Treatments for idiopathic membranous nephropathy, a common cause of nephrotic syndrome, can be very toxic. In view of the pathogenic potential of B cells in this disease, we studied the effects of four weekly infusions of rituximab (375 mg/m(2)-- the monoclonal antibody to B-cell antigen CD20--in eight patients who had idiopathic membranous nephropathy with persistent nephrotic syndrome. At weeks 4 and 20, urinary protein decreased from mean (SE) 8.6 g/24 h (1.4) to 3.8 (0.8) and 3.7 (0.9), respectively (p<0.0001). At week 20, albuminuria and albumin fractional clearance decreased by 70% and 65%, and serum albumin increased by 31%. CD20 B lymphocytes fell below normal ranges up to study end. The short-term risk-benefit profile of rituximab seems more favourable to that of any other immunosuppressive drug used to treat idiopathic membranous nephropathy.

Abstract. Currently available monoclonal antibodies against the B cell surface antigen CD20 have been employed to explore whether specific inhibition of B cells may help improve the outcome of idiopathic membranous nephropathy (IMN) and may avoid the side effects of steroids and immunosuppressants. This prospective, observational study evaluated the 1-yr outcome of eight IMN patients with persistent (Ͼ6 mo) urinary protein excretion Ͼ 3.5 g/24 h given four weekly infusions of the anti-CD20 antibody rituximab (375 mg/m 2 ). At 3 and 12 mo, proteinuria significantly decreased from mean (Ϯ SD) 8.6 Ϯ 4.2 to 4.3 Ϯ 3.3 (Ϫ51%, P Ͻ 0.005) and 3.0 Ϯ 2.5 (Ϫ66%, P Ͻ 0.005) g/24 h, albumin fractional clearance from 2.3 Ϯ 2.1 to 1.2 Ϯ 1.7 (Ϫ47%, P Ͻ 0.05) and 0.5 Ϯ 0.6 (Ϫ76%, P Ͻ 0.003), and serum albumin concentration increased from 2.7 Ϯ 0.5 to 3.1 Ϯ 0.3 (ϩ21%, P Ͻ 0.05) and 3.5 Ϯ 0.4 (ϩ41%, P Ͻ 0.05) mg/dl. At 12 mo, proteinuria decreased to Յ0.5 g/24 h or Յ3.5 g/24 h in two and three patients, respectively. Proteinuria decreased in the remaining patients by 74%, 44%, and 41%, respectively. Body weight, diastolic BP, and serum cholesterol progressively decreased in parallel with an improvement of edema in all patients. Renal function stabilized (⌬1/creatinine: ϩ0.002 Ϯ 0.007). CD20 B lymphocytes fell below normal ranges up to study-end. No patient had major drug-related events or major changes in other laboratory parameters. Rituximab thus promotes sustained disease remission in patients otherwise predicted to progress to ESRD, and it is safe. The long-term risk/benefit profile of this novel, diseasespecific approach seems much more favorable to that of commonly employed immunosuppressive drugs.Idiopathic membranous nephropathy (IMN) is an immunemediated disease of deposits of immunoglobulins G and complement components on the subepithelial layer of the glomerular capillary wall (1). Data from studies in animals suggest that the immune deposition resulting from B cell activation promotes injury to the glomerular filtering barrier and consequent proteinuria (2). Thus, agents that limit or prevent B cell production of nephritogenic immunoglobulins should block at an early step the sequence of pathogenic events and eventual progressive renal dysfunction in IMN. So far, however, therapeutic approaches to IMN relied on steroids and immunosuppressant drugs, which are not fully specific and carry the risk of severe toxic effects. This may explain why the outcome of IMN has not substantially improved over the past 30 yr and why up to 40% of patients still progress to end-stage renal failure despite treatment with glucocorticoids and alkylating agents. The long-term effectiveness of cyclosporine is also questionable due to the high relapse rates and associated toxic effects of the drug (3,4).Availability of monoclonal antibodies against the cell surface antigen CD20 of B cells allowed to explore whether more specific B cell inhibition (5) may help improving the outcome of IMN and avoiding the side effects of steroids and immunosup...

