Version July 2025
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 thioflavin 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 thioflavin 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 the unfolding of the light chain, which increases the likelihood of forming tissue aggregates [11]. By 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 Clinic 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 who 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
When to suspect the diagnosis — The diagnosis of MIDD should be suspected in the following patients:
●All patients with a monoclonal gammopathy who present with unexplained kidney function impairment and/or proteinuria. The general approach to evaluating such patients is presented separately. (See "Kidney disease in multiple myeloma and other monoclonal gammopathies: Etiology and evaluation", section on 'Evaluation'.)
●All patients who present with unexplained kidney function impairment and/or proteinuria and are found to have a monoclonal gammopathy (ie, by serum or urine protein electrophoresis or immunofixation or by serum free light chain [FLC] assay) during their evaluation of kidney disease.
Establishing the 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). In most patients suspected of having MIDD, we usually perform a kidney biopsy unless contraindicated.
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, thioflavin 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 despite 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.
Evaluation to identify an underlying clone — The presence of monoclonal immunoglobulin deposits in the kidney indicates the existence of a plasma cell, lymphoplasmacytic, or B cell clone that is responsible for the production of the monoclonal protein. Patients with a confirmed diagnosis of MIDD should undergo further evaluation to characterize this clone to guide appropriate therapy.
In patients with MIDD, we perform the following evaluation, if not yet completed:
●Monoclonal protein testing – We perform a serum protein electrophoresis and immunofixation (or MALDI-TOF mass spectrometry [Mass-Fix]), 24-hour urine protein electrophoresis and immunofixation, and serum FLC assay. The combination of these studies maximizes the sensitivity of detecting a monoclonal protein, especially in patients with a small clone that may produce low levels of circulating monoclonal protein [36]. Most patients with MIDD have evidence of a monoclonal plasma cell proliferative disorder as displayed by the presence of a serum or urine monoclonal protein, an abnormal serum FLC ratio, or clonal plasma cells in the bone marrow [27]. The circulating monoclonal protein, if detected, must match the type of monoclonal protein present within the kidney deposits. Identifying a serum or urine monoclonal protein, if present, is also important in monitoring the response to therapy. (See "Laboratory methods for analyzing monoclonal proteins" and 'Monitoring response to therapy' below.)
●Bone marrow aspirate and biopsy – Analysis of the bone marrow should include immunohistochemistry and flow cytometry for surface and intracellular markers of plasma cells and B cells. In addition, staining for kappa and lambda light chains should be performed to demonstrate that an identified clone exhibits the same light chain restriction as the monoclonal deposits in the kidney. Cytogenetic and fluorescence in situ hybridization analysis are increasingly used to help direct therapy and may be helpful in some cases.
The bone marrow of patients with light chain deposition disease 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 (table 1) or other conditions, such as lymphoma or Waldenström macroglobulinemia [3,28,37].
●Imaging – In patients who do not have a detectable clone with the above testing or who have an immunoglobulin M (IgM) monoclonal protein, we perform computed tomography (CT) of the abdomen and pelvis or whole-body positron emission tomography (PET)/CT (if available) to evaluate for lymphadenopathy (which may be due to underlying lymphoma, including Waldenström macroglobulinemia). Biopsy of enlarged lymph nodes may identify the responsible clone. In patients with a non-IgM monoclonal protein, we perform whole-body CT, PET/CT, or magnetic resonance imaging (MRI) to evaluate for bone lesions (which may be due to underlying multiple myeloma).
●Peripheral blood flow cytometry – In patients who do not have a detectable clone with the above testing, we perform flow cytometry of peripheral blood lymphocytes, which can detect small, low-grade clones, such as those in chronic lymphocytic leukemia or monoclonal B cell lymphocytosis.
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 thioflavin 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 —
In general, the kidney is the main organ affected in patients with MIDD, and progression with involvement of other organs is less of a concern compared with AL amyloidosis. Treatment consists of providing general supportive measures for kidney disease and administering clone-directed chemotherapy to target the pathologic plasma, lymphoplasmacytic, or B cell population responsible for producing the monoclonal protein.
