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Kidney disease in multiple myeloma and other monoclonal gammopathies: Etiology and evaluation

Kidney disease in multiple myeloma and other monoclonal gammopathies: Etiology and evaluation
Authors:
Nelson Leung, MD
Gerald B Appel, MD
Frank Bridoux, MD, PhD
Section Editors:
Richard J Glassock, MD, MACP
S Vincent Rajkumar, MD
Deputy Editor:
Albert Q Lam, MD
Literature review current through: Dec 2022. | This topic last updated: Nov 15, 2022.

INTRODUCTION — Kidney disease is a common complication of multiple myeloma and other monoclonal gammopathies (paraproteinemias). A wide range of kidney manifestations and pathologies involving different mechanisms have been described with these disorders.

This topic provides a review of the epidemiology, pathogenesis, etiology, clinical presentation, and evaluation of kidney disease in patients with multiple myeloma or other malignant monoclonal gammopathies. The treatment and prognosis of kidney diseases associated with multiple myeloma or other malignant monoclonal gammopathies are discussed separately. (See "Kidney disease in multiple myeloma and other monoclonal gammopathies: Treatment and prognosis".)

The diagnosis and treatment of kidney diseases associated with nonmalignant or premalignant monoclonal gammopathies (ie, monoclonal gammopathy of renal significance [MGRS]) are discussed elsewhere. (See "Diagnosis and treatment of monoclonal gammopathy of renal significance".)

EPIDEMIOLOGY — Kidney disease is one of the most common complications in multiple myeloma. The reported frequency of kidney impairment in multiple myeloma varies depending upon the definition used [1-6]:

Approximately 50 percent of patients with multiple myeloma experience acute kidney injury (AKI) or chronic kidney disease (CKD) at some time during the course of their disease [2].

Among newly diagnosed patients, 20 to 50 percent have AKI or CKD at the time of diagnosis [1,3,4,6,7].

Severe kidney failure, acute or chronic, requiring dialysis generally occurs in 1 to 3 percent of patients with multiple myeloma but has been reported in up to 12 percent [5,7,8].

Nearly all of the different types of kidney disease seen in multiple myeloma can also occur with B cell lymphoproliferative disorders. The prevalence of different kidney lesions varies among the lymphoproliferative disorders:

In a single-center, retrospective analysis of 1391 patients with Waldenström macroglobulinemia, the cumulative incidence of biopsy-confirmed kidney disease was 5 percent at 15 years [9]. The most common pathologies were amyloidosis (25 percent), monoclonal IgM immunoglobulin deposition disease/cryoglobulinemia (23 percent), lymphoplasmacytic lymphoma infiltration (18 percent), light chain deposition disease (LCDD; 9 percent), and light chain cast nephropathy (9 percent). Other observational studies of patients with Waldenström macroglobulinemia and other immunoglobulin M (IgM)-producing B cell lymphoproliferative disorders have reported similar findings [10,11].

In a study of patients with chronic lymphocytic leukemia (CLL), membranoproliferative glomerulonephritis (20 percent) was the most common kidney lesion, followed by minimal change disease (10 percent), immunoglobulin light chain (AL) amyloidosis (7 percent), and light chain cast nephropathy (7 percent) [12]. Infiltration of CLL into the kidney parenchyma occurred in 40 percent of kidney biopsies.

Kidney disease may also occur in patients with nonmalignant or premalignant monoclonal gammopathies. These monoclonal gammopathies, classified as monoclonal gammopathy of renal significance (MGRS), are discussed in detail elsewhere. (See "Diagnosis and treatment of monoclonal gammopathy of renal significance".)

PATHOGENESIS — Kidney disease in patients with monoclonal gammopathies usually results from the production of monoclonal immunoglobulin or immunoglobulin fragments (ie, light or heavy chains) by a clonal proliferation of plasma cells or B cells. Kidney injury may also result from causes unrelated to monoclonal proteins, such as hypercalcemia, hyperuricemia, and side effects of therapy. (See "Laboratory methods for analyzing monoclonal proteins".)

Special properties of pathogenic light and heavy chains — The biochemical characteristics of the individual light or heavy chain appear to be a major determinant of which kidney disease (if any) occurs [13]. As an example, infusion of monoclonal light chains from individual patients into mice produces the same form of kidney injury (cast nephropathy, amyloid deposition, or lack of disease) in the mouse as was seen in the patient [14]. In vitro studies suggest that almost all toxic light chains, and a few of those that are nontoxic, are able to undergo self-association, leading to the formation of high-molecular-weight aggregates [15]. These aggregates in vivo would then lead to cast formation in light chain cast nephropathy and tissue deposits with or without fibril formation in primary amyloidosis and light chain deposition disease (LCDD), respectively.

Additional light chain characteristics may be important in the determination of nephrotoxicity. Lambda light chains are found in roughly two-thirds of all (immunoglobulin light chain [AL]) amyloidosis, while nearly three-quarters of LCDD and light chain proximal tubulopathy are caused by a monoclonal kappa light chain [16-19]. Differential organ involvement in AL amyloidosis may be determined by the clonal sequence and germline donor patterns for the light chain variable region (immunoglobulin V-lambda [IgV-lambda]) [20,21]. Light chains of the V-Lambda VI subgroup account for greater than 40 percent of renal AL amyloidosis, while V-kappa I and IV subgroups are overrepresented in LCDD [22-25].

The properties of abnormal heavy chains are discussed elsewhere. (See "The heavy chain diseases".)

Mechanisms of injury caused by monoclonal proteins

Intratubular cast formation — Light chain cast nephropathy can occur when large amounts of monoclonal free light chains (FLCs) are produced by plasma cell clones in multiple myeloma or, less commonly, by a B cell lymphoproliferative disorder [26]. Light chains are freely filtered across the glomerulus and largely reabsorbed by proximal tubular cells (figure 1). The normal rate of light chain excretion is <30 mg/day. However, reabsorptive capacity can be exceeded due to light chain overproduction in multiple myeloma, resulting in an increase in excretion that can range from 100 mg to >20 g/day. (See 'Light chain cast nephropathy' below.)

Light chains precipitate in the tubules as a result of binding with uromodulin (formerly called Tamm-Horsfall mucoprotein, or THMP), a protein normally secreted by cells of the thick ascending limb of the loop of Henle and which constitutes the matrix of all urinary casts [27,28]. The binding and precipitation lead to the formation of obstructing, dense, intratubular casts in the distal and collecting tubules that may initiate a giant cell reaction and lead to interstitial inflammation and fibrosis (picture 1A-C) [27-30]. The obstructing casts cause tubular rupture, which allows extravasation of monoclonal light chain into the interstitium, further promoting the interstitial inflammatory process.

Factors that may promote intratubular cast formation include:

Volume depletion, possibly by slowing flow within the tubules and by promoting the formation of large aggregates [13,15,27].

Metabolic acidosis, possibly by lowering urinary pH and promoting the binding of light chains to uromodulin (THMP) [28,31,32].

Loop diuretics, at least in part by increasing luminal sodium chloride [27]. This may be important clinically since loop diuretics are often given empirically (and perhaps deleteriously) to patients with light chain cast nephropathy in an attempt to wash out obstructing casts.

Hypercalcemia and increased urinary calcium, through volume depletion, renal vasoconstriction, and other mechanisms [13,33].

Radiocontrast media (particularly high-osmolar agents), which may interact with light chains and promote intratubular obstruction [31,34].

Nonsteroidal antiinflammatory drugs (NSAIDs), which may precipitate acute kidney injury (AKI) in 7 to 30 percent of affected patients [35-37]. Risk of AKI associated with these drugs is highest in patients with light chain cast nephropathy.

The potential nephrotoxicity of different light chains is variable [13,14,27,28,30,32,38]. Thus, although patients with light chain cast nephropathy generally excrete >1 g of light chains per day, much larger quantities are occasionally excreted without any substantial change in kidney function [39,40].

An important determinant of the ability of a particular light chain to form intratubular casts is the affinity of its binding to uromodulin (THMP) [13,28]. A specific binding site for immunoglobulin light chains has been identified on uromodulin (THMP) [28]. This nine-amino acid segment binds to the complementary determining region 3 (CDR3) of immunoglobulin light chains. Light chains with high affinity appear to be more likely to produce obstructing intratubular casts. However, light chains with only moderate affinity for uromodulin (THMP) may still induce cast formation if tubular concentration is increased by high serum concentration or hypovolemia [28]. A competitive inhibitor peptide that prevents binding of light chains to uromodulin (THMP) decreased intratubular cast formation and prevented AKI in an animal model [41].

Another contributing factor to uromodulin (THMP) binding and the predisposition to light chain cast nephropathy may be the isoelectric point (pI) of the light chain [13,30,31]. Light chains (Bence Jones proteins) with a pI >5.1 (that is, above the tubular fluid pH in the distal nephron) will have a net positive charge, which may promote binding via charge interaction to anionic uromodulin (THMP; pI = 3.2) [27,31,32]. Urinary alkalinization might be beneficial in some patients by reducing binding of the light chain to uromodulin (THMP), causing them to become less cationic, or even anionic, and by changing the charge on a single histidine residue in the binding site of uromodulin (THMP) [28,31,32].

