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.
Primary Purpose: Treatment
Reduction of proteinuria as compared to the baseline level in each participant.
After 10 patients have completed the study
Jeffrey B Kopp, M.D.
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
United States: Federal Government
|National Institutes of Health Clinical Center, 9000 Rockville Pike||Bethesda, Maryland 20892|
|Mt. Sinai Medical Center||New York, New York 10029|