Supportive measures for kidney disease — All patients with MIDD should receive general supportive measures for kidney disease, including dietary sodium and protein restriction, blood pressure control, minimization of proteinuria with renin-angiotensin system inhibition, and treatment of dyslipidemia (if present). Sodium-glucose cotransporter 2 (SGLT2) inhibitors may also be of benefit, although studies in patients with MIDD are lacking. These issues are discussed in greater detail elsewhere:
●Dietary sodium and protein restriction. (See "Dietary recommendations for patients with nondialysis chronic kidney disease", section on 'Salt intake' and "Dietary recommendations for patients with nondialysis chronic kidney disease", section on 'Protein intake'.)
●Antihypertensive therapy. (See "Antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults".)
●Renin-angiotensin system inhibition. (See "Antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults", section on 'Renin-angiotensin system inhibitors'.)
●SGLT2 inhibitors. (See "Overview of the management of chronic kidney disease in adults", section on 'Patients with albuminuria'.)
●Lipid lowering. (See "Overview of the management of chronic kidney disease in adults", section on 'Dyslipidemia'.)
Initial clone-directed therapy — Patients with MIDD are at risk for progressive kidney disease and should be treated to prevent further kidney damage and decline of kidney function. This treatment focuses on eradication of the pathologic clone in these patients.
Detectable clone — For most patients with MIDD who have a detectable pathologic plasma, lymphoplasmacytic, or B cell clone, we suggest treatment with clone-directed chemotherapy (algorithm 1). The goal is to control the clonal disorder to preserve kidney function and improve survival. An exception is in patients who have advanced chronic kidney disease (CKD) or end-stage kidney disease (ESKD), in whom recovery of kidney function is unlikely with clone-directed chemotherapy. We generally observe such patients and prepare them for kidney replacement therapy. (See 'End-stage kidney disease' below.)
The selection of clone-directed therapy is based upon the nature of the detected clone (see 'Evaluation to identify an underlying clone' above):
●Plasma cell clone – In patients with a detectable plasma cell clone, we administer a treatment regimen that consists of agents used to treat multiple myeloma. Preferred options include monotherapy with an anti-CD38 monoclonal antibody (eg, daratumumab); triplet therapy with bortezomib, cyclophosphamide, and dexamethasone (VCd); or glucocorticoids alone (for select patients). In general, the intensity of therapy is less than that used for multiple myeloma. The choice of therapy depends on access and availability, especially with daratumumab, which is not approved or covered for this indication. We prefer daratumumab, if possible, and reserve VCd for those not able to access or receive daratumumab. Glucocorticoids alone are only used for patients who have issues with access or tolerance to daratumumab and VCd. (See "Multiple myeloma: Initial treatment".)
Dosing and administration of therapies used for multiple myeloma can be complicated, often requiring dose adjustments and adjunctive therapies. Administration considerations are discussed separately. (See "Multiple myeloma: Administration considerations for common therapies", section on 'Anti-CD38 monoclonal antibodies'.)
●Lymphoplasmacytic or B cell clone – In patients with a detectable lymphoplasmacytic or B cell clone, we administer a treatment regimen that consists of agents used to treat Waldenström macroglobulinemia. Preferred options include monotherapy with an anti-CD20 monoclonal antibody (rituximab, obinutuzumab); combination therapy with rituximab, cyclophosphamide, and dexamethasone (RCd); or glucocorticoids alone (for select patients). In general, the intensity of therapy is less than that used for Waldenström macroglobulinemia. The choice of therapy depends on access and availability. We prefer an anti-CD20 monoclonal antibody as initial therapy for most patients and reserve combination therapy for patients who are refractory. Glucocorticoids alone are only used for patients who have issues with access or tolerance to our preferred regimens. (See "Treatment and prognosis of Waldenström macroglobulinemia", section on 'Choice of initial therapy'.)
