American Journal of Kidney Diseases
Volume 53, Issue 4 , Pages 715-718, April 2009

Proximal Tubule Cytoplasmic Fibrillary Inclusions Following Kidney Transplantation in a Patient With a Paraproteinemia

  • Sekiko Taneda, MD

      Affiliations

    • Department of Pathology, Kidney Center, Tokyo Women's Medical University, Tokyo, Japan
    • Corresponding Author InformationAddress correspondence to Sekiko Taneda, MD, 8-1 Kawada-cho, Shinjuku-ku, Tokyo, 162-8666, Japan
    • ,
  • Kazuho Honda, MD

      Affiliations

    • Department of Pathology, Kidney Center, Tokyo Women's Medical University, Tokyo, Japan
    • ,
  • Shigeru Horita, MS

      Affiliations

    • Department of Pathology, Kidney Center, Tokyo Women's Medical University, Tokyo, Japan
    • ,
  • Naohiko Tokumoto, MD

      Affiliations

    • Department of Urology, Kidney Center, Tokyo Women's Medical University, Tokyo, Japan
    • ,
  • Yoichiro Kawashima, MD

      Affiliations

    • Department of Nephrology, Toda Chuo General Hospital, Saitama, Japan
    • ,
  • Kazunari Tanabe, MD

      Affiliations

    • Department of Urology, Kidney Center, Tokyo Women's Medical University, Tokyo, Japan
    • ,
  • Yutaka Yamaguchi, MD

      Affiliations

    • Department of Pathology, Kashiwa Hospital, Jikei University School of Medicine, Chiba, Japan
    • ,
  • Hideaki Oda, MD

      Affiliations

    • Department of Pathology, Kidney Center, Tokyo Women's Medical University, Tokyo, Japan

Received 18 May 2008; accepted 6 August 2008. published online 28 October 2008.

Article Outline

Index Words: Kidney transplantation, proximal tubulopathy, cytoplasmic fibrillary inclusions, plasma cell dyscrasia

 

Plasma cell dyscrasias are characterized by excessive production of abnormal immunoglobulins, mainly of free light chains. These disorders are associated with a variety of kidney manifestations, including myeloma cast nephropathy, light and heavy chain deposition disease, amyloidosis, cryoglobulinemia, acute tubular necrosis, and inflammatory tubulointerstitial nephritis. Cast nephropathy has been well characterized in native kidneys, with reappearance after kidney transplantation in a few cases.1, 2 Casts in myeloma kidneys are seen most frequently in the distal tubules and collecting ducts,3 whereas involvement of the proximal tubules has been reported less commonly.4 In the rare case of acquired proximal tubular dysfunction complicating plasma cell dyscrasia, the characteristic pathological finding is the presence of cytoplasmic inclusions in the proximal tubular epithelium.5 These inclusions appear as crystalline bodies engorged with monoclonal light chains, causing functional disturbance of the lysosomal system in the proximal tubules and manifesting as an acquired form of Fanconi syndrome in patients with myeloma.5

Here, we report a patient who developed a progressive decrease in kidney function caused by plasma cell dyscrasia 3 months posttransplantation, with proximal tubulopathy induced by the accumulation of fibrillary cytoplasmic inclusions. Although light-chain monoclonality could not be detected in the cytoplasmic inclusions, it was observed in distal tubule casts.

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Case Report 

Clinical History 

A 64-year-old man underwent kidney transplantation from a deceased donor in June 2007 in China. The patient had been on dialysis therapy for 1 year for end-stage renal disease of unknown cause. After he returned to Japan in August 2007, he was referred to our hospital for clinical follow-up. He had been prescribed tacrolimus, mycophenolate mofetil, and methylprednisolone as immunosuppressive therapy. Because of the detection of mild proteinuria (protein, 0.7 g/dL) and rapid increase in serum creatinine level from 2.4 to 2.8 mg/dL (183 to 214 μmol/L; estimated glomerular filtration rate by using the 4-variable Modification of Diet in Renal Disease [MDRD] Study equation,6 23 to 19 mL/min/1.73 m2 [0.38 to 0.32 mL/s/1.73 m2]) within 10 days, a kidney biopsy was performed at 80 days posttransplantation.

