Introduction
Acute kidney injury (AKI) remains a common presentation of multiple myeloma (MM). Depending on the definition of AKI used, between 18% and 56% of patients with MM are affected. It is not infrequent that myeloma is first identified during the workup of a patient with unexplained AKI. When this AKI is severe, it has historically been associated with a limited chance of renal recovery and a greatly reduced survival for individuals with MM compared with those with no renal impairment.
Paraproteins, or M-proteins, are associated with many patterns of renal injury within the nephron, and in turn these different pathologies are associated with a diverse range of clinical presentations. In 2012 the International Kidney and Monoclonal Gammopathy Research Group (IKMG) introduced the classification, monoclonal gammopathy of renal significance (MGRS), to capture some of the rarer renal pathologies associated with small paraproteins in individuals who do not meet the diagnostic criteria for MM. Cast nephropathy does not fit into this diagnostic classification, as patients with cast nephropathy always meet the criteria for MM.
With the combination of improved diagnostic techniques and modern chemotherapy agents, the kidney and overall outcomes for patients with cast nephropathy have greatly improved in recent years.
Epidemiology
MM is a hematologic malignancy characterized by the clonal expansion of malignant plasma cells in the bone marrow and end organ dysfunction. MM accounts for 1% of all malignancies and 12% to 15% of hematologic malignancies. The annual age adjusted incidence is 5.6 cases per 100,000 persons in Western countries with a median age at presentation of 70 years. Renal impairment at diagnosis remains common with an incidence that ranges from 20% to 50%.
The development of AKI reduces 1-year survival in patients with MM, with recovery of renal function more predictive of survival than hematologic response. According to the European Renal Association-European Dialysis and Transplant Association registry study, the incidence rate of end-stage kidney disease (ESKD) secondary to complications of MM in Europe increased from 0.7 per million population (pmp) from 1986 to 1990 to 2.52 pmp between 2001 and 2005. The incidence rate was observed to be higher in the United States at 4.3 cases per million per year between 2001 and 2010. The mortality rates for patients with ESKD secondary to MM were significantly higher in comparison to patients without myeloma: 86.7, 41.4, and 34.4 per 100 person-years in the first 3 years of renal replacement therapy (RRT) compared with 32.3, 20.6, and 21.3, respectively. The overall adjusted hazard ratio for death was 2.5 in patients with ESKD caused by myeloma versus other causes.
Pathophysiology
Although there are diverse potential causes of AKI in patients with MM, the majority of individuals affected have the tubulointerstitial pathology of cast nephropathy, also known as myeloma kidney . In biopsy series, cast nephropathy accounts for between 66% and 100% of the pathologic diagnoses. This tubulointerstitial pathology is a direct consequence of the very high concentrations of monoclonal free light chains (FLC) present in the circulation of individuals with MM. These middle-molecular weight proteins are freely filtered at the glomeruli and pass with the ultrafiltrate into the proximal and then distal tubules.
Polyclonal free light chains and bence-jones proteins
About 500 mg of polyclonal FLCs are produced daily by the normal lymphoid system and catabolized by the proximal tubule. This system is highly efficient and only 1 to 10 mg of polyclonal FLCs normally appear in the urine each day. However, in the setting of a plasma cell dyscrasia, FLC production increases considerably, producing circulating levels of monoclonal FLCs that can be hundreds of fold higher than normal. When this increase occurs, the capacity of the multiligand endocytic receptor complex of the proximal tubule is quickly exceeded, and high concentrations of FLCs appear in the tubular fluid and finally in the urine. The FLCs that appear in the urine are traditionally termed Bence-Jones proteins (BJP) . Before the advent of serum assays for the measurement of monoclonal FLCs, the identification of BJP was a critical element of the workup of patients with suspect myeloma.