Major toxicities of anti-CD20 monoclonal antibodies include infusion reactions, infections related to immunosuppression, and hepatitis B virus reactivation among patients positive for hepatitis B surface antigen (HBsAg) or antibodies against hepatitis B core antigen (anti-HBc). These toxicities and potential prophylaxis for Pneumocystic pneumonia are discussed separately. (See "Secondary immunodeficiency induced by biologic therapies" and "Infusion-related reactions to monoclonal antibodies for cancer therapy" and "Hepatitis B virus reactivation associated with immunosuppressive therapy" and "Treatment and prevention of Pneumocystis pneumonia in patients without HIV".)
The optimal duration of clone-directed therapy is uncertain. In general, we aim for a limited duration of approximately six months and then follow the patient by observation. Patients who have not responded after six months of initial therapy may require modification of their treatment regimen. (See 'Monitoring response to therapy' below and 'Resistant disease' below.)
There is no high-quality evidence to guide the optimal therapy of patients with MIDD and a detectable clone. Supportive data come primarily from retrospective studies as well as extrapolation of data from other plasma cell dyscrasias [4,22,27,38-44].
Limited data describe outcomes in patients treated with older regimens. Outcomes are likely to be better with modern therapy, which achieves deeper responses. In a cohort study of patients with biopsy-proven light chain deposition disease (LCDD) and/or heavy chain deposition disease (HCDD) treated with older regimens, 67 percent achieved a response and 30 percent achieved a complete response [22]. Deeper responses were associated with higher rates of kidney survival at three years (86 versus 62 percent in patients with and without very good partial response or complete response, respectively). The use of bortezomib was associated with higher response rates, better kidney survival rates, and improved overall survival.
In patients with MIDD who are considered transplant-eligible, high-dose melphalan with autologous hematopoietic cell transplantation (HCT) has been associated with high rates of hematologic and kidney responses [22,40,45-47]. Whether incorporating autologous HCT improves outcomes seen with modern triplet and quadruplet myeloma regimens is unclear, and hence may not be necessary if an excellent response is already achieved with standard triplet or quadruplet therapy.
No detectable clone — In rare patients with MIDD who do not have a detectable plasma, lymphoplasmacytic, or B cell clone, our approach depends upon the presence or absence of a detectable monoclonal protein in the serum or urine (algorithm 1). There is no high-quality evidence to guide the optimal therapy in these patients, and our approach is based on our clinical experience.
●Detectable monoclonal protein in the serum or urine – In patients with MIDD who do not have a detectable clone but have monoclonal immunoglobulin deposition in the kidney and a monoclonal protein of the same isotype detectable in the serum or urine, there is evidence to support a causal relationship between the circulating monoclonal protein and the lesion of MIDD on kidney biopsy. We treat such patients with chemotherapy to target the "hypothesized clone" responsible for generating the monoclonal protein. An exception is in patients who have advanced CKD or ESKD, in whom recovery of kidney function is unlikely with clone-directed chemotherapy. We generally observe such patients and prepare them for kidney replacement therapy.
As the clone itself has not been identified in these patients, the choice of therapy depends on the isotype of the monoclonal immunoglobulin detected in the serum (or urine) and kidney:
•In patients who have a non-IgM type (eg, immunoglobulin G or A [IgG] or [IgA]) monoclonal protein in the serum (or urine) and kidney, we treat with a regimen like that used to treat patients with MIDD and a detectable plasma cell clone. (See 'Detectable clone' above.)
•In patients who have an IgM monoclonal protein in the serum (or urine) and kidney, we treat with a regimen like that used to treat patients with MIDD and a detectable lymphoplasmacytic or B cell clone. (See 'Detectable clone' above.)
The optimal duration of clone-directed therapy is uncertain. In general, we aim for a limited duration of approximately six months and then follow the patient by observation. Patients who have not responded after six months of initial therapy may require modification of their treatment regimen. (See 'Monitoring response to therapy' below and 'Resistant disease' below.)
