Version May 2024
INTRODUCTION — The monoclonal immunoglobulin deposition diseases (MIDD) are a group of disorders characterized by linear deposition of monoclonal immunoglobulin along glomerular, tubular, and vascular wall basement membranes by kidney biopsy immunofluorescence.
Based on the type of monoclonal immunoglobulin deposits, MIDD are classified into three types:
●Light chain deposition disease (LCDD) – Deposits are composed of light chains only.
●Heavy chain deposition disease (HCDD) – Deposits are composed of heavy chains only.
●Light and heavy chain deposition disease (LHCDD) – Deposits are composed of both light and heavy chains.
The abnormal immunoglobulin components are secreted by an abnormal plasma cell or a lymphoplasmacytic neoplasm. These disorders must be distinguished from the more common plasma cell dyscrasia AL amyloidosis. Unlike AL amyloidosis, LCDD, HCDD, and LHCDD do not bind Congo red or thioflavine T.
MIDD will be reviewed here. An overview of the amyloid disorders, as well as the diagnosis, prognosis, and treatment of AL amyloidosis are discussed separately:
●(See "Overview of amyloidosis".)
●(See "Treatment and prognosis of immunoglobulin light chain (AL) amyloidosis".)
HCDD is a different disorder from the heavy chain disorders (alpha, gamma, and mu), which are rare B cell proliferative disorders characterized by the production of a monoclonal protein consisting of a portion of the immunoglobulin heavy chain without a bound light chain. The heavy chain disorders do not cause fibrillar or granular tissue deposits. These are also discussed separately:
●(See "The heavy chain diseases".)
DEFINITIONS AND CLASSIFICATION — MIDD are a group of disorders characterized by the accumulation of nonorganized (granular) deposits of intact or fragmented immunoglobulins that do not bind Congo red or thioflavine T in visceral and soft tissues resulting in organ damage. The abnormal immunoglobulin components are secreted by an abnormal plasma cell or, rarely, a lymphoplasmacytic neoplasm.
Based on the type of monoclonal immunoglobulin deposits, MIDD (also called Randall disease) are classified into three types:
●Light chain deposition disease (LCDD; approximately 80 percent of cases) – Deposits are composed of light chains only. In approximately 80 to 90 percent of LCDD, the light chains are kappa light chains.
●Heavy chain deposition disease (HCDD; approximately 10 percent of cases) – Deposits are composed of heavy chains only, typically truncated gamma chain, and rarely mu or alpha chains.
●Light and heavy chain deposition disease (LHCDD; approximately 10 percent of cases) – Deposits are composed of both light and heavy chains.
PATHOGENESIS — In MIDD, the light and heavy chain fragments are secreted by an abnormal plasma cell or a lymphoplasmacytic neoplasm and accumulate as granular deposits in visceral and soft tissues resulting in organ damage. Unlike in AL amyloidosis, the fragments of light and heavy chain deposition diseases do not have the necessary biochemical characteristics to form amyloid fibrils [1-4].
It is unclear what factors determine whether fibrillar or granular deposits will occur with a given monoclonal light chain and the distribution of disease. It is likely that the biochemical characteristics of the light chain are an important determinant of toxicity. This hypothesis is supported by the observation that the infusion of monoclonal light chains from affected patients into mice produces the same kidney disease (cast nephropathy, amyloid deposition, or lack of disease) in the mouse as was seen in the patient [5]. Furthermore, the light chains in AL amyloidosis, light chain deposition disease (LCDD), and myeloma cast nephropathy have been demonstrated to cause different transformations of human mesangial cells in vitro [6].
One property that appears to be important is the ability of the light chain to self-associate and form high molecular weight aggregates [7-9]. These aggregates in vivo would then lead to tissue deposits with or without fibril formation in AL amyloidosis and LCDD, respectively, or to cast formation in myeloma kidney [5].
In vitro studies suggest that the amino acid composition at specific sites and/or the net charge of the protein [10] may be an important determinant of amyloidogenic potential. Certain amino acids may facilitate unfolding of the light chain, which increases the likelihood of forming tissue aggregates [11]. In contrast, the affinity of binding to Tamm-Horsfall mucoprotein may be a determinant of the likelihood of developing cast nephropathy. (See "Kidney disease in multiple myeloma and other monoclonal gammopathies: Etiology and evaluation", section on 'Intratubular cast formation'.)
