Version May 2024
INTRODUCTION — Kidney disease is a common complication in patients with multiple myeloma and other monoclonal gammopathies [1]. A wide range of kidney manifestations and pathologies involving different mechanisms have been described with these disorders. Kidney injury most often occurs in patients with a high tumor burden and can evolve as either an acute or chronic disorder [2].
This topic will review the treatment of kidney disease in patients with multiple myeloma or other monoclonal gammopathies, with a focus on light chain cast nephropathy. The epidemiology, pathogenesis, etiology, clinical features, evaluation, and diagnosis of kidney disease in multiple myeloma and other monoclonal gammopathies are presented separately:
●(See "Kidney disease in multiple myeloma and other monoclonal gammopathies: Etiology and evaluation".)
The diagnosis and treatment of monoclonal gammopathy of renal significance (MGRS) are presented separately:
●(See "Diagnosis and treatment of monoclonal gammopathy of renal significance".)
The pathogenesis and treatment of amyloidosis and light and heavy chain deposition diseases, and treatment of multiple myeloma, are discussed elsewhere:
●(See "Monoclonal immunoglobulin deposition disease".)
●(See "Treatment and prognosis of immunoglobulin light chain (AL) amyloidosis".)
●(See "Multiple myeloma: Overview of management".)
PATIENTS WITH ACUTE OR SUBACUTE KIDNEY INJURY — Acute (AKI) or subacute kidney injury in patients with multiple myeloma and other monoclonal gammopathies results from a variety of mechanisms. These include light chain cast nephropathy, hypercalcemia, nephrotoxic agents (eg, radiocontrast, nonsteroidal antiinflammatory drugs [NSAIDs]), and, infrequently, hyperviscosity syndrome, severe hyperuricemia, and monoclonal immunoglobulin-related glomerulopathies (such as type 1 cryoglobulinemic glomerulonephritis, proliferative glomerulonephritis with monoclonal immunoglobulin deposits [PGNMID], C3 glomerulopathy with monoclonal gammopathy, and immunotactoid glomerulopathy). Specific treatment is directed at the cause of AKI [3-8]. Dialysis should be performed for the usual indications.
●(See "Kidney disease in multiple myeloma and other monoclonal gammopathies: Etiology and evaluation".)
●(See "Indications for initiation of dialysis in chronic kidney disease".)
Light chain cast nephropathy (myeloma kidney) — Light chain cast nephropathy occurs most often in patients with high rates of production and excretion of immunoglobulin free light chains, which may be toxic to the tubules and form obstructing tubular casts, particularly if the patient is volume depleted [9]. Light chain cast nephropathy should be treated urgently to restore kidney function.
Overview of approach — In patients with multiple myeloma who have a confirmed or suspected diagnosis of light chain cast nephropathy, we recommend the following approach:
●We discontinue all potentially nephrotoxic agents, including NSAIDs, angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and diuretics.
●We correct hypercalcemia, if present. (See 'Hypercalcemia' below.)
●We administer intravenous or oral fluid therapy, with the goal of attaining a daily urine output of approximately 3 liters, unless contraindicated (eg, heart failure or persistent oligoanuric AKI). This decreases the light chain concentration within the tubular lumen and minimizes light chain precipitation. If volume depletion is clinically present, we provide isotonic fluids for initial volume replacement. In the absence of (or following the correction of) volume depletion, we administer one-half isotonic saline at an initial rate of 150 mL/hour, adjusted to maintain the urine output at approximately 100 to 150 mL/hour (approximately 3 L/day). Although debated, volume replacement with isotonic sodium bicarbonate may be useful, particularly when the urine pH is acidic, a condition that facilitates cast formation. We reserve the use of loop diuretics for patients who develop hypervolemia. (See 'Fluid management' below.)
●We initiate anti-myeloma therapy with bortezomib-based chemotherapy with high-dose dexamethasone to reduce the concentration of pathogenic free light chains as quickly as possible. (See 'Anti-myeloma therapy' below.)
Treatment — The treatment of light chain cast nephropathy consists of anti-myeloma therapy, fluid management, and, in patients with severe AKI, dialysis. Extracorporeal methods to remove serum free light chains (SFLCs), such as plasmapheresis and high-cutoff dialysis, can be used as adjunctive therapy. The benefits of extracorporeal light chain removal remain undetermined; however, the majority of UpToDate authors of this topic support its use. In patients who are unresponsive to therapy despite adequate suppression and removal of SFLCs, a kidney biopsy (if not yet performed) is typically performed to investigate causes other than light chain cast nephropathy and may be useful to evaluate the probability of renal response [10,11].
