Light-Chain Mediated Acute Tubular Interstitial Nephritis. A Poorly Recognized Pattern of Renal Disease in Patients With Plasma Cell Dyscrasia

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1 Light-Chain Mediated Acute Tubular Interstitial Nephritis A Poorly Recognized Pattern of Renal Disease in Patients With Plasma Cell Dyscrasia Xin Gu, MD; Guillermo A. Herrera, MD Context. Acute renal failure may be the first clinical presentation in patients with plasma cell dyscrasia. Recognition of the unusual interstitial inflammatory lesion associated with monoclonal light chains and renal failure described herein is important to guide clinicians in requesting appropriate tests to confirm plasma cell dyscrasia and providing adequate treatment. Objective. To describe an unusual pattern of tubular interstitial nephritis in patients with underlying plasma cell dyscrasia characterized by an interstitial inflammatory reaction associated with deposition of light chains along tubular basement membranes. Design. Eight cases of light-chain mediated acute tubular interstitial nephritis were identified from the archives of 4296 kidney biopsy specimens. In all cases, routine light microscopic examination, direct immunofluorescence, and electron microscopic examination were performed. Ultrastructural immunogold labeling was performed in specimens with inconclusive findings and in specimens from patients with no clinical history of plasma cell dyscrasia. Results. All patients presented with acute renal failure. Light microscopy revealed acute tubular interstitial nephritis. In some of the cases, direct immunofluorescence and electron microscopy failed to show definitive evidence of light-chain deposition along tubular basement membranes. Ultrastructural immunogold labeling aided the demonstration of monotypical light chains along some tubular basement membranes. light chains were present in other renal compartments. Conclusions. Accumulation of light chains along tubular basement membranes may induce an interstitial process that mimics acute tubular interstitial nephritis. Recognition of this unusual pattern of renal disease in patients with plasma cell dyscrasia requires ancillary diagnostic techniques. (Arch Pathol Lab Med. 2006;130: ) Renal involvement in patients with plasma cell dyscrasia (PCD) has been recognized since the description by Bence Jones of an unusual protein in the urine of a patient with multiple myeloma. 1 More than 50% of patients with PCD will experience impairment of renal function at some time during their illness. 2,3 Light-chain associated acute renal failure is a common renal complication of the disease and is regarded as one of major causes of death. 2,4 It is well known that some light chains coprecipitate with Tamm-Horsfall protein in the distal tubules, forming casts. 5,6 These tubular casts often obstruct distal tubules, occasionally breaking through tubular basement membranes and eliciting an intense interstitial inflammatory Accepted for publication September 13, From the Departments of Pathology (Drs Gu and Herrera), Medicine (Dr Herrera), and Cellular Biology and Anatomy (Dr Herrera), Louisiana State University Health Sciences Center, Shreveport. The authors have no relevant financial interest in the products or companies described in this article. Presented as an abstract and poster at the 93rd Annual Meeting of the United States and Canadian Academy of Pathology, Vancouver, British Columbia, March 9, Reprints: Guillermo A. Herrera, MD, Departments of Pathology, Medicine, and Cellular Biology and Anatomy, Louisiana State University Health Sciences Center, 1501 Kings Hwy, Shreveport, LA ( gherre@lsuhsc.edu). process that may include multinucleated giant cells. Light chains may also directly damage proximal tubular epithelial cells by overloading the lysosomal system, resulting in release of their catalytic enzymes and tubular damage. In the last 9 years, we have encountered some patients with an established diagnosis of multiple myeloma or with undiagnosed underlying PCD who presented with acute renal failure and, to our knowledge, a peculiar previously undocumented histologic lesion. The kidney biopsy specimens showed features of acute tubular interstitial nephritis; tubular casts were absent. Features of lightchain deposition disease (LCDD) and amyloidosis were also absent in the glomeruli, as well as in the tubulointerstitium and vasculature. Clinically, these patients had no history of nephrotoxic medication use, fluid depletion, or hypercalcemia that could explain the acute renal failure. On routine electron microscopy, no electron-dense deposits or widespread punctate electron-dense material typical of light-chain deposits was present along glomerular or tubular basement membranes. On close evaluation, subtle deposition of electron-dense material, consistent with light-chain deposits, could be found along rare tubular basement membranes on their outer aspect, where the interstitial inflammation was most pronounced in 2 cases. Nevertheless, using ultrastructural immunogold labeling, Arch Pathol Lab Med Vol 130, February 2006 Light-Chain Interstitial Nephritis Gu & Herrera 165