The sites of tissue deposition in AL amyloidosis and LCDD may be impacted by differences in the variable region of the monoclonal light chain (IGVL), the properties of the intact light chain, variations in light chain degradation, and the microenvironment [2,12-20]. As examples:
●Differences in IGVL – In a large cohort analysis that used mass spectrometry for tissue typing, IGVL gene usage was different in those with systemic versus localized AL amyloidosis, and patterns of tissue deposition (eg, kidney versus cardiac) correlated with certain IGVL gene usage [19]. Similarly, another study identified a high frequency of IGKV1-8 usage in cystic lung LCDD, a pattern not typically found in LCDD involving other organs [20].
●Variations in the microenvironment – In one study, a urinary paraprotein was isolated from a patient with AL amyloidosis. In vitro, this Bence Jones protein adopted a fibrillar conformation at acid pH but remained aggregated but not fibrillar at physiologic pH. Such variations in the microenvironment could explain the occasional deposition of both fibrillar and granular deposits in a single patient [2,17,18].
Differences in light chain metabolism could also explain why the combination of acute kidney injury due to myeloma light chain cast nephropathy and either AL amyloidosis or LCDD is unusual [2,3]. Tubular damage and tubular obstruction in myeloma kidney require the filtration of intact light chains, not the light chain fragments responsible for tissue deposition in amyloidosis or LCDD.
EPIDEMIOLOGY — The MIDD are uncommon and the exact incidence is unknown. Extrapolation of our experience at the Mayo center suggests that only a few hundred cases are diagnosed in the United States annually [21]. Most patients present in the fifth to sixth decade of life [22-24]. There is a male predominance with males accounting for 60 to 65 percent of patients.
MIDD can occur in association with another plasma cell dyscrasia (multiple myeloma, Waldenström macroglobulinemia) or, rarely, a B cell neoplasm (eg, chronic lymphocytic leukemia). In the absence of another disorder, they are classified as a monoclonal gammopathy of clinical significance (eg, monoclonal gammopathy of renal significance [MGRS]) [25,26]. In a nationwide cohort study of 255 patients with MIDD, the hematologic diagnosis was MGRS in 64 percent, symptomatic multiple myeloma in 34 percent, Waldenström macroglobulinemia in 1 percent, and chronic lymphocytic leukemia in 0.4 percent [22]. (See "Diagnosis and treatment of monoclonal gammopathy of renal significance" and "Clinical course and management of monoclonal gammopathy of undetermined significance", section on 'Monoclonal gammopathy of clinical significance'.)
CLINICAL PRESENTATION — MIDD are systemic disorders with prominent kidney involvement (up to 96 percent) and less frequent involvement of other organs, including the heart (21 percent), liver (19 percent), and peripheral nerves (8 percent) [23].
The clinical presentation of light chain deposition disease (LCDD) differs depending on the site of kidney involvement, which differs with the chain(s) involved. It typically presents as nephrotic syndrome and/or kidney function impairment [27], which frequently progresses to end-stage kidney disease requiring dialysis [22,28,29]. Patients with predominant glomerular deposition may present with nephrotic syndrome (similar to AL amyloidosis) [4], while those with predominant tubular deposition may present with kidney function impairment and relatively mild proteinuria [2]. In one series, patients with LCDD had, at the time of kidney biopsy, a higher plasma creatinine concentration (5.1 versus 2.4 mg/dL [451 versus 212 micromol/L]) and a lower rate of protein excretion (3.7 versus 6.9 g/day) than patients with AL amyloidosis [30].
Less frequently, patients present with liver involvement manifest as hepatomegaly and liver dysfunction, either alone or in combination with kidney involvement. Rarely, LCDD may involve the heart and lead to cardiomyopathy and heart failure or involve the peripheral nerves, salivary glands, gastrointestinal tract, and/or skin.
Heavy chain deposition disease (HCDD) and light and heavy chain deposition disease (LHCDD) have clinical characteristics that are similar to LCDD.
DIAGNOSIS — The diagnosis of MIDD requires the demonstration of aberrant immunoglobulin deposits on histologic evaluation of an affected organ (usually kidney) [31,32]. Tissue deposits can occur in the kidney (picture 1A-C), heart, liver (picture 2A-B), and gastrointestinal tract (picture 3).
