KIDNEY BIOPSY TEACHING CASE Light Chain Deposition Disease After Renal Transplantation

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1 KIDNEY BIOPSY TEACHING CASE Light Chain Deposition Disease After Renal Transplantation Sekiko Taneda, MD, 1 Kazuho Honda, MD, 1 Shigeru Horita, MS, 1 Ichiro Koyama, MD, 2 Satoshi Teraoka, MD, 2 Hideaki Oda, MD, 1 and Yutaka Yamaguchi, MD 3 INDEX WORDS: light chain deposition disease; transplantation; tubular basement membrane; retrospective; serial biopsies. Light chain deposition disease (LCDD) is characterized by the deposition of or immunoglobulin light chains in many organs, including the kidney. 1,2 The disease frequently is associated with multiple myeloma or other lymphoplasmacytic proliferative disorders, although a significant number of patients with LCDD show no evidence of bone marrow abnormalities. 3 LCDD frequently has been reported to recur after renal transplantation, inevitably followed by graft failure. Multiple myeloma also 3 has been considered a major cause of light chain deposition in renal allografts and to show a high rate of recurrence. 4,5 The most characteristic feature of LCDD is nodular glomerulopathy resembling diabetic glomerulosclerosis. The mesangial nodules are composed of extracellular matrix proteins admixed with the monoclonal light chain deposits. Glomerular basement membranes (GBMs), tubular basement membranes (TBMs), and vessel walls are variably thickened as a consequence of subendothelial light chain deposition. Clinically, various degrees of proteinuria and renal insufficiency are common manifestations, 2 and rapid deterioration in kidney function can occur as a consequence of disease progression. We report a case of LCDD progression more than 4 years after renal transplantation, with a retrospective analysis of serial biopsy specimens that showed gradual progression of light chain deposition in the renal allograft. CASEREPORT ClinicalHistory A 61-year-old man received an HLA-identical, blood group type ABO compatible renal transplant from his sister. The cause of his renal failure was unknown. Cyclosporine, mycophenolate mofetil, and methylprednisolone were administered as immunosuppressive therapy. A small amount of proteinuria, to by dipstick ( 0.5 g/d), had been found 3 days after the transplantation Fig ( 1). Renal biopsy was performed on postoperative days 18 and 43 because of a slight increase in serum creatinine level and showed no evidence of rejection and unremarkable glomerular changes (Fig 1). Two years later, serum creatinine level increased to 3 mg/dl (265 mol/l; estimated glomerular filtration rate, ml/min/1.73 m 2 [0.26 ml/s/1.73 m 2 ]), and renal biopsy was performed again on postoperative day 774. It showed very mild tubulointerstitial rejection without apparent glomerular changes. Although methylprednisolone therapy had been continued and the patient was additionally administered intravenous 15-deoxyspergualin (total, 1,750 mg), serum creatinine level remained high, and another renal biopsy was performed on postoperative day 913. The biopsy specimen showed chronic allograft nephropathy without apparent glomerular changes. To prevent further deterioration of graft function, cyclosporine therapy was replaced with tacrolimus, and the doses of mycophenolate mofetil and methylprednisolone were increased. However, despite these dose adjustments, kidney function gradually deteriorated. The final biopsy on postoperative day 1,543, when serum creatinine and blood urea nitrogen levels had increased to 6.0 mg/dl (530 mol/l; estimated glomerular filtration rate, 7.12 ml/min/ m[0.12 ml/s/1.73 m 2 ]) and 90 mg/dl (32 mmol/l) accompanied by slight proteinuria, respectively. KidneyBiopsyDiagnosis Light microscopic examination of the final biopsy specimen showed diffuse interstitial fibrosis with tubular atrophy, with no evidence of rejection Fig ( 2A). One third of glomeruli were globally sclerotic, and residual glomeruli showed widening of the mesangial area with sclerosis Fig ( 2B). The From the 1 Department of Pathology and 2 Department of Surgery, Kidney Center, Tokyo Women s Medical University, Tokyo; and 3 Department of Pathology, Kashiwa Hospital, Jikei University, Chiba, Japan. Received September 10, Accepted in revised form February 13, Originally published online as doi: /j.ajkd on June 12, Address correspondence to Sekiko Taneda, MD, 8-1 Kawada-cho, Shinjuku-ku, Tokyo, , Japan. staneda@research.twmu.ac.jp 2008 by the National Kidney Foundation, Inc /08/ $34.00/0 doi: /j.ajkd American Journal of Kidney Diseases, Vol 52, No 3 (September), 2008: pp

