Podocyte Retinoids
Condition: Collapsing Glomerulopathy; Glomerulosclerosis, Focal Segmental
MeSH terms: Glomerulosclerosis, Focal Segmental
Intervention: Isotretinoin
Intervention MeSH terms: Isotretinoin
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Intervention model description: Phase II, open-label pilot study
Masking: None (Open Label)
Enrollment: 12.0
Sex: All
Minimum age: 16 Years
Healthy volunteers: No
Keywords: Glomerulosclerosis; Proteinuria; Fibrosis; Chronic Kidney Disease; Nephrotic Syndrome

Summary:

      This is a pilot study of retinoids for patients with unsatisfactory response to conventional
      treatment of nephrotic syndrome due to focal segmental glomerulosclerosis or minimal change
      disease, two renal disorders associated with putatively pathogenic malfunctioning of
      glomerular podocytes. The hypothesis that retinoids may have reparative effects on these
      cells is based on previous research showing that retinoids promote the differentiation or
      redifferentiation of aberrant epithelial cells. Results obtained by 6 months of treatment
      with retinoids (that have been approved for non-renal indications) will be used as
      preliminary information upon which to base further testing of these agents in formal clinical
      trials in refractory cases of these nephrotic syndromes.
    

Eligibility criteria:

        -  INCLUSION CRITERIA:

          -  Patients with podocyte diseases, MCD, FSGS (including primary, secondary, and adaptive
             variants), and CG (including HIV-associated variant), who meet the following criteria:

             --An adequate renal biopsy, defined as having minimum 10 glomeruli for light
             microscopy and minimum 3 glomeruli for electron microscopy, unless the podocyte
             disease is diagnostic on fewer glomeruli. Patients who have non-diagnostic or
             technically inadequate biopsies will be offered the opportunity to undergo a research
             biopsy to determine eligibility. For some patients who have had a non-diagnostic or
             technically inadequate biopsy, a repeat renal biopsy may be clinically indicated in an
             effort to diagnose and treat a potentially serious kidney disease.

          -  Greater than or equal to 16 years of age. The rationale for excluding younger children
             is that retinoids may carry greater toxicity in children, as there are reports of
             premature epiphyseal closure, development of slender long bones, and periostal
             thickening.

          -  Prior treatment with at least two immunosuppressive agents that have been shown to
             induce remission in MCD and FSGS: glucocorticoids, cyclosporine, tacrolimus,
             cyclophosphamide, chlorambucil, and mycophenolate mofetil. Therapy with each agent
             must last at least 8 weeks. Exemptions will be made for those with contraindications
             to these medications or those who cannot tolerate these medications. The rationale is
             to recruit patients who have failed conventional therapy. All patients will be off
             immunosuppression for at least 4 weeks before starting retinoids in order to avoid a
             confounding effect.

          -  Three first void urine protein/creatinine ratios > 2 g/g obtained within one month
             prior to enrolling in the study. These urine collections will be obtained after the
             patient has been on a stable dose of angiotensin converting enzyme(ACE) inhibitor or
             angiotensin receptor blocker (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. Patients with steroid-sensitive
             frequently relapsing MCD will not be required to have used ACE inhibitor or ARB, as
             steroids alone are typically sufficient therapy to induce remission.

          -  If hypertensive: blood pressure of less than or equal to 140/90 on a stable dose of
             ACE inhibitor or ARB for at least 1 month or greater than or equal to 75 percent 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 aspartate aminotransferase (AST), alanine
             aminotransferase (ALT), total bilirubin, or protime. The rationale is that retinoids
             can be hepatotoxic. The only exception will be the following: if the cause of
             abnormality of liver function tests (LFT) is felt to be due to a specific hepatotoxic
             drug such as a statin and the levels are less than 2 times the upper limit of the
             normal AND normalize upon holding the offending drug, patients may be considered for
             study participation after consultation with hepatology service.

          -  Hypertriglyceridemia greater than 500 mg/dL despite statin/fibrate therapy. The
             rationale is that retinoids can increase lipids, particularly triglyceride as 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 percent, 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 cluster of differentiation 4 (CD4) count greater than or equal
             to 200. Both tretinoin and isotretinoin have been safely studied in HIV-infected
             patients for other indications.

          -  glomerular filtration rate (GFR) less than 40 ml/min/1.73m(2) estimated by 5-variable
             Modification of Diet in Renal Disease (MDRD) equation, as the metabolites of retinoids
             are excreted in part in urine, and there is a concern for increased toxicity. In
             participants less than 18 years of age, we will use Schwartz equation.

          -  Expansion of glomerulus or interstitial formation on the biopsy.

          -  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:
             unwillingness to accept blood transfusion, bleeding diathesis, single kidney, small
             kidneys (less than 9.5 cm).