Non-amyloid Monoclonal Immunoglobulin-Related Diseases

Non-amyloid Monoclonal Immunoglobulin-Related Diseases

Virginie Royal

Sabine Karam

Nelson Leung


Monoclonal gammopathy refers to the presence of a monoclonal protein detected in the plasma and/or urine, which is produced most often by clonal plasma cells and less commonly by B cells or lymphoplasmacytic cells.1 The M protein is present as a monoclonal immunoglobulin (MIg) in its intact form or as fragments and hence may be made of a monoclonal light chain or heavy chain.2 Hematologic malignancies such as multiple myeloma (MM) or chronic lymphocytic leukemia (CLL) are traditionally defined and classified according to the clonal mass and end-organ damage due to the tumor burden. For instance, MM is defined by at least 10% bone marrow infiltration by plasma cells or a monoclonal spike of more than 3 g/dL, as well as end-organ damage as defined by the CRAB criteria (hypercalcemia, kidney insufficiency, anemia, and bone lesions). In addition, three biomarkers can be considered synonymous with symptomatic myeloma (>60% bone marrow plasma cells, involved to uninvolved serum free light-chain ratio >100 with the level of the involved free light chain >10 mg/dL, and >1 bone lesion on magnetic resonance imaging).3 However, there exists a group of kidney diseases with monoclonal gammopathy that does not fulfill the criteria for hematologic malignancy, but in which the kidney damage is considered secondary to nephrotoxic properties of the monoclonal protein rather than the tumor mass. This group of diseases was named monoclonal gammopathy of renal significance (MGRS) in 2012 by the International Kidney and Monoclonal Gammopathy (IKMG) research group.4 Clinically, kidney diseases caused by MIg manifest with variable degrees of proteinuria, hematuria, and reduced glomerular filtration rate (GFR). The diagnosis is ultimately made through a kidney biopsy. A wide range of pathologic lesions exists. They can be classified based on the site or composition of deposition of MIg or according to histologic and ultrastructural findings.5 This chapter addresses the most common types of glomerular kidney diseases caused by MIg (Table 15.1 and Figure 15.1) except for immunoglobulin light chain (AL) amyloidosis, which is discussed in Chapter 14. The ultrastructural findings and clinical manifestations of the most common lesions will be reviewed along with general principles of management related to the underlying clone.


Monoclonal Immunoglobulin Deposition Disease

Monoclonal immunoglobulin deposition disease (MIDD) is a group of kidney diseases characterized by the nonorganized deposition of MIg or its components. The deposits are often referred to as Randall-type deposits (amorphous or granular and non-Congophilic) in reference to Dr. Randall, who first reported cases of nodular glomerulopathy in patients with nondiabetic myeloma.6 There are three subtypes that are determined by the immunoglobulin component deposited. Light-chain deposition disease (LCDD) is characterized by monoclonal immunoglobulin light-chain deposits and is the most common which makes up more than 80% of cases of MIDD.7,8 A κ light chain is responsible for more than 80% of cases of LCDD. When the deposits are composed of the entire immunoglobulin, it is called light-heavy chain deposition disease (LCHDD). Heavy-chain deposition disease (HCDD) is characterized by truncated immunoglobulin heavy chain, most often missing the CH1 portion making it incapable of binding the light chain.9 LCHDD and HCDD occur with similar frequencies. MIDD can occur with other lesions associated with monoclonal proteins. The most common is
light-chain cast nephropathy, which is found in about 20% of cases.7,10,11 Amyloid deposits have also been reported.

The clinical presentation of MIDD is dependent on the pathology. In pure MIDD, patients often present with heavy proteinuria (median 1.8-4.1 g/d), with nephrotic syndrome reported in 23%.7,8,12 Kidney function impairment is severe. The average serum creatinine at presentation ranges from 2.6 to 3.9 mg/dL. Severe acute kidney injury requiring dialysis is more common in patients with combined MIDD and light-chain cast nephropathy.10,13 Hypertension is present in 55% to 80% of patients. Extrarenal manifestations have been reported in the heart, liver, and brain.7,8 Liver involvement usually manifests as elevated transaminases and hepatomegaly. Heart involvement shares many features with immunoglobulin light-chain (AL) amyloidosis, including elevation of N-terminal pro b-type natriuretic peptide, increased septal thickness, diastolic dysfunction, and atrial arrhythmia.14 Patients with cardiac involvement have a poorer prognosis than those without.

