INDEX WORDS: B Cells; therapy; glomerular fibrils; immunoglobulins.
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ibrillary glomerulonephritis (FGN) is charac-terized by the deposition of randomly ar-
anged fibrils in the glomerular mesangium andasement membrane.1,2 These fibrils generally are0 nm or less in diameter and contain immuno-lobulin, especially immunoglobulin G 4 (IgG4),s a component.3 The prognosis for patients withGN is relatively poor, with 50% of patients pro-ressing to end-stage kidney disease within 3 to 5ears.1,4
No specific treatment is consistently effectiveor patients with FGN.5,6 Because glomerularnjury is related to aberrant immunoglobulineposition, we postulated that FGN may be sec-ndary to a B-cell dyscrasia,4 and anti–B-cellherapy may be useful.
In this report, we present 3 patients with FGNho improved clinically after treatment with
From the 1Ohio State University College of Medicine,olumbus, OH; 2University of Rochester Medical Center, Roch-ster; and 3Columbia University Medical Center, New York, NY.
Received February 5, 2008. Accepted in revised form July, 2008. Originally published online as doi:0.1053/j.ajkd.2008.07.011 on September 29, 2008.Drs Collins and Navaneethan contributed equally to this work.Address correspondence to Brad H. Rovin, MD, Nephrol-
ituximab, a monoclonal antibody directed againsthe B-cell antigen CD20.
CASE REPORTS
ase 1
A 50-year-old hypertensive white woman developed pro-einuria with urine protein of 3.6 g/d. Serum creatinine levelas 0.8 mg/dL (70.72 �mol/L). Physical examination find-
ngs were unremarkable except for blood pressure of 158/84m Hg and trace pedal edema. Workup showed normal
omplement levels, no antinuclear or double-stranded DNAntibodies, no cryoglobulins, and negative serum immuno-xation and urine protein electrophoresis results. The kidneyiopsy specimen (11 glomeruli) showed an increase inesangial matrix, glomerular basement membrane thicken-
ng, and segmental sclerosis on light microscopy (Fig 1A).mmunofluorescence showed diffuse patchy granular andesangial IgG (2�), IgM (1�), and C3 (1�; Fig 1B). IgA
nd C1q results were negative. Electron microscopy showedxtensive glomerular deposition of electron-dense fibrils inhe mesangium and glomerular basement membraneFig 1C, D). Fibrils ranged from 17 to 40 nm, with most 20o 30 nm. Crystal violet and Congo red stains were negative.
diagnosis of FGN with secondary focal segmental glomer-losclerosis was made. The patient was treated with anngiotensin receptor blocker, �-blocker, aldosterone antago-ist, and clonidine, but proteinuria worsened (protein � 6/d) and creatinine level increased to 1.3 mg/dL (114.9mol/L). She was treated with rituximab (375 mg/m2/wk forweeks) and tacrolimus (1 mg/d). Proteinuria decreased to
ess than 1 g/d of protein at the end of 2 months, butncreased to 4 g/d at 6 months, with a serum creatinine levelf 1.2 mg/dL (106 �mol/L; Fig 2A). She received a secondycle of rituximab therapy, and 2 months after finishing,roteinuria decreased to 1.6 g/d of protein and creatinine
evel was stable at 1.3 mg/dL (114 �mol/L).
Diseases, Vol 52, No 6 (December), 2008: pp 1158-1162
A39-year-old hypertensive white woman developed hematu-ia (3 to 4 nondysmorphic red blood cells/high-power field) androteinuria (protein, 0.68 g/d) with normal kidney functioncreatinine, 0.7 mg/dL [61.9 �mol/L]). Physical examinationndings were unremarkable. Workup showed negative resultsor cryoglobulins, urine immunofixation, and hepatitis profile;ormal complement levels; and no antinuclear antibody orntineutrophil cytoplasmic antibodies. The kidney biopsy speci-en had 9 glomeruli, and light microscopy showed diffuse and
lobal mild mesangial hypercellularity with mild to moderateesangial matrix expansion, patchy interstitial fibrosis, and
ubular atrophy. Immunofluorescence showed diffuse and globalesangial granular staining for IgG, C3, and � and � light
hains. IgA, IgM, C1q, albumin, and fibrinogen staining resultsere all negative. Electron microscopy showed mesangialypercellularity and prominent mesangial fibrils that had aean diameter of 19 nm (Fig 1E, F), leading to a diagnosis ofGN. Congo red stain was negative. She was treated conserva-ively with an angiotensin-converting enzyme inhibitor,
oop positivity. (C-G) Electron micrographs of fibrillary dephe mean diameter of fibrils is given on the micrographs. (O52,000, [G] �6,000.)
