Renal Amyloidosis - Tempo of Proteinuria Resolution in Bortezomib Era

Abstract

IntroductionAL amyloidosis is a systemic disease where the immunoglobin light chains produced by clonal plasma cells accumulate as insoluble fibrils causing end organ damage. In patients with AL amyloidosis, renal involvement is common, and proteinuria is frequently detected. Current treatment for AL amyloidosis aims at reducing production of these pathological immunoglobulin light chains by eliminating the clonal plasma cell population. Following treatment and normalisation of serum free light chains (SFLCs), improvement in end organ function, as demonstrated by reduction of proteinuria in patients with renal AL amyloidosis, occurs at a much slower rate. Although reduction in proteinuria has been linked to improved outcomes, the rate of this reduction has not been documented in detail in the literature. The purpose of this study is to analyse the tempo of proteinuria resolution in patients with renal AL amyloidosis following bortezomib based chemotherapy.MethodsCases were selected by retrospectively reviewing the hospital electronic database. All patients with biopsy confirmed renal AL amyloidosis were included. Induction chemotherapy was a combination of weekly bortezomib (1.6mg/m2), cyclophosphamide (300mg/m2) and dexamethasone (40mg) given in 4-weekly cycles. During the follow-up period, proteinuria was measured by urinary protein / creatinine ratio (PCR) from random urine samples. The results of the PCR over time were plotted on a scatter plot, and a best fit curve was fitted using IBM SPSS Statistics 20 software to determine the trend of PCR over time. Patients who did not complete bortezomib chemotherapy, or did not have follow-up urinary PCR were excluded.ResultsAfter applying the exclusion criteria, seven patients were analysed, and the baseline characteristics are listed in table 1. The median follow-up was 30.9 months (range: 13.2 – 44.1 months). The median age was 68.8 years (range: 52.5 – 80.5 years). Patients received a median of 6 cycles of chemotherapy (range: 2 – 9 cycles), and all patients received full doses of bortezomib based on their body surface area (average dose of 1.6mg/m2, range: 1.53 – 1.64mg/m2). Five of the 7 patients normalised their SFLCs after one cycle of chemotherapy, and the median time to normalisation was 26 days (range: 13 – 185 days).PCR was used to monitor the level of proteinuria following chemotherapy. One patient was excluded in this part of the analysis due to progressive diabetic and hypertensive nephropathy following an initial improvement in PCR after normalisation of SFLCs. Although there was marked fluctuation of PCR (figure 1), the PCRs followed an exponential decay pattern over time (R2 between 0.223 – 0.976). The median half-life of reduction was 6.2 months (range: 3.4 – 18.2 months).ConclusionsPCR from random urine samples is a useful and convenient way of assessing proteinuria in everyday outpatient setting. Although PCR fluctuates over time in patients with renal AL amyloidosis, there is a general downward trend following bortezomib based chemotherapy and normalisation of SFLCs. This downward trend appears to follow an exponential decay pattern, and most patients have a protracted delay between normalisation of SFLCs and improvement in proteinuria. In view of such delay, normalisation of SFLCs should be the goal of initial therapy, rather than reduction in proteinuria when treating patients with renal AL amyloidosis.Table 1Baseline patient characteristicsValue(range)Age (median)68.8 years(52.5 – 80.5 years)Male (%)55.6%Plasma cell burden (median)12.5%(6 – 25%)Kappa/Lambda light chain ratio (median)0.164(0.011 – 37.333)eGFR > 30ml/min (%)88.9%Protein / creatinine ratio at diagnosis (mean)698mg/L(243 – 1636mg/L) [Display omitted] DisclosuresSimpson:Onyx: Honoraria, Research Funding; Celgene: Honoraria; Janssen Cilag: Honoraria.