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• W2023891464 abstract "Idiopathic membranous nephropathy (IMN) remains the most common histologic entity associated with adult-onset nephrotic syndrome. The therapy for IMN is challenging. Steroids and various other immunosuppressive agents have been tried in IMN; however, current agents have not altered the course of IMN, are nonspecific and can be very toxic. In native kidneys affected by IMN, rituximab, a monoclonal antibody against the B-cell surface antigen CD20, has been shown to reduce proteinuria and prevent disease progression. In this report, we describe a 39-year-old white male with end-stage renal disease secondary to IMN that, 4 months post living unrelated kidney transplant, developed recurrent IMN with 18 g/day of proteinuria. In addition to angiotensin converting enzyme inhibitor and statins, the patient was treated with 4 weekly doses of 375 mg/m2 of rituximab with significant reduction in proteinuria, a corresponding increase in serum albumin and improvement in hypercholesterolemia. At 3 years post-transplant, his kidney function remains stable with 0.5 g/day of proteinuria. Idiopathic membranous nephropathy (IMN) remains the most common histologic entity associated with adult-onset nephrotic syndrome. The therapy for IMN is challenging. Steroids and various other immunosuppressive agents have been tried in IMN; however, current agents have not altered the course of IMN, are nonspecific and can be very toxic. In native kidneys affected by IMN, rituximab, a monoclonal antibody against the B-cell surface antigen CD20, has been shown to reduce proteinuria and prevent disease progression. In this report, we describe a 39-year-old white male with end-stage renal disease secondary to IMN that, 4 months post living unrelated kidney transplant, developed recurrent IMN with 18 g/day of proteinuria. In addition to angiotensin converting enzyme inhibitor and statins, the patient was treated with 4 weekly doses of 375 mg/m2 of rituximab with significant reduction in proteinuria, a corresponding increase in serum albumin and improvement in hypercholesterolemia. At 3 years post-transplant, his kidney function remains stable with 0.5 g/day of proteinuria. Idiopathic membranous nephropathy (IMN) is the most common cause of nephrotic syndrome in adults. Patients with this disease have a variable course. Up to one third of patients have a spontaneous complete or partial remission. The remaining patients have either persistent nephrotic syndrome or progress to end-stage renal disease (ESRD) within 10 years. Significant controversy remains regarding the treatment of IMN. Therapy still relies on steroids and immunosuppressant drugs, which are not fully specific and carry the risk of severe toxic effects. In renal transplant patients, IMN occurs mainly as a de novo disease (1Berger BE Vincenti F Biava C Amend WJJ Feduska N Salvatierra OJ De novo and recurrent membranous glomerulopathy following kidney transplantation.Transplantation. 1983; 35: 315-319Crossref PubMed Scopus (59) Google Scholar) with recurrent disease being relatively infrequent (5–10%) (2Josephson MA Spargo B Hollandsworth D Thistlethwaite JR The recurrence of recurrent membranous glomerulopathy in a renal-transplant recipient—Case-report and literature-review.Am J Kidney Dis. 1994; 24: 873-878Abstract Full Text PDF PubMed Scopus (39) Google Scholar). The course of IMN in renal transplant patients and the potential treatment options are even less clear than in non-renal transplant patients with IMN. Onset of proteinuria and nephrotic syndrome in de novo cases occur slower and later; at a mean of 18 to 21 months after transplantation, as compared to 10 months in recurrent cases (1Berger BE Vincenti F Biava C Amend WJJ Feduska N Salvatierra OJ De novo and recurrent membranous glomerulopathy following kidney transplantation.Transplantation. 