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Protocol Details

Pathogenesis of Glomerulosclerosis

This study is currently recruiting participants.

Summary | Eligibility | Citations | Contacts

Summary

Number

94-DK-0127

Sponsoring Institute

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

Recruitment Detail

Type: Participants currently recruited/enrolled
Gender: Male & Female
Min Age: 4
Max Age: N/A

Referral Letter Required

No

Population Exclusion(s)

None

Special Instructions

Currently Not Provided

Keywords

Retrovirus;
PCR;
Renal Failure;
HIV;
Rituximab

Recruitment Keyword(s)

None

Condition(s)

AIDS Associated Nephropathy;
Focal Glomerulosclerosis;
HIV Infections

Investigational Drug(s)

None

Investigational Device(s)

None

Intervention(s)

None

Supporting Site

National Institute of Diabetes and Digestive and Kidney Diseases

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.

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Eligibility

-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

---None

-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)


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Citations:

Associated focal and segmental glomerulosclerosis in the acquired immunodeficiency syndrome

The nephropathology in human immunodeficiency virus infection

Histopathological changes in simian immunodeficiency virus infection

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Contacts:

Principal Investigator

Referral Contact

For more information:

Jeffrey B. Kopp, M.D.
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
BG 10 RM 3N114
10 CENTER DR
BETHESDA MD 20814
(301) 594-3403
jeffreyk@mail.nih.gov

Jessica M. Warren
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
BG 10 RM 3N112
10 CENTER DR
BETHESDA MD 20814
(301) 451-9946
jessica.warren@nih.gov

Patient Recruitment and Public Liaison Office
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TTY: 301-594-9774 (local),1-866-411-1010 (toll free)
Fax: 301-480-9793

prpl@mail.cc.nih.gov

Clinical Trials Number:

NCT00001392

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