This study will determine the safety and effectiveness of retinoids for treating patients with minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS). These diseases involve increased loss of protein in the urine and are treated with steroids, cyclosporine, and cyclophosphamide. Some patients with MCD progress to FSGS, and about half of those patients develop end-stage kidney disease that will require dialysis or a kidney transplant. Some patients with MCD and FSGS do not respond to or cannot tolerate the standard treatments. Retinoids, which are derived from vitamin A, are important for maintaining healthy epithelial cells, a type of cell that lines many organs, including the kidney. Since MCD and FSGS are diseases of the epithelial cells of the kidney, it is possible that retinoids may have a beneficial effect on these diseases.

Patients 18 years of age and older with MCD or FSGS who have been treated with steroids or cyclosporine for at least 8 weeks and not benefited from this therapy may be eligible for this study. (Patients who cannot take these medications may also be enrolled.) Candidates are screened with blood and urine tests, blood pressure measurements for 4 weeks, psychiatric questionnaires, and a kidney needle biopsy if one has not been done within 6 months of enrolling in the study. For the biopsy, the skin over the kidney area is numbed and CT imaging is used to help guide the needle into the kidney. A small piece of tissue is withdrawn through the needle for microscopic examination. Prospective participants must also be taking either an ACE inhibitor, such as Lotensin, Capoten, Vasotec, or an angiotensin receptor blocker, such as Atacand, Avapro, Diovan, for at least 4 weeks before entering the study.

Participants undergo the following tests and procedures:

- DEXA scan before starting and after completing retinoid therapy to assess bone density. For this test, the patient lies still on a table while the spine and hip are scanned using a small amount of radiation.

- X-rays of the neck, upper back, and ankles before starting and after completing retinoid therapy to compare what the bones look like before and after treatment.

- Retinoid treatment. Patients are randomly assigned to receive one of two retinoids - tretinoin or isotretinoin - for 6 months. The dose is increased after the first month of therapy unless significant side effects develop, in which case the medication dose is lowered. A patient who cannot tolerate the medication at all and stops it within the first 2 months of the study has the option of trying the other retinoid.

- Follow-up. Patients are seen every month for laboratory tests and psychological evaluations. Patients whose protein leakage improves to normal can stop the medication 4 weeks after achieving this effect, even if it is before 6 months. If protein leakage subsequently increases, the patient may take the same study medication again, this time for the full 6 months. All patients have a follow-up kidney biopsy, except those who stop the drug early because of side effects. After completing 6 months of therapy, patients are followed with laboratory tests every 3 months for 1 year to monitor kidney function.

Condition	Treatment or Intervention	Phase
Kidney Diseases Glomerulosclerosis, Focal	Drug: Retinoids for Podocyte Disease  Procedure: Kidney needle biopsy  Procedure: DEXA Scan  Procedure: X-rays	Phase II

Further Study Details: 

Expected Total Enrollment:  22

Retinoids are analogues of vitamin A that regulate cellular differentiation, leading to therapeutic use in skin disease and malignancy. In animal models of kidney disease, retinoids restore podocyte phenotype toward normal and reduce proteinuria. The objective of this phase II trial is to evaluate safety and develop preliminary evidence of efficacy of retinoid treatment in patients with podocyte disease. The study is an open-label, randomized trial of two physiologic retinoids: tretinoin (all-trans retinoic acid) and isotretinoin (13-cis retinoic acid). The study will be performed under the auspices of an IND from the FDA. We will enroll 22 adult patients with biopsy-proven minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS), or collapsing glomerulopathy (CG). Inclusion criteria will include a prior trial of immunosuppressive therapy and proteinuria greater than or equal to 3.5 g/d while on angiotensin antagonist therapy. Eligibility will be limited to patients with less than 30% of globally sclerotic glomeruli and greater than 50% podocyte foot process effacement.

The duration of the trial will be 24 weeks. The primary clinical endpoint will be reduction in proteinuria as compared to the baseline value assessed by paired t test. The data from each group will be analyzed separately. The secondary clinical endpoints will be the fraction of patients who achieve complete remission (CR) or partial remission (PR) at 24 and 48 weeks, confirmed on urine collections four weeks apart. Retinoid therapy will be discontinued at the time a CR is confirmed. Follow-up will last 48 weeks after cessation of drug therapy. Patients who have had CR, who have had less than 12 weeks of retinoid therapy, and who experience a relapse with greater than 3.5 g/d proteinuria during follow-up will be eligible for a second 24 week course of the retinoid that induced remission. Patients who discontinue therapy within the first 8 weeks due to an adverse event may have the opportunity to cross-over to the other arm.

Research renal biopsy will be performed twice in most patients: 1) at baseline, unless renal biopsy has been done within 24 weeks of enrollment and 2) when the diagnosis of CR or increased proteinuria is confirmed or alternatively upon completing 24 weeks of therapy (patients who exit the trial before 24 weeks due to non-renal adverse events will not undergo renal biopsy). Histologic endpoints will include change in linear extent podocyte foot process effacement, extent of podocyte proliferation, and expression of podocyte genes at the RNA and protein levels. Laboratory endpoints will include serum and urine cytokine levels and urine levels of podocyte proteins, including nephrin. Toxicity screening will include serum and urine chemistries, psychological profiles, radiographic films of cervical, thoracic spines and calcanei, and bone mass assessment with dual photon excitation absorptiometry (DEXA) at spine and hip.