1983; 35: 315-319Crossref PubMed Scopus (59) Google Scholar, 2Josephson MA Spargo B Hollandsworth D Thistlethwaite JR The recurrence of recurrent membranous glomerulopathy in a renal-transplant recipient—Case-report and literature-review.Am J Kidney Dis. 1994; 24: 873-878Abstract Full Text PDF PubMed Scopus (39) Google Scholar). Approximately 25% of patients may ultimately lose their graft from recurrent membranous nephropathy (MN). Recurrent MN may have a more aggressive initial course; however, de novo disease has poorer outcomes, with graft loss as high as 50% (3Truong L Gelfand J D’Agati V et al.De novo membranous glomerulonephropathy in renal allografts: A report of ten cases and review of the literature.Am J Kidney Dis. 1989; 14: 131-144Abstract Full Text PDF PubMed Scopus (70) Google Scholar). Initial studies suggested that patients with living kidney transplants are at higher risk for recurrent MN (1Berger BE Vincenti F Biava C Amend WJJ Feduska N Salvatierra OJ De novo and recurrent membranous glomerulopathy following kidney transplantation.Transplantation. 1983; 35: 315-319Crossref PubMed Scopus (59) Google Scholar, 4Obermiller LE Hoy WE Eversole M Sterling WA Recurrent membranous glomerulonephritis in two renal transplants.Transplantation. 1985; 40: 100-102Crossref PubMed Scopus (21) Google Scholar), but further analyses have not confirmed this finding (1Berger BE Vincenti F Biava C Amend WJJ Feduska N Salvatierra OJ De novo and recurrent membranous glomerulopathy following kidney transplantation.Transplantation. 1983; 35: 315-319Crossref PubMed Scopus (59) Google Scholar). IMN may recur earlier in recipients of living donor kidney transplants than in recipients of deceased donor kidneys. The pathogenesis of IMN is linked to podocytes and their membrane-associated proteins which provide antigenic targets for circulating antibodies for in situ formation of glomerular deposits (5Ronco P Debiec H New insights into the pathogenesis of membranous glomerulonephritis [Renal immunology and pathology].Nephrol Hypertens. 2006; 15: 258-263Crossref PubMed Scopus (37) Google Scholar). The B-cell-produced autoantibodies directed against the subepithelial layer of the glomerular capillary wall result in deposits of immunoglobulin G and complement components (6Austin HA Antonovych TT Mackay K Boumpas DT Balow JE Membranous nephropathy.Ann Intern Med. 1992; 116: 672-682Crossref PubMed Scopus (40) Google Scholar). In MN, complement activation overpowers complement regulatory proteins, resulting in podocyte membrane insertion of sublytic quantities of C5b-9 membrane-attack complex, which induce podocyte dysfunction and proteinuria (7Nangaku M Shankland SJ Couser WG Cellular response to injury in membranous nephropathy.J Am Soc Nephrol. 2005; 16: 1195-1204Crossref PubMed Scopus (171) Google Scholar). Proteinuria is a major independent indicator of disease progression. Basement membrane thickening with little or no cellular proliferation is the primary histological finding (6Austin HA Antonovych TT Mackay K Boumpas DT Balow JE Membranous nephropathy.Ann Intern Med. 1992; 116: 672-682Crossref PubMed Scopus (40) Google Scholar, 8Wasserstein AG Membranous glomerulonephritis.J Am Soc Nephrol. 1997; 8: 664-674Crossref PubMed Google Scholar). Electron microscopy reveals electron-dense deposits in the subepithelium. Immunofluorescence demonstrates IgG, immunoglobulin and complement components (9Quigg RJ Why study membranous nephropathy in rats?.Kidney Int. 2003; 64: 2318-2319Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar). De novo MN is related to chronic renal allograft nephropathy, as biopsy reveals signs of vascular and interstitial rejection in addition to the classic findings of MN (3Truong L Gelfand J D’Agati V et al.De novo membranous glomerulonephropathy in renal allografts: A report of ten cases and review of the literature.Am J Kidney Dis. 1989; 14: 131-144Abstract Full Text PDF PubMed Scopus (70) Google Scholar). The pathophysiology of de novo disease may be related to a secondary antibody response to glomerular antigens exposed by rejection or to human leukocyte antigen (HLA) expressed on the graft. In addition, rejection-related capillary wall injury facilitates deposition of immune complexes. The common therapeutic approaches for IMN include (a) supportive care, (b) corticosteroids (usually prednisone or methylprednisolone) and (c) alkylating agents, such as chlorambucil or cyclophosphamide, with or without concurrent corticosteroid treatment (10Brenner BM Membranous glomerulopathy.in: Brenner BM The Kidney. 