Signaling molecules such as interleukin (IL) 6, IL-8, nuclear factor kappa B (NF-kB), monocyte chemoattractant protein 1 (MCP-1), apoptosis signal-regulating kinase 1 (ASK1), and others have been implicated in cellular damage as a result of cast formation [42-47].

Direct tubular toxicity — Intratubular cast formation is relatively minor in some patients; in such patients, the degree of kidney failure correlates best with tubular damage and atrophy [39,48]. Tubular injury, at least in the proximal tubule, presumably results from the reabsorption of massive quantities of filtered monoclonal light chains into the tubular cell. Their accumulation within the cell may then interfere with lysosomal function [32,48]. In addition, the formation of reactive oxygen species, particularly hydrogen peroxide, catalyzed by monoclonal light chains, may activate the signal transducer and activator of transcription 1 pathway in proximal tubule epithelium, leading to the production of proinflammatory cytokines such as interleukin-1beta and of the profibrotic agent transforming growth factor-beta, suggesting a potential mechanism of light chain-induced injury [49].

Rare patients with multiple myeloma develop signs of proximal tubular dysfunction (Fanconi syndrome) without kidney failure [50,51]. The light chains that cause proximal tubule dysfunction, which are almost always of the V-kappa 1 variability subgroup, are resistant to degradation by proteases in tubular cell lysosomes [52]. Accumulation of the variable domain fragments within lysosomes, with subsequent intracellular crystal formation, alters lysosome dynamics and proteolytic function through defective acidification, causing dedifferentiation and loss of reabsorptive capacity of proximal tubular cells [38,50,53]. (See 'Light chain proximal tubulopathy' below.)

Proximal tubular dysfunction may further decrease proximal light chain reabsorption, thereby increasing delivery to the distal nephron, where cast formation can occur. Light chains can also interfere with tubular function in the loop of Henle [30]. The ensuing increase in tubular fluid sodium chloride concentration (since less is being reabsorbed) can also promote cast formation by increasing the aggregation of light chains with locally released uromodulin (THMP) [27,28,30]. (See 'Intratubular cast formation' above.)

Deposition of light and heavy chains — Deposition of light chains, heavy chains, or both within different compartments of the kidney is responsible for the pathogenesis of immunoglobulin-associated amyloidosis and monoclonal immunoglobulin deposition diseases (MIDD). The pathogenesis of amyloid protein and MIDD is discussed separately. (See "Monoclonal immunoglobulin deposition disease".)

ETIOLOGY ACCORDING TO CLINICAL PRESENTATION — The causes of kidney disease in patients with multiple myeloma or other monoclonal gammopathies can be classified by clinical presentation (table 1).

Acute or subacute kidney injury — Approximately 20 to 50 percent of patients with multiple myeloma present with an elevated serum creatinine at the time of diagnosis [1,3,4,6,7]. The spectrum of kidney impairment ranges from mild injury that may be rapidly reversible (eg, volume depletion, hypercalcemia) to severe acute kidney injury (AKI) requiring hemodialysis (eg, light chain cast nephropathy). Most patients presenting with AKI have light chain cast nephropathy, although other common causes include hypercalcemia and exposure to nephrotoxic agents, such as nonsteroidal antiinflammatory drugs (NSAIDs) or, infrequently, radiocontrast agents (table 1).

Light chain cast nephropathy — Light chain cast nephropathy refers to acute or chronic kidney disease that results from the overproduction and filtration of toxic light chains, leading to tubular injury, intratubular cast formation and obstruction, and severe tubulointerstitial inflammation (picture 1A-C) [13,54]. The diagnosis of light chain cast nephropathy is considered a "myeloma-defining event" and can occur as the first manifestation of myeloma or develop later during the course of myeloma [55]. It has been rarely reported in patients with other monoclonal gammopathies such as Waldenström macroglobulinemia, lymphoma, and chronic lymphocytic leukemia (CLL). Light chain cast nephropathy may coexist with other light chain-related kidney lesions, particularly light chain deposition disease (LCDD) [56-59]. (See 'Intratubular cast formation' above and 'Direct tubular toxicity' above.)

In autopsy or biopsy studies, light chain cast nephropathy is the single most common finding among patients with multiple myeloma and clinical kidney involvement, accounting for 33 to >60 percent of cases. Monoclonal immunoglobulin deposition disease (MIDD) and amyloidosis are less commonly found [60-63]. As examples:

Among 118 patients with multiple myeloma, kidney biopsy demonstrated light chain cast nephropathy, MIDD, and amyloidosis in 41, 19, and 30 percent of cases, respectively [62]. Interstitial nephritis was observed among 10 percent of patients.

In a later series, among 190 patients with multiple myeloma who underwent a kidney biopsy, light chain cast nephropathy, MIDD, and amyloidosis were present in 33, 22, and 21 percent of patients, respectively [63]. Forty-eight patients (25 percent) had a nonparaprotein-associated disease including acute tubular necrosis (9 percent), hypertensive nephrosclerosis (6 percent), and diabetic nephropathy (5 percent).

It is likely that light chain cast nephropathy is far more common than these studies suggest since many patients with predominantly light chains in the urine who are already destined for antimyeloma therapy do not undergo a kidney biopsy. Those with albuminuria, as seen with MIDD and amyloidosis, are much more likely to undergo a kidney biopsy to define the disease and guide therapeutic decisions. (See 'Evaluation' below.)

Although light chain cast nephropathy typically progresses rapidly, with an increase in creatinine that is observed over one to three months, the disease should be suspected in all patients who are >40 years of age presenting with an unexplained documented creatinine increase over a period of less than six months and a bland urine sediment. However, it is uncommon for patients with untreated light chain cast nephropathy to have stable kidney function beyond six months.

The risk of light chain cast nephropathy is directly related to the urinary free light chain (FLC) concentration and the light chain affinity for uromodulin (THMP) [64]. In an analysis of 2592 patients enrolled in multicenter myeloma trials, kidney injury developed in up to 54 percent of patients who had a very high concentration of urinary FLC (defined as >12 g/g creatinine) but in less than 2 percent of patients with no urinary light chains [65]. The risk of kidney failure was approximately 8 to 18 percent among those who had urinary light chains of 0 to 4 g/g creatinine and 29 to 38 percent among those who had urinary light chains of 4 to 12 g/g creatinine.

However, urinary FLC measurements are rarely used in clinical practice since the intra-individual variation is high and the assay does not perform reliably in urine samples. In practice, the risk of light chain cast nephropathy is best estimated by 24-hour urine protein electrophoresis and by measurement of serum FLC (SFLC) levels. Light chain cast nephropathy generally occurs in the setting of high tumor burden. Light chain cast nephropathy is uncommon in patients with low SFLC concentrations (<500 mg/L). Even in patients with high SFLC concentrations, a urine M-spike >200 mg/day increases the risk of myeloma transformation by 2.7-fold within two years of diagnosis [66-68]. (See 'Patients with acute or subacute kidney injury' below.)

The diagnosis and treatment of light chain cast nephropathy are discussed separately:

(See 'Patients with acute or subacute kidney injury' below.)

(See "Kidney disease in multiple myeloma and other monoclonal gammopathies: Treatment and prognosis", section on 'Light chain cast nephropathy (myeloma kidney)'.)

Hypercalcemia — Hypercalcemia is a common finding in multiple myeloma, with 15 percent of patients having a calcium concentration >11 mg/dL at the time of diagnosis. (See "Multiple myeloma: Clinical features, laboratory manifestations, and diagnosis", section on 'Hypercalcemia' and "Hypercalcemia of malignancy: Mechanisms", section on 'Multiple myeloma'.)

Moderate to severe hypercalcemia can contribute to the development of AKI by causing renal vasoconstriction, promoting intratubular calcium deposition, or increasing the toxicity of filtered light chains through polyuria and volume depletion [33,69]. The decline in kidney function may be associated with patient complaints of polyuria and polydipsia due to nephrogenic diabetes insipidus. Both the kidney impairment and antidiuretic hormone (ADH) resistance induced by hypercalcemia are often reversible. (See "Clinical manifestations of hypercalcemia", section on 'Renal insufficiency' and "Clinical manifestations and causes of nephrogenic diabetes insipidus".)

Hyperuricemia — Hyperuricemia is present in up to 50 percent of patients with multiple myeloma at presentation and may contribute to AKI if the plasma or serum urate level is markedly elevated (generally above 15 mg/dL [893 micromol/L]) [70,71]. However, sufficiently rapid tumor turnover is unusual, even after chemotherapy; therefore, overt tumor lysis syndrome is rare [26,72]. (See "Uric acid kidney diseases", section on 'Acute uric acid nephropathy' and "Tumor lysis syndrome: Pathogenesis, clinical manifestations, definition, etiology and risk factors".)

Nephrotoxic agents — AKI in patients with multiple myeloma or other monoclonal gammopathies may be associated with the use of certain nephrotoxic agents:

Intravenous radiocontrast – AKI is a potential but rare complication of radiocontrast administration in patients with multiple myeloma [73]. Kidney injury in such patients may be due, at least in part, to the development of cast nephropathy.