The kidney biopsy shows distinctive findings in the glomeruli, interstitium, and vessels [4,28,33,34]:
●Light microscopy – On light microscopy, the glomeruli characteristically show nodule formation (nodular glomerulosclerosis) with features of membranoproliferative glomerulonephritis. The nodules are strongly periodic acid-Schiff (PAS) positive, trichrome-blue positive, and variably silver-positive. However, the pattern of injury may vary from mild mesangial expansion without nodule formation in early MIDD to crescentic glomerulonephritis. Another feature of MIDD is variable thickening, often called ribbon-like, of both the glomerular and tubular basement membranes. In addition, vessels show thickening of the walls by PAS-positive material; the material often surrounds myocytes. The extent of chronic changes can be variable from mild to severe with extensive global glomerulosclerosis, extensive tubular atrophy and interstitial fibrosis, and arteriosclerosis.
The monoclonal immunoglobulin deposits do not bind Congo red, thioflavine T, or serum amyloid P (SAP) component [1-3,35].
●Immunofluorescence microscopy – Immunofluorescence microscopy demonstrates linear staining of monoclonal immunoglobulin (most often kappa light chains) along the glomerular and tubular basement membranes and smudgy staining in the mesangium; staining is also present along the Bowman's capsule and along vessel walls. Tubular basement membrane staining is always present. Complement deposits of both C3 and C1q are often present in the mesangium and along glomerular and tubular basement membranes.
●Electron microscopy – Electron microscopy is diagnostic and shows punctate granular ("powdery") deposits in the mesangium and along the glomerular and tubular basement membranes. The deposits tend to occur along the rara interna of the glomerular basement membranes and the outer region of the tubular basement membranes. On occasion, it may be difficult to demonstrate the deposits on electron microscopy in spite of strong immunofluorescence staining for the monoclonal immunoglobulin.
MIDD can sometimes coexist with light chain cast nephropathy (myeloma kidney). In such cases, in addition to the biopsy findings of MIDD, distal tubules contain geometric, PAS-negative, fractured casts that stain positive for the pathogenic light chain.
Most patients with MIDD have evidence of a monoclonal plasma cell proliferative disorder as displayed by the presence of a serum or urine monoclonal (M) protein, an abnormal serum free light chain ratio, or clonal plasma cells in the bone marrow [27]. In some patients, routine electrophoretic techniques may not demonstrate a monoclonal protein in the serum or urine [36], but one is often detected using mass spectrometry or serum free light chain analysis. (See "Laboratory methods for analyzing monoclonal proteins".)
The bone marrow of patients with LCDD usually contains a population of monoclonal plasma cells (picture 4), expressing either kappa or lambda light chains (but not both). A subset of patients will meet diagnostic criteria for multiple myeloma or other conditions, such as lymphoma or Waldenström macroglobulinemia [3,28,37].
DIFFERENTIAL DIAGNOSIS — MIDD should be distinguished from amyloidosis because the clinical course and therapy are different.
In amyloidosis, the extracellular tissue deposits have a predominantly antiparallel beta-pleated sheet configuration (noted on x-ray diffraction) and can be identified on biopsy specimens both by their characteristic fibrillar appearance on electron microscopy and by their ability to bind Congo red (leading to green birefringence under polarized light) and thioflavine T (producing an intense yellow-green fluorescence). Importantly, immunofluorescence microscopy in AL amyloidosis does not show linear staining of monoclonal immunoglobulin along glomerular and tubular basement membranes as is observed in MIDD. These features distinguish amyloidosis from MIDD. (See "Clinical presentation, laboratory manifestations, and diagnosis of immunoglobulin light chain (AL) amyloidosis".)
The differential diagnosis of other causes of nodular glomerulosclerosis on kidney biopsy includes amyloidosis, diabetic glomerulosclerosis, and chronic thrombotic microangiopathy. The presence of bright, linear immunostaining of the monoclonal immunoglobulin and punctate powdery deposits along the glomerular and tubular basement membranes distinguishes MIDD; these features are absent in other causes of nodular glomerulosclerosis.
