Dysproteinemia-related nephropathy associated with crystal-storing histiocytosis
2006; Elsevier BV; Volume: 70; Issue: 3 Linguagem: Inglês
10.1038/sj.ki.5001524
ISSN1523-1755
AutoresMichael B. Stokes, B. Aronoff, David S. Siegel, Vivette D. D’Agati,
Tópico(s)Eosinophilic Disorders and Syndromes
ResumoCASE PRESENTATION A 41-year-old white man presented with a 6-month history of worsening neck pain accompanied by 20 lb weight loss. He was initially referred to an orthopedic surgeon and work-up including magnetic resonance imaging revealed shoulder bursitis for which he received a steroid injection. However, neck pain continued and laboratory tests revealed anemia and renal insufficiency, leading to his referral to an internist. The patient had no significant past medical history or family history of renal disease and he was not taking any medications. Physical examination revealed temporal wasting but was otherwise unremarkable. Laboratory investigations revealed the following: blood urea nitrogen 32 mg/dl (normal 7–25 mg/dl), serum creatinine 4.2 mg/dl (normal 0.5–1.4 mg/dl), serum calcium 9.8 mg/dl (normal 8.5–10.4 mg/dl), phosphorous 4.3 mg/dl (normal 2.5–4.5 mg/dl), sodium 143 mmol/l (normal 135–146 mmol/l), potassium 3.6 mmol/l (normal 3.5–5.3 mmol/l), chloride 109 mmol/l (normal 98–110 mmol/l), bicarbonate 17 mmol/l (normal 21–33 mmol/l), glucose 95 (normal 65–139 mg/dl), lactate dehydrogenase 505 (normal 105–333 IU/l), white blood cell count 9800/μl, hemoglobin 9.7 g/dl, hematocrit 28.3%, and platelet count 316 000/μl. Erythrocyte sedimentation rate was markedly elevated (>100 mm/h). Total serum protein was 8.8 g/dl (normal 6.0–8.3 g/dl), serum albumin was 4.2 g/dl (normal 3.5–4.9 g/dl), and β2-microglobulin was elevated (10.7 mg/l, normal <1.85 mg/l). Quantitative serum immunoglobulins (Ig) revealed elevated IgD (842 mg/dl, normal 0–14 mg/dl) and decreased levels of IgG (450 mg/dl, normal 694–1618 mg/dl), IgA (32 mg/dl, normal 81–463 mg/dl), and IgM (9.9 mg/dl, normal 48–271 mg/dl). Serum protein electrophoresis revealed a monoclonal spike (0.82 g/dl) with IgD kappa (κ) specificity, elevated free κ light chains (81 200 mg/l, normal range 3.3–19.4 mg/l), and normal level of lambda (λ) light chains (10.6 mg/l, normal range 5.7–26.3 mg/l). Urinalysis revealed 100 mg/dl glucose; these findings, together with the normal serum glucose, normal serum phosphate, and low serum bicarbonate levels, suggested partial Fanconi's syndrome. Urinalysis also revealed 1+protein; however, 24-h urine collection contained 20.2 g protein of which 13.975 g (69.2%) consisted of free κ light chains. Bone marrow examination revealed diffuse infiltration by IgD κ-positive plasma cells, accounting for 50% of overall cellularity, consistent with multiple myeloma. Based on the finding of significant urinary light chain excretion, the patient's multiple myeloma was stage III-B. A skeletal survey revealed no bony lesions, and magnetic resonance imaging of the axial skeleton revealed marrow abnormalities consistent with myeloma but no osseous lesions. Given the new onset of renal insufficiency and partial Fanconi's syndrome with massive urinary light chain excretion, a renal biopsy was performed to determine the pattern of dysproteinemia-related renal disease. Light microscopic examination revealed 12 glomeruli, two of which were globally sclerotic. The non-sclerotic glomeruli showed moderate hypertrophy and mild mesangial hypercellularity and accumulations of matrix. No mesangial nodules were seen. Glomerular basement membranes showed segmental duplication with cellular interposition but most peripheral capillary lumina were patent. Tubules contained fractured, intensely eosinophilic casts that stained weakly or negative with periodic acid-Schiff and showed polychromatic (blue–red) staining with trichrome stain, and were surrounded by mononuclear cells and focal multinucleate cells (Figure 1). Proximal tubules demonstrated widespread degenerative and regenerative changes, including cytoplasmic simplification, nuclear enlargement, and prominent nucleoli. Proximal tubular epithelial cells (Figure 2) and interstitial cells (Figure 3) contained abundant needle-shaped eosinophilic intracytoplasmic crystalline inclusions. The interstitial cells stained with the immunohistochemical marker CD68, confirming their histiocytic origin (Figure 4). Severe tubular atrophy and interstitial fibrosis were noted, accompanied by a patchy mononuclear