Clin Exp Nephrol DOI 10.1007/s10157-015-1187-y
LETTER TO THE EDITOR
Crystalline cast nephropathy in a patient with IgD lambda myeloma Satoshi Kumakura1 • Izaya Nakaya1 • Tsutomu Sakuma2 • Hiroshi Sato3 Jun Soma1
•
Received: 27 August 2015 / Accepted: 16 October 2015 Ó Japanese Society of Nephrology 2015
To the Editor A 72-year-old woman was admitted at our department for renal dysfunction with general fatigue and loss of appetite for 2 months. She had no remarkable past medical history except hypertension, which was treated with angiotensin-converting enzyme inhibitor and a calcium channel blocker. Physical examination was unremarkable, except for pale conjunctivae. Urinary protein to creatinine ratio was 9.5 g/gCr, revealing a large discrepancy from the result of mild proteinuria by urinary dipstick (2?; indicating 100–300 mg/L). No hematuria was found. Serum creatinine level was increased to 1.90 mg/ dL associated with anemia (hemoglobin 7.3 g/dL). Other findings were total protein 6.8 g/dL, serum albumin 4.67 g/ dL, serum IgG 516 mg/dL (normal 870–1700 mg/dL), serum IgA 17 mg/dL (normal 110–410 mg/dL), serum IgM 5 mg/ dL (normal 34–220 mg/dL), and serum IgD 306 mg/dL (normal 0–9 mg/dL). Serum and urine electrophoresis revealed a monoclonal spike and an IgD-type monoclonal k band, respectively. The free k light chain level was 3720 mg/ L; serum j/k ratio was 0.0017. On the 5th day after admission, kidney biopsy was performed (Fig. 1). On light microscopy, minor glomerular abnormalities were observed; furthermore, diffuse & Satoshi Kumakura [email protected] 1
Division of Nephrology, Iwate Prefectural Central Hospital, 1-4-1 Ueda, Morioka 020-0066, Japan
2
Division of Pathology, Iwate Prefectural Central Hospital, 1-4-1 Ueda, Morioka 020-0066, Japan
3
Department of Clinical Pharmacology and Therapeutics, Tohoku University Graduate School of Pharmaceutical Sciences and Medicine, 6-3 Aramaki-aza-Aoba Aoba-ku, Sendai 980-8578, Japan
mononuclear cell infiltration in the interstitium and crystalline casts in the proximal tubules were observed. These crystalline casts were hematoxylin and eosin positive but periodic acid-Schiff (PAS) negative. Moreover, only k light chain staining was positive. On electron microscopy, crystalline casts were found to form gigantic plate-shaped crystalline structures. Bone marrow aspiration cytology confirmed the diagnosis of multiple myeloma. She received bortezomib–dexamethasone therapy and achieved complete remission with normal renal function for 2 years. Cast nephropathy is the most common renal complication [1]. In rare cases, the casts exclusively comprise crystals. Myeloma-free light chains (MFLCs) are usually absorbed by proximal tubular cells, leading to acute proximal tubular damage associated with needle-shaped crystals in epithelial cells. This condition is well known as acquired light chain-related Fanconi syndrome [2]. Conversely, MFLCs that are not absorbed by the proximal tubules are distributed to the distal tubules and the ascending loop of Henle, where Tamm–Horsfall protein (THP) casts are exclusively synthesized [3]. These casts usually comprise needle-shaped or rhomboid crystals. THP is one of the glycoproteins, which is invariably PAS positive. The crystalline casts that were observed in this case were PAS negative and were distributed in the proximal tubule lumen. This is understandable, considering the site of THP synthesis. Some reports described crystal formation in organs except the kidneys. In these organs, crystal formation occurred in microvasculature due to low tissue temperature and/or blood circulation stasis; however, the precise mechanism is uncertain [4]. The characteristics of this case emphasized that MFLCs may form crystals independently or at least, without THP participation. Some have reported factors that may contribute to explain MFLC precipitation for crystal formation: a large MFLC amount
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Fig. 1 Histological findings in a patient with crystalline cast nephropathy secondary to IgD lambda myeloma. On Elastica Masson stain (9100), many crystals in a zigzag pattern are observed in the proximal tubules along with mononuclear cell infiltration in the interstitium (a). These crystals are negative for periodic acid-Schiff
stain (9200) and are transparent (b). Immunoperoxidase staining (9400) is positive for k (c) but negative for j (d). On electron microscopy, these crystals show gigantic plate-shaped crystalline structures (e)
that exceeds light chain reabsorption capacity in the proximal tubules; a surge production of MFLCs when dehydrated or with use of certain medications (i.e., diuretics); an interaction of immunological events among MFLCs; and decreased tissue blood flow, namely hypoxia [2, 5]. In this case, drug influence could be excluded. Finally, patients with IgD myeloma are at a particularly high risk of having renal disease [1], but the association between crystal formation and IgD is uncertain.