Mechanisms of injury
Monoclonal FLCs are known to induce isolated proximal tubular injury, cast nephropathy, or a combination of both. FLC interaction with proximal tubule cells (PTCs) can activate inflammatory cascades that lead to tubulointerstitial fibrosis, a major feature of myeloma kidney. Similarly, FLC interaction with Tamm-Horsfall proteins (THPs; also known as uromodulin ) and cast formation in the distal tubule can block glomerular flow and produce tubular atrophy and contribute to interstitial fibrosis.
Proximal tubule cell injury
FLCs can exert direct toxic effects on PTCs, the most abundant cell type in the kidney, and many of the renal consequences of myeloma involvement of the kidney are related to proximal tubular injury. Studies have shown that FLCs purified from the urine of myeloma patients without glomerular disease inhibited substrate transport in isolated brush border membrane vesicles, cultured PTCs in vitro, and in perfused proximal tubules in rats in vivo.
Although FLCs can be directly toxic to PTCs by blocking transport of glucose, amino acids, or phosphate, and by activating redox signaling upon contact with PTCs, most of the toxicity is mediated after endocytosis of FLCs, through the tandem endocytic receptors cubilin and megalin. , Excessive FLC endocytosis can induce a spectrum of inflammatory effects that include activation of redox pathways and expression of nuclear factor κB and mitogen-activated protein kinases, leading to transcription of inflammatory and profibrotic cytokines, such as interleukin (IL)-6, C-C motif chemokine 2 (also known as monocyte chemoattractant protein ), IL-8, and transforming growth factor β1. Excessive FLC endocytosis can also trigger apoptotic pathways and alter the phenotype of PTCs towards a fibroblastic one through epithelial–mesenchymal transition in vitro and in vivo. , Studies have shown that blocking FLC endocytosis, either by inhibition of endocytosis or by silencing the endocytic receptors cubilin and megalin, abrogates cytotoxicity. These observations support the principle that endocytosis is a prerequisite for these inflammatory processes and are the basis of three potential therapeutic strategies to prevent tubular injury: first, to eliminate or reduce the FLC burden in myeloma patients with renal involvement; second, to block the inflammatory pathways that are activated as a result of FLC toxicity; and third, to potentially block FLC endocytosis.
Cast nephropathy
In addition to this proximal tubule injury, the major mechanism of FLC-mediated tubule damage is intratubular obstruction from precipitation of FLCs in the lumen of the distal nephron ( Figs 7.1 A and B), which leads to interstitial inflammation and fibrosis. The clinical relevance of cast formation was initially revealed by an eloquent series of studies that infused nephrotoxic human FLCs in rats. These studies demonstrated that infusion of these FLCs resulted in increased proximal tubule pressure and simultaneously decreased single-nephron glomerular filtration rate. Intraluminal protein casts were identified in these rat kidneys. Persistence of intraluminal casts in vivo reduces single-nephron glomerular blood flow to the obstructed nephron and results in atrophy of the nephron proximal to the obstruction. , When infused directly into the rat nephron in vivo, monoclonal FLCs from patients with cast nephropathy produced dose-dependent intraluminal obstruction by precipitating in the distal nephron; casts were not observed before the tip of the loop of Henle. Obstruction was accelerated by the presence of furosemide. Pretreatment of rats with colchicine decreased urinary levels of THP and prevented intraluminal cast formation and obstruction. Additional studies demonstrated an integral relationship between monoclonal FLCs and THPs in cast formation and the associated kidney injury. In humans, casts are generally observed in the distal portion of the nephron, although they have also been found in proximal tubular segments and even in glomeruli in renal biopsy specimens. However, these casts also contained THP, suggesting intraluminal reflux of coprecipitated THP and FLC into the proximal nephron.
Cast formation in vivo is a complex process that is dictated by multiple variables, including the ionic composition of the tubule fluid, tubule fluid flow rates, the concentration of THP and FLC, the strength of binding interaction between THP and FLC, and the presence of furosemide. These observations have direct clinical relevance as many of these factors (except the intrinsic binding interaction between THP and FLC) can be modified with current treatment modalities.