7th ed. W.B. Saunders, 2004: 1314-1321Google Scholar). Numerous studies using corticosteroid treatment have demonstrated different outcomes. In a pooled analysis of these studies, corticosteroid therapy resulted in no better probability of renal survival than no treatment (11Hogan SL Muller KE Jennette JC Falk RJ A review of therapeutic studies of idiopathic membranous glomerulopathy.Am J Kidney Dis. 1995; 25: 862-875Abstract Full Text PDF PubMed Scopus (178) Google Scholar). Also, steroid treatment regimens show no difference in the recurrence rate of glomerular disease, as compared to those treated with a steroid-free immunosuppression (12Ibrahim H Rogers T Casingal V et al.Graft loss from recurrent glomerulonephritis is not increased with rapid steroid discontinuation protocol.Transplantation. 2006; 81: 214-219Crossref PubMed Scopus (33) Google Scholar). Besides, studies which did show a benefit with steroid monotherapy used toxic doses (cumulative prednisone dose averaged > 25 g), with inadequately proven efficacy. The risk-to-benefit ratio of aggressive treatment protocols with immunosuppressive agents should be weighed cautiously. Recent reports have indicated a potential therapeutic role of B cells depleting agents such as rituximab (a monoclonal antibody against the B-cell surface antigen CD20) in IMN with persistent nephrotic syndrome (13Remuzzi G Chiurchiu C Abbate M Brusegan V Bontempelli M Ruggenenti P Rituximab for idiopathic membranous nephropathy.Lancet. 2002; 360: 923-924Abstract Full Text Full Text PDF PubMed Scopus (283) Google Scholar, 14Ruggenenti P Chiurchiu C Brusegan V et al.Rituximab in idiopathic membranous nephropathy: A one year prospective study.J Am Soc Nephrol. 2003; 14: 1851-1857Crossref PubMed Scopus (199) Google Scholar). Rituximab thus attenuates antibody production in IMN. Therefore, we investigate the efficacy and safety of rituximab in a renal transplant patient with documented recurrent IMN. JC is a 39-year-old white male with ESRD secondary to IMN. During a routine follow-up visit at our renal transplant clinic, 4 months after receiving an HLA-identical renal transplant, he was found to have 3+ protein on a dipstick urinalysis. His review of system was negative for shortness of breath, orthopnea or paroxysmal nocturnal dyspnea. His physical examination was unremarkable, with his blood pressure (BP) around 140/80 mmHg on Lisinopril. His past medical history was positive for hypertension, IMN, gastro-esophageal reflux disease, chronic obstructive pulmonary disease and ESRD secondary to IMN. Our patient was diagnosed with IMN in 1999. He was treated only with angiotensin converting enzyme (ACE) inhibitors. No alkylating agents or corticosteroids were used. His native kidneys failed in 2001. He was on hemodialysis for 15 months prior to receiving a living unrelated kidney transplant on July 1, 2003. Patient was anuric prior to his renal transplant. His immunosuppressive therapy consisted of induction with alemtuzumab (Campath-1H) at the dose of 30 mg I.V. on the day of the surgery and 3 days of methylprednisolone at the dose of 500 mg I.V. on day 0, 250 mg I.V. on day 1 and 125 mg I.V. on day 2 postsurgery followed by no chronic steroid administration (rapid steroid elimination). His maintenance immunosuppressive therapy consisted of mycophenolate mofetil (Cellcept) at the dose of 1000 mg twice/day and tacrolimus (Prograf) at the dose of 1 mg twice/day, with a trough level between 6 and 9 ng/mL during the entire post-transplant follow-up. Work-up for his proteinuria included: Renal ultrasound that showed no hydronephrosis or renal vein thrombosis in either native or transplant kidney; a quantitative 24-h urine protein was consistent with 18 g/day; lipid profile that showed total cholesterol of 273 