Light Chain Proximal Tubulopathy: Clinical and Pathologic Characteristics in the Modern Treatment Era

Abstract

Light chain proximal tubulopathy (LCPT) is characterized by cytoplasmic inclusions of monoclonal LC within proximal tubular cells. The significance of crystalline versus noncrystalline LCPT and the effect of modern therapies are unknown. We reported the clinical-pathologic features of 40 crystalline and six noncrystalline LCPT patients diagnosed between 2000 and 2014. All crystalline LCPTs were κ-restricted and displayed acute tubular injury. One-third of noncrystalline LCPT patients displayed λ-restriction or acute tubular injury. Only crystalline LCPT frequently required antigen retrieval to demonstrate monoclonal LC by immunofluorescence. In five of 38 patients, crystals were not detectable by light microscopy, but they were visible by electron microscopy. Hematolymphoid neoplasms, known before biopsy in only 15% of patients, included 21 monoclonal gammopathies of renal significance; 15 multiple myelomas; seven smoldering multiple myelomas; and three other neoplasms. Biopsy indications included Fanconi syndrome (38%; all with crystalline LCPT), renal insufficiency (83%), and proteinuria (98%). Follow-up was available for 30 (75%) patients with crystalline LCPT and all six patients with noncrystalline LCPT, of whom 11 underwent stem cell transplant, 16 received chemotherapy only, and nine were untreated. Complete or very good partial hematologic remissions occurred in six of 22 treated crystalline LCPT patients. By multivariable analysis, the only independent predictor of final eGFR was initial eGFR, highlighting the importance of early detection. All patients with crystalline LCPT treated with stem cell transplant had stable or improved kidney function, indicating the effectiveness of aggressive therapy in selected patients.

Keywords: Renal pathology; multiple myeloma; renal proximal tubule cell.

Copyright © 2016 by the American Society of Nephrology.

Figures

Figure 1.

Light microscopic findings in crystalline LCPT. (A) Proximal tubular cells are engorged by abundant fuchsinophilic small crystalline inclusions that distort the nuclei and obscure the apical cell membrane, filling the tubular lumen. There is adjacent mild interstitial fibrosis and inflammation without tubulitis (trichrome, ×600). (B) Proximal tubular cells are distorted by elongated highly fuchsinophilic needle-shaped inclusions. Some of the tubular cells are flattened, and others display shedding of cytoplasmic fragments into the lumen. An atypical hard cast is present in a distal tubule (trichrome, ×600). (C) Distinct crystals of varying size and number are brightly trichrome-red and exhibit a variety of geometric shapes from rectangular to rhomboidal (trichrome, ×400). (D) The proximal tubular cells contain abundant large, elongated, optically clear, or weakly eosinophilic crystals that distort the cell architecture (hematoxylin and eosin stain, ×600). (E) There is variable individual proximal tubular cell vacuolation containing finely granular punctate eosinophilic inclusions that could be resolved as crystalline only at the ultrastructural level. Some proximal tubular nuclei appear to be undergoing apoptosis. (hematoxylin and eosin stain, ×600). (F) The same biopsy as Figure 1E shown with trichrome stain highlights the granular trichrome-red inclusions and vacuolated appearance of individual proximal tubular cells side by side with more normal appearing cells (trichrome, ×600). (G) Crystals are shed from the apical surfaces of injured proximal tubular cells into the tubular lumen, forming atypical loose casts with sharp edges. No giant cell reaction is seen. The adjacent interstitium is expanded by fibrosis and chronic inflammation (trichrome ×600). (H) A glomerulus with abundant crystalline inclusions within the cytoplasm of engorged podocytes (trichrome, ×600). (I) An example of crystal-storing histiocytosis with needle-shaped fuchsinophilic crystals within the cytoplasm of interstitial histiocytes. Similar crystals are present in the proximal tubular cells of an adjacent tubule at bottom left (trichrome, ×600).

Figure 2.

