Clinicopathologic predictors of renal outcomes in light chain cast nephropathy: a multicenter retrospective study

Abstract

Light chain cast nephropathy (LCCN) in multiple myeloma often leads to severe and poorly reversible acute kidney injury. Severe renal impairment influences the allocation of chemotherapy and its tolerability; it also affects patient survival. Whether renal biopsy findings add to the clinical assessment in predicting renal and patient outcomes in LCCN is uncertain. We retrospectively reviewed clinical presentation, chemotherapy regimens, hematologic response, and renal and patient outcomes in 178 patients with biopsy-proven LCCN from 10 centers in Europe and North America. A detailed pathology review, including assessment of the extent of cast formation, was performed to study correlations with initial presentation and outcomes. Patients presented with a mean estimated glomerular filtration rate (eGFR) of 13 ± 11 mL/min/1.73 m2, and 82% had stage 3 acute kidney injury. The mean number of casts was 3.2/mm2 in the cortex. Tubulointerstitial lesions were frequent: acute tubular injury (94%), tubulitis (82%), tubular rupture (62%), giant cell reaction (60%), and cortical and medullary inflammation (95% and 75%, respectively). Medullary inflammation, giant cell reaction, and the extent of cast formation correlated with eGFR value at LCCN diagnosis. During a median follow-up of 22 months, mean eGFR increased to 43 ± 30 mL/min/1.73 m2. Age, β2-microglobulin, best hematologic response, number of cortical casts per square millimeter, and degree of interstitial fibrosis/tubular atrophy (IFTA) were independently associated with a higher eGFR during follow-up. This eGFR value correlated with overall survival, independently of the hematologic response. This study shows that extent of cast formation and IFTA in LCCN predicts the quality of renal response, which, in turn, is associated with overall survival.

Graphical abstract

Figure 1.

Pathology illustrations. Intraluminal LC casts with the typical appearance. By light microscopy: (A) sharp-edged periodic acid–Schiff negative casts surrounded by a cellular reaction (magnification ×600), (B) fractured cast on trichrome stain (magnification ×600), (D) eosinophilic granular casts on hematoxylin and eosin stain (magnification ×400), and (E) multinucleated giant cell reaction around a fractured cast (magnification ×400). By immunofluorescence: (C) positive staining with anti-κ (magnification ×100) and (F) negative staining with anti-λ (magnification ×100). Images of pathology features that were recorded: (G) extensive interstitial fibrosis and tubular atrophy with scarce mononuclear interstitial inflammation (periodic acid–Schiff, magnification ×100), (H) tubular rupture with the interruption of the tubular basement membrane (arrow) (Jones methenamine silver, magnification ×400), (I) interstitial giant cells (arrow) (periodic acid–Schiff, magnification ×400), (J) interstitial inflammation with tubulitis (arrow) (periodic acid–Schiff, magnification ×600), (K) THP extravasation into the interstitium (asterisk) (periodic acid–Schiff, magnification ×200), and (L) THP protein in the Bowman’s space (asterisks) (periodic acid–Schiff, magnification ×400).

Figure 2.

Pathology findings. There was no cortex in 3 biopsy specimens and no medulla in 67 (38%), where no highest or mean number of casts could be determined.

Figure 3.

Renal outcomes according to mean and highest number of casts in the cortex.

Figure 4.

Interrelation between independent pathology findings with the initial and best follow-up eGFR.

Figure 5.

OS according to the renal and hematologic responses. (A) Renal response, (B) hematologic response. nCR, near CR; PR, partial response.