Christoph C. Haufe

Increased Binding of Beta-2-Microglobulin to Blood Cells in Dialysis Patients Treated with High-Flux Dialyzers Compared with Low-Flux Membranes Contributed to Reduced Beta-2-Microglobulin Concentrations

Background: Patients on long-term dialysis eventually develop amyloid deposits with β2-microglobulin as a predominant component. Although several studies have suggested that high-flux membranes reduce β2-microglobulin in plasma compared with low-flux dialyzers, the mechanisms underlying this observation are still discussed. Methods: We revisited this important subject and measured β2-microglobulin in the plasma of healthy individuals (n = 8), and patients undergoing hemodialysis (n = 20) who for assigned periods of time were either treated with a low-flux membrane (cuprophan) or high-flux (polyamide) dialyzer with an ELISA. The number of blood cells was determined by FACS. β2-Microglobulin was also measured on the surface of granulocytes, lymphocytes, and monocytes before, directly after, and 4 h after hemodialysis. Expression of β2-microglobulin, c-fos, tumor necrosis factor-α (TNF-α), and interleukin-1 mRNA was determined in whole blood samples with quantitative RT-PCR using an internal standard in parallel. In the second part of the study, patients were assigned in a two-group cross-over design either to low- or high-flux dialyzers (n = 9 in each group), and dialyzer membranes were changed every 4 weeks for two consecutive periods. Serum β2-microglobulin concentrations were measured at the end of each period. Results: Healthy controls had a low plasma β2-microglobulin level of 1.2 ± 0.3 mg/l. Before hemodialysis, patients on low-flux dialyzers had a plasma β2-microglobulin level of 42.0 ± 14.0 mg/l, patients treated with high-flux dialyzers 21.5 ± 10.8 mg/l (p < 0.05 vs. low-flux dialyzers). In contrast, there was no significant difference in plasma concentrations of active transforming growth factor-β1 with the two different membrane types. The difference in serum β2-microglobulin between low- and high-flux membranes was more prominent directly after hemodialysis as well as 4 h after hemodialysis compared with the values directly before the start of treatment. At all studied time-points, leukocytes and platelets were significantly higher in patients on low-flux membranes. Healthy control persons exhibited a significantly higher amount of β2-microglobulin bound to granulocytes, lymphocytes, and monocytes compared with dialysis patients. Interestingly, β2-microglobulin bound to granulocytes, lymphocytes, and monocytes was significantly increased in patients treated with high-flux membranes compared with low-flux filters. Quantitative RT-PCR revealed no significant difference in β2-microglobulin expression in whole blood before hemodialysis, directly after hemodialysis, and 4 h after hemodialysis. However, TNF-α and c-fos transcripts were significantly higher in whole blood obtained from patients treated with low-flux membranes compared to high-flux dialyzers. The two-group cross-over study over three periods of 4 weeks revealed that switching from low-flux to high-flux dialyzers significantly reduced serum β2-microglobulin levels. Conclusion: Patients treated with a polyamide high-flux membranehad lower β2-microglobulin concentrations compared with those patients on low-flux dialyzers. This difference might not be mediated by an increase in β2-microglobulin mRNA, but may be caused by less β2-microglobulin released from the blood cells in patients treated with high-flux dialyzers, in addition to a better β2-microglobulin clearance.

The German Glomerulonephritis Therapy Study: 10 Years of Controlled Randomized Trials for the Treatment of Idiopathic Glomerulonephritis

The German Collaborative Glomerulonephritis Therapy Study, which celebrated its 10th anniversary in 1996, has collected data on more than 1,000 patients with biopsy-proven glomerulonephritis. 929 patients could be evaluated and 500 were treated according to at least one of various protocols developed for a randomized controlled trial. Current results show that prednisolone is effective in minimal-change nephropathy, and in combination with other immunosuppressants it can reduce proteinuria in individual cases of focal and segmental glomerulosclerosis, membranous glomerulonephritis and nephrotic IgA nephropathy. The majority of tested treatment protocols did not prove to be superior to symptomatic therapy for long-term outcome.

[Treatment of idiopathic membranous nephropathy. Is the anti-CD20 antibody rituximab a reasonable option?].