Kidney Biopsy 

Light microscopic examination of the biopsy specimens showed swollen proximal tubules with cytoplasmic inclusions (Fig 1A) that were negative for periodic acid–Schiff staining (Fig 1B). Glomeruli and distal tubules were intact, and no evidence of rejection was detected. Direct immunofluorescence examination was negative for immunoglobulin G (IgG), IgA, IgM, IgD, and IgE and κ and λ light chains in the cytoplasm of the proximal tubules. Congo red staining was negative. Electron microscopy showed large lysosomes densely filled with fibrillary material, ranging in diameter from 15 to 20 nm (Fig 1C). Fibrillary material was composed of randomly arranged tubular structures with electron-lucent cores (Fig 1D). Some interstitial cell lysosomes were also found to contain these structures, but not glomeruli.

  • View full-size image.
  • Figure 1. 

    Pathological findings in the first biopsy specimen obtained on day 80 after transplantation. (A) Light microscopy shows engorged proximal tubular cells, whereas distal tubules and glomeruli are intact (periodic acid–Schiff; original magnification ×200). (B) Proximal tubular cells contain abundant cytoplasmic inclusion bodies, which stained negatively for periodic acid–Schiff (original magnification ×400). (C) Electron microscopy shows many enlarged lysosomes in the proximal tubular epithelium (original magnification ×6,000). (D) Proximal tubular cells show accumulation of fibrillary materials, composed of microtubular structures with an electron-lucent core and randomly arranged in longitudinal or cross-sectional arrays. Mitochondria were intact (original magnification ×15,000).

Because serum creatinine level continued to increase and reached 4.7 mg/dL (358 μmol/L; estimated glomerular filtration rate, 11 mL/min/1.73 m2 [0.18 mL/s/1.73 m2]) despite the steroid pulse therapy administered to prevent rejection, a second biopsy was conducted in the patient 180 days posttransplantation. The second biopsy specimen showed extension of the affected area of the proximal tubules compared with the first. Furthermore, cast formation in the distal tubules was also detected. Positive immunostaining for κ light chain was found in casts of distal tubules, but not in cytoplasmic inclusions of proximal tubules (Fig 2A). Immunohistochemical staining of paraffin sections using protease antigen retrieval also showed κ light chain predominance. Immunostaining for λ light chains was negative by means of both methods (Fig 2B). Electron microscopy showed numerous fibrillary materials not only in lysosomes of proximal tubular cells, but also in casts of distal tubules (Fig 2C and D). Small foci of interstitial cells containing fibrillary material were also found in the cytoplasm of interstitial cells, vascular endothelial cells, glomerular endothelial cells, podocytes, and mesangial cells (Fig 2E to H).

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  • Figure 2. 

    (A, B) Immunofluorescence examination of fibrillary materials in frozen sections of the second biopsy specimen obtained on day 180 after transplantation. Positive immunostaining for κ light chains was limited to (A) casts in the distal tubules and was not seen in the (A) proximal tubular epithelium. (B) No λ light chain deposition was detected ([A, B] original magnification ×200). (C-H) Electron micrographs of the (C, D) distal tubule and (E-H) glomerular tuft obtained from the second biopsy specimen on day 180 after transplantation. (E-H) Part of the tissue was retrieved from the paraffin block, deparaffinized, and reprocessed for electron microscopy because no glomeruli were included in the specimen for electron microscopy. (C) Casts in distal tubules contained abundant fibrillary materials, which were composed of (D) microtubular structures. Some fibrillary materials were also found in the cytoplasm of (D) vascular endothelial, (F) glomerular endothelial, (G) glomerular epithelial, and (H) mesangial cells.

Diagnosis 

Pathological changes were consistent mostly with light chain–associated proximal tubulopathy, although we were not able to reach the correct diagnosis at the first biopsy because of the lack of staining for monoclonality of κ or λ light chain.

Clinical Follow-up 

Immunoelectrophoresis of urine showed a κ type of Bence-Jones protein, and bone marrow biopsy showed an increased percentage of plasma cells (16%). Urinalysis also showed aminoaciduria. Based on these pathological and clinical findings, light chain proximal tubulopathy associated with myeloma was diagnosed. The patient underwent 3 courses of chemotherapy with the vincristine, doxorubicin, and dexamethasone regimen, and kidney function improved gradually (serum creatinine decreased from 5.6 to 3.3 mg/dL (427 to 252 μmol/L; estimated glomerular filtration rate, 9 to 16 mL/min/1.73 m2 [0.15 to 0.27 mL/s/1.73 m2]), but did not fully recover.

