Category: Urogenital

Categories : Ethics and Law UrogenitalTags :

Court Rules that UTI Drug Trade Names are Too Similar

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Photo by Bill Oxford on Unsplash

A court case over the trade names of two urinary tract infection (UTI) drugs has been settled. The court ordered that Cipla Medpro be restrained from using the trade name Furizome as it is too similar to Adcock Ingram’s UTI drug Urizone, leading to potential confusion by consumers. In his ruling, Justice James Lekhuleni of the High Court, Western Cape Division, who stated that despite safeguards against confusion in prescribing, ultimately “doctors are human”, so miscommunications could occur – and that the agency of patients cannot be ignored.

The trademark infringement case was brought by three applicants: Adcock Ingram Limited, Adcock Ingram Healthcare (Pty) LTD, and Italian company Zambon S.P.A. Zambon is the owner of the name Urizone, which is used under licence. Urizone had been launched in South Africa in 1993. The applicants stated that more than 3 million sachets had been sold between 2011 and 2023, with R5 million in advertising spent to promote the drug between 2018 and 2022 alone.

The applicants brought the case that Cipla Medpro’s Furizome, with the active ingredient fosfomycin, was too similar to their own product, Urizone, which contained the same ingredient in 3g sachets, and thus could confuse consumers. They alleged that Cipla Medpro sought to capitalise on the reputation earned by Urizone.

The applicants made the case that, despite Urizone being made available as a generic, none of the pharmaceutical companies producing it chose to use the name. When Furizome was launched, Adcock Ingram sent a letter of demand to Cipla to stop using the name due to its . Cipla, through its attorneys, rebutted the claim, saying that the two are sufficiently distinct to avoid confusion, with the “F” alluding to the fosfomycin ingredient. Cipla contended that it had already submitted the name through SAHPRA, and

Cipla also contended that the consumer – the patient – would not be misled during the prescribing and purchase of a schedule 4 medication as they would be informed by the pharmacist of the two different drugs.

In considering the judgment, the court noted that a test as to whether trademarks are be similar can be mode on a phonetic basis, or if they conceptually or visually similar. A trademark’s essential function is to indicate the origin of the goods in connection with which it is used. The “N” and “M” where seen as visually and phonetically similar, and “furi” was similar phonetically to “uri“. This could cause confusion and miscommunication even between doctors as to what drug they had prescribed a patient.

While Justice Lekhuleni acknowledged the safeguards of prescribing schedule 4 medications, he pointed out that the general public had become much more knowledgeable about prescription drugs in the past two decades. On this, he wrote “…the reality is that patients are involved in the process of deciding which medicines they will use, and that creates the risk of confusion. This situation in turn creates a responsibility upon pharmaceutical companies to make sure that they adopt trade marks that are not confusingly similar.”

Categories : Cardiovascular Disease UrogenitalTags :

Urinary Incontinence may Be Associated with Cardiovascular Disease

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Photo by Jan Antonin Kolar on Unsplash

A University of Iowa-led research team has found that urinary incontinence may be associated with a greater risk for cardiovascular disease in women.

Urinary incontinence is a common condition, especially in older adults. Previous studies have stated that it can affect between 38% and 60% of women. The researchers aimed to find out whether urinary incontinence was linked to a decline in physical activity, which can lead to a host of health issues, including greater risk for cardiovascular disease.

The findings were published in Preventive Medicine.

In the study, the researchers – led by Lisa VanWiel, assistant professor at the University of Wisconsin-La Crosse who in April earned her doctorate in health and human physiology from Iowa – analysed medical records over two years from more than 20 000 female patients in the Hartford Healthcare system in Connecticut. Of those patients, 5.4% reported through a questionnaire to have urinary incontinence. All patients were asked to rate their level of physical activity in the questionnaire.

The researchers found that the respondents with urinary incontinence did not report engaging in less physical activity than those who did not have the condition. But the team did find an association between patients with urinary incontinence and cardiovascular disease risk factors or events, such as dyslipidemia, type 2 diabetes, and stroke.