Anti-myeloma therapy — Patients with light chain cast nephropathy should receive bortezomib-based chemotherapy with high-dose dexamethasone (such as bortezomib, cyclophosphamide, and dexamethasone, or CyBorD) as rapidly as possible to decrease light chain production (with the possible exception of patients who are in preterminal stages of disease) [12,13]. The balance between efficacy and toxicity of chemotherapy should be carefully considered in patients with light chain cast nephropathy, who are often older and present with other comorbidities. In one randomized, controlled trial, the bortezomib, cyclophosphamide, and dexamethasone (CyBorD) triplet did not improve renal response rates compared with the bortezomib-dexamethasone doublet in patients with initial light chain cast nephropathy who did not require dialysis. However, there was a trend for higher probability of renal response with CyBorD in those with severe AKI (stage 3). Thus, a triplet regimen appears desirable in young, fit patients, particularly those presenting with severe AKI. In older and frail patients, the doublet bortezomib-dexamethasone regimen remains the standard first-line treatment [14]. Bortezomib can be administered to patients with kidney function impairment, including those with severe kidney function impairment (estimated glomerular filtration rate [eGFR] <30 mL/min per 1.73 m2) or on dialysis [15] and does not require renal dose adjustment. Although other proteasome inhibitors (eg, carfilzomib, ixazomib) are available for the treatment of multiple myeloma, we do not routinely use these agents to treat light chain cast nephropathy given that there is less robust evidence on the use and safety of these agents in patients with underlying kidney function impairment. In addition, the use of carfilzomib has been associated with AKI and thrombotic microangiopathy in some patients. (See "Nephrotoxicity of chemotherapy and other cytotoxic agents".)
For the first cycle, bortezomib is usually given twice weekly, on days 1, 4, 8, and 11 of a 21-day cycle, and dexamethasone is given at a dose of 40 mg on days 1 through 4, 8, and 15. This is different than the usual weekly administration of these agents in patients with multiple myeloma without AKI. However, beginning with the second cycle, these agents are administered as they are in patients with multiple myeloma who do not have AKI. Lenalidomide is typically avoided in patients with AKI unless the patient is refractory to other options (see "Treatment protocols for multiple myeloma"). Once stabilized, hematopoietic cell transplantation can be considered in eligible patients. Hematopoietic cell transplantation may be performed among patients with all stages of kidney disease, even among patients on dialysis, although morbidity and mortality rates increase with the severity of kidney failure [16]. (See "Multiple myeloma: Overview of management" and "Multiple myeloma: Use of hematopoietic cell transplantation".)
Fluid management — Intravenous fluid therapy, with the goal of attaining a daily urine output of approximately 3 liters, should be provided to all patients with light chain cast nephropathy unless contraindicated (eg, heart failure or persistent oligoanuric AKI). This will decrease the light chain concentration within the tubular lumen and minimize light chain precipitation. In addition, intravenous fluids are given to treat volume depletion, hypercalcemia, and hyperuricemia, if present. (See "Kidney disease in multiple myeloma and other monoclonal gammopathies: Etiology and evaluation", section on 'Mechanisms of injury caused by monoclonal proteins'.)
If volume depletion is clinically present (eg, hypotension, decreased skin turgor), isotonic fluids are given for initial volume replacement.
●(See "Etiology, clinical manifestations, and diagnosis of volume depletion in adults".)
●(See "Maintenance and replacement fluid therapy in adults".)
●(See "Treatment of severe hypovolemia or hypovolemic shock in adults".)
In the absence of (or following the correction of) volume depletion, a reasonable regimen is the administration of one-half isotonic saline at an initial rate of 150 mL/hour, adjusted to maintain the urine output at approximately 100 to 150 mL/hour (approximately 3 L/day). Alternatively, isotonic sodium bicarbonate can be administered, particularly in patients with acidic urine; achieving a urine pH >7.0 may decrease the precipitation of monoclonal light chains. Either of these regimens require careful monitoring and may require modification in patients who cannot excrete the administered fluid because of kidney or heart failure. A loop diuretic should be reserved for patients who develop hypervolemia. Loop diuretics should be used judiciously since there is some concern that they may promote cast formation [9]. (See 'Prevention' below.)
In patients with AKI and oliguria, we still administer the fluid regimen described above. Within 24 hours, reversal of oliguria should become evident. If oliguria persists, fluid administration should be modified or discontinued to prevent volume overload.
Dialysis — Until more evidence is available, conventional dialysis should be initiated for the usual indications (eg, fluid overload, hyperkalemia, and uremia) and not for the removal of free light chains. Among patients with AKI who require dialysis, hemodialysis is the preferred modality. Peritoneal dialysis is an option for patients who develop end-stage kidney disease (ESKD) and require chronic dialysis. (See "Dialysis-related factors that may influence recovery of kidney function in acute kidney injury (acute renal failure)".)
Extracorporeal methods for light chain removal — The removal of nephrotoxic free light chains can be enhanced with the use of extracorporeal methods such as plasmapheresis and high-cutoff dialysis (figure 1). High-cutoff dialysis employs dialyzers with pore sizes that are significantly larger than those of standard high-flux dialyzers and which permit the efficient passage of proteins as large as 25 to 50 kilodaltons. The larger pore size allows a higher rate of SFLC removal [17]. High-cutoff dialyzers are not commercially available in the United States but are available in Europe.