cryoglobulinemic nephropathies. In: Jennette JC, Olson JL, Schwartz MM, Silva FG, editors. Heptinstall’s pathology of the kidney. 6th ed. Philadelphia: Lippincott Williams & Wilkins; 2007. p. 855–910. Hutchison CA, Batuman V, Behrens J, Bridoux F, Sirac C, Dispenzieri A, Herrera GA, Lachmann H, Sanders PW. The pathogenesis and diagnosis of acute kidney injury in multiple myeloma. Nat Rev Nephrol. 2012;8:43–51. Gupta V, El Ters M, Kashani K, Leung N, Nasr SH. Crystalglobulin-induced nephropathy. J Am Soc Nephrol. 2015;26:525–9. Ball NJ, Wickert W, Marx LH, Thaell JF. Crystalglobulinemia syndrome. A manifestation of multiple myeloma. Cancer. 1993;71:1231–4. Chen KJ, Jan YJ, Chen CH, Cheng CH, Wu MJ, Shu KH. Multiple myeloma-associated cast nephropathy with crystal structure: case report and review of the literature. Nephrology (Carlton). 2005;10:594–6.
2.
3. 4.
Compliance with ethical standards 5. Conflict of interest interest exists.
The authors have declared that no conflict of
References 1. Herrera GA, Picken MM. Renal diseases associated with plasema cell dyscrasia, amyloidosis, Waldenstro¨m macroglobulinemia, and
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LETTER TO THE EDITOR
Crystalline cast nephropathy in a patient with IgD lambda myeloma Satoshi Kumakura1 • Izaya Nakaya1 • Tsutomu Sakuma2 • Hiroshi Sato3 Jun Soma1
•
Received: 27 August 2015 / Accepted: 16 October 2015 Ó Japanese Society of Nephrology 2015
To the Editor A 72-year-old woman was admitted at our department for renal dysfunction with general fatigue and loss of appetite for 2 months. She had no remarkable past medical history except hypertension, which was treated with angiotensin-converting enzyme inhibitor and a calcium channel blocker. Physical examination was unremarkable, except for pale conjunctivae. Urinary protein to creatinine ratio was 9.5 g/gCr, revealing a large discrepancy from the result of mild proteinuria by urinary dipstick (2?; indicating 100–300 mg/L). No hematuria was found. Serum creatinine level was increased to 1.90 mg/ dL associated with anemia (hemoglobin 7.3 g/dL). Other findings were total protein 6.8 g/dL, serum albumin 4.67 g/ dL, serum IgG 516 mg/dL (normal 870–1700 mg/dL), serum IgA 17 mg/dL (normal 110–410 mg/dL), serum IgM 5 mg/ dL (normal 34–220 mg/dL), and serum IgD 306 mg/dL (normal 0–9 mg/dL). Serum and urine electrophoresis revealed a monoclonal spike and an IgD-type monoclonal k band, respectively. The free k light chain level was 3720 mg/ L; serum j/k ratio was 0.0017. On the 5th day after admission, kidney biopsy was performed (Fig. 1). On light microscopy, minor glomerular abnormalities were observed; furthermore, diffuse & Satoshi Kumakura [email protected] 1
Division of Nephrology, Iwate Prefectural Central Hospital, 1-4-1 Ueda, Morioka 020-0066, Japan
2
Division of Pathology, Iwate Prefectural Central Hospital, 1-4-1 Ueda, Morioka 020-0066, Japan
3
Department of Clinical Pharmacology and Therapeutics, Tohoku University Graduate School of Pharmaceutical Sciences and Medicine, 6-3 Aramaki-aza-Aoba Aoba-ku, Sendai 980-8578, Japan
mononuclear cell infiltration in the interstitium and crystalline casts in the proximal tubules were observed. These crystalline casts were hematoxylin and eosin positive but periodic acid-Schiff (PAS) negative. Moreover, only k light chain staining was positive. On electron microscopy, crystalline casts were found to form gigantic plate-shaped crystalline structures. Bone marrow aspiration cytology confirmed the diagnosis of multiple myeloma. She received bortezomib–dexamethasone therapy and achieved complete remission with normal renal function