Tuesday, April 9, 2019

Topic Discussion: Hereditary transthyretin amyloidosis, inotersen and the kidney

Hereditary transthyretin amyloidosis is caused by pathogenic single-nucleotide variants in the gene encoding transthyretin (TTR) that induce transthyretin misfolding and systemic deposition of amyloid. Progressive amyloid accumulation leads to multiorgan dysfunction and death. Renal involvement is not as common as CNS and or cardiac involvement. A review in CJASN in 2012 had commented on the renal manifestations of this entity. Renal presentation usually is chronic kidney disease, proteinuria and kidney biopsy showing amyloid deposition.

Recently, novel therapies have emerged in the treatment of this entity in the neurology and the cardiology literature. Inotersen, a 2′-O-methoxyethyl–modified antisense oligonucleotide, inhibits hepatic production of transthyretin.  This study was published in NEJM last year and it was a randomized, double-blind, placebo-controlled, 15-month, phase 3 trial of inotersen in adults with stage 1 (patient is ambulatory) or stage 2 (patient is ambulatory with assistance) hereditary transthyretin amyloidosis with polyneuropathy. Inotersen improved the course of neurologic disease and quality of life in patients with hereditary transthyretin amyloidosis. What was interesting was that the most frequent serious adverse events in the inotersen group were glomerulonephritis(GN) (in 3 patients [3%]) and thrombocytopenia (in 3 patients [3%]), with one death associated with one of the cases of grade 4 thrombocytopenia. Apparently, it’s a black box warning now with this agent that is given SQ.

In reviewing the NEJM paper, they discuss that each of these three patients that developed the GN carried the Val30Met TTR mutation (148G→A) mutation. Two had shown a decline in the eGFR. In all three cases, the kidney biopsy showed complex pathologic features, consistent with crescentic glomerulonephritis superimposed on a background of amyloidosis and (in two cases) interstitial fibrosis. One patient was successfully treated with glucocorticoids and cyclophosphamide and regained clinically significant renal function. Another patient did not receive immunosuppressive therapy owing to delayed diagnosis, and permanent hemodialysis was initiated. A third patient was identified as having clinically significant proteinuria after the implementation of more frequent renal monitoring of every 2 to 3 weeks; this patient did not show a decline in renal function. Urinary protein excretion returned to baseline levels after treatment with glucocorticoids. There is no discussion on the serologies sent or if this was a vasculitic reaction that we see sometimes with anti TNF agents. After the notice of the GN in these patients, they instituted an enhanced monitoring system. After the implementation of enhanced monitoring, no additional cases of severe thrombocytopenia occurred, and a single case of glomerulonephritis was identified early without loss of renal function. There was also a single case of antineutrophil cytoplasmic autoantibody (ANCA)–positive systemic vasculitis reported. It is possible(speculative) that this drug induces an ANCA associated crescentic GN in certain cases. On a pubmed and google search, I found no further published cases of any GNs with this agent. Since the advent of this agent, several other agents are in the market for treatment of Transthyretin Amyloid neuropathy and cardiomyopathy.

A similar drug called Patisiran, an RNAi therapeutic for similar indication was published in 2018 as well. The investigators found that this drug significantly improved neuropathy in patients with hereditary transthyretin amyloidosis. This drug had no renal side effects reported in the side effect profile. This is an IV drug compared to the SQ version previously discussed. 

In another NEJM paper, in patients with transthyretin amyloid cardiomyopathy, tafamidis( oral transthyretin stabilizer)  was associated with reductions in all-cause mortality and cardiovascular-related hospitalizations and reduced the decline in functional capacity and quality of life as compared with placebo. The renal side effects were not significant in this drug and in equal frequency as the placebo arm.

So as the field of transthyretin amyloidosis is expanding, some of these novel targeted therapies can change the renal effects of this disease. As nephrologists, we need to be watchful for the glomerular side effects of inotersen.

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