SP005EFFECTS OF TRANSTHYRETIN STABILIZER-TAFAMIDIS ON ATTR AMYLOIDOSIS RENAL DAMAGE: PERSISTENT REDUCTION OF ALBUMINURIA

Abstract

Introduction and Aims: The transthyretin (ATTR) amyloidoses are rare hereditary diseases characterized by neuropathy and cardiomyopathy. Amyloid deposits induce progressive proteinuric nephropathy and end-stage renal disease, adversely affected by female gender. Val30Met is one of the most common amyloidogenic TTR mutations. Tafamidis, a ATTR-kinetic stabilizer, inhibits the protein dissociation into monomers, the rate-limiting step in amyloid formation. It is approved for use in early-stage disease to delay peripheral neurologic impairment. However, effectiveness in kidney involvement is unclear. This study investigated the long-term effect of tafamidis on albuminuria and eGFR in ATTR amyloidosis. Methods: A prospective, single centre, non-randomized cohort study was conducted. Men and nonpregnant women aged 18-75 years were eligible if they had neuropathy stage I, biopsy-confirmed ATTR amyloidosis, urinary albumin-to-creatinine ratio (UACR)> 300 mg/g and eGFR ≥ 60 mL/min. Exclusion criteria were TTR variants other than V30M, non-amyloid renal disease, renal or liver transplant, hepatitis B, C, HIV and diabetes mellitus. All patients received tafamidis 20 mg QD. Clinic visits and laboratory evaluations were scheduled at baseline, months 6, 12, 18 and 24. The changes from the pretreatment baseline to the end of the study by each period were compared using theWilcoxon rank sum test. Results: We screened 22 patients (18 F/4 M) of whom 10 completed 24 months of therapy. The mean duration of neuropathy at baseline was 4.5 ± 3.7 years, with a mean age at onset of 47 ± 12.3 years. The eGFR did not differ significantly. It was calculated using the CKD-EPI, MDRD and Cockcroft-Gault formulas. The values at enrolment and at the end of follow-up were 105.1 and 95.2; 93.0 and 82.9; 83.6 and 81.8 mL/min/ 1.73 m2, respectively. There was a sustained decrease of mean UACR values during the follow-up period (figure 1) with significant median changes per month (figure 2). Serum albumin significantly increased (P<0.01) between month 6 and 12 of treatment. In the 10 patients who completed 24 months of follow-up, the median levels of serum albumin improved from 3.6 (2.8-4.1) at baseline to 4.1 (3.6-4.6) g/dL. Conclusions: In ATTR V30M amyloidosis, tafamidis 20 mg QD decreases albuminuria with stable renal function. The treatment effect was sustained over 24 months. This is a new facet of the drug, since previous clinical trials did not include nephropathy as an end-point of treatment. Our findings suggest that recovering the quaternary structure stability of ATTR is critical to retard kidney amyloidosis. (Figure Presented).