mg/dL, triglycerides of 118 mg/dL, high density lipoprotein of 47 mg/dL, low density lipoprotein (LDL) of 164 mg/dL. His total plasma protein was 3.8 g/dL and plasma albumin 1.5 mg/dL. Secondary work-up included: antinuclear antibody, anti-double-stranded deoxyribonucleic acid antibody, complement (C3, C4 CH-50) levels, perinuclear antineutrophil cytoplasmic antibody, cytoplasmic antineutrophil cytoplasmic antibody, serum and urine protein electrophoresis, prostate specific antigen, hepatitis panel, colonoscopy, chest radiograph and cystoscopy. All these tests were negative. An allograft kidney biopsy was performed in November 2003 and it revealed recurrent IMN. Staining for C4d deposition was negative. The patient was immediately started on treatment with lisinopril and atorvastatin, which were maximized over 1-month time. Despite excellent BP control and the use of ACE inhibitor at full-dose, his repeated 24-h urine collection was 16 g/day. In December 2003, we decided, after obtaining written informed consent from the patient, to treat him with 4 weekly doses of rituximab 375 mg/m2. Patient was admitted for 24-h observation at the time of the weekly dose of rituximab. The total dose of rituximab at each admission was 770 mg given I.V. Proteinuria and other clinical variables were measured at baseline, weekly during the treatment period and every 6 months thereafter. At baseline, patient had 16 g/day of proteinuria, a systolic BP of 125 mmHg and diastolic BP of 70 mmHg, a serum creatinine of 1.8 mg/dL with and estimated glomerular filtration rate (eGFR) by Modification of Diet in Renal Disease Study (MDRD) equation of 45 mL/min/1.73 m2. The CD19 + CD20 positive B lymphocytes measured at baseline, prior to rituximab infusion, was 34% (normal range 4–28) with an absolute B-cell count 126/μL. After the first dose of rituximab, CD20 + CD19 B lymphocytes decreased to <1% (absolute B-cell count 2.5/μL). The time course eGFR calculated using the MDRD equation, 24-h urinary protein and percentage of CD20 + CD19 B lymphocytes during the entire follow-up are shown in Figure 1. After 1 month of rituximab infusion, there was significant reduction in proteinuria from 16 to 2.3 g/day and a corresponding increase in serum albumin and total protein (Figure 2). Post rituximab infusion, proteinuria continued to decline to a recent (December 2005) 24-h urine collection consistent with 0.5 g/day. Reduction in proteinuria and increase in serum albumin was followed by a significant improvement in lipid profile (data not shown) with recent total cholesterol of 125 mg/dL and LDL of 63 mg/dL from baseline, prior to correction of hypo-albuminemia, of 273 mg/dL and 164 mg/dL, respectively. At 6 and 12 months post-rituximab, the percentage of CD20 + CD 19 B lymphocytes was still <1% (Figure 1) with an absolute B-cell count 12 months post-rituximab of 4.24/μL. Patient’s BP during the entire follow-up after rituximab infusion, ranged between 120 and 130/60 and 70 mmHg.Figure 2Proteinuria and serum albumin at baseline and post rituximab infusion during the entire follow-up.View Large Image Figure ViewerDownload Hi-res image Download (PPT) IMN remains one of the most common causes of nephrotic syndrome in adults. Current therapy consisting of immunosuppressive agents and steroids are not specific and have a high incidence of adverse reactions (13Remuzzi G Chiurchiu C Abbate M Brusegan V Bontempelli M Ruggenenti P Rituximab for idiopathic membranous nephropathy.Lancet. 2002; 360: 923-924Abstract Full Text Full Text PDF PubMed Scopus (283) Google Scholar). In spite of treatment with steroids and alkylating agents, the outcome of IMN has not significantly improved, with 40% of the patients developing ESRD (15Remuzzi G Rituximab for idiopathic membranous nephropathy (vol 360, pg 923, 2002).Lancet. 2002; 360 (2090–2090)Abstract Full Text Full Text PDF Scopus (285) Google Scholar). Cyclosporine is associated with high relapse rates and toxic effects (16Schieppati A Perna A Remuzzi G Recent developments in the management of membranous nephropathy.Expert Opin Investig Drugs. 