Abstract
Acute kidney injury (AKI) is a frequent complication of multiple myeloma and is associated with increased short-term mortality. Additionally, even a single episode of AKI can eventually lead to end-stage renal disease (ESRD), significantly reducing quality of life and long-term survival. In the setting of multiple myeloma, severe AKI (requiring dialysis) is typically secondary to cast nephropathy (CN). Renal injury in CN is due to intratubular obstruction from precipitation of monoclonal serum free light chains (sFLC) as well as direct tubular toxicity of sFLC via stimulation of nuclear factor (NF)κB inflammatory pathways. Current mainstays of CN treatment are early removal of precipitating factors such as nephrotoxic drugs, acidosis and dehydration, together with rapid reduction of sFLC levels. Introduction of the proteasome inhibitor bortezomib has significantly improved the response rates in multiple myeloma due to its ability to rapidly reduce sFLC levels and has been referred to as “renoprotective” therapy. As an adjunct to chemotherapy, several new extracorporeal techniques have raised interest as a further means to reduce sFLC concentrations in the treatment of CN. Whether addition of extracorporeal therapies to renoprotective therapy can result in better renal recovery is still a matter of debate and there are currently no guidelines in this field. In this positon paper, we offer an overview of the available data and the authors’ perspectives on extracorporeal treatments in CN.
Similar content being viewed by others
References
Dimopoulos MA, Terpos E, Chanan-Khan A et al (2010) Renal impairment in patients with multiple myeloma: a consensus statement on behalf of the International Myeloma Working Group. J Clin Oncol 28:4976–4984
Gaballa MR, Laubach JP, Schlossman RL, Redman K, Noonan K, Mitsiades CS, Ghobrial IM, Munshi N, Anderson KC, Richardson PG (2012) Management of myeloma-associated renal dysfunction in the era of novel therapies. Expert Rev Hematol 5:51–66
Chanan-Khan AA, San Miguel JF, Jagannath S, Ludwig H, Dimopoulos MA (2012) Novel therapeutic agents for the management of patients with multiple myeloma and renal impairment. Clin Cancer Res 18:2145–2163
Hutchison CA, Batuman V, Behrens J, Bridoux F, Sirac C, Dispenzieri A, Herrera GA, Lachmann H, Sanders PW, International Kidney and Monoclonal Gammopathy Research Group (2011) The pathogenesis and diagnosis of acute kidney injury in multiple myeloma. Nat Rev Nephrol 8(1):43–51
Abbott KC, Agodoa LY (2001) Multiple myeloma and light chain-associated nephropathy at end-stage renal disease in the United States: patient characteristics and survival. Clin Nephrol 56(3):207–210
Uttervall K, Duru AD, Lund J, Liwing J, Gahrton G, Holmberg E, Aschan J, Alici E, Nahi H (2014) The use of novel drugs can effectively improve response, delay relapse and enhance overall survival in multiple myeloma patients with renal impairment. PLoS One 9(7):e101819. doi:10.1371/journal.pone.0101819
Rodrigues L, Neves M, Sá H, Gomes H, Pratas J, Campos M (2014) Severe acute kidney injury and multiple myeloma: evaluation of kidney and patient prognostic factors. Eur J Intern Med 25:652–656
Tsakiris DJ, Stel VS., Finne P, Fraser E, Heaf J, de Meester J, Schmaldienst S, Dekker F, Verrina E, Jager KJ (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 Trasplant 25:1200–1206
Reule S, Sexton DJ, Solid CA, Chen SC, Foley RN (2013) End stage renal disease due to multiple myeloma in the United States, 2001–2010. J Am Soc Nephrol 27(5):1487–1494
Miettinen TA, Kekki M (1967) Effect of impaired hepatic and renal function on Bence Jones protein catabolism in human subjects. Clin Chim Acta 18:395–407
Wochner RD, Strober W, Waldmann TA (1967) The role of the kidney in the catabolism of Bence Jones proteins and immunoglobulin fragments. J Exp Med 126:207–221
Bradwell AR (2006) Serum Free light chain analysis, 4th edn. The Binding Site Ltd., Birmingham, pp 104–107
Takagi K, Kin K, Itoh Y, Enomoto H, Kawai T (1980) Human alpha 1-microglobulin in various body fluids. J Clin Pathol 33:786–791