If used, extracorporeal free light chain removal should be performed in conjunction with bortezomib- and dexamethasone-containing chemotherapy, which is needed to reduce the rate of light chain production, and should not be performed without chemotherapy. (See "Multiple myeloma: Initial treatment".)
The benefit of extracorporeal free light chain removal in patients with AKI has not been established. Thus, the use of extracorporeal methods in the treatment of light chain cast nephropathy remains controversial, and some clinicians do not use these therapies in this setting.
However, given a possible reduction in dialysis dependency among survivors, the majority of authors of this topic suggest the use of extracorporeal light chain removal, using plasmapheresis or high-cutoff hemodialysis, in individuals with AKI who have a diagnosis of light chain cast nephropathy. The authors recognize that the strength of this recommendation is weak.
If access to both plasmapheresis and high-cutoff hemodialysis is available, three authors (S.V.R., N.L., and F.B.) would prefer to use high-cutoff hemodialysis, whereas one author (A.K.) would prefer to use plasmapheresis. (See 'Efficacy studies' below.)
Protocol for plasmapheresis — The typical plasmapheresis regimen for light chain cast nephropathy is five to seven exchanges within 7 to 10 days, using albumin as the replacement fluid. However, the duration of plasmapheresis should be guided by SFLC levels, which we measure daily. The plasmapheresis prescription is presented elsewhere. (See "Therapeutic apheresis (plasma exchange or cytapheresis): Indications and technology", section on 'Technology'.)
The goal of plasmapheresis is a 50 to 60 percent or greater reduction in the pathogenic SFLC level; this degree of light chain reduction is associated with higher probability of recovery of kidney function [17,18]. If the SFLC level is not reduced to this degree after five to seven plasmapheresis treatments, it is likely that the concomitantly administered chemotherapy is not effectively controlling light chain production. Alternative treatments for multiple myeloma are warranted in such patients. Some patients are dependent upon plasmapheresis to lower SFLC levels; in these patients, the decision to continue plasmapheresis is based upon the availability of other chemotherapeutic options. If other treatment options are available, we continue plasmapheresis; otherwise, we stop plasmapheresis.
In patients who also require dialysis on the same day, dialysis should be performed after plasmapheresis. Dialysis corrects the alkalemia that can develop among patients receiving citrate anticoagulation with plasmapheresis. (See 'Dialysis' above.)
If plasmapheresis is initiated following a kidney biopsy, there is a potential risk of postbiopsy bleeding from apheresis-induced removal of coagulation factors. Partial replacement of the fluid removed with fresh frozen plasma (FFP; 1 to 2 liters toward the end of the apheresis) rather than albumin should attenuate the coagulopathy. Replacement with FFP may also be reasonable for the final treatment prior to catheter removal. (See "Therapeutic apheresis (plasma exchange or cytapheresis): Indications and technology".)
Protocol for high-cutoff hemodialysis — As mentioned above, high-cutoff dialyzers are not available in the United States but are available in Europe. Clinicians who have access to high-cutoff dialyzers and wish to perform extracorporal light chain removal with high-cutoff hemodialysis should use the regimen described in the Studies in Patients with Multiple Myeloma and Renal Failure Due to Myeloma Cast Nephropathy (MYRE) trial [19] (see 'Efficacy studies' below). In this randomized multicenter trial, patients with light chain cast nephropathy and severe AKI who were treated with high-cutoff hemodialysis received eight five-hour sessions (blood flow rate ≥250 mL/min and dialysate flow rate ≥500 mL/min) over 10 days. If needed, patients received three additional weekly sessions until completion of three cycles of chemotherapy.
Patients treated with high-cutoff hemodialysis may develop hypoalbuminemia due to losses of albumin through the larger membrane pores. Thus, a serum albumin level should be obtained at the beginning of each dialysis session, and, if low, intravenous albumin should be administered following completion of dialysis.
As with plasmapheresis, the goal of high-cutoff hemodialysis is to obtain the best possible (50 to 60 percent or greater) reduction in the pathogenic SFLC level. If the SFLC level is not reduced to this degree after eight high-cutoff hemodialysis treatments, it is likely that the concomitantly administered chemotherapy is not effectively controlling light chain production, and alternative therapies may be warranted. In the MYRE trial, achievement of a pathogenic SFLC level less than 500 mg/L after the first cycle of chemotherapy was an independent predictor of hemodialysis independence [19].
Efficacy studies — The evidence evaluating the effectiveness of extracorporeal light chain removal in patients with AKI due to multiple myeloma is conflicting [4,6,8,17,19-24], and some patients clearly improve without treatment with extracorporeal methods. However, substantial benefit in kidney outcomes has been shown in some studies that enrolled patients who had circulating free light chains in the plasma or significant Bence Jones proteinuria. The following studies illustrate the range of findings:
●One trial performed before the era of novel antimyeloma agents involved 29 patients with multiple myeloma, AKI, and significant Bence Jones proteinuria, 24 of whom required dialysis [6]. The patients were randomly assigned to plasmapheresis (for five consecutive days) together with glucocorticoids, cytotoxic drugs, and hemodialysis (if required) or to glucocorticoids, cytotoxic drugs, and peritoneal dialysis (if required). Among the 15 patients assigned to receive plasmapheresis, 13 (87 percent) recovered kidney function (most to a plasma creatinine concentration of <2.5 mg/dL [<220 micromol/L]), whereas improvement occurred in only 2 of 14 controls (14 percent), with most patients requiring chronic dialysis. Patient survival was also improved in the plasmapheresis group.
