#amyloidosisJC 3/28/16 @ 9 pm EST: Eprodisate for the Treatment of Renal Disease in AA #amyloidosis

This installment of #amyloidosisJC examines the not-positive-enough results of a randomized trial comparing the effects of eprodisate to placebo in AA amyloidosis patients with amyloid-related renal disease. Click HERE for a link to the actual article. I'd like once again to thank Dr. Naresh Bumma (@NB191186) for his assistance preparing this post. 

Dember, Laura M., et al. "Eprodisate for thetreatment of renal disease in AA amyloidosis." New England Journal of Medicine 356.23 (2007): 2349-2360.  

Background: The amyloidoses are a group of diseases characterized by extracellular deposition of fibrils comprised of misfolded proteins and other molecules such as glycosaminoglycans and SAP. End organ damage may result from either the fibrillar deposits or toxic oligomers and/or protofilaments. AA amyloidosis is a rare entity, almost always seen in the setting of an underlying chronic inflammatory condition. The amyloid-forming protein is a proteolytic product of serum amyloid A protein (SAA), an acute phase reactant protein produced by the liver. The kidney is the most commonly affected organ, though the GI tract and other organs can also be involved.

AA Amyloidosis pathophysiology from T. Nakamura (click HERE for link to paper)

Eprodisate (Kiacta), a negatively charged molecule with structural similarities to heparin sulfate, inhibits fibrillogenesis (fibril formation) by interfering with the interaction between SAA and GAGs. The premise of this trial was that if Eprodisate could inhibit fibril formation, organ damage would be prevented. 

Trial Design: Multicenter, randomized, double-blind, placebo-controlled comparison of eprodisate to placebo (1:1 randomization)

13 countries, 27 centers, 261 patients screened and 183 enrolled (7/11/2001-2/14/2003)

Key Inclusion criteria : 

• Tissue diagnosed AA amyloidosis by histologic demonstration of Congo red staining and birefringence with the use of polarized microscopy and reactivity with anti-AA antibodies by IHC 
• Kidney involvement (24hr urine protein >1g x 2 OR CrCl <60ml/min x 2)

Key Exclusion criteria: 

• Kidney disease other than AA amyloidosis, 
• Severe renal disease: CrCl <20ml/min OR SCr >3, DM
• Abnormal liver function: LFTs or alk phos >5 xULN, t bili >1.5xULN
• Diabetes Mellitus

Stratification: 

• Nephrotic syndrome (Y/N)
• Treatment center

Patient Allocation: 

Treatment: 800-2400 mg (depending on renal function) eprodisate/placebo in two divided doses each day for 24 months. Alternating office visits and telephone follow-up calls every two months. 

Primary Endpoint: 

• Composite endpoint of worsening renal function (SCr >2x BL, CrCL <0.5 BL, or progression to dialysis-requiring ESRD) or death

Key Secondary Endpoints:

• Slope of decline in CrCl over time
• Change in proteinuria
• Change in amyloid quantitation in abdominal fat
• Resolution or development of chronic diarrhea

Noted Patient Characteristics: F>M, ~1/3 pts had "normal" SAA levels, eprodisate group had slightly better baseline SCr (1.1 vs 1.3) but no statistically significant difference in CrCl, ~40% had nephrotic syndrome. The chronic underlying inflammatory condition was usually RA in both groups, but the eprodisate grp had a higher incidence of chronic infection as an alternative condition. 

Results:

• Primary composite endpoint: 42% reduction in the risk of worsening renal function or death (HR 0.58 [95% CI 0.37 - 0.93; p=0.02]). Teasing this apart: renal function worsened in 27% of eprodisate-treated patients vs 40% placebo-treated pts (p=0.06). There was no difference in mortality (HR 0.95 [95% CI 0.27 - 3.29; p=0.94]).
• Secondary endpoints: Mean slope (+/- SE) of change in CrCl (in ml/min/1.73m2) was -10.9(+/-5.1) for the eprodisate grp versus -15.6(+/- 4.1) in the placebo grp (p=0.02), though no statistical difference in risk of progressing to ESRD (E: 7 pts, P: 13 pts, HR 0.54 ([95% CI 0.22 - 1.37; p=0.20]). Also, no difference in change in urine protein loss, change in abdominal fat amyloid content, or incidence of developing chronic diarrhea.
• Safety: Similar rates of AEs and SAEs between grps

Our Analysis: 

• "Sample size...substantial for the rare disease," but not large enough to be powered to assess differences in lower frequency events like progression to ESRD or death
• Finite versus indefinite therapy may have mattered
• PK analysis could have been informative, since more than half of eprodisate pts received modified doses of medication (authors posited that pts with less severe BL renal disease might have been more likely to benefit)
• Modest benefit may be in part due to mechanism of action: SAA oligomers and protofibril levels not reduced (predictably, since blocking SAA-GAG interaction should only affect mature AA fibril formation). Also, persisting albuminuria itself is nephrotoxic (as explained in an old post about kidney injury in AL amyloidosis) and therapy did not reduce proteinuria.