“There is an association between incontinence and cardiovascular disease (CVD) risk,” the study authors write. “Women should be screened for incontinence regularly as it may contribute to CVD risk, and women with CVD risk factors should be screened for undiagnosed incontinence.” 

Source: University of Iowa

Categories : UrogenitalTags :

UTI Pain Stems from Hypersensitivity in Nerves for Bladder Fullness

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Photo by Jan Antonin Kolar on Unsplash

New insights into what causes the painful and disruptive symptoms of urinary tract infections (UTIs) could offer hope for improved treatment. Nearly one in three women will experience UTIs before the age of 24, and many elderly people and those with bladder issues from spinal cord injuries can experience multiple UTI’s in a single year.

Findings from a new study led by Flinders University’s Dr Luke Grundy and SAHMRI’s Dr Steven Taylor show that UTIs cause the nerves in the bladder to become hypersensitive resulting in the extremely painful and frequent urge to urinate, pelvic pain, and burning pain while urinating.

“We found that UTIs, caused by bacterial infections such as E. coli, can significantly alter the function and sensitivity of the nerves that usually detect bladder fulness, a phenomenon known as ‘bladder afferent hypersensitivity’, says Dr Grundy, from the College of Medicine and Public Health.

“The study was the first of its kind to explore the impact of UTIs on the sensory signals that travel from the bladder to the brain, and the direct link this response has to causing bladder pain and dysfunction.”

A normal bladder will expand to store urine and can store up to two cups of urine for several hours.  Once full, the bladders nervous system will signal that it is time to urinate, or empty the bladder.

Described in Brain, Behavior, & Immunity – Health, researchers analysed how UTIs cause sensory nerves that respond to bladder distension to become hypersensitive, so that they send signals of bladder fulness, even when the bladder is not yet full.

“Our findings show that UTIs cause the nerves in the bladder to become overly sensitive, which means that even when the bladder is only partly filled, it can trigger painful bladder sensations that would signal for the need to urinate,” he says.

“We think that these heightened sensory responses may serve as a protective mechanism, alerting the body to the infection and prompting more frequent urination to expel the bacteria.”

Building on previous research, the new study reveals a deeper understanding of how UTIs affect bladder function and the nervous system, and raises important questions about the role of bladder hypersensitivity in the development of UTI-related symptoms.

“Our findings go further in identifying the significant changes that occur during UTIs and provide a clearer picture of the mechanisms behind the painful and disruptive bladder sensations often associated with these infections,” says Dr Grundy.

The study also suggests that better understanding and targeting of bladder afferent hypersensitivity could improve treatment options for patients suffering from recurrent UTIs or other bladder conditions where sensory dysfunction plays a role.

“Theoretically we should be able to find a way to address hypersensitive nerves in the bladder and reduce or eliminate the painful and debilitating symptoms of a UTI,” he adds. This would improve quality of life whilst antibiotics are taking care of the infection.

Researchers are striving to address the limited treatments available for bladder pain by exploring how the findings may translate into clinical practice and improve the management of UTIs in patients.

Source: Flinders University

Categories : Neurology UrogenitalTags :

Scientists Identify a Type of Brain Cell That is a Master Controller of Urination

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Researchers have identified a subset of brain cells in mice that act as the master regulators of urination.

The research, published as a Reviewed Preprint in eLife, is described by editors as an important study with convincing data showing that oestrogen receptor 1-expressing neurons (ESR1+) in the Barrington’s nucleus of the mouse brain coordinate both bladder contraction and relaxation of the external urethral sphincter.

Urination requires the coordinated function of two units of the lower urinary tract. The detrusor muscle of the bladder wall relaxes to allow the bladder to fill and empty, while the external sphincter opens when it’s appropriate to allow urine to flow out, but otherwise keeps tightly shut.

“Impairment of coordination between the bladder muscle and the sphincter leads to various urinary tract dysfunctions and can significantly degrade a person’s quality of life,” says first author Xing Li, Advanced Institute for Brain and Intelligence, School of Physical Science and Technology, Guangxi University, Nanning, China. “But although we know the individual nerve signalling pathways that control each of these urinary tract components, we don’t know which brain areas ensure they cooperate at the right time.”