●Less compelling results were reported from a multicenter trial, also performed before the era of novel antimyeloma agents, that included 97 patients with newly diagnosed multiple myeloma and AKI who were randomly assigned to plasmapheresis and chemotherapy or to chemotherapy alone [23]. Patients were included if they met the following criteria: progressive worsening of kidney function (serum creatinine of >2.3 mg/dL [200 micromol/L], with an increase of >0.6 mg/dL [50 micromol/L] over the preceding two weeks) despite correction of hypercalcemia and hypovolemia; monoclonal light chains in urine, plasma, or kidney tissue; and no other identifiable, precipitating cause of AKI.
In the control and plasmapheresis groups, 14 and 15 patients (36 and 26 percent), respectively, were on dialysis at baseline, and five and nine patients (13 and 16 percent), respectively, began dialysis during treatment. At six months, mortality was 33 percent in each group. The following additional results were noted:
•The composite outcome (death, dialysis dependence, or glomerular filtration rate [GFR] of <30 mL/min/1.73 m2) was not significantly different (58 versus 69 percent in the plasmapheresis and control patients, respectively [95% CI -8.3 to 29.1 percent]).
•Among six-month survivors, fewer patients in the plasmapheresis group remained dialysis dependent, but the difference was not significant (13 versus 27 percent, respectively [95% CI -5.1 to 34.6 percent]).
However, it is uncertain that all patients in this trial had light chain cast nephropathy as the cause of AKI and, therefore, not all patients would have benefited from plasmapheresis [25]. Only 78 percent of the patients had increased free light chains in the plasma, and only 61 percent had light chains in the urine; relatively few patients had a tissue diagnosis of cast nephropathy by biopsy. The potential benefits of plasmapheresis may also have been obscured since more patients in the control group received a dexamethasone-containing regimen, which leads to faster reduction in light chain production than melphalan and prednisone. (See "Multiple myeloma: Management in resource-limited settings".)
This study does not disprove a benefit from plasmapheresis; the procedure was associated with a 52 percent reduction in dialysis dependency among survivors at six months (13 versus 27 percent). The ability to show a statistically significant benefit in kidney function recovery was probably limited by the large number of deaths in both arms, an outcome unlikely to have been affected by plasmapheresis.
●To address some of the limitations described above, a retrospective study analyzed the efficacy of plasmapheresis in patients in whom the diagnosis of cast nephropathy was confirmed by biopsy and in whom SFLC levels were used to guide therapy [26,27]. Fourteen patients had biopsy-proven cast nephropathy and SFLCs measured before and after plasmapheresis. A renal response, defined as a 50 percent reduction in serum creatinine and dialysis independence at 180 days, occurred in seven of nine patients (77.8 percent) in whom SFLCs were reduced by 50 percent or more. Early institution of plasmapheresis along with effective therapy to treat myeloma resulted in complete renal response in approximately 40 percent of patients [28]. Bortezomib-based chemotherapy is preferred in the setting of myeloma and AKI (eg, bortezomib, cyclophosphamide, dexamethasone [CyBorD] or bortezomib, thalidomide, dexamethasone [VTD]).
●The efficacy of high-cutoff dialysis was evaluated in a multicenter randomized trial (MYRE) of 98 patients with newly diagnosed multiple myeloma, severe AKI requiring hemodialysis, and biopsy-confirmed light chain cast nephropathy [19]. All patients received bortezomib-dexamethasone and were randomly assigned to receive intensive hemodialysis (eight five-hour sessions over 10 days) with either a high-cutoff dialyzer (46 patients) or a conventional high-flux dialyzer (48 patients). Although high-cutoff hemodialysis produced a greater reduction in SFLCs (68 versus 31 percent) after the first hemodialysis session, there was no significant difference in the primary endpoint of hemodialysis independence at three months between the two groups (41 versus 33 percent for high-cutoff and conventional hemodialysis, respectively). At 6 and 12 months, however, rates of hemodialysis independence were higher among patients in the high-cutoff group compared with those in the conventional hemodialysis group (57 versus 35 percent at 6 months and 61 versus 38 percent at 12 months). There was no difference in mortality at 12 months between the two groups, and both groups had similar rates of hemodialysis-related and chemotherapy-related adverse effects.
