Straight Dope on Medicine: Chinook Kidney Recovery

Author

Scott Ganser
November 28, 2022

Sometimes you have to argue that you exist. French existentialists, Sartre and Camus, would have a field day with this. However, recognition is problematic when acknowledgement of your existence carries liabilities.

Lack of federal recognition means the Chinook, who are based north of the Columbia in rural Pacific County, have no reservation and remain deprived of many resources and assistance available to sister tribes — including money for infrastructure and tsunami protection, housing, education, public health and COVID resources, mental health and drug treatment, several speakers said during the rally.

“Without federal recognition, we don’t have the means of dealing with any of it, and it’s so damned frustrating,” Johnson said.

Much progress is finally being made by the 574 federally recognized tribes in the U.S., Johnson said, but the Chinook cannot share in it. “It’s allowing (sister tribes) a type of nation building. It hurts to not be a part of it,” he said.[i]

The Chinook were granted federal status in January 2001. In the last days of Bill Clinton’s administration, the Bureau of Indian Affairs published a notice of final determination in the Federal Register declaring that the Chinook tribe “exists as an Indian tribe within the meaning of federal law.”[i]

It lasted just 18 months.

In 2002, when then–Tribal Chairman Gary Johnson was in Washington, D.C., for the Lewis and Clark bicentennial, he received a call on his cellphone. Under George W. Bush’s administration, their recognition had been revoked.

But the Chinook, a tribe of 3,000, doesn’t want to get into the casino game. They just want to be able to feed themselves, Johnson said — to hunt and fish, to have a land base, to provide care for elders and preserve its history and language.

“I’ve never asked anything from my government,” said Brignone, who served in the Navy for 20 years. “I’m not looking for anything for my tribe except that the government recognize that we are a people.”

Their society focused on water-type activities, they took ceremonies seriously, they were mainly peaceful, and they had contact with the American explorers Meriwether Lewis and William Clark.[ii]

They were superb canoe builders, navigators, and fishermen. The river was a rich source of salmon, which was the basis of the region's economy, and the Chinook had plenty of the dried fish to use for trade and as a type of currency. They were also famous as traders, using the waterways to make routes and to make contact with many other Indian tribes. Not only did the Chinook trade dried fish, they also traded canoes, and ornamental shells.

The fishing and land rights are the crux of the problem.

Owning nothing doesn’t make anyone happy. It is a severe form of dispossession.

As captivating as the Chinook Nation story is, these aren’t the Chinooks we are looking for. Under the heading of cultural appropriation, a Chinook Therapeutics has arisen.[iii]

Kidney Diseases

Many, many, many things can go awry with the kidney. All told, it is a grand filtration device installed by the Maker Himself. Having properly functioning kidneys is a blessing we can sometimes take for granted.

Mayo lists diseases marked by proteinuria.[iv]

· Glomerulonephritis (inflammation in the kidney cells that filter waste from the blood)

· IgA nephropathy (Berger's disease) (kidney inflammation resulting from a buildup of the antibody immunoglobulin A)

· Lupus

· Nephrotic syndrome (damage to small filtering blood vessels in the kidneys)

At Chinook they are looking at chronic kidney disease, immunoglobulin A nephropathy and other proteinuric[v] glomerular diseases.[vi] 

IgAN is the leading cause of primary glomerulonephritis, with a global incidence of 2.5 per 100,000 individuals per year.[vii]

Approximately 30-45% of IgAN patients progress to end-stage kidney disease (ESKD) over a period of 20-25 years.[viii]

“There are very few therapeutics to stop the progression of kidney disease," Eric Dobmeier, CEO, Chinook Therapeutics, told BioSpace. "Consequently, the vast majority of patients are prescribed medication to lower blood pressure. That’s changing as researchers gain insights into the disease."

“If you can get a 20-30% proteinuria reduction on top of the blood pressure lowering medication, that’s clinically meaningful,” Dobmeier said. At ASN (American Society of Nephrology), Chinook reported it is seeing 50- to 60% proteinuria reductions with additional patients. “It shows we can preserve kidney function for longer periods of time.”

The reduction is actually increasing over time, which is fantastic!

· Atrasentan demonstrated mean proteinuria reductions of 38.1% proteinuria at six weeks of treatment, 48.3% at 12 weeks of treatment and 54.7% at 24 weeks of treatment[ix]

Other benefits have been recorded as well

· There were no meaningful changes in blood pressure or acute eGFR, suggesting proteinuria reductions were not primarily due to hemodynamic effects of atrasentan, and there were no increases in brain natriuretic peptide (BNP) or mean bodyweight, suggesting minimal fluid retention

  • Atrasentan was well-tolerated with no treatment-related serious adverse events (SAEs)

Another compound in development at Chinook, BION-1301, is also in Phase II. It tackles IgAN earlier in its development when it sees galactose-deficient IgA molecules.

Dobmeier said Chinook is seeing up to 70% proteinuria reductions. But, he cautioned, “It’s in a small number of patients, and it’s a single-arm trial.

Atrasentan?