●No detectable monoclonal protein in the serum or urine – In patients who have monoclonal immunoglobulin deposition in the kidney but no detectable clone and no detectable monoclonal protein in the serum or urine, the decision to treat with chemotherapy is more challenging since there is no clear evidence that a pathologic clone is responsible for the kidney disease.
•In patients who present with kidney function impairment or significant proteinuria (≥1 g/day), we prefer to initiate clone-directed chemotherapy. An exception is in patients who have advanced CKD or ESKD, in whom recovery of kidney function is unlikely with clone-directed chemotherapy. We generally observe such patients and prepare them for kidney replacement therapy. Our approach to selecting a regimen is as follows:
-For patients with non-IgM (eg, IgG or IgA) monoclonal protein deposits in the kidney, we would administer plasma cell-directed therapy with an anti-CD38 monoclonal antibody (eg, daratumumab).
Issues regarding administration of anti-CD38 monoclonal antibodies are discussed separately. (See "Multiple myeloma: Administration considerations for common therapies", section on 'Anti-CD38 monoclonal antibodies'.)
-For patients who have IgM monoclonal protein deposits in the kidney, we would administer B cell-directed therapy with an anti-CD20 monoclonal antibody (rituximab, obinutuzumab). We prefer these agents in this setting because most IgM-producing cells are CD20 positive.
Major toxicities of anti-CD20 monoclonal antibodies include infusion reactions, infections related to immunosuppression, and hepatitis B virus reactivation. These toxicities and potential prophylaxis for Pneumocystic pneumonia are discussed separately. (See "Secondary immunodeficiency induced by biologic therapies" and "Infusion-related reactions to monoclonal antibodies for cancer therapy" and "Hepatitis B virus reactivation associated with immunosuppressive therapy" and "Treatment and prevention of Pneumocystis pneumonia in patients without HIV".)
•In patients with normal kidney function and proteinuria <1 g/day, we prefer a more conservative approach. We treat with antiproteinuric therapy (angiotensin-converting enzyme [ACE] inhibitors or angiotensin receptor blockers [ARBs]) and blood pressure control. In patients who develop worsening proteinuria or kidney function, a trial of clone-directed therapy as discussed above is reasonable.
The optimal duration of clone-directed therapy is uncertain. In general, we aim for a limited duration of approximately six months and then follow the patient by observation. Patients who have not responded after six months of initial therapy may require modification of their treatment regimen. (See 'Monitoring response to therapy' below and 'Resistant disease' below.)
Monitoring response to therapy — All patients undergoing active treatment should be closely monitored for their response to therapy. We obtain the following studies monthly to monitor both the hematologic and renal response to therapy:
●Monoclonal protein testing – In patients with LCDD or light and heavy chain deposition disease (LHCDD), we monitor the hematologic response with serial free light chain assays and a 24-hour urine protein electrophoresis. In patients with HCDD, we use serial monoclonal protein levels on serum protein electrophoresis and a 24-hour urine protein electrophoresis.
The laboratory should be notified if the patient has received a therapeutic monoclonal antibody (eg, daratumumab, isatuximab). IgG kappa monoclonal antibodies like these may be detected on serum protein electrophoresis and immunofixation assays, or by serum mass spectrometry. The laboratory may be able to modify the assay or use another assay to better estimate the monoclonal protein level in this scenario.
●24-hour urine protein excretion.
●Serum creatinine (and estimated glomerular filtration rate [eGFR]).
●Serum albumin (in patients with the nephrotic syndrome).
In patients who have completed active treatment, we obtain these studies every two to three months.
Rarely, patients with MIDD do not have detectable circulating monoclonal proteins at baseline. In such patients, it is not possible to assess a hematologic response, and serum creatinine and quantification of proteinuria may be the only parameters that can be used to monitor the response to therapy. Nevertheless, we continue to monitor monoclonal protein studies as described above because some monoclonal proteins that are initially undetectable may be detectable later in the course of the disease. (See 'No detectable clone' above.)