Identifying nephrotoxic light chains
Not all monoclonal FLCs are nephrotoxic. Although the risk of AKI in patients with MM is increased when FLC proteinuria reaches 2 g per day, some patients do not develop kidney disease despite high FLC urine concentrations. Because no tool to predict toxicity of a given FLC is currently available, preventive measures and removal of precipitating factors are mandatory.
The mechanisms involved in the renal pathogenic effects of individual monoclonal FLCs remain incompletely understood. Nephrotoxicity appears to be an intrinsic property of some FLCs, as indicated by the recurrence of similar renal lesions after kidney transplantation, and by animal studies that have specifically reproduced human FLC-related nephropathies using injections of purified human FLCs, intraperitoneal injections of transfected plasmacytomas secreting a pathogenic human FLC, , or gene-targeted insertion. Growing evidence shows that the pattern of renal injury is governed by both structural peculiarities of monoclonal FLCs, particularly of the variable (V) domain, and is influenced by environmental factors, such as pH, urea concentration, or local tissue proteolysis. In addition, intrinsic host factors are likely to have an important role in determining both the type and severity of any renal response to a given FLC.
Pathogenic FLCs purified from patients’ urine are characterized by their propensity to form high-order aggregates or polymers in vitro, which differ according to the sequence variability of the V domain. The peculiarities of the V domain are observed in many types of renal disease induced by light chains. Myeloma-associated Fanconi syndrome, for example, is characterized by proximal tubule dysfunction secondary to FLC reabsorption and crystallization within the lysosomal compartment of PTCs. FLCs associated with Fanconi syndrome are nearly always of the Vκ1 subgroup and are derived from only two germ line genes, immunoglobulin kappa variable (IGKV)1-39 and IGKV1-33 . In immunoglobulin light chain (AL) amyloidosis and light chain deposition disease, the pathogenic role of V regions is suggested by overrepresentation of the Vλ6 and Vκ462 subgroups, respectively, N-glycosylation of the V region, and substitutions of key amino acids induced by somatic mutations that might account for the propensity of certain FLCs to aggregate and influence tropism of deposition. FLCs associated with light chain deposition disease are characterized by cationic isoelectric points, whereas the isoelectric point profile of FLCs involved in AL amyloidosis is heterogeneous. This observation suggests that fibrillar amyloid deposits form by electrostatic interaction between oppositely charged polypeptides, whereas granular deposits in light chain deposition disease result from the binding of cationic polypeptides to anionic basement membranes.
The role of the molecular characteristics of FLCs in myeloma kidney is less clear. In high-mass myeloma, the capacity of the proximal tubule to reabsorb and degrade FLCs is rapidly overwhelmed by the dramatic increase in the burden of filtered FLCs. Large amounts of FLCs reach the distal tubule lumen where they interact with THP. Huang and Sanders identified a binding domain for FLCs on THP, which consisted of nine amino acids and was termed light chain binding domain . Importantly, all FLCs tested bound to this FLC-binding domain. In turn, the CDR3 domain in the variable region of both κ and λ FLCs interacted with THP. The binding affinities of FLCs for THP are related to the amino acid composition of the CDR3 domain.
Despite our growing understanding of the pathogenic mechanisms by which immunoglobulin (Ig) FLCs induce renal injury, there are currently no clinically relevant tools for identifying the potential nephrotoxicity of a specific monoclonal FLC.
Diagnostic approach to myeloma kidney
Myeloma kidney should be high on the differential diagnosis list for patients with unexplained AKI across a wide spectrum of ages. Although frequently considered a disease of the elderly, myeloma kidney has been reported in early to mid-adult life and should be particularly considered in the setting of a severe AKI with an acellular urine. When approaching these patients, there are two key considerations: (1) is there a monoclonal protein present, which can be responsible for the renal injury? and (2) are the criteria for MM met? With the advent of the serum free light chain assays (FLC) this diagnostic workup can be undertaken rapidly at little cost.
