Nephropathology
   
Case 7
Diagnosis and discussion
 
     
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Diagnosis: Light-chain deposit disease

Light microscopy features in the present case can suggest several kidney diseases: Diabetic nephropathy, amyloidosis, some cases of membranoproliferative glomerulonephritis, fibrillary and immunotactoide glomerulonephritis, and light-chain deposition disease (LCDD).

In diabetic nephropathy can be difficult differential diagnosis with LCDD at the light microscopic level of examination. However, a distinctive feature is in the arterioles: the demonstration of hyalinization of both afferent and efferent vessels is virtually limited to diabetes. Also, the glomerular basement membrane is thickened in diabetes. Glomerular nodules in diabetic nephropathy are intensively positive with methenamine-silver stain.

In amyloidosis Congo-red stain deposits in mesangium, capillary walls, interstitium, and blood vessels, demonstrating apple-green birefringence when examined in polarized light.

Some cases of membranoproliferative glomerulonephritis (MPGN) can be difficult to differentiate of other nodular glomerulonephritis, but we will find the other morphological and clinical features of this MPGN.

Fibrillary and immunotactoid glomerulonephritis are rare diseases; there are characteristic ultrastructural changes: the deposits are non-branching fibrils or microtubules that are distributed throughout the mesangial matrix and basement membranes (diameter range 10–45 nm). Usually is less nodular than LCDD.

In the present case Congo-red stain was negative and immunohistochemical study shown positive kappa ligh-chains deposits (Figure 7)

Immunoflurescence failed to show staining for IgG, IgA, IgM, C3, C1q, or lambda ligh-chains.

Complementary studies found multiple myeloma (kappa) confirmed with bone marrow aspirate and biopsy.

Figure 7. Left: Congo-red stain: negative in glomerular and tubular deposits. There was not birefringence when examined in polarized light, X400. Right: Immunostain with anti-kappa antibodies show intense positiviti in basal tubular membranas. There was positiviti in glomerular nodules too, X200.

Light-chain deposition disease (LCDD) is the deposition of monoclonal, amorphous, noncongophilic light chains in multiple organs that do not exhibit a fibrillar structure when examined ultrastructurally. Renal disease: renal insufficiency, proteinuria, and nephrotic syndrome, is the major manifestation. LCDD may be associated with multiple myeloma or lymphoproliferative disease, but as many as 50% of patients have no evidence of neoplastic plasma cell proliferation. Approximately 85% of cases are associated with kappa light-chain deposition. A monoclonal protein of the same light-chain type is usually demonstrated in serum or urine, but approximately 25% of patients have no demonstrable light chain in serum or urine by immunoelectrophoresis or immunofixation. Even in the absence of a monoclonal light chain in serum or urine, immunofluorescence usually demonstrates a monoclonal population of plasma cells in the bone marrow of these patients.

The renal lesion is usually a nodular mesangial lesion that is often indistinguishable from diabetic lesions by light microscopy. Immunofluorescence and electron microscopy are essential in making the diagnosis, and the findings on renal biopsy are often the first evidence of LCDD.

The frequency of LCDD is unknown. Treatment with cytotoxic chemotherapy may result in disease stabilization and/or improvement in end-organ damage.

Sites of light-chain deposition include the kidney, liver, heart, small intestine, spleen, skin, nervous system, and bone marrow. Renal involvement in the form of proteinuria or renal insufficiency is the most common manifestation. Sites of deposit in the kidney can vary and include the tubular basement membrane, the Bowman capsule, and the glomeruli.

Nodular glomerulosclerosis, the characteristic lesion of LCDD, is demonstrated in light microscopy by amorphous PAS-positive, Congo-red negative material and poorly argyrophilic widened mesangium. The diagnosis of light-chain deposition nephropathy is based on the immunohistochemical demonstration of monoclonal light-chain deposits within connective tissue matrix, and on the presence at the ultrastructural level of electron-dense granular deposits along glomerular and tubular basement membranes. Nodular glomerulosclerosis is the characteristic lesion of LCDD but not universal to this condition, since it is present in less than 50–60% of patients [3].