inflammatory cell infiltrate. Arterial vessels showed moderate medial sclerosis and intimal fibrosis. Congo Red stain was negative for amyloid.Figure 2Tubular epithelium displays eosinophilic needle-shaped intracytoplasmic crystalline inclusions (arrow) (hematoxylin and eosin stain; original magnification × 1000).View Large Image Figure ViewerDownload (PPT)Figure 3Numerous interstitial cells display eosinophilic needle-shaped intracytoplasmic crystalline inclusions (hematoxylin and eosin stain; original magnification × 1000).View Large Image Figure ViewerDownload (PPT)Figure 4Interstitial cells stain for CD68 confirming histiocytic phenotype. Some of these cells display intracytoplasmic crystals (arrow) (immunoperoxidase stain, original magnification × 600).View Large Image Figure ViewerDownload (PPT) Immunofluorescence microscopy performed on frozen tissue revealed intense (3+) staining of the atypical tubular casts for κ light chain only. Interstitial histiocytes and tubular epithelial cells showed 2+ cytoplasmic staining for κ light chain. In addition, there was diffuse 2+ linear staining of glomeruli, tubular basement membranes, and perimyocyte basement membranes for κ light chain. There was no specific staining of glomeruli, tubular basement membranes, interstitium, or vessels for IgG, IgA, IgM, C3, C1, fibrinogen, albumin, or λ light chain. Electron microscopy revealed needle-shaped and rhomboid intracytoplasmic inclusions in interstitial histiocytes and proximal tubular epithelium (Figure 5), but not in podocytes or other glomerular cells. These inclusions were mostly electron dense, with focal areas of electron lucency, but did not show a periodic substructure. In some areas, the inclusions were associated with a single unit membrane (Figure 6). Tubules contained amorphous electron dense casts. No fibrillar, granular, or immune type electron densities were seen. Podocytes showed minimal foot process effacement.Figure 6Tubular epithelium contains intracytoplasmic rhomboid-shaped electron-dense crystalline structures, focally accompanied by a unit membrane (arrow) (electron micrograph; original magnification × 12 000).View Large Image Figure ViewerDownload (PPT) No histiocyte aggregates were seen by light microscopy in the bone marrow biopsy and no electron microscopy was performed. 1.Light chain cast nephropathy (LCCN), κ type.2.Light chain Fanconi's syndrome (LCFS), κ type3.Crystal-storing histiocytosis (CSH). The findings of fractured crystalline tubular casts staining for κ light chain and surrounded by mononuclear inflammatory cells were diagnostic of LCCN, κ type. The presence of numerous, needle-shaped crystalline inclusions staining for κ light chain within proximal tubular epithelium, together with the clinical evidence of tubular dysfunction (low serum bicarbonate and glycosuria, with normal blood glucose), was consistent with LCFS, whereas the finding of numerous crystal-laden interstitial histiocytes indicated renal involvement by CSH. The patient was treated initially with pulse dexamethasone, followed by a combination of pulse dexamethasone, thalidomide 200 mg/day, and bortezomib 1.5 mg/m2 in a standard administration regimen. The patient also received monthly zoledronate, allopurinol, furosemide, sodium bicarbonate, and erythropoietin. Following one cycle of chemotherapy, serum creatinine had declined to 2.4 mg/dl and urinary protein excretion had decreased to 2.2 g/day, with trace urine monoclonal component and free κ light chains detected by immunofixation. Repeat serum protein electrophoresis and immunofixation revealed no monoclonal IgD component and markedly reduced free κ light chains 23 mg/dl (normal range 3.3–19.4 mg/l). A repeat bone marrow biopsy performed after 4 months showed no evidence of residual plasma cell myeloma. Five months following the diagnosis of myeloma, the patient underwent autologous stem cell transplantation conditioned by melphalan 200 mg/m2, followed 4 months later by low-dose total body irradiation and allogeneic peripheral blood stem cell transplantation from a human leukocyte antigen-identical sibling. Post-transplant immunosuppression consisted of cyclosporine 400 mg b.i.d and mycophenolate mofetil 1250 mg b.i.d. At last follow-up (2 months post-allogeneic peripheral blood stem cell transplantation and 11 months post-renal biopsy), serum bicarbonate was 22 mg/dl (normal 21–33 mmol/l) and urinalysis was negative for glucose, indicating improvement of Fanconi's syndrome. However, serum creatinine remained elevated at 2.2 mg/dl. Dysproteinemia, characterized by synthesis of a monoclonal Ig by neoplastic B lymphocytes, is associated with diverse forms of kidney disease including several that are related to precipitation or deposition of monoclonal Ig in the form of casts, fibrils, granular deposits, or crystals.1.Markowitz G.S. Dysproteinemia and the kidney.Adv Anat Pathol. 