MD Frank Bridoux
email: f.bridoux@chu-poitiers.fr

Nelson Leung

Mohamed Belmouaz

Virginie Royal

Pierre Ronco

Samih H Nasr

Jean Paul Fermand

Management of acute kidney injury in symptomatic multiple myeloma

Keywords: Multiple myeloma, monoclonal light chains, chemotherapy, high cutoff hemodialysis, plasma exchange, kidney biopsy

INTRODUCTION

Multiple myeloma (MM) is defined by the malignant proliferation of clonal plasma cells that usually secrete a monoclonal immunoglobulin (MIg) detectable in the serum and/or urine. [START_REF] Myeloma | Criteria for the classification of monoclonal gammopathies, multiple myeloma and related disorders: a report of the International Myeloma Working Group[END_REF][START_REF] Rajkumar | International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma[END_REF] MM is typically preceded by a variable clinically asymptomatic period during which the abnormal plasma cell clone is quiescent and only manifests by the presence of a MIg. This situation is referred to as monoclonal gammopathy of unknown significance (MGUS). [START_REF] Kyle | Monoclonal gammopathy of undetermined significance[END_REF][START_REF] Kyle | Long-term follow-up of monoclonal gammopathy of undetermined significance[END_REF] An active uncontrolled plasma cell proliferation causes symptomatic MM, where organ damage results either from the tumor mass, or from its effect on the immune system leading to secondary immune deficiency and its inherent infectious risk. The MIg may also cause tumormass related symptoms, the most common being hyperviscosity and light chain cast nephropathy (LCCN). [START_REF] Gertz | Hyperviscosity syndrome[END_REF][START_REF] Hutchison | The pathogenesis and diagnosis of acute kidney injury in multiple myeloma[END_REF] The intermediate condition between MGUS and symptomatic MM defines indolent or smoldering MM. [START_REF] Myeloma | Criteria for the classification of monoclonal gammopathies, multiple myeloma and related disorders: a report of the International Myeloma Working Group[END_REF][START_REF] Rajkumar | International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma[END_REF] When corresponding to MGUS or smoldering MM, the plasma cell proliferation does not cause tumor-related symptoms by definition. However, it may be associated with organ lesions, either MIg-mediated or due to other mechanisms. These situations, which are featured by a small dangerous B-cell clone causing renal and/or extra renal manifestations, fit with the definition of monoclonal gammopathy of renal significance (MGRS) [START_REF] Leung | Monoclonal gammopathy of renal significance: when MGUS is no longer undetermined or insignificant[END_REF] or monoclonal gammopathy of clinical significance (MGCS). [START_REF] Fermand | Monoclonal gammopathy of clinical significance: a novel concept with therapeutic implications[END_REF] Consensus expert recommendations regarding the diagnosis and treatment of MG(C)RS have been published. [START_REF] Fermand | How I treat monoclonal gammopathy of renal significance (MGRS)[END_REF][START_REF] Bridoux | Diagnosis of monoclonal gammopathy of renal significance[END_REF][START_REF] Leung | The evaluation of monoclonal gammopathy of renal significance: a consensus report of the International Kidney and Monoclonal Gammopathy Research Group[END_REF] The present review will encompass only renal complications of symptomatic MM, focusing on the management of acute kidney injury (AKI) due to LCCN.

EPIDEMIOLOGY

MM is the second most common hematologic malignancy after non-Hodgkin lymphoma, with a global age-standardized incidence of 2.1/100,000 in 2016. [START_REF] Cowan | Global burden of multiple myeloma: a systematic analysis for the Global Burden of Disease Study 2016[END_REF] The risk increases with age, with a peak around 65 years. MM is slightly more common in males, about twice more frequent in subjects of African ancestry compared to Caucasians, and has the lowest incidence in Asians. [START_REF] Cowan | Global burden of multiple myeloma: a systematic analysis for the Global Burden of Disease Study 2016[END_REF][START_REF] Kyle | Review of 1027 patients with newly diagnosed multiple myeloma[END_REF][START_REF] Waxman | Racial disparities in incidence and outcome in multiple myeloma: a population-based study[END_REF] Renal complications are frequent in MM, since acute or chronic renal impairment is thought to occur in half of patients during the course of the disease. [START_REF] Kyle | Multiple myeloma: review of 869 cases[END_REF] AKI is a common initial presentation, but it may also develop at relapse. The prevalence of AKI in patients with newly diagnosed symptomatic MM remains unclear, depending on the definition used. [START_REF] Dimopoulos | International Myeloma Working Group recommendations for the diagnosis and management of myeloma-related renal impairment[END_REF] It was reported around 30%, 20% and 15% using a serum creatinine level of 1.5 mg/dl, 2 mg/dl (threshold for renal impairment according to the historical International Myeloma Working Group [IMWG] criteria [START_REF] Myeloma | Criteria for the classification of monoclonal gammopathies, multiple myeloma and related disorders: a report of the International Myeloma Working Group[END_REF] ), or 2.3 mg/dl, respectively. [START_REF] Knudsen | Renal function in newly diagnosed multiple myeloma--a demographic study of 1353 patients. The Nordic Myeloma Study Group[END_REF][START_REF] Bladé | Renal failure in multiple myeloma: presenting features and predictors of outcome in 94 patients from a single institution[END_REF] In studies using eGFR, prevalence of AKI was 17% [START_REF] Gonsalves | Improvement in renal function and its impact on survival in patients with newly diagnosed multiple myeloma[END_REF] using the current IMWG criterion (<40 ml/min/1.73m 2 ) [START_REF] Dimopoulos | International Myeloma Working Group recommendations for the diagnosis and management of myeloma-related renal impairment[END_REF] , and varied between 10% and 25% when considering an eGFR of 30ml/min/1.73m 2 or 60 ml/min/1.73m [START_REF] Rajkumar | International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma[END_REF] , respectively. [START_REF] Terpos | The Chronic Kidney Disease Epidemiology Collaboration cystatin C (CKD-EPI-CysC) equation has an independent prognostic value for overall survival in newly diagnosed patients with symptomatic multiple myeloma; is it time to change from MDRD to CKD-EPI-CysC equations?[END_REF] The use of eGFR has been criticized because it is appropriate for the definition and staging of chronic kidney disease (CKD), but questionable for AKI. However, the usual lack of a baseline serum creatinine level often precludes an accurate assessment of AKI. In the sole study that used the RIFLE (Risk, Injury, Failure, Loss of kidney function, and Endstage kidney disease) criteria, 35% of MM patients had AKI with 5% staged as Risk, 5% as Injury and 25% as Failure. [START_REF] Shi | Application of RIFLE criteria in patients with multiple myeloma with acute kidney injury: a 15-year retrospective, single center, cohort study[END_REF] The establishment of a definitive diagnosis of LCCN relies upon a kidney biopsy. Since no series of patients with renal impairment or AKI and systematic renal examination has been reported, the true incidence of LCCN is unknown. In a cohort of 127 MM patients who presented with AKI, 72 underwent a kidney biopsy, either because of severe renal failure, or significant albuminuria (>30% of total urine proteins). Among these, pure LCCN was diagnosed in 41, while 4 patients had another pathology coexisting with LCCN. Around 25% of patients who presented with AKI had another LC-induced renal disease, including AL amyloidosis (n=12), light chain deposition disease (LCDD) (n=6), or Fanconi syndrome (n=1). Finally 8 patients had renal lesions unrelated to MM, 6 of whom with vascular atherosclerotic renal disease. [START_REF] Ecotière | Prognostic value of kidney biopsy in myeloma cast nephropathy: a retrospective study of 70 patients[END_REF]

SPECTRUM OF RENAL IMPAIRMENT IN SYMPTOMATIC MM

Renal complications not related to the monoclonal Ig.

In symptomatic MM, obstruction of the urinary tract due to expansion of bladder or ureteral extra-medullary plasmocytoma has been rarely described. [START_REF] Bigé | Urinary tract obstruction due to extramedullary plasmacytoma: report of two cases[END_REF] Similarly, renal parenchymal plasma cell infiltration is uncommon, and is exceptional as the sole cause of renal impairment.