To explore this, the authors used state-of-the-art live cell imaging to study the activity of brain cells in anaesthetised and awake mice during urination. They focused on a brain region called the pontine micturition centre (PMC), otherwise known as the Barrington’s nucleus, and compared the activity of different PMC nerve cell subtypes.

In their first experiments, they measured the activity of the cells as the bladder empties by measuring changes in levels of calcium. This revealed that the electrical firing rate of a subset of PMC cells expressing estrogen receptors (PMCESR1+ cells) was tightly linked to bladder emptying. When they combined this with monitoring bladder physiology, they found that it was not only the timing of PMCESR1+ cell activity that correlated with bladder emptying, but the strength of cell electrical activity, too.

Next, they tested what happened to urination if they blocked or triggered the PMCESR1+ cells. They found that when PMCESR1+ cell activity was blocked, the amount of urine the mice passed was significantly reduced and ongoing urination was suspended from the moment the cells were inactive. To understand the mechanism behind this, they measured the activity of the bladder muscle and sphincter. They discovered that both increase of bladder pressure and sphincter muscle bursting activity associated with bladder emptying both stopped when PMCESR1+ cell activity was blocked during an ongoing voiding even. Similarly, when PMCESR1+ cells were artificially activated using light, bladder emptying occurred 100% of the time. This suggests that PMCESR1+ cells work as a reliable master switch that either initiates or suspends bladder emptying.

To test whether PMCESR1+ cells can influence bladder emptying independently of controlling the sphincter, they disconnected either the nerve carrying messages from the brain to the sphincter, or the nerve carrying messages from the brain to the bladder. They found that PMCESR1+ cell control of the bladder was fully operational even when communication to the sphincter was blocked, and vice versa. This showed the cells could control the bladder and sphincter independently of one another, but the question remained: could they coordinate the action of the bladder muscle and sphincter together? That is, operate them in a controlled, perfectly timed manner, to trigger bladder emptying when appropriate?

To explore this, they simultaneously recorded bladder pressure and electromyography measurements of sphincter activity. The timing of bladder pressure changes immediately before sphincter bursting activity was consistent for both spontaneous bladder emptying and emptying caused by activating the PMCESR1+ cells, showing that these cells can coordinate the two steps in a precisely temporal sequence and controlled way.

“Our study shows that a subset of cells in the Barrington’s nucleus of the brain can initiate and suspend bladder emptying with 100% accuracy when needed, for example, to release only a small volume for landmarking by animals, or for a human to urinate into a small sample tube for a health check,” concludes senior author Xiaowei Chen, Third Military Medical University, and Chongqing Institute for Brain and Intelligence, China. “While other cells will no doubt be involved in perfect urination control, our pinpointing of PMCESR1+ cells’ crucial role in bladder–sphincter coordination will aid the development of targeted therapies for treating urination dysfunction caused by brain or spinal cord injury or peripheral nerve damage.”

Source: eLife

Categories : Metabolic Disorders UrogenitalTags :

GLP-1 Receptor Agonists also Protect the Kidneys, Study Shows

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GLP-1 agonists significantly reduced kidney deterioration and failure, regardless of diabetes status

Chronic kidney disease (CKD). Credit: Scientific Animations CC4.0

The biggest and most comprehensive analysis of glucagon-like peptide-1 (GLP-1) receptor agonists on kidney and cardiovascular outcomes shows they have significant benefits in people with and without diabetes.1 Findings appear in The Lancet Diabetes & Endocrinology.

Originally developed to treat diabetes, GLP-1 receptor agonists mimic the action of glucagon-like peptide 1, a hormone which stimulates insulin production and lowers blood sugar levels. More recently, they have emerged as effective treatments for obesity – slowing digestion, increasing satiety and reducing hunger. 

