Monoclonal Immunoglobulin Deposition Disease

Lynn D. Cornell, MD

Key Facts

Clinical Issues

Nephrotic syndrome
Acute or chronic renal failure
Multiple myeloma diagnosable in ˜ 40% of patients with pure MIDD
Monoclonal protein in serum, urine, or both
˜ 15-20% of patients do not have detectable serum or urine paraprotein at time of diagnosis, even by immunofixation

Microscopic Pathology

Tubular basement membrane monoclonal immunoglobulin deposition
Nodular glomerulopathy
PAS positive nodules, nonargyrophilic
By IF, linear basement membrane staining (glomerular, tubular, vascular) for kappa or lambda light chain (LCDD), plus a heavy chain (LHCDD), or heavy chain only (HCDD)
Kappa light chain in ˜ 80% of LCDD
By EM, finely granular, punctate, “powdery” electron-dense deposits distributed along basement membranes; nonfibrillary

Top Differential Diagnoses

Light chain deposition by immunofluorescence only
Light chain tubulointerstitial nephritis
Dense deposit disease (DDD)
Nodular diabetic glomerulosclerosis
Light chain Fanconi syndrome

MIDD has many patterns. One classic pattern is nodular glomerulosclerosis, which shows PAS-positive mesangial nodules

and can mimic diabetic glomerulosclerosis.

MIDD is often manifested in EM by finely granular electron-dense deposits along the tubular

and glomerular basement membranes.

TERMINOLOGY

Abbreviations

Monoclonal immunoglobulin deposition disease (MIDD)

Synonyms

Systemic light chain disease
Light chain deposition disease (LCDD)
Heavy chain deposition disease (HCDD)
Light and heavy chain deposition disease (LHCDD)
Nonamyloidogenic light chain deposition
Monoclonal immunoglobulin deposition disease, Randall type

Definitions

Deposition of monoclonal immunoglobulin along glomerular and tubular basement membranes (GBMs/TBMs) and within mesangium
Deposits are characterized by linear GBM and TBM staining by immunofluorescence (IF) and finely granular deposits by electron microscopy (EM)

ETIOLOGY/PATHOGENESIS

LCDD Deposits

Differ from normal light chains in variable region, especially complementarity-determining regions and framework regions
Composed of glycosylated light chains, resulting in larger molecule than normal light chain

HCDD Deposits

Deletion of the CH1 constant domain of gamma heavy chain

CLINICAL ISSUES

Presentation

Acute renal failure
Chronic renal failure
Nephrotic syndrome
Proteinuria (58%; non-light chain)
Multiple myeloma diagnosable in ˜ 40% of patients with pure MIDD (without concurrent cast nephropathy or amyloidosis)
Hypocomplementemia
- Present in gamma-HCDD with complement-fixing IgG subclass deposited (gamma-1 or gamma-3)

Laboratory Tests

Monoclonal protein in serum, urine, or both
- M spike on serum or urine protein electrophoresis in ˜ 50% of patients with pure MIDD
- ˜ 15-20% of patients do not have detectable serum or urine paraprotein at time of diagnosis, even by immunofixation
  - Serum or urine free light chain tests can increase sensitivity
Elevated kappa or lambda free light chains in serum or urine
Emerging test for free heavy chains in gamma heavy chain deposition disease
Free light or heavy chain tests useful for monitoring response to therapy

Other Organ Involvement

Cardiac disease (estimated ˜ 19-80%)
Peripheral neuropathy (20%)
Other: Gastrointestinal, liver, pulmonary nodules, muscle, skin

MICROSCOPIC PATHOLOGY

Histologic Features

Nodular glomerulopathy
- PAS-positive nodules, nonargyrophilic
Interstitial inflammation
Interstitial edema
Acute tubular injury
TBM thickening may be present
Congo red negative deposits
- Concurrent amyloidosis may be present
Rare cases may show thickened glomerular basement membranes with an associated membranoproliferative pattern
- These cases must show linear GBM and TBM monoclonal immunoglobulin deposits to be diagnosed as MIDD
Concurrent light chain cast nephropathy present in nearly 1/3 of renal biopsies with MIDD
Concurrent amyloidosis in 13% of MIDD cases
Necrotizing and crescentic glomerulonephritis (rare)
- Seen more frequently in alpha-HCDD