Tubular basement membrane thickening and wrinkling, as seen in our case, is a very charcateristic and useful feature, in fact, tubular lesions may be more conspicuous than the glomerular damage. Tubular lesions are characterized by the deposition of a refractile, eosinophilic, PAS-positive, ribbon-like material along the tubular basement membrane. The deposits predominate around the distal tubules, the loops of Henle, and, in some instances, the collecting ducts whose epithelium is flattened and atrophied. Typical myeloma casts are only occasionally seen in pure forms of LCDD. In advanced stages, a marked interstitial fibrosis including refractile deposits frequently is associated with tubular lesions.

Glomerular lesions are much more heterogeneous. Nodular glomerulosclerosis (NGS) is the most characteristic; it is found in 60 to 100% of patients with LCDD. Mesangial nodules are composed of PAS-positive material and often are accompanied by mild mesangial hypercellularity. The capillary loops stretch at the periphery of florid nodules and may undergo aneurysmal dilation. Bowman's capsule may contain a material that is identical to that present in the center of the nodules. These lesions resemble nodular diabetic glomerulosclerosis, but some characteristics are distinctive: the distribution of the nodules is fairly regular in a given glomerulus, the nodules are poorly argyrophilic, and exudative lesions as "fibrin caps" and extensive hyalinosis of the efferent arterioles are not observed. In occasional cases with prominent endocapillary cellularity and mesangial interposition, the glomerular features mimic lobular glomerulonephritis. Milder forms of LCDD simply show an increase in mesangial matrix and sometimes in mesangial cells and a modest thickening of the basement membranes that are abnormally bright and rigid. Glomerular lesions may not even be detected by light microscopy but require ultrastructural examination. These lesions may represent early stages of glomerular disease or be induced by LC with a weak pathogenic potential. Their diagnosis would be unrecognized without the immunostaining results. Arteries, arterioles, and peritubular capillaries all may contain PAS-positive deposits in close contact with their basement membranes. Deposits do not show the staining characteristics of amyloid, but they may be associated with Congo red—positive amyloid deposits in approximately 10% of patients. (Ronco PM, et al. Light chain deposition disease: a model of glomerulosclerosis defined at the molecular level. J Am Soc Nephrol. 2001;12:1558-65. [PubMed link] [Free full text link])

Crescentic glomerulonephritis is not an usual feature in LCDD, however in the present case some glomeruli show cellular crescents (figure 5); this feature not necessarily indicate a different clinical evolution.

The long post-transplant time (10 years) and non-identification of clinical signs of the disease previous to transplantation, to indicate de novo disease (this case is not a recurrence of a previous disease).

See the chapter [Amiloidosis, mieloma múltiple, enfermedad por depósitos de cadenas ligeras... ] (only in spanish).

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Bibliography

  • Suzuki K. Light- and heavy-chain deposition disease (LHCDD): difficulty in diagnosis and treatment. Intern Med. 2005;44:915-6. [PubMed link][Free full text link]
  • Pozzi C, D'Amico M, Fogazzi GB, Curioni S, Ferrario F, Pasquali S, Quattrocchio G, Rollino C, Segagni S, Locatelli F. Light chain deposition disease with renal involvement: clinical characteristics and prognostic factors. Am J Kidney Dis. 2003; 42:1154-63. [PubMed link]
  • Ronco PM, Alyanakian MA, Mougenot B, Aucouturier P. Light chain deposition disease: a model of glomerulosclerosis defined at the molecular level. J Am Soc Nephrol. 2001;12:1558-65. [PubMed link] [Free full text link]
  • Buxbaum J, Gallo G. Nonamyloidotic monoclonal immunoglobulin deposition disease. Light-chain, heavy-chain, and light- and heavy-chain deposition diseases. Hematol Oncol Clin North Am. 1999;13:1235-48. [PubMed link]
  • Fanning SR, Hussein MA, Jutiri J. Light-Chain Deposition Disease. In: eMedicine: http://www.emedicine.com/med/topic1300.htm Consulted: October 16th, 2006.

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