ZusammenfassungHintergrund:Die membranöse Glomerulonephritis (MGN) ist durch eine Proteinurie > 3,5 g/d und weitere Symptome des nephrotischen Syndroms gekennzeichnet. In vielen Fällen ist die Ätiologie idiopathisch. Ob und wie die MGN zu behandeln ist, bleibt kontrovers. Trotz der Therapie mit Kortikosteroiden, Ciclosporin oder Alkylanzien entwickeln bis zu 40% der Patienten eine terminale Niereninsuffizienz.Fallbeschreibung:Ein 40-jähriger Patient mit nierenbioptisch gesicherter idiopathischer MGN wurde aufgrund der hohen initialen Proteinurie von 22 g/d bei einer normalen Nierenfunktion mit Chlorambucil und Prednisolon behandelt. Da das nephrotische Syndrom nach 6 Monaten persistierte, wurde eine Ciclosporintherapie begonnen. Die Proteinurie konnte durch diese Therapie bis auf 4 g/d gesenkt werden. Diese Therapie wurde nach 17 Monaten beendet, und es kam zum schnellen Wiederauftreten des nephrotischen Syndroms. Eine erneute Nierenbiopsie zeigte eine MGN im Stadium II, teils III nach Ehrenreich & Churg ohne wesentlichen chronischen tubulointerstitiellen Schaden. Eine Therapie mit ACE-Hemmern und AT1-Rezeptor-Antagonisten sowie die erneute Ciclosporingabe reduzierten nochmals die Proteinurie. Ciclosporin wurde nach insgesamt 24 Monaten abgesetzt. 5 Monate danach kam es zu einem erneuten Rezidiv der Erkrankung mit einer Proteinurie bis 34 g/d. Der monoklonale Anti-CD20-Antikörper Rituximab wurde in einer Dosis von 4 × 375 mg/m2 alle 4 Wochen zusätzlich zu einer Prednisolontherapie verabreicht. Nach 4 Wochen reduzierte sich die Proteinurie auf 780 mg/d, 4 Monate nach Therapieende betrug sie < 150 mg/d. Die Nierenfunktion blieb allerdings reduziert (Kreatininclearance 65 ml/min, Stadium 2 nach K/DOQI). 2 Jahre nach Beendigung der Rituximabgabe ist die Proteinurie in anhaltend stabiler Remission (< 150 mg/d). Die Nierenfunktion verschlechterte sich jedoch weiter (Kreatininclearance 45 ml/min, Stadium 3 nach K/DOQI).Schlussfolgerung:Rituximab eröffnet die Möglichkeit einer zielgerichteten Therapie der idiopathischen MGN. Auf der Basis der existierenden Evidenz kann Rituximab als eine neue Therapieoption der MGN, wahrscheinlich noch vor dem Einsatz zytotoxischer Substanzen und hochdosierter Prednisolongaben, die das Risiko schwerer Nebenwirkungen haben, empfohlen werden. Langzeitergebnisse dieser Therapie sind allerdings noch nicht verfügbar.AbstractBackground:Membranous nephropathy (MN) is characterized by proteinuria and other symptoms of the nephrotic syndrome. In many cases, the etiology is unknown. Whether and how to treat MN is still a controversial question. Despite the use of corticosteroids and alkylating agents, up to 40% of patients still progress to end-stage renal failure.Case Report:A 40-year-old male patient with biopsy-proven idiopathic MN was initially treated with prednisolone and chlorambucil because of a proteinuria of 22 g/d. Treatment with cyclosporine was started because the nephrotic syndrome failed to improve. Proteinuria was reduced to a minimum of 4 g/d. Cyclosporine was stopped after 17 months leading to a fast relapse. Therapy with an ACE inhibitor and AT1 receptor antagonist and retreatment with cyclosporine improved proteinuria. Cyclosporine was terminated after a total of 24 months. 5 months later, relapse occurred with a high proteinuria of 34 g/d. The monoclonal anti-CD20 antibody rituximab (375 mg/m2) was given four times every 4 weeks. 