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Diagnosis: Light Chain Proximal Tubulopathy (with Crystals)
Light chain proximal tubulopathy (LCPT) is characterized by cytoplasmic inclusions of monoclonal light chains within proximal tubular cells. The significance of crystalline versus noncrystalline LCPT and the effect of modern therapies are unknown.
In normal physiologic states, small amounts of free light chains are reabsorbed via the megalin/cubilin scavenger receptor on the apical surface of the proximal tubular epithelium followed by endosomal uptake and intralysosomal degradation. In the setting of dysproteinemias, the degree of light chain excretion may exceed the proximal tubule’s reabsorptive capacity, or Tmax, resulting in light chain (Bence–Jones) proteinuria. In LCPT, the reabsorbed light chains have innate physicochemical properties that resist proteolysis and promote self-aggregation and crystal formation. Proximal tubular endocytosis of monoclonal light chains generates intracellular oxidative stress, which activates inflammatory mediators and apoptosis. The pathologic spectrum of LCPT has been expanded to include noncrystalline morphology. The clinical characteristics and prognostic significance of noncrystalline LCPT are uncertain. Early reports suggested that LCPT was often associated with low-mass multiple myeloma (MGUS) and had a relatively indolent course. Therefore, chemotherapy was usually deferred unless hematologic disease worsened or progressive renal dysfunction ensued, reflecting the serious side effects of alkylating antineoplastic agents (Stokes MB, et al. Light Chain Proximal Tubulopathy: Clinical and Pathologic Characteristics in the Modern Treatment Era. J Am Soc Nephrol. 2016;27(5):1555-65. [PubMed link]). The current recommendations from the International Kidney and Monoclonal Gammopathy Research Group include chemotherapy or stem cell transplant (SCT) for LCPT, to delay renal progression, and to minimize the risk of recurrence after renal transplantation. (Fermand JP, et al. International Kidney and Monoclonal Gammopathy Research Group. How I treat monoclonal gammopathy of renal significance (MGRS). Blood. 201;122:3583-90. [PubMed link]).
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References
- Li X, Xu F, Liang D, Liang S, Zhu X, Zhang M, Huang X, Liu Z, Zeng C. Clinicopathologic characteristics of light chain proximal tubulopathy with light chain inclusions involving multiple renal cell types . Clin Nephrol. 2018;89(2):83-92. [PubMed link]
- Stokes MB, Valeri AM, Herlitz L, Khan AM, Siegel DS, Markowitz GS, D'Agati VD. Light Chain Proximal Tubulopathy: Clinical and Pathologic Characteristics in the Modern Treatment Era. J Am Soc Nephrol. 2016;27(5):1555-65. [PubMed link]
- Sethi S, Fervenza FC, Rajkumar SV. Spectrum of manifestations of monoclonal gammopathy-associated renal lesions. Curr Opin Nephrol Hypertens. 2016;25(2):127-37. [PubMed link]
- Fermand JP, Bridoux F, Kyle RA, Kastritis E, Weiss BM, Cook MA, Drayson MT, Dispenzieri A, Leung N; International Kidney and Monoclonal Gammopathy Research Group. How I treat monoclonal gammopathy of renal significance (MGRS). Blood. 2013;122(22):3583-90. [PubMed link]