2004; 11: 49-63Crossref PubMed Scopus (69) Google Scholar The commonest form of nephropathy disease in myeloma patients with acute renal failure is LCCN, also known as myeloma cast nephropathy, characterized by crystalline intratubular casts composed of monoclonal κ or λ light chain, together with Tamm-Horsfall protein. Fibrillar Ig deposits occur in light chain amyloidosis (AL) and amorphous granular deposits are seen in monoclonal immunoglobulin deposition disease.2.Lin J. Markowitz G.S. Valeri A.M. et al.Renal monoclonal immunoglobulin deposition disease: the disease spectrum.J Am Soc Nephrol. 2001; 12: 1482-1492PubMed Google Scholar Less commonly, monoclonal Ig forms intracellular crystals within the cytoplasm of infiltrating neoplastic plasma cells, histiocytes, or renal epithelial cells, or forms massive extracellular crystalline deposits in Bowman space, interstitium, or within blood vessels.3.Chen K.J. Jan Y.J. Chen C.H. et al.Multiple myeloma-associated cast nephropathy with crystal structure: case report and review of the literature.Nephrology (Carlton). 2005; 10: 594-596Crossref PubMed Scopus (14) Google Scholar, 4.Dornan T.L. Blundell J.W. Morgan A.G. et al.Widespread crystallisation of paraprotein in myelomatosis.Q J Med. 1985; 57: 659-667PubMed Google Scholar, 5.Hirota S. Miyamoto M. Kasugai T. et al.Crystalline light-chain deposition and amyloidosis in the thyroid gland and kidneys of a patient with myeloma.Arch Pathol Lab Med. 1990; 114: 429-431PubMed Google Scholar, 6.Kanno Y. Okada H. Nemoto H. et al.Crystal nephropathy: a variant form of myeloma kidney – a case report and review of the literature.Clin Nephrol. 2001; 56: 398-401PubMed Google Scholar The present case displayed an unusual combination of morphologic findings that has not been described previously in myeloma-associated nephropathy, namely LCCN with coexistent intracytoplasmic crystalline Ig deposits within interstitial histiocytes and proximal tubular epithelial cells. Intracytoplasmic crystalline Ig deposits may occur in proximal tubular epithelial cells, infiltrating neoplastic plasma cells, interstitial histiocytes, and glomerular epithelial cells. Proximal tubular Ig crystals, usually of κ light chain, are associated with LCFS and clinical signs of tubular dysfunction including glycosuria, aminoaciduria, hypophosphatemia, metabolic acidosis, and renal insufficiency.1.Markowitz G.S. Dysproteinemia and the kidney.Adv Anat Pathol. 2004; 11: 49-63Crossref PubMed Scopus (69) Google Scholar In rare LCFS patients with coexistent LCCN, as in the present case, the clinical presentation is usually dominated by acute renal failure. Crystalline Ig deposits occur within the cytoplasm of interstitial histiocytes in CSH, a rare complication of multiple myeloma or other lymphoproliferative disorders showing plasmacytic differentiation including plasma cell granuloma or extramedullary plasmacytoma.7.Garcia J.F. Sanchez E. Lloret E. et al.Crystal-storing histiocytosis and immunocytoma associated with multifocal fibrosclerosis.Histopathology. 1998; 33: 459-464Crossref PubMed Scopus (46) Google Scholar, 8.Ionescu D.N. Pierson D.M. Qing G. et al.Pulmonary crystal-storing histiocytoma.Arch Pathol Lab Med. 2005; 129: 1159-1163PubMed Google Scholar, 9.Jones D. Bhatia V.K. Krausz T. Pinkus G.S. Crystal-storing histiocytosis: a disorder occurring in plasmacytic tumors expressing immunoglobulin kappa light chain.Hum Pathol. 1999; 30: 1441-1448Abstract Full Text PDF PubMed Scopus (116) Google Scholar, 10.Lebeau A. Zeindl-Eberhart E. Muller E.C. et al.Generalized crystal-storing histiocytosis associated with monoclonal gammopathy: molecular analysis of a disorder with rapid clinical course and review of the literature.Blood. 2002; 100: 1817-1827PubMed Google Scholar, 11.Schaefer H.E. Gammopathy-related crystal-storing histiocytosis, pseudo- and pseudo-pseudo-Gaucher cells. Critical commentary and mini-review.Pathol Res Pract. 