1997; 6: 521-532Crossref PubMed Scopus (5) Google Scholar). With better understanding of the pathogenesis of IMN, agents acting against B cells constitute a more selective form of therapy. Rituximab therapy has been reported to be successfully used for treatment of various autoimmune diseases, such as systemic lupus erythematosus, rheumatoid arthritis, autoimmune thrombocytopenia, cold agglutinin disease, mixed cryglobulinemia, myasthenia gravis, autoantibodies associated neuropathies, Wegeners’ granulomatous disease and IMN (14Ruggenenti P Chiurchiu C Brusegan V et al.Rituximab in idiopathic membranous nephropathy: A one year prospective study.J Am Soc Nephrol. 2003; 14: 1851-1857Crossref PubMed Scopus (199) Google Scholar, 17Johnson PWM Glennie MJ Rituximab: Mechanisms and applications.Br J Cancer. 2001; 85: 1619-1623Crossref PubMed Scopus (96) Google Scholar, 18Rossi P Demoux AL Granel B Bagneres D Bonin-Guillaume S Frances Y Anti-CD20 monoclonal antibody for the treatment of refractory autoimmune haemolytic anaemia associated with idiopathic membranous nephropathy.Rheumatology. 2005; 44: 403-405Crossref PubMed Scopus (10) Google Scholar). Rituximab is well tolerated and has only very limited toxic profile. Circulating CD 20 cell depletion has been observed up to 1 year after rituximab infusions (14Ruggenenti P Chiurchiu C Brusegan V et al.Rituximab in idiopathic membranous nephropathy: A one year prospective study.J Am Soc Nephrol. 2003; 14: 1851-1857Crossref PubMed Scopus (199) Google Scholar). Remuzzi used rituximab infusions (375 mg/m2) every 4 weeks for 5 months, in 7 patients with IMN in native kidney disease, and found a reduction in proteinuria, which was closely associated with circulating CD20 cell depletion (15Remuzzi G Rituximab for idiopathic membranous nephropathy (vol 360, pg 923, 2002).Lancet. 2002; 360 (2090–2090)Abstract Full Text Full Text PDF Scopus (285) Google Scholar). The decreased proteinuria resulted in a corresponding increase in serum albumin levels, reduction in edema and hypercholesterolemia. In a 1-year prospective study, Ruggenenti et al. showed a significant persistent decrease in proteinuria after 4 weekly-rituximab infusions (375 mg/m2) in 8 patients with IMN (14Ruggenenti P Chiurchiu C Brusegan V et al.Rituximab in idiopathic membranous nephropathy: A one year prospective study.J Am Soc Nephrol. 2003; 14: 1851-1857Crossref PubMed Scopus (199) Google Scholar). Rituximab prevented disease progression and it was well tolerated. Rossi et al. reported complete recovery of corticoresistant autoimmune hemolytic anemia associated with IMN with rituximab infusions (375 mg/m2), given once-weekly for 4 doses, then once-monthly for 5 more doses (18Rossi P Demoux AL Granel B Bagneres D Bonin-Guillaume S Frances Y Anti-CD20 monoclonal antibody for the treatment of refractory autoimmune haemolytic anaemia associated with idiopathic membranous nephropathy.Rheumatology. 2005; 44: 403-405Crossref PubMed Scopus (10) Google Scholar). We decided to treat our patient with recurrent IMN post renal transplant and with persistent, severe proteinuria despite full-dose ACE inhibitors with 4 weekly-doses of 375 mg/m2 of rituximab intravenous infusions to control disease progression by reducing proteinuria. After 1 month of rituximab infusion, there was significant reduction in proteinuria from 16 g/day to 2.3 g/day, a corresponding increase in serum albumin and total protein and improvement of hypercholesterolemia. The reduction in proteinuria was paralleled to the depletion of CD20 and CD19 B lymphocytes induced by rituximab. During the entire post-transplant follow-up, proteinuria continued to decline to 0.5 g/day. Furthermore, renal allograft function remained stable with a recent eGFR of 51 mL/min/1.73 m2. Treatment with rituximab was well tolerated with no adverse events such as infections, malignancy or bone marrow suppression. The speculative role of rituximab as a renoprotective medication to treat IMN has already been described (14Ruggenenti P Chiurchiu C Brusegan V et al.Rituximab in idiopathic membranous nephropathy: A one year prospective study.J Am Soc Nephrol. 