Results from a second trial of high-cutoff dialysis (European Trial of Free Light Chain Removal by Extended Hemodialysis [EuLITE]) of 90 patients with newly diagnosed multiple myeloma and light chain cast nephropathy requiring acute dialysis have found no short- or long-term benefits with high-cutoff dialysis [29,30]. In this study, all patients were treated with triple bortezomib-based therapy (doxorubicin-bortezomib-dexamethasone) and randomly assigned to extended hemodialysis with a high-cutoff dialyzer (eight eight-hour sessions over the first 10 days, followed by eight-hour sessions on alternate days) or conventional hemodialysis with a standard high-flux dialyzer (three four-hour sessions per week). At three months, there was no difference in kidney function recovery between the two groups (56 versus 51 percent for high-cutoff and conventional hemodialysis, respectively), and patients in the high-cutoff group had a higher rate of lung infections and mortality. Among patients who recovered kidney function, estimated GFR at two years was comparable between the two groups.
These trials are small in size and have produced conflicting results. It is also important to note that there were significant differences in the methodology, dialysis procedure, and treatment of the patients, with more intensive chemotherapy used in EuLITE. Thus, additional studies are needed to clarify the role of extracorporeal removal of free light chains in patients with light chain cast nephropathy. Since the overall risks are low and potential benefits in terms of reversing kidney dysfunction are high, the results of the MYRE trial support our suggestion to perform extracorporeal light chain removal, using either plasmapheresis or high-cutoff dialysis, in patients with light chain cast nephropathy.
Prevention — Minimizing the risk factors that promote light chain filtration and subsequent tubular obstruction by casts may prevent the development of light chain cast nephropathy [4]. Preventive measures are important in patients at high risk for light chain cast nephropathy (ie, SFLC concentration >1500 mg/L) and include the following:
●High intake of fluids to prevent volume depletion and maintain a high urine output (approximately 3 L/day), unless contraindicated. The goals of fluid therapy are to decrease the light chain concentration within the tubular lumen and to produce a high urine flow rate to minimize light chain precipitation. Alkaline fluids may be considered in patients with acidic urine. (See 'Fluid management' above.)
●Bortezomib- and dexamethasone-based chemotherapy (eg, bortezomib, cyclophosphamide, and dexamethasone) to decrease light chain production. (See "Multiple myeloma: Initial treatment".)
●Avoidance of NSAIDs and, if possible, intravenous radiocontrast agents, as well as any other potential nephrotoxins.
●Avoidance of loop diuretics unless the patient develops severe fluid overload. By raising the tubular fluid sodium chloride concentration, these drugs create an environment that appears to favor the coaggregation of light chains with Tamm-Horsfall protein [9]. Diuretics may also promote cast formation by inducing volume depletion.
Prognosis — Patients with significant kidney dysfunction at presentation tend to have worse outcomes than those without, despite aggressive therapy [2,3,31].
With directed and supportive therapies, reported rates of improvement in kidney function in patients with newly diagnosed myeloma treated with bortezomib-based chemotherapy range between 50 and 80 percent [3-8,20]. Many of these studies included patients who initially required dialysis or had a plasma creatinine concentration of ≥5 mg/dL (440 micromol/L) prior to therapy; posttreatment values were often below 2 mg/dL (176 micromol/L).
Recovery of kidney function with therapy appears to have prognostic value. In one study of patients with multiple myeloma and AKI, patients with recovery of kidney function had a longer median survival compared with patients who did not recover kidney function (28 versus 4 months) [1]. Patients who recovered kidney function had comparable survival to those with normal kidney function at the time of diagnosis. Other studies have reported a similar association between reversibility of kidney failure and improved survival [3,11,32,33].
Patients with AKI due to hypercalcemia and volume depletion are most likely to recover kidney function. By comparison, those with dense cast formation and significant tubular damage are less likely to recover kidney function [20]. In one study of 178 patients with light chain cast nephropathy and multiple myeloma, a higher number of casts/mm2 in the cortex was independently associated with a lower follow-up eGFR and a higher risk of remaining on dialysis [10].
Future directions — A cyclized peptide designed to interfere with the binding of immunoglobulin light chain to Tamm-Horsfall protein was successfully tested in animals [34]. This cyclic peptide mimics the complementarity-determining region 3 (CDR3) on the immunoglobulin light chain and competitively inhibits the binding of Tamm-Horsfall protein to the immunoglobulin light chain. In animal models, coadministration of the cyclized peptide with monoclonal immunoglobulin light chains capable of causing light chain cast nephropathy prevented the development of AKI, which occurred in the vehicle-treated animals. In the rescue experiment, injection of the cyclized peptide four hours after the immunoglobulin light chains provided protection from AKI. Experiments with longer duration between immunoglobulin light chains and cyclized peptide are needed to confirm its efficacy in the treatment of light chain cast nephropathy. However, the concept represents a new paradigm in the treatment of immunoglobulin light chain-related kidney diseases.
Hypercalcemia — The treatment of hypercalcemia in patients with multiple myeloma is presented elsewhere. (See "Multiple myeloma: Overview of management", section on 'Other complications'.)