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Discussion 

Tubulointerstitial damage associated with plasma cell dyscrasias often is caused by cast formation in distal tubules and collecting ducts, which appears after urinary excretion of light chains exceeds the reabsorption capacity of the proximal tubules.7 Conversely, decreased proximal tubular function associated with plasma cell dyscrasias, as seen in this case, results from the cytotoxicity of light-chain immunoglobulin after it is reabsorbed into the proximal tubular cells and digested partially by cellular lysosomes.8, 9 The incidence of light chain proximal tubulopathy in renal allografts is extremely low. One case was reported of light chain proximal tubulopathy occurring 4 years posttransplantation with a progressive decrease in graft function.10 We report light chain proximal tubulopathy detected much earlier after transplantation (80 days posttransplantation). The lesions were limited primarily to proximal tubules. However, in the second biopsy specimen obtained 3 months after the first, lesions had extended to the cytoplasm of vascular endothelial and intrinsic glomerular cells, as well as the appearance of cast formation in the distal tubules. Cytoplasmic inclusions in our patient were prominent on light microscopy, and electron microscopy allowed their morphological characterization as fibrils in cellular lysosomes wrapped by a single membrane. Positive monoclonal light-chain staining usually suggests the presence of an underlying plasma cell dyscrasia.11, 12 However, unlike previously reported cases, we could not confirm monoclonal light-chain immunostaining by either immunofluorescence or immunohistochemical methods. Although we failed to identify the light-chain monoclonality in cytoplasmic inclusions, the fibrillary structures observed by using electron microscopy strongly suggested the presence of plasma cell dyscrasia as the underlying disease, and it was speculated that light chains partially digested by lysosomal enzymes may not be detectable with the available antisera because of a modification of its antigenicity.13

One clinical manifestation of light-chain proximal tubulopathy is rapid deterioration in kidney function,3 sometimes associated with Fanconi syndrome, characterized as aminoaciduria, glycosuria, and phosphaturia. The prognosis of light chain proximal tubulopathy in native kidneys is favorable if lesions are limited to the proximal tubules, and it may be possible to restore tubular function by controlling the amount of circulating light chains.3 In our case, the patient had a progressive decrease in kidney function with aminoaciduria before treatment, and kidney function improved slightly after chemotherapy.

It is not uncommon that a specific morphological finding in kidney biopsy specimens leads to proper diagnosis before clinical manifestations become apparent in patients with underlying plasma cell dyscrasia. Accumulation of fibrillary material observed on electron microscopy strongly suggests the presence of underlying plasma cell dyscrasia, and further explorations to detect monoclonality of immunoglobulin components (light or heavy chain) is necessary to make a correct diagnosis of plasma cell dyscrasia. Furthermore, this case suggests that we must be aware of the potential failure to identify light chain monoclonality in intracytoplasmic inclusions of proximal tubules because of the lack of antigenicity. Light chain proximal tubulopathy is very rare, but careful ultrastructural observation gives us a strong suspicion of this disease, and additional examination to detect an underlying plasma cell disorder is required for proper diagnosis and treatment in the early stage of this disease.

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Acknowledgements 

We gratefully acknowledge the technical assistance of Hideki Nakayama and Mayuko Kawashima.

Support: None.

Financial Disclosure: None.

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References 

  1. Taheri D, Chehrei A, Fesharakizadeh M, et al. Recurrent multiple myeloma following renal transplantation: A case report. Transplant Proc. 2007;39:1063–1065
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  12. Said SM, Assaad AM, Cerda J, Nasr SH. Light chain tubulopathy without Fanconi syndrome. Nephrol Dial Transplant. 2006;21:3589–3590
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 Originally published online as doi:10.1053/j.ajkd.2008.08.023 on October 28, 2008.

PII: S0272-6386(08)01352-8

doi:10.1053/j.ajkd.2008.08.023

American Journal of Kidney Diseases
Volume 53, Issue 4 , Pages 715-718, April 2009

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