4 weeks and 4 months after the end of treatment, proteinuria decreased to 780 mg/d and < 150 mg/d, but renal function remained impaired (creatinine clearance 65 ml/min, stage 2 according to K/DOQI). Now, remission of proteinuria (< 150 mg/d) has been stable for almost 2 years. However, renal insufficiency progressed further (creatinine clearance 45 ml/min, stage 3 according to K/DOQI).Conclusion:Rituximab offers the possibility for a targeted treatment of idiopathic MN. Based on the existing evidence and experience from this case, rituximab can be recommended as a new treatment option for MN, possibly before starting any treatment with cytotoxic agents and high-dose prednisolone carrying the risk of severe side effects. However, long-term results of this treatment are still lacking.BACKGROUND Membranous nephropathy (MN) is characterized by proteinuria and other symptoms of the nephrotic syndrome. In many cases, the etiology is unknown. Whether and how to treat MN is still a controversial question. Despite the use of corticosteroids and alkylating agents, up to 40% of patients still progress to end-stage renal failure. CASE REPORT A 40-year-old male patient with biopsy-proven idiopathic MN was initially treated with prednisolone and chlorambucil because of a proteinuria of 22 g/d. Treatment with cyclosporine was started because the nephrotic syndrome failed to improve. Proteinuria was reduced to a minimum of 4 g/d. Cyclosporine was stopped after 17 months leading to a fast relapse. Therapy with an ACE inhibitor and AT(1) receptor antagonist and retreatment with cyclosporine improved proteinuria. Cyclosporine was terminated after a total of 24 months. 5 months later, relapse occurred with a high proteinuria of 34 g/d. The monoclonal anti-CD20 antibody rituximab (375 mg/m(2)) was given four times every 4 weeks. 4 weeks and 4 months after the end of treatment, proteinuria decreased to 780 mg/d and <150 mg/d, but renal function remained impaired (creatinine clearance 65 ml/min, stage 2 according to K/DOQI). Now, remission of proteinuria (<150 mg/d) has been stable for almost 2 years. However, renal insufficiency progressed further (creatinine clearance 45 ml/min, stage 3 according to K/DOQI). CONCLUSION Rituximab offers the possibility for a targeted treatment of idiopathic MN. Based on the existing evidence and experience from this case, rituximab can be recommended as a new treatment option for MN, possibly before starting any treatment with cytotoxic agents and high-dose prednisolone carrying the risk of severe side effects. However, long-term results of this treatment are still lacking.

Schwangerschaftsassoziierte thrombotische Mikroangiopathie – eine diagnostische und therapeutische Herausforderung

Zusammenfassung.Hintergrund: Thrombotische Mikroangiopathien treten selten im Zusammenhang mit einer Schwangerschaft auf. Pathogenetisch bestehen Ähnlichkeiten mit dem HELLP-Syndrom und der schweren Eklampsie. Fallbericht: Im Mai 2000 kam eine 26-jährige Erstgebärende zur stationären Aufnahme, bei der aufgrund der Befundkonstellation Anämie, Thrombozytopenie und ansteigende Leberfermente die klinische Diagnose eines HELLP-Syndroms gestellt wurde. In der 39. Woche wurden dementsprechend die Geburt eingeleitet und ein gesundes Kind entbunden. Nachfolgend verschlechterte sich die Anämie, Thrombozytopenie und die vorbestehende arterielle Hypertonie. Die Leberfunktion normalisierte sich; hinzu trat ein kontinuierlicher Nierenfunktionsverlust mit Dialysepflichtigkeit 12 Tage post partum. Die initial sowie nach 34 und 60 Tagen durchgeführten Nierenbiopsien erbrachten den Befund einer renalen thrombotischen Mikroangiographie, anfangs in einem floriden Stadium ohne Reparationszeichen, später mit hochgradiger Fibrose präglomerulärer Arterien und Arteriolen, mesangialer und fokal globaler glomerulärer Sklerose sowie progredienter tubulointerstitieller Schädigung. Wegen der Floridität des ersten Biopsiebefunds wurde eine umtägige Therapie mit insgesamt 28 Plasmapheresen eingeleitet; die Substitution erfolgte mit Fresh-frozen-Plasma (FFP). Gleichzeitig wurde eine Immunsuppression mit Kortikosteroiden vorgenommen. Nach 24 Tagen begannen wir additiv mit einer Cyclophosphamid-Pulstherapie. Trotz des aggressiven Therapieregimens kam es zu keiner Besserung der Nierenfunktion. 