Identifying monoclonal free light chains by immunoassays
During the assessment of an individual with AKI, it is often appropriate and necessary to screen for the presence of a potentially nephrotoxic monoclonal FLC ( Fig. 7.2 ). In such cases, it is essential that the nephrologist and laboratories work together to minimize diagnostic delays to enable the rapid initiation of disease-specific treatment. In patients with AKI, the most rapid way to assess for a monoclonal protein of renal significance is by the quantitative measurement of FLC in the serum by nephelometric immunoassays. , These immunoassays provide a quantitative measurement of both κ and λ FLCs; an overproduction of one of these monoclonal FLCs will lead to a ratio of the two FLCs that deviates outside the normal range (0.26–1.65). Use of these assays as a screening tool can help overcome logistic delays and analytic inaccuracies associated with other laboratory methods used for the identification of monoclonal FLCs (such as serum and urine protein electrophoresis and immunofixation).
In an assessment of 1877 patients with plasma cell dyscrasias, Katzmann et al. found that serum protein electrophoresis and a quantitative serum FLC assay identified 100% of patients with MM and macroglobulinemia, 99.5% of patients with smoldering MM, 96.5% of patients with AL amyloidosis, and 78% of patients with light chain deposition disease. International guidelines now recommend that screening of serum alone (with serum protein electrophoresis and a quantitative serum FLC assay) for plasma cell dyscrasias is a viable alternative to urinary assessment. , Despite the accumulation of serum polyclonal FLCs in renal impairment, the assay remains useful in patients with renal failure, but absolute values are raised and the normal range for the FLC ratio is changed from that in the general population to 0.37 to 3.17. By using this renal range in a dialysis-dependent AKI population, the number of false positives was reduced. In addition to these diagnostic advantages, the FLC immunoassays offer the ability to monitor clonal disease response, which has particular relevance in patients with myeloma kidney in whom an early reduction in serum FLC concentrations is associated with renal recovery.
Diagnostic assessment for multiple myeloma
Once MM has been suspected, a targeted hematologic assessment should be undertaken. This should include: full assessment of the paraprotein (serum FLC, serum protein electrophoresis and immunofixation; urinary assessment is optional); skeletal survey (magnetic resonance imaging or low dose computed tomography are now recommended opposed to plain film); bone marrow aspirate and biopsy; full blood count; and serum calcium.
The role of a renal biopsy
The utility of a renal biopsy in suspected myeloma kidney remains undetermined. Advocates argue that undertaking a renal biopsy in patients with a paraprotein is safe, when ultrasound guidance is used with no significant increased risk of a major hemorrhagic complication, compared with the population without a paraprotein. The biopsy clarifies the diagnosis of AKI in patients with MM, when it is secondary to a pathology other than cast nephropathy. The review of the renal histology also allows the chronicity of the process to be determined, potentially guiding how aggressive therapy should be.
However, in a patient with severe AKI and a high serum FLC concentration (greater than 500 mg/L), the biopsy in the vast majority of patients will reveal myeloma kidney or an associated acute tubular necrosis secondary to the FLCs without casts. In this setting undertaking a renal biopsy puts the patient at unnecessary risk and potentially delays more relevant hematologic investigations and early treatment.
Although both approaches have merit, the most important consideration is time. A rapid diagnosis allows early disease specific treatment to be started and potentially prevents irreversible tubulointerstitial fibrosis, which can occur over a short time frame. Therefore in centers where same day, or very rapid FLC results, are available, the combination of a high serum FLCs and a significant AKI makes myeloma kidney the most likely diagnosis. In this setting, the focus should then be on clarifying the diagnosis of MM by bone marrow biopsy as quickly as possible. However, in centers where there is potentially a significant delay in FLC results being available, then a renal biopsy can provide rapid light microscopy to confirm the presence or absence of casts. This should be undertaken whenever there is a high clinical index of suspicion of myeloma kidney causing AKI, when serum FLCs are not rapidly available.