1996; 192: 1152-1162Crossref PubMed Scopus (53) Google Scholar, 12.Sethi S. Cuiffo B.P. Pinkus G.S. Rennke H.G. Crystal-storing histiocytosis involving the kidney in a low-grade B-cell lymphoproliferative disorder.Am J Kidney Dis. 2002; 39: 183-188Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar CSH usually involves the bone marrow but may also involve extramedullary sites, including cornea and kidney.7.Garcia J.F. Sanchez E. Lloret E. et al.Crystal-storing histiocytosis and immunocytoma associated with multifocal fibrosclerosis.Histopathology. 1998; 33: 459-464Crossref PubMed Scopus (46) Google Scholar, 13.Papla B. Spolnik P. Rzenno E. et al.Generalized crystal-storing histiocytosis as a presentation of multiple myeloma: a case with a possible pro-aggregation defect in the immunoglobulin heavy chain.Virchows Arch. 2004; 445: 83-89PubMed Google Scholar, 14.Zioni F. Giovanardi P. Bozzoli M. et al.Massive bone marrow crystal-storing histiocytosis in a patient with IgA-lambda multiple myeloma and extensive extramedullary disease. A case report.Tumori. 2004; 90: 348-351PubMed Google Scholar In addition to the present case, nine previous case reports described dysproteinemia-related nephropathy with renal interstitial infiltration by Ig crystal-containing histiocytes (Table 1).7.Garcia J.F. Sanchez E. Lloret E. et al.Crystal-storing histiocytosis and immunocytoma associated with multifocal fibrosclerosis.Histopathology. 1998; 33: 459-464Crossref PubMed Scopus (46) Google Scholar, 10.Lebeau A. Zeindl-Eberhart E. Muller E.C. et al.Generalized crystal-storing histiocytosis associated with monoclonal gammopathy: molecular analysis of a disorder with rapid clinical course and review of the literature.Blood. 2002; 100: 1817-1827PubMed Google Scholar, 13.Papla B. Spolnik P. Rzenno E. et al.Generalized crystal-storing histiocytosis as a presentation of multiple myeloma: a case with a possible pro-aggregation defect in the immunoglobulin heavy chain.Virchows Arch. 2004; 445: 83-89PubMed Google Scholar, 15.Takahashi K. Naito M. Takatsuki K. et al.Multiple myeloma, IgA kappa type, accompanying crystal-storing histiocytosis and amyloidosis.Acta Pathol Jpn. 1987; 37: 141-154PubMed Google Scholar, 16.Carstens P.H. Woo D. Crystalline glomerular inclusions in multiple myeloma.Am J Kidney Dis. 1989; 14: 56-60Abstract Full Text PDF PubMed Scopus (29) Google Scholar, 17.Yamamoto T. Hishida A. Honda N. et al.Crystal-storing histiocytosis and crystalline tissue deposition in multiple myeloma.Arch Pathol Lab Med. 1991; 115: 351-354PubMed Google Scholar, 18.Keller L.S. Faull R.J. Smith P. et al.Crystalloid deposits in the kidney.Nephrology (Carlton). 2005; 10: 81-83Crossref PubMed Scopus (24) Google Scholar, 19.Tomioka M. Ueki K. Nakahashi H. et al.Widespread crystalline inclusions affecting podocytes, tubular cells and interstitial histiocytes in the myeloma kidney.Clin Nephrol. 2004; 62: 229-233Crossref PubMed Google Scholar, 20.Tholouli E. Krebs M. Reeve R. Houghton J.B. Crystal-storing histiocytosis in a patient with IgG kappa multiple myeloma.Br J Haematol. 2005; 128: 412Crossref PubMed Scopus (11) Google Scholar Nine patients had multiple myeloma and one had multiorgan involvement by immunocytoma.7.Garcia J.F. Sanchez E. Lloret E. et al.Crystal-storing histiocytosis and immunocytoma associated with multifocal fibrosclerosis.Histopathology. 1998; 33: 459-464Crossref PubMed Scopus (46) Google Scholar Eight of these 10 subjects also had crystal-containing cells in bone marrow (involving either histiocytes or neoplastic plasma cells). Seven patients had acute renal failure, and renal function status for the other three individuals was not provided.7.Garcia J.F. Sanchez E. Lloret E. et al.Crystal-storing histiocytosis and immunocytoma associated with multifocal fibrosclerosis.Histopathology. 1998; 33: 459-464Crossref PubMed Scopus (46) Google Scholar, 10.Lebeau A. Zeindl-Eberhart E. Muller E.C. et al.Generalized crystal-storing histiocytosis associated with monoclonal gammopathy: molecular analysis of a disorder with rapid clinical course and review of the literature.Blood. 