Monoclonal Immunoglobulin Deposition Disease



Monoclonal Immunoglobulin Deposition Disease


Lynn D. Cornell, MD










MIDD has many patterns. One classic pattern is nodular glomerulosclerosis, which shows PAS-positive mesangial nodules image and can mimic diabetic glomerulosclerosis.






MIDD is often manifested in EM by finely granular electron-dense deposits along the tubular image 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 image, to nodular glomerulosclerosis. (Right) A silver stain shows very mild mesangial expansion image 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 image, 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 image.

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Jul 7, 2016 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on Monoclonal Immunoglobulin Deposition Disease
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