Rituximab effectively reduces proteinuria in patients with idiopathic membranous nephropathy (IMN), but response to treatment may vary from patient to patient. The association between baseline clinical, laboratory, and histology covariates and proteinuria reduction was evaluated retrospectively by multiple linear regression analysis at 3 mo after rituximab therapy in 14 patients with IMN with proteinuria >3.5 g/24 h while on angiotensin-converting enzyme inhibition for at least 6 mo and no previous remissions. The association strength was expressed by standardized ␤ coefficients (S␤C). Glomerular (S␤C ‫؍‬ 0.48, P ‫؍‬ 0.049) and tubulointerstitial (TI) scores (S␤C ‫؍‬ 0.61, P ‫؍‬ 0.003) predicted the outcome. Among glomerular and TI score components, tubular atrophy (S␤C ‫؍‬ 0.59, P ‫؍‬ 0.003) and interstitial fibrosis (S␤C ‫؍‬ 0.60, P ‫؍‬ 0.001) were significantly associated with 3-mo proteinuria. Urinary protein excretion decreased from 9.1 ؎ 4.0 to 4.6 ؎ 3.5 g/24 h (P < 0.001) in eight patients with TI score <1.7 but did not change in six with a score >1.7. Nine additional patients with IMN then were allocated prospectively to rituximab treatment on the basis of a TI score <1.7. Three-month proteinuria decreased in all patients from 8.9 ؎ 5.3 to 4.9 ؎ 3.9 g/24 h (P < 0.001) and serum albumin increased from 2.2 ؎ 0.6 to 2.8 ؎ 0.5 mg/dl (P < 0.01). Changes in serum albumin and cholesterol were inversely correlated (P < 0.02, r ‫؍‬ ؊0.44). Rituximab achieved CD 20 and CD 19 depletion in all patients. In patients with IMN and nephrotic proteinuria despite angiotensin-converting enzyme inhibition therapy, renal biopsy findings may help in predicting response to rituximab and defining selection criteria for randomized trials that aim to assess the risk/benefit profile of B cell target therapy as compared with aspecific immunosuppressants and/or conservative therapy alone.

In hypertensive type 2 diabetes patients with microalbuminuria, verapamil added-on trandolapril did not improve renal or cardiovascular outcomes. Independent of verapamil, trandolapril normalized albuminuria in half of patients and this translated into significant cardioprotection.

About two thirds of patients on renal replacement therapy irreversibly lose their kidney function because of progressive nephropathies, such as diabetic nephropathy and nondiabetic chronic renal disease. Halting the progression of these patients to end-stage renal disease (ESRD) is instrumental to substantially decrease the need and cost for renal replacement therapy. A large number of experimental studies have demonstrated that chronic nephropathies share common pathogenic mechanisms that contribute to renal disease progression, even independently of the original etiology. Actually, a variety of insults may result in a common pathway of systemic hypertension, increased glomerular pressure and protein ultrafiltration, glomerular and tubular protein overload, chronic inflammation and, ultimately, scarring. Experimental and clinical data converge to indicate that in chronic renal disease increased protein traffic is nephrotoxic, proteinuria predicts disease progression, and proteinuria reduction is renoprotective. Initial clinical trials, mostly in patients with no or mild proteinuria, failed to demonstrate that ACE inhibition therapy is renoprotective in nondiabetic chronic nephropathies. Consistently, meta-analyses based on data generated by these trials failed to detect a specific, blood pressure-independent, renoprotective effect of ACE inhibition therapy. The Ramipril Efficacy In Nephropathy (REIN) study found that ACE inhibitors, by reducing urinary proteins, may contribute to improve the outcome of nondiabetic renal disease, and reduce the risk of progression to ESRD by about 50%. Cumulative meta-analyses, including the REIN study results, confirmed and extended these findings. Thus, well-designed trials in properly selected and carefully monitored study populations continue to be the best approach to test the efficacy of novel treatments. The meta-analyses may help confirming the consistency of these findings and their generalizability to larger cohorts of patients.