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.
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
investigational new drug (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 >2.0g/g proteinuria during follow-up
will be eligible for further retinoid therapy. Patients will undergo a renal biopsy prior to
initiating therapy, in order to evaluate the extent of glomerular injury and interstitial
fibrosis, unless they have had a kidney biopsy within the preceding 24 months that is
available for review. 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 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
- 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
- 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.
- 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
- 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).