Urinary light chain excretion and hypovolemia are present in almost all cases of radiocontrast-associated AKI in patients with multiple myeloma. Intratubular obstruction may develop via an interaction between the contrast agent and urinary light chains [31]. It is not known whether other chemical characteristics of the contrast agent (such as charge or osmolality), which have been shown to alter the nephrotoxic potential of contrast agents in the general population, modulate the interaction between the contrast agent and the light chains. Volume depletion may predispose to AKI in these patients by enhancing light chain precipitation within the tubules. Volume repletion prior to the contrast study is likely to be protective if contrast must be given. (See "Contrast-associated and contrast-induced acute kidney injury: Clinical features, diagnosis, and management" and "Prevention of contrast-associated acute kidney injury related to angiography".)

Nonsteroidal antiinflammatory drugs – Nonsteroidal antiinflammatory drugs (NSAIDs) may increase the risk of AKI in patients with multiple myeloma who have light chain cast nephropathy [37], hypercalcemia, and/or volume depletion. As a result, NSAID therapy should be avoided in patients with multiple myeloma. (See "NSAIDs: Acute kidney injury".)

Bisphosphonates – Bisphosphonates are commonly used among patients with multiple myeloma and lytic bone lesions. These agents have been associated with acute tubular necrosis (zoledronate) and the collapsing form of focal and segmental glomerulosclerosis (pamidronate) [74,75]. (See "Multiple myeloma: The use of osteoclast inhibitors" and "Risks of therapy with bone antiresorptive agents in patients with advanced malignancy", section on 'Proteinuria and kidney injury'.)

Antimyeloma agents – Certain agents used in the treatment of multiple myeloma have been associated with AKI [76]. As examples:

The immunomodulatory agent, lenalidomide, has been reported to cause AKI in patients treated for multiple myeloma or amyloidosis [76-80]. The mechanism of injury is unclear, although kidney biopsies in some cases demonstrated acute interstitial nephritis. In addition, lenalidomide was associated with the development of Fanconi syndrome in case reports [81]. (See "Chemotherapy nephrotoxicity and dose modification in patients with kidney impairment: Conventional cytotoxic agents", section on 'Lenalidomide'.)

The proteasome inhibitors, bortezomib, carfilzomib, and ixazomib, are rarely associated with the development of thrombotic microangiopathy (TMA). In addition, carfilzomib may produce AKI through other mechanisms, including prerenal insults, a tumor lysis-like syndrome, and acute tubular necrosis [82-87]. (See "Chemotherapy nephrotoxicity and dose modification in patients with kidney impairment: Conventional cytotoxic agents", section on 'Proteasome inhibitors'.)

Less common causes of AKI

Interstitial nephritis – AKI resulting from acute tubulointerstitial nephritis has been described in patients with plasma cell disorders including myeloma. This tubulointerstitial nephritis is associated with light chain deposition in the tubular basement membrane. However, distinct granular electron-dense deposits are not seen, thereby distinguishing this disorder from that of LCDD [88]. Immunogold labeling reveals light chain deposition in the outer aspect of the tubular basement membranes and lysosomes of tubular epithelial cells. Glomerular deposits are absent.

Plasma cell infiltration – Plasma cell invasion of the kidney can occur in multiple myeloma but, by itself, is rarely severe enough to impair kidney function [61,63]. In addition to the direct myeloma infiltration, extramedullary hematopoiesis has been reported in these patients [89]. Interstitial infiltration of malignant B cells resulting in kidney impairment is more common in patients with CLL or monoclonal B cell lymphoproliferative disorders [9,10,12,90].

Thrombotic microangiopathy – There are rare reports of TMA occurring in patients with multiple myeloma treated with proteasome inhibitors, particularly carfilzomib and bortezomib [86,91,92]. Patients present with AKI, microangiopathic hemolytic anemia, thrombocytopenia, elevated lactate dehydrogenase levels, and low haptoglobin levels. Discontinuation of the proteasome inhibitor results in resolution of TMA in most but not all patients. Recurrent TMA may occur with rechallenge of the drug. Carfilzomib can also produce AKI through a number of other mechanisms [82-85]. (See "Drug-induced thrombotic microangiopathy (DITMA)" and 'Nephrotoxic agents' above.)

There have also been reports of monoclonal gammopathy-associated TMA in patients with multiple myeloma, Waldenström macroglobulinemia, or monoclonal gammopathy of undetermined significance [93-95]. Some evidence suggests that this monoclonal gammopathy-associated TMA may be a complement-mediated disease similar to complement-mediated TMA [95]. (See "Thrombotic microangiopathies (TMAs) with acute kidney injury (AKI) in adults: CM-TMA and ST-HUS".)

Hyperviscosity – Hyperviscosity is rare in multiple myeloma and more common in Waldenström macroglobulinemia, which involves a monoclonal IgM. However, monoclonal immunoglobulin A (IgA), monoclonal immunoglobulin G (IgG), and even monoclonal light chains are also capable of causing hyperviscosity. This can lead to impairment in the microcirculation of the central nervous system, as well as other possible findings including kidney failure [96]. (See "Multiple myeloma: Clinical features, laboratory manifestations, and diagnosis", section on 'Monoclonal proteins'.)

Crystal-storing histiocytosis – Crystal-storing histiocytosis (CSH) is a rare complication of multiple myeloma and B cell lymphoproliferative disorders characterized by the accumulation of light chain crystals in histiocytes, primarily in the bone marrow but also in the kidney [97,98]. Most cases are caused by monoclonal kappa light chains [97,98]. With kidney involvement, crystal-laden histiocytes localize to the interstitium or, rarely, within glomerular capillary loops or the mesangium [98,99]. The crystals in CSH resemble those present within proximal tubule cells in patients with light chain proximal tubulopathy. In addition, some patients have both lesions, suggesting a common pathogenesis [100-102]. (See 'Light chain proximal tubulopathy' below.)

Chronic kidney disease — Some patients with multiple myeloma may experience a gradual or progressive increase in serum creatinine over a period of six months or more. These patients are less likely to have a diagnosis of light chain cast nephropathy. However, patients who have experienced one or more prior episodes of light chain cast nephropathy without complete kidney recovery can develop chronic kidney disease (CKD). CKD as a presenting clinical feature is more commonly seen in patients with immunoglobulin light chain (AL) amyloidosis, MIDD, or light chain proximal tubulopathy. Other factors unrelated to multiple myeloma may also contribute to CKD in patients with multiple myeloma, particularly in those with a prior history of hypertension or diabetes mellitus. (See "Chronic kidney disease (newly identified): Clinical presentation and diagnostic approach in adults".)

Albuminuria or nephrotic syndrome — While many forms of kidney disease in patients with multiple myeloma or lymphoproliferative disorders can present with some degree of proteinuria, albuminuria as the principal presenting feature occurs more commonly in patients with AL amyloidosis, MIDD, immunotactoid glomerulopathy, monoclonal cryoglobulinemic glomerulonephritis, proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID), or C3 glomerulopathy (table 1). These patients may also present with nephrotic syndrome. Patients with light chain cast nephropathy frequently have both AKI and proteinuria. However, the proteinuria in light chain cast nephropathy is predominantly (90 percent) composed of monoclonal light chains (Bence Jones protein); by contrast, in patients with AL amyloidosis and other monoclonal immunoglobulin-related glomerular disorders, the urinary monoclonal light chain component is usually small and albumin is predominant. Patients with LCDD a form of MIDD, can have both albuminuria from glomerular damage and light chain excretion with associated cast nephropathy. (See "Overview of heavy proteinuria and the nephrotic syndrome".)

Amyloidosis — Amyloidosis is a systemic disorder characterized by the extracellular deposition of Congo red positive fibrils in soft tissues. In immunoglobulin-associated amyloidosis, the fibrils can be composed of monoclonal light chains (AL), heavy chains (AH), or both light and heavy chains (AHL). AL amyloidosis is by far the most common, accounting for more than 94 percent of cases [103]. Kidney involvement in AL amyloidosis occurs in approximately 70 percent of patients and most often presents as asymptomatic proteinuria or nephrotic syndrome (50 percent).

The pathogenesis, clinical and pathological manifestations, diagnosis, and treatment of renal amyloidosis are discussed elsewhere:

(See "Overview of amyloidosis".)

(See "Renal amyloidosis".)

(See "Monoclonal immunoglobulin deposition disease".)

(See "Clinical presentation, laboratory manifestations, and diagnosis of immunoglobulin light chain (AL) amyloidosis".)

(See "Treatment and prognosis of immunoglobulin light chain (AL) amyloidosis".)

Monoclonal immunoglobulin deposition disease — MIDD differs from amyloidosis in that the light (or heavy) chain fragments do not form fibrils and the deposits are Congo red negative [104]. Three subtypes of MIDD have been reported based upon the composition of the deposits: LCDD, heavy chain deposition disease (HCDD), and light and heavy chain deposition disease (LHCDD). Of these, LCDD is the most common, accounting for up to 80 percent of cases of biopsy-proven MIDD [25,59,105].

Patients with these disorders typically present with the nephrotic syndrome and kidney impairment [19,59,105,106]. However, rare cases of LCDD without significant proteinuria (<0.5 g/day) have also been reported [107]. Associated light chain cast nephropathy is found far more commonly in LCDD than in AL amyloidosis.

The pathogenesis, clinical and pathological manifestations, diagnosis, and treatment of MIDD are discussed elsewhere:

(See "Monoclonal immunoglobulin deposition disease".)

