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.

The urine light chain/glomerular filtration rate (GFR) quotient shows a high sensitivity and specificity to detect cast nephropathy in monoclonal light chain disease

“…Once on dialysis, the renal recovery varies between different studies from 9.1% 5 to 44%. 22 In the study of Knudsen et al, 6 the reversibility of renal failure was associated with an improved outcome. The median survival was 43 months for patients with normal renal function at the time of diagnosis, 31 months for patients with reversible renal failure and 25 months for patients with irreversible renal failure.…”

The Clone Wars: Diagnosing and Treating Dysproteinemic Kidney Disease in the Modern Era

“…These structural interactions are determinants of cast formation, and can be inhibited by competitor peptides in a rodent model of LCCN, highlighting the importance of interventions which increase intratubular flow, in addition to chemotherapy [2,3]. The extent of cast formation, and tubular atrophy and interstitial fibrosis have been associated with renal outcome [38]. Light chain casts may also show amyloid-like properties, with birefringence on Congo Red stain under polarized light; this intratubular amyloid in LCCN has been associated with systemic AL amyloidosis [39].…”

“…Rapid light chain reduction is associated with improved kidney outcomes, including reversal of kidney injury and dialysis-discontinuation [47,48]. Older age, lower initial kidney function, higher baseline light chain level, and higher B2-microglobulin (partially due to diminished renal clearance) levels were associated with worse kidney function during follow-up [38]. Reassuringly, as therapies have improved, the proportion of end-stage kidney disease patients with multiple myeloma has declined and rates of kidney recovery have improved [49,50].…”

Monoclonal Gammopathies of Renal Significance: Renal Biopsy and Beyond

“…Most frequently, the request for a nephrology consultation arises in such cases from an abrupt impairment of renal function. This type of AKI is usually related to tubular obstruction by large amounts of filtered LC, a histological feature known as "cast nephropathy" [31,32]. A renal biopsy is useful to confirm this suspicion and guide rescue therapy.…”

“…A renal biopsy is useful to confirm this suspicion and guide rescue therapy. As cast nephropathy is also seen in the NS, a setting in which tubular obstruction by proteins is one of the recognized causes of AKI, the distinguishing feature of MGRS is a strong positivity of the immunofluorescence for κ or λ chains within the tubular lumina [6,8,31,32]. Since LC in a normal κ/λ ratio of approximately 1:1 are frequently found in the biopsies of patients with the NS, resulting from tubular injury by filtered serum proteins, the pathologist should attribute obstruction to an MGRS if just one subclass of LC is represented, either κ or λ.…”