May 2023 – Renal Pathology

Light chain proximal tubulopathy (LCPT), kappa-restricted, with crystals.

LCPT is a monoclonal gammopathy of renal significance (MGRS) characterized by light chain deposition that occurs intracellularly, within proximal tubular cells.¹ Immunoglobulin light chains can be mutated in the variable domain, become resistant to intracellular enzymatic breakdown, and eventually form intracytoplasmic crystals (particularly when the κ light chain precipitates, like in the current case); the light-chain crystals disrupt lysosomal function and induce cell injury.^2,3 The proximal tubular dysfunction can manifest as chronic kidney disease and/or Fanconi’s syndrome and electrolyte disturbances. When crystals are present, standard immunofluorescence could be negative and pronase digestion for antigen retrieval should be performed.¹

Many patients with this condition have an underlying plasma cell dyscrasia, including multiple myeloma, which may not be known at the time of the kidney biopsy.⁴ In fact, once a diagnosis of LCPT is made, a laboratory workup to exclude a hematologic malignancy is warranted.

Incorrect answers:

Light chain cast nephropathy: Light chain cast nephropathy is characterized by crystalline precipitates of monoclonal light chain (either κ or λ) within the lumen of distal tubules.

Heavy chain deposition disease (HCDD): It is a rare monoclonal immunoglobulin deposition disease (MIDD) characterized by glomerular mesangial nodular sclerosis on light microscopy, and finely granular, powdery deposits along the basement membranes. As the name describes, this entity is characterized by deposition of monotypic mutated heavy chains (not light chains) by immunofluorescence (usually IgG). Therefore, “HCDD, kappa-restricted” not only is the incorrect answer but is also conceptually incorrect.

Light chain deposition disease (LCDD): It is an MIDD characterized by deposition of monotypic immunoglobulin light chains. Histologically, it is distinguished from HCDD by the immunofluorescence findings (either κ or λ light chain-restriction, without monotypic heavy chains).

References

1. Stokes, Michael B.; Valeri, Anthony M.; Herlitz, Leal; Khan, Abdullah M.; Siegel, David S.; Markowitz, Glen S.; D’Agati, Vivette D. J Am Soc Nephrol. 27(5):1555-1565, May 2016. doi:10.1681/ASN.2015020185
2. Leung N, Bridoux F, Nasr SH. Monoclonal gammopathy of renal significance. N Engl J Med. 2021 Vol. 384 Issue 20 Pages 1931-1941. Accession Number: 34010532 doi:10.1056/NEJMra1810907
3. Luciani A, Sirac C, Terryn S, et al. Impaired lysosomal function underlies monoclonal light chain-associated renal Fanconi syndrome. J Am Soc Nephrol. 2016; 27:2049-2061.
4. Larsen C, Bell J, Harris A, et al. The morphologic spectrum and clinical significance of light chain proximal tubulopathy with and without crystal formation. Mod Pathol. 24,1462–1469 (2011). https://doi.org/10.1038/modpathol.2011.104