Nephrology News

A novel methodology for assessing urine extracellular vesicles (uEVs) in urine samples reveals abnormalities in the kidneys sooner than traditional methods and can also predict renal function deterioration.
A group of researchers from the University of Tokyo examined eurine samples from children with and without chronic kidney disease (CKD). They discovered that when kidney function declines, the size and composition of uEVs vary. This proof of concept might aid in the development of new urine tests that detect the disease early, as well as analogous testing for other disorders. The kidneys are the body’s primary filtration mechanism.

These bean-shaped, fist-sized organs are made up of millions of microscopic filtration units known as nephrons that work tirelessly to keep our blood clean. Unfortunately, chronic kidney disease (CKD) affects 9% of the worldwide population, and the number of cases is increasing.
When nephrons are destroyed, whether by lifestyle, genetic and congenital disorders, or injury, CKD occurs. Many patients may not experience significant symptoms and, as a result, do not seek treatment until the problem has progressed. Because it is difficult to replace injured nephrons entirely, the sooner the diagnosis, the better the prognosis.
Typically, a urine or blood test may inform doctors if a patient has kidney impairment.

These tests, however, can still miss the very early phases of nephron loss that herald the onset of CKD. Researchers at the University of Tokyo sought to see whether there were any additional early indicators of kidney disease, particularly in youngsters.
“We discovered that alterations in microscopic structures called extracellular vesicles in urine are useful in the detection of renal illness,” said Graduate School of Medicine Associate Professor Yutaka Harita. “With reduced renal function, the fraction of bigger vesicles rose. We were also astonished to discover that changes in the chemicals contained in the vesicles may be used to diagnose and predict renal function decrease.”

Extracellular vesicles are particles that are released by nearly all types of cells in our body and perform a variety of tasks. Because urinary extracellular vesicles (uEVs) include proteins from nephrons, they may be exploited as a source of biomarkers (molecules that indicate normal or aberrant processes) for a variety of disorders.
The researchers examined uEVs in urine samples from 26 children with healthy kidneys and 94 children with various kinds of CKD, including those born with smaller-than-average kidneys with fewer nephrons. The causes of CKD in children are less likely to be acquired factors and more likely to be structural abnormalities.

This made it easy for the researchers to identify and understand the alterations in uEVs that are linked to aberrant kidney anatomy.
“We employed nanoscale magnetic microbeads (made of iron oxide particles) coated with a chemical that attaches to EVs to collect extracellular vesicles in urine,” Harita added. “This approach allowed for the effective collection of uEVs even from renal disease patients who could only generate diluted urine. The size and quantity of protein present in the purified extracellular vesicles were measured. We discovered numerous distinct alterations in uEVs from children with CKD. Children with CKD, for example, have reduced amounts of a protein called MUC1 in their uEVs, which is critical for renal function.”

According to an international study conducted by a Rutgers expert evaluating new and older medicines for complex urinary tract infections, a novel drug combination has been found to be more effective, particularly against chronic, drug-resistant infections.

Describing the results in the Journal of the American Medical Association (JAMA), researchers in the ALLIUM Phase 3 clinical trial showed that a combination of the drugs cefepime and enmetazobactam was more effective in treating both complicated urinary tract infections and acute pyelonephritis (AP), a bacterial infection causing kidney inflammation, than a standard treatment combining piperacillin and tazobactam.

“Urinary tract infections are considered complicated when they are associated with risk factors – including fevers, sepsis, urinary obstruction or catheters – that increase the danger of failing antibiotic therapy. “This new antibiotic was superior to the standard-of-care therapy,” said Keith Kaye, chief of the Division of Allergy, Immunology and Infectious Diseases and a professor of medicine at Rutgers Robert Wood Johnson Medical School.

“It represents an exciting option for treatment,” said Kaye, the principal investigator of the study and lead author on the publication.

Kaye added this drug combination also fights an often-dangerous category of bacterial illnesses caused by pathogens known as extended spectrum beta-lactamase (ESBL) infections, named for an enzyme the bacteria produce. ESBL-producing bacteria can’t be killed effectively by many of the antibiotics conventionally used to treat infections, such as penicillins and cephalosporins.

“We are looking for antibiotics that are active against resistant bacteria, such as ESBLs, and we found this new combination to be highly effective,” Kaye said.

The trial was conducted at 90 sites in Europe, North and Central America, South America and South Africa from September 2018 to November 2019. More than 1,000 patients participated in the study. Some 79 percent of the patients receiving the new combination of cefepime and enmetazobactam were successfully treated for their illness, as opposed to 58.9 percent of those receiving the conventional treatment of piperacillin and tazobactam.

Of the 20 percent of patients from the overall group belonging to the subset of those with ESBL infections, 73 percent of the patients receiving cefepime and enmetazobactam achieved a clinical cure, as opposed to 51 percent of the patients on the standard therapy.

The antibiotic cefepime is a fourth-generation cephalosporin that was approved for use in the 1990s and is available generically. Enmetazobactam, an experimental drug made by the French biopharmaceutical company Allecra Therapeutics, is a beta-lactamase inhibitor, meaning it attacks the beta-lactamases, including the types of enzymes produced by ESBL-producing bacteria. The drug combination has been granted Qualified Infectious Disease Product and Fast Track designation by the U.S. Food and Drug Administration (FDA).