Genders Eligible for Study:  Both

Criteria

INCLUSION CRITERIA
-Patients with podocyte diseases, MCD, FSGS (including idiopathic,secondary, and hyperfiltration variants), and CG (including HIV-associated variant), who meet all of the following criteria:
-An adequate renal biopsy, defined as having minimum 10 glomeruli for light microscopy and minimun 3 glomeruli for electron microscopy. Patients who have biopsies that contain fewer glomeruli will be offered the opportunity to undergo a research biopsy to determine Eligibiliy.
-Global glomerulosclerosis less than 30% on baseline biopsy. The rationale to exclude patients with more advanced glomerulosclerosis is that retinoids are not expected to reverse fibrosis.
-Foot process effacement greater than 50% on baseline biopsy. The rationale is to select patients with significant podocyte dedifferentiation.
-Adults greater than 18 years of age. The rationale for excluding children is that retinoids may carry greater toxicity in children, as there are reports of premature epiphyseal closure, development of slender long bones, and periostial thickening.
-Prior treatment with steroids and cyclosporine for greater than and equal to 8 weeks, either in monotherapy or combination.
Exceptions will be made for those with contraindications to either medication or those who cannot tolerate either medication. the rationale is to recruit patients who have failed conventional therapy. We have required that our patients be resistant to both prednisone and cyclosporine because up to 70% of patients with steroid resistance can have some response with cyclosporine. Moreover, these two agents are only proven therapies for FSGS. All patients will be off immunosuppression for at least 4 weeks before starting retinoids in order to avoid a confounding effect.
-Three 24h urine collections with mean protein excretion greater than or equal to 3.5 g/d obtained within one month prior to enrolling in the study. These 24hr urine collections will be collected after the patient has been on a stable dose of ACE inhibitor or ARB for at least 4 weeks (the maximal antiproteinuric effect of these medications occurs after 4 weeks). The rationale is that patients with nephrotic-range proteinuria are at high risk for progressive renal disease, justifying participation in a clinical trial with novel agents.
-Blood pressure of less than or equal to 130/80 on a stable dose of ACE inhibitor or ARB for at least 1 month on greater than or equal to 75% of measurements before the entry of the study. The rationale is that uncontrolled hypertension can exacerbate proteinuria.
EXCLUSION CRITERIA
-Pregnancy, breastfeeding, or unwillingness to use at least two contraceptive methods (at least one of which must be primary, including tubal ligation, partner vasectomy, oral contraceptives, implanted contraceptives, and intrauterine device. The rationale is that retinoids are teratogenic and are excreted in breast milk.
-Abnormal liver function test, including AST, ALT, total bilirubin, or protime. The rationale is that retinoids can be hepatotoxic.
-Hypertriglyceridemia greater than 500 mg/dL despite statin/fibrate therapy. The rationale is that retinoids can increase lipids, particularly triglyceride and this can lead to pancreatitis.
-Any medical conditions requiring concurrent immunosuppression, as this pilot study is designed to evaluate the effect of retinoids as a monotherapy.
-Any medical conditions requiring concurrent use of tetracycline, minocycline, or doxycycline, due to enhanced risk of increased intracranial pressure.
-Hypersensitivity to retinoids.
-Presence of any unstable cardiovascular disease, uncontrolled diabetes with hemoglobin A1c greater than 8% g/dL, chronic inflammatory or infectious conditions except HIV-1 infection. Retinoids have been associated with chest pain of unclear etiology, increased serum glucose, myelosuppression and increased risk of infection. The etiology of infection is not clear but may be related to myelosuppression.
-Those with HIV-1 infection must not have any evidence for opportunistic infectious complications and have CD4 count greater than or equal to 200. Both tretinoin and isotretinoin have been safely studied in HIV-infected patients for other indications.
-GFR less than 25 ml/min/1.73m(2)estimated by 5-variable MDRD equation, as the metabolities of retinoids are excreted in part in urine, and there is a concern for increased toxicity.
-Untreated depression, as retinoids have been associated with depression, suicidal ideation, and aggressive behavior. If patients manifest significant depressive symptoms, they will be included in the study only if assessed and agreed by a psychiatrist (either at NIH or other) and if they have regular follow-up visits with a psychiatrist.
-Factors that increase the risk of renal biopsy. These include the following: unwillingnesss to accept blood transfusion, bleeding diathesis, single kidney, small kidneys (less than 9.5 cm).
-Inability or unwillingness to undergo research renal biopsy.

Maryland
      National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), 9000 Rockville Pike,  Bethesda,  Maryland,  20892,  United States; Recruiting

Study ID Numbers:  050015; 05-DK-0015
Record last reviewed:  November 23, 2004
Last Updated:  January 28, 2005
Record first received:  December 1, 2004
ClinicalTrials.gov Identifier:  NCT00098020
Health Authority: United States: Federal Government
ClinicalTrials.gov processed this record on 2005-04-08