Kidney Outcomes in Patients With Hereditary Transthyretin Amyloid Nephropathy Treated With Transthyretin Stabilizers And Gene-Silencer Therapies

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Introduction Kidney involvement is underestimated in patients with hereditary transthyretin amyloidosis (ATTRv), and few data are available about the renal outcomes of patients treated with targeted therapies. Methods Patients with ATTRv nephropathy (ATTRv-N) from 6 French referral centers were retrospectively included. The evolution of estimated glomerular filtration rate (eGFR) and proteinuria, and the specific treatments of ATTRv were collected. Renal survival was assessed by using a renal composite end point, including an eGFR decline > 50% from baseline and/or dialysis requirement. Results Twenty-three patients (70% female) with a median age at ATTRv-N diagnosis of 50 (interquartile range [IQR]: 37–63) years were included. Baseline eGFR was 60 (39–83) ml/min per 1.73 m 2 . Median urine protein-to-creatinine ratio (UPCR) was 100 (IQR: 20–240) mg/mmol. ATTRv-N was documented by kidney biopsy in 20 of 23 patients (87%). Eleven patients were treated with the transthyretin (TTR) stabilizer, tafamidis; 6 patients with a small interfering RNA (siRNA); 4 with exclusive orthotopic liver transplantation (OLT); whereas 2 received no specific treatment. After a median follow-up of 5.8 (IQR: 3.3–18.6) years, all patients with OLT or no treatment had a progressive eGFR decline, requiring dialysis in 3 of 6 patients. Among patients treated with tafamidis, 8 of 11 (73%) had a progressive eGFR decline, requiring dialysis in 1 patient; and proteinuria was either stable or increasing over time in all patients. All patients who received siRNA therapy had stable or improving eGFR. Renal survival was 44%, 44%, and 100% at 60 months for the patients with exclusive OLT or no treatment, TTR stabilizers, and siRNA, respectively ( P = 0.12). Four patients with baseline nephrotic syndrome or high-grade proteinuria, including 3 patients resistant to tafamidis, responded dramatically to siRNA therapy, with a fast, complete, and sustained remission of proteinuria within 1 year. Conclusion Our study highlights the underrecognized risk of chronic kidney disease (CKD) and end-stage kidney disease in ATTRv and suggests that siRNA could be a promising therapeutic option for the stabilization of kidney function.