An eye opener!

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Call it serendipity or mere coincidence, I recently saw a patient with Prostate cancer treated with an experimental chemotherapy protocol that was sent to our clinic for evaluation of Fanconi syndrome and proteinuric stage 3 chronic kidney disease (1.5 g/d).I did a kidney biopsy which revealed extensive proximal tubulopathy with moderate interstitial fibrosis but no glomerular disease was noted. Interestingly, serum and urine protein electrophoresis with immunofixation was negative. Work up to find the underlying etiology of Fanconi syndrome was an exercise in vain. The etiology remained a puzzle until a case presented at ASN in Denver was an eye opener for me. This case introduced to me the possibility of Isolated Light chain proximal tubulopathy (LCPT) as a cause of Fanconi syndrome in my patient despite a negative serum and urine protein electrophoresis.
Briefly, plasma cell dyscrasias are characterized by excessive bone marrow production of immunoglobulin freely circulating in the plasma. Several pathologies are noted in the kidney and include:
1) Light chain (myeloma) cast nephropathy.
2) Monoclonal Immunoglobulin deposition disease
3) Amyloidosis
4) Tubulointerstitial nephritis
5) Cryoglobulenemia
Rarely, LCPT has been reported and often precedes the diagnosis of multiple myeloma, MGUS, and less commonly amyloidosis.Light chains, almost always, are kappa chains.
In a normal state, the light chains that cross the glomerular filtration barrier are endocytosed through glycoprotein receptors megalin/cubilin in the proximal tubule and are subsequently degraded by the lysosomal proteolytic enzymes into several amino acids. However, in patients with LCPT, the variable segment (VK1) of the kappa light chains is resistant to degradation by the lysosomal proteolytic enzymes and binds other fragments of light chains to form crystals that get deposited in the proximal tubular epithelium and cause disease. Clinical presentation is very varied and often includes renal dysfunction with fanconi syndrome, although these findings are not universal.
Histologically, on light microscopy (high power), pale, rhomboid intracytoplasmic crystals are seen in the proximal tubular epithelium. Immunofluorescence (IF) often stains positive for kappa light chains and electron microscopy is confirmatory for the pale crystalline structures in the proximal tubule epithelium.
However, the diagnosis of this condition may be difficult due to several reasons:
1) Clinical presentation is often heterogeneous and fanconi syndrome is not a universal presentation.
2) Detection of intracytoplasmic crystals in proximal tubule can often be missed without heightened suspicion.
3) SPEP with immunofixation can be negative and UPEP with immunofixation may be a less sensitive study (read this blog).
4) Standard IF staining for kappa light chain can be negative as antiserum may not always bind partially degraded kappa light chains.
It is therefore recommended that free light chain assays be performed along with IF following pronase-digestion (details here) or immunoelectron microscopy in cases where the diagnosis is not clear. Once the diagnosis of LCPT is made, extensive work up including skeletal survey and bone marrow biopsy is recommended to rule out plasma cell dyscrasias.
With this enlightenment, I called my pathologist, who reminded me that IF could not be done on my patient due to only one core of tissue, but she did promise to send the paraffin embedded section for IF. I have also asked my patient to get the free light chain assay.
Viresh Mohanlal, MD

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