(2R,3R,4S)-4-(1,3-benzodioxol-5-yl)-1-[2-(dibutylamino)-2-oxoethyl]-2-(4-methoxyphenyl)pyrrolidine-3-carboxylic acid

Atrasentan is a potent and selective endothelin A (ETA) receptor antagonist that has the potential to provide benefit in multiple chronic kidney diseases by reducing proteinuria and having direct anti-inflammatory and anti-fibrotic effects to preserve kidney function. Chinook selected IgAN as the lead indication for atrasentan due to the role of ETA activation in driving proteinuria, mesangial cell activation, kidney inflammation and fibrosis, the hallmarks of IgAN disease progression.

Here is a video. You can click on it and see how it works. Yes, this is an interactive newsletter. Very few of its kind.

If this is safe, and it looks like it is, this stuff should be approved yesterday. Proteinuria is a five alarm fire, medically speaking.

Any time you can keep people off dialysis, it improves their lives dramatically. Like a lot.

Who does proteinuria affect?

Anyone can get proteinuria. However, you may be more likely to get proteinuria if you:[x]

  • Are 65 years old or older.

  • Have a family member who has or had kidney disease.

  • Have diabetes or another condition that affects your kidneys.

  • Are Black, Hispanic, Native American or Pacific Islander.

How common is proteinuria?

Proteinuria is relatively common. About 6.7% of the United States population has proteinuria.

By the 1950s, kidney disease was clearly recognized as a common complication of diabetes, with as many as 50% of patients with diabetes of more than 20 years having this complication.[xi]

Diabetic Kidney Disease has further complications: thickening of the glomerular basement membrane and mesangial expansion.[xii]

Is protein in urine serious?

Yes, protein in your urine is serious. Proteinuria may increase your risk of death from heart disease and cardiovascular disease.

NephJC

What are the signs and symptoms of proteinuria?

You may not have any symptoms in the early stages of proteinuria. In advanced stages of proteinuria, symptoms may include:

  • Swelling (edema) in your face, belly, feet or ankles.

  • More frequent urination.

  • Shortness of breath.

  • Tiredness.

  • Nausea and vomiting.

  • Lack of appetite.

  • Muscle cramping at night.

  • Puffiness around your eyes, especially in the morning.

  • Foamy or bubbly urine.

Tom Petty once said that “the waiting is the hardest part.”[xiii] 

If you really don’t want to wait, something else is presently deployed.

However, there is a BIG DIFFERENCE between improvement and delayed worsening. Bear that in mind.

Conclusion

The landscape in this research area has been barren for some time now. There were trials with ACE inhibitors and Angiotension blockers, but even full dosage did not dramatically affect GFR (glomerular filtration rate). In placebo, the GFR loss was 5.2cc/min/year, whereas full dosage was 4.4 cc/min/year. People still advanced toward end stage renal disease, but slower.[xiv]

Before atrasentan was avosentan, another endothelin antagonist, but not as specific.

Specificity matters.

Avosentan reduced proteinuria, but brought on cardiovascular events. Fluid build-up and heart failure were two negative adverse events that accompanied avosentan administration.[xv]

Atrasentan is much safer, but there is a slight tendency to fluid build-up. It must be monitored. Also this class of agents has a “narrow therapeutic window.” It’s the fluid retention that brings on the heart problems.

Chinook has settled on 0.75mg daily.

Diabetes is becoming the major cause of kidney failure and is also rapidly increasing.

Atrasentan has previously demonstrated clinically significant and sustained proteinuria reduction with an acceptable safety profile in over 5,100 patients with diabetic kidney disease (DKD).[xvi]

References

[i] https://chinooknation.org/tribes-that-arent-federally-recognized-face-unique-challenges-2/

[i] http://america.aljazeera.com/articles/2015/12/28/chinook-northwest-tribe-continue-recognition-fight.html

[ii] https://study.com/academy/lesson/chinook-facts-history-religion.html

[iii] https://www.chinooktx.com/

[iv] https://www.mayoclinic.org/symptoms/protein-in-urine/basics/causes/sym-20050656

[v] https://www.lowerproteinuria.com/?gclid=EAIaIQobChMIxf7XmebC-wIV5MiUCR11-wpHEAAYAiAAEgInfvD_BwE

[vi] https://www.biospace.com/article/kidney-therapeutics-to-halt-disease-progression-make-late-stage-push-toward-nda/

[vii] Mcgrogan et al, 2011, NDT

[viii] . Reich et al, 2007, JASN

[ix] https://investors.chinooktx.com/news-releases/news-release-details/chinook-therapeutics-presents-updated-data-atrasentan-phase-2

[x] https://my.clevelandclinic.org/health/diseases/16428-proteinuria#:~:text=How%20common%20is%20proteinuria%3F,United%20States%20population%20has%20proteinuria.

[xi] https://emedicine.medscape.com/article/238946-overview

[xii] J.A. Jefferson, S.J. Shankland, R.H. Pichler, Proteinuria in diabetic kidney disease: A mechanistic viewpoint,

Kidney International, Volume 74, Issue 1, 2008, Pages 22-36.

[xiii] https://www.youtube.com/watch?v=uMyCa35_mOg

[xiv] https://www.youtube.com/watch?v=pkkQbb-isog

[xv] Mann JF, Green D, Jamerson K, Ruilope LM, Kuranoff SJ, Littke T, Viberti G; ASCEND Study Group. Avosentan for overt diabetic nephropathy. J Am Soc Nephrol. 2010 Mar;21(3):527-35.

[xvi] . Sasser et al, JASN, 2007; 17.