TREATMENT AND PROGNOSIS
Treatment and outcomes — Data on the treatment of MIDD are limited. The therapeutic approaches are similar to those employed for patients with multiple myeloma or B cell lymphoproliferative disorders. The goal is to control the plasma cell or B cell proliferative disorder in order to preserve kidney function and improve survival, using chemotherapy and, in selected cases, autologous hematopoietic cell transplantation (HCT) [4,27,38-44].
In general, the kidney is the main organ affected, and progression with involvement of other organs is less of a concern compared with AL amyloidosis. As such, the approach to treatment depends on whether the kidney damage is reversible or permanent.
●Recovery of kidney function is unlikely in patients with dialysis-dependent kidney failure lasting more than a few months, and in patients with imaging that indicates end-stage kidney disease (ie, small, scarred kidneys); for such patients, we suggest observation without plasma cell- or B cell-directed therapy.
●Other patients may recover kidney function, and for such patients we suggest therapy similar to that used for multiple myeloma or B cell lymphoproliferative disorders rather than observation. Treatment is continued until a good paraprotein response is achieved. (See "Multiple myeloma: Overview of management".)
Follow-up depends on the type of chain involved:
●In light chain deposition disease (LCDD), we monitor response to treatment using serial free light chain assays, 24 hour urine protein electrophoresis, and kidney function assessments [45].
●In heavy chain deposition disease (HCDD), we monitor response to therapy using the serum monoclonal protein levels on electrophoresis, and by monitoring 24 hour urine protein excretion and kidney function.
This approach is supported by retrospective studies and extrapolation of data from other plasma cell dyscrasias. In a nationwide cohort study of 255 patients with biopsy-proven LCDD and/or HCDD, 169 patients were treated with chemotherapy agents, including bortezomib (58 percent), alkylators (17 percent), thalidomide or lenalidomide (10 percent), doxorubicin (9.5 percent), rituximab (2.4 percent), or steroids alone (<1 percent) [22]. High-dose melphalan with autologous HCT was performed in 38 patients. The following were noted:
●The overall response rate was 67 percent, and 30 percent (50 patients) achieved a complete response (CR). Responses were higher among patients receiving bortezomib.
●After a median follow-up of 27 months, three-year kidney survival was 86 versus 62 percent in patients with and without very good partial response or complete response (VGPR/CR), respectively, and 91 versus 63 percent in kidney responders versus nonresponders.
●Median overall survival (OS) was shorter in patients with baseline estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m2 (65 months versus unreached in those with higher eGFR).
●Use of bortezomib was associated with higher response rates, better kidney survival rates, and improved OS.
In patients with MIDD, high-dose melphalan with autologous HCT has been associated with high rates of hematologic and kidney responses [22,40,46]. Whether incorporating autologous HCT improves on outcomes seen with bortezomib-based regimens alone is unclear. In one retrospective study, patients who received high-dose melphalan and autologous HCT were on average younger and had better kidney function at baseline than those treated with bortezomib-based regimens alone [46].
The anti-CD38 monoclonal antibody daratumumab may be effective for patients with refractory disease. In one series of eight patients with LCDD and multiple myeloma who were refractory to multiple lines of therapy, treatment with daratumumab resulted in a hematologic response in seven patients [47]. Two patients achieved a kidney response, four had stabilization or improvement of kidney function, and two progressed to end-stage kidney disease.
Kidney transplantation is associated with recurrence of LCDD in the transplanted kidney unless hematological remission is achieved prior to transplantation. As such, kidney transplantation should only be entertained if accompanied by chemotherapy or HCT to control the plasma cell or B cell proliferative disorder [38,42,43].
Prognostic factors — As with AL amyloidosis, the prognosis of MIDD vary considerably depending on the nature, number, and extent of organ involvement. In a study of 63 patients with LCDD, the following prognostic factors were determined [28]:
●Age and serum creatinine at presentation were the major predictive factors for the development of kidney failure.
●Age, presence of coexisting multiple myeloma, and evidence of extra-kidney light chain deposition were independent predictors of OS.
Further information regarding the impact on kidney function comes from a prospective study of 53 patients with LCDD followed for a median of 6.2 years [29]:
●Among the 43 patients who were not receiving dialysis at the time of diagnosis, GFR declined by a mean of 3.7 mL/min/year and 23 patients initiated dialysis at a median of 5.4 years from diagnosis.
