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Erschienen in: Annals of Hematology 5/2012

01.05.2012 | Original Article

Extracorporeal light chain elimination: high cut-off (HCO) hemodialysis parallel to chemotherapy allows for a high proportion of renal recovery in multiple myeloma patients with dialysis-dependent acute kidney injury

verfasst von: Nils Heyne, Barbara Denecke, Martina Guthoff, Katharina Oehrlein, Lothar Kanz, Hans-Ulrich Häring, Katja C. Weisel

Erschienen in: Annals of Hematology | Ausgabe 5/2012

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Abstract

Acute kidney injury (AKI) is frequent in multiple myeloma (MM) patients and strongly affects prognosis, with particularly poor outcomes in patients requiring hemodialysis. Introduction of the novel therapeutic agents to MM therapy has improved myeloma response and renal outcome. This case series reviews the efficacy of combined systemic and extracorporeal therapy to further optimize time to light chain (serum-free light chain (sFLC)) reduction and renal recovery in MM patients with dialysis-dependent AKI (n = 19). High cut-off (HCO) hemodialysis for extracorporeal sFLC removal was initiated in parallel to chemotherapy. Combined therapy resulted in early sFLC response after a median of 13 (range 4–48) days and 6 (3–22) HCO hemodialysis sessions. Time to sFLC response was shorter in patients recovering renal function. Median time to dialysis independence was 15 (4–64) days. By intent-to-treat analysis, sustained renal recovery was achieved in 73.7% (77.8% adjusted for death) of patients. In multivariate analysis, duration of AKI prior to initiation of therapy was an independent predictor of renal functional outcome. Combining HCO hemodialysis for extracorporeal sFLC elimination and effective chemotherapy is a novel treatment strategy allowing for early and sustained sFLC reduction and a high proportion of renal recovery in these patients. Timely diagnosis and onset of therapy is essential for improving renal outcome.
Literatur
1.
Zurück zum Zitat Alexanian R, Barlogie B, Dixon D (1990) Renal failure in multiple myeloma. Pathogenesis and prognostic implications. Arch Intern Med 150:1693–1695PubMedCrossRef Alexanian R, Barlogie B, Dixon D (1990) Renal failure in multiple myeloma. Pathogenesis and prognostic implications. Arch Intern Med 150:1693–1695PubMedCrossRef
2.
Zurück zum Zitat Bladé J, Fernandez-Llama P, Bosch F, Montoliù J, Lens XM, Montoto S et al (1998) Renal failure in multiple myeloma: presenting features and predictors of outcome in 94 patients from a single institution. Arch Intern Med 158:1889–1893PubMedCrossRef Bladé J, Fernandez-Llama P, Bosch F, Montoliù J, Lens XM, Montoto S et al (1998) Renal failure in multiple myeloma: presenting features and predictors of outcome in 94 patients from a single institution. Arch Intern Med 158:1889–1893PubMedCrossRef
3.
Zurück zum Zitat Kyle RA, Gertz MA, Witzig TE, Lust JA, Lacy MQ, Dispenzieri A et al (2003) Review of 1027 patients with newly diagnosed multiple myeloma. Mayo Clin Proc 78:21–33PubMedCrossRef Kyle RA, Gertz MA, Witzig TE, Lust JA, Lacy MQ, Dispenzieri A et al (2003) Review of 1027 patients with newly diagnosed multiple myeloma. Mayo Clin Proc 78:21–33PubMedCrossRef
4.
Zurück zum Zitat Eleutherakis-Papaiakovou V, Bamias A, Gika D, Simeonidis A, Pouli A, Anagnostopoulos A et al (2007) Renal failure in multiple myeloma: incidence, correlations, and prognostic significance. Leuk Lymphoma 48:337–341PubMedCrossRef Eleutherakis-Papaiakovou V, Bamias A, Gika D, Simeonidis A, Pouli A, Anagnostopoulos A et al (2007) Renal failure in multiple myeloma: incidence, correlations, and prognostic significance. Leuk Lymphoma 48:337–341PubMedCrossRef
5.