Bisphosphonates must be used cautiously in patients with significant kidney impairment or vitamin D deficiency, as the risk of inducing hypocalcemia is increased. In addition, nephrotic syndrome and AKI due to collapsing focal segmental glomerulosclerosis and other glomerular lesions have been described among patients with multiple myeloma following treatment with bisphosphonates. There may also be an increased risk of AKI associated with the use of zoledronic acid, and, therefore, pamidronate is preferred in patients with kidney impairment [35]. (See "Collapsing focal segmental glomerulosclerosis (collapsing glomerulopathy)", section on 'Bisphosphonates and other drugs'.)
Denosumab is an alternative option for patients with hypercalcemia that is refractory to zoledronic acid or in whom bisphosphonates are contraindicated due to severe kidney function impairment. However, it is very expensive when compared with pamidronate [36].
Nephrotoxic agents — NSAIDs, ACE inhibitors, or ARBs should be stopped, and loop diuretics and radiocontrast dye should be avoided, if possible, to prevent further kidney injury. However, in patients with myeloma, the use of novel low-osmolality contrast media appears to be rarely implicated in the development of severe AKI due to light chain cast nephropathy [19].
Less common causes of AKI
Plasma cell infiltration — Plasma cell infiltration of the kidney is a rare cause of acute kidney injury (AKI) among patients with multiple myeloma. If treatment for multiple myeloma has not already been initiated, patients with plasma cell infiltration should receive anti-myeloma therapy to prevent further progression of kidney injury. However, these patients frequently have advanced disease that is refractory to most chemotherapy. (See "Treatment protocols for multiple myeloma".)
Hyperuricemia — Hyperuricemia, if present, should be treated. This is discussed separately. (See "Uric acid kidney diseases".)
Hyperviscosity — Hyperviscosity is a rare cause of AKI among patients with multiple myeloma and Waldenström macroglobulinemia. Patients with hyperviscosity should be treated with plasmapheresis and appropriate chemotherapy. (See "Treatment and prognosis of Waldenström macroglobulinemia", section on 'Emergency management of hyperviscosity' and "Multiple myeloma: Overview of management", section on 'Other complications'.)
Thrombotic microangiopathy — Thrombotic microangiopathy is a rare complication in patients with multiple myeloma who are treated with proteasome inhibitors, particularly carfilzomib and bortezomib [37-39] but also ixazomib [40]. In these patients, we recommend discontinuing the proteasome inhibitor and switching to a proteasome inhibitor from a different class, if possible (ie, switching from carfilzomib to bortezomib or ixazomib). We do not recommend rechallenging the patient with the same drug, since recurrent thrombotic microangiopathy can occur. Patients with thrombotic microangiopathy as a result of these drugs are not typically responsive to plasmapheresis. (See "Drug-induced thrombotic microangiopathy (DITMA)", section on 'Management'.)
PATIENTS WITH CHRONIC KIDNEY DISEASE — Optimal therapy is uncertain in slowly progressive disease that appears to be due to light chain cast nephropathy. Plasmapheresis plus chemotherapy has been used in uncontrolled studies, with some patients who have preserved urine output showing improvement in kidney function [7,21]. Benefit from plasmapheresis is much less likely in patients with diffuse, dense intratubular cast formation and tubulointerstitial fibrosis on kidney biopsy [7,11].
Given limited data supporting the use of plasmapheresis in patients with chronic kidney disease (CKD) due to progressive light chain cast nephropathy, we suggest chemotherapy alone to reduce light chain production.
Patients who develop irreversible CKD from multiple myeloma-related kidney disease should be managed similarly to patients with CKD from other causes. Patients with CKD resulting from light chain cast nephropathy should undergo routine monitoring of serum free light chain (SFLC) concentrations since recurrent cast nephropathy may occur in the setting of rising SFLC levels. Issues related to the general management of complications of CKD are discussed elsewhere. (See "Overview of the management of chronic kidney disease in adults".)
End-stage kidney disease — Patients with progression to end-stage kidney disease (ESKD) can be treated with hemodialysis or peritoneal dialysis [41-48]. Of patients with ESKD due to multiple myeloma who survive the first two months, survival is approximately 45 percent at one year and 25 to 30 percent at two to three years [41]. Patients with ESKD who respond to chemotherapy with a reduction in light chain production appear to do much better, with a mean survival of 47 months in one study (versus only 17 months in nonresponders) [42].
The survival of patients requiring dialysis for kidney failure may be similar to that of patients with less severe kidney impairment if they are candidates for hematopoietic cell transplantation [49]. In one report, the median survival of 38 patients on hemodialysis was more than 51 months following autologous hematopoietic cell transplantation, which was similar to the reported survival of 43 patients with kidney impairment but not on hemodialysis who received the same treatment [50]. (See "Multiple myeloma: Use of hematopoietic cell transplantation".)
Kidney transplantation — The experience with kidney transplantation in multiple myeloma is limited to case reports and case series, with fewer than 50 patients being reported [51-54]. A review of eight case reports noted kidney and patient survival of 14 to >96 months [51].