120 Tage nach Krankheitsbeginn wurde die permanente Nierenersatztherapie mittels kontinuierlicher ambulanter Peritonealdialyse (CAPD) eingeleitet. Schlussfolgerung: Der Krankheitsverlauf zeigt, dass durch eine frühzeitige Nierenersatztherapie und Plasmapherese das Überleben der Patientin zu sichern war, die renale Prognose einer postpartalen thrombotischen Mikroangiopathie jedoch als schlecht einzuschätzen ist. Dies unterstreicht die Notwendigkeit der Etablierung spezifischer Therapieansätze.Abstract.Background: Thrombotic microangiopathies are diseases rarely associated with pregnancy. The pathogenesis might be related to severe preeclampsia and HELLP syndrome. Case Report: In May 2000, we saw a 26-year-old primigravida in the 39th gestational week with worsening anemia, thrombocytopenia, and increasing liver enzymes. The diagnosis of HELLP syndrome was made and delivery initiated. Postpartum liver function stabilized, but anemia, thrombocytopenia, and preexisting hypertension worsened. Additionally, renal function deteriorated, and she had to be dialyzed 12 days after delivery. Renal biopsies were performed on day 12, 34, and 60 after delivery. The material showed a thrombotic microangiopathy, initially in an active stage. Later, fibrosis of the preglomerular arterioles and the glomeruli as well as progressive tubulointerstitial damage could be shown. Plasmapheresis was started; substitution was performed with fresh frozen plasma (FFP). Simultaneously, the patient was treated with corticosteroids. After 24 days, we began with cyclophosphamide pulses were given. In spite of this aggressive regimen, renal function did not recompensate, and renal replacement therapy with continuous ambulatory peritoneal dialysis (CAPD) was initiated. Conclusion: This course shows that mortality could be decreased using plasmapheresis therapy, but further research is needed to introduce more specific, kidney-protective regimens.

Behandlung der idiopathischen membranösen Glomerulonephritis

ZusammenfassungHintergrund:Die membranöse Glomerulonephritis (MGN) ist durch eine Proteinurie > 3,5 g/d und weitere Symptome des nephrotischen Syndroms gekennzeichnet. In vielen Fällen ist die Ätiologie idiopathisch. Ob und wie die MGN zu behandeln ist, bleibt kontrovers. Trotz der Therapie mit Kortikosteroiden, Ciclosporin oder Alkylanzien entwickeln bis zu 40% der Patienten eine terminale Niereninsuffizienz.Fallbeschreibung:Ein 40-jähriger Patient mit nierenbioptisch gesicherter idiopathischer MGN wurde aufgrund der hohen initialen Proteinurie von 22 g/d bei einer normalen Nierenfunktion mit Chlorambucil und Prednisolon behandelt. Da das nephrotische Syndrom nach 6 Monaten persistierte, wurde eine Ciclosporintherapie begonnen. Die Proteinurie konnte durch diese Therapie bis auf 4 g/d gesenkt werden. Diese Therapie wurde nach 17 Monaten beendet, und es kam zum schnellen Wiederauftreten des nephrotischen Syndroms. Eine erneute Nierenbiopsie zeigte eine MGN im Stadium II, teils III nach Ehrenreich & Churg ohne wesentlichen chronischen tubulointerstitiellen Schaden. Eine Therapie mit ACE-Hemmern und AT1-Rezeptor-Antagonisten sowie die erneute Ciclosporingabe reduzierten nochmals die Proteinurie. Ciclosporin wurde nach insgesamt 24 Monaten abgesetzt. 5 Monate danach kam es zu einem erneuten Rezidiv der Erkrankung mit einer Proteinurie bis 34 g/d. Der monoklonale Anti-CD20-Antikörper Rituximab wurde in einer Dosis von 4 × 375 mg/m2 alle 4 Wochen zusätzlich zu einer Prednisolontherapie verabreicht. Nach 4 Wochen reduzierte sich die Proteinurie auf 780 mg/d, 4 Monate nach Therapieende betrug sie < 150 mg/d. Die Nierenfunktion blieb allerdings reduziert (Kreatininclearance 65 ml/min, Stadium 2 nach K/DOQI). 