Renal histopathological scoring of amyloid deposits predicts renal and overall prognosis in light-chain (al) amyloidosis: a multicentre study

Background and Aims Renal involvement is common in light-chain (AL) amyloidosis (60%-80% cases). To date, renal biopsy is not recommended as a routine examination in patients with AL amyloidosis and renal involvement. However, renal histology can have an important prognostic role. Amyloid load, representing the quantification of amyloid deposits into the kidney, might be linked to both systemic disease severity and temporal exposure to amyloid deposition in different organs. We proposed an amyloid load scoring system in order to predict renal and overall survival in patients with AL amyloidosis. Method We retrospectively collected AL cases who underwent to renal biopsy from 17 Italian Institutions. The primary composite outcome includes time to death and time to end-stage kidney disease development. We applied an Amyloid load score characterized by a semiquantitative evaluation for amyloid deposition in glomeruli, interstitium, and vessels. Each lesion was scored from 1 to 3. The sum of damage (0–9) associated with amyloid deposition was calculated, indicating total numeric codes of renal pathologic damage. Results Between 2008 to 2022, we recruited 162 patients. Their median age at diagnosis was 66.5 (±10) years, serum creatinine was 1.95 (±1.92) mg/dl and proteinuria was 5.4 (±4.6) grams per 24hr. After a median follow-up of 4.1 (± 3.6) years and a 6-month landmark analysis, the primary composite outcome was achieved by 46/122 (38%) patients. Seventy-eight patients (60%) experienced a hematologic response, classified as a complete response or very good partial response, while 49 (37.4%) patients obtained a renal response. Among them, 39 (80%) patients had an amyloid score ≤4 and only 4 had an amyloid score> 5. Higher values of Amyloid load score, as an expression of amyloid load linked to both disease severity and temporal exposure, were significantly associated with an increased risk of end-stage kidney disease (ESKD) (log rank 12.80, p = 0.005) (Figure 1A) and death (log rank 44.97, p<0.0001) (Figure 1B). Interestingly, 6/162 (3.7%) patients had a negative Congo red stain in renal biopsy (AL amyloidosis diagnosis through an abdominal fat pad aspiration plus monoclonal restriction at immunofluorescence staining or amyloid fibrils detected by electron microscopy). Moreover, 49/156 (31.4%) patients did not show a monotypic (kappa or lambda) immunofluorescence staining. Despite the widely accepted clinical definition of renal amyloidosis is “more than 0.5 g/24hr of non-Bence Jones proteinuria in presence of a positive fat pad aspiration”, 8/162 (4.9%) patients with a biopsy-proven renal AL amyloidosis showed less than 0.5 g/24hr of non-Bence Jones proteinuria. AL amyloidosis showed to overlap in 14/153 (9.2%) patients with other Monoclonal gammopathy of renal significance (MGRS), such as LCDD (4 cases), C3 nephropathy (4 cases), light-chain proximal tubulopathy (2 cases), light chainrelated tubulointerstitial nephritis (2 cases), cast nephropathy (1 case), type 1 crioglobulinemia (1 case). Conclusion Conclusions: Renal histopathological scoring of amyloid deposits is crucial to assess disease progression in patients with AL amyloidosis, and in particular a score ≥5 identifies patients at greater risk of evolution of renal damage and mortality. If these data were also confirmed in a larger independent cohort, they could support the use of renal biopsy as an essential prognostic (as well as diagnostic) tool to be included as a routine investigation in all patients with suspected AL amyloidosis.