One small series of four patients showed that kidney transplantation was feasible in patients who had achieved at least a very good partial response (VGPR) with chemotherapy and autologous stem cell transplantation at the time of kidney transplant [54]. All patients had functioning allografts at one year posttransplant, and none experienced rejection or infection with BK polyomavirus or cytomegalovirus over a median of 45 months. One patient had progression of myeloma but responded well to antimyeloma therapy. It should be noted, however, that treatment with lenalidomide, an agent commonly used as initial and maintenance therapy for multiple myeloma, may increase the risk of acute T cell-mediated (cellular) rejection [55].
However, without control of excessive light chain production, outcomes are not favorable. This was illustrated in a retrospective review of seven patients with light chain deposition disease (LCDD) who underwent kidney transplantation [52]. One patient died from progression of multiple myeloma shortly after transplant, and LCDD recurred in five patients after a median of 33 months (range of 2 to 45). Four of the patients with recurrent disease died shortly after recurrence; only one patient had a successful transplant outcome.
However, kidney transplantation is an option for highly selected patients who have undergone successful hematopoietic cell transplantation and have achieved a hematologic stringent complete response. Successful combined allogeneic stem cell and kidney transplantation has been reported in a small number of patients [56,57].
PATIENTS WITH ALBUMINURIA OR NEPHROTIC SYNDROME — Albuminuria or nephrotic syndrome in patients with multiple myeloma or other monoclonal gammopathies can be caused by a number of different mechanisms, including amyloidosis, monoclonal immunoglobulin deposition disease (MIDD), and, less commonly, monoclonal cryoglobulinemia, proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID), C3 glomerulopathy, and immunotactoid glomerulopathy. A kidney biopsy is required to establish a diagnosis.
Issues related to the general management of nephrotic syndrome (eg, proteinuria, edema, hyperlipidemia, and hypercoagulability) are discussed separately. (See "Overview of heavy proteinuria and the nephrotic syndrome", section on 'Treatment'.)
Amyloidosis — The treatment of patients with albuminuria or nephrotic syndrome from immunoglobulin light chain (AL) amyloidosis targets the underlying plasma cell clone, aiming to prevent further production and renal deposition of amyloid protein. We avoid the use of angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs), particularly in patients who have hypotension due to cardiac involvement or autonomic dysregulation. Diuretics should be used with caution in patients with volume overload due to the risk of precipitating hypotension. The specific treatment of immunoglobulin light chain amyloidosis is discussed elsewhere. (See "Treatment and prognosis of immunoglobulin light chain (AL) amyloidosis", section on 'General concepts'.)
Monoclonal immunoglobulin deposition disease — In patients with MIDD, the goal is to control the plasma cell or B cell disorder that is responsible for producing the pathogenic light and/or heavy chains found within deposits in the kidney. The treatment of MIDD is discussed separately. (See "Monoclonal immunoglobulin deposition disease".)
Monoclonal cryoglobulinemia — Monoclonal (type I) cryoglobulinemia is a rare cause of glomerular disease among patients with multiple myeloma and other monoclonal gammopathies. The treatment of these patients is directed at eradicating the clonal population of plasma cells or B cells that is responsible for monoclonal cryoglobulin production. (See "Treatment protocols for multiple myeloma" and "Treatment and prognosis of Waldenström macroglobulinemia" and "Treatment protocols for lymphoma".)
Proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID) and C3 glomerulopathy associated with monoclonal gammopathy — Given the rarity of these disorders, there have been no randomized trials to determine the optimal approach to therapy, and most treatment recommendations are based upon clinical opinion and experience. In general, treatment of these disorders should be primarily directed at eliminating the clonal proliferation of plasma cells or B cells that is responsible for producing the pathogenic monoclonal protein. (See "Diagnosis and treatment of monoclonal gammopathy of renal significance", section on 'Patients with PGNMID' and "Diagnosis and treatment of monoclonal gammopathy of renal significance", section on 'Patients with C3 glomerulopathy with monoclonal gammopathy'.)
Immunotactoid glomerulopathy — The treatment of immunotactoid glomerulopathy is discussed elsewhere. (See "Glomerular diseases due to nonamyloid fibrillar deposits", section on 'Treatment'.)
PATIENTS WITH ELECTROLYTE ABNORMALITIES
Light chain proximal tubulopathy (Fanconi syndrome) — Electrolyte abnormalities (eg, hypophosphatemia, hypokalemia) in patients with light chain proximal tubulopathy should be managed with oral or intravenous supplementation depending upon the severity of the deficiency. Patients with evidence of a renal tubular acidosis should receive alkali therapy (eg, sodium bicarbonate, sodium citrate, potassium citrate) to correct their metabolic acidosis [58].
●(See "Hypophosphatemia: Evaluation and treatment".)
●(See "Clinical manifestations and treatment of hypokalemia in adults", section on 'Treatment'.)
The treatment of patients who have light chain proximal tubulopathy and significant kidney function impairment and/or proteinuria is discussed elsewhere. (See "Diagnosis and treatment of monoclonal gammopathy of renal significance", section on 'Light chain proximal tubulopathy'.)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Acute kidney injury in adults" and "Society guideline links: Multiple myeloma" and "Society guideline links: Immunoglobulin light chain (AL) amyloidosis" and "Society guideline links: Monoclonal gammopathy of undetermined significance" and "Society guideline links: Waldenström macroglobulinemia".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on “patient info” and the keyword(s) of interest.)