The diagnosis of MIDD is noted on 0.5% to 0.7% of kidney biopsies on native kidneys.8,10 Median age of diagnosis is between 56 and 64 years, with a slight male predominance.7,8,10,12,14 The hematologic condition most commonly associated with MIDD is MGRS in nearly 2/3 of patients.7,15 MM is diagnosed in about 1/3 of patients whereas Waldenstrom macroglobulinemia (3%) and CLL (1%) make up the majority of the B-cell lymphoproliferative disorders.

The characteristic kidney biopsy findings of MIDD include diffuse mesangial expansion, often forming nodules (Figure 15.2). The nodular glomerulosclerosis is found in virtually all cases of HCDD, and the majority of LCDD.7,8,10 Mesangial expansion and nodules are usually periodic acid-Schiff (PAS) positive, non-argyrophilic, and negative on Congo red stain. It is often accompanied by mild mesangial hypercellularity. Tubular involvement consists of basement membrane thickening that is usually mild and sometimes prominent, resulting in a ribbon-like appearance. Importantly, some cases may present with predominant tubular involvement without significant glomerular alterations.16 Rarely, interstitial deposition of PAS-positive material may be seen (Figure 15.3A). Vascular involvement is characterized by the deposition of PAS-positive material in
vascular walls, replacing or surrounding the myocytes (Figure 15.3B). Immunofluorescence shows diffuse linear staining along the basement membranes, corresponding to the involved immunoglobulin chain; it is always present along the tubular basement membranes and frequent along glomerular basement membranes and mesangium (Figure 15.4A). When vascular involvement is present, staining around arteriolar myocytes is observed. Associated deposits of complement components C3 and C1q may be present more frequently in HCDD. Electron microscopy reveals characteristic powdery, granular deposits along the inner aspect of the glomerular basement membrane and the outer aspect of the tubular basement membrane that can be segmental (Figure 15.4B). Expanded mesangial areas by nonorganized deposits are more frequent in HCDD. A subset of patients may present with MIDD by immunofluorescence only. Those are characterized
by linear staining by immunofluorescence, without the characteristic light microscopy and electron microscopy findings. Most of these cases are seen in the context of a combined diagnosis with light-chain cast nephropathy. The significance of this finding is not entirely defined but may represent an early stage of the disease.17

Proliferative Glomerulonephritis With Monoclonal Immunoglobulin Deposits

Proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID) is a disease limited to the kidneys, characterized by deposits of entire monoclonal immunoglobulin.18 The incidence of this disease is unknown. In one retrospective analysis, PGNMID was the second most frequent finding among patients with MGRS (the most common being AL amyloidosis).19 The most common immunoglobulin is IgG3 κ which accounts for half the cases.20 IgG3 λ deposits make up another 15% of cases. IgA and IgM variants can occur.21 More recently, a light-chain-only variant was noted.22 The hematologic characteristics of PGNMID are unusual among the MGRS-related diseases in that a circulating monoclonal protein is detectable in less than 30% of patients.20,21 On the other hand, the monoclonal protein detection rate is more than 80% in the patients with the light-chain-only variant.22 The odds of detecting the pathologic clone are dependent on whether the circulating monoclonal protein can be isolated by the traditional laboratory methods.21 In patients whose serum and urine immunofixation are negative, the clonal detection rate is less than 5%. The clonal detection is also higher in the patients with the light-chain-only variant reaching nearly 90%.22 Of the clones identified, 50% are plasma cell in origin, and 50% are B-cell expressing CD20.21,23 Nearly half of the CD20+ clones also coexpress CD138, consistent with a lymphoplasmacytic lymphocyte. Only 4% of patients present with MM, but progression to MM has been described.24