2 622 Taneda et al Figure 1. Clinical course of the patient. Abbreviations: CsA, cyclosporine A; FK, tacrolimus; MMF, mycophenolate mofetil; MP, methylprednisolone; DSG, 15-deoxyspergualin; scr, serum creatinine; U-P, urinary-protein; Bx, graft biopsy; Tx, transplantation; AZP, azathioprine; HD, hemodialysis; Ccr, creatinine clearance. basement membrane of Bowman s capsule, TBM, and vessel walls were thickened and tortuous. Arteriolar hyalinosis was severe. Direct immunofluorescence examination showed diffuse linear deposition of light chains along the GBM, mesangial area, TBM, and Bowman s capsule (Fig 2C). However, staining for light chain was negative (Fig 2D), as well as immunoglobulin G, immunoglobulin M, and immunoglobulin A. Congo red staining for amyloid was negative. Electron microscopy showed band-like subendothelial electron-dense deposits along the GBM (Fig 2E). Electron-dense deposits were also present along the TBM (Fig 2F) and Bowman s capsule and showed deposition of granular to powdery electron-dense material. Pathological changes were mostly consistent with the diagnosis of LCDD. Retrospective Study of Serial Biopsy Specimens Staining for light chains was negative in the biopsy specimens from day 43 (Fig 3E). In biopsy specimens obtained on day 774, weak immunofluorescence staining for light chain was detected along the GBM, TBM, and Bowman s capsule basement membrane (Fig 3I), which had become more intense in the biopsy specimens obtained on day 913 (Fig 3M). Electron microscopy showed no deposits in the GBM or TBM on day 0 (Fig 3B and C) or43(fig 3F and G). In the biopsy performed on day 774, electron-dense deposits were detected along the GBM and TBM, but the deposits were very fine and powdery, without continuity (Fig 3J and K). However, the deposits had become more apparent in the biopsy specimen from day 913 (Fig 3N and O). The intensity of light chain deposition was proportional to the amount of the electron-dense deposits. Clinical Follow-up The patient needed to be started on hemodialysis therapy again 5 days after the final biopsy. Serum and urine immunoelectrophoresis showed neither the M spike nor Bence-Jones proteins. However, immunofixation electrophoresis of urine showed the type of Bence-Jones protein. Bone marrow biopsy showed a moderately hypocellular bone marrow with small collections of atypical plasmacytoid cells. The myelogram showed an increase in percentage of plasma cells (11.6%). Flow cytometric analysis of bone marrow specimens showed monoclonality of the plasmacytoid fraction gated by CD38 for cytoplasmic chain (86.4%). DISCUSSION LCDD in renal allografts is uncommon and in general is associated in most patients with recurrent myeloma, rather than as a de novo disease. 6,7 Recurrence of LCDD in renal allografts has been reported to occur at an incidence of more than 50% within 4 years of renal transplantation and frequently is associated with graft failure Conversely, de novo multiple myeloma or LCDD arising in a renal allograft is very rare, and only a few cases have been reported 7-9 despite the high frequency of monoclonal gammopathy in transplant recipients. 11 In the native kidney, LCDD is associated with various degrees of renal insufficiency in most patients, and rapid deterioration of kidney function could also occur during the advanced stage of the disease. 12 However, acute renal failure could be present at the time of diagnosis in approximately 30% of patients with LCDD. 13 Other paraprotein-related kidney diseases, including heavy chain deposition disease, 14 cryoglobulinemia, 15 immunotactoid glomerulopathy, and amyloidosis also have been reported after renal transplantation. One transplant patient with heavy chain deposition disease developed recurrent disease approximately 1.5 years after transplantation. 14 Cryoglobulinemic nephropathy may develop either de novo or as

3 LCDD in Renal Allograft 623 Figure 2. (A-F) Pathological findings of the graft biopsy performed on day 1,540. (A) Light microscopy shows diffuse interstitial fibrosis with tubular atrophy without evidence of rejection. Tubular basement membranes (TBMs) were thickened and tortuous (periodic acid Schiff; original magnification 200). (B) Glomeruli show typical nodular lesions resembling those in diabetic glomerulosclerosis. The basement membrane of Bowman s capsule and proximal and distal tubules were irregularly thickened. Severe arteriolar hyalinosis was noted (periodic acid-silver methenamine; original magnification 400). (C) Immunofluorescence study shows intense staining in the nodular glomerular lesions, glomerular capillaries, tubules, Bowman s capsule, and small-vessel walls (original magnification 400). (D) Immunofluorescence study shows negative staining for light chains (original magnification 400). (E, F) Electron microscopy shows fine granular electron-dense deposits along the (E) glomerular basement membrane and (F) TBM (original magnification: [E] 6,000; [F] 7,000). (F inset). Electron-dense material along the TBM shows a granular to powdery appearance (original magnification 10,000). recurrent cryoglobulinemic nephropathy in patients with active hepatitis. 15 Although recurrent immunotactoid glomerulopathy after renal transplantation has been reported to occur in approximately half the cases, graft function has been reported to remain adequate after 5 to 11 years of follow-up in most cases Several cases of de novo immunotactoid glomerulopathy in renal allografts have been reported. 16,20,21 However, the recurrence rate of amyloidosis after renal transplantation has been reported to be 10% to 20% for AL amyloidosis 22,23 and 4% for AA amyloidosis, 24 and the graft loss rate from recurrent amyloidosis was only 3%. 22 The accumulated experiences of LCDD in renal transplantation suggest that transplantation is not a valid option for patients with LCDD because of the high frequency of recurrence and progression to graft failure. However, in some recipients in whom the original kidney disease remains uncertain, such as in this case, recurrent LCDD can be a possible reason for graft dysfunction. Immunohistochemical analysis for light chains and careful electron microscopic observa-