In a recent randomized controlled study, where 176 MM patients with AKI due to LCCN underwent a kidney biopsy, malignant plasma cells invading the tubulo-interstitial compartment were found in 4 (2.2%), and always concurrent with LCCN. [START_REF] Bridoux | Effect of high-cutoff hemodialysis vs conventional hemodialysis on hemodialysis independence among patients with myeloma cast nephropathy: A randomized clinical trial[END_REF][START_REF] Bridoux | Randomized trial comparing double versus triple bortezomib-based regimen in patients with multiple myeloma and acute kidney injury due to cast nephropathy[END_REF] Hypercalcemia is present in about 15% of MM patients at presentation [START_REF] Blimark | Outcome and survival of myeloma patients diagnosed 2008-2015. Real-world data on 4904 patients from the Swedish Myeloma Registry[END_REF] , but the prevalence is 2 to 3 fold higher (25% to 45%) in those with an elevated serum creatinine level. [START_REF] Knudsen | Renal function in newly diagnosed multiple myeloma--a demographic study of 1353 patients. The Nordic Myeloma Study Group[END_REF][START_REF] Eleftherakis-Papapiakovou | Renal impairment is not an independent adverse prognostic factor in patients with multiple myeloma treated upfront with novel agent-based regimens[END_REF] Hypercalcemia may induce pre-renal AKI by dehydration and vasoconstriction and it is a common precipitating factor of LCCN. 22,28,29. Similarly, infections which are major cause of morbidity and death in MM patients are often associated with AKI. A large study reported a 7-fold increase risk of any bacterial infection for MM patients as compared to control, including a 15.6, 7.7 and 2.9-fold increase risk of septicemia, pneumonia and pyelonephritis, respectively. [START_REF] Blimark | Multiple myeloma and infections: a population-based study on 9253 multiple myeloma patients[END_REF] Any cause of dehydration and the use of nephrotoxic drugs, such as nonsteroidal anti-inflammatory drugs (NSAIDS), diuretics and renin-angiotensin-aldosterone system (RAS) blockers may be implicated in the development of pre-renal AKI, but usually trigger also the formation of light chain casts. [START_REF] Hutchison | The pathogenesis and diagnosis of acute kidney injury in multiple myeloma[END_REF][START_REF] Bridoux | Effect of high-cutoff hemodialysis vs conventional hemodialysis on hemodialysis independence among patients with myeloma cast nephropathy: A randomized clinical trial[END_REF][START_REF] Bridoux | Randomized trial comparing double versus triple bortezomib-based regimen in patients with multiple myeloma and acute kidney injury due to cast nephropathy[END_REF][START_REF] Rabb | Acute renal failure from multiple myeloma precipitated by ACE inhibitors[END_REF] This probably explains why acute tubular necrosis (ATN) is rarely observed without concurrent LCCN in myeloma patients with severe AKI, as described in only 17 (9%) of a series of 190 patients. [START_REF] Nasr | Clinicopathologic correlations in multiple myeloma: a case series of 190 patients with kidney biopsies[END_REF] AKI can also complicate the treatment of MM. Bisphosphonates, especially zoledronic acid used to treat hypercalcemia and myeloma bone disease, have been rarely involved in the development of ATN. [START_REF] Weide | Renal toxicity in patients with multiple myeloma receiving zoledronic acid vs. ibandronate: a retrospective medical records review[END_REF][START_REF] Raje | Denosumab versus zoledronic acid in bone disease treatment of newly diagnosed multiple myeloma: an international, double-blind, double-dummy, randomised, controlled, phase 3 study[END_REF] Renal thrombotic microangiopathy is a rare cause of myeloma-associated renal damage, [START_REF] Ravindran | Thrombotic microangiopathy associated with monoclonal gammopathy[END_REF] and more commonly a potential complication of proteasome inhibitors, particularly carfilzomib. [START_REF] Lodhi | Thrombotic microangiopathy associated with proteasome inhibitors[END_REF][START_REF] Yui | Proteasome inhibitor associated thrombotic microangiopathy[END_REF][START_REF] Yui | Ixazomib-induced thrombotic microangiopathy[END_REF] Lenalidomide has been associated with acute reversible non light chain-related Fanconi syndrome. [START_REF] Wesner | Two cases of reversible Fanconi syndrome induced by lenalidomide[END_REF] Anecdotal observations of acute interstitial nephritis with the use of lenalidomide [START_REF] Lipson | Lenalidomide-induced acute interstitial nephritis[END_REF] and bortezomib [START_REF] Cheungpasitporn | Bortezomib-induced acute interstitial nephritis[END_REF] have been reported. With the recent development of highly effective anti-myeloma chemotherapeutic regimens, tumor lysis syndrome, very unusual in the past, is increasingly described at the initiation of chemotherapy, particularly in patients with altered renal function receiving proteasome inhibitor-based regimens. [START_REF] Oiwa | High risk of tumor lysis syndrome in symptomatic patients with multiple myeloma with renal dysfunction treated with bortezomib[END_REF]

Renal complications related to the monoclonal Ig

The main mechanism of kidney injury due to MIg is deposition or precipitation of the entire MIg or a fragment thereof (usually the monoclonal LC). [START_REF] Hutchison | The pathogenesis and diagnosis of acute kidney injury in multiple myeloma[END_REF][START_REF] Fermand | Monoclonal gammopathy of clinical significance: a novel concept with therapeutic implications[END_REF] Physicochemical peculiarities of the pathogenic MIg, particularly of the variable domain, govern the localization and pattern of renal lesions. [START_REF] Comenzo | The tropism of organ involvement in primary systemic amyloidosis: contributions of Ig V(L) germ line gene use and clonal plasma cell burden[END_REF][START_REF] Sirac | Role of the monoclonal kappa chain V domain and reversibility of renal damage in a transgenic model of acquired Fanconi syndrome[END_REF][START_REF] Ying | Mechanism and prevention of acute kidney injury from cast nephropathy in a rodent model[END_REF][START_REF] Doshi | American Society of Nephrology Onco-Nephrology Forum. Paraprotein-related kidney disease: kidney injury from paraproteins-what determines the site of injury?[END_REF][START_REF] Bridoux | Unravelling the immunopathological mechanisms of heavy chain deposition disease with implications for clinical management[END_REF][START_REF] Sirac | Animal models of monoclonal immunoglobulin-related renal diseases[END_REF][START_REF] Joly | Randall-type monoclonal immunoglobulin deposition disease: novel insights from a nationwide cohort study[END_REF] Some renal complications can only occur in patients with a high tumor mass underlying clone. The paradigm is LCCN which always complicates a symptomatic monoclonal gammopathy, most commonly myeloma (and exceptionally Waldenström macroglobulinemia [START_REF] Chauvet | Kidney diseases associated with monoclonal immunoglobulin M-secreting B-cell lymphoproliferative disorders: a case series of 35 patients[END_REF][START_REF] Vos | Renal disease related to Waldenström macroglobulinaemia: incidence, pathology and clinical outcomes[END_REF][START_REF] Higgins | Kidney involvement of patients with Waldenström macroglobulinemia and other IgM-producing B cell lymphoproliferative disorders[END_REF] or chronic lymphocytic leukemia [START_REF] Strati | Renal complications in chronic lymphocytic leukemia and monoclonal B-cell lymphocytosis: the Mayo Clinic experience[END_REF] ). The other MIg-related nephropathies are not dependent on tumor mass and usually do not manifest with severe AKI.

They are mainly diagnosed in patients with MGRS, i.e. with an indolent monoclonal gammopathy or MGUS, although they may also develop during the course of a high tumor mass clonal disorder, including symptomatic MM.