Hutchison CA, Cockwell P, Reid S, Chandler K, Mead GP, Harrison J, Hattersley J, Evans ND, Chappell MJ, Cook M, Goehl H, Storr M, Bradwell AR (2007) Efficient removal of immunoglobulin free light chains by hemodialysis for multiple myeloma: in vitro and in vivo studies. J Am Soc Nephrol 18:886–895
Walther C, Podoll AS, Finkel KW (2014) Treatment of acute kidney injury with cast nephropathy. Clin Nephrol 82(1):1–6
Dimopoulos MA, Delimpasi S, Katodritou E et al (2014) Significant improvement in the survival of patients with multiple myeloma presenting with severe renal impairment after the introduction of novel agents. Ann Oncol 25:195–200
Dimopoulos MA, Roussou M, Gkotzamanidou M et al (2013) The role of novel agents on the reversibility of renal impairment in newly diagnosed symptomatic patients with multiple myeloma. Leukemia 27:423–429
Cohen C, Royer B, Javaugue V et al (2015) Bortezomib produces high hematological response rates with prolonged renal survival in monoclonal immunoglobulin deposition disease. Kidney Int 88:1135–1143. doi:10.1038/ki.2015.201
Sarközi R, Perco P, Hochegger K, Enrich J, Wiesinger M, Pirklbauer M, Eder S, Rudnicki M, Rosenkranz AR, Mayer B, Mayer G, Schramek H (2008) Bortezomib-induced survival signals and genes in human proximal tubular cells. J Pharmacol Exp Ther 327(3):645–656
Jagannath S, Barlogie B, Berenson JR, SUMMIT/CREST Investigators et al (2005) Bortezomib in recurrent and/or refractory multiple myeloma: initial clinical experience in patients with impaired renal function. Cancer 103:1195–1200
Chanan-Khan AA, Kaufman JL, Mehta J et al (2007) Activity and safety of bortezomib in multiple myeloma patients with advanced renal failure: a multicenter retrospective study. Blood 109:2604–2606
Dimopoulos MA, Richardson PG, Schlag R et al (2009) VMP (bortezomib, melphalan, and prednisone) is active and well tolerated in newly diagnosed patients with multiple myeloma with moderately impaired renal function, and results in reversal of renal impairment: cohort analysis of the phase III VISTA study. J Clin Oncol 27:6086–6093
Scheid C, Sonneveld P, Schmidt-Wolf IGH et al (2014) Bortezomib before and after autologous stem cell transplantation overcomes the negative prognostic impact of renal impairment in newly diagnosed multiple myeloma: a subgroup analysis from the HOVON-65/GMMG-hd4 trial. Haematologica 99:148–154
Rajkumar SV, Dimopoulos MA, Palumbo A et al (2014) International Myeloma Working Group updated criteria for diagnosis of multiple myeloma. Lancet Oncol 15:e538–e548
Bridoux F, Leung N, Hutchison CA, Touchard G, Sethi S, Fermand JP, Picken MM, Herrera GA, Kastritis E, Merlini G, Roussel M, Fervenza FC, Dispenzieri A, Kyle RA, Nasr SH, International Kidney and Monoclonal Gammopathy Research Group (2015) Diagnosis of monoclonal gammopathy of renal significance. Kidney Int 87:698–711
L’Imperio V, Fabbrini P, Ferrario F, Pieruzzi F, Tosoni A, Brivio R, Pogliani EM, Pagni F (2015) Monoclonal gammopathy of renal significance: systemic involvement by benign condition. Kidney Int 88(1):200–202
Bradwell AR, Carr-Smith HD, Mead GP, Tang LX, Showell PJ, Drayson MT, Drew R (2001) Highly sensitive, automated immunoassay for immunoglobulin free light chains in serum and urine. Clin Chem 47(4):673–680
Leung N, Gertz M, Kyle RA et al (2012) Urinary albumin excretion patterns of patients with cast nephropathy and other monoclonal gammopathy-related kidney diseases. Clin J Am Soc Nephrol 7(12):1964–1968
Nasr SH, Valeri AM, Sethi S, Fidler ME, Cornell LD, Gertz MA, Lacy M, Dispenzieri A, Rajkumar SV, Kyle RA, Leung N (2012) Clinicopathologic correlations in multiple myeloma: a case series of 190 patients with kidney biopsies. Am J Kidney Dis 59(6):786–794
Fish R, Pinney J, Jain P, Addison C, Jones C, Jayawardene S, Booth J, Howie AJ, Ghonemy T, Rajabali S, Roberts D, White L, Khan S, Morgan M, Cockwell P, Hutchison CA (2010) The incidence of major hemorrhagic complications after renal biopsies in patients with monoclonal gammopathies. Clin J Am Soc Nephrol 5(11):1977–1980
Ecotière L, Thierry A, Debiais-Delpech C, Chevret S, Javaugue V, Desport E, Belmouaz S, Quellard N, Kaaki S, Goujon JM, Fermand JP, Touchard G, Bridoux F (2015) Prognostic value of kidney biopsy in myeloma cast nephropathy: a retrospective study of 70 patients. Nephrol Dial Transplant 31(1):64–72