(See "Clinical presentation, laboratory manifestations, and diagnosis of immunoglobulin light chain (AL) amyloidosis".)

(See "Treatment and prognosis of immunoglobulin light chain (AL) amyloidosis".)

Membranoproliferative glomerulonephritis — Both the glomerular "pattern-of-injury" lesions of membranoproliferative and crescentic glomerulonephritis have been described in some patients with monoclonal gammopathies [108,109]. A significant proportion (40 percent in one series) of what was formerly considered to be "idiopathic" membranoproliferative glomerulonephritis is associated with and may be causally related to a monoclonal protein [110,111]. Most of these patients have either PGNMID or C3 glomerulopathy. (See "Membranoproliferative glomerulonephritis: Classification, clinical features, and diagnosis", section on 'Monoclonal gammopathies'.)

Proliferative glomerulonephritis with monoclonal immunoglobulin deposits — PGNMID is a monoclonal gammopathy-associated kidney disease that mimics immune-complex glomerulonephritis [112,113]. Patients present with the nephrotic syndrome, kidney function impairment, and hematuria [113]. On kidney biopsy, most patients will have a histologic pattern of membranoproliferative glomerulonephritis or endocapillary proliferative glomerulonephritis with membranous features. Immunofluorescence reveals glomerular deposits that stain positive for a single light chain isotype and single heavy chain subtype (usually IgG3 kappa). Electron microscopy shows granular, nonorganized deposits. Approximately 20 percent of patients will have a detectable monoclonal serum protein with the same heavy and light chain isotypes as the glomerular deposits [114]. Only a minority of patients have or develop frank multiple myeloma over time [113].

The diagnosis and treatment of PGNMID are discussed elsewhere:

(See "Diagnosis and treatment of monoclonal gammopathy of renal significance", section on 'Diagnosis'.)

(See "Diagnosis and treatment of monoclonal gammopathy of renal significance", section on 'Patients with PGNMID'.)

C3 glomerulopathy with monoclonal gammopathy — Some patients with C3 glomerulonephritis or dense deposit disease have a monoclonal gammopathy identified at the time of diagnosis. This occurs most commonly in patients over the age of 50 years. No mutation in the complement regulatory peptides is typically identified. Although C3/C4 nephritic factor and autoantibodies to factor H have been identified in a small percentage of cases, the mechanism of dysregulation of the complement alternative pathway, which is central in the pathogenesis of C3 glomerulopathy, remains unknown in the majority of cases [115-119]. In some patients, a direct role of the monoclonal immunoglobulin in the dysregulation of the complement alternative pathway has been demonstrated [120], and improved kidney survival has been reported in patients who achieve deep hematological response after clone-targeted chemotherapy [118]. (See "C3 glomerulopathies: Dense deposit disease and C3 glomerulonephritis".)

Less common causes of albuminuria

Monoclonal cryoglobulinemia – Type I cryoglobulinemia is a rare cause of glomerular disease in patients with multiple myeloma [121]. In this setting, the monoclonal immunoglobulin forms cryoprecipitates that can lead to a membranoproliferative pattern with intraluminal "thrombi" on kidney biopsy. Type II cryoglobulinemia is uncommon in myeloma but more common in B cell lymphoproliferative disorders, especially Waldenström macroglobulinemia. (See "Mixed cryoglobulinemia syndrome: Clinical manifestations and diagnosis".)

Crystalline podocytopathy – Crystalline podocytopathy is a rare entity (fewer than 20 reported cases) in which deposits of light chains crystallize within podocytes, resulting in a clinical presentation of proteinuria or nephrotic syndrome [50,122-124]. Focal segmental glomerulosclerosis is the most common histologic pattern on kidney biopsy, and patients will have additional crystalline deposits within other cells in the kidney, including proximal tubular cells, endothelial cells, and mesangial cells. Patients may have or develop multiple myeloma. (See 'Light chain proximal tubulopathy' below.)

Immunotactoid glomerulopathy and fibrillary glomerulonephritis – Immunotactoid glomerulopathy is a rare disorder that has been associated with monoclonal gammopathies, including multiple myeloma [125-130]. Immunotactoid glomerulopathy is associated with a monoclonal gammopathy in up to 67 percent of cases, and approximately 50 percent of the patients have a clone in the lineage of CLL [127,129,131]. DnaJ heat shock protein family (Hsp40) member B9 (DNAJB9)-positive monotypic fibrillary glomerulonephritis is very rare and is not associated with monoclonal gammopathy in the vast majority of patients [132,133]. These disorders are discussed in more detail elsewhere. (See "Glomerular diseases due to nonamyloid fibrillar deposits", section on 'Fibrillary and immunotactoid disease'.)

Electrolyte abnormalities — Hypercalcemia is the most common electrolyte abnormality in patients with multiple myeloma, occurring in more than 10 percent of patients at the time of diagnosis [3]. (See 'Hypercalcemia' above and "Multiple myeloma: Clinical features, laboratory manifestations, and diagnosis", section on 'Hypercalcemia'.)

Other electrolyte disorders include a partial or complete Fanconi syndrome and pseudohyponatremia (table 1). Patients with Fanconi syndrome have tubular dysfunction with varying degrees of kidney impairment. A low anion gap is often found in patients with large amounts of IgG monoclonal protein in the blood. (See "Causes of hyponatremia without hypotonicity (including pseudohyponatremia)", section on 'Patients with a plasma cell dyscrasia'.)

Light chain proximal tubulopathy — In some patients, monoclonal light chains cause only tubular dysfunction without a reduction in glomerular filtration rate (GFR). The proximal tubules are most prominently affected due to the reabsorption and subsequent accumulation of filtered light chains in proximal tubular cells [48].

The clinical manifestations of tubular dysfunction include signs of the Fanconi syndrome such as normoglycemic glycosuria, aminoaciduria, proximal renal tubular acidosis, hypouricemia, and phosphate wasting; phosphate wasting can lead to hypophosphatemia and osteomalacia [50,51,134,135]. Proximal tubular dysfunction can also exacerbate light chain cast nephropathy by decreasing light chain reabsorption, thereby increasing light chain delivery to and promoting precipitation in the distal nephron. (See "Etiology and diagnosis of distal (type 1) and proximal (type 2) renal tubular acidosis" and "Hypophosphatemia: Causes of hypophosphatemia".)

One series reported 46 patients with tubular dysfunction associated with crystalline (40 patients) and noncrystalline (6 patients) light chain proximal tubulopathy [50]. Of the patients, 21 had monoclonal gammopathies of renal significance, 15 had multiple myeloma, 7 had smoldering myeloma, and 3 had other neoplasms. Thirty-eight percent presented with the Fanconi syndrome, 83 percent with kidney function impairment, and 98 percent with proteinuria.

The monoclonal light chains that produce Fanconi syndrome appear to have a variable domain with unique biochemical characteristics, which render them resistant to degradation by proteases in lysosomes in the tubular cells [52]. Accumulation of the variable domain fragments, with subsequent intracellular crystal formation, is presumably responsible for the impairment in tubular function [38]. Nearly 90 percent of the light chains involved are kappa and belong to the V-kappa 1 variability subgroup [136].

Pseudohyponatremia — Pseudohyponatremia can occur in patients with multiple myeloma who have severe hyperproteinemia. This is discussed in more detail elsewhere. (See "Causes of hyponatremia without hypotonicity (including pseudohyponatremia)", section on 'Patients with a plasma cell dyscrasia'.)

EVALUATION — The diagnostic approach to a patient with kidney disease and a malignant monoclonal gammopathy depends upon the clinical presentation. The overall goal of evaluation is to determine whether a monoclonal protein is involved in the pathogenesis of the kidney disease. In many cases, a kidney biopsy is required to establish this association and to guide therapy. However, if a clinical diagnosis and treatment plan have already been established by other means (eg, diagnosis of multiple myeloma based upon bone marrow findings and lytic bone lesions, or evidence of immunoglobulin light chain [AL] amyloidosis based upon biopsy of non-kidney tissues), a kidney biopsy may not be necessary. Laboratory testing of monoclonal proteins can assist with narrowing the differential diagnosis and plays an important role in monitoring the response to treatment. (See "Laboratory methods for analyzing monoclonal proteins".)

Patients with acute or subacute kidney injury — Acute kidney injury (AKI) or subacute kidney injury is a common clinical presentation of kidney disease in patients with multiple myeloma and other monoclonal gammopathies. Etiologies responsible for AKI in these patients include light chain cast nephropathy, hypercalcemia, volume depletion, nephrotoxic agents (eg, radiocontrast, nonsteroidal antiinflammatory drugs [NSAIDs]), and, less frequently, hyperuricemia or rarely hyperviscosity. Among these, light chain cast nephropathy is the most common. AKI or subacute kidney injury can also be a clinical feature of monoclonal immunoglobulin deposition disease (MIDD) and amyloidosis, but these diseases more commonly present with proteinuria or nephrotic syndrome. Proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID), C3 glomerulopathy, cryoglobulinemic glomerulonephritis, and immunotactoid glomerulopathy may also present with AKI or subacute injury, particularly in patients with a membranoproliferative or crescentic pattern of injury. (See 'Acute or subacute kidney injury' above.)

