Kristie Kahl

Conservative management of uncomplicated renal colic patients may be a feasible consideration following positive urine cultures (UCs), according to a retrospective analysis presented at the 2022 AUA Annual Meeting.

“Though septic stones are well recognized as a medical emergency, patients with uncomplicated renal colic (without systemic inflammatory responses or renal impairment) and positive urine cultures pose a dilemma in management considerations,” the investigators explained in the abstract.

Therefore, they aimed to assess the rate of incidental positive urine cultures in patients with ureteral stones referred to their Stone Clinic, and to determine the risk of infectious adverse events (IAEs) in patients with ureteral stones and positive urine cultures.

In the retrospective chart review, investigators evaluated 1029 patient referrals between November 10, 2019, and October 1, 2020, excluding urgent referrals requiring immediate intervention.

In total, 374 (35.4%) patients had UCs drawn at presentation and 655 patients did not. Among those with no UCs, 0.6% (n = 6) went on to have sepsis and required urgent renal decompression. However, 87% (n = 333) of those with UCs were negative, and none of these patients went on to have an IAE.

Overall, 13% of UCs were positive (n = 39), but only 2 IAEs (5.13%) were identified from 2 to 30 days after patients’ initial presentation. Both patients had normal acute phase reactants and a history of recurrent urinary tract infections.

“Approximately one-third of patients referred to our Acute Stone clinic had UC at presentation, with an overall delayed IAE rate of 0.7%,” the investigators concluded. “Of those with positive urine cultures, only 5% experienced an IAE, suggesting conservative management may be a reasonable consideration in this patient population.”

1. Mookerji N, Mancuso M, Gandhi V, et al. Assessing the Risks of a Positive Urine Culture in Uncomplicated Renal Colic Patients. 

. 207(55);5S:e1045. doi:JU.0000000000002670.10

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“Though septic stones are well recognized as a medical emergency, patients with uncomplicated renal colic (without systemic inflammatory responses or renal impairment) and positive urine cultures pose a dilemma in management considerations,” the investigators explained in their abstract.

Conservative management feasible for uncomplicated renal colic patients with positive urine cultures

How can we help educate other providers? Similarly, how can we educate patients about the disease?

: I think the provider should be knowledgeable about the disease process. Some of it is just talking about it, like we’re doing here today, but also getting the information out there. There are plenty of groups that are looking at this. For example, the Oxalosis & Hyperoxaluria Foundation, does a lot of these clinical trials. You can have patient testimonies, which families can access. There are community-based points of access to educate patients and providers of disease awareness. That’s an education process—talking to providers and presenting the data. With anything in medicine, when we have a treatment, we often become more knowledgeable and educated about it because we actually have a tool in our toolbox to treat these patients. Again, with enteric hyperoxaluria [EH], there isn’t a drug currently approved to treat it. We manage EH through dietary means and medical means. If we do eventually have a drug that is approved for this condition, we’ll become more knowledgeable on it.

What are the implications from this data and what do we have to look forward to?

: I think, obviously, it’s a great study. There’s never been a group to bring 115 enteric hyperoxaluria patients through a medication study like this. However, with the data, I think we are taking a step back. The enthusiasm’s tempered right now because there was a reduction in their primary end point, which was urinary oxalate excretion. I think, as a community, we’re still wondering whether that will translate into a clinical benefit. Currently, we’re waiting on this next study. The implications are that we know these things work. The studies have shown that the primary end point is statistically significant so we know, with oxalate degrading enzymes, we can reduce urinary oxalate excretion. I think the next step is trying to understand whether that reduction translates into clinical benefit. Once that can be shown, there’s going to be a lot of enthusiasm about it and the implication will be significant. The other issue is that this medication relies heavily on patient compliance because the patient needs 3 to 5 doses per day. As we move forward, hopefully, there’ll be development opportunities where patients don’t need as many dosages, and compliance would be easier. The future of drug development is bright. I think this clinical trial demonstrates that working through these mechanisms can reduce urinary oxalate excretion. There’s still a lot to be seen.

What are the unmet needs for the treatment and management of this disease?

