83 Year-Old Diabetic Male with Circulating Kappa Light Chains

Guillermo A. Herrera, M.D.

Specimen Type:

Kidney

History:

83 y/o diabetic male with circulating kappa light chains who developed rapidly progressive renal dysfunction. Renal biopsy is performed to investigate the reason for the renal failure. Serum creatinine at the time of the renal biopsy was 6.5 mg/dl which had increased from a documented baseline level of 1 mg/dl measured 6 months prior.

Pathologic Features:

Light microscopy:

At least 20 glomeruli are identified in the specimen submitted for light microscopic evaluation. Approximately 25% of the glomeruli are globally sclerosed. The viable glomeruli are unremarkable or show mild reactive mesangial changes (Figure 1). No thickening of peripheral capillary walls or formation of mesangial nodules is noted. A patchy interstitial inflammatory infiltrate focally associated with tubulitis is noted (Figures 2 and 3). Trichrome stain shows focal, mild interstitial fibrosis and generalized interstitial edema. There is also prominent proximal tubular damage noted in areas associated with the interstitial inflammatory infiltrate and also away from these areas with inflammation (Figure 4). A few small hyaline tubular casts are present. No casts with fracture planes, surrounding reactive-appearing tubular cells, or multinucleated cells surrounding the casts are noted. Some tubules are lined by simplified and lined by flattened cells.

Mild thickening of the walls of arterioles and small size arteries is identified. Intimal fibrous thickening is apparent in the medium size arteries. No vasculitis is identified.

Immunofluorescence:

No glomerular, interstitial, or vascular staining is identified for albumin, IgG, IgA, C1q, fibrinogen, and lambda light chain. Focal and segmental mesangial granular staining is seen for IgM and C3 (1+). Distinct linear staining is identified along tubular basement membranes in several interstitial areas, predominantly where the inflammatory reaction is present, for kappa light chains (Figure 5). In contrast, there is no staining for lambda light chains, confirming light chain restriction (Figure 6). Furthermore, no casts staining for monoclonal light chains are identified.

Electron microscopy:

Glomeruli are normal. Prominent proximal tubular damage is seen. Cytoplasmic vacuolization, prominence of lysosomes, segmental loss of microvillous borders, apical blebbing, and desquamation of tubular cells is identified (Figure 7). There is focal, interrupted deposition of fluffy to punctate electron dense material at the outer aspect of the tubular basement membranes in some proximal and distal tubules, predominantly in areas with interstitial inflammation. No fibrillary material is seen in any of the renal compartments. No punctate electron dense material is identified in the glomeruli or vasculature. No tubular casts are present.

Differential Diagnosis:

Not applicable for this case, please continue to the Diagnosis

Diagnosis:

Acute tubular interstitial inflammatory process (acute tubular interstitial nephritis) associated with monoclonal deposition of kappa light chains along tubular basement membranes consistent with interstitial inflammatory reaction associated with underlying plasma cell dyscrasia.

This type of interstitial manifestation of plasma cell dyscrasia-associated renal disease mimics a garden variety of acute tubular interstitial nephritis and is easily missed (1). Associating the findings in the renal biopsy with an underlying plasma cell dyscrasia may not be readily apparent. A high index of suspicion and careful evaluation of the immunofluorescence and ultrastructural findings are generally required.

Interstitial inflammatory infiltrates associated with variable degrees of tubulitis represent the typical light microscopic finding associated with this condition. Eosinophiles may be present in the interstitial inflammatory infiltrates. Although tubulitis is a constant finding, the inflammatory process may be quite focal (1,2). No tubular casts are present. Demonstration of an association with an underlying neoplastic lymphoplasmacytic disorder is crucial to make a definitive diagnosis. Therefore, confirming light chain deposition and restriction in association with the interstitial inflammatory process is key to make the correct diagnosis. The majority of these cases are kappa light chain-restricted.

Immunofluorescence and electron microscopy individually may or may not be helpful, but both combined provide sufficient evidence to support the diagnosis in the majority of the cases (1). Immunohistochemistry for light chains may also be used to demonstrate monoclonality of light chain deposits along tubular basement membranes, but, unfortunately, this technique is often associated with significant background staining making assessment of light chain restriction virtually impossible. In the present case, immunofluorescence revealed characteristic monoclonal linear staining along tubular basement membranes in focal interstitial areas for kappa light chains making a definitive diagnosis possible. The ultrastructural findings were much less convincing. Ultrastructural labeling has also been used to show light chain monoclonality associated with the tubular interstitial manifestations with excellent results, even in cases when other techniques have failed (1,3,4,5).

Glomeruli and vasculature are normal in this pattern of light chain-associated interstitial disease, unless other coexistent conditions are present (i.e. vascular nephrosclerosis, as seen in this case). This pattern of interstitial disease could be conceptualized as an interstitial form of light chain deposition disease without manifestations in other renal compartments (1). Interestingly in cases of light chain cast nephropathy, a similar interstitial inflammatory infiltrate is characteristically seen but in this entity the presence of the light chain containing tubular casts represents the differentiating diagnostic feature (5). The clinical presentation seen in this patient is rather classical for this entity. Although most patients exhibit rapid deterioration of renal function, it is also important to realize that some may manifest a much slower pace of deterioration of renal function and renal impairment may occur over a period of 12 months or more. Checking for the presence of monoclonal light chains (in urine and in serum) in any patient older that 50 years of age presenting with progressive renal dysfunction is highly recommended.

The pathophysiology associated with this condition is rather interesting. It is proposed that binding of monotypical light chains to the tubular basement membranes alters intrinsic tissue antigens resulting in the release of cytokines inducing chemoattraction and activation of interstitial inflammatory cells, including eosinophiles. Monotypical light chains reach tubular basement membranes by either transcytosis after reabsorption in the proximal tubules (thus the lysosomal prominence seen ultrastructurally) and / or by passive diffusion from peritubular capillaries (1).

It is imperative to recognize this unusual manifestation of renal damage associated with an underlying plasma cell disorder, so that a prompt diagnosis can be followed by proper and aggressive treatment aiming at controlling the neoplastic plasma cell clone responsible for the renal manifestations, before irreversible renal parenchymal changes occur.

References:

  1. Gu X, Herrera GA: Light-chain-mediated acute tubular interstitial nephritis: a poorly recognized pattern of renal disease in patients with plasma cell dyscrasia. Arch Pathol Lab Med 130:165-169, 2006.
  2. Venkataseshan VS, Faraggiana T, Hughson MD, Buchwald D, Olesnicky L, Goldstein MH: Morphologic variants of light-chain deposition disease in the kidney. Am J Nephrol 8:272-279, 1988.
  3. Herrera GA, Sanders PW, Reddy BV, Hasbargen JA, Hammond WS, Brook JD: Ultrastructural immunolabeling: A unique diagnostic tool in monoclonal light chain related renal diseases. Ultrastruct Pathol 18:401-416, 1994.
  4. Herrera GA: The contributions of electron microscopy to the understanding and diagnosis of plasma cell dyscrasia-related renal lesions. Med Elect Mic 34:1-18, 2001.
  5. Herrera GA: Renal lesions associated with plasma cell dyscrasias. Practical approach to diagnosis, new concepts, and challenges. Arch Pathol Lab Med 133: 249-267, 2009.