for 2 years. Cast nephropathy is the most common renal complication [1]. In rare cases, the casts exclusively comprise crystals. Myeloma-free light chains (MFLCs) are usually absorbed by proximal tubular cells, leading to acute proximal tubular damage associated with needle-shaped crystals in epithelial cells. This condition is well known as acquired light chain-related Fanconi syndrome [2]. Conversely, MFLCs that are not absorbed by the proximal tubules are distributed to the distal tubules and the ascending loop of Henle, where Tamm–Horsfall protein (THP) casts are exclusively synthesized [3]. These casts usually comprise needle-shaped or rhomboid crystals. THP is one of the glycoproteins, which is invariably PAS positive. The crystalline casts that were observed in this case were PAS negative and were distributed in the proximal tubule lumen. This is understandable, considering the site of THP synthesis. Some reports described crystal formation in organs except the kidneys. In these organs, crystal formation occurred in microvasculature due to low tissue temperature and/or blood circulation stasis; however, the precise mechanism is uncertain [4]. The characteristics of this case emphasized that MFLCs may form crystals independently or at least, without THP participation. Some have reported factors that may contribute to explain MFLC precipitation for crystal formation: a large MFLC amount
123
Clin Exp Nephrol
Fig. 1 Histological findings in a patient with crystalline cast nephropathy secondary to IgD lambda myeloma. On Elastica Masson stain (9100), many crystals in a zigzag pattern are observed in the proximal tubules along with mononuclear cell infiltration in the interstitium (a). These crystals are negative for periodic acid-Schiff
stain (9200) and are transparent (b). Immunoperoxidase staining (9400) is positive for k (c) but negative for j (d). On electron microscopy, these crystals show gigantic plate-shaped crystalline structures (e)
that exceeds light chain reabsorption capacity in the proximal tubules; a surge production of MFLCs when dehydrated or with use of certain medications (i.e., diuretics); an interaction of immunological events among MFLCs; and decreased tissue blood flow, namely hypoxia [2, 5]. In this case, drug influence could be excluded. Finally, patients with IgD myeloma are at a particularly high risk of having renal disease [1], but the association between crystal formation and IgD is uncertain.
cryoglobulinemic nephropathies. In: Jennette JC, Olson JL, Schwartz MM, Silva FG, editors. Heptinstall’s pathology of the kidney. 6th ed. Philadelphia: Lippincott Williams & Wilkins; 2007. p. 855–910. Hutchison CA, Batuman V, Behrens J, Bridoux F, Sirac C, Dispenzieri A, Herrera GA, Lachmann H, Sanders PW. The pathogenesis and diagnosis of acute kidney injury in multiple myeloma. Nat Rev Nephrol. 2012;8:43–51. Gupta V, El Ters M, Kashani K, Leung N, Nasr SH. Crystalglobulin-induced nephropathy. J Am Soc Nephrol. 2015;26:525–9. Ball NJ, Wickert W, Marx LH, Thaell JF. Crystalglobulinemia syndrome. A manifestation of multiple myeloma. Cancer. 1993;71:1231–4. Chen KJ, Jan YJ, Chen CH, Cheng CH, Wu MJ, Shu KH. Multiple myeloma-associated cast nephropathy with crystal structure: case report and review of the literature. Nephrology (Carlton). 2005;10:594–6.
2.
3. 4.
Compliance with ethical standards 5. Conflict of interest interest exists.
The authors have declared that no conflict of
References 1. Herrera GA, Picken MM. Renal diseases associated with plasema cell dyscrasia, amyloidosis, Waldenstro¨m macroglobulinemia, and
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