But while the benefits of GLP-1 receptor agonists for the treatment of type 2 diabetes, obesity and cardiovascular disease are well known, their impact on chronic kidney disease (CKD) has been less certain.

Researchers conducted a meta-analysis of 11 large-scale clinical trials of GLP-1 receptor agonists involving a total of 85 373 people (79.4% with type 2 diabetes and 20.6% with overweight or obesity and cardiovascular disease but without diabetes). Seven different GLP-1 receptor agonists were investigated among the trials. 

The results showed that compared to placebo, GLP-1 receptor agonists reduced the risk of kidney failure by 16% and the worsening of kidney function by 22% (defined by a drop in estimated glomerular filtration rate – a measure of how much blood the kidneys filter clean every minute – of at least 50%). The combined reduction in the risk of kidney failure, worsening kidney function, and death due to kidney disease was 19%. 

The analysis also confirmed previous findings that GLP-1 receptor agonists protect cardiovascular health, with a 14% reduction in the risk of cardiovascular death, non-fatal heart attack, and non-fatal stroke, compared to placebo. Death by any cause was 13% lower among patients treated with GLP-1 receptor agonists.

Lead author Professor Sunil Badve, Professorial Fellow at The George Institute for Global Health and UNSW Sydney said the study expanded current knowledge about this class of drugs in key areas, including benefits in people with CKD, and in people with and without diabetes. 

“This is the first study to show a clear benefit of GLP-1 receptor agonists on kidney failure or end-stage kidney disease, suggesting they have a key role in kidney-protective and heart-protective treatment for patients with common medical conditions like type 2 diabetes, overweight or obesity with cardiovascular disease, or CKD,” he said.

“These results are particularly important for patients with chronic kidney disease. It is a progressive condition eventually leading to kidney failure requiring dialysis or kidney transplantation and is associated with premature death, mostly from heart disease. It has a significant impact on patients’ quality of life and incurs substantial healthcare costs.” 

CKD is estimated to affect one in ten people worldwide, equivalent to around 850 million people.2 It is the tenth leading cause of death and is projected to become the fifth most common cause of death by 2050.3 Diabetes, cardiovascular disease and obesity are independent risk factors for CKD and represent a major global health burden.4

Source: George Institute for Global Health

References

  1. Badve S et al. Effects of glucagon-like peptide-1 receptor agonists on kidney and cardiovascular disease outcomes: a meta-analysis of randomised controlled trials. Lancet Diabetes Endocrinol. 2024. https://doi.org/10.1016/S2213-8587(24)00271-7
  2. Jager KJ, et al. A single number for advocacy and communication-worldwide more than 850 million individuals have kidney diseases. Kidney Int. 2019. https://doi.org/10.1016/j.kint.2019.07.012 
  3. GBD 2021 Forecasting Collaborators. Burden of disease scenarios for 204 countries and territories, 2022–2050: a forecasting analysis for the Global Burden of Disease Study 2021. Lancet. 2024. https://doi.org/10.1016/S0140-6736(24)00685-8 
  4. The Global Burden of Metabolic Risk Factors for Chronic Diseases Collaboration. Cardiovascular disease, chronic kidney disease, and diabetes mortality burden of cardio-metabolic risk factors between 1980 and 2010: comparative risk assessment. Lancet Diabetes Endocrinol. 2015. https://doi.org/10.1016/S2213-8587(14)70102-0 
Categories : Cancer UrogenitalTags :

Open Surgery for Lymph Node Removal is Still the Gold Standard in Testicular Cancer

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Photo by cottonbro studio

A new study published in BJU International has found that the conventional, versatile open surgery approach to removal of the lymph nodes behind the intestines for patients whose testicular cancer has not advanced beyond the abdomen is the gold standard of care for men in this condition.

Open surgery involves making an incision on the abdomen for a direct view and access to the surgical area. In the appropriate patients, cancer cure rates are excellent with this surgery alone due to continued clinician experience and refinement of technique, particularly at high-volume centres.