Basnayake K, Cheung CK, Sheaff M, Fuggle W, Kamel D, Nakoinz S, Hutchison CA, Cook M, Stoves J, Bradwell AR, Cockwell P (2010) Differential progression of renal scarring and determinants of late renal recovery in sustained dialysis dependent acute kidney injury secondary to myeloma kidney. J Clin Pathol 63(10):884–887
Leung N, Gertz MA, Zeldenrust SR et al (2008) Improvement of cast nephropathy with plasma exchange depends on the diagnosis and on reduction of serum free light chains. Kidney Int 73(11):1282–1288
Zannetti BA, Zamagni E, Santostefano M et al (2015) Bortezomib-based therapy combined with high cut-off hemodialysis is highly effective in newly diagnosed multiple myeloma patients with severe renal impairment. Am J Hematol 90:647–652
Hutchison CA, Heyne N, Airia P, Schindler R, Zickler D, Cook M, Cockwell P, Grima D (2012) Immunoglobulin free light chain levels and recovery from myeloma kidney on treatment with chemotherapy and high cut-off haemodialysis. Nephrol Dial Transplant 27(10):3823–3828
Vanholder R, De Smet R, Glorieux G, Argilés A, Baurmeister U, Brunet P, Clark W, Cohen G, De Deyn PP, Deppisch R, Descamps-Latscha B, Henle T, Jörres A, Lemke HD, Massy ZA, Passlick-Deetjen J, Rodriguez M, Stegmayr B, Stenvinkel P, Tetta C, Wanner C, Zidek W, European Uremic Toxin Work Group (EUTox) (2003) Review on uremic toxins: classification, concentration, and interindividual variability. Kidney Int 63:1934–1943
Cohen G, Rudnicki M, Schmaldienst S, Hörl WH (2002) Effect of dialysis on serum/plasma levels of free immunoglobulin light chains in end-stage renal disease patients. Nephrol Dial Transplant 17(5):879–883
Zucchelli P, Pasquali S, Cagnoli L, Ferrari G (1988) Controlled plasma exchange trial in acute renal failure due to multiple myeloma. Kidney Int 33(6):1175–1180
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(4):863–869
Clark WF, Stewart AK, Rock GA, Sternbach M, Sutton DM, Barrett BJ, Heidenheim AP, Garg AX, Churchill DN, Canadian Apheresis Group (2005) Plasma exchange when myeloma presents as acute renal failure: a randomized, controlled trial. Ann Intern Med 143(11):777–784.
Movilli E, Jeannin G, Turina S, Scolari F, Cancarini G (2007) Plasma exchange in the treatment of acute renal failure of myeloma. Nephrol Dial Transplant 22(4):1270–1271
Burnette BL, Leung N, Rajkumar SV (2011) Renal improvement in myeloma with bortezomib plus plasma exchange. N Engl J Med 364(24):2365–2366
Madore F (2015) Plasmapheresis in cast nephropathy: yes or no? Curr Opin Nephrol Hypertens 24(2):177–182
Sinisalo M, Silvennoinen R, Wirta O (2012) High cut-off hemodialysis and bortezomib-based therapy to rescue kidneys in myeloma-dependent cast nephropathy. Am J Hematol 87:640
Tan J, Lam-Po-Tang M, Hutchison CA, de Zoysa JR (2014) Extended high cut-off haemodialysis for myeloma cast nephropathy in Auckland, 2008–2012. Nephrology (Carlton) 19(7):432–435
Marn Pernat A, Medved B, Gubenšek J, Premru V, Knap B, Buturovic-Ponikvar J, Ponikvar R (2016) Citrate extended high cut-off hemodiafiltration for renal recovery in patients with multiple myeloma. Ther Apher Dial 20(3):251–255
Hutchison CA, Bradwell AR, Cook M, Basnayake K, Basu S, Harding S, Hattersley J, Evans ND, Chappel MJ, Sampson P, Foggensteiner L, Adu D, Cockwell P (2009) Treatment of acute renal failure secondary to multiple myeloma with chemotherapy and extended high cut-off hemodialysis. Clin J Am Soc Nephrol 4(4):745–754
Berni Wennekers A, Martín Azara MP, Dourdil Sahun V, Bergasa Liberal B, Ruiz Laiglesia JE, Vernet Perna P, Alvarez Lipe R. (2016) Thirteen treated of acute renal failure secondary to multiple myeloma with high cut off filters. Nefrologia 36(4):418–426
Heyne N, Denecke B, Guthoff M, Oehrlein K, Kanz L, Häring HU, Weisel KC (2012) 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. Ann Hematol 91(5):729–735
Gerth HU, Pohlen M, Görlich D, Thölking G, Kropff M, Berdel WE, Pavenstädt H, Brand M, Kümpers P (2016) Impact of high-cut-off dialysis on renal recovery in dialysis-dependent multiple myeloma patients: results from a case-control study. PLoS One 11(5):e0154993