2003; 14: 1851-1857Crossref PubMed Scopus (199) Google Scholar). Specifically, it has been suggested that rituximab, by eliminating auto-reactive B lymphocyte clones committed to produce nephritogenic immunoglobulins, can ameliorate the clinical course of IMN. Given the rapidity (within 4 months) of the recurrent IMN post renal transplant, it is tempting to say that also in our patient a B-cell-dependent pathway causing the production of nephrogenic immunoglobulin did play a significant role in the pathophysiology of this disease. In fact, reduction of proteinuria followed the depletion of CD20 and CD19 B cells. It is also interesting to note that our patient received an HLA-identical renal transplant, raising the possibility of pre-existing (before renal transplant) cross-reactive ‘auto-allo’ B cells. Is it possible that the significant reduction of proteinuria was secondary to the use of ACE inhibitors? There is a dose-response relationship with ACE inhibitors, with an effect noticed as early as 1 month, with a maximal effect at 14 months (19Brenner BM Pharmacology of the nondiuretic antihypertensive drugs; Angiotensin-converting enzyme inhibitors.in: Brenner BM The Kidney. 7th ed. W.B. Saunders, 2004: 2381-2388Google Scholar). In our patient, despite full dose of ACE inhibitors for more than a month, severe proteinuria still persisted and it improved only after therapy with rituximab. Furthermore, our patient was started on ACE inhibitors, once diagnosed with IMN affecting his native kidneys. This treatment did not impact the clinical course of his disease. In fact, he lost his native kidney function within 2 years from the diagnosis. Could this be a spontaneous complete remission? Our patient lost his native kidneys secondary to IMN and developed recurrent IMN shortly after receiving his renal transplant. This implies a severe underlying disease that despite aggressive immunosuppression given post-transplant, still recurred in the renal allograft. Furthermore, proteinuria improved only after rituximab was given. For these reasons, we believe that the possibility for spontaneous remission is remote. Lastly, our patient received Campath 1H as induction agent. Campath is a humanized mAb against CD52, a small glycosylphosphatidylinositol-anchored glycoprotein determinant that is highly expressed on both T and B cells. However, despite its reactivity against B cells, it has been unable to prevent and in fact may result in increased rates of C4d-positive acute humoral rejections (20Jordan SC Pescovitz MD Presensitization: The problem and its management.Clin J Am Soc Nephrol. 2006; 1: 421-432Crossref PubMed Scopus (104) Google Scholar). Our patient, in November 2003, 4 months after his renal transplant, had normal or slightly increased number of circulating B cells (34%, with an absolute count 126/μL) despite lymphopenia (total lymphocytes 7%, with a normal range of 15–50%). It is outside the scope of this case report to further speculate on the role of Campath 1H in prevention and treatment of recurrent IMN, given the paucity of available published data. But based on few reports, we can suggest that B cells tend to repopulate faster than T cells after Campath induction; and as a consequence, in our patient this rapid repopulation could have been linked to the rapid reoccurrence of IMN in the renal allograft. Rituximab was effective in depleting potential auto-reactive B lymphocyte clones committed to producing nephritogenic immunoglobulins, and could explain the associated clinical improvement observed during the follow-up. In conclusion, this report suggests the use of rituximab as a potential therapeutic option for recurrent IMN in a renal transplant patient, which warrants further exploration." @default.
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• W2023891464 title "Anti-CD20 Monoclonal Antibody (Rituximab) for the Treatment of Recurrent Idiopathic Membranous Nephropathy in a Renal Transplant Patient" @default.
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