A 70-Year-Old Woman With Acute Renal Failure

A 70-year-old woman with severe peripheral vascular disease developed progressive renal insufficiency 2 months after a systemic reaction to sulfa drugs. Her creatinine increased to 2.8 mg/dL, and testing results for cytoplasmic antineutrophil cytoplasmic antibody were positive. Clinical considerations included interstitial nephritis, atheroembolism, and possible Wegener granulomatosis.

A renal biopsy was performed. Glomeruli were essentially normal. Small arteries showed moderate arteriosclerosis but no evidence of atheroembolism. Moderate chronic tubulointerstitial injury with tubular atrophy was present (Figure 1). Cortical tubules were separated by a combination of fibrosis, mild chronic inflammation, and abundant macrophages with prominent periodic acid-Schiff-positive globoid cytoplasmic inclusions (Figure 2). Electron microscopy demonstrated that these inclusions have an internal crystalline substructure (Figure 3). Immunofluorescence microscopy showed globular staining of the histiocytes for ? light chain (Figure 4) but not ? light chain (Figure 5). Serum protein immunoelectrophoresis showed a small M-component spike of ? light chain. A subsequent bone marrow biopsy showed no evidence of multiple myeloma. The patient died about 6 months later of a stroke related to her peripheral vascular disease.

What is your diagnosis?

Crystal-storing histiocytosis (CSH) is a rare disorder characterized by a poorly understood accumulation of immunoglobulin light chain in histiocytes within one or more organ systems. The characteristic microscopic appearance is that of accumulated histiocytes distended by globoid cytoplasmic inclusions. The inclusions have a crystalline substructure when examined by electron microscopy; occasionally, this substructure is also evident by light microscopy. In the bone marrow, CSH can easily be confused with other histiocytic storage disorders, such as Gaucher disease, if the crystalline nature of the inclusions is not recognized.1

CSH is most typically associated with multiple myeloma but has also been described in association with lymphoplasmacytic lymphoma, the use of certain drugs such as clofazimine (used to treat leprosy), and even polyclonal hypergammaglobulinemia.1-4 This last association suggests that this uncommon histiocytosis is not specific to lymphoplasmacytic neoplasms but may result from high levels of either normal or abnormal immunoglobulins in certain individuals.4,5 The reason why these crystalline inclusions accumulate and persist in some patients but not in others is unknown.1 Only one organ is affected in the majority of cases (usually bone marrow, kidney, or cornea), but multiorgan involvement may occur.1,2 Fanconi-type renal tubular dysfunction may be present. In our patient, CSH appears to have been the primary basis of her progressive renal insufficiency by means of secondary chronic injury of the tubules and interstitial fibrosis, likely with an additional contribution from her nephrosclerosis.

The light chain crystals of CSH are most likely formed either within the endoplasmic reticulum of plasma cells, before extrusion into the extracellular space, or within the lysosomal compartment of macrophages during lysosomal digestion and degradation of the ingested immunoglobulins.6,7 Overproduction of light chains may also play a role, as suggested by a murine model in which intraperitoneal injection of free ? light chain from multiple myeloma patients resulted in accumulation of intracellular crystals in the kidneys that were identical to those found in CSH.1 Paraprotein crystallization may be promoted by abnormal hydrophobicity, poor solubility in the cold or in acid pH, or other changes that promote overproduction of light chain and/or inhibit intralysosomal degradation.1,7 However, overproduction alone does not generally result in CSH, and other factors are most likely involved. In one report, electron microscopy demonstrated tubular structures associated with the crystals in plasma cells, suggesting a possible nidus for crystal formation.1

CSH is a distinctly uncommon complication of multiple myeloma. More common renal manifestations of plasma cell dyscrasia include renal amyloidosis, nonamyloidotic light chain deposition disease, and myeloma cast nephropathy. In renal amyloidosis, extensive accumulation of light chain-derived amyloid in glomeruli typically results in high-grade proteinuria or nephrotic syndrome, with eventual progressive renal insufficiency. Light chain deposition disease results from clonal light chain accumulation in the kidney, either primarily as linear deposits along basement membranes or as nodular masses expanding the glomerular mesangium (morphologically mimicking the nodular glomerular sclerosis of diabetes). Patients with myeloma cast nephropathy often present with acute renal failure, and on biopsy are shown to have characteristic large, retractile "cracked" casts in renal tubules that are of mixed composition.

For reasons that are poorly understood, most renal amyloidoses of paraprotein origin are derived from ? light chains, while light chain deposition disease is more commonly of ? light chain type. In terms of its light chain origin, CSH appears to be even more restrictive, with nearly all of the reported cases (more than 60) being of ? light chain type; only 4 cases of ? light chain storage, and one case of heavy chain CSH are on record.1,7 In both CSH and amyloidosis, aberrant synthesis and/or proteolytic degradation likely play an important pathogenetic role.8

Interestingly, many myeloma patients with CSH have reported survival of 5 to 15 years, which is longer than the median survival for myeloma in general.1 A likely explanation for this difference is diagnosis at an earlier stage of disease in CSH-myeloma patients, due to the associated renal failure, organomegaly, or keratopathy. In the absence of renal failure, the additional finding of CSH does not appear to be associated with a poorer prognosis for myeloma patients.1

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