2002; 100: 1817-1827PubMed Google Scholar All 10 cases were associated with a κ-containing serum paraprotein (IgG κ, seven; IgA κ, two; IgD κ, one) and nine also displayed κ Bence–Jones proteinuria. Eight cases showed intracytoplasmic crystals within other renal cells besides interstitial histiocytes, including tubular epithelium,13.Papla B. Spolnik P. Rzenno E. et al.Generalized crystal-storing histiocytosis as a presentation of multiple myeloma: a case with a possible pro-aggregation defect in the immunoglobulin heavy chain.Virchows Arch. 2004; 445: 83-89PubMed Google Scholar, 16.Carstens P.H. Woo D. Crystalline glomerular inclusions in multiple myeloma.Am J Kidney Dis. 1989; 14: 56-60Abstract Full Text PDF PubMed Scopus (29) Google Scholar, 17.Yamamoto T. Hishida A. Honda N. et al.Crystal-storing histiocytosis and crystalline tissue deposition in multiple myeloma.Arch Pathol Lab Med. 1991; 115: 351-354PubMed Google Scholar, 18.Keller L.S. Faull R.J. Smith P. et al.Crystalloid deposits in the kidney.Nephrology (Carlton). 2005; 10: 81-83Crossref PubMed Scopus (24) Google Scholar, 19.Tomioka M. Ueki K. Nakahashi H. et al.Widespread crystalline inclusions affecting podocytes, tubular cells and interstitial histiocytes in the myeloma kidney.Clin Nephrol. 2004; 62: 229-233Crossref PubMed Google Scholar, 20.Tholouli E. Krebs M. Reeve R. Houghton J.B. Crystal-storing histiocytosis in a patient with IgG kappa multiple myeloma.Br J Haematol. 2005; 128: 412Crossref PubMed Scopus (11) Google Scholar visceral epithelial cells,13.Papla B. Spolnik P. Rzenno E. et al.Generalized crystal-storing histiocytosis as a presentation of multiple myeloma: a case with a possible pro-aggregation defect in the immunoglobulin heavy chain.Virchows Arch. 2004; 445: 83-89PubMed Google Scholar, 15.Takahashi K. Naito M. Takatsuki K. et al.Multiple myeloma, IgA kappa type, accompanying crystal-storing histiocytosis and amyloidosis.Acta Pathol Jpn. 1987; 37: 141-154PubMed Google Scholar, 16.Carstens P.H. Woo D. Crystalline glomerular inclusions in multiple myeloma.Am J Kidney Dis. 1989; 14: 56-60Abstract Full Text PDF PubMed Scopus (29) Google Scholar, 17.Yamamoto T. Hishida A. Honda N. et al.Crystal-storing histiocytosis and crystalline tissue deposition in multiple myeloma.Arch Pathol Lab Med. 1991; 115: 351-354PubMed Google Scholar, 18.Keller L.S. Faull R.J. Smith P. et al.Crystalloid deposits in the kidney.Nephrology (Carlton). 2005; 10: 81-83Crossref PubMed Scopus (24) Google Scholar, 19.Tomioka M. Ueki K. Nakahashi H. et al.Widespread crystalline inclusions affecting podocytes, tubular cells and interstitial histiocytes in the myeloma kidney.Clin Nephrol. 2004; 62: 229-233Crossref PubMed Google Scholar and parietal epithelial cells;16.Carstens P.H. Woo D. Crystalline glomerular inclusions in multiple myeloma.Am J Kidney Dis. 1989; 14: 56-60Abstract Full Text PDF PubMed Scopus (29) Google Scholar, 17.Yamamoto T. Hishida A. Honda N. et al.Crystal-storing histiocytosis and crystalline tissue deposition in multiple myeloma.Arch Pathol Lab Med. 1991; 115: 351-354PubMed Google Scholar two cases described crystals within mesangial cells and glomerular endothelial cells.13.Papla B. Spolnik P. Rzenno E. et al.Generalized crystal-storing histiocytosis as a presentation of multiple myeloma: a case with a possible pro-aggregation defect in the immunoglobulin heavy chain.Virchows Arch. 2004; 445: 83-89PubMed Google Scholar, 16.Carstens P.H. Woo D. Crystalline glomerular inclusions in multiple myeloma.Am J Kidney Dis. 1989; 14: 56-60Abstract Full Text PDF PubMed Scopus (29) Google Scholar In two cases, renal infiltration by neoplastic plasma cells was identified,15.Takahashi K. Naito M. Takatsuki K. et al.Multiple myeloma, IgA kappa type, accompanying crystal-storing histiocytosis and amyloidosis.Acta Pathol Jpn. 1987; 37: 141-154PubMed Google Scholar, 17.Yamamoto T. Hishida A. Honda N. et al.Crystal-storing histiocytosis and crystalline tissue deposition in multiple myeloma.Arch Pathol Lab Med. 1991; 115: 351-354PubMed Google Scholar including one subject who also showed AL amyloid deposits in other organs, but not in the kidney.17.Yamamoto T. Hishida A. Honda N. et al.Crystal-storing histiocytosis and crystalline tissue deposition in multiple myeloma.Arch Pathol Lab Med. 1991; 115: 351-354PubMed Google Scholar In addition to the present case, two other patients displayed atypical crystalline casts consistent with coexistent LCCN.17.Yamamoto T. Hishida A. Honda N. et al.Crystal-storing histiocytosis and crystalline tissue deposition in multiple myeloma.Arch Pathol Lab Med. 1991; 115: 351-354PubMed Google Scholar, 19.Tomioka M. Ueki K. Nakahashi H. et al.Widespread crystalline inclusions affecting podocytes, tubular cells and interstitial histiocytes in the myeloma kidney.Clin Nephrol. 