The study, led by urologist and health services researcher Clint Cary, MD, MPH, MBA, of the Indiana University School of Medicine and the Regenstrief Institute, was conducted using information from the on 165 patients with clinical stage I or II testicular cancer and no prior chemotherapy. One of the highest-volume testicular cancer treatment groups in the US, IU School of Medicine’s Department of Urology is among those groups setting the bar for both better surgical results and fewer negative outcomes such as infertility. Study benchmarks included low blood loss, short hospital stay and rare major postoperative complications.

Dr Cary notes that the paper, which includes analysis of risk factors for complications, clearly indicates that prior to treatment, men and their families should have conversations with their local urologist about their experience level across risk factors, such as high body mass index (BMI), as well as have detailed discussions of complication rates. He adds that both patients and clinicians can use the findings of this paper as a bar for comparison as they make choices.

“In my clinical role at Indiana University in the operating room, I frequently perform lymph node dissections for men with a lower burden of metastatic cancer who have not had chemotherapy or may never receive it for this cancer. In my complementary role as a Regenstrief Institute health services researcher, I study the impact of clinical decisions,” said Dr Cary. “For this study, I wanted to know that this and other treatments I perform are making a difference and I want to know – whether we are continuing established treatments or introducing new approaches to surgery – how these decisions and the resulting care will impact patients’ quality of life and their cancer outcomes.

“This study is an example of how the benefit of providing clinical care and also being in a research environment enables us to learn from what we’re doing and to report it in a manner that is meaningful to both patients and physicians. We’re always looking for ways to improve upon surgical outcomes. Going beyond the scope of this paper, we are now expanding our work to begin a randomised trial comparing two surgical techniques for removing lymph nodes to understand if one is better than the other regarding postoperative recovery.”

The paper did not compare robot-assisted surgery with traditional open surgery, which may allow a more complete lymph node dissection. While robotic surgery in general offers potential benefits to both surgeons and patients, the authors note that the head to head comparison between these two approaches is limited due to small experiences with the robotic approach in testicular cancer.

The authors conclude that for patients undergoing removal of lymph nodes for testicular cancer and certainly more complex and challenging patients at higher risk of post-operative complications, the traditional open surgery remains the most effective approach and the gold standard.

Source: Regenstrief Institute

Categories : UrogenitalTags :

Pushing Kidney-stone Fragments Reduces Stones’ Recurrence

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Kidney and ureteral stones. Credit: Scientific Animations CC4.0

Sometimes all it takes is a little push. That is the conclusion of a study, published recently in the Journal of Urology, in which doctors used a handheld ultrasound device to nudge patients’ kidney-stone fragments.

As many as 50% of patients who have kidney stones removed surgically still have small fragments remaining in the kidneys afterward. Of those patients, about 25% find themselves returning for another operation within five years to remove the now-larger fragments.

UW Medicine researchers found, however, that patients who underwent the stone-moving ultrasound procedure had a 70% lower risk of such a recurrence.

“I think the main takeaways of this study are removing fragments reduces relapse and using a noninvasive, hand-held ultrasound device to help clear these kidney stone fragments,” said UW Medicine urologist Dr Jonathan Harper, the study’s senior author.

The multisite, randomised and controlled trial was conducted from May 2015 to April 2024. Almost all of the 82 participants were from the UW Medicine or the VA Puget Sound health systems. All had stone fragments that had persisted in their kidneys for months, and their ureters were free of stones and fragments.

In the study, 40 underwent ultrasound treatment to encourage fragments to clear from the kidneys, while 42 control-group members received no such treatment.

With patients awake in a clinic office setting, doctors used a wand that generated ultrasonic pulses through the skin to move the fragments closer to the ureter, where they could be naturally expelled, sometimes with the next urination, Harper noted.

Harper and his co-lead author on the paper, urologist Dr Mathew Sorensen, have worked on this technology and treatment for 15 years. They also use this technology, called burst wave lithotripsy, to blast larger stones into smaller pieces; those successes were published in 2022.

The pushing and breaking technologies are used with the same ultrasound platform.

Harper expressed hope that both clinical uses of the technology would become commonplace. A company, SonoMotion, is commercialising the technology, which was developed at the University of Washington, he added.