●Kidney failure requiring dialysis was more common among those with more severe kidney impairment at the time of diagnosis (chronic kidney disease stage 4 or 5).
●Hematologic CR and VGPR after therapy were associated with improvements in GFR over time.
●Although treatment was not randomized and the number of patients was small, deeper responses were more common among those receiving proteasome inhibitor-based or alkylator-based therapy and among those who received melphalan plus autologous HCT when compared with those receiving immunomodulators or steroids.
These data suggest that better kidney outcomes may be achieved with early diagnosis and intervention with chemotherapy with or without HCT.
SUMMARY AND RECOMMENDATIONS
●Definitions – Monoclonal immunoglobulin deposition diseases (MIDD) are very rare plasma cell dyscrasias characterized by the accumulation of intact or fragmented abnormal immunoglobulin in visceral and soft tissues resulting in organ damage. The abnormal immunoglobulin components are secreted by an abnormal plasma cell or a lymphoplasmacytic neoplasm. (See 'Definitions and classification' above.)
Based on the type of monoclonal immunoglobulin deposits, MIDD are classified into three types:
•Light chain deposition disease (LCDD) – Deposits are composed of light chains only.
•Heavy chain deposition disease (HCDD) – Deposits are composed of heavy chains only.
•Light and heavy chain deposition disease (LHCDD) – Deposits are composed of both light and heavy chains.
●Epidemiology – MIDD are rare disorders usually presenting in the fifth to sixth decade of life. There is a male predominance. (See 'Epidemiology' above.)
MIDD can occur in association with another plasma cell dyscrasia (multiple myeloma, Waldenström macroglobulinemia) or, rarely, a B cell neoplasm (eg, chronic lymphocytic leukemia). In the absence of another disorder, they are classified as a monoclonal gammopathy of clinical significance (eg, monoclonal gammopathy of renal significance).
●Clinical presentation – MIDD are systemic disorders with prominent kidney involvement (up to 96 percent) and less frequent involvement of other organs, including the heart (21 percent), liver (19 percent), and peripheral nerves (8 percent). The clinical presentation reflects the site of involvement, which differs with the chain(s) involved. Most patients present with nephrotic syndrome and/or kidney impairment, which frequently progresses to end-stage kidney disease requiring dialysis. (See 'Clinical presentation' above.)
●Diagnosis – The diagnosis of MIDD requires the demonstration of aberrant immunoglobulin deposits on histologic evaluation of an affected organ (usually kidney). In contrast to amyloid deposits, these tissue deposits (see 'Diagnosis' above):
•Are granular, not fibrillar.
•Do not bind Congo red, thioflavine T, or serum amyloid P (SAP) component.
•Usually include the constant region of the immunoglobulin. As a result, immunofluorescence microscopy is typically strongly positive for the monoclonal light chain.
Kidney biopsy shows nodular glomerulosclerosis on light microscopy, linear staining for the monoclonal immunoglobulin on immunofluorescence microscopy, and punctate powdery deposits on electron microscopy along the glomerular and tubular basement membranes, as well as in the mesangium and vessel walls.
●Treatment – Treatment of MIDD targets the underlying plasma cell dyscrasia using therapies employed for patients with multiple myeloma. The goal is to control the plasma cell proliferative disorder in order to preserve kidney function and improve survival, using chemotherapy and, in selected cases, autologous hematopoietic cell transplantation (HCT).
In general, the kidney is the main organ affected, and progression with involvement of other organs is less of a concern compared with AL amyloidosis. As such, the approach to treatment depends on whether the kidney damage is reversible or permanent:
•Recovery of kidney function is unlikely in patients with dialysis-dependent kidney failure lasting more than a few months, and in patients with imaging that indicates end-stage kidney disease (ie, small, scarred kidneys); for such patients, we suggest observation without plasma cell- or B cell-directed therapy (Grade 2C). (See 'Treatment and prognosis' above.)
•Other patients may recover kidney function, and for such patients we suggest clone-directed therapy similar to that used for multiple myeloma or B cell lymphoproliferative disorders rather than observation (Grade 2C). Treatment is continued until a good paraprotein response is achieved. (See "Multiple myeloma: Overview of management".)
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