The incidence of PGNMID is not known, but a recent study suggests it is less common than AL amyloidosis but more common than MIDD.19 The average age at diagnosis is in the mid to late 50s, although the range is from 20 to 81.20,23,25 Patients with light-chain-only variant are slightly older with a median age of 62 years. Studies suggest PGNMID occurs equally between men and women.18,20,21,22,23,25 Median proteinuria range between 3.6 and 5.7 g/d, with half of the patients diagnosed with nephrotic syndrome. Microscopic hematuria and hypertension are also common. Kidney impairment is moderately severe, with average presenting eGFR in the mid-30s. Hypocomplementemia is seen in 10% of the patients but is more common in the light-chain-only variant.20,22 Prognosis of the early patients was poor, 37.5% recovered kidney function, 37.5% developed persistent kidney dysfunction, and 22% progressed to end-stage kidney disease.20 More recent experience suggests kidney response can be achieved with treatment, notably with clone-directed therapy. Factors associated with inferior kidney response include a baseline eGFR less than 20 mL/min/1.73 m2 and severe interstitial fibrosis.

Recurrence is common in patients with PGNMID who undergo kidney transplantation. One study found a recurrence rate of 86% with a median time to recurrence of less than 6 months.25 In this study, 44% of allografts were lost at a median time of 36 months after diagnosis, and the majority was due to recurrence. Recurrence is manifested clinically as allograft dysfunction and proteinuria. Nearly all patients experienced proteinuria greater than 1 g/d and hematuria. The diagnosis of recurrence was made by protocol biopsy in 27% of patients who were asymptomatic. A thorough hematologic workup should be performed if patients presenting with kidney impairment and hematuria are found to have monoclonal Ig deposits with proliferative glomerulonephritis on biopsy.

The defining histopathologic features of PGNMID include a proliferative pattern of injury by light microscopy, glomerular deposits composed of an entire monoclonal immunoglobulin by immunofluorescence, and nonorganized deposits by electron microscopy.18,20 A membranoproliferative pattern is seen in nearly half of the patients (Figure 15.5). A diffuse endocapillary or mesangioproliferative pattern, or a mix of these patterns, can also be observed. Focal cellular crescents are reported in a minority of patients. Deposits may be present on the outer aspect of the glomerular basement membrane, resulting in a membranous pattern. Immunofluorescence shows granular staining of the mesangium and capillary walls, with fixation for a single heavy chain and a single light chain. When an IgG is involved, IgG subclasses demonstrate fixation for a single IgG subclass, most commonly IgG3 (Figure 15.6). Immunofluorescence studies using antibodies for heavy chain/light chain may provide additional evidence of the monoclonal nature of the deposits.26 Exceptionally, immunofluorescence shows staining for a single light chain, corresponding to the rare light-chain-only variant.22 Electron microscopy typically shows nonorganized “immune-type” electron-dense deposits found in the mesangium and subendothelial, sometimes subepithelial, location (Figure 15.7).

Immunotactoid Glomerulopathy

Immunotactoid glomerulopathy is rare nephropathy associated with microtubular deposits. Studies suggest immunotactoid glomerulopathy accounts for 0.04% to 0.06% of kidney biopsies.27,28 In the literature, it may also be referred to as glomerulonephritis with organized microtubular monoclonal immunoglobulin deposits.29 Immunotactoid glomerulopathy can be distinguished from amyloidosis and fibrillary glomerulonephritis by the size and structure of the microtubules on electron microscopy and by its inability to bind either Congo red or Dnaj heat-shock protein family member B9 (DNAJB9).28 The microtubular deposits appear to be confined to the kidney.