When studied at the ultrastructural level, MGRS-related renal diseases are characterized with either organized or non-organized deposits. Organized deposits may display a fibrillar appearance, such as in AL amyloidosis, or a microtubular structure, as in type I or type II cryoglobulinemic glomerulonephritis and immunotactoid glomerulopathy. Non-organized linear "powdery punctuate" glomerular and tubular basement membrane deposits are characteristic of monoclonal immunoglobulin deposition diseases (MIDD). In contrast, proliferative glomerulonephritis with MIg deposits (PGNMID) is featured by non-organized granular deposits of MIg and complement. [START_REF] Bridoux | Diagnosis of monoclonal gammopathy of renal significance[END_REF][START_REF] Leung | The evaluation of monoclonal gammopathy of renal significance: a consensus report of the International Kidney and Monoclonal Gammopathy Research Group[END_REF] Monoclonal LC can also injure proximal tubules causing Fanconi's syndrome. [START_REF] Messiaen | Adult Fanconi syndrome secondary to light chain gammopathy. Clinicopathologic heterogeneity and unusual features in 11 patients[END_REF][START_REF] Ma | Acquired Fanconi syndrome is an indolent disorder in the absence of overt multiple myeloma[END_REF][START_REF] Stokes | Light chain proximal tubulopathy: linical and Pathologic Characteristics in the Modern Treatment Era[END_REF][START_REF] Vignon | Current anti-myeloma therapies in renal manifestations of monoclonal light chain-associated Fanconi syndrome: a retrospective series of 49 patients[END_REF] Recently, other renal diseases not involving MIg deposition have been described, including glomerulopathies with deposits of C3 only [START_REF] Sethi | Dense deposit disease associated with monoclonal gammopathy of undetermined significance[END_REF][START_REF] Bridoux | Glomerulonephritis with isolated C3 deposits and monoclonal gammopathy: a fortuitous association?[END_REF][START_REF] Zand | C3 glomerulonephritis associated with monoclonal gammopathy: a case series[END_REF][START_REF] Chauvet | Treatment of B-cell disorder improves renal outcome of patients with monoclonal gammopathy-associated C3 glomerulopathy[END_REF][START_REF] Ravindran | C3 glomerulopathy associated with monoclonal Ig is a distinct subtype[END_REF] and thrombotic microangiopathy. [START_REF] Ravindran | Thrombotic microangiopathy associated with monoclonal gammopathy[END_REF] Both disorders derive from deregulation of the complement alternative pathway, likely to be caused by the MIg through autoantibody activity against complement regulatory proteins or direct activation of the complement alternative pathway. [START_REF] Chauvet | Both monoclonal and polyclonal immunoglobulin contingents mediate complement activation in monoclonal gammopathy associated-C3 glomerulopathy[END_REF]

LIGHT CHAIN CAST NEPHROPATHY

Although all MIg-related nephropathies may be observed in patients with symptomatic MM, LCCN is the main cause of AKI in these patients.