2 Patient Presentation and Characteristics of Plasma Cell Dyscrasia (PCD) at the Time of Renal Biopsy* Age, y/sex 55/F 88/F 74/M 72/M 66/F 68/F 80/F 68/F Creatinine, mg/dl Proteinuria, g/d Diagnosis of PCD at Time of Biopsy Monoclonal Immunoglobulin Light Chains (serum, urine) (serum) (serum) * indicates not available. All patients presented with acute renal failure. patient demonstrated tubular casts or glomerulopathy. The conversion factor for creatinine concentration in mol/l is mg/ dl Light-chain amount detected in proteinuria not known. monotypical light-chain deposits could be documented in all cases. Our findings suggest that accumulation of light chains along tubular basement membranes might be the cause of acute tubular interstitial nephritis in a subset of patients with PCD who have no other lesions detectable by histologic examination. It is important to recognize this pattern of light-chain mediated acute tubular interstitial nephritis. It may be the first manifestation of underlying undiagnosed PCD and/ or may be the explanation for the acute renal failure in these patients. MATERIALS AND METHODS Eight cases of light-chain mediated acute tubular interstitial nephritis were identified retrospectively from the archives of 4296 kidney biopsy specimens evaluated in the Department of Pathology at Louisiana State University Health Sciences Center Shreveport from 1996 through During that period, there were 82 cases of monoclonal immunoglobulin related renal disease diagnosed, accounting for approximately 2% of all specimens evaluated. This entity accounts for about 10% of all monoclonal immunoglobulin related renal disease. All patients experienced rapidly progressive renal insufficiency and presented with acute renal failure. At the time of biopsy, 4 patients had a history or laboratory test results suggestive of PCD. The other 4 patients were diagnosed as having underlying PCD after the renal biopsy. Bone marrow aspirates or biopsy specimens confirmed the diagnosis of PCD in all patients. All biopsy specimens were processed for light microscopy, direct immunofluorescence, and electron microscopy according to standard techniques. The fluorescence-labeled rabbit polyclonal antibodies to and light chains (DakoCytomation, Carpinteria, Calif) were used at 1:20 dilution. Polyclonal antibodies to and light chains (Ventana Medical Systems, Tucson, Ariz) used for immunohistochemistry were prediluted. In all cases, routine electron microscopy was used initially to examine the specimens. In specimens from patients with no history of PCD or laboratory test results suggestive of PCD at the time of the renal biopsy, or with inconclusive light microscopy, immunofluorescence, and ultrastructural findings, ultrastructural immunogold labeling was performed by means of the modified Herrera technique, as previously reported. 7 Polyclonal antibodies to and light chains (DakoCytomation) were used at 1:20 to 1:40 dilutions for ultrastructural immunogold labeling. RESULTS As summarized in the Table, the 8 patients described herein included 2 men and 6 women (age range, years). Clinically, all patients presented with acute renal failure. Two patients also had proteinuria. At the time of evaluation of kidney biopsy specimens, 4 patients had a clinical history suggestive of PCD. Serum and urine immunoelectrophoresis data for these 4 patients showed 3 patients with light-chain associated PCD and 1 patient with light-chain associated PCD. The other 4 patients had no history or laboratory test results suggestive of PCD. The immunophenotypes were confirmed with immunofluorescence or ultrastructural immunogold labeling. glomerular lesions were present in any of the specimens (Figure 1). A mean number of 7 glomeruli per specimen were available for evaluation by light microscopy. The arterioles and small arteries were unremarkable or showed mild thickening of the vascular walls. Features of LCDD or amyloidosis were not noted in the glomerular or vascular compartments. The interstitial process presented as multiple foci with inflammatory infiltrates, which were composed predominantly of lymphocytes and plasma cells and associated with tubulitis (Figure 2). In- Figure 1. The glomerulus is unremarkable. Infiltration by mononuclear inflammatory cells is seen in the interstitium (hematoxylin-eosin, original magnification 500). Figure 2. Acute tubular interstitial nephritis. The interstitial mononuclear inflammatory cells are predominantly lymphocytes and plasma cells. Rare eosinophils are also present. There is obvious tubulitis (periodic acid Schiff, original magnification 750). 166 Arch Pathol Lab Med Vol 130, February 2006 Light-Chain Interstitial Nephritis Gu & Herrera