Median age of presentation is in the early 60s, with equal proportions of men and women. Proteinuria is heavy (median 6.6 g/d), and most have a nephrotic syndrome or microhematuria.28 Kidney impairment is modest, with a median

creatinine of 1.6 mg/dL. Results of a large multicenter cohort showed 1/3 of the cases to be secondary to polyclonal IgG whereas 2/3 are owing to monoclonal gammopathy. The most common hematologic condition is lymphoma, especially CLL, which is found in up to half of the patients.30,31 MGRS accounts for 15% to 20% of cases.28 End-stage kidney disease (ESKD) is reported in approximately 25% of patients with immunotactoid glomerulonephritis.28,30 Interestingly, patients with immunotactoid glomerulopathy secondary to CLL or MGRS were found significantly less likely (11% vs 53% respectively, P < .01) to develop ESKD as compared to patients with immunotactoid glomerulopathy due to other causes.28 One explanation may be due to patients with CLL and MGRS being much more likely to be treated with clone-directed therapy.30

Kidney biopsy findings in the monoclonal and polyclonal variants of immunotactoid glomerulopathy are identical by light microscopy and electron microscopy. Only immunofluorescence findings differ between those two forms of the disease; the monoclonal variant demonstrating fixation for a monotypic IgG in most cases, more frequently composed of an IgG1 subclass.28 Detailed kidney biopsy findings of immunotactoid glomerulopathy are described in Chapter 9.

Cryoglobulinemia Glomerulonephritis

Cryoglobulinemia is a complication of temperature-sensitive immunoglobulins that precipitate in cooler temperatures.32 Three types of cryoglobulins have been described, and they are characterized by the nature of the immunoglobulins (Table 15.2). Type I is composed of monoclonal immunoglobulin and is most commonly comprised of IgM but can also be IgG, IgA, and rarely immunoglobulin light chain.33 Type II is a mixed cryoglobulin composed typically of a monoclonal IgM against polyclonal IgG (rheumatoid factor), although monoclonal IgA and IgG have been described. Type III is also mixed, but it is made up of polyclonal IgG or IgM against polyclonal IgG. For the purpose of this chapter, only cryoglobulins secondary to a clonal disorder (type I and some type II) will be discussed.

Cryoglobulinemia is a systemic disease. The most common manifestations involve hyperviscosity syndrome and cryoglobulinemia vasculitis.32 Purpura is the most common sign occurring in approximately 55% of patients.33,34,35 Other skin manifestations include the Raynaud phenomenon, acrocyanosis, digital
ischemia, and ulcers.36 Peripheral neuropathy and arthralgia are other common extrarenal manifestations, whereas abdominal pain is a rarer complication. Approximately 20% to 30% of patients will present or develop kidney involvement during the course of their disease.32,33,34,35 Patients with type II cryoglobulinemia are more likely to present with kidney manifestations whereas it is the least common in type III. Nephrotic syndrome is slightly more common than nephritic syndrome (21% vs 14%, respectively).35 Median creatinine and proteinuria at presentation are 3.6 mg/dL and 4 g/d, respectively. Hypertension is common and often difficult to control. This may explain why cardiovascular disease accounts for more than 60% of the mortality in patients with kidney involvement.37 Elevated creatinine is reported in 40% to 60% of patients.32,38 Recurrence after kidney transplantation has been reported in patients with mixed cryoglobulinemia.39

Median age of presentation is between 58 and 63 years.34,35 Majority of the hematologic conditions in type 1 cryoglobulinemia are owing to B-cell lymphoproliferative disorders including non-Hodgkin lymphoma and Waldenstrom macroglobulinemia.33,40 MM makes up between 11% and 24% of type 1 cryoglobulinemia.40 Hematologic clonal disorders were reported in 63% of patients with type II cryoglobulinemia from an older study, whereas it is noted in only 25% of patients in a more recent study.33,34 In the more recent study, hepatitis C was involved in 58% of the cases of type II cryoglobulinemia, where 8% of cases also involved a B-cell lymphoproliferative disorder or lymphoma.34 This is due to the lymphotropic effect of the hepatitis C virus, which leads to a lymphoproliferative disorder usually after 8 to 10 years of infection.

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Apr 18, 2023 | Posted by in NEPHROLOGY | Comments Off on Non-amyloid Monoclonal Immunoglobulin-Related Diseases

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