The definition of kidney injury and the assessment of kidney function in patients with multiple myeloma or other malignant monoclonal gammopathy are the same as for patients without these disorders. (See "Definition and staging criteria of acute kidney injury in adults" and "Assessment of kidney function".)

In patients with a known diagnosis of multiple myeloma, smoldering multiple myeloma, or high-risk monoclonal gammopathy of undetermined significance (MGUS) who are being evaluated for unexplained reduced kidney function, we recommend the following initial steps in the evaluation:

Determination of possible nephrotoxic exposures (eg, NSAIDs, radiocontrast)

Assessment of volume and acid-base status

Urinalysis with sediment examination

Measurement of serum calcium (corrected for serum albumin concentration)

Measurement of serum uric acid

Measurement of serum phosphorus

Serum protein electrophoresis and immunofixation

Serum free light chain (SFLC) assay

24-hour urine electrophoresis with immunofixation

Kidney ultrasound

We do not perform urinary free light chain (FLC) assays, since this test is not helpful in the evaluation of AKI or subacute kidney injury in patients with multiple myeloma or other monoclonal gammopathies.

Our subsequent evaluation progresses as follows:

Patients with evidence of obstructive uropathy (eg, hydronephrosis), moderate to severe hypercalcemia, hypovolemia, or urate nephropathy (suspected if the serum urate is severely elevated) should be treated to correct these disorders. (See "Clinical manifestations and diagnosis of urinary tract obstruction (UTO) and hydronephrosis" and "Treatment of hypercalcemia" and "Uric acid kidney diseases", section on 'Prevention and treatment' and "Overview of the management of acute kidney injury (AKI) in adults".)

In patients without the above reversible causes of AKI, or if correction of these disorders does not improve kidney function, our approach to diagnosis is as follows:

A presumptive diagnosis of light chain cast nephropathy can be made without performing a kidney biopsy in patients who have a bland urine sediment, an SFLC concentration of ≥1500 mg/L, and a predominance of monoclonal light chains by 24-hour urine protein electrophoresis with immunofixation, or in patients with a prior diagnosis of light chain cast nephropathy whose clinical presentation is suggestive of recurrence. (See 'Light chain cast nephropathy' above.)

We perform a kidney biopsy in patients with an abnormal urine sediment, an SFLC concentration of <1500 mg/L, or a predominance of albumin by 24-hour urine electrophoresis with immunofixation.

A kidney biopsy provides a definitive diagnosis and distinguishes between light chain cast nephropathy and other forms of myeloma-related kidney disease (eg, MIDD, amyloidosis, PGNMID, and plasma cell infiltration) that would warrant specific treatment. Occasionally, the kidney biopsy may reveal causes of kidney impairment that are unrelated to monoclonal gammopathy, such as acute tubular necrosis or interstitial nephritis. However, we do not routinely perform a kidney biopsy in most patients with a bland urine sediment, an SFLC level of ≥1500 mg/L, and low urinary albumin excretion, as these patients are presumed to have a diagnosis of light chain cast nephropathy [67,137]. In patients with light chain cast nephropathy and severe AKI who do not respond to appropriate therapy, a kidney biopsy can be considered to investigate causes other than light chain cast nephropathy and to evaluate the probability of kidney response [138]. (See "Kidney disease in multiple myeloma and other monoclonal gammopathies: Treatment and prognosis".)

Light chain cast nephropathy should also be suspected in patients who do not carry a diagnosis of multiple myeloma but have evidence of a monoclonal protein (M-protein) in the urine or an abnormal SFLC ratio. These patients should undergo additional testing to evaluate multiple myeloma, including bone marrow aspiration and biopsy and bone imaging studies. Once a diagnosis of multiple myeloma is established by bone marrow evaluation, the need for a kidney biopsy is determined by the degree of elevation of the SFLC concentration and by the absence or presence of clinical features that are atypical for light chain cast nephropathy (significant albuminuria and active urine sediment). Patients who have an SFLC concentration of ≥1500 mg/L and no atypical features are presumed to have light chain cast nephropathy, and a kidney biopsy is generally not performed. (See "Multiple myeloma: Clinical features, laboratory manifestations, and diagnosis", section on 'Evaluation'.)

Patients with albuminuria or nephrotic syndrome — Patients with multiple myeloma or other malignant monoclonal gammopathy can present with albuminuria or nephrotic syndrome as the predominant clinical feature of kidney disease. The most common etiologies responsible in these patients are AL amyloidosis and MIDD. (See 'Albuminuria or nephrotic syndrome' above.)

We perform a kidney biopsy in most patients with multiple myeloma or malignant monoclonal gammopathy who present with albuminuria or nephrotic syndrome. A kidney biopsy can define the site and pattern of kidney injury induced by the monoclonal protein and exclude nonmonoclonal gammopathy-related causes of albuminuria. However, we do not perform a kidney biopsy in patients who already have a specific diagnosis of AL amyloidosis based upon biopsies of other non-kidney tissues. Such patients are presumed to have a diagnosis of renal amyloidosis and do not require a kidney biopsy. (See "Clinical presentation, laboratory manifestations, and diagnosis of immunoglobulin light chain (AL) amyloidosis".)

In addition to biopsy, the evaluation of these patients should include a serum protein electrophoresis and immunofixation, 24-hour urine protein electrophoresis and immunofixation, and SFLC assay in order to monitor the patient after initiation of therapy. (See "Laboratory methods for analyzing monoclonal proteins", section on '24-hour urine protein electrophoresis (UPEP)' and "Laboratory methods for analyzing monoclonal proteins", section on 'Urine immunofixation'.)

In the absence of a bleeding diathesis (eg, thrombocytopenia or abnormal coagulation studies) or uncontrolled hypertension, the risk of bleeding among patients with AL amyloidosis who undergo a kidney biopsy is similar to that of patients without AL amyloidosis. In one study of kidney biopsies among patients with or without systemic amyloidosis (93 percent with AL amyloidosis), there was no difference in the rate of overall (9.9 versus 10.6 percent, respectively) or major (4.0 versus 2.1 percent, respectively) postbiopsy bleeding complications [139].

Patients with electrolyte abnormalities — Among patients with multiple myeloma or other malignant monoclonal gammopathy, common electrolyte abnormalities include hypercalcemia, hyponatremia, and Fanconi syndrome. The evaluation of hypercalcemia and hyponatremia is discussed separately. (See "Diagnostic approach to hypercalcemia" and "Diagnostic evaluation of adults with hyponatremia".)

Patients who present with hypokalemia, metabolic acidosis, and/or hypophosphatemia should be suspected of having Fanconi syndrome (see 'Light chain proximal tubulopathy' above). The diagnosis of generalized proximal tubule dysfunction as a cause of these abnormalities is presented elsewhere. In many cases, patients do not require a kidney biopsy and are presumed to have light chain proximal tubulopathy; however, some experts perform a kidney biopsy to confirm the diagnosis and evaluate kidney prognosis [50,51,140]. Some patients with light chain proximal tubulopathy may have significant proteinuria, but serum albumin levels are usually normal. It is important to note that electrolyte abnormalities can be absent in patients with advanced kidney impairment. (See "Evaluation of the adult patient with hypokalemia" and "Etiology and diagnosis of distal (type 1) and proximal (type 2) renal tubular acidosis".)

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

General principles – Kidney disease is one of the most common complications in multiple myeloma. A wide range of kidney manifestations and pathologies involving different mechanisms have been described. Nearly all of the different types of kidney disease seen in multiple myeloma can also occur with B cell lymphoproliferative disorders and nonmalignant monoclonal gammopathies (eg, monoclonal gammopathy of renal significance [MGRS]). (See 'Introduction' above and 'Epidemiology' above.)

Pathogenesis – Kidney disease in patients with monoclonal gammopathies usually results from the production of monoclonal immunoglobulin or immunoglobulin fragments (ie, light or heavy chains) by a clonal proliferation of plasma cells or B cells. The biochemical characteristics of the individual light or heavy chain appear to be a major determinant of which kidney disease (if any) occurs. Monoclonal proteins can cause kidney injury by intratubular cast formation (eg, in light chain cast nephropathy) (figure 1), direct tubular toxicity (eg, in light chain proximal tubulopathy), or deposition within different compartments of the kidney (eg, in amyloidosis and monoclonal immunoglobulin deposition disease [MIDD]). Kidney injury may also result from causes unrelated to monoclonal proteins. (See 'Pathogenesis' above.)

Etiology according to clinical presentation – The causes of kidney disease in patients with multiple myeloma or other monoclonal gammopathies can be classified by clinical presentation (table 1):

Patients presenting with acute kidney injury (AKI) or subacute kidney injury most commonly have light chain cast nephropathy. Other common causes of AKI include hypercalcemia and nephrotoxic agents (eg, nonsteroidal antiinflammatory drugs [NSAIDs], bisphosphonates, and, rarely, radiocontrast agents). (See 'Acute or subacute kidney injury' above.)

Patients presenting with proteinuria or nephrotic syndrome typically have amyloidosis or MIDD (ie, light chain deposition disease [LCDD], heavy chain deposition disease [HCDD], or light and heavy chain deposition disease [LHCDD]). (See 'Albuminuria or nephrotic syndrome' above.)

