Non-crystalline light chain proximal tubulopathy, a morphologically protean entity

Abstract

Background: Light chain proximal tubulopathy (LCPT) is a rare form of paraprotein-related disease, occurring in two main histopathological forms: crystalline and non-crystalline. The clinicopathological features, treatment strategies and outcomes, especially of the non-crystalline form, are not well described.

Methods: We conducted a single-centre retrospective case series of 12 LCPT patients, 5 crystalline and 7 non-crystalline, between 2005 and 2021.

Results: The median age was 69.5 years (range 47-80). Ten patients presented with CKD and significant proteinuria (median estimated glomerular filtration rate of 43.5 ml/min/1.73 m2; urine protein:creatinine ratio 328 mg/mmol). Only six patients had known haematological disease at the time of renal biopsy. Multiple myeloma (MM) was diagnosed in seven patients cases and monoclonal gammopathy of renal significance (MGRS) in five patients. A clone was detected in all cases combining serum/urine electrophoresis and free light chain (LC) assays. Crystalline and non-crystalline variants had similar clinical presentations. For the non-crystalline variant, a diagnosis was reached based on a combination of CKD without another cause, haematological workup, LC restriction on immunofluorescence and abnormalities on electron microscopy (EM). Nine of 12 patients received clone-directed treatment. Patients who achieved haematological response (including all non-crystalline LCPT) had improved renal outcomes over a median follow-up of 79 months.

Conclusions: The non-crystalline variant may go unrecognised because of its subtle histopathological features and requires EM to distinguish it from 'excessive LC resorption without tubular injury'. Clone-directed treatment with good haematological response improves renal outcomes in both variants but limited data exist in MGRS. Multicentre prospective studies are needed to better define the clinicopathological characteristics associated with poor outcomes and optimize treatment strategies in patients with MGRS.

Keywords: Fanconi syndrome; chronic kidney disease; monoclonal gammopathy of renal significance; multiple myeloma; proximal tubular cells.

Figure 1:

Light Microscopy features. 1a–f: H&E stains. (a) Focally “plump” proximal tubular epithelial cell cytoplasm (PTEC) (b) Diffusely “shaggy” cytoplasm in PTEC (c) Diffusely vacuolated cytoplasm in PTEC (d) Cytoplasmic clearing in PTEC (e) Eosinophilic vacuoles in PTEC (f) Rhomboid crystals in PTEC. 1g–j Semi-thin toluidine blue (TB)-stained sections of the samples for EM. (g) Dark rhomboid intracytoplasmic crystals; (h) Light/clear intracytoplasmic spicules; (i) Light intracytoplasmic rounded vacuoles; (j) Extensive areas of cytoplasmic clearing.

Figure 2:

Immunofluorescence features (a) Kappa light chain-positive intracytoplasmic spicules; (b) Kappa light chain-positive intracytoplasmic rhomboid crytals; (c+d) Non-crystalline variant with granular preponderance of kappa (c) light chain over lambda (d) light chain.

Figure 3:

Electron Microscopy features, crystalline variant. Variety of appearances. (a) Case with electron dense rhomboid intra-cytoplasmic crystals in PTEC; (b) Case with interstitial macrophage containing electron dense spicules (c) Case with electron lucent spicules in PTEC; (d) High magnification showing a grid-like pattern, with 2 sets of parallel lines crossing in near-orthogonal directions in a case with electron dense intracytoplasmic rhomboid crystals; (e) Electron dense intra-cytoplamic elongated spicules with terminal swelling; (f) Electron dense and lucent intra-cytoplasmic elongated spicules, one with a terminal swelling giving it a “cotton ear-bud” appearance; (g) Lightly electron dense elongated spicule with a darker central swelling.

Figure 4:

Electron Microscopy features, non-crystalline variant. Variety of appearances. (a) Low power, membrane-bound intracytoplasmic vacuoles; (b) Same case as (a). Membrane-bound vacuoles containing parallel fibrils; (c) Case with membrane-bound vacuoles containing randomly arranged fibrils; (d) Membrane-bound structures containing light and dark granulofibrillar material; (e) Same case as (d), higher magnification; (f) Case with intra-cytoplasmic finger-print-like structures; (g) Case with membrane-bound structures containing granular material; (h) Case with bundles on intracytoplasmic fibrils intersecting at variable angles; (i+j) Case with lysosomal dark “mottled” granules at low (i) and high (j) power; this appearance can be seen with a number of tubular insults and is not specific to LCPT.