| Abstract|| |
The renal diseases commonly associated with myeloma include primary amyloidosis, cast nephropathy, and light chain deposition disease. Less frequent forms of renal involvement encountered in the course of myeloma are crystalline and non-crystalline proximal tubulopathies, neoplastic plasma cell infiltration, and immunoglobulin crystallization in interstitial histiocytes and glomerular cells including podocytes. Light chain proximal tubulopathy (LCPT) caused by aggregation of non-crystalline and rarely crystalline deposits of monoclonal light chains in the cytoplasm of proximal tubular epithelial cells, accounts for less than 5% of monoclonal gammopathy-associated kidney diseases. We report the case of a 48-year-old Indian woman with multiple myeloma, who presented with acute kidney injury and nephrotic syndrome, in whom the renal biopsy revealed widespread crystalline inclusions in extraglomerular and glomerular compartments. We present illustrative light microscopic (LM) and diagnostic electron microscopic (EM) findings of this case which enabled a diagnosis of crystalline LCPT, crystal storing histiocytosis, and crystalline podocytopathy occurring synchronously with myeloma cast nephropathy. While documenting this unique juxtapositioning of multicompartmental paraproteinemic renal injury in multiple myeloma, diagnosed after EM analysis of the patient's renal biopsy, we discuss the pathogenetic pathways of this condition along with the clinical implications. Due to intrinsic structural properties of the crystals, they frequently escape detection by routine LM, necessitating EM analysis for their diagnosis. Given the prognostic implications of tubulopathies complicating myeloma, LCPT is a critically important diagnosis, highlighting the need for a comprehensive renal biopsy evaluation inclusive of EM for the practice of precision medicine in such scenarios.
Keywords: Acute kidney injury, crystalline tubulopathy, crystal storing histiocytosis, crystalline podocytopathy, Fanconi's anemia, light chain deposition disease, myeloma kidney, myeloma cast nephropathy
|How to cite this article:|
Matthai SM, Alexander S, Jacob S, Duhli N, David VG, Varughese S. Crystals, crystals everywhere but not a clue till late… Light chain crystalline proximal tubulopathy with concomitant myeloma cast nephropathy. Indian J Pathol Microbiol 2020;63:463-6
|How to cite this URL:|
Matthai SM, Alexander S, Jacob S, Duhli N, David VG, Varughese S. Crystals, crystals everywhere but not a clue till late… Light chain crystalline proximal tubulopathy with concomitant myeloma cast nephropathy. Indian J Pathol Microbiol [serial online] 2020 [cited 2020 Nov 29];63:463-6. Available from: https://www.ijpmonline.org/text.asp?2020/63/3/463/291688
| Introduction|| |
Renal involvement is common in multiple myeloma and is the second leading cause of mortality in myeloma, after infection. Deposition of paraproteins produced by the clonal plasma cells in myeloma is responsible for the characteristic renal abnormalities of this disease. Commonly encountered paraproteinemic kidney manifestations include primary amyloidosis, cast nephropathy and light chain deposition disease., Intracellular crystallization of immunoglobulin light chains occurs very infrequently and can involve proximal convoluted tubules causing light chain proximal tubulopathy (LCPT), or even more rarely, interstitial histiocytes and glomerular podocytes causing crystal storing histiocytosis (CSH) and crystalline podocytopathy (CP), respectively.,,
LCPT characterized by accumulation of monoclonal light chains (LCs) in the cytoplasm of proximal tubular epithelial (PTE) cells accounts for 0.5–5% of monoclonal gammopathy-associated kidney diseases and is usually associated with clinical presentation of Fanconi syndrome., LCPT occurs with or without crystal formation in an incidence ratio reported to be 1:3, highlighting the rarity of crystalline LCPT, reports of which are limited to small case studies. CSH and CP are uncommon entities, documentation of which are confined to solitary case reports.,
We report an unprecedented simultaneous occurrence of florid LCPT, CSH, and CP along with concomitant myeloma cast nephropathy in a 48-year-old Indian woman with myeloma, who presented with acute kidney injury, nephrotic syndrome, and anemia without Fanconi-like symptoms. Demonstration of crystalline light chain deposition in the kidney required EM analysis of the renal biopsy of the patient.