-blocker, and protein and sodium restriction and achieved n
lood pressure control (124/86 mm Hg). Two years later, sheeveloped lower-extremity edema and proteinuria increased to.5 g/d of protein. Creatinine clearance remained normal. Theatient was treated with rituximab (375 mg/m2/wk for 4 weeks),nd 1 month after treatment, had no detectable circulatingD19 or CD20 B cells. Initially, there was a small decrease inroteinuria, but 4 months after treatment, proteinuria was 5.6/d of protein (Fig 2B). Interestingly, peripheral B cells wereeturning by this time (CD19 and CD20 were both 212/�L;ormal, 20 to 400/�L). Urine sediment showed numeroushite blood cell casts and acanthocytes, which was different
rom all previous urinalyses. This was believed to possiblyepresent acute interstitial nephritis on top of FGN; therefore, ahort course of prednisone (60 mg/d tapered by 10 mg/wk) wasiven.Although no additional rituximab or corticosteroids weresed, urine sediment cleared and, over time, proteinuria com-letely resolved (Fig 2A).
ase 3
A 46-year-old hypertensive white woman presented with
from patient 1 shows mild periodic acid–Schiff–positiveoglobulin G from patient 1 shows mesangial and capillary
und in patient 1 (C, D), patient 2 (E, F), and patient 3 (G).magnification: [C] �30,000, [D] �60,000, [E] �42,000, [F]
as controlled to less than 140/90 mm Hg on angiotensin-onverting enzyme inhibitor and angiotensin receptor blockerherapy, and serum creatinine level was 0.6 mg/dL (53 �mol/). Physical examination findings were normal. Urinalysishowed 3� protein, no microscopic hematuria, and no urineediment. Antinuclear antibodies, anti–double-stranded DNA,nd antinuclear cytoplasmic antibodies were absent. Serologi-al test results for hepatitis B antigens and hepatitis C antibodyere negative. A kidney biopsy was performed (12 glomeruli),hich showed diffuse mesangial proliferative glomerulonephri-
is with membranoproliferative and segmental sclerosis. Immu-ofluorescence showed global mesangial and capillary walleposits that stained 3� for IgG, 2� for C3, and 3� for � and, and electron microscopy showed global mesangial andapillary deposits with fibrillary substructure. The fibrils wereandomly oriented, with a mean diameter of 30 nm (range, 26o 35 nm; Fig 1G). Congo red stain was negative.Adiagnosis ofGN was made. The patient received intravenous rituximab1,000 mg for 2 doses), and the response over time is shown inig 2C.
DISCUSSION
These cases suggest that anti-CD20 monoclo-al antibody therapy may be useful in the treat-
Figure 2. Clinical course of patients. (A) Time course oFGN) was diagnosed in patient 1; arrows, first and secondnd kidney function after FGN was diagnosed in patiendministered. (C) Time course of proteinuria and kidney fdministered. To convert serum creatinine in mg/dL to �mo
ent of patients with FGN. All patients im- p
roved after therapy, and no adverse effectsaused by rituximab were observed. One patientxperienced a relapse and received another cyclef rituximab therapy with improvement. Thereave been no previous reports of patients withGN treated with anti–B-cell therapies.Concomitant immunotherapy was adminis-
ered to 2 patients. In patient 1, rituximab wassed with low-dose tacrolimus. Although weannot determine whether the rapid improve-ent in proteinuria was caused by rituximab or
acrolimus, no study has shown a beneficial ef-ect of tacrolimus, and the patient experienced aelapse on tacrolimus therapy. However, re-reatment with rituximab alone induced a signifi-ant decrease in proteinuria within 2 months. Inatient 2, urine sediment became inflammatorynd proteinuria acutely worsened when B cellsegan to recover. A short course of corticoste-oids was given. The inflammatory urine sedi-ent cleared, and over time, proteinuria com-
nuria and kidney function after fibrillary glomerulonephritiss of rituximab administered. (B) Time course of proteinuriarow, rituximab therapy initiated; asterisk, corticosteroids
after FGN was diagnosed in patient 3; arrow, rituximabltiply by 88.4.
f proteicourset 2; ar
letely resolved. This response was believed to
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Rituximab and Fibrillary Glomerulonephritis 1161
e caused by corticosteroid-induced remission ofcute interstitial nephritis, rather than an FGNesponse to the brief administration of corticoste-oids. The patient in case 3 was treated with onlyituximab, showing that it can be effective with-ut adjunctive immunosuppressive therapy andupporting a primary benefit from rituximabherapy in our other patients.