2 Jahre nach Beendigung der Rituximabgabe ist die Proteinurie in anhaltend stabiler Remission (< 150 mg/d). Die Nierenfunktion verschlechterte sich jedoch weiter (Kreatininclearance 45 ml/min, Stadium 3 nach K/DOQI).Schlussfolgerung:Rituximab eröffnet die Möglichkeit einer zielgerichteten Therapie der idiopathischen MGN. Auf der Basis der existierenden Evidenz kann Rituximab als eine neue Therapieoption der MGN, wahrscheinlich noch vor dem Einsatz zytotoxischer Substanzen und hochdosierter Prednisolongaben, die das Risiko schwerer Nebenwirkungen haben, empfohlen werden. Langzeitergebnisse dieser Therapie sind allerdings noch nicht verfügbar.AbstractBackground:Membranous nephropathy (MN) is characterized by proteinuria and other symptoms of the nephrotic syndrome. In many cases, the etiology is unknown. Whether and how to treat MN is still a controversial question. Despite the use of corticosteroids and alkylating agents, up to 40% of patients still progress to end-stage renal failure.Case Report:A 40-year-old male patient with biopsy-proven idiopathic MN was initially treated with prednisolone and chlorambucil because of a proteinuria of 22 g/d. Treatment with cyclosporine was started because the nephrotic syndrome failed to improve. Proteinuria was reduced to a minimum of 4 g/d. Cyclosporine was stopped after 17 months leading to a fast relapse. Therapy with an ACE inhibitor and AT1 receptor antagonist and retreatment with cyclosporine improved proteinuria. Cyclosporine was terminated after a total of 24 months. 5 months later, relapse occurred with a high proteinuria of 34 g/d. The monoclonal anti-CD20 antibody rituximab (375 mg/m2) was given four times every 4 weeks. 4 weeks and 4 months after the end of treatment, proteinuria decreased to 780 mg/d and < 150 mg/d, but renal function remained impaired (creatinine clearance 65 ml/min, stage 2 according to K/DOQI). Now, remission of proteinuria (< 150 mg/d) has been stable for almost 2 years. However, renal insufficiency progressed further (creatinine clearance 45 ml/min, stage 3 according to K/DOQI).Conclusion:Rituximab offers the possibility for a targeted treatment of idiopathic MN. Based on the existing evidence and experience from this case, rituximab can be recommended as a new treatment option for MN, possibly before starting any treatment with cytotoxic agents and high-dose prednisolone carrying the risk of severe side effects. However, long-term results of this treatment are still lacking.BACKGROUND Membranous nephropathy (MN) is characterized by proteinuria and other symptoms of the nephrotic syndrome. In many cases, the etiology is unknown. Whether and how to treat MN is still a controversial question. Despite the use of corticosteroids and alkylating agents, up to 40% of patients still progress to end-stage renal failure. CASE REPORT A 40-year-old male patient with biopsy-proven idiopathic MN was initially treated with prednisolone and chlorambucil because of a proteinuria of 22 g/d. Treatment with cyclosporine was started because the nephrotic syndrome failed to improve. Proteinuria was reduced to a minimum of 4 g/d. Cyclosporine was stopped after 17 months leading to a fast relapse. Therapy with an ACE inhibitor and AT(1) receptor antagonist and retreatment with cyclosporine improved proteinuria. Cyclosporine was terminated after a total of 24 months. 5 months later, relapse occurred with a high proteinuria of 34 g/d. The monoclonal anti-CD20 antibody rituximab (375 mg/m(2)) was given four times every 4 weeks. 4 weeks and 4 months after the end of treatment, proteinuria decreased to 780 mg/d and <150 mg/d, but renal function remained impaired (creatinine clearance 65 ml/min, stage 2 according to K/DOQI). Now, remission of proteinuria (<150 mg/d) has been stable for almost 2 years. However, renal insufficiency progressed further (creatinine clearance 45 ml/min, stage 3 according to K/DOQI). CONCLUSION Rituximab offers the possibility for a targeted treatment of idiopathic MN. Based on the existing evidence and experience from this case, rituximab can be recommended as a new treatment option for MN, possibly before starting any treatment with cytotoxic agents and high-dose prednisolone carrying the risk of severe side effects. However, long-term results of this treatment are still lacking.

Behandlung der idiopathischen membranösen Glomerulonephritis@@@Treatment of Idiopathic Membranous Nephropathy. Is the Anti-CD20 Antibody Rituximab a Reasonable Option?: Ist der Anti-CD20-Antikörper Rituximab eine sinnvolle Therapieoption?

