Rituximab in the Treatment of Idiopathic Membranous Nephropathy
Rituximab in the Treatment of Idiopathic Membranous Nephropathy
Membranous glomerulopathy (MN) is still the most common glomerular disease associated with
 nephrotic proteinuria (NS). Up to 40% of patients reach end stage renal failure (ESRD),
 making MN the 2nd or 3rd most common cause of ESRD caused by a primary glomerulopathy.
 Current treatment options include corticosteroids, alkylating agents, and cyclosporin, but
 their use is controversial and the associated adverse effects and high cost temper their
 usage. Experimental data in MN suggests that B cell activation results in immunoglobulin
 deposition along the glomerular basement membrane causing injury to the membrane and
 subsequent proteinuria. Drugs that non-selectively inhibit B cells and, these pathogenic
 antibodies, are closely associated with improved outcomes. Based on the rationale that
 selective depletion of B cells in humans would prevent the production of ?nephrotoxic?
 immunoglobulins and subsequent renal injury we recently treated 15 patients with MN with
 rituximab 1g i.v. twice (day 1 and day 15). Baseline proteinuria of 13.0±5.5g/24h decreased
 to 9.1±7g, 9.7±8g and 6.5±6 g/24h at 3, 6, and 9 months, respectively (mean ± SD). Analysis
 of the pharmacokinetic data obtained from this study, however, suggests that in heavily
 nephrotic patients, rituximab dosed in this fashion results in patients being under-treated.
 The present study propose to test the hypothesis that rituximab, given in accordance to the
 standard lymphoma protocol (375mg/m2 x 4), will result in a more effective and profound
 depletion of B cells, a more complete suppression of pathogenic antibodies, and a higher
 remission rate of the NS while maintaining a favorable safety profile.
a. Study Overview: Once a patient with idiopathic MN and proteinuria >5g/24h is identified
 and meets other entry criteria, he/she will receive a minimum of 4 months of
 non-immunosuppressive therapy aimed at maximizing Ang II blockade (run-in phase). The target
 blood pressure (<130 mmHg systolic BP >75% of the readings; but not <100 mmHg systolic) is
 chosen based on recent recommendations by the JNC VII.(38) 1) The first step will be the
 administration of an ARB. This is chosen because ARBs are as effective as ACEIs in blocking
 the AT1 mediated adverse effects of Ang II, while being better tolerated, with minimal cough
 or angioedema, and less hyperkalemia. Because this part of the study aims to maximize Ang II
 blockade, ARB dose will continue to be increased every 2 weeks until the maximum
 tolerated/FDA approved dose is achieved or until intolerable side effects occur (e.g.
 development of postural hypotension, light headed, hyperkalemia, etc). 2) Once ARB dose has
 been maximize and there are no observable side-effects, and/or blood pressure is not at
 target, a long acting ACEi will be added. ACEi dose will be increased every 2 weeks aiming to
 achieve maximum tolerated or maximum approved dosage. For patients whose blood pressure
 control is not at target additional medication will be added in the following order: 3) a
 loop diuretic, 4) a cardioselective &#946;-blocker, 5) a non-dihydropyridine calcium channel
 blocker (CCB), and 6) clonidine. The selection of these drugs adheres to the recommendation
 of the JNC VII.(38) The choice of a non-dihydropyridine CCB was made because of concerns that
 dihydropyridine-type CCB may obscure the anti-proteinuric effects of the above therapy. In
 order to further ensure that any potential adverse effect is minimized we have limited CCB to
 be used as a fifth agent, and to be used only when the combination of ARB/ACEi, diuretic, and
 &#946;-blocker have failed to reduce BP to target level. Concomitant Treatment: 1. At the
 start of the run-in/conservative phase of the study, and as part of the standard of care for
 patients with NS and severe hyperlipidemia, patients will be started on atorvastatin 10 mg a
 day (or its equivalent) and if tolerated (no evidence of persistent elevation of liver
 transaminase >3x upper limit of normal, muscle pain, high CK, or rhabdomyolysis) the dose can
 be increased according to the recently published KDOQI-dyslipidemia guidelines.(39) The dose
 should not be increased above the maximum of 40 mg/day. The rationale for not using a higher
 statin dose is because of the risk of developing proteinuria with the use of statins at high
 doses. Patients will remain at the highest tolerated dose for the entire duration of the
 study. Serum lipids will be measured at baseline and every 3 months thereafter. 2. High
 sodium intake (e.g. >200 mm NaCl/d or 4.6 g sodium/d) can significantly impair the beneficial
 effects of Ang II blockade.(40) Therefore patients will be instructed to go on a low salt
 diet (2-3g/day). 3. Patients will receive dietary counseling at enrollment regarding a
 dietary protein target intake of 0.8 g/kg ideal body weight/day of high quality protein and
 will be encouraged to maintain the same diet throughout the duration of the study.

 Rituximab: If at the end of this period the patient still meets entry criteria he/she will be
 treated with rituximab, 375 mg/m2 i.v. on days 1, 8, 15 and 22, with subsequent follow-up of
 at least one year. Patients will be retreated at month 6th once B-cells return to circulation
 and will be independent of the clinical status of the patient. B-cell return is defined as
 CD19+B cell count > 15/microliter or >5% of baseline count. There will be a +/- 3 day window
 for each study visit, to account for weekends, holidays, and scheduling conflicts.

 Figure 3. Schematic time-line for the study. Primary endpoint.

 1. Change in proteinuria from baseline to 12 months. This approach was selected taking in
 consideration that B cell recovery following administration of rituximab usually begins at 6
 months after the last infusion, but it is not complete until 9-12 months later, (complete
 recovery is defined as normalization of CD19+ B cell counts; normal CD19+ count is 71-567
 cells/&#956;l).

 Secondary endpoints.

 1. Complete and partial remission rates at 6, 9, and 12 months (see definitions in Table 3)

 2. Pharmacokinetics/bioavailability

 3. Rate of decline in urinary protein

 4. Frequency of relapse after CR

 5. Toxicity
-  Idiopathic MN with diagnostic biopsy performed within the past 24 months.

 -  Age > 18 years

 -  If female, must be post-menopausal, surgically sterile or practicing a medically
 approved method of contraception

 -  Patients need to be treated with an ACEI and/or ARB, for at least 4 months prior to
 rituximab treatment and have adequately controlled blood pressure (BP <130/75 mm Hg in
 >75% of the readings).

 -  Proteinuria as measured by urinary proteinuria / urinary creatinine > 5.0 on a spot
 sample aliquot from a 24-hour urine collection.

 -  Estimated GFR &#8805; 30 ml/min/1.73m2 while taking ACEI/ARB therapy.