“I see a lot of potential in this It could become as common as getting your teeth cleaned. If you have a couple of small stones which could cause future problems, you make an office appointment and in 30 minutes you’re done.

“This could really revolutionise kidney stone treatment,” Harper said.

Source: University of Washington School of Medicine

Categories : Gastrointestinal UrogenitalTags :

Recurrent Chlamydia Results from Bacteria Settling in the Intestine

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Immunofluorescence staining of human gastric cells grown in a microplate and infected with Chlamydia trachomatis. Blue: cell nuclei, green: C. trachomatis, grey: actin. (Image: Pargev Hovhannisyan / Universität Würzburg)

A phenomenon is known from everyday clinical practice that can occur after successful antibiotic treatment: when people who have already been treated come to the doctor with a new chlamydia infection, they are often infected with exactly the same strains of bacteria as the previous infection.

“It is therefore reasonable to assume that the bacteria find a niche in the body where they are not yet vulnerable, that they form a permanent reservoir there and can become active again later,” says Professor Thomas Rudel, chlamydia expert and Head of the Chair of Microbiology at the Biocentre of Julius-Maximilians-Universität (JMU) Würzburg in Germany. This phenomenon is known as persistence. It is problematic because the chlamydia that persist in the body become increasingly resistant to antibiotics over time.

Intestinal Organoids Experimentally Infected with Chlamydia

Experiments on mouse models have shown that chlamydia can persist in the intestines of animals. In humans the bacteria also seem to make themselves at home there. This is reported by the research groups of Thomas Rudel and Sina Bartfeld in the journal PLOS Pathogens. Professor Bartfeld worked at JMU until 2021; she now heads the Department of Medical Biotechnology at Technische Universität Berlin.

The researchers identified the intestine as a niche with the help of artificial organs in miniature format, so-called organoids. These are structures produced in the laboratory from human intestinal cells that are very similar in structure and function to the model organ.

The teams from Würzburg and Berlin tried to infect the intestinal organoids with chlamydia. They discovered that the inner cell layer of the organoids is very resistant to the bacteria: the pathogens could only penetrate there if the cell epithelium was damaged. From the blood side, however, the chlamydia were able to infect very efficiently. “In this case, we repeatedly found the persistent forms of the bacteria, which can be clearly identified with their typical shape under the electron microscope,” says JMU researcher Pargev Hovhannisyan, first author of the publication.

Clinical Studies and Further Experiments Must Follow

Transferred to the human organism, this would mean that chlamydia infection with subsequent persistence can only occur with difficulty via the inner side of the intestine, but very easily via the blood. However, whether this actually happens in the human body has yet to be confirmed in clinical studies, says Thomas Rudel.

The next step for Thomas Rudel and Sina Bartfeld is to to find out whether the chlamydia select certain cell types for their persistence – no easy task, as the intestine consists of hundreds of different cell types. But perhaps it is also factors from the surrounding tissue that trigger persistence. These and other details are now to be investigated.

Source: University of Würzburg

Categories : UrogenitalTags :

Study Shows Fewer Kidney Stones with Higher Doses of Thiazides

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Human kidney. Credit: Scientific Animations CC0

Higher thiazide doses are associated with greater reductions in urine calcium, which in turn correlate with fewer symptomatic kidney stone events, according to a Vanderbilt University Medical Center study out now in JAMA Network Open.  

Thiazide diuretics, commonly prescribed to prevent kidney stone recurrence, are drugs that act directly on the kidneys to promote diuresis by inhibiting the sodium/chloride cotransporter located in the distal convoluted tubule of a nephron. Thiazides are also used as a common treatment for high blood pressure and to clear fluid from the body in conditions such as heart failure. 

First author Ryan Hsi, MD, FACS, associate professor in the Department of Urology at VUMC, said the study data help explain the findings of the multicentre Hydrochlorothiazide for Kidney Stone Recurrence Prevention (NOSTONE) trial, which reported that hydrochlorothiazide did not reduce recurrence of kidney stone events.  