ZusammenfassungHintergrund:Die membranöse Glomerulonephritis (MGN) ist durch eine Proteinurie > 3,5 g/d und weitere Symptome des nephrotischen Syndroms gekennzeichnet. In vielen Fällen ist die Ätiologie idiopathisch. Ob und wie die MGN zu behandeln ist, bleibt kontrovers. Trotz der Therapie mit Kortikosteroiden, Ciclosporin oder Alkylanzien entwickeln bis zu 40% der Patienten eine terminale Niereninsuffizienz.Fallbeschreibung:Ein 40-jähriger Patient mit nierenbioptisch gesicherter idiopathischer MGN wurde aufgrund der hohen initialen Proteinurie von 22 g/d bei einer normalen Nierenfunktion mit Chlorambucil und Prednisolon behandelt. Da das nephrotische Syndrom nach 6 Monaten persistierte, wurde eine Ciclosporintherapie begonnen. Die Proteinurie konnte durch diese Therapie bis auf 4 g/d gesenkt werden. Diese Therapie wurde nach 17 Monaten beendet, und es kam zum schnellen Wiederauftreten des nephrotischen Syndroms. Eine erneute Nierenbiopsie zeigte eine MGN im Stadium II, teils III nach Ehrenreich & Churg ohne wesentlichen chronischen tubulointerstitiellen Schaden. Eine Therapie mit ACE-Hemmern und AT1-Rezeptor-Antagonisten sowie die erneute Ciclosporingabe reduzierten nochmals die Proteinurie. Ciclosporin wurde nach insgesamt 24 Monaten abgesetzt. 5 Monate danach kam es zu einem erneuten Rezidiv der Erkrankung mit einer Proteinurie bis 34 g/d. Der monoklonale Anti-CD20-Antikörper Rituximab wurde in einer Dosis von 4 × 375 mg/m2 alle 4 Wochen zusätzlich zu einer Prednisolontherapie verabreicht. Nach 4 Wochen reduzierte sich die Proteinurie auf 780 mg/d, 4 Monate nach Therapieende betrug sie < 150 mg/d. Die Nierenfunktion blieb allerdings reduziert (Kreatininclearance 65 ml/min, Stadium 2 nach K/DOQI). 2 Jahre nach Beendigung der Rituximabgabe ist die Proteinurie in anhaltend stabiler Remission (< 150 mg/d). Die Nierenfunktion verschlechterte sich jedoch weiter (Kreatininclearance 45 ml/min, Stadium 3 nach K/DOQI).Schlussfolgerung:Rituximab eröffnet die Möglichkeit einer zielgerichteten Therapie der idiopathischen MGN. Auf der Basis der existierenden Evidenz kann Rituximab als eine neue Therapieoption der MGN, wahrscheinlich noch vor dem Einsatz zytotoxischer Substanzen und hochdosierter Prednisolongaben, die das Risiko schwerer Nebenwirkungen haben, empfohlen werden. Langzeitergebnisse dieser Therapie sind allerdings noch nicht verfügbar.AbstractBackground:Membranous nephropathy (MN) is characterized by proteinuria and other symptoms of the nephrotic syndrome. In many cases, the etiology is unknown. Whether and how to treat MN is still a controversial question. Despite the use of corticosteroids and alkylating agents, up to 40% of patients still progress to end-stage renal failure.Case Report:A 40-year-old male patient with biopsy-proven idiopathic MN was initially treated with prednisolone and chlorambucil because of a proteinuria of 22 g/d. Treatment with cyclosporine was started because the nephrotic syndrome failed to improve. Proteinuria was reduced to a minimum of 4 g/d. Cyclosporine was stopped after 17 months leading to a fast relapse. Therapy with an ACE inhibitor and AT1 receptor antagonist and retreatment with cyclosporine improved proteinuria. Cyclosporine was terminated after a total of 24 months. 5 months later, relapse occurred with a high proteinuria of 34 g/d. The monoclonal anti-CD20 antibody rituximab (375 mg/m2) was given four times every 4 weeks. 4 weeks and 4 months after the end of treatment, proteinuria decreased to 780 mg/d and < 150 mg/d, but renal function remained impaired (creatinine clearance 65 ml/min, stage 2 according to K/DOQI). Now, remission of proteinuria (< 150 mg/d) has been stable for almost 2 years. However, renal insufficiency progressed further (creatinine clearance 45 ml/min, stage 3 according to K/DOQI).Conclusion:Rituximab offers the possibility for a targeted treatment of idiopathic MN. Based on the existing evidence and experience from this case, rituximab can be recommended as a new treatment option for MN, possibly before starting any treatment with cytotoxic