Rituximab treatment of patients with otherlomerulopathies characterized by immune com-lex or immunoglobulin-containing deposits pro-ides additional evidence for a primary benefit ofnti–B-cell therapy. Eight patients with idio-athic membranous nephropathy received 375g/m2/wk of rituximab for 4 weeks, and all
howed improvement in proteinuria, with 5 pa-ients showing a decrease in proteinuria greaterhan 50%.7 In a related prospective study, 15atients with membranous disease were treatedith 1 g of rituximab twice, and 60% achieved
omplete or partial remission by 12 months, withn average decrease in proteinuria of 48%.8
imilarly, 5 patients with hepatitis C–associatedixed essential cryoglobulinemia were treatedith rituximab alone (375 mg/m2/wk for 4eeks), and all showed significant decreases inroteinuria.9
Attenuation of proteinuria after rituximabherapy generally was seen within 1 to 3 monthsn our patients, although continued improvementften occurred during the next several months. Aimilar time course was found in patients withembranous nephropathy, cryoglobulinemia, and
upus nephritis.9-12
Taken together, these data suggest that if glo-erular immunoglobulin deposition can be haltedy depleting B cells, glomeruli can undergoepair. However, decreasing immunoglobulin pro-uction is not the only mechanism of action ofituximab. Depletion of B cells also modulates-cell activity,10,11 probably because B cells canroduce cytokines and growth factors, and presentntigens to T cells.12
We observed no adverse effects of rituximab,n agreement with its good safety profile in thereatment of patients with other immune-medi-ted diseases.13 The safety of rituximab therapyay be improved further by adjusting administra-
ion to B-cell levels. A recent study of patientsith membranous nephropathy showed that cir-
ulating B cells disappeared in most patients I
ithin a week of the first dose.14 These patientshowed a decrease in proteinuria similar to thatf patients given 4 weekly doses. In addition toost savings and avoidance of unnecessary expo-ure, dosing to effect rather than according to anrbitrary regimen may prevent infusion reactionsnd the development of antibodies to rituximab.
In summary, these 3 cases suggest that ritux-mab can be used safely to induce complete orartial remission in patients with FGN. Severaluestions remain, including the optimal dosingegimen, duration of response, ultimate outcomen terms of chronic kidney disease and end-stageidney disease, relevance of re-treatment in pa-ients who experience relapse or achieve onlyartial remission, and whether rituximab shoulde combined with other immunosuppressivegents. Nonetheless, this report provides evi-ence for conducting a prospective trial ofnti–B-cell therapy in patients with a diseaseraditionally considered treatment resistant andf poor renal prognosis.
ACKNOWLEDGEMENTSSupport: None.Financial Disclosure: Drs Rovin and Appel are consult-
ogic features of fibrillary glomerulonephritis. Kidney Int2:1401-1407, 19925. Scwartz MM, Korbet SM, Lewis EJ: Immunotactoid
lomerulopathy. J Am Soc Nephrol 13:1390-1397, 20026. Dickenmann M, Schaub S, Nickeleit V, Mihatsch M,
teiger J, Brunner F: Fibrillary glomerulonephritis: Earlyiagnosis associated with steroid responsiveness. Am J Kid-ey Dis 40:E9, 20027. Remuzzi G, Chiurchiu C, Abbate M, Brusegan V,
ontempelli M, Ruggeneti P: Rituximab for idiopathic mem-ranous nephropathy. Lancet 360:923-924, 20028. Fervenza FC, Cosio FG, Erickson SB, et al: Rituximab
reatment of idiopathic membranous nephropathy. Kidney
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9. Quartuccio L, Soardo G, Romano G, et al: Treatmentor glomerulonephritis in HCV-associated mixed cryoglobu-inaemia—Anti-viral therapy vs rituximab. RheumatologyOxford) 45:842-846, 2006
10. Sfikakis PP, Boletis JN, Lionaki S, et al: Remission ofroliferative lupus nephritis following B cell depletionherapy is preceded by down-regulation of the T cell costimu-atory molecule CD40 ligand: An open-label trial. Arthritisheum 52:501-513, 200511. Vigna-Perez M, Hernández-Castro B, Paredes-Sahar-
pulos O, et al: Clinical and immunological effects of
ituximab in patients with lupus nephritis refractory to a
onventional therapy: A pilot study. Arthritis Res Ther:E83, 200612. Bhat P, Radhakrishnan J: B Lymphocytes and lupus
ephritis: New insights into pathogenesis and targeted thera-ies. Kidney Int 73:261-268, 200813. Fleischmann RM: Safety of biologic therapy in rheu-atoid arthritis and other autoimmune diseases: Focus on