| Case Report|| |
A 48-year-old Indian woman was admitted with complaints of fever, vomiting, and loose stools. She gave a history of generalized weakness and loss of appetite for one year, for which she had been evaluated and found to be anemic (Hemoglobin 6.4 g/dL), receiving 4 units of blood transfusion for the same. She had also been on regular medication and follow up for Type II Diabetes for the past 5 years. Physical examination showed a pale, febrile, middle-aged woman, normotensive but fluid overloaded. There was no hepatosplenomegaly or lymphadenopathy. Her peripheral blood haemoglobin level was 7.7 g/dL, platelet count 55000/cumm and white blood cell count 9900. Serum creatinine was 6.42 mg/dL, urine protein excretion was 4.6 g in 24 hours, and urine analysis showed protein (1+), no crystals or casts, no glycosuria and 4–5 RBCs/high power field. Serum ASO titer, 3rd and 4th components of the complement, hepatitis A IgM antibody, hepatitis B surface antigen, hepatitis C antibody, HIV test, anti-nuclear and anti-neutrophil cytoplasmic antibodies, and cryoglobulins were all either negative or normal. Serum electrophoresis showed M band in gamma region (M = 0.3 G%). Urine tested positive for Bence Jones Protein. Serum-free light chain assay showed kappa 580, lambda 25 with Kappa: Lambda ratio of 23 and serum immunofixation electrophoresis showed kappa only. Bone marrow biopsy revealed 70% plasma cells, confirming diagnosis of myeloma. Skeletal survey did not show any lytic lesions. Her fever subsided on treatment with antibiotics for 10 days and she was offered one session of hemodialysis prior to renal biopsy.
Light microscopic (LM) examination of renal biopsy tissue showed a total of 7 glomeruli which were normocellular with mild mesangial expansion. The extraglomerular compartment showed foci of interstitial fibrosis, dense chronic inflammatory cell infiltrate, and many dilated distal convoluted tubules containing pale eosinophilic casts with fractured appearance, surrounded by inflammatory cells consistent with myeloma cast nephropathy [Figure 1]a and [Figure 1]b. There was equivocal staining on direct immunofluorescence (IF) for kappa and lambda in the casts. The glomeruli and tubular epithelium showed no demonstrable light chain restriction on IF. Special stains for amyloid yielded negative results. Extensive damage of PTE with eosinophilic “debris” showing angulated appearance [Figure 1]c and [Figure 1]d was noted and attributed to necrotic epithelium of acute tubular injury.
|Figure 1: (a) Light microscopic examination at low power shows dilated distal convoluted tubules with mildly PAS positive casts in their lumen (Per iodic acid Schiff stain × 100); (b) Higher magnification of tubular casts demonstrate their fractured nature and surrounding inflammatory cell reaction (Per iodic acid Schiff stain ×400); (c) Damaged PTE showing pale eosinophilic material which is difficult to distinguish from necrotic epithelial debris. The angulated edges of the deposits are appreciated focally, on high power examination (Per iodic acid Schiff stain × 200); (d) High power magnification reveals angulated outlines of deposits within the PTE and tubular lumen (Per iodic acid Schiff stain × 400); (e) Semithin sections display numerous inclusions in PTE at low power examination along with concomitant myeloma cast nephropathy (toluidine blue stain × 200); (f) Higher magnification of PTE inclusions reveal them to be angulated crystalloid structures (oil immersion, toluidine blue stain × 1000)|
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Following a preliminary diagnosis of myeloma cast nephropathy, an examination of toluidine blue-stained 1 μ sections revealed numerous darkly staining inclusions in PTE [Figure 1]e which appeared crystalloid at higher magnification [Figure 1]f. EM analysis confirmed extensive crystalline deposits in PTE, interstitial histiocytes, and glomerular podocytes with demonstrable fine crystal lattice substructure [Figure 2]a, [Figure 2]b, [Figure 2]c, [Figure 2]d, [Figure 2]e, [Figure 2]f, [Figure 2]g. A final diagnosis of “Light chain crystalline proximal tubulopathy, crystal storing histiocytosis and crystalline podocytopathy with concomitant myeloma cast nephropathy” was given out based on these findings.
|Figure 2: (a) Transmission electron microscopic examination confirms presence of abundant crystalline structures in PTE (transmission electron microscopy × 1050); (b) Crystals spilling over into the lumen of proximal convoluted tubules with destruction of the lining epithelial cells (transmission electron microscopy × 1250); (c) Interstitial histiocytes brimming with crystals (transmission electron microscopy × 1250); (d) Localisation of crystals in cytoplasm of interstitial histiocytes (transmission electron microscopy × 4200); (e) Damaged podocyte bodies containing crystalline inclusions (transmission electron microscopy × 2550); (f) Crystals in cytoplasm of an injured podocyte with degenerative changes (transmission electron microscopy × 8200); (g) High magnification displays fine crystal lattice substructure (transmission electron microscopy × 20,500)|
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| Discussion|| |
The kidney is a major target organ for paraproteinemic damage in plasma cell dyscrasias including myeloma. Monoclonal immunoglobulin LCs are the major cause of renal impairment in myeloma, variant manifestations of which depend on the amount of LCs filtered across glomerular filtration barrier (LC load), type of LCs, physiochemical properties of the LCs including interaction with other urine contents like Tamm–Horsfall protein (THP), and tubular epithelial receptors like megalin, cubilin etc.