Have a great Easter (for those who celebrate) and hope a bunch of people can join us this coming Monday!

Japanese Scientists Debunk Longstanding Avian Behavioral Theory

Recent research published in the Journal Amyloid casts doubt on the widely accepted concept that chickens cross the road merely to get to the other side. It appears that at least some of them may actually be searching for an amyloidosis specialist. 

Tomoaki Murakami and colleagues describe their research related to an outbreak of AA amyloidosis occurring at a Japanese poultry farm. Avian AA amyloidosis is well characterized (as indicated by its inclusion in Table II from the most recent amyloid fibril nomenclature committee guidelines). AA amyloidosis has been described in waterfowl (due to chronic inflammatory conditions) and chickens (due to bacterial infections or repeated vaccinations). AA amyloid has also been detected in the livers of force-fed ducks and geese used for foie gras. 

A photomicrograph of a hepatic venule from a sample of commercially-available foie gras
(top panel, h/e stain; middle, congo red stain under polarized light; bottom IHC confirming AA amyloid).
Ref: http://www.ncbi.nlm.nih.gov/pubmed/17578924

The authors studied four breeds of chickens, one of which has previously been shown to have a propensity for developing systemic AA amyloidosis after repeated vaccinations for Salmonella enteritidis (SE) and/or Mycoplasma gallisepticum (MG). In this study, chickens were inoculated with a single dose of one of two SE vaccines ("SE(a)" or "SE(b)") or an MG vaccine. Then some of the chickens were also given a dose of an AA amyloid fibril solution which the authors had prepared from the livers of other chickens with AA amyloidosis. Additionally, there were some chickens who received only vaccine without AA fibrils, only fibrils without vaccine, or neither.

The findings: 

• 29 out of 38 chickens (all breeds studied) who got both vaccine SE(a) and a dose of AA fibrils (either orally or intravenously) developed AA amyloidosis. If the AA fibrils were administered orally, then the amyloidosis tended to develop in the chickens' spleens; the chickens who got the AA fibrils intravenously developed more widespread systemic amyloidosis (including the birds' intestines). 
• ZERO out of 113 other chickens developed systemic AA amyloidosis.
• Serum AA precursor protein levels (SAA levels) did not correlate with risk of developing systemic AA amyloidosis. The SE(a) vaccine did not induce an increase in SAA in any subgroup of chickens (including those who developed amyloidosis) and the MG vaccine did induce a rise in SAA (with no cases of associated amyloidosis).

The scientists (and another author providing commentary in the same issue of the journal) concluded that the outbreak of avian AA amyloidosis was likely the result of chickens ingesting amyloid-contaminated feed and/or droppings after having had industry-standard vaccinations which may have pre-disposed them to developing amyloidosis. 

Not an unprecedented finding. Fecal transmission is suspected to contribute to the high incidence of systemic AA amyloidosis in captive cheetahs (like cheetahs don't have enough problems). Also, the same scientists who discovered amyloidosis in foie gras fed it to amyloid-susceptible mice and found it accelerated the rate at which systemic AA amyloidosis developed. They concluded foie gras was a potential Amyloid Enhancing Factor (AEF), and that 

"It would seem prudent for children and adults with rheumatoid arthritis or other diseases who are at risk for [AA amyloidosis] to avoid foods that may be contaminated with AA fibrils." 

Then, citing studies such as one in which formation of a specific type of amyloidosis (AApoAII) could be accelerated in predisposed experimental mice by intravenous injection of any of several different types of human amyloid fibrils (AL, ATTR, Abeta2-MG, and others), they suggest

"...that it may be hazardous for individuals who are prone to develop other types of amyloid-associated disorders, e.g., Alzheimer's disease or type II diabetes, to consume such products."

Which nags at me. I don't so much wonder about whether my father, the son of a woman who died of Alzheimer's disease, should enjoy foie gras as much as he does (though maybe I should - it's Fathers' Day). I worry a little bit about whether diet could be affecting the outcome of my patients with documented systemic amyloidosis. Is our carnivorous American diet full of AEFs? Possibly. An examination of the kidneys and other organs from 302 apparently healthy cattle slaughtered for meat revealed AA amyloidosis in 5% of the animals (take a look). The incidence was lower (0.4% - 2%) in other studies. A largely vegetarian diet has been cited as a possible explanation for the virtual absence of secondary amyloidosis in leprosy patients in India compared to the fairly high incidence amongst leprosy patients in the United States, Malaysia, Brazil, and other countries.  Check out this 1965 article by Amyloid Guru Alan S. Cohen and colleagues which explores this very topic.  At this time, though, there is no compelling evidence for transmission or acceleration of amyloidosis (AA or any other type) in humans from ingestion of AA-containing bovine meat or organs.  Additionally, a search of the medical literature did not turn up any studies looking at the impact of diet on prognosis in AL amyloidosis. So for now, I'll just worry a little bit. Comments welcome.