Resistant disease — Patients who do not respond to initial clone-directed therapy after six months of treatment may require modification of their regimen. We typically switch to a different regimen that targets the same type of clone. As an example, in a patient with MIDD and a detectable plasma cell clone who did not respond to initial therapy with daratumumab, we might treat with VCd for six months. There is no uniform approach to modifying therapy, and the choice of regimen must be individualized.
End-stage kidney disease — In patients with MIDD who develop ESKD, the goal of therapy is no longer to preserve kidney function. We generally do not treat such patients with clone-directed therapy unless they are candidates for kidney transplantation.
Dialysis and kidney transplantation are potential options for patients with ESKD. Kidney transplantation is associated with the recurrence of MIDD in the transplanted kidney unless hematologic remission is achieved prior to transplantation. As such, kidney transplantation should only be considered if preceded by adequate chemotherapy or HCT to control the plasma cell, lymphoplasmacytic, or B cell proliferative disorder [38,42,43].
PROGNOSIS —
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 light chain deposition disease (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 overall survival.
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, glomerular filtration rate (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 complete response and very good partial response 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 hematopoietic cell transplantation (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 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, lymphoplasmacytic, or B cell clonal population. (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.
●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 (ESKD) requiring dialysis. (See 'Clinical presentation' above.)
●Diagnosis – The diagnosis of MIDD should be suspected in patients with a monoclonal gammopathy who have unexplained kidney function impairment and/or proteinuria. In most patients suspected of having MIDD, we perform a kidney biopsy to confirm the diagnosis, unless contraindicated. 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. (See 'When to suspect the diagnosis' above and 'Establishing the diagnosis' above.)
Patients with confirmed MIDD should undergo further evaluation to look for a pathologic plasma, lymphoplasmacytic, or B cell clone. (See 'Evaluation to identify an underlying clone' above.)
●Treatment – Treatment consists of providing general supportive measures for kidney disease and administering clone-directed chemotherapy to target the pathologic plasma, lymphoplasmacytic, or B cell population responsible for producing the monoclonal protein (algorithm 1). (See 'Supportive measures for kidney disease' above.)
•Detectable clone – For most patients who have a detectable pathologic plasma, lymphoplasmacytic, or B cell clone, we suggest treatment with clone-directed chemotherapy rather than nonclone-directed immunosuppressive therapy or conservative therapy (Grade 2C). An exception is in patients who have advanced chronic kidney disease (CKD) or ESKD, in whom recovery of kidney function is unlikely with clone-directed chemotherapy. The selection of clone-directed therapy is based upon the nature of the detected clone. (See 'Detectable clone' above.)
•No detectable clone – In rare patients with MIDD who do not have a detectable plasma, lymphoplasmacytic, or B cell clone, our approach depends upon the presence or absence of a detectable monoclonal protein in the serum or urine. (See 'No detectable clone' above.)
-For patients who have no detectable clone but have monoclonal immunoglobulin deposition in the kidney and a monoclonal protein of the same isotype in the serum or urine, we suggest clone-directed therapy rather than nonclone-directed immunosuppressive therapy or conservative therapy (Grade 2C). An exception is in patients who have advanced CKD or ESKD, in whom recovery of kidney function is unlikely with clone-directed chemotherapy. The choice of therapy depends on the isotype of the monoclonal immunoglobulin detected in the serum (or urine) and kidney.
-For patients who have no detectable clone and no detectable monoclonal protein in the serum or urine, the decision to treat with chemotherapy is more challenging since there is no clear evidence that a pathologic clone is responsible for the kidney disease. In patients who present with kidney function impairment or significant proteinuria (≥1 g/day), we suggest clone-directed chemotherapy based on the MIDD lesion on kidney biopsy (Grade 2C). For those with normal kidney function and proteinuria <1 g/day, we prefer a more conservative approach and suggest treating with antiproteinuric therapy and blood pressure control alone (Grade 2C).
