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Retinoids for Podocyte Disease

Phase 2
16 Years
Open (Enrolling)
Kidney Diseases, Glomerulosclerosis, Focal

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Trial Information

Retinoids for Podocyte Disease

Retinoids are analogues of vitamin A that regulate cellular differentiation, leading to
therapeutic use in skin diseases and malignancy. In animal models of kidney diseases,
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 design is an open-label
trial of isotretinoin (13-cis retinoic acid). The study will be performed under the auspices
of an IND from the FDA. We will enroll 10 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.

The duration of the trial will be 6 months with possible additional 6-month extension for
patients who only develop partial response (PR) or limited response (LR). Those who have
complete response (CR) will continue the treatment for one additional month, for no more
than 7 months total. Non-responders will stop at the end of 6 months. The primary clinical
endpoint will be reduction in proteinuria as compared to the baseline value assessed by
paired t test. The secondary clinical endpoints will be the fraction of patients who achieve
CR or PR at 6 months and at one year, confirmed on urine collections four weeks apart.
Retinoid therapy will be discontinued at the time a CR is confirmed, one month after the
first detection of CR. Follow-up will last one year after cessation of drug therapy.
Patients who have had a CR or PR but experience a relapse with greater than 3.5 g/d
proteinuria during follow-up will be eligible for further retinoid therapy.

All Participants will have an option of undergoing two research kidney biopsies: 1) at
baseline, unless renal biopsy has been done within 24 weeks of enrollment; 2) when the
diagnosis of CR or increased proteinuria is confirmed or alternatively upon completing 6
months of therapy (patients who exit the trial before 6 months due to non-renal adverse
events will not undergo renal biopsy) or; 3) when one year of therapy is completed for those
undergoing 6-month extension. 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.

Inclusion Criteria


- Patients with podocyte diseases, MCD, FSGS (including idiopathic, secondary, and
hyperfiltration 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.

- Adults 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
periostial 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 retiniods 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 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.


- 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. The only exception will be the
following: if the cause of abnormality of LFTs 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 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 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 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. In participants less than 18 years of age, we will use Schwartz

- 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).

Type of Study:


Study Design:

Primary Purpose: Treatment

Outcome Measure:

Reduction of proteinuria as compared to the baseline level in each participant.

Outcome Time Frame:

After 10 patients have completed the study

Safety Issue:


Principal Investigator

Jeffrey B Kopp, M.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

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


United States: Federal Government

Study ID:




Start Date:

November 2004

Completion Date:

December 2015

Related Keywords:

  • Kidney Diseases
  • Glomerulosclerosis, Focal
  • Glomerulosclerosis
  • Proteinuria
  • Fibrosis
  • Chronic Kidney Disease
  • Nephrotic Syndrome
  • Glomerulosclerosis, Focal Segmental
  • Kidney Diseases
  • Nephrosis, Lipoid



National Institutes of Health Clinical Center, 9000 Rockville Pike Bethesda, Maryland  20892
Mt. Sinai Medical Center New York, New York  10029