Medications show promise for treating kidney disease in ATTRv
Better outcomes seen for patients given Onpattro, Amvuttra: Study
Kidney disease is an underrecognized complication of hereditary transthyretin amyloidosis (ATTRv) — a group of diseases that includes familial amyloid polyneuropathy (FAP) — but may be effectively controlled with a class of medications known as siRNA therapies, among them Onpattro (patisiran) and Amvuttra (vutrisiran).
That’s according to an observational study, conducted in France, that involved 23 adults with ATTRv-related kidney problems.
Patients who received approved siRNA therapies — medications that reduce the production of the faulty protein causing these diseases — had better kidney-related outcomes than those who received other therapies or who were not treated, the data showed.
“Our study highlights the underrecognized risk of chronic kidney disease (CKD) and [kidney failure] in ATTRv and suggests that siRNA could be a promising therapeutic option for the stabilization of kidney function,” the researchers wrote.
The study, “Kidney Outcomes in Patients With Hereditary Transthyretin Amyloid Nephropathy Treated With Transthyretin Stabilizers And Gene-Silencer Therapies,” was published in Kidney International Reports.
In ATTRv, mutations in the TTR gene give rise to an abnormal and misfolded version of the transthyretin protein, which subsequently forms toxic clumps that accumulate and damage the body’s tissues.
ATTRv commonly affects the heart and peripheral nerves — those that reside outside of the brain and spinal cord. FAP is a form of the disease in which symptoms of peripheral nerve damage, known as peripheral neuropathy, are its hallmark.
Kidney involvement is also possible in ATTRv, with data suggesting that the prevalence of chronic kidney disease in this population is underestimated, according to the researchers.
Scant data on medications for treating kidney disease in ATTRv
In recent years, the availability of new treatments has improved the outlook for people with ATTRv, particularly in terms of neurological and heart-related outcomes. Among these new treatments are two siRNA therapies, Onpattro and Amvutrra, that work to lower transthyretin production by essentially silencing the TTR gene.
But because kidney issues are often overlooked, the possible benefits of these treatments on kidney-related outcomes have not been fully established.
Now, a team of researchers at institutions in France examined the real-world evolution of kidney parameters among adults with ATTRv who had kidney disease that was definitively or considered very likely to be directly related to toxic transthyretin clumps.
The researchers retrospectively analyzed the medical records of 23 such individuals, who were seen across six French specialty centers. The patients, who had a median age of 50, had experienced their first ATTRv-related symptoms at a median age of 43. Common disease manifestations included peripheral neuropathy, experienced by 96%, and heart involvement, seen among 70%.
Kidney issues led to the initial ATTRv diagnosis for seven of these individuals. Eight patients were diagnosed with ATTRv-related kidney disease while receiving treatment for ATTRv: either a liver transplant or tafamidis, a transthyretin stabilizer therapy sold as Vyndaqel and Vyndamax.
Kidney function was monitored via the estimated glomerular filtration rate (eGFR), a blood test that estimates how well the kidneys are working to filter waste from the blood, and a urine test to assess proteinuria, or excess protein in urine. Declines in eGFR and elevations in urine protein levels are signs that the kidneys aren’t working as they should.
At the start of their kidney disease diagnosis, 83% of the patients showed substantial reductions in eGFR and/or significant proteinuria.
Observational study monitored patients’ kidney outcomes over 5 years
Kidney outcomes were then monitored over a median follow-up of 5.8 years. During that time, 11 patients were treated with tafamidis alone, six received an siRNA medication (with or without tafamidis), and four exclusively received a liver transplant. The remaining two people did not receive treatment.
All six people who underwent a liver transplant or did not receive treatment (group 1) experienced progressive eGFR declines. Half of them needed dialysis, a treatment that filters waste from the blood when the kidneys are failing and can no longer do so.
Among those who received tafamidis alone (group 2), 73% experienced eGFR declines, with one person requiring dialysis. Proteinuria was generally stable or further worsened over time.
Meanwhile, 5 of the 6 people who received siRNA therapy (group 3) had stable or increasing eGFR, and urine protein levels were “dramatically reduced” in all patients in this treatment group, the researchers wrote.
After five years, all people in the siRNA group had achieved an outcome called renal survival, meaning they had avoided dialysis and an eGFR decline of more than 50%. This was achieved by 44% of those in the other two groups, but the differences in risk between groups were not statistically significant.
Our study is the first to provide data about [kidney] outcomes under targeted therapies in [ATTRv-related kidney disease]; and suggests that siRNA therapy could be particularly effective.
Four people who showed signs of relatively severe kidney disease, including three who did not respond adequately to tafamidis, subsequently responded well to siRNA therapy, according to the researchers.
“Our study is the first to provide data about [kidney] outcomes under targeted therapies in [ATTRv-related kidney disease]; and suggests that siRNA therapy could be particularly effective,” the team wrote.
The scientists recommended routine screening for kidney issues in people with ATTRv, including blood and urine tests, as well as kidney tissue biopsies.
Further, better documenting such kidney involvement, especially in clinical trials, will enable scientists “to better assess the effectiveness of targeted therapies in ATTRv-associated [kidney] disease,” the team concluded.
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