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.

ESRD represents a major health problem. The number of patients who enter kidney replacement programs has increased at an average of 7% per year in the past 10 yr. A large number of experimental and clinical studies have demonstrated that chronic nephropathies share common pathogenic mechanisms that contribute to renal disease progression, even independent of the original cause. Clinical studies found a significant correlation between the extent of urinary protein excretion and the rate of GFR decline in both diabetic and nondiabetic chronic nephropathies. Randomized trials, in particular the Ramipril Efficacy In Nephropathy (REIN) study, also showed that treatments that reduce proteinuria (namely angiotensin-converting enzyme [ACE] inhibitors) are renoprotective and limit progression to ESRD. Meta-analyses of randomized clinical trials also evaluated the role of proteinuria and of ACE inhibition therapy in chronic renal disease progression. Their findings were consistent with those of the REIN study and confirmed in larger series of patients the predictive value of proteinuria and the renoprotective effect of proteinuria reduction by ACE inhibition therapy. Thus, the meta-analyses may confirm and extend previous findings generated by randomized clinical trials. Conceivably, well-designed studies in properly selected and carefully monitored patients who are at increased risk continue to be the best approach to test novel hypotheses. The meta-analyses, however, represent a valuable tool to evaluate the consistency and generalizability of trial results to larger cohorts of patients.

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.

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Abstract-To assess whether angiotensin-converting enzyme inhibitors and third-generation dihydropyridine calcium channel blockers ameliorate diabetic complications, we compared glomerular filtration rate (GFR; primary outcome), cardiovascular events, retinopathy, and neuropathy in 380 hypertensive type 2 diabetics with albuminuria Ͻ200 mg/min included in a multicenter, double-blind, placebo-controlled trial (DEMAND [Delapril and Manidipine for Nephroprotection in Diabetes]) and randomized to 3-year treatment with manidipine/delapril combination (10/30 mg/d; nϭ126), delapril (30 mg/d; nϭ127), or placebo (nϭ127). GFR was centrally measured by iohexol plasma clearance. Median monthly GFR decline (interquartile range ) on placebo (Pϭ0.87 and Pϭ0.53 versus combined therapy or delapril, respectively). Similar findings were observed when baseline GFR values were not considered for slope analyses. Albuminuria was stable in the 3 treatment groups. The hazard ratio (95% CI) for major cardiovascular events between combined therapy and placebo was 0.17 Pϭ0.023). Among 192 subjects without retinopathy at inclusion, the hazard ratio for developing retinopathy between combined therapy and placebo was 0.27 (0. Pϭ0.048). Among 200 subjects with centralized neurological evaluation, the odds ratios for peripheral neuropathy at 3 years between combined therapy or delapril and placebo were 0.45 (0.24 -0.87; Pϭ0.017) and 0.52 (0.27-0.99; Pϭ0.048), respectively. Glucose disposal rate decreased from 5.8Ϯ2.4 to 5.3Ϯ1.9 mg/kg per min on placebo (Pϭ0.03) but did not change on combined or delapril therapy. Treatment was well tolerated. In hypertensive type 2 diabetic patients, combined manidipine and delapril therapy failed to slow GFR decline but safely ameliorated cardiovascular disease, retinopathy, and neuropathy and stabilized insulin sensitivity. (Hypertension. 2011;58:776-783.) • Online Data Supplement Key Words: ACE inhibitors Ⅲ calcium channel blockers Ⅲ manidipine Ⅲ diabetic nephropathy Ⅲ cardiovascular complications Ⅲ diabetic neuropathy Ⅲ diabetic retinopathy Received April 11, 2011; first decision April 26, 2011; revision accepted August 25, 2011. From the Mario Negri Institute for Pharmacological Research (P.R., I.P.I., A.F., A.P.I., S.R., C.C., N.R., G.N., N.M., B.E.-I., F.G., A.P., G.R.), Clinical Research Center for Rare Diseases "Aldo e Cele Daccò," Ranica, Bergamo, Italy; Unit of Nephrology (P.R., S.R., G.R.), Azienda Ospedaliera Ospedali Riuniti di Bergamo, Bergamo, Italy; Neuromuscular Diseases Unit (G.L., A.S., R.L., P.P.), Istituto Di Ricovero e Cura a Carattere Scientifico Foundation "Carlo Besta" Neurological Institute, Milan, Italy; Department for Endocrinology, Diabetes and Metabolic Diseases (P.B., J.Z.), University Medical Centre, Ljubljana, Slovenia; Department of Neuroscience and Biomedical Technologies (G.C. A ngiotensin-converting enzyme (ACE) inhibitors and angiotensin II antagonists are the antihypertensive agents that more effectively reduce macrovascular disease 1 and limit the onset and progression o...