Pathophysiology

Physiologically, around 500 mg polyclonal free light chains (FLC) are produced daily, of which 15% only are distributed in the intravascular space. These FLC circulate as monomers of 22kDA, but may assemble into dimers of 45kDA, particularly lambda FLC. [START_REF] Hutchison | The pathogenesis and diagnosis of acute kidney injury in multiple myeloma[END_REF][START_REF] Solomon | Light chains of human immunoglobulins[END_REF] Serum FLC (sFLC) undergo glomerular filtration, followed by reabsorption in the proximal tubules through endocytosis via the tandem receptors megalin and cubulin, and are ultimately degraded in the lysosomes of proximal tubular cells. [START_REF] Li | Silencing megalin and cubilin genes inhibits myeloma light chain endocytosis and ameliorates toxicity in human renal proximal tubule epithelial cells[END_REF][START_REF] Sanders | Mechanisms of light chain injury along the tubular nephron[END_REF][START_REF] Batuman | Myeloma light chains are ligands for cubilin (gp280)[END_REF][START_REF] Christensen | Endocytic receptors in the renal proximal tubule[END_REF] Consequently, only very low amounts are excreted in the final urine. In symptomatic MM featured by massive FLC production, this tubular processing may be overwhelmed, resulting in high luminal FLC concentration in the loop of Henle. In addition, reabsorption of huge quantities of monoclonal LC alters proximal tubular cells and reduces their catabolic capacities. [START_REF] Sanders | Human Bence Jones protein toxicity in rat proximal tubule epithelium in vivo[END_REF] FLC reaching the distal loop of Henle may interact with locally produced uromodulin (Tamm Horsfall protein), through the LC CDR3 hypervariable region that binds to a 9 aminoacid sequence of uromodulin. [START_REF] Huang | Localization of a single binding site for immunoglobulin light chains on human Tamm-Horsfall glycoprotein[END_REF][START_REF] Ying | Mapping the binding domain of immunoglobulin light chains for Tamm-Horsfall protein[END_REF] LC-uromodulin complexes co-aggregate to form casts, which are most commonly found in the distal tubules, and rarely in the proximal tubule or in the glomerulus. [START_REF] Ecotière | Prognostic value of kidney biopsy in myeloma cast nephropathy: a retrospective study of 70 patients[END_REF][START_REF] Rota | Multiple myeloma and severe renal failure: a clinicopathologic study of outcome and prognosis in 34 patients[END_REF][START_REF] Start | Myeloma cast nephropathy: immunohistochemical and lectin studies[END_REF][START_REF] Royal | Clinicopathologic predictors of renal outcomes in light chain cast nephropathy: a multicenter retrospective study[END_REF] These casts, which occasionally display a crystalline organization, obstruct the urine flow, producing a sudden decrease in the glomerular filtration rate, and may cause tubular rupture and extravasation of uromodulin [START_REF] Rota | Multiple myeloma and severe renal failure: a clinicopathologic study of outcome and prognosis in 34 patients[END_REF][START_REF] Start | Myeloma cast nephropathy: immunohistochemical and lectin studies[END_REF][START_REF] Royal | Clinicopathologic predictors of renal outcomes in light chain cast nephropathy: a multicenter retrospective study[END_REF][START_REF] Weiss | Pathophysiology of acute Bence-Jones protein nephrotoxicity in the rat[END_REF][START_REF] Smolens | Myeloma kidney cast nephropathy in a rat model of multiple myeloma[END_REF] This cascade of events results in severe local inflammation, often featuring giant cell reaction around casts, that further worsens renal damage. [START_REF] Ecotière | Prognostic value of kidney biopsy in myeloma cast nephropathy: a retrospective study of 70 patients[END_REF][START_REF] Rota | Multiple myeloma and severe renal failure: a clinicopathologic study of outcome and prognosis in 34 patients[END_REF][START_REF] Start | Myeloma cast nephropathy: immunohistochemical and lectin studies[END_REF][START_REF] Royal | Clinicopathologic predictors of renal outcomes in light chain cast nephropathy: a multicenter retrospective study[END_REF] In the absence of appropriate therapeutic intervention, irreversible tubulo-interstitial fibrosis rapidly develops. [START_REF] Ecotière | Prognostic value of kidney biopsy in myeloma cast nephropathy: a retrospective study of 70 patients[END_REF][START_REF] Rota | Multiple myeloma and severe renal failure: a clinicopathologic study of outcome and prognosis in 34 patients[END_REF][START_REF] Royal | Clinicopathologic predictors of renal outcomes in light chain cast nephropathy: a multicenter retrospective study[END_REF] In proximal tubules, the endocytosis of massive amounts of pathogenic monoclonal FLC induces generation of hydrogen peroxide and redox signaling. [START_REF] Sanders | Mechanisms of light chain injury along the tubular nephron[END_REF][START_REF] Sengul | Role of MAPK pathways in light chain-induced cytokine production in human proximal tubule cells[END_REF][START_REF] Wang | Immunoglobulin light chains generate hydrogen peroxide[END_REF][START_REF] Basnayake | Immunoglobulin light chains activate tubular epithelial cells through redox signaling[END_REF][START_REF] Ying | Immunoglobulin light chains activate nuclear factor-κB in renal epithelial cells through a Src-dependent mechanism[END_REF] This oxidative stress leads to the activation of several pro-inflammatory pathways, including the mitogen-activated protein kinases ERK1/2, JNK, p38, [START_REF] Sengul | Role of MAPK pathways in light chain-induced cytokine production in human proximal tubule cells[END_REF] and nuclear factor-kappa B (NF-κB), [START_REF] Ying | Immunoglobulin light chains activate nuclear factor-κB in renal epithelial cells through a Src-dependent mechanism[END_REF] leading to the production of inflammatory cytokines such as IL-6 and MCP-1 and the upregulation of apoptotic pathways. [START_REF] Ying | Pivotal role of apoptosis signal-regulating kinase 1 in monoclonal free light chain-mediated apoptosis[END_REF] The mechanisms of injury were recently elucidated by Ying et al., who showed in vivo and in vitro that STAT1 activation is the main pro-inflammatory mechanism triggered by FLC reabsorption, leading to the production of IL-1β and of the pro-fibrotic agent TGF-β. These effects are specifically induced by the generation of hydrogen peroxide by the pathogenic LC, which appears to depend on the molecular characteristics of the variable domain, i.e. the presence of an invariable tryptophan at amino acid residue 40. [START_REF] Ying | Immunoglobulin light chains generate proinflammatory and profibrotic kidney injury[END_REF] Mechanisms of distal tubulo-interstitial inflammation are incompletely understood. A role for the crystalline organization of light chain casts in triggering inflammation and giant cell reaction through activation of NLRP3 inflammasome and secretion of mature IL-1β remains to be investigated. [START_REF] Mulay | Crystal nephropathies: mechanisms of crystal-induced kidney injury[END_REF] The probability of cast formation increases with the serum level of the pathogenic FLC and the amount of its urinary excretion. [START_REF] Hutchison | The pathogenesis and diagnosis of acute kidney injury in multiple myeloma[END_REF][START_REF] Drayson | Effects of paraprotein heavy and light chain types and free light chain load on survival in myeloma: an analysis of patients receiving conventional-dose chemotherapy in Medical Research Council UK multiple myeloma trials[END_REF][START_REF] Yadav | Serum free light chain level at diagnosis in myeloma cast nephropathy-a multicentre study[END_REF] LCCN exceptionally occurs below a serum concentration of <500 mg/l. [START_REF] Yadav | Serum free light chain level at diagnosis in myeloma cast nephropathy-a multicentre study[END_REF] The risk varies with the molecular characteristics of each individual FLC which affinity for uromodulin is governed by the CDR3 amino acid sequence. [START_REF] Ying | Mechanism and prevention of acute kidney injury from cast nephropathy in a rodent model[END_REF] Thus, both affinity and concentration of the FLC determine the pathogenesis of LCCN. Neither LC isotype (kappa or lambda) nor variability subgroups, which are independent from CDR3 molecular sequence correlate with the risk of LCCN. [START_REF] Ying | Mechanism and prevention of acute kidney injury from cast nephropathy in a rodent model[END_REF][START_REF] Ying | Mapping the binding domain of immunoglobulin light chains for Tamm-Horsfall protein[END_REF] In addition to LC serum concentration and intrinsic characteristics, several extrinsic factors potentiate cast formation. [START_REF] Hutchison | The pathogenesis and diagnosis of acute kidney injury in multiple myeloma[END_REF] The main contributor is reduced urine flow, whatever its cause, that rises urinary FLC concentration and thus favors the FLC-uromodulin interaction. [START_REF] Sanders | Pathobiology of cast nephropathy from human Bence Jones proteins[END_REF] Any concurrent condition leading to dehydration including infection/sepsis, gastrointestinal losses, are potential precipitating factors of LCCN. Hypercalcemia is a frequent trigger, through polyuria and increased urine calcium concentration which promotes cast formation per se. [START_REF] Sanders | Mechanisms of intranephronal proteinaceous cast formation by low molecular weight proteins[END_REF] Aggregation of LC with uromodulin is also enhanced in acidic urine and in the presence of high NaCl concentrations. [START_REF] Sanders | Mechanisms of intranephronal proteinaceous cast formation by low molecular weight proteins[END_REF] Besides dehydration, these mechanisms participate to the potential deleterious effect of the loop diuretics. [START_REF] Sanders | Pathobiology of cast nephropathy from human Bence Jones proteins[END_REF] In addition, furosemide has been shown to cause a dose-dependent increase in uromodulin aggregation independent of urine electrolyte modifications. [START_REF] Sanders | Pathobiology of cast nephropathy from human Bence Jones proteins[END_REF] RAS blockers may be potential triggers through modification of renal vascular resistance and redistribution of intra-renal blood flow. [START_REF] Rabb | Acute renal failure from multiple myeloma precipitated by ACE inhibitors[END_REF] Similar hemodynamic mechanisms account for the nephrotoxicity of NSAIDs, which are currently the most frequent precipitating factor of LCCN, [START_REF] Bridoux | Effect of high-cutoff hemodialysis vs conventional hemodialysis on hemodialysis independence among patients with myeloma cast nephropathy: A randomized clinical trial[END_REF][START_REF] Bridoux | Randomized trial comparing double versus triple bortezomib-based regimen in patients with multiple myeloma and acute kidney injury due to cast nephropathy[END_REF] because of their common use as pain killers. Finally, iodinated contrast media have been classically associated with the development of AKI in MM. However, with modern low-osmolality agents the risk is low, estimated at 1.6% in a retrospective review [START_REF] Stacul | Iodine-based contrast media, multiple myeloma and monoclonal gammopathies: literature review and ESUR Contrast Media Safety Committee guidelines[END_REF] and established at 1.8% in a recent large prospective study. [START_REF] Bridoux | Effect of high-cutoff hemodialysis vs conventional hemodialysis on hemodialysis independence among patients with myeloma cast nephropathy: A randomized clinical trial[END_REF][START_REF] Bridoux | Randomized trial comparing double versus triple bortezomib-based regimen in patients with multiple myeloma and acute kidney injury due to cast nephropathy[END_REF]