Patients presenting with electrolyte abnormalities and evidence of tubular dysfunction (especially Fanconi syndrome) may have light chain proximal tubulopathy. (See 'Electrolyte abnormalities' above.)

Evaluation – The diagnostic approach to a patient with kidney disease and a monoclonal plasma or B cell disorder or monoclonal protein depends upon the clinical presentation of the patient. The overall goal of the evaluation is to determine whether a monoclonal protein is involved in the pathogenesis of the kidney disease. In most cases, a kidney biopsy is required to establish this association and to guide therapy. Laboratory testing of monoclonal proteins can assist with narrowing the differential diagnosis and has an important role in monitoring the response to treatment. (See 'Evaluation' above.)

  1. Bladé J, Fernández-Llama P, Bosch F, et al. Renal failure in multiple myeloma: presenting features and predictors of outcome in 94 patients from a single institution. Arch Intern Med 1998; 158:1889.
  2. Kyle RA. Multiple myeloma: review of 869 cases. Mayo Clin Proc 1975; 50:29.
  3. Kyle RA, Gertz MA, Witzig TE, et al. Review of 1027 patients with newly diagnosed multiple myeloma. Mayo Clin Proc 2003; 78:21.
  4. Knudsen LM, Hippe E, Hjorth M, et al. Renal function in newly diagnosed multiple myeloma--a demographic study of 1353 patients. The Nordic Myeloma Study Group. Eur J Haematol 1994; 53:207.
  5. Torra R, Bladé J, Cases A, et al. Patients with multiple myeloma requiring long-term dialysis: presenting features, response to therapy, and outcome in a series of 20 cases. Br J Haematol 1995; 91:854.
  6. Knudsen LM, Hjorth M, Hippe E. Renal failure in multiple myeloma: reversibility and impact on the prognosis. Nordic Myeloma Study Group. Eur J Haematol 2000; 65:175.
  7. Alexanian R, Barlogie B, Dixon D. Renal failure in multiple myeloma. Pathogenesis and prognostic implications. Arch Intern Med 1990; 150:1693.
  8. Johnson WJ, Kyle RA, Pineda AA, et al. Treatment of renal failure associated with multiple myeloma. Plasmapheresis, hemodialysis, and chemotherapy. Arch Intern Med 1990; 150:863.
  9. Vos JM, Gustine J, Rennke HG, et al. Renal disease related to Waldenström macroglobulinaemia: incidence, pathology and clinical outcomes. Br J Haematol 2016; 175:623.
  10. Chauvet S, Bridoux F, Ecotière L, et al. Kidney diseases associated with monoclonal immunoglobulin M-secreting B-cell lymphoproliferative disorders: a case series of 35 patients. Am J Kidney Dis 2015; 66:756.
  11. Higgins L, Nasr SH, Said SM, et al. Kidney Involvement of Patients with Waldenström Macroglobulinemia and Other IgM-Producing B Cell Lymphoproliferative Disorders. Clin J Am Soc Nephrol 2018; 13:1037.
  12. Strati P, Nasr SH, Leung N, et al. Renal complications in chronic lymphocytic leukemia and monoclonal B-cell lymphocytosis: the Mayo Clinic experience. Haematologica 2015; 100:1180.
  13. Sanders PW. Pathogenesis and treatment of myeloma kidney. J Lab Clin Med 1994; 124:484.
  14. Solomon A, Weiss DT, Kattine AA. Nephrotoxic potential of Bence Jones proteins. N Engl J Med 1991; 324:1845.
  15. Myatt EA, Westholm FA, Weiss DT, et al. Pathogenic potential of human monoclonal immunoglobulin light chains: relationship of in vitro aggregation to in vivo organ deposition. Proc Natl Acad Sci U S A 1994; 91:3034.
  16. Buxbaum JN, Chuba JV, Hellman GC, et al. Monoclonal immunoglobulin deposition disease: light chain and light and heavy chain deposition diseases and their relation to light chain amyloidosis. Clinical features, immunopathology, and molecular analysis. Ann Intern Med 1990; 112:455.
  17. Ganeval D, Noël LH, Preud'homme JL, et al. Light-chain deposition disease: its relation with AL-type amyloidosis. Kidney Int 1984; 26:1.
  18. Kyle RA, Gertz MA. Primary systemic amyloidosis: clinical and laboratory features in 474 cases. Semin Hematol 1995; 32:45.
  19. Pozzi C, D'Amico M, Fogazzi GB, et al. Light chain deposition disease with renal involvement: clinical characteristics and prognostic factors. Am J Kidney Dis 2003; 42:1154.
  20. Comenzo RL, Wally J, Kica G, et al. Clonal immunoglobulin light chain variable region germline gene use in AL amyloidosis: association with dominant amyloid-related organ involvement and survival after stem cell transplantation. Br J Haematol 1999; 106:744.
  21. Sirac C, Herrera GA, Sanders PW, et al. Animal models of monoclonal immunoglobulin-related renal diseases. Nat Rev Nephrol 2018; 14:246.
  22. Ozaki S, Abe M, Wolfenbarger D, et al. Preferential expression of human lambda-light-chain variable-region subgroups in multiple myeloma, AL amyloidosis, and Waldenström's macroglobulinemia. Clin Immunol Immunopathol 1994; 71:183.
  23. Cogné M, Preud'homme JL, Bauwens M, et al. Structure of a monoclonal kappa chain of the V kappa IV subgroup in the kidney and plasma cells in light chain deposition disease. J Clin Invest 1991; 87:2186.
  24. Vidal R, Goñi F, Stevens F, et al. Somatic mutations of the L12a gene in V-kappa(1) light chain deposition disease: potential effects on aberrant protein conformation and deposition. Am J Pathol 1999; 155:2009.
  25. Joly F, Cohen C, Javaugue V, et al. Randall-type monoclonal immunoglobulin deposition disease: novel insights from a nationwide cohort study. Blood 2019; 133:576.
  26. Leung N, Behrens J. Current approach to diagnosis and management of acute renal failure in myeloma patients. Adv Chronic Kidney Dis 2012; 19:297.
  27. Sanders PW, Booker BB. Pathobiology of cast nephropathy from human Bence Jones proteins. J Clin Invest 1992; 89:630.
  28. Huang ZQ, Sanders PW. Localization of a single binding site for immunoglobulin light chains on human Tamm-Horsfall glycoprotein. J Clin Invest 1997; 99:732.
  29. Pirani CL, Silva F, D'Agati V, et al. Renal lesions in plasma cell dyscrasias: ultrastructural observations. Am J Kidney Dis 1987; 10:208.
  30. Sanders PW, Booker BB, Bishop JB, Cheung HC. Mechanisms of intranephronal proteinaceous cast formation by low molecular weight proteins. J Clin Invest 1990; 85:570.
  31. Holland MD, Galla JH, Sanders PW, Luke RG. Effect of urinary pH and diatrizoate on Bence Jones protein nephrotoxicity in the rat. Kidney Int 1985; 27:46.
  32. Sanders PW, Herrera GA, Chen A, et al. Differential nephrotoxicity of low molecular weight proteins including Bence Jones proteins in the perfused rat nephron in vivo. J Clin Invest 1988; 82:2086.
  33. Smolens P, Barnes JL, Kreisberg R. Hypercalcemia can potentiate the nephrotoxicity of Bence Jones proteins. J Lab Clin Med 1987; 110:460.
  34. Morgan C Jr, Hammack WJ. Intravenous urography in multiple myeloma. N Engl J Med 1966; 275:77.
  35. Sakhuja V, Jha V, Varma S, et al. Renal involvement in multiple myeloma: a 10-year study. Ren Fail 2000; 22:465.
  36. Magee C, Vella JP, Tormey WP, Walshe JJ. Multiple myeloma and renal failure: one center's experience. Ren Fail 1998; 20:597.
  37. Bridoux F, Carron PL, Pegourie B, et al. Effect of High-Cutoff Hemodialysis vs Conventional Hemodialysis on Hemodialysis Independence Among Patients With Myeloma Cast Nephropathy: A Randomized Clinical Trial. JAMA 2017; 318:2099.
  38. Decourt C, Rocca A, Bridoux F, et al. Mutational analysis in murine models for myeloma-associated Fanconi's syndrome or cast myeloma nephropathy. Blood 1999; 94:3559.
  39. DeFronzo RA, Cooke CR, Wright JR, Humphrey RL. Renal function in patients with multiple myeloma. Medicine (Baltimore) 1978; 57:151.
  40. Kyle RA, Greipp PR. "Idiopathic" Bence Jones proteinuria: long-term follow-up in seven patients. N Engl J Med 1982; 306:564.
  41. Ying WZ, Allen CE, Curtis LM, et al. Mechanism and prevention of acute kidney injury from cast nephropathy in a rodent model. J Clin Invest 2012; 122:1777.
  42. Ying WZ, Wang PX, Aaron KJ, et al. Immunoglobulin light chains activate nuclear factor-κB in renal epithelial cells through a Src-dependent mechanism. Blood 2011; 117:1301.