Zurück zum Zitat Knudsen LM, Hjorth M, Hippe E (2000) Renal failure in multiple myeloma: reversibility and impact on the prognosis. Nordic Myeloma Study Group. Eur J Haematol 65:175–181PubMedCrossRef Knudsen LM, Hjorth M, Hippe E (2000) Renal failure in multiple myeloma: reversibility and impact on the prognosis. Nordic Myeloma Study Group. Eur J Haematol 65:175–181PubMedCrossRef
6.
Zurück zum Zitat Torra R, Blade J, Cases A, López-Pedret J, Montserrat E, Rozman C et al (1995) Patients with multiple myeloma requiring long-term dialysis: presenting features, response to therapy, and outcome in a series of 20 cases. Br J Haematol 91:854–859PubMedCrossRef Torra R, Blade J, Cases A, López-Pedret J, Montserrat E, Rozman C et al (1995) Patients with multiple myeloma requiring long-term dialysis: presenting features, response to therapy, and outcome in a series of 20 cases. Br J Haematol 91:854–859PubMedCrossRef
7.
Zurück zum Zitat Hutchison CA, Bradwell AR, Cook M, Basnayake K, Basu S, Harding S et al (2009) Treatment of acute renal failure secondary to multiple myeloma with chemotherapy and extended high cut-off hemodialysis. Clin J Am Soc Nephrol 4:745–754PubMedCrossRef Hutchison CA, Bradwell AR, Cook M, Basnayake K, Basu S, Harding S et al (2009) Treatment of acute renal failure secondary to multiple myeloma with chemotherapy and extended high cut-off hemodialysis. Clin J Am Soc Nephrol 4:745–754PubMedCrossRef
8.
Zurück zum Zitat Santostefano M, Zanchelli F, Zaccaria A, Poletti G, Fusaroli M (2005) The ultrastructural basis of renal pathology in monoclonal gammopathies. J Nephrol 18:659–675PubMed Santostefano M, Zanchelli F, Zaccaria A, Poletti G, Fusaroli M (2005) The ultrastructural basis of renal pathology in monoclonal gammopathies. J Nephrol 18:659–675PubMed
9.
Zurück zum Zitat Huang ZQ, Sanders PW (1995) Biochemical interaction between Tamm-Horsfall glycoprotein and Ig light chains in the pathogenesis of cast nephropathy. Lab Invest 73:810–817PubMed Huang ZQ, Sanders PW (1995) Biochemical interaction between Tamm-Horsfall glycoprotein and Ig light chains in the pathogenesis of cast nephropathy. Lab Invest 73:810–817PubMed
10.
Zurück zum Zitat Ying WZ, Sanders PW (2001) Mapping the binding domain of immunoglobulin light chains for Tamm-Horsfall protein. Am J Pathol 158:1859–1866PubMedCrossRef Ying WZ, Sanders PW (2001) Mapping the binding domain of immunoglobulin light chains for Tamm-Horsfall protein. Am J Pathol 158:1859–1866PubMedCrossRef
11.
Zurück zum Zitat Sanders PW, Booker BB, Bishop JB, Cheung HC (1990) Mechanisms of intranephronal proteinaceous cast formation by low molecular weight proteins. J Clin Invest 85:570–576PubMedCrossRef Sanders PW, Booker BB, Bishop JB, Cheung HC (1990) Mechanisms of intranephronal proteinaceous cast formation by low molecular weight proteins. J Clin Invest 85:570–576PubMedCrossRef
12.
Zurück zum Zitat Sanders PW, Booker BB (1991) Pathobiology of cast nephropathy from human Bence Jones proteins. N Engl J Med 324:1845–1851CrossRef Sanders PW, Booker BB (1991) Pathobiology of cast nephropathy from human Bence Jones proteins. N Engl J Med 324:1845–1851CrossRef
13.