2004; 62: 229-233Crossref PubMed Google Scholar Nine patients received therapy for the hematologic malignancy that included chemotherapy in seven, prednisone only in one, and autologous stem cell transplantation in three. Six patients died (from 7 to 60 months post-diagnosis) and four had stable renal function following therapies that included autologous stem cell transplantation and chemotherapy.Table 1Dysproteinemia-related nephropathy associated with crystal-containing interstitial histiocytesParaproteinLocation of crystal-containing cellsAuthorRef.Age/sexSerumUrineRenal failureBone marrowGlomerulusTEHistiocyteAtypical castsOtherDiagnosisTakahashi et al.15.Takahashi K. Naito M. Takatsuki K. et al.Multiple myeloma, IgA kappa type, accompanying crystal-storing histiocytosis and amyloidosis.Acta Pathol Jpn. 1987; 37: 141-154PubMed Google Scholar60/mIgA κκYesHVECUYesNoMM cellsMM–AL–CSHCarstens and Woo16.Carstens P.H. Woo D. Crystalline glomerular inclusions in multiple myeloma.Am J Kidney Dis. 1989; 14: 56-60Abstract Full Text PDF PubMed Scopus (29) Google Scholar57/mIgGκYesPCVEC; PEC; mes; endoYesYesNoMM–renal CSHYamamoto et al.17.Yamamoto T. Hishida A. Honda N. et al.Crystal-storing histiocytosis and crystalline tissue deposition in multiple myeloma.Arch Pathol Lab Med. 1991; 115: 351-354PubMed Google Scholar71/mIgG κκYesPC; HVEC; PECYesYesYesMM cellsMM–CSH–LCCNGarcia et al.7.Garcia J.F. Sanchez E. Lloret E. et al.Crystal-storing histiocytosis and immunocytoma associated with multifocal fibrosclerosis.Histopathology. 1998; 33: 459-464Crossref PubMed Scopus (46) Google Scholar44/mIgG κNoneUHNoNoYesNoImmunocytoma–CSHLebeau et al.10.Lebeau A. Zeindl-Eberhart E. Muller E.C. et al.Generalized crystal-storing histiocytosis associated with monoclonal gammopathy: molecular analysis of a disorder with rapid clinical course and review of the literature.Blood. 2002; 100: 1817-1827PubMed Google Scholar73/mIgA κκUPC; HNoNoYesNoMM–CSHKeller et al.18.Keller L.S. Faull R.J. Smith P. et al.Crystalloid deposits in the kidney.Nephrology (Carlton). 2005; 10: 81-83Crossref PubMed Scopus (24) Google Scholar56/mIgG κκYesYesVECYesYesNoMM–CSHPapla et al.13.Papla B. Spolnik P. Rzenno E. et al.Generalized crystal-storing histiocytosis as a presentation of multiple myeloma: a case with a possible pro-aggregation defect in the immunoglobulin heavy chain.Virchows Arch. 2004; 445: 83-89PubMed Google Scholar51/mIgG κκUHVEC; endo; mesYesYesNoMM–CSHTomioka et al.19.Tomioka M. Ueki K. Nakahashi H. et al.Widespread crystalline inclusions affecting podocytes, tubular cells and interstitial histiocytes in the myeloma kidney.Clin Nephrol. 2004; 62: 229-233Crossref PubMed Google Scholar46/fIgG κκYesPC; HVECYesYesYesMM–CSH–LCCNTholouli et al.20.Tholouli E. Krebs M. Reeve R. Houghton J.B. Crystal-storing histiocytosis in a patient with IgG kappa multiple myeloma.Br J Haematol. 2005; 128: 412Crossref PubMed Scopus (11) Google Scholar62/fIgG κκYesNoNoYesYesNoMM–renal CSHPresent case41/mIgD κκYesNoNoYesYesYesMM–renal CSH–LCCNAL, light chain amyloidosis; BM, bone marrow; CSH, crystal-storing histiocytosis; endo, glomerular endothelial cell; f, female; FSGS, focal segmental glomerulosclerosis; H, histiocyte; LCCN, light chain cast nephropathy; LCFS, light chain Fanconi's syndrome; m, male; mes, mesangial cell; MM, multiple myeloma; MZL, marginal zone lymphoma; PC, plasma cell; PEC, parietal epithelial cell; SRF, stable renal function; STTx, stem cell transplant; TE, tubular epithelial cell; U, unknown/not stated; VEC, visceral epithelial cell. Open table in a new tab AL, light chain amyloidosis; BM, bone marrow; CSH, crystal-storing histiocytosis; endo, glomerular endothelial cell; f, female; FSGS, focal segmental glomerulosclerosis; H, histiocyte; LCCN, light chain cast nephropathy; LCFS, light chain Fanconi's syndrome; m, male; mes, mesangial cell; MM, multiple myeloma; MZL, marginal zone lymphoma; PC, plasma cell; PEC, parietal epithelial cell; SRF, stable renal function; STTx, stem cell transplant; TE, tubular epithelial cell; U, unknown/not stated; VEC, visceral epithelial cell. Several additional case reports have described nephropathy with crystalline Ig involving renal cells other than interstitial histiocytes. In one patient who developed renal failure in the setting of CSH and multiple myeloma crystalline Ig deposits were confined to Bowman's space. Hirota et al.5.Hirota S. Miyamoto M. Kasugai T. et al.Crystalline light-chain deposition and amyloidosis in the thyroid gland and kidneys of a patient with myeloma.Arch