Nephrologists recently congregated for the virtual American Society of Nephrology’s (ASN) Kidney Week 2021 to discuss the latest research, innovations, and insight in kidney care. David S. Goldfarb, MD, clinical director of the division of nephrology at NYU Langone Health, in New York City, shared his assessment of research into rare kidney disease presented at the annual conference.
What were some highlights of rare kidney disease research presented at Kidney Week 2021?
The research presented on lumasiran is clearly important for the treatment of the rare kidney disease, primary hyperoxaluria type 1 (PH1).1 Lumasiran is a small-interfering RNA therapy targeting HAO1 in advanced PH1. This is potentially a life-saving drug because it lowers oxalate to a degree that has never been achieved by any other means. The ability to reduce urinary oxalate has a direct correlation to kidney failure prevention. While there are no available data yet, this level of urinary oxalate reduction may enable patients to avoid a liver transplant.
That said, lumasiran is an expensive drug. Prior to its development, pyridoxine and other forms of vitamin B6 were used to reduce oxalate in patients with certain PH1 genotypes. Some of my patients still required liver transplantation — and have had to undergo kidney transplantation due to kidney failure — despite therapy with pyridoxine, pyridoxal, and pyridoxamine.
I would like to participate in a study to evaluate lumasiran as a treatment option for patients with elevated urinary oxalate who do not have PH. While it is not yet known whether this type of therapy is practical from a cost perspective, we do know that some patients have idiopathic hyperoxaluria not related to PH. Very often, this idiopathic condition is thought to have a dietary cause, and patients are asked to modify their diets to reduce the amount of oxalate in their urine. In patients without a known type of PH, interfering with hepatic oxalate production is a very interesting and novel idea.
In your perspective, where are treatments for rare kidney diseases headed?
I think genetic modification is further off in the future. For now, we are using RNA interference to reduce oxalate production. It clearly works, it is safe, and it is much less complicated than doing genetic manipulation. For the moment, small-interfering RNA therapy is extremely important and will likely be a cornerstone of therapy for certain rare kidney diseases.
One of the abstracts presented at Kidney Week 2021 examined modification of Oxalobacter-derived peptides as a potential therapeutic target for reducing oxalate in the urine by promoting excretion through the colon.2 What are your thoughts on that approach as opposed to targeting DNA or RNA?
I think it’s a brilliant idea and I approve of this approach. SLC26A6, the oxalate transporter in the intestinal lumen, appears to be stimulated by some product from Oxalobacter formigenes. Hatim Hassan, MD, PhD, associate professor of medicine at the University of Chicago, has been studying the induction of colonic oxalate excretion by O formigenes, which results in reduced urinary oxalate excretion via a secretagogue. His work in locating the secretagogue and demonstrating its efficacy will be key in developing a novel targeted drug for hyperoxaluria.2 This stimulation of oxalate secretion appears to be a reasonable target for a molecule that will move oxalate from the blood into the intestinal lumen, causing less oxalate to be presented to the kidney.
For now, we are using RNA interference to reduce oxalate production. It clearly works, it is safe, and it is much less complicated than doing genetic manipulation. For the moment, small-interfering RNA therapy is extremely important and will likely be a cornerstone of therapy for certain rare kidney diseases.
Would adding exogenous protein have any potential impact on the state of O formigenes?
If the intestinal Oxalobacter colony is well fed and proliferates, that is a good thing. It is not a pathogen; it is a symbiotic microorganism. Oxalobacter is an important part of the intestinal microbiome in that it protects against kidney stones, for example, but it is not likely to be completely self-sufficient. The presence of other bacteria is likely required in order for Oxalobacter to thrive in the colonic lumen. Other organisms may be an important part of the process, either by degrading oxalate directly or by downstream effects, and that interplay will allow Oxalobacter to be successful.
Are there any final thoughts you would like to share with your colleagues regarding the current state of nephrology?
As many are aware, kidney stones cause a lot of pain and suffering for patients and are very expensive to treat. I am a patient with kidney stones myself, and I have been treating kidney stones for more than 25 years. In that time, there has been an increasing focus within the pharmaceutical industry on kidney stone management. That is wonderful because I can recall a time when kidney stones were not considered an important topic of medical research.
In the kidney stone session, there was a discussion about the important progress made regarding the pharmacology and genetics of kidney cancer. While I think our understanding of kidney stones may be lagging a bit compared with renal cancer research, there has been good progress in uncovering the genetics of kidney stone diseases and that is very gratifying.
- Current research into PH1 shows that kidney failure may be prevented by reducing urinary oxalate.
- Modification of Oxalobacter-derived peptides may protect against kidney stones in PH1 by promoting oxalate excretion through the colon and thereby reducing oxalate levels in the urine.
- Lumasiran, a small-interfering RNA, targets hydroxy acid oxidase 1 and is part of a drug class that may be a cornerstone of therapy for patients with certain rare kidney diseases.
This Q&A was edited for clarity and length.
David S. Goldfarb, MD, reported an affiliation with Alnylam Pharmaceuticals.
- Michael M, Groothoff JW, Shasha-Lavsky H, et al. ILLUMINATE-C, a single-arm, phase 3 study of lumasiran in patients with primary hyperoxaluria type 1 and CKD stages 3b-5, including those on hemodialysis. Presented at: Kidney Week 2021, November 2-7, 2021. Presentation FR-OR64.
- Hassan H, Alshaikh A, Zerweck, J. Optimization of Oxalobacter formigenes-derived small peptides with therapeutic potential for hyperoxalemia, hyperoxaluria, and related kidney stones. Presented at: Kidney Week 2021, November 2-7, 2021. Abstract PO0524.
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Reviewed December 2021