Identification Of Reversible Organ Damage and Of Early Markers Of Response To Treatment In Renal AL Amyloidosis: A Study On 461 Patients
Authors: Palladini Giovanni , Milani Paolo , Rosin Marta Vidus , Foli Andrea , Merlini Giampaolo 
Published: October 2019

Abstract
A recent consensus revised the criteria for hematologic and cardiac response to treatment in AL amyloidosis based on patients’ survival. However, although the kidney is involved in approximately 70% of patients with AL amyloidosis, the criteria for renal response have not been updated since 2005 and have never been validated. The UK Group showed that progression to dialysis is more likely with increasing CKD (Chronic Kidney Disease) stage and less likely in patients who achieve a >90% dFLC decrease after chemotherapy. More recently, the Mayo Clinic group reported that a profound reduction (>95%) in proteinuria at 1 year is associated with longer patients’ survival. However, since renal involvement has less relevant impact on patients’ survival compared to cardiac involvement, the criteria of renal response and progression should predict progression to dialysis and not necessarily death. Moreover, dialysis is associated with significant morbidity and mortality. Finally, considering that the median time to a profound proteinuria reduction is approximately 1 year, long after hematologic response is assessed, it is important to identify early markers of renal response that can allow timely changes in the therapeutic strategy.
In the present study we evaluated 461 consecutive previously untreated patients with AL amyloidosis and renal involvement (defined as albuminuria >0.5 g/24h as per current criteria) diagnosed between 2004 and 2012. Median age was 64 years, and 264 patients (57%) were males. The heart was involved in 311 patients (67%) and 160 (35%) were Mayo stage III. Thirty-one (7%) patients had liver and 21 (4%) peripheral nervous system involvement. At diagnosis the median estimated glomerular filtration rate (eGFR) by the CKD-EPI formula was 62 mL/min per 1.73 m2 and median proteinuria was 5 g/24h. The CKD stage was 1 in 94 patients (20%), 2 in 148 (32%), 3 in 139 (30%), 4 in 67 (15%), and 5 in 13 (3%). Seventy-one patients (15%) required dialysis after a median time of 10 months (range 1-94 months). Patients who died off-dialysis were considered censored for the purpose of the analysis. The median survival from diagnosis was 47 months, and the median survival from dialysis initiation was 39 months. At univariate analysis the only baseline variables predicting renal survival were eGFR and proteinuria. We adopted values close to the medians as clinical cutoffs. At multivariate analysis eGFR <60 mL/min (HR 10.0, 95%CI 2.5-40.6, P=0.001) and urinary protein loss >5 g/24h (HR 3.5, 95%CI 2.0-6.3, P<0.001) were independent predictors of renal survival. These cutoffs allowed discriminating 3 groups with increasing risk of progression to dialysis (Figure 1). Importantly, no patient with proteinuria £5 g/24h and eGFR ³60 mL/min required dialysis during follow-up. Both eGFR and proteinuria did not affect overall survival. The analysis of early response/progression criteria was performed on the 314 patients who had a complete dataset at 3 months. A ROC analysis showed that the cutoffs best predicting renal survival were a 25% eGFR decrease, a 20% proteinuria decrease, and a dFLC concentration <40 mg/L, which, remarkably, corresponds to the current definition of very good partial response (VGPR). A multivariate analysis showed that these cutoffs were independent predictors of renal survival and were also independent from the baseline stage based on proteinuria and eGFR (Table 1). Partial hematologic response (dFLC decrease by >50%) and the current definition of renal response (proteinuria decrease of >50% in the absence of progressing renal failure) were less powerful predictors not reaching statistical significance.Figure 1Staging system for progression to dialysisFigure 1. Staging system for progression to dialysisTable 1Multivariate analysis of renal survivalVariableHR (95%CI)PAmyloid renal stage4.5 (2.3-8.7)<0.001eGFR decrease >25%4.6 (2.5-8.5)<0.001proteinuria decrease >20%0.4 (0.2-0.7)0.004CR/VGPR0.5 (0.2-0.8)0.013
Early diagnosis, when proteinuria is <5 g/24h and eGFR >60 mL/min, allows intervention when renal damage is still reversible. Patients who obtain VGPR or CR according to the novel criteria are protected from loss of renal function. A reduction of proteinuria >20% and an eGFR decrease >25% at 3 months are markers of response and progression of amyloid kidney involvement, respectively, and can be used for early assessment of treatment efficacy.

Disclosures:
Merlini: Millennium-Takeda: Honoraria; Pfizer: Honoraria.