Zurück zum Zitat Blade J, Rosinol L (2005) Renal, hematologic and infectious complications in multiple myeloma. Best Pract Res Clin Haematol 18:635–652PubMedCrossRef Blade J, Rosinol L (2005) Renal, hematologic and infectious complications in multiple myeloma. Best Pract Res Clin Haematol 18:635–652PubMedCrossRef
14.
Zurück zum Zitat Basnayake K, Cheung CK, Sheaff M, Fuggle W, Kamel D, Nakoinz S et al (2010) Differential progression of renal scarring and determinants of late recovery in sustained dialysis dependent acute kidney injury secondary to myeloma kidney. J Clin Pathol 63:884–887PubMedCrossRef Basnayake K, Cheung CK, Sheaff M, Fuggle W, Kamel D, Nakoinz S et al (2010) Differential progression of renal scarring and determinants of late recovery in sustained dialysis dependent acute kidney injury secondary to myeloma kidney. J Clin Pathol 63:884–887PubMedCrossRef
15.
Zurück zum Zitat Tsakiris DJ, Stel VS, Finne P, Fraser E, Heaf J, de Meester J et al (2010) Incidence and outcome of patients starting renal replacement therapy for end-stage renal disease due to multiple myeloma or light-chain deposit disease: an ERA-EDTA Registry Study. Nephrol Dial Transplant 25:1200–1206PubMedCrossRef Tsakiris DJ, Stel VS, Finne P, Fraser E, Heaf J, de Meester J et al (2010) Incidence and outcome of patients starting renal replacement therapy for end-stage renal disease due to multiple myeloma or light-chain deposit disease: an ERA-EDTA Registry Study. Nephrol Dial Transplant 25:1200–1206PubMedCrossRef
16.
Zurück zum Zitat Richardson PG, Barlogie B, Berenson J, Shingal S, Jagannath S, Irwin DH, SUMMIT Investigators et al (2005) Clinical factors predictive of outcome with bortezomib in patients with relapsed, refractory multiple myeloma. Blood 106:2977–2981PubMedCrossRef Richardson PG, Barlogie B, Berenson J, Shingal S, Jagannath S, Irwin DH, SUMMIT Investigators et al (2005) Clinical factors predictive of outcome with bortezomib in patients with relapsed, refractory multiple myeloma. Blood 106:2977–2981PubMedCrossRef
17.
Zurück zum Zitat Rajkumar SV, Jacobus S, Callander NS, Fonseca R, Vesole DH, Williams ME et al (2010) Lenalidomide plus high-dose dexamathasone versus lenalidomide plus low-dose dexamethasone as initial therapy for newly diagnosed multiple myeloma: an open-label randomised controlled trial. Lancet Oncol 11:29–37PubMedCrossRef Rajkumar SV, Jacobus S, Callander NS, Fonseca R, Vesole DH, Williams ME et al (2010) Lenalidomide plus high-dose dexamathasone versus lenalidomide plus low-dose dexamethasone as initial therapy for newly diagnosed multiple myeloma: an open-label randomised controlled trial. Lancet Oncol 11:29–37PubMedCrossRef
18.
Zurück zum Zitat Dimopoulos MA, Terpos E, Chanan-Khan A, Leung N, Ludwig H, Jagannath S et al (2010) Renal impairment in patients with multiple myeloma: a consensus statement on behalf of the International Myeloma Working Group. J Clin Oncol 28:4976–4984PubMedCrossRef Dimopoulos MA, Terpos E, Chanan-Khan A, Leung N, Ludwig H, Jagannath S et al (2010) Renal impairment in patients with multiple myeloma: a consensus statement on behalf of the International Myeloma Working Group. J Clin Oncol 28:4976–4984PubMedCrossRef
19.