Kaye predicted that the corporation would seek FDA approval early next year.
According to a research from the Centers for Disease Control and Prevention, more than 2.8 million antimicrobial-resistant infections occur in the United States each year, and more than 35,000 people die as a result of them (CDC). The CDC classified ESBLs as a severe hazard to human health in a 2019 research on antibiotic resistance.

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According to a research, a novel treatment that combines the use of two ultrasound technologies may provide an alternative for moving moving kidney stones out of the ureter with minimal discomfort and no anaesthetic.

The new study’s findings were published in The Journal of Urology. The physician directs ultrasonic waves towards the stone using a portable transducer put on the skin during the treatment. The ultrasound can then be used to shift and rearrange the stones to facilitate passage, a procedure known as ultrasonic propulsion, or to break up the stone, a procedure known as burst wave lithotripsy (BWL).

Unlike shock wave lithotripsy, which is the standard procedure now in use and requires sedation, this technology doesn’t hurt, said lead author Dr. M. Kennedy Hall, a UW Medicine emergency medicine doctor. “It’s nearly painless, and you can do it while the patient is awake, and without sedation, which is critical.”

The research team hopes that, with this new technology, the procedure of moving or breaking up the stones could eventually be performed in a clinic or emergency room setting, Hall added.

Stones in the ureter, which leads from the kidney to the bladder, can cause severe pain and are a common reason for emergency department visits. Most patients with ureteral stones are advised to wait to see if the stone will pass on its own.

However, this observation period can last for weeks, with nearly one-fourth of patients eventually requiring surgery, Hall noted.

One in 11 Americans will have a urinary stone over the course of their lifetime. The incidence appears to be increasing, according to one UW Medicine study looking at this same technology. Up to 50% of patients with a stone event will recur within five years, the study noted.

Hall and colleagues evaluated the new technique to meet the need for a way to treat stones without surgery.
The study was designed to test the feasibility of using the ultrasonic propulsion or using BWL to break up stones in awake, unanaesthetized patients, Hall said.

Twenty-nine patients participated in the study. Sixteen were treated with propulsion alone and 13 with propulsion and burst wave lithotripsy. In 19 patients, the stones moved. In two cases, the stones moved out of the ureter and into the bladder.

Burst wave lithotripsy fragmented the stones in seven of the cases. At a two-week follow up, 18 of 21 patients (86%) whose stones were located lower in the ureter, closer to the bladder, had passed their stones. In this group, the average time to stone passage was about four days, the study noted.

One of these patients felt “immediate relief” when the stone was dislodged from the ureter, the study stated.

The next step for the researchers would be to perfom a clinical trial with a control group, which would not receive either BWL bursts or ultrasound propulsion, to evaluate the degree to which this new technology potentially aids stone passage, Hall said.

Development of this technology first started five years ago, when NASA funded a study to see if kidney stones could be moved or broken up, without anesthesia, on long space flights, such as the Mars missions.

The technology has worked so well that NASA has downgraded kidney stones as a key concern.

“We now have a potential solution for that problem,” Hall said.

This study began in 2018 and was conducted on patients at Harborview Medical Center, University of Washington Medical Center-Montlake and the Northwest Kidney Stone Center at University of Washington Medical Center-Northwest. It involved the University of Washington School of Medicine’s departments of emergency medicine, urology and radiology, and the UW Applied Physics Laboratory.

Other UW Medicine trials have looked at breaking apart kidney stones inside the kidneys. This is the first trial to look at moving the stones or breaking them apart in the ureter with BWL, Hall said.

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When kidney stones are surgically removed from patients, little stones that do not appear to be causing problems are commonly left behind. According to a recent randomised controlled study, leaving these asymptomatic stones left significantly increases the probability of a patient developing a recurrence in the five years that follow.

The study’s findings were published in the journal ‘New England Journal of Medicine.’ Stones less than 6mm in diameter that are not the primary target of a procedure are generally not removed but are monitored because “secondary” stones have a high rate of successful passage if they move into the ureter, according to lead author Dr Mathew Sorensen, a urologist at the University of Washington School of Medicine.

“Before this study, the clinical views were pretty mixed on whether some of these stones should be treated,” he said. “Most clinicians would decide, based on the size of the kidney stone, whether it hit the bar for treatment, and if it did not, you would often ignore the little stones.”

The investigators studied 75 patients who were treated at multiple institutions over a span from 2015 to 2021. About half of the patients had only their large primary stone treated, while the others had primary and secondary kidney stones removed. Relapse was defined as having to go to the emergency room or undergo an additional procedure due to a recurrence or if a follow-up CT scan showed that the secondary stones grew.

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Removal of the secondary stones reduced the relapse rate by 82 per cent, the researchers found, leading the authors to recommend that smaller stones should not be left behind.

“Results of our trial support the removal of small asymptomatic kidney stones at the time of surgery with a larger stone,” their paper concluded. The authors noted that while the removal of smaller stones could add to the procedure’s duration and cost, those costs would likely be less than those associated with a patient’s repeat procedure or visit to the emergency room.

Some patients in the study visited the emergency department multiple times and then required surgery, the report noted.
Sorensen said he would share the study results with colleagues with the hope of changing their sensibility toward smaller stones. Further study is needed to determine whether treatment of small kidney stones alone is justified, as technology improves and the costs and risks of an intervention diminish, he said.

“I think we have proven through this rigorous study that removal of the small asymptomatic stones is beneficial when feasible and in patients that are candidates to have all their stones treated in one procedure,” he noted. “Leaving the stones behind risks trouble in the future.”

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