●Beyond the Basics topics (see "Patient education: Multiple myeloma symptoms, diagnosis, and staging (Beyond the Basics)" and "Patient education: Multiple myeloma treatment (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●Overview – Kidney disease is a common complication in patients with multiple myeloma and other monoclonal gammopathies. A wide range of kidney manifestations and pathologies involving different mechanisms have been described with these disorders. Kidney injury most often occurs in patients with a high tumor burden and can evolve as either an acute or chronic disorder.
●Acute (AKI) or subacute kidney injury
•Light chain cast nephropathy – For patients with multiple myeloma who have a confirmed or suspected diagnosis of light chain cast nephropathy, we use the following approach:
-We recommend anti-myeloma therapy with bortezomib-based chemotherapy with high-dose dexamethasone (such as bortezomib, cyclophosphamide, and dexamethasone, or CyBorD) rather than other anti-myeloma chemotherapy regimens (Grade 1B). This therapy should be initiated as rapidly as possible to decrease light chain production. (See 'Anti-myeloma therapy' above.)
-We administer intravenous or oral fluid therapy, with the goal of attaining a daily urine output of approximately 3 liters, unless contraindicated (eg, heart failure or persistent oligoanuric AKI). If volume depletion is clinically present, we provide isotonic fluids for initial volume replacement. In the absence of (or following the correction of) volume depletion, we administer one-half isotonic saline. We reserve the use of loop diuretics for patients who develop hypervolemia. (See 'Fluid management' above.)
In patients with AKI and oliguria, we still administer the fluid regimen described above. Within 24 hours, reversal of oliguria should become evident. If oliguria persists, fluid administration should be modified or discontinued to prevent volume overload.
-We discontinue all potentially nephrotoxic agents, including nonsteroidal antiinflammatory agents (NSAIDs), diuretics, angiotensin-converting enzyme (ACE) inhibitors, and angiotensin receptor blockers (ARBs).
-We correct hypercalcemia, if present. (See 'Hypercalcemia' above.)
-Dialysis should be initiated for the usual indications (eg, fluid overload, hyperkalemia, and uremia) and not for the removal of free light chains. Among patients with AKI who require dialysis, hemodialysis is the preferred modality. Peritoneal dialysis is an option for patients who develop end-stage kidney disease (ESKD) and require chronic dialysis. (See 'Dialysis' above.)
-We suggest the use of extracorporeal light chain removal using plasmapheresis or, where available, high-cutoff hemodialysis (Grade 2B). This is based upon a possible reduction in dialysis dependency among survivors. However, the use of extracorporeal methods in the treatment of light chain cast nephropathy remains controversial, and some clinicians do not use these therapies in this setting. The suggested plasmapheresis and high-cutoff-dialysis regimens and therapeutic goals are presented in detail above. Plasmapheresis and high-cutoff hemodialysis must always be used with early institution of regimens designed to reduce light chain production, most commonly bortezomib-based regimens. (See 'Extracorporeal methods for light chain removal' above.)
For patients at high risk for light chain cast nephropathy, we usually treat with intravenous fluids, unless contraindicated, to prevent volume depletion and maintain a high urine output (approximately 3 L/day). We also treat with bortezomib- and dexamethasone-based chemotherapy (eg, bortezomib, cyclophosphamide, dexamethasone). (See 'Prevention' above.)
•Hypercalcemia – In patients with AKI due to hypercalcemia, we treat with isotonic fluids, glucocorticoids, and, depending upon the serum calcium concentration, bisphosphonates (preferably pamidronate). (See 'Hypercalcemia' above.)
●Albuminuria or nephrotic syndrome – Proteinuria or nephrotic syndrome in patients with multiple myeloma or other monoclonal gammopathies can be caused by a number of different mechanisms, including amyloidosis, monoclonal immunoglobulin deposition disease (MIDD), and, less commonly, monoclonal cryoglobulinemia, proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID), C3 glomerulopathy with monoclonal gammopathy, and immunotactoid glomerulopathy. A kidney biopsy is required to establish a diagnosis. Treatment of these disorders should be directed at eliminating the clonal proliferation of plasma cells or B cells that is responsible for producing the pathogenic monoclonal protein. In general, this involves the administration of chemotherapeutic agents. (See 'Patients with albuminuria or nephrotic syndrome' above.)
●Electrolyte abnormalities – Electrolyte abnormalities (eg, hypophosphatemia, hypokalemia) in patients with light chain proximal tubulopathy should be managed with oral or intravenous supplementation depending upon the severity of the deficiency. Patients with evidence of a renal tubular acidosis should receive alkali therapy (eg, sodium bicarbonate, sodium citrate, potassium citrate) to correct their metabolic acidosis. (See 'Light chain proximal tubulopathy (Fanconi syndrome)' above.)
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