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Effects of Rituximab on Morphofunctional Abnormalities of Membranous Glomerulopathy

Piero Ruggenenti^*,, Paolo Cravedi^*,, Maria Chiara Sghirlanzoni, Elena Gagliardini^*, Sara Conti^*, Flavio Gaspari^*, Gianfranco Marchetti, Mauro Abbate^*, and Giuseppe Remuzzi^*,

^* Clinical Research Centre for Rare Diseases "Aldo e Cele Daccò," Mario Negri Institute for Pharmacological Research, Bergamo, Italy; and Unit of Nephrology, Azienda Ospedaliera Ospedali Riuniti, Bergamo, Italy

Correspondence: Dr. Piero Ruggenenti, "Mario Negri" Institute for Pharmacological Research, Negri Bergamo Laboratories, Via Gavazzeni, 11–24125 Bergamo, Italy. Phone: +39 035 319 888; Fax: +39 035 319 331; E-mail: manuelap{at}marionegri.it or pruggenenti{at}ospedaliriuniti.bergamo.it

Background and objectives: In idiopathic membranous nephropathy (IMN), CD₂₀ B-cell depletion by rituximab may induce nephrotic syndrome (NS) remission. Whether this is associated with kidney function restoration and regression of the glomerular pathology was evaluated.

Design, setting, participants, & measurements: Treatment-induced morphofunctional changes were evaluated in 7 IMN patients consenting to repeat functional and morphologic evaluations after stable disease remission achieved by four weekly rituximab (375 mg/m²) infusions.

Results: Over a median of 21 mo from rituximab administration, NS remission was associated with 8.5-fold increase versus baseline in sodium fractional clearance from 1.56 to 13.25, decrease in renal plasma flow from 440.8 to 276.6 ml/min per 1.73 m², stable glomerular filtration rate, and increased renal vascular resistances. Changes in sodium fractional clearance and hemoglobin concentration were positively correlated (r = 0.82). Biopsy reevaluations showed complete or partial reabsorption of subepithelial deposits. Median (interquartile range) IgG4 staining score decreased from 3 (3–3) to 1 (0–2), whereas total numbers of slit diaphragms (0.27; range, 0.19 to 0.30 versus 0.86; range, 0.53 to 1.16 slits/µm glomerular basement membrane) and percentages of those with electron-dense diaphragm (55.2; range, 42.0 to 62.0 versus 78.5; range, 73.0 to 82.7 of all slits) significantly increased in parallel with amelioration of glomerular ultrastructural changes. Changes in slit frequency and albumin fractional clearance were negatively correlated (r = –0.79).

Conclusions: In human IMN, treatment-induced NS remission is associated with restoration of sodium homeostasis and kidney hemodynamics, and regression of the glomerular changes underlying proteinuria. These effects are likely to translate into long-term renoprotection.