3 Figure 3. Immunohistochemistry. A, light-chain staining along the tubular basement membrane is clearly seen. B, There was no staining for light chains in the same case (peroxidase-antiperoxidase staining, prediluted antibodies, original magnification 750). terstitial edema and rare eosinophils were present. recognizable myeloma casts or multinucleated giant cell reaction was seen in any of the cases. A mean number of 5 glomeruli per specimen were available for immunofluorescence examination. nspecific segmental mesangial staining for immunoglobulin M and C3 was seen in 2 cases. Specific glomerular staining for light chains or immunoglobulins was not identified in any of the cases. Linear staining for monotypical light chains along tubular basement membranes was noted in 2 cases by immunofluorescence and confirmed by immunohistochemistry (Figure 3, A and B); this finding was focal and localized to where the interstitial inflammation was most pronounced. A mean number of 3 glomeruli per specimen were identified in the thick sections available for evaluation. On routine electron microscopy, the glomeruli showed nonspecific changes, such as mild segmental thickening and wrinkling of capillary walls and mild expansion of mesangium. Granular punctate electron-dense material, organized deposits, or amyloid fibrils were not identified in glomeruli, tubular interstitium, or vascular walls, except for 1 specimen with focal deposition of light-chain material along the outer aspects of some tubular basement membranes (Figure 4, A and B). Immunohistochemistry revealed monotypical light chains along some tubular basement membranes in cases with doubtful immunomorphological findings, such as that illustrated in Figure 3. In most cases, the ultrastructural immunogold labeled light chains appeared along the basement membranes of some proximal and distal tubules but were most prominent in the distal tubules (Figure 4, C). Highly concentrated monotypical light chains were also noted focally in the proteinaceous material in tubular lumina that did not organize into well-formed casts. ultrastructural immunogold labeled light chains were noted in the glomeruli or vascular walls. COMMENT Most renal disease associated with PCD results from the deposition of monoclonal light chains in the renal parenchyma, including glomeruli, tubulointerstitium, and vessels. Depending on the physicochemical characteristics of the individual light chain, the renal manifestations include LCDD, AL amyloidosis, acute tubulopathy, or myeloma cast nephropathy. 8 It is well known that some light chains interact with Tamm-Horsfall protein in the distal tubules and form casts. Occasionally, the casts disrupt tubular basement membranes and induce destructive acute tubular interstitial nephritis with multinucleated giant cells. In a previous report, histologic evaluation of kidneys from 42 patients with multiple myeloma revealed 20 patients with cast nephropathy, 7 patients with nonobstructive interstitial nephritis, and 15 patients with other pathologic changes, including amyloidosis, myeloma infiltration, and acute tubular necrosis. 9 In those patients with nonobstructive interstitial nephritis, the cause of acute renal failure was unclear. In a recent autopsy series of 77 patients with multiple myeloma, 3% of them showed nonobstructive interstitial nephritis. 4 Sporadic reports in the literature have documented inflammatory tubular interstitial changes, isolated tubular basement membrane light-chain deposits, or fluorescence staining for monotypical light chains in some patients with myeloma with no associated glomerular or vascular pathologic features or light-chain deposition. 10,11 These patients were diagnosed as having atypical LCDD. In last 9 years, we have identified 8 patients with a history of PCD or a subsequent diagnosis of PCD who presented with acute renal failure with features of acute tubular interstitial nephritis in their kidney biopsy specimens. Based on clinical histories, there were no common causes of acute tubular interstitial nephritis, such as nephrotoxic medication use, hypercalcemia, or urinary tract infections. As noted in the Results section, features of myeloma cast nephropathy were not present on histologic examinations. The glomeruli were unremarkable. glomerular changes that indicated light- or heavy-chain deposition disease or amyloidosis were identified using light microscopy, immunofluorescence, or ultrastructural immunogold labeling. The most prominent renal changes occurred in the tubular interstitial compartment, which showed variable tubular injury associated with multiple foci with mononuclear cell infiltrates and tubulitis. Most mononuclear cells were lymphocytes. Plasma cells and rare eosinophils were also present. Occasionally, there was subtle Arch Pathol Lab Med Vol 130, February 2006 Light-Chain Interstitial Nephritis Gu & Herrera 167