Pathol Lab Med. 1990; 114: 429-431PubMed Google Scholar described a case of multiple myeloma and AL amyloidosis with Bence–Jones λ light chain proteinuria, with features of LCCN, renal amyloidosis, and extracellular λ crystals that localized in the vicinity of Bowman's capsule and vessels and Truong et al.21.Truong L.D. Mawad J. Cagle P. Mattioli C. Cytoplasmic crystals in multiple myeloma-associated Fanconi's syndrome. A morphological study including immunoelectron microscopy.Arch Pathol Lab Med. 1989; 113: 781-785PubMed Google Scholar described a case of multiple myeloma with λ LCFS and massive renal infiltration by crystal-laden neoplastic plasma cells. In one case associated with a low-grade B-cell lymphoproliferative disorder, renal involvement was limited to mesangial infiltration by crystal-laden histiocytes.12.Sethi S. Cuiffo B.P. Pinkus G.S. Rennke H.G. Crystal-storing histiocytosis involving the kidney in a low-grade B-cell lymphoproliferative disorder.Am J Kidney Dis. 2002; 39: 183-188Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar One other report described a patient with benign monoclonal gammopathy and nephrotic syndrome whose renal biopsy showed crystalline Ig predominantly involving podocytes, with focal involvement of parietal epithelial cells and distal tubular epithelial cells.22.Matsuyama N. Joh K. Yamaguchi Y. et al.Crystalline inclusions in the glomerular podocytes in a patient with benign monoclonal gammopathy and focal segmental glomerulosclerosis.Am J Kidney Dis. 1994; 23: 859-865Abstract Full Text PDF PubMed Scopus (30) Google Scholar Most cases with renal crystalline Ig deposits are associated with multiple myeloma and Bence–Jones proteinuria, suggesting that the filtered load of paraprotein might be an important determinant of renal Ig crystallogenesis. This interpretation is supported by the observation that 60% of patients with renal crystal-laden interstitial histiocytes also display visceral epithelial cell crystals. The presence of interstitial histiocytes in these cases is presumably a reaction to leakage of filtered κ paraprotein via damaged or over-burdened tubules. However, the relative rarity of renal crystalline Ig deposition in patients with multiple myeloma and Bence–Jones proteinuria implies that other factors besides filtered Ig load must play a role. These factors likely include inherent physicochemical properties related to the primary amino-acid sequence that influence protein folding, resistance to proteolytic degradation, and interactions with other molecules in the local environment, as well as general environmental factors, such as dehydration and metabolic acidosis, that have been shown to play a role in LCCN and other forms of dysproteinemia-related Ig deposition.23.Davis D.P. Gallo G. Vogen S.M. et al.Both the environment and somatic mutations govern the aggregation pathway of pathogenic immunoglobulin light chain.J Mol Biol. 2001; 313: 1021-1034Crossref PubMed Scopus (51) Google Scholar Most crystalline Ig deposits, including those seen in LCFS and CSH, consist of κ light chain deposits, strongly suggesting that the light chain isotype is a major determinant of crystallogenesis. The majority of light chains that crystallize in the proximal tubules in LCFS belong to the Vκ1 variability subgroup and most of these are encoded by the LC02/012 germ line.24.Messiaen T. Deret S. Mougenot B. et al.Adult Fanconi syndrome secondary to light chain gammopathy. Clinicopathologic heterogeneity and unusual features in 11 patients.Medicine (Baltimore). 2000; 79: 135-154Crossref PubMed Scopus (170) Google Scholar In addition, these κ light chains frequently display an unusual hydrophobic residue in position 30 of the V domain that may contribute to crystal formation.25.Aucouturier P. Bauwens M. Khamlichi A.A. et al.Monoclonal Ig L chain and L chain V domain fragment crystallization in myeloma-associated Fanconi's syndrome.J Immunol. 1993; 150: 3561-3568PubMed Google Scholar Leboulleux et al.26.Leboulleux M. Lelongt B. Mougenot B. et al.Protease resistance and binding of Ig light chains in myeloma-associated tubulopathies.Kidney Int. 1995; 48: 72-79Abstract Full Text PDF PubMed Scopus (98) Google Scholar have shown that the crystals in LCFS are resistant to proteolytic cleavage in vitro, suggesting that crystal accumulation within lysosomes may result from resistance to degradation. By analogy, the persistence of crystals within histiocytes in CSH suggests impaired degradation. Interestingly, in a recent case report of CSH that later evolved to myeloma, Lebeau et al.10.Lebeau A. Zeindl-Eberhart E. Muller E.C. et al.Generalized crystal-storing histiocytosis associated with monoclonal gammopathy: molecular analysis of a disorder with rapid clinical course and review of the literature.Blood. 