Technical considerations for processing the biopsy
The most common renal findings seen in patients with circulating monoclonal FLC and AKI are tubulointerstitial lesions. FLC cast nephropathy is most frequent and is well recognized by pathologists. However, there are two other principal abnormalities that are not always correctly identified. These include proximal tubulopathy (also referred to as acute tubular necrosis or acute tubulopathy ) and an inflammatory tubular interstitial process without casts that has morphologic features identical to those seen in classic acute tubulointerstitial nephritis. Although the main pathologic processes seen in the latter two entities may be recognized by pathologists in renal biopsy samples, the association of those lesions with an underlying plasma cell dyscrasia is frequently missed.
Even in the diagnosis of FLC cast nephropathy, there is currently a need to define definitive criteria as to how many distal nephron casts are needed to make a diagnosis, with the understanding that sampling can have an important role in this situation. Carefully controlled studies are therefore required to define parameters in renal biopsy samples that correlate with recovery or irreversibility of renal damage although some parameters, such as the degree of interstitial damage, are intuitive.
Other renal lesions related to monoclonal light and heavy chains, such as AL amyloidosis, heavy chain (AH) amyloidosis, or light/heavy chain deposition disease, tend to present less acutely, but can also exhibit (or mimic) AKI and need to be considered in the differential diagnosis of AKI in patients with monoclonal gammopathies. It is not uncommon that more than one pathology can be present at the same time.
Evaluation of renal biopsy samples must include staining for κ and λ FLCs and careful examination of the Ig stains. This approach will help to determine isotype restriction for light and/or heavy chains and enable the morphologic manifestations to be directly related to the underlying plasma cell dyscrasia. Heavy chains have not been documented to be involved in tubulointerstitial pathology although, in rare cases, a coexisting FLC can result in a cast nephropathy. The evaluations must carefully assess not only immunofluorescence, but also ultrastructural findings and correlate these with the light microscopic features.
Immunofluorescence evaluation is key in defining the presence of monoclonal light or heavy chain deposition in the renal biopsy sample to make a definitive diagnosis. However, available commercial antibodies do not detect some of the abnormal monoclonal Igs that may be deposited in the various renal compartments, and that are directly responsible for renal dysfunction. This lack of recognition is caused by the fact that the monoclonal proteins can be quite abnormal physiochemically or truncated to such an extent that the epitopes recognized by routine polyclonal antibodies are no longer present.
Timing of later or repeat biopsies
In selected cases, a late or repeat kidney biopsy should be considered when a patient is not responding to treatment as expected, for example, a good clonal response but ongoing significant kidney dysfunction. The results from a biopsy sample can establish therapeutic response and whether additional therapy is recommended. In this situation, a renal biopsy can provide evidence of improvement (or lack thereof) by comparing the findings in the initial biopsy sample with repeat biopsies. This approach has been documented in the literature primarily in patients with plasma cell dyscrasias and glomerular lesions. , A renal biopsy may also provide evidence that further treatment may be of no, or rather limited, value as the renal parenchymal damage is deemed to be extensive and/or irreversible.
Treatment options in myeloma kidney
Supportive therapy in patients with myeloma kidney
As with all causes of AKI, the importance of generalized supportive therapies cannot be overstated. Stopping nephrotoxins, and early correction of hypercalcemia and dehydration can reduce the precipitation of FLCs with Tamm-Horsfall protein. Nonsteroidal antiinflammatory drugs and loop diuretics are both associated with the formation of casts and should be stopped on suspicion of myeloma kidney. Hypercalcemia is independently associated with cast formation and early correction should occur following local guidelines, potentially using steroids and bisphosphonates. Replacement fluids, for patients who are intravascularly depleted, should be approached with caution. Although a high urine output will reduce the rate of cast formation, by simply dilution of the urine, increased distal delivery of sodium with the use of normal saline has been associated with cast formation. Historically, there has been interest in the alkalization of the urine to reduce the rate of cast formation. However, this approach has not been validated in robust clinical trials.