“In light of our research, the calcium reductions in that study were modest and likely insufficient to affect recurrence risk,” Hsi said.   

“What this means for patients is that thiazides remain an important option in the toolkit for preventing kidney stone recurrence. It may be beneficial to monitor calcium excretion while on thiazide therapy to adjust dose and diet to attain an adequate reduction in urine calcium.” 

A total of 634 participants were studied, revealing significant associations between higher thiazide doses and urine calcium reductions greater than those achieved in the NOSTONE trial, where participants took different doses of hydrochlorothiazide.  

For next steps, the researchers are interested in understanding which subtypes of thiazides and their dosing work best, and how best to optimise medication adherence, since these therapies are often administered long term.

Source: Vanderbilt University Medical Center

Categories : UrogenitalTags :

Cutting Down on Salt Levels Stimulates Kidney Regeneration

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Photo by Robina Weermeijer on Unsplash

A loss of salt and body fluid can stimulate kidney regeneration and repair in mice, according to a study published in The Journal of Clinical Investigation. This innate regenerative response relies on a small population of kidney cells in a region known as the macula densa (MD), which senses salt and exerts control over filtration, hormone secretion, and other key functions of this vital organ.

“Our personal and professional mission is to find a cure for kidney disease, a growing global epidemic affecting one out of seven adults, which translates to 850 million people worldwide…” said study leader Janos Peti-Peterdi, a professor of physiology, neuroscience and medicine at the Keck School of Medicine of USC. “Currently, there is no cure for this silent disease. By the time kidney disease is diagnosed, the kidneys are irreversibly damaged and ultimately need replacement therapies, such as dialysis or transplantation.”

To address this growing epidemic, Peti-Peterdi, first author Georgina Gyarmati, and their colleagues took a highly non-traditional approach. As opposed to studying how diseased kidneys fail to regenerate, the scientists focused on how healthy kidneys originally evolved.

“From an evolutionary biology perspective, the primitive kidney structure of the fish turned into more complicated and more efficiently working kidneys to absorb more salt and water,” said Peti-Peterdi. “This was necessary for adaptation to the dry land environment when the animal species moved from the salt-rich seawater. And that’s why birds and mammals have developed MD cells and this beautiful, bigger, and more efficient kidney structure to maintain themselves and functionally adapt to survive. These are the mechanisms that we are targeting and trying to mimic in our research approach.”

With this evolutionary history in mind, the research team fed lab mice a very low salt diet, along with a commonly prescribed drug called an ACE inhibitor that furthered lowered salt and fluid levels. The mice followed this regimen for up to two weeks, since extremely low salt diets can trigger serious health problems if continued long term.

In the region of the MD, the scientists observed regenerative activity, which they could block by administering drugs that interfered with signals sent by the MD. This underscored the MD’s key role in orchestrating regeneration.

When the scientists furthered analysed mouse MD cells, they identified both genetic and structural characteristics that were surprisingly similar to nerve cells. This is an interesting finding, because nerve cells play a key role in regulating the regeneration of other organs such as the skin.

In the mouse MD cells, the scientists also identified specific signals from certain genes, including Wnt, NGFR, and CCN1, which could be enhanced by a low-salt diet to regenerate kidney structure and function. In keeping with these findings in mice, the activity of CCN1 was found to be greatly reduced in patients with chronic kidney disease (CKD).

To test the therapeutic potential of these discoveries, the scientists administered CCN1 to mice with a type of CKD known as focal segmental glomerulosclerosis. They also treated these mice with MD cells grown in low-salt conditions. Both approaches were successful, with the MD cell treatment producing the biggest improvements in kidney structure and function. This might be due to the MD cells secreting not only CCN1, but also additional unknown factors that promote kidney regeneration.

“We feel very strongly about the importance of this new way of thinking about kidney repair and regeneration,” said Peti-Peterdi. “And we are fully convinced that this will hopefully end up soon in a very powerful and new therapeutic approach.”

Source: Keck School of Medicine of USC