Clinical presentation and diagnosis

LCCN is still a frequent mode of discovery of a previously unknown MM, being one of the myeloma-defining events, regrouped under the acronym CRAB (hypercalcemia, renal failure, anemia and bone lesions). [START_REF] Myeloma | Criteria for the classification of monoclonal gammopathies, multiple myeloma and related disorders: a report of the International Myeloma Working Group[END_REF][START_REF] Rajkumar | International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma[END_REF] Clinical presentation associates AKI of variable severity, usually associated with symptoms of high tumor mass MM. [START_REF] Hutchison | The pathogenesis and diagnosis of acute kidney injury in multiple myeloma[END_REF][START_REF] Bridoux | Effect of high-cutoff hemodialysis vs conventional hemodialysis on hemodialysis independence among patients with myeloma cast nephropathy: A randomized clinical trial[END_REF][START_REF] Bridoux | Randomized trial comparing double versus triple bortezomib-based regimen in patients with multiple myeloma and acute kidney injury due to cast nephropathy[END_REF][START_REF] Royal | Clinicopathologic predictors of renal outcomes in light chain cast nephropathy: a multicenter retrospective study[END_REF][START_REF] Hutchison | High cutoff versus high-flux haemodialysis for myeloma cast nephropathy in patients receiving bortezomib-based chemotherapy (EuLITE): a phase 2 randomised controlled trial[END_REF] Concomitant infection is a frequent circumstance of diagnosis. [START_REF] Bridoux | Effect of high-cutoff hemodialysis vs conventional hemodialysis on hemodialysis independence among patients with myeloma cast nephropathy: A randomized clinical trial[END_REF][START_REF] Bridoux | Randomized trial comparing double versus triple bortezomib-based regimen in patients with multiple myeloma and acute kidney injury due to cast nephropathy[END_REF] With recent improvement in management and increased life expectancy of MM patients, LCCN often occurs in the context of relapsing or refractory disease, either as AKI or as progressive CKD with parallel increase in LC proteinuria and serum creatinine level. [START_REF] Ecotière | Prognostic value of kidney biopsy in myeloma cast nephropathy: a retrospective study of 70 patients[END_REF] When facing AKI of unknown origin, particularly in the elderly and when other MM manifestations are missing or misleading, it is crucial to consider LCCN. Initial diagnostic workup should include serum and urine protein electrophoresis. In addition, measurement of sFLC should be performed systematically. Importantly, although nephelometric assays such as the Freelite® test are only semi-quantitative and do not measure the actual concentration of the monoclonal LC, they represent a reliable and invaluable tool for the diagnosis and management of LCCN. A monoclonal spike or hypogammaglobulinemia, a urine albumin/protein ratio <10%, and/or significantly increased level of one LC isotype with abnormal kappa/lambda ratio, should prompt to perform a bone marrow examination. [START_REF] Hutchison | The pathogenesis and diagnosis of acute kidney injury in multiple myeloma[END_REF] This will establish MM diagnosis by showing clear infiltration by atypical plasma cells, which clonality is indicated by phenotypic and molecular characteristics. Myeloma work-up should be completed by bone imaging techniques. [START_REF] Rajkumar | Multiple myeloma: 2020 update on diagnosis, risk-stratification and management[END_REF] In any MM patient who presents with or develops renal insufficiency, the combination of low urinary albumin excretion (urine albumin/total protein ratio <10% and urinary albumin/creatinine <30 mg/mmol), and high sFLC level (>500 mg/l) strongly argues for the diagnosis of LC-CN. [START_REF] Hutchison | The pathogenesis and diagnosis of acute kidney injury in multiple myeloma[END_REF][START_REF] Leung | Monoclonal gammopathy of renal significance: when MGUS is no longer undetermined or insignificant[END_REF][START_REF] Bridoux | Diagnosis of monoclonal gammopathy of renal significance[END_REF][START_REF] Leung | The evaluation of monoclonal gammopathy of renal significance: a consensus report of the International Kidney and Monoclonal Gammopathy Research Group[END_REF] and systematic histological confirmation is not required. [START_REF] Yadav | Serum free light chain level at diagnosis in myeloma cast nephropathy-a multicentre study[END_REF] In contrast, a kidney biopsy should be considered if significant albuminuria is present, particularly if sFLC is below 500 mg/L. More generally, monitoring and characterization of proteinuria is mandatory during follow-up of any monoclonal gammopathy including MM, and urine albumin/protein ratio >10% (or urine albumin/creatinine >30mg/mmol) should raise suspicion of MIg-related glomerulopathy such as AL amyloidosis or monoclonal immunoglobulin deposition disease (MIDD), rather than LCCN. [START_REF] Bridoux | Diagnosis of monoclonal gammopathy of renal significance[END_REF][START_REF] Leung | The evaluation of monoclonal gammopathy of renal significance: a consensus report of the International Kidney and Monoclonal Gammopathy Research Group[END_REF] Indication for a kidney biopsy should take into account renal and extra-renal presentation, characteristics of the monoclonal gammopathy and also alternative or superimposed causes of renal disease such as diabetes, or atherosclerosis. A clinical suspicion of AL amyloidosis should lead to perform a non-invasive biopsy at first, due to the risk of bleeding complications. [START_REF] Bridoux | Diagnosis of monoclonal gammopathy of renal significance[END_REF][START_REF] Leung | The evaluation of monoclonal gammopathy of renal significance: a consensus report of the International Kidney and Monoclonal Gammopathy Research Group[END_REF]

Pathology and role of the kidney biopsy

As already mentioned, kidney biopsy is required whenever the diagnosis of LCCN is clinically questionable. Studies have shown that it can be safely performed in MM patients, with risk similar as in other populations. [START_REF] Ecotière | Prognostic value of kidney biopsy in myeloma cast nephropathy: a retrospective study of 70 patients[END_REF][START_REF] Bridoux | Effect of high-cutoff hemodialysis vs conventional hemodialysis on hemodialysis independence among patients with myeloma cast nephropathy: A randomized clinical trial[END_REF][START_REF] Bridoux | Randomized trial comparing double versus triple bortezomib-based regimen in patients with multiple myeloma and acute kidney injury due to cast nephropathy[END_REF][START_REF] Royal | Clinicopathologic predictors of renal outcomes in light chain cast nephropathy: a multicenter retrospective study[END_REF][START_REF] Hutchison | High cutoff versus high-flux haemodialysis for myeloma cast nephropathy in patients receiving bortezomib-based chemotherapy (EuLITE): a phase 2 randomised controlled trial[END_REF][START_REF] Fish | The incidence of major hemorrhagic complications after renal biopsies in patients with monoclonal gammopathies[END_REF] Histologically, LCCN is defined by the presence of atypical casts in distal tubules and collecting ducts that exhibit LC restriction on immunofluorescence or immunohistochemistry.

The casts typically show irregular shapes and lamellated appearance and are often cracked or fractured. They appear hypereosinophilic on hematoxylin and eosin, periodic acid-Schiff negative, and silver-negative (Figure 1). [START_REF] Ecotière | Prognostic value of kidney biopsy in myeloma cast nephropathy: a retrospective study of 70 patients[END_REF][START_REF] Rota | Multiple myeloma and severe renal failure: a clinicopathologic study of outcome and prognosis in 34 patients[END_REF][START_REF] Start | Myeloma cast nephropathy: immunohistochemical and lectin studies[END_REF][START_REF] Royal | Clinicopathologic predictors of renal outcomes in light chain cast nephropathy: a multicenter retrospective study[END_REF] Ultrastructurally, they display highly electron dense homogeneous granular texture or exhibit lattice-like substructure. [START_REF] Royal | Clinicopathologic predictors of renal outcomes in light chain cast nephropathy: a multicenter retrospective study[END_REF] They are almost always associated with acute tubular injury (luminal ectasia, epithelial simplification and vacuolization, enlarged nuclei with hyperchromasia) and intratubular inflammatory reaction. [START_REF] Ecotière | Prognostic value of kidney biopsy in myeloma cast nephropathy: a retrospective study of 70 patients[END_REF][START_REF] Rota | Multiple myeloma and severe renal failure: a clinicopathologic study of outcome and prognosis in 34 patients[END_REF][START_REF] Start | Myeloma cast nephropathy: immunohistochemical and lectin studies[END_REF][START_REF] Royal | Clinicopathologic predictors of renal outcomes in light chain cast nephropathy: a multicenter retrospective study[END_REF] A hallmark of LCCN is giant cell reaction around the casts, but this feature is lacking in about a third of cases. [START_REF] Royal | Clinicopathologic predictors of renal outcomes in light chain cast nephropathy: a multicenter retrospective study[END_REF] Interstitial inflammation may vary from minimal to intense, depending on the severity and duration of cast formation, and progressive interstitial fibrosis and tubular atrophy ensue if the kidney biopsy is performed late. Other features include variable degree of tubulitis, tubular rupture, and uromodulin extravasation into the interstitium and/or accumulation in Bowman's space due to tubular obstruction. [START_REF] Ecotière | Prognostic value of kidney biopsy in myeloma cast nephropathy: a retrospective study of 70 patients[END_REF][START_REF] Rota | Multiple myeloma and severe renal failure: a clinicopathologic study of outcome and prognosis in 34 patients[END_REF][START_REF] Start | Myeloma cast nephropathy: immunohistochemical and lectin studies[END_REF][START_REF] Royal | Clinicopathologic predictors of renal outcomes in light chain cast nephropathy: a multicenter retrospective study[END_REF] Glomeruli and vessels appear unremarkable or show changes related to co-existing conditions, including diabetes, hypertension and atherosclerosis. [START_REF] Ecotière | Prognostic value of kidney biopsy in myeloma cast nephropathy: a retrospective study of 70 patients[END_REF][START_REF] Royal | Clinicopathologic predictors of renal outcomes in light chain cast nephropathy: a multicenter retrospective study[END_REF] LC casts should be distinguished from myoglobin and hemoglobin casts which typically do not induce an adjacent inflammatory reaction. [START_REF] Dvanajscak | A practical approach to the pathology of renal intratubular casts[END_REF] Cast formation can be observed in patients with pancreatic acinar or mixed acinar neuroendocrine carcinoma. [START_REF] Nasr | Paraneoplastic cast nephropathy associated with pancreatic mixed acinar-neuroendocrine carcinoma: a case report[END_REF] In these situations, immunofluorescence studies are determinant by showing the absence of LC restriction.