Once these simple measures have been undertaken, focus must then be on achieving an early rapid reduction in the serum concentrations of the monoclonal FLCs, which has been demonstrated to be directly related to kidney outcomes. To enable this, effective treatment of the underlying plasma cell clone is required.
Treatment of the plasma cell clone in patients with myeloma kidney
The treatment of MM has progressed considerably over recent decades. Complete response (disappearance of all detectable monoclonal component from the serum and urine, as well as < 5% bone marrow plasmacytosis) rates have improved from less than 5% with melphalan and prednisolone to more than 80% with combination novel agent approaches. These improved responses have led to prolonged disease control and improved overall survival in clinical trials, as well as population-based studies. Alkylation-based regimens have been replaced by novel agent combinations including the proteasome inhibitors (bortezomib, carfilzomib, ixazomib), immunomodulatory agents (thalidomide, lenalidomide, pomalidomide), histone deacetylase inhibitors (panobinostat), monoclonal antibodies (daratumumab, elotuzumab, isatuximab), and numerous other agents and immunotherapies in clinical development.
The treatment of the plasma cell clone in patients with myeloma kidney differs in a number of respects from the treatment of patients with normal renal function. Firstly, because of the importance of renal recovery to avoid the long-term complications of end-stage renal failure, therapies that produce rapid hematologic responses are vital. Secondly, given the setting of renal impairment, chemotherapeutics with minimal renal excretion have particular advantages. Thirdly, renal impairment increases the toxicity profile of most therapies and needs to be considered when making treatment decisions.
There is good evidence from prospective clinical trials conducted specifically in patients with myeloma kidney that recovery of renal function following chemotherapy is predicted by the achievement of hematologic response. This equates to a reduction in the monoclonal Ig or the difference between the involved and uninvolved FLCs of at least 90%. The goal of any antimyeloma chemotherapy therefore is the achievement of such responses, as quickly as possible. The best evidence to date comes from prospective randomized trials, which included patients with mild to moderate renal impairment. In these studies, renal recovery and survival were superior in the bortezomib containing arms. , Recent prospective studies of bortezomib-based regimens show renal recovery rates in patients, initially dialysis-dependent, are approximately 60%. Because of its pharmacokinetics, bortezomib can be used at full doses in patients with renal impairment and numerous studies have shown that bortezomib is safe and effective in this population. On the basis of these data, bortezomib is the agent recommended in current consensus guidelines addressing myeloma-related renal impairment. There is also retrospective evidence that three drug proteasome inhibitor-based regimens result in improved response rates when compared with two drug regimens. All such regimens include a corticosteroid, typically dexamethasone, which has pronounced antiplasma cell activity. The third drug may be a traditional chemotherapeutic agent, such as cyclophosphamide, which has been used extensively in patients with renal disease, and in one randomized study was associated with improved responses compared with adriamycin in patients with myeloma and mild renal impairment. Bendamustine, a chemotherapeutic with both alkylating and antimetabolite actions, does not accumulate in end-stage renal failure and has been combined with bortezomib and prednisolone to successfully treat patients with myeloma kidney. Bortezomib and dexamethasone may also be combined with an immunomodulatory agent, such as thalidomide in the Velcade, Thalidomide, Dexamethasone (VTD) regimen, which has been successfully used in renal impairment. Thalidomide’s pharmacokinetics are unaltered by renal impairment and no dose modification is required. Such bortezomib-based triplets are now the cornerstone of management of newly diagnosed myeloma presenting with AKI.
Treatment options for myeloma kidney are not limited to bortezomib-based regimens, particularly in the relapsed setting where the underlying plasma cell clone may be resistant to bortezomib. The other proteasome inhibitors, carfilzomib and ixazomib, appear safe in patients with renal impairment, but more data are required before their routine use as initial therapy of myeloma kidney can be recommended. Of the immunomodulatory agents, lenalidomide is renally excreted, requires dose modification in renal impairment, and there is some evidence that its antimyeloma activity is blunted in this setting. Pomalidomide appears not to require dose modification in severe renal impairment or dialysis. The monoclonal antibodies daratumumab, isatuximab, and elotuzumab have not been specifically studied in patients with renal impairment, but given their lack of renal elimination should be able to be used safely. The ability of daratumumab to achieve faster hematologic responses with minimal additional toxicity, when combined with bortezomib-based chemotherapy, makes it an attractive option to further improve outcomes in myeloma kidney.
