and sex, or diabetes mellitus
    • Subjects with idiopathic FSGS or collapsing glomerulopathy
    • Subjects with eGFR greater than or equal to 50 mL/min/1.73 m^2 at screening or at some time in preceding 6 months.
  • EXCLUSION CRITERIA

    • Age < 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.
    • Treatment with rituximab within the last two years.
    • Prior intolerance of cyclosporine.
    • Subjects 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.
    • Subjects with genetic FSGS due to a high penetrance mutation, e.g. NPHS2 mutation. There is not a strong rationale 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 is defined as home BP measurements >140/90 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.

      • FINDING THE CAUSE OF CHRONIC KIDNEY DISEASE IN AGRICULTURAL WORKERS IN THE NORTH AND NORTH CENTRAL PROVINCE, SRI LANKA: A SYSTEMS BIOLOGY APPROACH
  • INCLUSION CRITERIA, BY GROUP

    • Sri Lankans with CKDu with all the following features

      • A member of the North or North Central Province for at least 15 years.
      • A negative history of prior renal disease.
      • A fasting blood glucose less than or equal to 110 mg/dL, a BMI less than or equal to35 kg/m^2 and a blood pressure less than or equal to 140/90 during one screening.
      • An average random urine protein/creatinine ratio greater than or equal to 250 mg/g, two urine protein/creatinine ratio greater than or equal to 200 mg/g and eGFR (Bullet)40 ml/min/1.73m^2 on two screenings, four or five weeks apart.
      • A urine albumin/protein ratio less than or equal to 25% to exclude glomerular proteinuria
      • An ultrasound that shows both kidneys greater than or equal to 8.5 cm and the presence of well-defined corticomedullary demarcation. The ultrasound should lack more than moderate echogenicity, multiple renal cysts and evidence of renal obstruction, which will reduce the chance of bleeding or other complications
      • Males and non-pregnant females between the ages 20-60 years old.
    • Sri Lankans without CKDu

      • A resident of the North or North Central Province for at least 15 years.
      • A negative history of prior renal disease.
      • A fasting blood glucose less than or equal to 110 mg/dL, a BMI less than or equal to 35 kg/m^2, blood pressure less than or equal to140/90 during one screening.
      • A random urine protein/creatinine ratio less than or equal to100 mg/g and an eGFR greater than or equal to 60 ml/min/1.73m^2 on one screening. Males and non-pregnant females between the ages 20-60 years old.
      • Controls will be matched 1:1 with cases: race, sex, age (within 5 years)

        • ANALYSIS OF LIPID-CONTAINING PARTICLES CHARACTERISTICS UNDER NUCLEAR MAGNETIC RESONANCE SPECTROSCOPY (NMR-S) AMONG NEPHROTIC SUBJECTS
  • INCLUSION CRITERIA:

    • We will enroll adult subjects (greater than or equal to 18 years of age), male or female, and of all racial backgrounds/ethnicities. In this cohort, we will include subjects with kidney disease or without kidney disease (healthy volunteers). We will start with subjects with preserved glomerular filtration rate (eGFR-Cr greater than or equal to 60 ml/min/1.73m2) but may expand to include individuals with lower GFR in a later study. We will estimate glomerular filtration rate (eGFR) using the 2009 CKD-EPI creatinine equation.
    • In respect to proteinuria, we will accept both urine protein-to-creatinine ratio (uPCR) or urine protein excretion rate (PER) per 24 hours as a selection criteria. We will divide enrolled subjects in 3 groups as shown below:
    • Group 1. Subjects with nephrotic range proteinuria (uPCR greater than or equal to 2 g/g or PER greater than or equal to 3 gr/24hs.) and eGFR-Cr greater than or equal to 60 ml/min/1.73m2, regardless of their albumin levels.
    • Group 2. Subjects with sub-nephrotic range proteinuria (uPCR greater than or equal to 0.2 g/g but < 2 g/g or PER greater than or equal to 300 mg/24hs. but < 3 gr/24hs.) and eGFR-Cr greater than or equal to 60 ml/min/1.73m2, regardless of their albumin levels.
    • Group 3. Volunteers with normal eGFR and normal protein excretion and normal fasting clinical lipid testing.
    • For those subjects undergoing lipid lowering therapies for primary prevention, including statins, fibrates, niacin, ezetimibe, bile acid resins, fish oil or red yeast rice, we will stop those treatments at least 4 weeks but no more than 6 weeks prior their admission. Lipid lowering therapy will not be stopped for more than 8 weeks. We will not enroll subjects who are receiving statins or other lipid lowering therapies for secondary prevention. Also, we will not enroll subjects with history of triglycerides levels >1000 mg/dl.
    • The blood and urine sample collection and brief interruption of statin treatment performed in this pilot study to involve no more than minimal risk to individual subjects, with no prospect of direct benefit to subjects, but likely to yield generalizable knowledge to further society's understanding of the lipoprotein profiles of nephrotic and non-nephrotic subjects.
  • EXCLUSION CRITERIA:

    • We will exclude subjects with any of the following:

      • Diabetes mellitus
      • Body mass index (BMI) greater than or equal to 40,
      • Pregnant or breastfeeding women
      • Untreated or uncontrolled thyroid disorder
      • Active oncologic condition
      • Acute infections
      • Chronic infections including HIV
      • Subjects receiving lipid lowering medications for secondary prevention (e.g. coronary artery disease, stroke, heart failure)
      • Subjects receiving estrogen therapy or contraceptive therapy
      • Subjects receiving cyclosporine, azathioprine or sirolimus
      • Subjects who are unable to eat the required meals due to allergy, intolerance, or dietary preferences
      • Subjects with history of pancreatitis
      • Subjects with reported history of triglycerides >1000 mg/dl
      • Subjects unable or unwilling to give their consent
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00001392


Contacts
Contact: Emily C Brede, Ph.D. (301) 451-9946 emily.brede@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
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Investigators
Principal Investigator: Jeffrey B Kopp, M.D. National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
  More Information

Additional Information:
Publications:
Responsible Party: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
ClinicalTrials.gov Identifier: NCT00001392     History of Changes
Other Study ID Numbers: 940127
94-DK-0127
First Submitted: November 3, 1999
First Posted: November 4, 1999
Last Update Posted: October 6, 2017
Last Verified: September 22, 2017

Keywords provided by National Institutes of Health Clinical Center (CC) ( National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) ):
Retrovirus
PCR
Renal Failure
HIV
Rituximab

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