In 12-16% of cases, LCCN may coexist with other monoclonal Ig-related kidney lesions, particularly AL amyloidosis, classic LCDD and light chain proximal tubulopathy. [START_REF] Ecotière | Prognostic value of kidney biopsy in myeloma cast nephropathy: a retrospective study of 70 patients[END_REF][START_REF] Bridoux | Effect of high-cutoff hemodialysis vs conventional hemodialysis on hemodialysis independence among patients with myeloma cast nephropathy: A randomized clinical trial[END_REF][START_REF] Bridoux | Randomized trial comparing double versus triple bortezomib-based regimen in patients with multiple myeloma and acute kidney injury due to cast nephropathy[END_REF][START_REF] Nasr | Clinicopathologic correlations in multiple myeloma: a case series of 190 patients with kidney biopsies[END_REF][START_REF] Royal | Clinicopathologic predictors of renal outcomes in light chain cast nephropathy: a multicenter retrospective study[END_REF] Identification of any of these superimposed lesions requires clinical assessment for extrarenal involvement and yields prognostic value regarding kidney outcome. [START_REF] Royal | Clinicopathologic predictors of renal outcomes in light chain cast nephropathy: a multicenter retrospective study[END_REF][START_REF] Zand | Clinical and prognostic differences among patients with light chain deposition disease, myeloma cast nephropathy and both[END_REF] Associated direct interstitial infiltration by malignant plasma cells is rare. [START_REF] Bridoux | Randomized trial comparing double versus triple bortezomib-based regimen in patients with multiple myeloma and acute kidney injury due to cast nephropathy[END_REF] Some cases of LCCN exhibit concomitant diffuse linear staining of glomerular, tubular and vascular basement membranes for one Ig light chain by immunofluorescence without features of LCDD by light or electron microscopy, a pattern referred to as "LCDD by immunofluorescence only". [START_REF] Lin | Renal monoclonal immunoglobulin deposition disease: the disease spectrum[END_REF] A distinctive histologic variant of LCCN is congophilic "amyloidogenic" LCCN, where atypical casts are composed of Congo red-positive amyloid fibrils. A minority of patients with this variant have evidence for concurrent renal and/or extrarenal amyloidosis. [START_REF] Gibier | Intratubular amyloid in light chain cast nephropathy is a risk factor for systemic light chain amyloidosis[END_REF] Kidney biopsy may be helpful in the prognostication of LCCN. [START_REF] Ecotière | Prognostic value of kidney biopsy in myeloma cast nephropathy: a retrospective study of 70 patients[END_REF][START_REF] Rota | Multiple myeloma and severe renal failure: a clinicopathologic study of outcome and prognosis in 34 patients[END_REF][START_REF] Pasquali | Renal histological lesions and clinical syndromes in multiple myeloma. Renal Immunopathology Group[END_REF] In a recent retrospective study of 178 MM patients with LCCN, of whom 47% required dialysis at presentation, the number of casts/mm 2 in the cortex and, to a lesser extent, the degree of IFTA were independent prognostic factors of renal outcome. Importantly, the extent of cast formation could not be predicted by initial clinical data, including the level of the involved FLC. [START_REF] Royal | Clinicopathologic predictors of renal outcomes in light chain cast nephropathy: a multicenter retrospective study[END_REF]

Therapeutic management of LCCN

Treatment of AKI due to LCCN is an emergency. It is based on the combination of symptomatic measures, high dose steroids, and chemotherapy. In addition, extracorporeal removal of circulating FLC may be considered.

Symptomatic measures and chemotherapy

Symptomatic measures are crucial, aiming at correcting precipitating factors and optimizing hemodynamic conditions to decrease intra-luminal precipitation of monoclonal LC with uromodulin. Unless contraindicated (oliguric AKI or heart failure), a high urine flow should be established through vigorous rehydration using saline fluids. Half normal saline fluid may be used to limit the afflux of sodium and chloride in distal tubules. Although controversial, the administration of isotonic sodium bicarbonate may be considered to obtain a urine pH ≥7. [START_REF] Sanders | Pathogenesis and treatment of myeloma kidney[END_REF][START_REF] Leung | Current approach to diagnosis and management of acute renal failure in myeloma patients[END_REF][START_REF] Sathick | Myeloma light chain cast nephropathy, a review[END_REF][100] However, sodium bicarbonate should be avoided in hypercalcemic patients, due to the risk of calcium-phosphate precipitation. Treatment of hypercalcemia is based or rehydration combined with IV bisphosphonates (which are not contraindicated, provided that dose and infusion modalities are adapted to eGFR value). Pamidronate should be preferred to zoledronic acid, because of a lower risk of renal complications. [START_REF] Weide | Renal toxicity in patients with multiple myeloma receiving zoledronic acid vs. ibandronate: a retrospective medical records review[END_REF]101 Alternatively the anti-RANL ligand monoclonal antibody denosumab that inhibits osteoclasts may be proposed. [START_REF] Raje | Denosumab versus zoledronic acid in bone disease treatment of newly diagnosed multiple myeloma: an international, double-blind, double-dummy, randomised, controlled, phase 3 study[END_REF] The use of loop diuretics should be considered only in the situation of severe fluid overload.

RAS blockers and NSAIDS should be stopped. Any concurrent infection should be treated with non-nephrotoxic antibiotics. [START_REF] Sanders | Pathogenesis and treatment of myeloma kidney[END_REF][START_REF] Leung | Current approach to diagnosis and management of acute renal failure in myeloma patients[END_REF][START_REF] Sathick | Myeloma light chain cast nephropathy, a review[END_REF][100]

High-dose steroids and chemotherapy

High-dose dexamethasone is a key component in the treatment of LCCN, because of its potent cytotoxic, anti-inflammatory and catabolic properties. It should be introduced rapidly, immediately after the diagnosis of AKI. 102,103 Anti-plasma cell chemotherapeutic agents are required to decrease the tumor burden, in order to reduce the pathogenic monoclonal LC secretion. Only few prospective studies have addressed the issue of the best combinations of anti-myeloma drugs in patients with LCCN.

Current recommendations rely upon expert opinion derived from small retrospective series and advocate for rapid introduction of chemotherapeutic agents, the choice of which should consider their renal metabolism and toxicity profile. [START_REF] Dimopoulos | International Myeloma Working Group recommendations for the diagnosis and management of myeloma-related renal impairment[END_REF] Among conventional anti-myeloma agents, cyclophosphamide is more commonly used than melphalan which is eliminated by the kidneys, [START_REF] Bridoux | Effect of high-cutoff hemodialysis vs conventional hemodialysis on hemodialysis independence among patients with myeloma cast nephropathy: A randomized clinical trial[END_REF][START_REF] Bridoux | Randomized trial comparing double versus triple bortezomib-based regimen in patients with multiple myeloma and acute kidney injury due to cast nephropathy[END_REF][START_REF] Rajkumar | Multiple myeloma: 2020 update on diagnosis, risk-stratification and management[END_REF] whereas the cardiac toxicity of doxorubicin limits its indications. The so-called novel anti-myeloma agents comprise two main categories, immunomodulatory drugs (IMiDs) and proteasome inhibitors. Among IMiDs, thalidomide is associated with a dose-dependent risk of irreversible peripheral neuropathy when used for more than 3 months. 104 The renal benefit of pomalidomide, which contrary to lenalidomide does not undergo renal elimination, 105 has not been assessed yet. Regarding proteasome inhibitors, carfilzomib induces higher hematologic response rates compared to bortezomib. 106,107 However, its potential cardiac and renal toxicity, 108 including thrombotic microangiopathy, [START_REF] Lodhi | Thrombotic microangiopathy associated with proteasome inhibitors[END_REF][START_REF] Yui | Proteasome inhibitor associated thrombotic microangiopathy[END_REF]108 precludes its use as a standard for LCCN. Finally, monoclonal anti-CD38 monoclonal antibodies, which significantly improve the rapidity and depth of hematologic responses in both newly diagnosed and refractory myeloma, 109-112 represent a promising tool for the treatment of LCCN.