4 Figure 4. Low-power (A) and high-power (B) transmission electron microscopy views reveal tubulitis with infiltration of lymphocytes into tubules. Granular punctate electron-dense material is noted along the outer aspect of the tubular basement membrane (uranyl acetate and lead citrate stain, original magnifications 7000 [A] and 8500 [B]). C, Immunogold labeling shows accumulation of light chains along the tubular basement membrane (ultrastructural immunogold labeling for light chains, original magnification ). Asterisk indicates lymphocyte; L, tubular lumen; and arrow, powdery electron-dense material along the tubular basement membrane. light-chain deposition along tubular basement membranes, best confirmed by ancillary techniques. Routine electron microscopic examination performed in renal biopsy specimens did not reveal diagnostic findings, except for 1 case in which characteristic light-chain deposits were noted (Figure 4, A and B). Using ultrastructural immunogold labeling, we detected conclusive evidence of monoclonal light-chain deposition along tubular basement membranes in 4 doubtful cases (Figure 4, C). In these cases, different from LCDD and amyloidosis, the light chains generally did not form distinct granular punctate electron-dense deposits or fibrils. Ultrastructural immunogold labeling revealed monotypical light chains embedded in tubular basement membranes and along their outer aspects. Monoclonal light chains were also noted in the lysosomes in tubular epithelial cells. There was no ultrastructural immunogold light-chain labeling in glomeruli or vasculature. All of the specimens submitted for ultrastructural immunogold labeling revealed diagnostic findings. The exact mechanism of how light chains promote acute tubular interstitial nephritis remains speculative. In most interstitial nephritis, cytokines are believed to play an important role. 12,13 The binding of light chains to tubular basement membranes might alter intrinsic tissue antigens, resulting in the release of cytokines and inducing chemoattraction and activation of interstitial mononuclear inflammatory cells. Light chains may reach tubular basement membranes by transcytosis after reabsorption or by passive tissue diffusion from peritubular capillaries. Our results showed little correlation between the degree of light-chain accumulation at tubular basement membranes and the severity of the histologic changes. The accumulation of light chains was rarely detected by immunofluorescence or routine electron microscopy. Specific physicochemical characteristics may be responsible for imparting to some light chains the propensity to bind to tubular basement membranes and to induce cytokine activation. In all but 1 of the specimens, light chains were responsible for the pattern of interstitial pathologic features described herein. In conclusion, we have described an unusual pattern of renal involvement in patients with underlying PCD characterized clinically by acute renal failure with focal accumulation of light chains along some tubular basement membranes. In these patients, previously documented pathologic patterns such as cast nephropathy or extensive paraprotein tissue deposits were not present. A high index of suspicion is needed to make the correct diagnosis. In patients with negative or inconclusive immunofluorescence and ultrastructural findings, ultrastructural immunogold labeling should be used to confirm the diagnosis. Light-chain associated acute interstitial nephritis may be the first manifestation among patients with paraproteinemia, making it important to recognize this pattern of renal injury. This observation should guide clinicians to request appropriate tests to confirm the PCD diagnosis and provide adequate treatment. Likewise, in patients with known PCD, recognition of this pattern of renal injury should lead to appropriate therapeutic intervention. Conceptually speaking, this pattern of renal disease could be considered a type of LCDD restricted to the tubular interstitial compartment and associated with a prominent inflammatory component. 168 Arch Pathol Lab Med Vol 130, February 2006 Light-Chain Interstitial Nephritis Gu & Herrera

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