Autologous stem cell transplantation in patients following a presentation with myeloma kidney
Autologous stem cell transplantation, following high-dose melphalan, is standard consolidation therapy in younger patients with myeloma. Several different conditioning regimens and doses have been compared over time, but intravenous melphalan at a dose of 200 mg/m 2 has been confirmed as the optimal conditioning before stem cell reinfusion, in patients with normal renal function. Such transplants were initially shown to improve myeloma control and overall survival when compared with multiagent chemotherapy and, more recently, has been shown to provide the best long-term disease control in randomized comparisons to bortezomib, lenalidomide, or combined bortezomib-lenalidomide regimens. These trials excluded patients over 65 years of age, as well as patients with more severe degrees of renal impairment. In the three most recent randomized studies, the lower limit of allowed renal function was a creatinine clearance of 15, 20, and 50 mL/min, respectively. To date, none of these studies has reported outcomes specifically for the subgroup of patients with reduced creatinine clearance, and thus we have no high-level evidence to support the use of autologous stem cell transplantation in patients with renal impairment.
In retrospective studies, it appears that transplantation is associated with an increased risk of morbidity and mortality in patients with renal impairment compared with patients with normal renal function. Transplant related mortality ranges from 0% to 38% in this setting; however, the most recent and largest study from an international transplant registry found a transplant related mortality rate of 0%, for transplants performed in severe renal impairment, including patients on dialysis at the time of transplantation. Because of melphalan’s predominant renal clearance, the standard 200 mg/m 2 dose results in excess nonhematologic toxicity in patients with renal impairment. An initial report found a melphalan dose of 140 mg/m 2 reduced toxicity without compromising efficacy among 21 patients with a creatinine greater than 2 mg/dL. Subsequent retrospective studies have suggested that the standard melphalan dose of 200 mg/m 2 can be used in patients with a creatinine clearance greater than 30 mL/min whereas those with creatinine clearance less than 30 mL/min or on dialysis should be treated with a dose of 140 mg/m 2 .
There is likely to be a fair degree of patient selection in these retrospective studies and so it is debatable how generalizable these findings are to all patients with myeloma kidney who may otherwise be transplant candidates. Balancing the limitations of these data with the known importance of autologous stem cell transplantation in younger patients, with myeloma kidney, is a challenge. As the transplant procedure becomes safer with better renal function, it is important to maximize the chance of renal recovery before transplantation by using the most effective pretransplant induction therapy. If the patient maintains good performance status with minimal comorbidity, then the available evidence would suggest that consolidation with autologous stem cell transplantation is not unreasonable, albeit with a reduced melphalan dose of 140 mg/m 2 for those with severe renal impairment at the time of transplantation.
Direct removal of free light chains in myeloma kidney
Although the pathophysiology of myeloma kidney is clear, with the high concentrations of monoclonal FLCs undoubtedly being responsible for the AKI, the role for the removal of these pathogenic molecules remains in debate. In 2005 the Canadian Apheresis Group appeared to publish the definitive study to demonstrate that FLC removal by plasma exchange did not provide clinical benefit to patients with severe AKI secondary to MM. This large randomized clinical trial evaluated standard chemotherapy plus plasma exchange or standard chemotherapy alone for patients with severe AKI in the setting of MM. The trial showed no benefit to patients in terms of renal outcomes or overall survival. Future discussions identified limitations of the study in terms of lack of a kidney biopsy to clarify the diagnosis and questioned whether the dose of FLCs removed by plasma exchange was clinically relevant. A series of studies then explored methods by which an increased dose of FLC removal could be given using high cut-off hemodialysis.
