P0052EMERGING CONCEPTS IN KIDNEY ATTR AMYLOIDOSIS: CHRONIC ADMINISTRATION OF TAFAMIDIS
Authors: Tavares Joana , Campos Andreia , Rocha Ana , Beirão Idalina , Fonseca Isabel , Silva Ana , Cardoso Márcio , Alves Cristina , Sousa Ana , Coelho Teresa , Lobato Luísa 
Published: June 2020

Abstract

Background and Aims
Transthyretin (TTR) amyloidosis is a disease characterized by destabilization of the native TTR tetramer. It can be caused by aging or due to pathogenic mutations, and its diagnosis is often missed. Hereditary transthyretin amyloidosis (ATTRv), due to Val50Met mutation, is frequently linked with polyneuropathy but it can cause nephropathy too, causing wide range levels of albuminuria and renal dysfunction. Tafamidis, a TTR tetramer stabilizer, has been associated with significant decrease of albuminuria in ATTRv. However, TTR nephropathy is not an approved indication for its use. Plus, the renal effects of chronic oral administration of this TTR stabilizer are yet to be understood. This study evaluated longitudinal changes of eGFR-EPI within 72 months of therapy with tafamidis and identified factors associated with these changes.

Method
A retrospective cohort, single centre study was conducted. We have followed consecutive ATTRv Val50Met patients on tafamidis therapy from July 2012 to March 2019. Men and women aged 18-85 years were eligible if they had neuropathy stage I, were anti-amyloid treatment-naïve patients that accomplished at least 60 months of tafamidis therapy and had eGFR over 45 ml/min/1.73m2 with any grade of albuminuria. Exclusion criteria were: pregnancy, malignancies, diabetes and concurrent etiologies for nephropathy. Statistical analyses included Mann-Whitney test and linear mixed models to analyze the longitudinal changes in eGFR of the two groups of patients (albumunuric/ non-albuminuric at baseline), by controlling for variables that could be associated with eGFR EPI Cystatin C course.

Results
From 366 patients, biopsy-proven ATTR amyloidosis, treated with tafamidis, 122 patients met our criteria (56 males, 66 females) and had a median age of 36 (IQR: 32-46) years old. Twenty-eight had pathological urinary albumin-to-creatinine ratio (ACR), defined by ACR &gt;30 mg/dL, and ACR &gt;300 mg/dL was only found in females. In univariate analysis no significant differences were found between median eGFR decline in albuminuric versus non-albuminuric patients (p=0.330). At all time points, mean eGFR levels were significantly lower in baseline albuminuric patients. According to our estimation, eGFR at baseline was 11.2 mL/min/1.73 m2 lower in baseline albuminuric patients, adjusted for age at the disease onset and time between symptom onset and tafamidis initiation. Baseline albuminuria status (p=0,005), age at the disease onset (p&lt;0,001) and time between initiation of symptoms and initiation of tafamidis (p=0,016) were the only independent factors associated with longitudinal changes of eGFR (higher age at the disease onset and higher time between symptom onset and tafamidis initiation were associated with lower levels of eGFR). Figure 1 shows the predicted eGFR EPI trajectories over time for baseline albuminuric/ non-albuminuric subjects.

Conclusion
This study represents a real-life experience of oral chronic administration of tafamidis and its effects on ATTR nephropathy, concerning albuminuria reduction and renal function decline. Our analysis had shown similar decline rates in eGFR, irrespectively the degree of albuminuria at baseline, differently from what would be expected, since higher grades of albuminuria are related with more rapidly kidney function deterioration. Besides its capacity of stabilizing TTR tetramers, tafamidis could have an enhancing role in the podocyte regeneration process through potential cofactors for amyloid fibrils toxic effect, that could be present in the glomerular basement membrane and mesangium. This nephroprotector effect should be considered when a switch of therapy is demanded by the neuropathy status and a second line treatment is considered. Presence of renal disease may be an indication for tafamidis maintenance and combined therapy.