Zurück zum Zitat Johnson WJ, Kyle RA, Pineda AA, O’Brien PC, Holley KE (1990) Treatment of renal failure associated with multiple myeloma. Plasmapheresis, hemodialysis and chemotherapy. Arch Intern Med 150:863–869PubMedCrossRef Johnson WJ, Kyle RA, Pineda AA, O’Brien PC, Holley KE (1990) Treatment of renal failure associated with multiple myeloma. Plasmapheresis, hemodialysis and chemotherapy. Arch Intern Med 150:863–869PubMedCrossRef
20.
Zurück zum Zitat Clark WF, Stewart AK, Rock GA, Sternbach M, Sutton DM, Barret BJ et al (2005) Plasma exchange when myeloma presents as acute renal failure: a randomized controlled trial. Ann Intern Med 143:777–784PubMed Clark WF, Stewart AK, Rock GA, Sternbach M, Sutton DM, Barret BJ et al (2005) Plasma exchange when myeloma presents as acute renal failure: a randomized controlled trial. Ann Intern Med 143:777–784PubMed
21.
Zurück zum Zitat Weisel KC, Heyne N, Hutchison CA, Göhl H, Risler T, Kanz L (2007) Effective light chain elimination via a high cut-off protein permeable filter in patients with light chain myeloma disease. Onkologie 30(suppl 3):80 Weisel KC, Heyne N, Hutchison CA, Göhl H, Risler T, Kanz L (2007) Effective light chain elimination via a high cut-off protein permeable filter in patients with light chain myeloma disease. Onkologie 30(suppl 3):80
22.
Zurück zum Zitat Hutchison CA, Cockwell P, Reid S, Chandler K, Mead GP, Harrison J et al (2007) Efficient removal of immunoglobulin free light chains by hemodialysis for multiple myeloma: in vitro and in vivo studies. J Am Soc Nephrol 18:886–895PubMedCrossRef Hutchison CA, Cockwell P, Reid S, Chandler K, Mead GP, Harrison J et al (2007) Efficient removal of immunoglobulin free light chains by hemodialysis for multiple myeloma: in vitro and in vivo studies. J Am Soc Nephrol 18:886–895PubMedCrossRef
23.
Zurück zum Zitat Bellomo R, Ronco C, Kellum JA, Mehta RL, Palevsky P (2004) Acute renal failure—definition, outcome measures, animal models, fluid therapy and information technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) group. Crit Care 8:R204–R212PubMedCrossRef Bellomo R, Ronco C, Kellum JA, Mehta RL, Palevsky P (2004) Acute renal failure—definition, outcome measures, animal models, fluid therapy and information technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) group. Crit Care 8:R204–R212PubMedCrossRef
24.
Zurück zum Zitat Mehta RL, Kellum JA, Shah SV (2007) Acute Kidney Injury Network: report of an initiative to improve outcomes in acute kidney injury. Crit Care 11:R31PubMedCrossRef Mehta RL, Kellum JA, Shah SV (2007) Acute Kidney Injury Network: report of an initiative to improve outcomes in acute kidney injury. Crit Care 11:R31PubMedCrossRef
25.
Zurück zum Zitat Verfoord G, Willems HL, Wetzels JF (2002) Assessment of glomerular filtration rate in healthy subjects and normoalbuminuric diabetic patients: validity of a new (MDRD) prediction equation. Nephrol Dial Transplant 17:1909–1913CrossRef Verfoord G, Willems HL, Wetzels JF (2002) Assessment of glomerular filtration rate in healthy subjects and normoalbuminuric diabetic patients: validity of a new (MDRD) prediction equation. Nephrol Dial Transplant 17:1909–1913CrossRef
26.
Zurück zum Zitat Dimopoulos MA, Roussou M, Gavriatopoulou M, Zagouri F, Mikou M, Matsuoka C et al (2009) Reversibility of renal impairment in patients with multiple myeloma treated with bortezomib-based regimens. Clin Lymphoma Myeloma 9:302–306PubMedCrossRef Dimopoulos MA, Roussou M, Gavriatopoulou M, Zagouri F, Mikou M, Matsuoka C et al (2009) Reversibility of renal impairment in patients with multiple myeloma treated with bortezomib-based regimens. Clin Lymphoma Myeloma 9:302–306PubMedCrossRef
27.