As opposed to myeloma cast nephropathy (CN), which is the more common manifestation of tubulopathic LCs manifesting as fractured casts in distal tubular lumina, LCPT shows intracellular deposition of LCs within PTE and sparing of distal tubules. This selective pattern of involvement has been attributed to differences in the intrinsic properties of the paraprotein causing LCPT, which confer resistance to proteolytic activity by lysosomes in PTE and thereby facilitate its accumulation and precipitation in these cells., Whereas the pathogenic LCs in CN have demonstrable susceptibility to lysosomal proteolysis in PTE, it is their high serum concentrations (CN is commonly associated with high serum free LC concentrations of above 70–100 mg/dL) which overwhelm the reabsorbing capacity of PTE and they pass on to Loop of Henle where they bind with THP to form distal tubular casts. The LCs in crystalline LCPT, on the other hand, possess a protease resistant variable domain postulated to be due to mutations in the gene encoding CDR-L1 (complementarity determining region L1 which contributes to immunoglobulin antigen binding sites of LCs) rendering resistance to proteolysis by PTE lysosomal enzymes pepsin and cathepsin B. Additionally, a subtype V kappa1 LC has been identified in crystalline LCPT, which promotes self-aggregation and crystalline precipitation in PCT, but has low affinity for THP, resulting in lower propensity to cast formation in distal tubules.,,
These mechanistic differences due to innate physiochemical dissimilarities of LCs involved in LCPT and CN, ensure that simultaneous occurrence of both in same patient is an extremely rare occurrence. There have been very few reported cases of combined LCPT and CN in the same patient. A possible explanation for this rare anomaly could be the existence of borderline LCs which share features of both types of tubulopathic LCs.
Crystal storing histiocytosis (CSH) is an unusual phenomenon with intra histiocytic accumulation of immunoglobulin crystals, exclusively of kappa LC subtype. CSH-related renal disorder observed in our case, associated with widespread crystalline inclusions in extraglomerular compartments may explain the rapid progression of renal failure in our patient contrary to expected slow progression of disease in CN. The clinical presentation of nephrotic range proteinuria, infrequent in myeloma kidney, could be attributed to the rare entity crystalline podocytopathy,, along with the other morphological forms of renal injury documented in our patient.
In consideration of the subtlety of LM findings and oft times encountered inability to demonstrate LC restriction on IF due to interference by crystal lattices, the diagnosis of this condition usually requires EM analysis with the first clue to diagnosis emerging on toluidine blue stained 1 μsections.
In summary, this case illustrates a one off confluence of divergent pathological processes of renal injury in myeloma, accurate diagnosis of which requires heightened awareness and availability of routine EM facilities in the diagnostic armamentarium of the renal pathologist.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
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Conflicts of interest
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| References|| |
Korbet SM, Schwartz MM. Multiple myeloma. J Am Soc Nephrol 2006; 17:2533-45.
Larsen CP, Bell JM, Harris AA, Messias NC, Wang YH, Walker PD. The morphologic spectrum and clinical significance of light chain proximal tubulopathy with and without crystal formation. Mod Pathol 2011; 24:1462-9.
Wu CK, Yang AH, Lai HC, Lin BS. Combined proximal tubulopathy, crystal storing histiocytosis and cast nephropathy in a patient with light chain multiple myeloma. BMC Nephrol 2017; 18:170-5.
Nasr SH, Preddie DC, Markowitz GS, Appel GB, D'Agati VD. Multiple myeloma, nephrotic syndrome and crystalloid inclusions in podocytes. Kidney Int 2006; 69:616-20.
Stokes MB, Valeri AM, Herlitz L, Khan AM, Siegel DS, Markowitz GS, et al
. Light chain proximal tubulopathy: Clinical and pathologic characteristics in the modern treatment era. J Am Soc Nephrol 2016; 27:1555-65.
Leboulleux M, Lelongt B, Mougenot B, Touchard G, Makdassi R, Rocca A, et al
. Protease resistance and binding of Ig light chains in myeloma-associated tubulopathies. Kidney Int 1995; 48:72-9.
Sanders PW, Booker BB, Bishop JB, Cheung HC. Mechanisms of intranephronal proteinaceous cast formation by low molecular weight proteins. J Clin Invest 1990; 85:570-6.
Aucouturier P, Bauwens M, Khamlichi AA, Denoroy L, Spinelli S, Touchard G, et al
. Monoclonal Ig L chain and L chain V domain fragment crystallization in myeloma-associated fanconi's syndrome. J Immunol 1993; 150:3561-68.
Hutchison CA, Batuman V, Behrens J, Bridoux F, Sirac C, Dispenzieri A, et al
. The pathogenesis and diagnosis of acute kidney injury in multiple myeloma. Nat Rev Nephrol 2011; 8:43-51.
Gowda KK, Joshi K, Nada R, Ramachandran R, Sachdeva M. Light chain proximal tubulopathy with cast nephropathy in a case of multiple myeloma. Indian J Nephrol 2015; 25:119-22.
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Smita Mary Matthai
Department of Pathology, Central Electron Microscopy Facility, Wellcome Trust Research Laboratory, Christian Medical College, Vellore - 632 004, Tamil Nadu
Source of Support: None, Conflict of Interest: None
[Figure 1], [Figure 2]