Currently, the standard of treatment combines high-dose dexamethasone with the proteasome inhibitor bortezomib, which efficacy and tolerance are established without dose adaptation, whatever the degree of renal impairment, including in patients requiring dialysis. [113][114][115][116][117][118] The bortezomib-dexamethasone doublet can be reinforced to further improve hematologic responses, 119,120 as documented in patients with newly-diagnosed or relapsed MM with preserved renal function. 121,122 Using a triplet regimen increases the risk of deleterious events such as infection, hemodynamic instability and drug toxicity, and finally may compromise renal recovery in patients with LCCN. [START_REF] Hutchison | High cutoff versus high-flux haemodialysis for myeloma cast nephropathy in patients receiving bortezomib-based chemotherapy (EuLITE): a phase 2 randomised controlled trial[END_REF] In these patients, often old and frail with pre-existing co-morbidities, a careful assessment of the efficacy/toxicity balance of anti-myeloma combinations is crucial. The sole randomized study that compared a doublet to a triplet regimen [START_REF] Bridoux | Randomized trial comparing double versus triple bortezomib-based regimen in patients with multiple myeloma and acute kidney injury due to cast nephropathy[END_REF] did not document a beneficial effect for renal outcomes of reinforcing BD with cyclophosphamide for renal outcomes. The slightly higher efficacy of C-BD in reducing pathogenic LC was not sufficient to counterbalance the incidence of adverse events, particularly severe infections. The later study strengthened the bortezomib-dexamethasone doublet as the reference treatment of inaugural LCCN, especially in frail patients. [START_REF] Bridoux | Randomized trial comparing double versus triple bortezomib-based regimen in patients with multiple myeloma and acute kidney injury due to cast nephropathy[END_REF] In fit patients, a triplet regimen may be considered, although the best drug combination remains to be defined. In the near future, the association of bortezomib with monoclonal anti-CD38 antibodies is likely to become the backbone of chemotherapy for optimizing renal recovery in LCCN. 123

Extracorporeal FLC removal

Even if chemotherapy could completely suppress the malignant plasma cell production, considering an additional strategy dedicated to remove the pathogenic LC from the circulation is logical. Indeed, in LCCN and AKI the reduced renal catabolism of the monoclonal LC results in a marked increase in its half-life (from few hours to 2-3 days) and huge accumulation in both vascular and extra-vascular compartments. [START_REF] Hutchison | The pathogenesis and diagnosis of acute kidney injury in multiple myeloma[END_REF][START_REF] Solomon | Light chains of human immunoglobulins[END_REF] Rapid FLC depuration may be achieved either through plasmapheresis or intensive hemodialysis using new generation "high cutoff" protein leaking dialyzers with very high permeability to proteins. 124 It should be stressed that these therapies are pointless if used without efficient chemotherapy.

The renal effect of their combination with anti-plasma cell regimens is debated. A randomized trial, performed before the era of novel anti-myeloma agents and limited by the absence of pathological demonstration of LCCN, failed to show a benefit of plasmapheresis. 125 This was later challenged by retrospective data in patients with biopsy-proven LCCN, in whom the combination of plasmapheresis with high-dose dexamethasone and bortezomib or thalidomide, was reported to produce renal response rates of up to 75%. 126,127 In myeloma patients requiring dialysis, hemodialysis using conventional high-flux dialyzers with a protein cutoff of 15 to 20 kDa, provides only limited clearance of FLC. High cutoff (HCO) dialyzers, which allow the removal of proteins up to 65kDa, produce highly efficient clearing of both kappa and lambda LC, at the price of significant but acceptable albumin loss.

Because of the predominant (around 80 to 85%) extravascular distribution of FLC, prolonged HCO hemodialysis sessions are needed to remove high quantities of FLC, given the postdialysis intravascular rebound. 128 In pioneering retrospective studies, the combination of intensive HCO hemodialysis and novel anti-myeloma regimens was associated with hemodialysis independence rates of about 60%, 124,129-134 which compared favorably with the usual 30% rate reported in patients receiving conventional hemodialysis. 114,[117][118][119] Other techniques of FLC depuration have been investigated in a limited number of MM patients with AKI. The main consisted of hemodialysis using adsorptive polymethylmetacrylate dialyzers 135 , hemodiafiltration using high-flux or very high-flux membranes, 136,137 supra-hemodiafiltration with endogenous reinfusion after FLC adsorption (« SupraHFR »), 138 or continuous venovenous hemofiltration with high cutoff filters. 139 Their efficacy on FLC removal as compared to HCO hemodialysis remains to be assessed. Two randomized trials, MYRE [START_REF] Bridoux | Effect of high-cutoff hemodialysis vs conventional hemodialysis on hemodialysis independence among patients with myeloma cast nephropathy: A randomized clinical trial[END_REF] and EuLite 89 , evaluated HCO hemodialysis in comparison with standard high-flux hemodialysis. Their design presented noticeable differences (Table 1).

Briefly, i) in EuLite randomization was upfront. In MYRE it was preceded by a pre-inclusion phase dedicated to symptomatic measures and high-dose dexamethasone, and accordingly, only patients with persisting AKI still requiring hemodialysis were randomized. ii) In EuLite, the HCO hemodialysis schedule was very intensive whereas the control group used a standard regimen. In MYRE, both HCO and control groups received the same intensive dialysis dose.

iii) EuLite involved few specialized centers. MYRE was conducted in standard hemodialysis facilities from many centers iii) In EuLite, the chemotherapeutic regimen used three drugs. In MYRE, patients received the BD doublet.

In the HCO groups of both studies, dialysis independence rates at 6 months were around 60%.

In contrast, results differed in control groups, being significantly lower in MYRE (35%), and not different in EuLite. Of note, the primary endpoint in MYRE was set at 3 months, where hemodialysis withdrawal rates were not significantly different (Table 1). Tolerance of HCO hemodialysis was good in MYRE. [START_REF] Bridoux | Effect of high-cutoff hemodialysis vs conventional hemodialysis on hemodialysis independence among patients with myeloma cast nephropathy: A randomized clinical trial[END_REF] The HCO group of EuLite experienced a high rate of serious adverse events, particularly of severe infections, which resulted in frequent treatment interruptions. [START_REF] Hutchison | High cutoff versus high-flux haemodialysis for myeloma cast nephropathy in patients receiving bortezomib-based chemotherapy (EuLITE): a phase 2 randomised controlled trial[END_REF] Finally, overall survival was similar in the two groups of the MYRE study, whereas mortality rate was higher in the HCO group of EuLite, as compared to the control group. Both studies confirmed the efficacy of HCO dialyzers for removing circulating FLC, whatever the isotype, kappa or lambda. Despite the discordant results of these trials, many investigators currently consider that combining an effective chemotherapy with HCO hemodialysis is still a relevant therapeutic option in patients with LCCN. Whether or not novel anti-plasma cell regimens introducing monoclonal anti-CD38 antibodies will push to the side extracorporeal treatment requires evaluation through specific phase 2 studies, which are much realistic than large randomized phase 3 trials.

Determinants of outcomes

Since precipitating factors, particularly dehydration and the use of NSAIDs are often implicated in the development of LCCN, preventing measures based on patient and medical staff information are of paramount importance. Early diagnosis with adapted energetic intervention is also crucial. The combination of supportive measures with high-dose dexamethasone may be sufficient enough to induce rapid recovery of renal function by preventing the emergence and/or the worsening of LCCN. 102 For those patients with persisting AKI, hematologic response is the main predicting factor of renal survival. This particularly holds true for patients requiring dialysis, in whom achievement of serum level of the involved sFLC level below 500 mg/L after the first cycle of chemotherapy is an independent factor of renal recovery. [START_REF] Bridoux | Effect of high-cutoff hemodialysis vs conventional hemodialysis on hemodialysis independence among patients with myeloma cast nephropathy: A randomized clinical trial[END_REF] Among patients without indication for dialysis, a ≥90% reduction in pathogenic sFLC level is also associated with an increased probability of renal response. [START_REF] Bridoux | Randomized trial comparing double versus triple bortezomib-based regimen in patients with multiple myeloma and acute kidney injury due to cast nephropathy[END_REF] In any case, early assessment of hematologic response based on serial sFLC measurements is crucial. If a rapid and deep hematologic response is not achieved, reinforcing the previous regimen should be considered, either by introducing an IMiD and/or an anti-CD38 monoclonal antibody.