Zurück zum Zitat Kidney Disease Outcomes Quality Initiative (K/DOQI) (2002) Executive summary. Am J Kidney Dis 39(suppl 1):S17–S31 Kidney Disease Outcomes Quality Initiative (K/DOQI) (2002) Executive summary. Am J Kidney Dis 39(suppl 1):S17–S31
28.
Zurück zum Zitat Durie BG, Harousseau JL, Miguel JS, Bladé J, Barlogie B, Anderson K, International Myeloma Working Group et al (2006) International uniform response criteria for multiple myeloma. Leukemia 20:1467–1473PubMedCrossRef Durie BG, Harousseau JL, Miguel JS, Bladé J, Barlogie B, Anderson K, International Myeloma Working Group et al (2006) International uniform response criteria for multiple myeloma. Leukemia 20:1467–1473PubMedCrossRef
29.
Zurück zum Zitat Dimopoulos MA, Kastritis E, Rosinol L, Bladé J, Ludwig H (2008) Pathogenesis and treatment of renal failure in multiple myeloma. Leukemia 22:1485–1493PubMedCrossRef Dimopoulos MA, Kastritis E, Rosinol L, Bladé J, Ludwig H (2008) Pathogenesis and treatment of renal failure in multiple myeloma. Leukemia 22:1485–1493PubMedCrossRef
30.
Zurück zum Zitat Chanan-Khan AA, Kaufman JL, Mehta J, Richardson PG, Miller KC, Lonial S et al (2007) Activity and safety of bortezomib in multiple myeloma patients with advanced renal failure: a multicenter retrospective study. Blood 109:2604–2606PubMedCrossRef Chanan-Khan AA, Kaufman JL, Mehta J, Richardson PG, Miller KC, Lonial S et al (2007) Activity and safety of bortezomib in multiple myeloma patients with advanced renal failure: a multicenter retrospective study. Blood 109:2604–2606PubMedCrossRef
31.
Zurück zum Zitat Ludwig H, Drach J, Graf H, Lang A, Meran JG (2007) Reversal of acute renal failure by bortezomib-based chemotherapy in patients with multiple myeloma. Haematologica 92:1411–1414PubMedCrossRef Ludwig H, Drach J, Graf H, Lang A, Meran JG (2007) Reversal of acute renal failure by bortezomib-based chemotherapy in patients with multiple myeloma. Haematologica 92:1411–1414PubMedCrossRef
32.
Zurück zum Zitat Ludwig H, Adam Z, Hajek R, Greil R, Tóthová E, Keil F et al (2010) Light chain-induced acute renal failure can be reversed by bortezomib-doxorubicin-dexamethasone in multiple myeloma: results of a phase II study. J Clin Oncol 28:4635–4641PubMedCrossRef Ludwig H, Adam Z, Hajek R, Greil R, Tóthová E, Keil F et al (2010) Light chain-induced acute renal failure can be reversed by bortezomib-doxorubicin-dexamethasone in multiple myeloma: results of a phase II study. J Clin Oncol 28:4635–4641PubMedCrossRef
33.
Zurück zum Zitat Dimopoulos MA, Christoulas D, Roussou M, Kastritis E, Anagnostou D, Koureas A et al (2010) Lenalidomide and dexamethasone for the treatment of refractory/relapsed multiple myeloma: dosing of lenalidomide according to renal function and effect on renal impairment. Eur J Haematol 85:1–5PubMedCrossRef Dimopoulos MA, Christoulas D, Roussou M, Kastritis E, Anagnostou D, Koureas A et al (2010) Lenalidomide and dexamethasone for the treatment of refractory/relapsed multiple myeloma: dosing of lenalidomide according to renal function and effect on renal impairment. Eur J Haematol 85:1–5PubMedCrossRef
34.