ANCILLARY TESTS

Immunohistochemistry

In absence of IF material, cases may show glomerular and TBM deposits for kappa or lambda light chain

Immunofluorescence

Linear basement membrane staining (glomerular, tubular, vascular) for monoclonal immunoglobulin
- Usually monotypic kappa light chain in LCDD (73-91% kappa)
- Kappa or lambda light chain in LCDD
- Heavy chain only in HCDD
  - Usually IgG
  - All IgG subclasses (1, 2, 3, and 4) have been reported to cause gamma-HCDD
  - Rare cases of IgA-HCDD
- 1 heavy chain and 1 light chain in LHCDD
Smudgy staining of mesangium for monoclonal protein
Staining for IgG subclasses helps determine monoclonal nature of deposits in gamma-HCDD

Electron Microscopy

Finely granular, punctate, “powdery” electron-dense deposits distributed along basement membranes; nonfibrillary
- Similar appearing deposits in LCDD, LHCDD, and HCDD
Monoclonal deposits may be seen by immunogold labeling

DIFFERENTIAL DIAGNOSIS

Light Chain Deposition by Immunofluorescence Only

Monotypic light chain staining of GBM and TBM by IF, but no deposits detectable by EM and no changes by light microscopy
Seen especially in cases of light chain cast nephropathy
Uncertain significance
- May be artifactual IF staining representative of monoclonal protein in urine

Light Chain Tubulointerstitial Nephritis

Pattern of acute tubulointerstitial nephritis
Absence of a glomerulopathy
Negative IF and routine EM
In some cases, light chain deposits seen in some TBMs by EM with immunogold labeling or by immunoperoxidase staining

Proliferative Glomerulonephritis with Monoclonal IgG Deposits

Proliferative glomerulonephritis pattern by light microscopy
Monotypic IgG kappa or IgG lambda staining by IF; IgG is restricted to 1 subclass
Amorphous electron-dense deposits in glomeruli by EM
Absence of TBM deposits by IF and EM
Low incidence of associated multiple myeloma

Dense Deposit Disease (DDD)

Some cases of DDD are associated with serum paraprotein, which may have C3 nephritic factor activity
DDD shows staining by IF for C3 only, not monoclonal immunoglobulins
Very electron-dense deposits along GBMs and in mesangium, distinct from finely granular deposits in GBMs and TBMs in MIDD

Nodular Diabetic Glomerulosclerosis

Similar PAS positive nodular glomerulopathy to MIDD but without IF or EM findings of MIDD

Fibrillary or Immunotactoid Glomerulonephritis

May show monotypic glomerular staining by IF, especially immunotactoid glomerulonephritis
- Smudgy IgG kappa or IgG lambda mesangial staining and glomerular basement membrane staining
Fibrillary substructure to deposits by EM
Usual absence of TBM deposits

Type 1 Cryoglobulinemic Glomerulonephritis or Waldenström Macroglobulinemic Glomerulonephritis

Deposition of a monoclonal immunoglobulin in glomeruli
Membranoproliferative pattern of glomerular injury
Absence of finely granular deposits along glomerular and TBMs

Light Chain Fanconi Syndrome (Light Chain Proximal Tubulopathy)

Light chain deposits within tubular epithelial cells rather than within basement membranes
Crystalline deposits within epithelial cytoplasm

Amyloidosis

Congo red positive, amorphous, PAS negative deposits
Fibrillary structure by EM
Amyloid may be present in glomeruli, vessels, and interstitium