2002; 100: 1817-1827PubMed Google Scholar also identified Vκ1 light chain with several unusual amino-acid substitutions, some of which were previously described in cases of AL amyloidosis. These findings support a common pathomechanism in LCFS and CSH involving sequence abnormalities at specific amino-acid sites in the κ light chain molecule that promote crystallogenesis or interfere with intralysosomal degradation. No association with specific Ig heavy chain subtype has been identified in CSH.5.Hirota S. Miyamoto M. Kasugai T. et al.Crystalline light-chain deposition and amyloidosis in the thyroid gland and kidneys of a patient with myeloma.Arch Pathol Lab Med. 1990; 114: 429-431PubMed Google Scholar However, Papla et al.13.Papla B. Spolnik P. Rzenno E. et al.Generalized crystal-storing histiocytosis as a presentation of multiple myeloma: a case with a possible pro-aggregation defect in the immunoglobulin heavy chain.Virchows Arch. 2004; 445: 83-89PubMed Google Scholar identified a biochemically abnormal IgG κ in a case of CSH, characterized by abnormally high proteolytic susceptibility of the γ heavy chain and increased aggregation tendency that likely resulted from its low structural stability. Although the identity of κ light chain in tubular epithelium and interstitial histiocytes was not confirmed in the present case, it seems reasonable to speculate that similar mechanisms contributed to intracytoplasmic crystal formation in tubular epithelium and in interstitial histiocytes. The unusual finding in the present case of coexistence of LCCN with crystalline Ig deposits in interstitial histiocytes and proximal tubular epithelium supports a major role for post-synthetic handling of filtered monoclonal κ light chain in determining the localization of monoclonal Ig deposits within renal subcompartments in dysproteinemia-related nephropathy. The prognostic significance of renal biopsy findings of CSH is unknown. Interestingly, prolonged survival has been reported in some myeloma patients with CSH, perhaps reflecting earlier detection of hematologic disease owing to organ involvement by crystal-laden cells.9.Jones D. Bhatia V.K. Krausz T. Pinkus G.S. Crystal-storing histiocytosis: a disorder occurring in plasmacytic tumors expressing immunoglobulin kappa light chain.Hum Pathol. 1999; 30: 1441-1448Abstract Full Text PDF PubMed Scopus (116) Google Scholar On the other hand, renal involvement by CSH, particularly if accompanied by signs of renal failure, may have a poor prognosis.9.Jones D. Bhatia V.K. Krausz T. Pinkus G.S. Crystal-storing histiocytosis: a disorder occurring in plasmacytic tumors expressing immunoglobulin kappa light chain.Hum Pathol. 1999; 30: 1441-1448Abstract Full Text PDF PubMed Scopus (116) Google Scholar Therapy should be directed at the underlying hematologic malignancy. Although the presence of coexistent myeloma cast nephropathy might be predicted to adversely affect renal outcome, aggressive therapy of the underlying hematologic disorder may stabilize renal function in patients with renal CSH, as per the present case, presumably via reduced synthesis and glomerular filtration of the pathogenic light chain. In summary, renal infiltration by histiocytes containing crystalline Ig is a rare complication of dysproteinemia that is usually associated with multiple myeloma, κ light chain Bence–Jones proteinuria, and bone marrow involvement by CSH. Most cases also display Ig crystals in other renal epithelial cells, and a minority display coexistent LCCN. The renal presentation is usually dominated by acute renal failure that is likely related to a combination of tissue infiltration by crystal-laden histiocytes and acute tubular injury owing to the presence of intracytoplasmic crystals and/or LCCN. Despite the striking histologic injury, the findings of coexistent myeloma cast nephropathy, LCFS, and renal CSH do not necessarily portend a poor renal outcome. As this case illustrates, aggressive therapy directed to the hematologic malignancy can reverse the Fanconi's syndrome and stabilize renal function.
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