agents and high-dose prednisolone carrying the risk of severe side effects. However, long-term results of this treatment are still lacking.BACKGROUND Membranous nephropathy (MN) is characterized by proteinuria and other symptoms of the nephrotic syndrome. In many cases, the etiology is unknown. Whether and how to treat MN is still a controversial question. Despite the use of corticosteroids and alkylating agents, up to 40% of patients still progress to end-stage renal failure. CASE REPORT A 40-year-old male patient with biopsy-proven idiopathic MN was initially treated with prednisolone and chlorambucil because of a proteinuria of 22 g/d. Treatment with cyclosporine was started because the nephrotic syndrome failed to improve. Proteinuria was reduced to a minimum of 4 g/d. Cyclosporine was stopped after 17 months leading to a fast relapse. Therapy with an ACE inhibitor and AT(1) receptor antagonist and retreatment with cyclosporine improved proteinuria. Cyclosporine was terminated after a total of 24 months. 5 months later, relapse occurred with a high proteinuria of 34 g/d. The monoclonal anti-CD20 antibody rituximab (375 mg/m(2)) was given four times every 4 weeks. 4 weeks and 4 months after the end of treatment, proteinuria decreased to 780 mg/d and <150 mg/d, but renal function remained impaired (creatinine clearance 65 ml/min, stage 2 according to K/DOQI). Now, remission of proteinuria (<150 mg/d) has been stable for almost 2 years. However, renal insufficiency progressed further (creatinine clearance 45 ml/min, stage 3 according to K/DOQI). CONCLUSION Rituximab offers the possibility for a targeted treatment of idiopathic MN. Based on the existing evidence and experience from this case, rituximab can be recommended as a new treatment option for MN, possibly before starting any treatment with cytotoxic agents and high-dose prednisolone carrying the risk of severe side effects. However, long-term results of this treatment are still lacking.

Behandlung der idiopathischen membranösen Glomerulonephritis Ist der Anti-CD20-Antikörper Rituximab eine sinnvolle Therapieoption?

ZusammenfassungHintergrund:Die membranöse Glomerulonephritis (MGN) ist durch eine Proteinurie > 3,5 g/d und weitere Symptome des nephrotischen Syndroms gekennzeichnet. In vielen Fällen ist die Ätiologie idiopathisch. Ob und wie die MGN zu behandeln ist, bleibt kontrovers. Trotz der Therapie mit Kortikosteroiden, Ciclosporin oder Alkylanzien entwickeln bis zu 40% der Patienten eine terminale Niereninsuffizienz.Fallbeschreibung:Ein 40-jähriger Patient mit nierenbioptisch gesicherter idiopathischer MGN wurde aufgrund der hohen initialen Proteinurie von 22 g/d bei einer normalen Nierenfunktion mit Chlorambucil und Prednisolon behandelt. Da das nephrotische Syndrom nach 6 Monaten persistierte, wurde eine Ciclosporintherapie begonnen. Die Proteinurie konnte durch diese Therapie bis auf 4 g/d gesenkt werden. Diese Therapie wurde nach 17 Monaten beendet, und es kam zum schnellen Wiederauftreten des nephrotischen Syndroms. Eine erneute Nierenbiopsie zeigte eine MGN im Stadium II, teils III nach Ehrenreich & Churg ohne wesentlichen chronischen tubulointerstitiellen Schaden. Eine Therapie mit ACE-Hemmern und AT1-Rezeptor-Antagonisten sowie die erneute Ciclosporingabe reduzierten nochmals die Proteinurie. Ciclosporin wurde nach insgesamt 24 Monaten abgesetzt. 5 Monate danach kam es zu einem erneuten Rezidiv der Erkrankung mit einer Proteinurie bis 34 g/d. Der monoklonale Anti-CD20-Antikörper Rituximab wurde in einer Dosis von 4 × 375 mg/m2 alle 4 Wochen zusätzlich zu einer Prednisolontherapie verabreicht. Nach 4 Wochen reduzierte sich die Proteinurie auf 780 mg/d, 4 Monate nach Therapieende betrug sie < 150 mg/d. Die Nierenfunktion blieb allerdings reduziert (Kreatininclearance 65 ml/min, Stadium 2 nach K/DOQI). 