Pathologic features of noncrystalline LCPT. (A) The proximal tubular cells are variably distended by abundant PAS-negative vacuoles associated with focal loss of brush border (PAS, ×600). (B) By immunofluorescence performed on pronase-digested paraffin sections, the vacuoles stain intensely for κ light chain (FITC-conjugated antisera to κ light chain, ×400). (C) By EM, the vacuoles appear rounded or ovoid and contain finely granular material without crystal formation. The numerous membrane-bound vesicles extend from the apical to the basal cytoplasm and crowd out the mitochondria, which appear reduced in size and number (Magnification, ×5000). (D) A different case of noncrystalline LCPT exhibits membrane-bound phagolysosomes with a mottled appearance owing to rounded electron-dense particulate inclusions suspended free on an electron-lucent background or within a moderately electron-dense amorphous matrix. The adjacent mitochondria appear well preserved (Magnification, ×40,000).

Figure 3.

Immunofluorescence characteristics of crystalline LCPT. (A) An instance with needle-shaped crystals of κ light chain seen by immunofluorescence performed on pronase-digested paraffin sections. These crystals were not visible by routine IF performed on frozen sections (not shown). (FITC-conjugated antisera to κ light chain, ×600). (B) An instance with both needles and smaller granular inclusions is revealed after pronase digestion on paraffin-embedded formalin-fixed tissue (FITC-conjugated antisera to κ light chain, ×600). (C) An instance with proximal tubular engorgement by granular inclusions staining for κ light chain after pronase digestion on paraffin-embedded tissue. These inclusions were visible to a lesser extent by staining of frozen tissue (not illustrated) (FITC-conjugated antisera to κ light chain, ×600). (D) The same biopsy as Figure 3C shown with negative staining for λ light chain performed on pronase-digested paraffin sections (FITC-conjugated antisera to λ light chain, ×600).

Figure 4.

Ultrastructural findings in crystalline LCPT. (A) A low power view shows full thickness (apical to basal) engorgement of individual proximal tubular cells by crystals of varying size and shape, causing compression of the nuclear contours. The apical brush border is swollen or lost. The less-involved cells have an increased number of electron lucent endosomes and electron dense phagolysosomes (Magnification, ×3000). (B) A severely injured proximal tubular cell contains multiple membrane-bound phagolysosomes distended by randomly oriented crystals, some of which appear to have broken out into the cytosol. There is complete loss of the apical brush border with cytolysis and shedding of crystals and mitochondria into the tubular lumen (Magnification, ×10,000). (C) A higher power view of an individual membrane-bound phagolysosome from Figure 3B illustrates fusion of endosomes (smaller membrane-bound vesicles) within the larger phagolysosome, which is distended by randomly oriented crystals exhibiting predominantly rhomboidal shapes. The adjacent mitochondria appear swollen with disrupted and dysmorphic cristae (Magnification, ×20,000). (D) On low power view, some proximal tubular cells are markedly engorged by crystals, whereas others are completely spared but show degenerative changes with loss of brush border and epithelial simplification (Magnification, ×4000). (E) A high-power view of a proximal tubular cell from the same instance as Figure 3D illustrates a range of crystalline shapes from hexagonal to pentagonal or triangular. Most of the crystals appear to lie free within the cytosol (Magnification, ×10,000). (F) On high-power examination, individual crystals exhibit a periodicity seen as cross-hatching or vague striations (Magnification, ×80,000). (G) An example of elongated feathery phagolysosomes with branching architecture containing solid, needle-like, or fibrillary structures, some of which lie free in the cytoplasm (Magnification, ×15,000). (H) At 100,000× magnification, individual crystals are seen to be composed or repeating smaller subunits with 10 nm periodicity, shown longitudinally and in cross-section. These smaller repeating structures may represent individual light chain molecules arrayed in linear parallel sequence within the larger crystal. Rounded ribosomes are adherent to the edge of the crystal (Magnification, ×120,000). (I) A patient with elongated rectangles forms rod-shaped structures that were present both within the podocyte cytoplasm and the proximal tubular epithelium (not shown). Each of these rectangles is composed of parallel linear arrays (Magnification, ×60,000).