Rousseau-Gagnon M, Agharazii M, De Serres SA, Desmeules S (2015) Effectiveness of haemodiafiltration with heat sterilized high-flux polyphenylene HF dialyzer in reducing free light chains in patients with myeloma cast nephropathy. PLoS One 10(10):e0140463
Hutchison CA, Cook M, Heyne N et al (2008) European trial of free light chain removal byextended haemodialysis in cast nephropathy (EuLITE): a randomised control trial. Trials 9:55–62
ClinicalTrials.Gov (2015) Studies in patients with multiple myeloma and renal failure due to myeloma cast nephropathy (MYRE). https://clinicaltrials.gov/ct2/show/NCT01208818
Testa A, Dejoie T, Lecarrer D, Wratten M, Sereni L, Renaux JL (2010) Reduction of free immunoglobulin light chains using adsorption properties of hemodiafiltration with endogenous reinfusion. Blood Purif 30:34–36
Pasquali S, Iannuzzella F, Corradini M, Mattei S, Bovino A, Stefani A, Palladino G, Caiazzo M (2015) A novel option for reducing free light chains in myeloma kidney: supra-hemodiafiltration with endogenous reinfusion (HFR). J Nephrol 28(2):251–254
Pendón-Ruiz de Mier MV, Alvarez-Lara MA, Ojeda-López R, Martín-Malo A, Carracedo J, Caballero-Villarraso J, Alonso C, Aljama P (2013) Effectiveness of haemodiafiltration with ultrafiltrate regeneration in the reduction of light chains in multiple myeloma with renal failure. Nefrologia 33(6):788–796
Fabbrini P, Sirtori S, Casiraghi E, Pieruzzi F, Genovesi S, Corti D, Brivio R, Gregorini G, Como G, Carati ML, Viganò MR, Stella A (2013) Polymethylmethacrylate membrane and serum free light chain removal: enhancing adsorption properties. Blood Purif 35(Suppl 2):52–58
Santoro A, Grazia M, Mancini E (2013) The double polymethylmethacrylate filter (DELETE system) in the removal of light chains in chronic dialysis patients with multiple myeloma. Blood Purif 35(Suppl 2):5–13
Fabbrini P, Sirtori S, Pieruzzi F, Stella A, Vigano MR (2014). Acute cast nephropathy in multiple myeloma: effects of intensive polymethylmethacrylate-enhanced adsorption dialysis on renal survival. J Am Soc Nephrol 25:586 A (abstract, available at http://www.asn-online.org/education/kidneyweek/archives/)
Mancini E, Sestigiani E, Gissara Z, Palladino G, Santoro A (2011) Light chain removal by means of adsorption in the extracorpeal treatment of myeloma-induced cast nephropathy. XLVIII ERA-EDTA Congress, Prague, Czech (abstract available at http://www.abstracts2view.com/era_archive/view.php?nu=ERA11L_1648)
Pasquali S, Mancini E, Mambelli E, Santoro A (2009) Studio cinetico di rimozione delle catene leggere: confronto fra plasmaferesi tradizionale, plasmaferesi a cascata con resine adsorbenti, emodialisi mediante una membrana ad alto cut-off. Giorn Ital Nefrol S-47:S89 (Abstract)
Pasquali S, Mancini E, de Sanctis LB, Mambell Ei, Wratten M, Santoro A (2008) Coupled plasmafiltration adsorption: a new technology for free light chain removal. XLV ERA-EDTA congress, Stockholm, 2008 (abstract available at http://www.abstracts2view.com/era_archive/view.php?nu=ERA08L_1571)
Meletios A, Dimopoulos, Pieter Sonneveld, Nelson Leung et al (2016) International Myeloma Working Group recommendations for the diagnosis and management of myeloma-related renal impairment. J Clin Oncol 34(13):1544–1557
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
All the authors declare that they have no conflict of interest.
Ethical approval
For this type of study formal consent is not required.
Informed consent
No informed consent was obtained.
Research involving human participants and/or animals
This Position Paper include authors’ opinions on previous published researches and no new unpublished specific research involving human participants and/or animals has been done.
Rights and permissions
About this article
Cite this article
Fabbrini, P., Finkel, K., Gallieni, M. et al. Light chains removal by extracorporeal techniques in acute kidney injury due to multiple myeloma: a position statement of the Onconephrology Work Group of the Italian Society of Nephrology. J Nephrol 29, 735–746 (2016). https://doi.org/10.1007/s40620-016-0347-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s40620-016-0347-9