  43. Fattori E, Della Rocca C, Costa P, et al. Development of progressive kidney damage and myeloma kidney in interleukin-6 transgenic mice. Blood 1994; 83:2570.
  44. Sengul S, Zwizinski C, Simon EE, et al. Endocytosis of light chains induces cytokines through activation of NF-kappaB in human proximal tubule cells. Kidney Int 2002; 62:1977.
  45. Sengul S, Zwizinski C, Batuman V. Role of MAPK pathways in light chain-induced cytokine production in human proximal tubule cells. Am J Physiol Renal Physiol 2003; 284:F1245.
  46. Arimura A, Li M, Batuman V. Potential protective action of pituitary adenylate cyclase-activating polypeptide (PACAP38) on in vitro and in vivo models of myeloma kidney injury. Blood 2006; 107:661.
  47. Sanders PW. Mechanisms of light chain injury along the tubular nephron. J Am Soc Nephrol 2012; 23:1777.
  48. Sanders PW, Herrera GA, Lott RL, Galla JH. Morphologic alterations of the proximal tubules in light chain-related renal disease. Kidney Int 1988; 33:881.
  49. Ying WZ, Li X, Rangarajan S, et al. Immunoglobulin light chains generate proinflammatory and profibrotic kidney injury. J Clin Invest 2019; 129:2792.
  50. Stokes MB, Valeri AM, Herlitz L, et al. Light Chain Proximal Tubulopathy: Clinical and Pathologic Characteristics in the Modern Treatment Era. J Am Soc Nephrol 2016; 27:1555.
  51. Vignon M, Javaugue V, Alexander MP, et al. Current anti-myeloma therapies in renal manifestations of monoclonal light chain-associated Fanconi syndrome: a retrospective series of 49 patients. Leukemia 2017; 31:123.
  52. Leboulleux M, Lelongt B, Mougenot B, et al. Protease resistance and binding of Ig light chains in myeloma-associated tubulopathies. Kidney Int 1995; 48:72.
  53. Luciani A, Sirac C, Terryn S, et al. Impaired Lysosomal Function Underlies Monoclonal Light Chain-Associated Renal Fanconi Syndrome. J Am Soc Nephrol 2016; 27:2049.
  54. Sanders PW, Herrera GA, Kirk KA, et al. Spectrum of glomerular and tubulointerstitial renal lesions associated with monotypical immunoglobulin light chain deposition. Lab Invest 1991; 64:527.
  55. Kyle RA, Rajkumar SV. Criteria for diagnosis, staging, risk stratification and response assessment of multiple myeloma. Leukemia 2009; 23:3.
  56. Isaac J, Herrera GA. Cast nephropathy in a case of Waldenström's macroglobulinemia. Nephron 2002; 91:512.
  57. Gnemmi V, Leleu X, Provot F, et al. Cast nephropathy and light-chain deposition disease in Waldenström macroglobulinemia. Am J Kidney Dis 2012; 60:487.
  58. Burke JR Jr, Flis R, Lasker N, Simenhoff M. Malignant lymphoma with "myeloma kidney" acute renal failure. Am J Med 1976; 60:1055.
  59. Lin J, Markowitz GS, Valeri AM, et al. Renal monoclonal immunoglobulin deposition disease: the disease spectrum. J Am Soc Nephrol 2001; 12:1482.
  60. Pasquali S, Zucchelli P, Casanova S, et al. Renal histological lesions and clinical syndromes in multiple myeloma. Renal Immunopathology Group. Clin Nephrol 1987; 27:222.
  61. Iványi B. Renal complications in multiple myeloma. Acta Morphol Hung 1989; 37:235.
  62. Montseny JJ, Kleinknecht D, Meyrier A, et al. Long-term outcome according to renal histological lesions in 118 patients with monoclonal gammopathies. Nephrol Dial Transplant 1998; 13:1438.
  63. Nasr SH, Valeri AM, Sethi S, et al. Clinicopathologic correlations in multiple myeloma: a case series of 190 patients with kidney biopsies. Am J Kidney Dis 2012; 59:786.
  64. Ying WZ, Sanders PW. Mapping the binding domain of immunoglobulin light chains for Tamm-Horsfall protein. Am J Pathol 2001; 158:1859.
  65. Drayson M, Begum G, Basu S, et al. 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. Blood 2006; 108:2013.
  66. Hutchison CA, Cockwell P, Stringer S, et al. Early reduction of serum-free light chains associates with renal recovery in myeloma kidney. J Am Soc Nephrol 2011; 22:1129.
  67. Leung N, Gertz MA, Zeldenrust SR, et al. Improvement of cast nephropathy with plasma exchange depends on the diagnosis and on reduction of serum free light chains. Kidney Int 2008; 73:1282.
  68. Visram A, Rajkumar SV, Kapoor P, et al. Monoclonal proteinuria predicts progression risk in asymptomatic multiple myeloma with a free light chain ratio ≥100. Leukemia 2022; 36:1429.
  69. Benabe JE, Martinez-Maldonado M. Hypercalcemic nephropathy. Arch Intern Med 1978; 138:777.
  70. Kapadia SB. Multiple myeloma: a clinicopathologic study of 62 consecutively autopsied cases. Medicine (Baltimore) 1980; 59:380.
  71. Uchida M, Kamata K, Okubo M. Renal dysfunction in multiple myeloma. Intern Med 1995; 34:364.
  72. Fassas AB, Desikan KR, Siegel D, et al. Tumour lysis syndrome complicating high-dose treatment in patients with multiple myeloma. Br J Haematol 1999; 105:938.
  73. McCarthy CS, Becker JA. Multiple myeloma and contrast media. Radiology 1992; 183:519.
  74. Markowitz GS, Appel GB, Fine PL, et al. Collapsing focal segmental glomerulosclerosis following treatment with high-dose pamidronate. J Am Soc Nephrol 2001; 12:1164.
  75. Markowitz GS, Fine PL, Stack JI, et al. Toxic acute tubular necrosis following treatment with zoledronate (Zometa). Kidney Int 2003; 64:281.
  76. Wanchoo R, Abudayyeh A, Doshi M, et al. Renal Toxicities of Novel Agents Used for Treatment of Multiple Myeloma. Clin J Am Soc Nephrol 2017; 12:176.
  77. Batts ED, Sanchorawala V, Hegerfeldt Y, Lazarus HM. Azotemia associated with use of lenalidomide in plasma cell dyscrasias. Leuk Lymphoma 2008; 49:1108.
  78. Lipson EJ, Huff CA, Holanda DG, et al. Lenalidomide-induced acute interstitial nephritis. Oncologist 2010; 15:961.
  79. Shaaban H, Layne T, Guron G. A case of DRESS (drug reaction with eosinophilia and systemic symptoms) with acute interstitial nephritis secondary to lenalidomide. J Oncol Pharm Pract 2014; 20:302.
  80. Specter R, Sanchorawala V, Seldin DC, et al. Kidney dysfunction during lenalidomide treatment for AL amyloidosis. Nephrol Dial Transplant 2011; 26:881.
  81. Glezerman IG, Kewalramani T, Jhaveri K. Reversible Fanconi syndrome due to lenalidomide. NDT Plus 2008; 1:215.
  82. Jhaveri KD, Chidella S, Varghese J, et al. Carfilzomib-related acute kidney injury. Clin Adv Hematol Oncol 2013; 11:604.
  83. Jhaveri KD, Wanchoo R. Carfilzomib-induced nephrotoxcity. Kidney Int 2015; 88:199.
  84. Wanchoo R, Khan S, Kolitz JE, Jhaveri KD. Carfilzomib-related acute kidney injury may be prevented by N-acetyl-L-cysteine. J Oncol Pharm Pract 2015; 21:313.
  85. Shely RN, Ratliff PD. Carfilzomib-associated tumor lysis syndrome. Pharmacotherapy 2014; 34:e34.
  86. Yui JC, Van Keer J, Weiss BM, et al. Proteasome inhibitor associated thrombotic microangiopathy. Am J Hematol 2016; 91:E348.
  87. Yui JC, Dispenzieri A, Leung N. Ixazomib-induced thrombotic microangiopathy. Am J Hematol 2017; 92:E53.
  88. Gu X, Herrera GA. Light-chain-mediated acute tubular interstitial nephritis: a poorly recognized pattern of renal disease in patients with plasma cell dyscrasia. Arch Pathol Lab Med 2006; 130:165.
  89. Nasr SH, Alobeid BB, Otrakji JA, Markowitz GS. Myeloma cast nephropathy, direct renal infiltration by myeloma, and renal extramedullary hematopoiesis. Kidney Int 2008; 73:517.
  90. Javaugue V, Debiais-Delpech C, Nouvier M, et al. Clinicopathological spectrum of renal parenchymal involvement in B-cell lymphoproliferative disorders. Kidney Int 2019; 96:94.
  91. Hobeika L, Self SE, Velez JC. Renal thrombotic microangiopathy and podocytopathy associated with the use of carfilzomib in a patient with multiple myeloma. BMC Nephrol 2014; 15:156.
  92. Lodhi A, Kumar A, Saqlain MU, Suneja M. Thrombotic microangiopathy associated with proteasome inhibitors. Clin Kidney J 2015; 8:632.
  93. Yui JC, Garceau D, Jhaveri KD, et al. Monoclonal gammopathy-associated thrombotic microangiopathy. Am J Hematol 2019; 94:E250.