High cut-off hemodialysis uses a conventional hollow-fiber dialyzer with a higher molecular weight cut-off, allowng the removal of all large middle-molecules including FLCs. Pilot studies demonstrated that both κ at 22.5 kDa and λ at 45 kDa were effectively cleared into the dialysate using these membranes, with reduction ratios of up to 80% per dialysis session. Early single-center pilot studies showed high rates of renal recovery from dialysis-dependent AKI when these dialyzers were used in patients with AKI secondary to MM. However, these studies also demonstrated that use of these dialyzers was associated with a significant degree of albumin loss with potential adverse consequences.
Interest in this new treatment culminated in two multicenter European studies exploring FLC removal by high cut-off hemodialysis in patients with AKI secondary to myeloma kidney. , The now reported French study Multiple Myeloma and Renal Failure due to Myeloma Cast Nephropathy (MYRE) shows high cut-off hemodialysis resulted in improved renal outcomes for patients at 6 and 12 months. In comparison, The European Trial of Free Light Chain Removal by Extended Hemodialysis in Cast Nephropathy (EuLITE) study showed no definitive patient benefit. , Analysis of the full results will be required to fully understand why there is a difference in results, but likely explanations will be in relation to the studies being underpowered and differences in enrollment criteria. Unfortunately, when both studies were being designed, the only renal outcome data available to power the studies were from historical studies, where chemotherapy was based around thalidomide or older generations of chemotherapy. With the advent of bortezomib-based chemotherapy, renal recovery rates more than doubled, thus fundamentally changing the numbers of patients who were required in these studies.
In 2016 a further “next generation” of hemodialysis membrane became available that may be of relevance to the treatment of patients with myeloma kidney. Like the high cut-off membranes, these new “medium cut-off” membranes have a molecular weight cut-off that enables the effective removal of both κ and λ FLCs, but because the pores in these membranes are more uniform, there is limited albumin loss. This may be of particular relevance in this setting, as the high degree of albumin loss seen with the high cut-off membranes could potentially have led to adverse outcomes, through reduced efficiency of chemotherapy or higher rates of infections. Early studies are just starting to report patient outcomes with these medium cut-off membranes, and future clinical studies should assess their use in combination with effective chemotherapy.
At this stage, we can conclude that bortezomib-based chemotherapy, in combination with dexamethasone, remains the standard of care for severe AKI in patients with MM. FLC removal by high cut-off hemodialysis may complement the use of this effective chemotherapy, but evidence is currently contradictory.
Long-term surveillance and follow-up of patients in remission
Once hematologic and hopefully renal response has been achieved, patients with myeloma kidney require careful long-term monitoring. As a generalization, in myeloma the pattern of relapse is similar to the initial clinical presentation. As such, patients who present with myeloma kidney are at particular risk for developing AKI at relapse, as their pathologic FLC has already displayed a predilection for combining with Tamm-Horsfall protein, leading to cast nephropathy. These patients need close monitoring every 1 to 3 months (more frequently in the early posttreatment period), which must include FLC and creatinine measurement in addition to the other modalities of myeloma assessment. In relation to FLC measurement, biochemical relapse is defined as a 25% increase in the difference between involved and uninvolved FLC levels (absolute increase must be > 100 mg/L) but salvage treatment in myeloma is not always indicated at the first sign of biochemical relapse. In fact, the International Myeloma Working Group has suggested that treatment is indicated when there is either a clinical relapse (reoccurrence of end-organ damage) or a significant and quick paraprotein increase (doubled monoclonal protein within 2 months, with an increase in the absolute levels of monoclonal protein of 1 g/dL or more in serum or of 500 mg or more per 24 hours in urine confirmed by two consecutive measurements). However, in the presence of a high-risk clinical feature, such as prior light chain-induced renal impairment, it would seem reasonable that treatment should be commenced at the stage of biochemical relapse before renal injury develops.
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