4 624 Taneda et al A B C Day 0 D E F G Day 43 H I J K Day 774 L M N O Day 913 Figure 3. Serial changes in (A, D, H, L) glomerular histological characteristics, (E, I, M) immunofluorescent staining for light chains, and electron microscopy of the (B, F, J, N) glomerular and (C, G, K, O) tubular basement membranes. (A-C) Day 0, (D-G) day 43 (biopsy [Bx] 3), (H-K) day 774 (Bx 4), and (L-O) day 913 (Bx 5). Immunofluorescent staining was not performed in the 0-hour biopsy because frozen sections were not obtained. tion to identify inconspicuous light chain deposition can be helpful for the diagnosis of LCDD, which should prompt further examination to detect an underlying plasma cell disorder in the course of patient management. ACKNOWLEDGEMENTS We gratefully acknowledge the technical assistance of Hideki Nakayama and Mayuko Ohno. Support: None. Financial Disclosure: None. REFERENCES 1. Colombat M, Stern M, Groussard O, et al: Pulmonary cystic disorder related to light chain deposition disease. Am J Respir Crit Care Med 173: , Randall RE, Williamson WC Jr, Mullinax F, Tung MY, Still WJ: Manifestations of systemic light chain deposition. Am J Med 60: , Ganeval D, Noel LH, Preud homme JL, Droz D, Grunfeld JP: Light-chain deposition disease: Its relation with AL-type amyloidosis. Kidney Int 26:1-9, Walker F, Bear RA: Renal transplantation in lightchain multiple myeloma. Am J Nephrol 3:34-37, Gerlag PG, Koene RA, Berden JH: Renal transplantation in light chain nephropathy: Case report and review of the literature. Clin Nephrol 25: , Ecder T, Tbakhi A, Braun WE, et al: De novo lightchain deposition disease in a cadaver renal allograft. Am J Kidney Dis 28: , Howard AD, Moore J Jr, Tomaszewski MM: Occurrence of multiple myeloma three years after successful

5 LCDD in Renal Allograft 625 renal transplantation. Am J Kidney Dis 10: , Penn I: Occurrence of cancers in immunosuppressed organ transplant recipients. Clin Transpl 4:53-62, Sheil AGR: Cancer in Dialysis and Transplant Patients. Kidney Transplantation. Philadelphia, PA, Saunders, 1994, pp Leung N, Lager DJ, Gertz MA, et al: Long-term outcome of renal transplantation in light-chain deposition disease. Am J Kidney Dis 43: , Radl J, Valentijn RM, Haaijman JJ, Paul LC: Monoclonal gammapathies in patients undergoing immunosuppressive treatment after renal transplantation. Clin Immunol Immunopathol 37:98-102, Markowitz GS: Dysproteinemia and the kidney. Adv Anat Pathol 11:49-63, Korbet SM, Schwartz MM: Multiple myeloma. J Am Soc Nephrol 17: , Buxbaum J, Gallo G: Nonamyloidotic monoclonal immunoglobulin deposition disease. Light-chain, heavychain, and light- and heavy-chain deposition diseases. Hematol Oncol Clin North Am 13: , Dussol B, Tsimaratos M, Lerda D, et al: [Viral hepatitis C and membranoproliferative glomerulonephritis in a renal transplant patient]. Nephrologie 16: , Rosenstock JL, Markowitz GS, Valeri AM, et al: Fibrillary and immunotactoid glomerulonephritis: Distinct entities with different clinical and pathologic features. Kidney Int 63: , Pronovost PH, Brady HR, Gunning ME, Espinoza O, Rennke HG: Clinical features, predictors of disease progression and results of renal transplantation in fibrillary/immunotactoid glomerulopathy. Nephrol Dial Transplant 11: , Alpers CE, Rennke HG, Hopper J Jr, Biava CG: Fibrillary glomerulonephritis: An entity with unusual immunofluorescence features. Kidney Int 31: , Korbet SM, Rosenberg BF, Schwartz MM, Lewis EJ: Course of renal transplantation in immunotactoid glomerulopathy. Am J Med 89:91-95, Calls Ginesta J, Torras A, Ricart MJ, et al: Fibrillary glomerulonephritis and pulmonary hemorrhage in a patient with renal transplantation. Clin Nephrol 43: , Rao KV, Hafner GP, Crary GS, Anderson WR, Crosson JT: De novo immunotactoid glomerulopathy of the renal allograft: Possible association with cytomegalovirus infection. Am J Kidney Dis 24:97-103, Hartmann A, Holdaas H, Fauchald P, et al: Fifteen years experience with renal transplantation in systemic amyloidosis. Transpl Int 5:15-18, Pasternack A, Ahonen J, Kuhlback B: Renal transplantation in 45 patients with amyloidosis. Transplantation 42: , Sherif AM, Refaie AF, Sobh MA, et al: Long-term outcome of live donor kidney transplantation for renal amyloidosis. Am J Kidney Dis 42: , 2003