2 Jahre nach Beendigung der Rituximabgabe ist die Proteinurie in anhaltend stabiler Remission (< 150 mg/d). Die Nierenfunktion verschlechterte sich jedoch weiter (Kreatininclearance 45 ml/min, Stadium 3 nach K/DOQI).Schlussfolgerung:Rituximab eröffnet die Möglichkeit einer zielgerichteten Therapie der idiopathischen MGN. Auf der Basis der existierenden Evidenz kann Rituximab als eine neue Therapieoption der MGN, wahrscheinlich noch vor dem Einsatz zytotoxischer Substanzen und hochdosierter Prednisolongaben, die das Risiko schwerer Nebenwirkungen haben, empfohlen werden. Langzeitergebnisse dieser Therapie sind allerdings noch nicht verfügbar.AbstractBackground:Membranous nephropathy (MN) is characterized by proteinuria and other symptoms of the nephrotic syndrome. In many cases, the etiology is unknown. Whether and how to treat MN is still a controversial question. Despite the use of corticosteroids and alkylating agents, up to 40% of patients still progress to end-stage renal failure.Case Report:A 40-year-old male patient with biopsy-proven idiopathic MN was initially treated with prednisolone and chlorambucil because of a proteinuria of 22 g/d. Treatment with cyclosporine was started because the nephrotic syndrome failed to improve. Proteinuria was reduced to a minimum of 4 g/d. Cyclosporine was stopped after 17 months leading to a fast relapse. Therapy with an ACE inhibitor and AT1 receptor antagonist and retreatment with cyclosporine improved proteinuria. Cyclosporine was terminated after a total of 24 months. 5 months later, relapse occurred with a high proteinuria of 34 g/d. The monoclonal anti-CD20 antibody rituximab (375 mg/m2) was given four times every 4 weeks. 4 weeks and 4 months after the end of treatment, proteinuria decreased to 780 mg/d and < 150 mg/d, but renal function remained impaired (creatinine clearance 65 ml/min, stage 2 according to K/DOQI). Now, remission of proteinuria (< 150 mg/d) has been stable for almost 2 years. However, renal insufficiency progressed further (creatinine clearance 45 ml/min, stage 3 according to K/DOQI).Conclusion:Rituximab offers the possibility for a targeted treatment of idiopathic MN. Based on the existing evidence and experience from this case, rituximab can be recommended as a new treatment option for MN, possibly before starting any treatment with cytotoxic agents and high-dose prednisolone carrying the risk of severe side effects. However, long-term results of this treatment are still lacking.BACKGROUND Membranous nephropathy (MN) is characterized by proteinuria and other symptoms of the nephrotic syndrome. In many cases, the etiology is unknown. Whether and how to treat MN is still a controversial question. Despite the use of corticosteroids and alkylating agents, up to 40% of patients still progress to end-stage renal failure. CASE REPORT A 40-year-old male patient with biopsy-proven idiopathic MN was initially treated with prednisolone and chlorambucil because of a proteinuria of 22 g/d. Treatment with cyclosporine was started because the nephrotic syndrome failed to improve. Proteinuria was reduced to a minimum of 4 g/d. Cyclosporine was stopped after 17 months leading to a fast relapse. Therapy with an ACE inhibitor and AT(1) receptor antagonist and retreatment with cyclosporine improved proteinuria. Cyclosporine was terminated after a total of 24 months. 5 months later, relapse occurred with a high proteinuria of 34 g/d. The monoclonal anti-CD20 antibody rituximab (375 mg/m(2)) was given four times every 4 weeks. 4 weeks and 4 months after the end of treatment, proteinuria decreased to 780 mg/d and <150 mg/d, but renal function remained impaired (creatinine clearance 65 ml/min, stage 2 according to K/DOQI). Now, remission of proteinuria (<150 mg/d) has been stable for almost 2 years. However, renal insufficiency progressed further (creatinine clearance 45 ml/min, stage 3 according to K/DOQI). CONCLUSION Rituximab offers the possibility for a targeted treatment of idiopathic MN. Based on the existing evidence and experience from this case, rituximab can be recommended as a new treatment option for MN, possibly before starting any treatment with cytotoxic agents and high-dose prednisolone carrying the risk of severe side effects. However, long-term results of this treatment are still lacking.