Module 1: EVALUATION AND TREATMENT OF GLOMERULOSCLEROSIS
INCLUSION CRITERIA:
Children of all ages and adults, including pregnant women, and impaired subjects, all with kidney disease. For pathogenetic studies, we will also include healthy volunteers, including children greater than 12 yrs of age and adults.
EXCLUSION CRITERIA:
None
Module 2: RESEARCH RENAL BIOPSY
1) Clinically-indicated renal biopsy, with use of a portion of a second biopsy core for research.
INCLUSION CRITERIA:
All adults or children with past renal biopsy which demonstrated a glomerulosclerotic disease or in all adults or children without prior renal biopsy and clinical suspicion of glomerulosclerotic disease.
EXCLUSION CRITERIA;
Pregnant women.
2) Clinically-indicated renal biopsy, obtaining a third biopsy core for research purposes.
INCLUSION CRITERIA:
All adults with past renal biopsy which demonstrated a glomerulosclerotic disease or in all adult patients without prior renal biopsy and high pre-test likelihood of a glomerulosclerotic disease.
EXCLUSION CRITERIA:
Pregnant women, patients with a single kidney, impaired subjects, and children less than 18 yr.
3) Research renal biopsy, performed largely or exclusively for research purposes.
INCLUSION CRITERIA:
Adults with collapsing glomerulopathy.
EXCLUSION CRITERIAN:
Pregnant women, patients with a single kidney, impaired subjects, and children less than 18 yr.
Module 3: RENAL FUNCTION AND STRUCTURE IN LEAN, OVERWEIGHT, AND OBESE YOUNG ADULTS
INCLUSION CRITERIA:
Young adults aged 18 to 21, including lean young adults with BMI less than 25 kg/m2 and obese young adults with BMI greater than 30 kg/m2. Participants with a history of hyperlipidemias or high fasting glucose will still be eligible for the study as these co-morbidities are often consequence of being obese.
EXCLUSION CRITERIA:
Young adults with proteinuria (random urine protein to creatinine ratio greater than 0.2, microalbuminuria (spot urine albumin to cretinine ratio greater than 20 mg/g), creatinine clearance less than 80 mL/min/1.73m2, chronic kidney disease, high blood pressure (systolic blood pressure greater than 140 and diastolic blood pressure greater than 90 on 3 blood pressure readings obtained at least one week apart), diabetes, and pregnant women.
Module 4: PILOT STUDY OF RITUXIMAB AND CYCLOSPORINE
Many patients with idiopathic FSGS are refractory to standard immunosuppressive therapies, which include glucocorticoids, cyclosporine, cyclophosphamide (chiefly in those with glucocorticoid dependence) and mycophenolate. Recently some success with rituximab has been reported in FSGS, in case reports and short series. We now wish to carry out a pilot study combining rituximab and cyclosporine therapy in up to 20 adult and pediatric patients with idiopathic FSGS and collapsing glomerulopathy) and heavy proteinuria, defined as proteinuria >=3.5 g/d (adults) and urine protein/creatinine > 2.0 g/g children).
Our objective is to develop preliminary evidence of the efficacy, defined as the number of complete and partial remissions, and of the safety of this regimen. The rationale for this approach is that it combines B cell suppression and T cell suppression and combines two agents that appear to have activity against podocyte diseases but which appear to have frequent relapses when used as a single agent.
There are no published studies that specifically evaluate the safety of combining rituximab and cyclosporine. However, patients undergoing stem cell transplants as well as renal transplant frequently receive both of these drugs simultaneously for a variety of reasons without apparent excessive toxicity.
INCLUSION CRITERIA: (Up to 20 patients)
-Inclusion criteria for all patients (ages > 4 years)
-Patients with idiopathic FSGS or collapsing glomerulopathy
-Patients who refused to take glucocorticoids
-Patients with diabetes mellitus
Inclusion criteria for adult patients
-Estimated average proteinuria > 3.5 g/d despite optimal use of an ACE inhibitor or ARB (or possibly both), last dose increase at least 4 weeks before qualifying proteinuria determination
-Women must use reliable birth control method to avoid pregnancy while participating in the study.
-Patients who have failed to respond with a complete remission or partial remission after at least 8 weeks of prednisone at a dose of at least 60 mg.
-Patients who have compelling contraindications to the use of glucocorticoids, such as morbid obesity, defined as BMI > 35
Inclusion criteria for minors (between ages 4 and 18 years)
-Estimated average protein to creatinine ratio > 2.0 g/g despite use of an ACE inhibitor or ARB. At least one-first void urine will be obtained and must have a urine protein/creatinine ratio > 2.0 g/g to exclude the diagnosis of orthostatic proteinuria
-Girls who are going through puberty and/or have menstrual periods must use reliable birth control method to avoid pregnancy while participating in the study
-Failed to respond with a complete remission or partial remission after at least 8 weeks of prednisone at a dose of at least 1 mg/kg
-Compelling contraindications to the use of glucocorticoids, such as morbid obesity, defined as 99th percentile for age and sex
EXCLUSION CRITERIA:
-Age < 4 years.
-Prior intolerance of rituximab or other monoclonal antibody therapy, including severe infusion reaction or hypersensitivity to murine proteins
-History of cardiac arrhythmias, unless cardiology consult approves the use of rituximab. -Prior total lifetime rituximab dose exceeding 1500 mg/m(2).
-Prior intolerance of cyclosporine.
-Severely impaired GFR, defined as Schwartz and MDRD eGFR < 50 ml/min/1.73m2. -The rationale is that immunologic therapy is less likely to provide a clinical benefit in the presence of advanced renal fibrosis.
-Patients with post-adaptive FSGS (including obesity-associated FSGS, reflux nephropathy, reduced nephron mass). There is not a strong rationale for the use of immunologic therapy in this population.
-Patients with genetic FSGS due to a high penetrance mutation, e.g. NPHS2 mutation. There is not a strong rational for the use of immunologic therapy in this population.
-Medication-associated FSGS.
-Recurrent FSGS following renal transplant
-Chronic viral infection, such as HIV-1, hepatitis B, and hepatitis C. The safety of aggressive immunologic therapy in these diseases is in question.
-Chronic bacterial infection. At baseline, if the patient gives a history of BCG vaccination or prior positive PPD, we will consult with an infectious disease clinician before enrolling the patient.
-Active malignancy
-Poorly controlled hypertension, defined as home BP measurements > 140/90 or controlled blood pressure requiring 4 or more medications. The rationale is that blood pressure elevation is common on cyclosporine therapy.
-Women and girls who are pregnant or trying to become pregnant or are unwilling to practice birth control. Rituximab is in pregnancy class C: no systematic evidence of safety. In humans, cyclosporine crosses the placenta. Cyclosporine lacks genotoxic effects in human and animal studies. However, growth restriction and prematurity occur in up to 40% of neonates born to mothers with organ transplants who are treated with cyclosporine, but no congenital abnormalities have been documented.
-Women and girls who are breastfeeding (possible immune suppression in infants as well as the unknown effects on growth or association with carcinogenesis.)
-Predicted requirement for live vaccines over the 24 months following enrollment.
National Institutes of Health Clinical Center
Bethesda, Maryland 20892. Last update: 11/25/2009