IgA Nephropathy

Alpha-HCDD, in part due to its rarity, may be misdiagnosed as IgA nephropathy
Like IgA nephropathy, alpha-HCDD may show necrotizing and crescentic glomerulonephritis
By IF, alpha-HCDD shows linear TBM staining for IgA along with glomerular staining
By EM, alpha-HCDD shows granular GBM and TBM deposits typical of MIDD
Usual absence of TBM deposits in IgA nephropathy

Recurrent or De Novo MIDD in Allograft

May be seen on protocol biopsies when clinically inapparent

DIAGNOSTIC CHECKLIST

Clinically Relevant Pathologic Features

31-45% of patients with pure MIDD have overt multiple myeloma at time of MIDD diagnosis
91% of patients with concurrent MIDD and cast nephropathy have multiple myeloma
M spike on serum or urine protein electrophoresis in ˜ 50% of patients with pure MIDD
Hypocomplementemia
- Present in gamma-HCDD with complement-fixing IgG subclass deposited (gamma-1 or gamma-3)

SELECTED REFERENCES

1. Herrera GA et al: Ultrastructural immunolabeling in the diagnosis of monoclonal light-and heavy-chain-related renal diseases. Ultrastruct Pathol. 34(3):161-73, 2010

2. Sethi S et al: Dense deposit disease associated with monoclonal gammopathy of undetermined significance. Am J Kidney Dis. 56(5):977-82, 2010

3. Alexander MP et al: Alpha heavy chain deposition disease: a comparison of its clinicopathological characteristics with gamma and mu heavy chain deposition disease. Mod Pathol. 20(Suppl. 2):270A, 2007

4. Salant DJ et al: A case of atypical light chain deposition disease—diagnosis and treatment. Clin J Am Soc Nephrol. 2(4):858-67, 2007

5. Gu X et al: Light-chain-mediated acute tubular interstitial nephritis: a poorly recognized pattern of renal disease in patients with plasma cell dyscrasia. Arch Pathol Lab Med. 130(2):165-9, 2006

6. Rosenstock JL et al: Fibrillary and immunotactoid glomerulonephritis: Distinct entities with different clinical and pathologic features. Kidney Int. 63(4):1450-61, 2003

7. Lin J et al: Renal monoclonal immunoglobulin deposition disease: the disease spectrum. J Am Soc Nephrol. 12(7):1482-92, 2001

8. Buxbaum J et al: Nonamyloidotic monoclonal immunoglobulin deposition disease. Light-chain, heavy-chain, and light- and heavy-chain deposition diseases. Hematol Oncol Clin North Am. 13(6):1235-48, 1999

9. Kambham N et al: Heavy chain deposition disease: the disease spectrum. Am J Kidney Dis. 33(5):954-62, 1999

10. Cheng IK et al: Crescentic nodular glomerulosclerosis secondary to truncated immunoglobulin alpha heavy chain deposition. Am J Kidney Dis. 28(2):283-8, 1996

11. Buxbaum J: Mechanisms of disease: monoclonal immunoglobulin deposition. Amyloidosis, light chain deposition disease, and light and heavy chain deposition disease. Hematol Oncol Clin North Am. 6(2):323-46, 1992

12. Randall RE et al: Manifestations of systemic light chain deposition. Am J Med. 60(2):293-9, 1976

Image Gallery

Light Chain Deposition Disease

(Left) Light chain MIDD can show a variety of histologic patterns ranging from very mild mesangial expansion by PAS positive material, shown here

, to nodular glomerulosclerosis. (Right) A silver stain shows very mild mesangial expansion

by nonargyrophilic material in a patient with light chain MIDD. The diagnosis would not be suspected without immunofluorescence demonstration of a single light chain and the electron-dense deposits by EM.

(Left) Tubules are dilatated and show flattening of the epithelium, both features of acute injury. This patient had proteinuria and acute renal failure. Tubular symptoms, such as polyuria, can dominate in light chain MIDD. (Right) IF staining reveals bright linear tubular basement membrane staining for kappa light chain

, the most common light chain in MIDD, with negative staining for lambda light chain (not shown). Tubular protein reabsorption droplets are also present and stain for kappa