The morphologic spectrum and clinical significance of light chain proximal tubulopathy with and without crystal formation

Abstract

The renal diseases most frequently associated with myeloma include amyloidosis, monoclonal immunoglobulin deposition disease, and cast nephropathy. Less frequently reported is light chain proximal tubulopathy, a disease characterized by j-restricted crystal deposits in the proximal tubule cytoplasm. Light chain proximal tubulopathy without crystal deposition is only loosely related to the typical light chain proximal tubulopathy, and little is known about this entity. A search was performed of the 10 081 native kidney biopsy samples processed by our laboratory over the past 2 years for cases that had light chain restriction limited to the proximal tubule cytoplasm. A total of 10 cases of light chain proximal tubulopathy without crystal deposition were found representing 3.1% of light chain-related diseases. Nine of these 10 showed k-light chain restriction. Only three cases of light chain proximal tubulopathy with crystals were found accounting for 0.9% of light chain-related diseases. Two of these three were j subtype. Plasma cell dyscrasia was unsuspected in seven of the 10 patients with light chain proximal tubulopathy without crystals at the time of renal biopsy. After the biopsy was reported, follow-up was available on 9/10 patients with 9/9 showing a plasma cell dyscrasia including 8/9 with multiple myeloma. We found that light chain proximal tubulopathy without crystal formation, despite being rarely described in the literature, is over three times more common than light chain proximal tubulopathy with crystal formation in our series. And given that it is often associated with previously unrecognized myeloma, it is a critically important diagnosis.

Renal Light Chain Deposition Associated with the Formation of Intracellular Crystalline Inclusion Bodies in Podocytes: A Rare Case Report

“…Larsen et al (10) studied 10,081 cases of renal biopsy specimens and found that there were only 13 cases of proximal tubular damage caused by light chain proteins, including 3 cases with crystalloid formation (2 of 3 cases showing κ light chains). In this previous study, the diagnosis of malignant plasma cells could not be established for some patients at the time of renal biopsy, although the patients were diagnosed later in a follow-up study with the gradual emergence of corresponding clinical manifestations (10). In contrast, it is very rare to present large quantities of crystalline inclu- sions deposited in podocytes and only 10 cases have been reported to date (2,5,6,(11)(12)(13)(14)(15)(16)(17) (Table).…”

Proximal Tubulopathies Associated With Monoclonal Light Chains: The Spectrum of Clinicopathologic Manifestations and Molecular Pathogenesis

“…Two series of patients manifesting this pattern of proximal tubulopathy have been published in the literature. 48,49 Although both j and k light chains have been documented to occur in association with this variant, a predominance of j light chains has been observed. Those light chains associated with interstitial inflammatory reactions are also delivered to the lysosomal compartment, and catabolism is also impaired.…”

“…The manifestations associated with unique cytoplasmic inclusions, which are generally crystalline in proximal tubular cells, represent the lesion that has been recognized in the literature as light chain Fanconi syndrome 49,[53][54][55][56][57] (Figures 13 through 16). Clinically, it is characterized by progressive renal dysfunction with defects in proximal tubule reabsorption and typically exhibits a rather slow, protracted clinical course.…”

Unusual manifestation of crystalline light chain tubulopathy in patient with multiple myeloma: case report and review of the literature

“…Both LC and kLC are found within PTEC deposits, although crystalline-like deposits almost exclusively are formed by k chains (certain subtypes, such as subtype Vk1 LC have been identified as having particular properties to form crystals). 5,9 It has been postulated, that the mutations of the gene encoding CDR-L1 (complementarity-determining region L1 of LCs, contributing to formation of immunoglobulin antigen-binding site) may facilitate resistance to proteases, causing the accumulation of LC in PTEC lysosomes where they serve as a nidus for crystal formation. Such a resistance to proteolysis seems to be a peculiar characteristic of LC involved in the pathophysiology of Fanconi syndrome, since it was never documented in cast nephropathy patients or myeloma patients without renal involvement.…”