: We still have many unmet needs—drugs and other management strategies—to manage these patients. I think there are unmet needs. We need more research on this population. As we talked about, there are multiple causes. We still don’t have a great understanding regarding the number of people who have enteric hyperoxaluria. We still don’t understand whether we’ve classified as idiopathic or secondary hyperoxaluria, which could be a component of enteric hyperoxaluria. We don’t have a real grasp of the population. We can learn more about the pathophysiology of the disease. We could do a lot of research on phenotyping our enteric hyperoxaluria population and understanding who would most likely benefit from certain drug treatments and options. I don’t think we’ve done enough with intensive medicine and dietary management of this population so we can see how much a patient could truly benefit in regards to oxalate. A lot needs to be done on the research front. There’s a lot that needs to be done on the drug development front, although it looks promising. We need to educate both the providers, as well as the patients, and build a community where patients, families, and providers can gather information. Providers have to learn how to treat these individuals and have resources available to them.

What are your final thoughts on the future management of enteric hyperoxaluria?

: I think we’re at a great point where there’s a lot more interest in it. There’s drug development and more research focused on this disease state. I think it’s a bright future. I think we’re seeing a lot of positives and recognizing a lot of the limitations as well. This population is a large population. It’s a patient population that suffers from recurrent kidney stone disease. The more we look at EH as a chronic disease instead of an episodic event, I think we’re going to do more and more for this patient population and benefit them significantly.

Absolutely. Thank you so much Dr. Wood. Thank you to our viewing audience. We hope you’ve found this 

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Dr. Kyle Wood discusses optimal avenues to increase patient and provider education on enteric hyperoxaluria and provides closing thoughts on the future management of enteric hyperoxaluria.

Unmet Needs for the Treatment of Enteric Hyperoxaluria

Following an increase of adoption among surgeons, segmental ureterectomy (SU) appeared to be non-inferior to radical nephroureterectomy (RNU) in treating patients with high-risk upper tract urothelial carcinoma (UTUC), according to findings presented at the 2021 Society of Urologic Oncology Annual Meeting.

“Radical nephroureterectomy is widely considered the gold standard for high-risk upper tract urothelial carcinoma. Segmental ureterectomy has had increased adoption for high-risk UTUC, particularly for distal ureteric tumors, but its oncological equivalence remains unclear,” Siv Venkat, MD, FRCS, urology fellow, Weill Cornell Medical College, said in a virtual presentation of the findings. “The purpose of this poster was to examine current trends in RNU and SU for upper tract disease, look at patient factors contributing to the performance of SU, look at the rates of lymph node dissection, and look at survival for RNU and SU in this high-risk disease population.”

The researchers utilized the National Cancer Database to identify 30,861 patients with nonmetastatic UTUC with urothelial histology who underwent extirpative surgery from 2004 to 2016. In total, 26,153 patients (84.7%) underwent RNU and 4,708 (15.3%) underwent SU.

Overall, patients who underwent SU were older; were more likely to have surgery at an academic/research hospital; had lower cT, cN, pT, and pN stages; had pM0 disease; had low grade tumors; had procedures done through open surgery; and had a higher rate of positive margins (

SU for lymph node dissection was more likely, compared with RNU (32.3% vs 23.0%; 

 < .001). “This was consistent across high-grade tumors, tumors over 2 cm, and pT2-3 disease,” Venkat said.

Among those with lymph node dissection, SU induced higher nodal yields (mean, 6.07 nodes), compared with RNU (mean, 5.69 nodes).

Lastly, SU demonstrated improved median overall survival, compared with RNU (66.1 months vs 64.9 months, respectively; 

 = .025). However, Venkat noted, this trend was not consistent across the high-risk subgroups, including high-grade tumors (median OS, 53.1 months vs 52.3 months, respectively; 

 = .14), tumors over 2 cm (58.5 months vs 61.2 months; 

 = .37), pT2 disease (54.0 months vs 60.3 months; 

Venkat and colleagues acknowledged the study was limited by potential selection bias andconfounders because it was a national registry-based study; lack of representation of an international population; detection bias, as patients and clinicians were not blinded; potential coding errors; no central pathology review; unknown templates used for surgical approaches; and potential challenges with clinically staging UTUC.

