Light Chain Proximal Tubulopathy – The Tip of the Iceberg?
In recent years, there has been increased recognition of the spectrum of kidney diseases associated with paraproteinemias. The fact that the pathogenetically related categories of “monoclonal immunoglobulin deposition disease” and “light chain amyloidosis” have entirely different histopathologies is not always well appreciated. The best course of action when a patient is identified as having a paraproteinemia is not always clear. The well established entity of monoclonal gammopathy of undetermined significance (MGUS) is now recognized to be more significant than originally thought, leading to the emergence of a new entity: monoclonal gammopathy of renal significance (MGRS). This realization was largely based on information obtained through the wider use of the kidney biopsy in the context of paraproteinemias. Consequently, kidney pathologists now play a central role in determining if the kidney histopathology present on the biopsy is monoclonal associated, and thus whether MGUS or MGRS is the appropriate syndromic designation for the patient.
Angioi et al present a beautifully illustrated case of kappa light chain proximal tubulopathy (LCPT) that subsequently recurred in the kidney allograft. Proximal tubules were markedly abnormal, with cytoplasmic distention by eosinophilic, intensely fuchsinophilic, Periodic acid–Schiff and silver–negative droplets that had a crystalline appearance. Immunofluorescence studies revealed droplets within the proximal tubular epithelium that were monotypic for kappa light chain. Ultrastructural evaluation confirmed the presence of numerous cytoplasmic and lysosomal inclusions with geometric shapes, including rectangular, rhomboidal, and needle shaped. Such well developed and distinctive changes are almost always associated with kappa light chain, and given the increased awareness of this entity in recent years, are usually not difficult to recognize when widespread.
Unfortunately, these characteristic lesions of LCPT represent only a portion of the tubular pathologies associated with monoclonal light chains, particularly when they are lambda light chain related. Tubular lesions may be indistinguishable from the usual changes of acute tubular injury/necrosis (ATI/ATN) by light microscopy. Therefore, immunohistology and electron microscopy are required to associate these otherwise very commonly seen tubular lesions with the paraprotein. Several other diagnostic problems add to the challenge of recognition. Abnormal light chains may not contain the epitopes that the commercially available antibodies to kappa and lambda light recognize. Thus, the absence of monotypic staining on immunostains does not exclude the diagnosis. Furthermore, tubular lysosomal monotypic staining in the absence of demonstrable tubular injury may reflect reabsorption “overload” as opposed to a true tubulopathy. Increased tissue background staining for one of the light chains may merely reflect altered levels of circulating light chains rather than kidney injury. Ultrastructural studies may show only vague lysosomal alterations that are insufficient for a definitive diagnosis. The kidney pathologist must therefore consider the possibility of a paraprotein-related lesion in every case. As always, clinical/pathologic correlation, with attention to signs of tubular dysfunction, is essential for proper diagnosis.
This category of monoclonal-associated ATI/ATN (also known as non-crystalline LCPT) is easy to miss, particularly when the patient is not known to have a paraprotein, and may be more common than classic (crystalline) LCPT. Consequently, difficulty in determining if the patient with MGUS really has MGRS is not unusual. When present as an isolated process, non-crystalline LCPT may be quite reversible if light chain production can be controlled. However, this lesion can also be seen in combination with other paraprotein-related diagnoses, and thus have a much more guarded prognosis.
We have made significant progress since the days when paraprotein-related kidney disease was assumed to be cast nephropathy. However, much remains to be learned about the relatively subtle tubular lesions under discussion and their relationship to tubular dysfunction and acute kidney injury. In particular, newer techniques that might enable more definitive pathologic diagnosis of this entity are necessary. Greater recognition of its existence is the first step.
Isaac E. Stillman, MD
Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA
AJKD Blog Contributor and AJKD Kidney Biopsy Teaching Case Advisory Board member
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I suggest that (if not done yet) the experts in the field formulate an algorithm within upcoming consensus meetings for when we should call definitive evidence of LCPT vs. features suggestive of/ cannot exclude vs. no clear evidence/ not diagnostic of paraprotein.
This is becoming very challenging and I feel like I should be decreasing my threshold more and more. For example: I had a recent case of only mildly (less than 2-fold kappa-to-lambda free LCs and negative IFE). Focally prominent protein droplets and vacuolization but PAS positive in tubules. Kappa much stronger than lambda even if I removed the background. EM did not show inclusions (crystalline or non-crystalline but had swollen mitochondria and vaguely large lysosomes). Therefore called it findings suggestive of LCPT… but not without a lot of self debating and struggling… to add to the difficulty, the patient is diabetic and there is well documented evidence that diabetic patients tend to excrete more kappa.