  94. Ravindran A, Go RS, Fervenza FC, Sethi S. Thrombotic microangiopathy associated with monoclonal gammopathy. Kidney Int 2017; 91:691.
  95. Martins M, Bridoux F, Goujon JM, et al. Complement Activation and Thrombotic Microangiopathy Associated With Monoclonal Gammopathy: A National French Case Series. Am J Kidney Dis 2022; 80:341.
  96. Cohen HJ, Rundles RW. Managing the complications of plasma cell myeloma. Arch Intern Med 1975; 135:177.
  97. Yamamoto T, Hishida A, Honda N, et al. Crystal-storing histiocytosis and crystalline tissue deposition in multiple myeloma. Arch Pathol Lab Med 1991; 115:351.
  98. Sethi S, Cuiffo BP, Pinkus GS, Rennke HG. Crystal-storing histiocytosis involving the kidney in a low-grade B-cell lymphoproliferative disorder. Am J Kidney Dis 2002; 39:183.
  99. Shah S, Sethi S, Arend L, Geetha D. Crystal-storing histiocytosis. Kidney Int 2016; 89:507.
  100. Stokes MB, Aronoff B, Siegel D, D'Agati VD. Dysproteinemia-related nephropathy associated with crystal-storing histiocytosis. Kidney Int 2006; 70:597.
  101. Farooq U, Bayerl MG, Abendroth CS, et al. Renal crystal storing histiocytosis in a patient with multiple myeloma. Ann Hematol 2009; 88:807.
  102. El Hamel C, Thierry A, Trouillas P, et al. Crystal-storing histiocytosis with renal Fanconi syndrome: pathological and molecular characteristics compared with classical myeloma-associated Fanconi syndrome. Nephrol Dial Transplant 2010; 25:2982.
  103. Said SM, Sethi S, Valeri AM, et al. Renal amyloidosis: origin and clinicopathologic correlations of 474 recent cases. Clin J Am Soc Nephrol 2013; 8:1515.
  104. Dimopoulos MA, Kastritis E, Rosinol L, et al. Pathogenesis and treatment of renal failure in multiple myeloma. Leukemia 2008; 22:1485.
  105. Nasr SH, Valeri AM, Cornell LD, et al. Renal monoclonal immunoglobulin deposition disease: a report of 64 patients from a single institution. Clin J Am Soc Nephrol 2012; 7:231.
  106. Kambham N, Markowitz GS, Appel GB, et al. Heavy chain deposition disease: the disease spectrum. Am J Kidney Dis 1999; 33:954.
  107. Sicard A, Karras A, Goujon JM, et al. Light chain deposition disease without glomerular proteinuria: a diagnostic challenge for the nephrologist. Nephrol Dial Transplant 2014; 29:1894.
  108. Alpers CE, Cotran RS. Neoplasia and glomerular injury. Kidney Int 1986; 30:465.
  109. Bourke E, Campbell WG Jr, Piper M, Check IJ. Hypocomplementemic proliferative glomerulonephritis with C3 nephritic-factor-like activity in multiple myeloma. Nephron 1989; 52:231.
  110. Sethi S, Fervenza FC. Membranoproliferative glomerulonephritis--a new look at an old entity. N Engl J Med 2012; 366:1119.
  111. Sethi S, Zand L, Leung N, et al. Membranoproliferative glomerulonephritis secondary to monoclonal gammopathy. Clin J Am Soc Nephrol 2010; 5:770.
  112. Nasr SH, Markowitz GS, Stokes MB, et al. Proliferative glomerulonephritis with monoclonal IgG deposits: a distinct entity mimicking immune-complex glomerulonephritis. Kidney Int 2004; 65:85.
  113. Nasr SH, Satoskar A, Markowitz GS, et al. Proliferative glomerulonephritis with monoclonal IgG deposits. J Am Soc Nephrol 2009; 20:2055.
  114. Bhutani G, Nasr SH, Said SM, et al. Hematologic characteristics of proliferative glomerulonephritides with nonorganized monoclonal immunoglobulin deposits. Mayo Clin Proc 2015; 90:587.
  115. Zand L, Kattah A, Fervenza FC, et al. C3 glomerulonephritis associated with monoclonal gammopathy: a case series. Am J Kidney Dis 2013; 62:506.
  116. Bridoux F, Desport E, Frémeaux-Bacchi V, et al. Glomerulonephritis with isolated C3 deposits and monoclonal gammopathy: a fortuitous association? Clin J Am Soc Nephrol 2011; 6:2165.
  117. Sepandj F, Trillo A. Dense deposit disease in association with monoclonal gammopathy of unknown significance. Nephrol Dial Transplant 1996; 11:2309.
  118. Chauvet S, Frémeaux-Bacchi V, Petitprez F, et al. Treatment of B-cell disorder improves renal outcome of patients with monoclonal gammopathy-associated C3 glomerulopathy. Blood 2017; 129:1437.
  119. Ravindran A, Fervenza FC, Smith RJH, Sethi S. C3 glomerulopathy associated with monoclonal Ig is a distinct subtype. Kidney Int 2018; 94:178.
  120. Chauvet S, Roumenina LT, Aucouturier P, et al. Both Monoclonal and Polyclonal Immunoglobulin Contingents Mediate Complement Activation in Monoclonal Gammopathy Associated-C3 Glomerulopathy. Front Immunol 2018; 9:2260.
  121. Nasr SH, Markowitz GS, Reddy BS, et al. Dysproteinemia, proteinuria, and glomerulonephritis. Kidney Int 2006; 69:772.
  122. Carstens PH, Woo D. Crystalline glomerular inclusions in multiple myeloma. Am J Kidney Dis 1989; 14:56.
  123. Akilesh S, Alem A, Nicosia RF. Combined crystalline podocytopathy and tubulopathy associated with multiple myeloma. Hum Pathol 2014; 45:875.
  124. Jeon YL, Lee WI, Choi Y, et al. Crystalloid podocytopathy with focal segmental glomerulosclerosis in PCM: a case report. Diagn Pathol 2015; 10:213.
  125. Fogo A, Qureshi N, Horn RG. Morphologic and clinical features of fibrillary glomerulonephritis versus immunotactoid glomerulopathy. Am J Kidney Dis 1993; 22:367.
  126. Nasr SH, Valeri AM, Cornell LD, et al. Fibrillary glomerulonephritis: a report of 66 cases from a single institution. Clin J Am Soc Nephrol 2011; 6:775.
  127. Bridoux F, Hugue V, Coldefy O, et al. Fibrillary glomerulonephritis and immunotactoid (microtubular) glomerulopathy are associated with distinct immunologic features. Kidney Int 2002; 62:1764.
  128. Iskandar SS, Falk RJ, Jennette JC. Clinical and pathologic features of fibrillary glomerulonephritis. Kidney Int 1992; 42:1401.
  129. Rosenstock JL, Markowitz GS, Valeri AM, et al. Fibrillary and immunotactoid glomerulonephritis: Distinct entities with different clinical and pathologic features. Kidney Int 2003; 63:1450.
  130. Pronovost PH, Brady HR, Gunning ME, et al. Clinical features, predictors of disease progression and results of renal transplantation in fibrillary/immunotactoid glomerulopathy. Nephrol Dial Transplant 1996; 11:837.
  131. Nasr SH, Fidler ME, Cornell LD, et al. Immunotactoid glomerulopathy: clinicopathologic and proteomic study. Nephrol Dial Transplant 2012; 27:4137.
  132. Andeen NK, Troxell ML, Riazy M, et al. Fibrillary Glomerulonephritis: Clinicopathologic Features and Atypical Cases from a Multi-Institutional Cohort. Clin J Am Soc Nephrol 2019; 14:1741.
  133. Said SM, Leung N, Alexander MP, et al. DNAJB9-positive monotypic fibrillary glomerulonephritis is not associated with monoclonal gammopathy in the vast majority of patients. Kidney Int 2020; 98:498.
  134. Maldonado JE, Velosa JA, Kyle RA, et al. Fanconi syndrome in adults. A manifestation of a latent form of myeloma. Am J Med 1975; 58:354.
  135. Rao DS, Parfitt AM, Villanueva AR, et al. Hypophosphatemic osteomalacia and adult Fanconi syndrome due to light-chain nephropathy. Another form of oncogenous osteomalacia. Am J Med 1987; 82:333.
  136. Ma CX, Lacy MQ, Rompala JF, et al. Acquired Fanconi syndrome is an indolent disorder in the absence of overt multiple myeloma. Blood 2004; 104:40.
  137. Leung N, Gertz M, Kyle RA, et al. Urinary albumin excretion patterns of patients with cast nephropathy and other monoclonal gammopathy-related kidney diseases. Clin J Am Soc Nephrol 2012; 7:1964.
  138. Royal V, Leung N, Troyanov S, et al. Clinicopathologic predictors of renal outcomes in light chain cast nephropathy: a multicenter retrospective study. Blood 2020; 135:1833.
  139. Soares SM, Fervenza FC, Lager DJ, et al. Bleeding complications after transcutaneous kidney biopsy in patients with systemic amyloidosis: single-center experience in 101 patients. Am J Kidney Dis 2008; 52:1079.
  140. Leung N, Nasr SH. A Patient with Abnormal Kidney Function and a Monoclonal Light Chain in the Urine. Clin J Am Soc Nephrol 2016; 11:1073.
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