“Prospective studies are still needed to be done,” Venkat said. “So segmental ureterectomy appears to be non-inferior to radical nephroureterectomy in patients. It does appear that surgeons are having a better level of dissection [with] segmental ureterectomy.”

1. Venkat S, Lewicki P, Basourakos S, Borregales L, Scherr D. Comparison of Radical Nephroureterectomy and Segmental Ureterectomy in Upper Tract Urothelial Carcinoma. Presented at: SUO 22nd Annual Meeting; December 1-3, 2021; Orlando, Florida. Poster 114.

Findings presented at the 2021 Society of Urologic Oncology Annual Meeting demonstrate that segmental ureterectomy may be comparable to radical nephroureterectomy.

Segmental ureterectomy non-inferior to radical nephroureterectomy in high-risk UTUC

You mentioned 1 of the concerns is trying to address the underlying condition. What are some of the ongoing trials for the treatment of enteric hyperoxaluria [EH]?

: The leading trial is the URIROX-1 trial, which is a phase 3 study being performed by Allena Pharmaceuticals. It is an enzyme that breaks down oxalate. It’s an oxalate degrading enzyme. The data that we have is from the first phase 3 trial. They’re in a second phase 3 trial now, but their first phase 3 trial was looking at 115 individuals with enteric hyperoxaluria and kidney stone disease. They observed them for 4 weeks of treatment: Having baseline data, treating them with their enzyme, and then looking at urinary oxalate excretion as their primary end point. Their primary end point was reduction in urinary oxalate excretion, and they saw a reduction, or an absolute reduction, of 12.9%. So both the placebo arm and the drug arm had an effect. Again, when you look at the absolute reduction it was close to 13%. One of the problems with this drug is that it has to be dosed 3 to 5 times a day. It’s given with meals so you’re breaking down the oxalate load that comes with diet. If they’re having 3 meals or snacking, you might have to take upwards of 3 to 5 doses per day. It’s heavily reliant on patient compliance. Their secondary end points were looking at say, greater than 20% reduction, and urinary oxalate excretion from baseline. They didn’t see a difference between the treatment arm and the placebo arm. The 

 value was .06, which is a slight concern because we don’t know how much oxalate needs to be reduced in order to see a clinical benefit, or a reduction in kidney stone events. A lot of us believe that you would need to see a reduction greater than 20% in urinary oxalate excretion to see a clinical benefit. With the phase 3 trial data, there’s still some concerns about whether the data, although significant, will translate into a clinically significant benefit. They are currently pursuing their other phase 3 trial, which will have significantly more individuals over a longer time frame. We’ll have some more conclusive data about the benefits of that. The other ongoing trials are looking at other oxalate degrading enzymes. For example, Oxidien Pharmaceuticals is looking at an oxalate degrading enzyme and has published some data from early studies that show a benefit. Other companies are looking at bacteria that have been modified to degrade oxalates. This bacterium has been engineered and modified to degrade oxalate. There are 2 types of synthetic bacteria that can be used. You either colonize the gut with it—that would be like, for example, Synlogic Theraputics where you colonize the gut—or you give the bacteria and when it’s transiently present within the gut, you have to keep redosing it. That would be like the no volumes clinical trial. There are multiple ongoing trials looking at degrading enzymes, as well as trials with bacterial modifications that degrade oxalate. I think the future is bright. Hopefully we’ll see some benefit from those trials.

Kyle Wood, MD, reviews data and clinical implications for the use of reloxaliase in enteric hyperoxaluria as seen in the phase 3 URIROX-1 trial and shares insight on additional ongoing trials.

Kristie Kahl

Articles

Conservative management feasible for uncomplicated renal colic patients with positive urine cultures

Unmet Needs for the Treatment of Enteric Hyperoxaluria

Segmental ureterectomy non-inferior to radical nephroureterectomy in high-risk UTUC

Phase 3 URIROX-1 Trial for Enteric Hyperoxaluria