The severity of renal impairment also conditions renal prognosis. In the absence of dialysis requirement, AKIN stage 3 was recently shown as an independent predictor of poor renal outcome, in addition to preexisting CKD. [START_REF] Bridoux | Randomized trial comparing double versus triple bortezomib-based regimen in patients with multiple myeloma and acute kidney injury due to cast nephropathy[END_REF] In these patients, performing a kidney biopsy may help predicting renal prognosis and potentially guide therapeutic decisions, such as the reinforcement of chemotherapy with extracorporeal FLC removal. [START_REF] Royal | Clinicopathologic predictors of renal outcomes in light chain cast nephropathy: a multicenter retrospective study[END_REF] We suggest that the kidney biopsy report of LCCN cases may include two key predictive histologic features, i.e. highest number of casts/mm 2 in the cortex and degree of IFTA (Table 2). We propose that such a standardized approach of kidney biopsy reporting should be used in future studies of AKI in myeloma, to evaluate whether it translates into improved management and renal outcomes.

Life expectancy of patients with end-stage renal failure due to LCCN has increased over the last decade, but remains inferior to 2 years in those established on chronic dialysis. 140,141 Because of improved overall prognosis, a growing number of patients are potential candidates for kidney transplantation, but eligibility criteria remain to be defined. Transplantation may be considered in young patients with newly diagnosed MM lacking high-risk cytogenetic abnormalities (particularly del17p) and who have achieved sustained complete hematologic response as defined by negative minimal residual disease (MRD) using flow cytometry or molecular analysis. 141,142 Although it has been shown that renal recovery can lead to improved survival in patients with MM, 143-145 a cohort of 1135 consecutive patients showed that the life expectancy of patients with reversal of renal impairment remains inferior to patients with normal renal function at diagnosis. [START_REF] Gonsalves | Improvement in renal function and its impact on survival in patients with newly diagnosed multiple myeloma[END_REF] Criteria for renal response were proposed by the IMWG, defining complete, partial and minor responses, but their clinical relevance at the individual level remains to be evaluated. [START_REF] Dimopoulos | International Myeloma Working Group recommendations for the diagnosis and management of myeloma-related renal impairment[END_REF] Practically, improvement in renal function, defined by a stable eGFR value ≥40 ml/min/1.73m 2 , is likely to be a desirable goal, [START_REF] Gonsalves | Improvement in renal function and its impact on survival in patients with newly diagnosed multiple myeloma[END_REF][START_REF] Bridoux | Randomized trial comparing double versus triple bortezomib-based regimen in patients with multiple myeloma and acute kidney injury due to cast nephropathy[END_REF] particularly in young patients otherwise eligible for high dose chemotherapy and autologous stem cell transplantation (ASCT). ASCT is still a reference treatment for newly-diagnosed myeloma. However, many investigators consider that it should be considered with caution in patients with severe renal impairment (i.e. eGFR <40 ml/min/1.73m2), because of a questionable benefit to risk ratio.

Conclusions and future directions

Recent advances in the management of monoclonal gammopathies, particularly MM, have resulted in a frank improvement in patient survival. In parallel, the introduction of the concept of MGRS/MGCS has clarified the diagnostic process of the various associated renal disorders.

For LCCN, which is still a frequent and critical complication of symptomatic MM, further progress is eagerly required. Prevention and early diagnosis should be improved. The introduction of monoclonal anti-CD38 antibodies is likely to optimize the efficacy/toxicity balance of the indispensable chemotherapy, and ultimately to enhance renal recovery which strongly affects morbidity and mortality. In patients requiring dialysis, further studies addressing the modalities of the combination of HCO-HD with chemotherapy are warranted.

Therapeutic decisions may be guided by improved prediction of renal outcomes, through wider use of the kidney biopsy in patients with severe AKI. Collaboration between nephrologists and hematologists is mandatory throughout the disease evolution.

Legend to figure 1 Figure 1 .

 11 Figure 1. Biopsy findings in light chain cast nephropathy. (A) Numerous periodic acid-Schiff [PAS]-negative cortical casts associated interstitial fibrosis and tubular atrophy (PAS, original magnification ×100). (B) Intraluminal hypereosinophilic casts distending the tubules, resulting in tubular ruptures (hematoxylin and eosin, original magnification ×200). (C) Sharpedged and fractured PAS-negative cast surrounded by a cellular reaction (PAS, original magnification ×400). Immunofluorescence staining for anti-κ (D) and anti-λ (E) showing kappa light chain restriction (original magnification ×100). (F) Congo Red staining showing anomalous colors under polarized light in congophilic "amyloidogenic" variant of light chain cast nephropathy (Congo Red, original magnification ×400).

Table 1 . Main differences between MYRE and EuLite randomized controlled trials (HCO hemodialysis vs. conventional high-flux hemodialysis) MYRE EuLite Number of randomized patients

 1

		98	90
	Randomization	After a pre-inclusion period of (4	Upfront
		to 15 days) including
		symptomatic measures and high -
		dose steroids (Dexamethasone 40
		mg/d orally, 4 days)
	Chemotherapy	Bortezomib Dexamethasone	Bortezomib-Dexamethasone-
	regimens	(± Cyclophosphamide in patients	Doxorubicin
		without hematological response
		after 3 cycles)
	Hemodialysis schedule Identical in HCO and control	Intensive HD in HCO group
		groups
		8 sessions of 5hours over the first	Daily sessions of 8hours over
		10 days, then thrice weekly	the first 10 days, then 8hour-
			sessions thrice weekly from day
			12 to D21, then 6 hour-sessions
			thrice weekly.
			Standard HD in the control
			group
			4hour-sessions thrice weekly
	HCO dialyzers	Single HCO Theralite® dialyzer	2 1.1m 2 HCO dialyzers in series
		of 2.1 m 2 in surface
	Premature treatment	4 (8.7%) in HCO group*	9 (20.9%) in HCO group
	discontinuation	2 (4.2%) in control group	2 (4.2%) in control group
	Dialysis independence
	At 3 months #	41% (HCO) vs. 33% (Control)	56% (HCO) vs. 51% (Control)
		p= 0.42	p= 0.81
	At 6 months	56.5% (HCO) vs. 35% (Control)	58% (HCO) vs. 66% (Control)
		p= 0.04	p= 0.76
	At 12 months	61% (HCO) vs. 37.5% (Control)	58% (HCO) vs. 66% (Control)
		p= 0.02	p= 0.76
	* including 1 patient for intolerance of the hemodialysis protocol

# Primary endpoint

Abbreviations: HCO, high cutoff; HD, hemodialysis

Table 2 . Definitions and scores of the predictive histologic features in kidney biopsy report for light chain cast nephropathy

 2 Adapted from reference 74 Royal V, Leung N, Troyanov S, et al. Blood. 2020;135:1833-1846

	Variable	Definition	Score
	Highest number of light chain	Highest number of light chain casts in	Ca1: <5 casts/mm 2
	casts per millimeter square in	one 20x field divided by the area of one	Ca2: 5 to 10 casts/mm 2
	the cortex (Ca)	20x field in mm 2	Ca3: >10 casts/mm 2
	Interstitial fibrosis/tubular	Thickened tubular basement membranes	T0: <10%
	atrophy (T)	with flattened epithelial cells, expanded	T1: 10%-24%
		interstitium with fibrosis, whichever is	T2: 25%-50%
		the highest	T3: >50%