Zurück zum Zitat Dimopoulos M, Alegre A, Stadtmauer EA, Goldschmidt H, Zonder JA, de Castro CM et al (2010) The efficacy and safety of lenalidomide plus dexamethasone in relapsed and/or refractory multiple myeloma patients with impaired renal function. Cancer 116:3807–3814PubMedCrossRef Dimopoulos M, Alegre A, Stadtmauer EA, Goldschmidt H, Zonder JA, de Castro CM et al (2010) The efficacy and safety of lenalidomide plus dexamethasone in relapsed and/or refractory multiple myeloma patients with impaired renal function. Cancer 116:3807–3814PubMedCrossRef
35.
Zurück zum Zitat Matsue K, Fujiwara H, Iwama KI, Kimura S, Yamakura M, Takeuchi M (2010) Reversal of dialysis-dependent renal failure in patients with advanced multiple myeloma: single institutional experiences over 8 years. Ann Hematol 89:291–297PubMedCrossRef Matsue K, Fujiwara H, Iwama KI, Kimura S, Yamakura M, Takeuchi M (2010) Reversal of dialysis-dependent renal failure in patients with advanced multiple myeloma: single institutional experiences over 8 years. Ann Hematol 89:291–297PubMedCrossRef
36.
Zurück zum Zitat Kastritis E, Anagnostopoulos A, Roussou M, Gika D, Matsuoka C, Barmparousi D et al (2007) Reversibility of acute renal failure in newly diagnosed multiple myeloma patients treated with high dose dexamethasone containing regimens and the impact of novel agents. Haematologica 92:546–549PubMedCrossRef Kastritis E, Anagnostopoulos A, Roussou M, Gika D, Matsuoka C, Barmparousi D et al (2007) Reversibility of acute renal failure in newly diagnosed multiple myeloma patients treated with high dose dexamethasone containing regimens and the impact of novel agents. Haematologica 92:546–549PubMedCrossRef
37.
Zurück zum Zitat Wynckel A, Vuiblet V, Schneider N, Kolb B, Melin JP, Journet J et al (2010) Comparison of plasma exchange and hemodialysis using a high cut-off membrane (HCO) for removal of immunoglobulin free light chains in multiple myeloma. J Am Soc Nephrol 21:39A Wynckel A, Vuiblet V, Schneider N, Kolb B, Melin JP, Journet J et al (2010) Comparison of plasma exchange and hemodialysis using a high cut-off membrane (HCO) for removal of immunoglobulin free light chains in multiple myeloma. J Am Soc Nephrol 21:39A
38.
Zurück zum Zitat Hutchison CA, Cook M, Heyne N, Weisel KC, Billingham L, Bradwell A et al (2008) European trial of free light chain removal by extended haemodialysis in cast nephropathy (EuLITE). A randomised control trial. Trials 9:55PubMedCrossRef Hutchison CA, Cook M, Heyne N, Weisel KC, Billingham L, Bradwell A et al (2008) European trial of free light chain removal by extended haemodialysis in cast nephropathy (EuLITE). A randomised control trial. Trials 9:55PubMedCrossRef
Metadaten
Titel
Extracorporeal light chain elimination: high cut-off (HCO) hemodialysis parallel to chemotherapy allows for a high proportion of renal recovery in multiple myeloma patients with dialysis-dependent acute kidney injury
verfasst von
Nils Heyne
Barbara Denecke
Martina Guthoff
Katharina Oehrlein
Lothar Kanz
Hans-Ulrich Häring
Katja C. Weisel
Publikationsdatum
01.05.2012
Verlag
Springer-Verlag
Erschienen in
Annals of Hematology / Ausgabe 5/2012
Print ISSN: 0939-5555
Elektronische ISSN: 1432-0584
DOI
https://doi.org/10.1007/s00277-011-1383-0

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