Urine levels of adenine, a metabolite produced in the kidney, are predictive and a causative biomarker of looming progressive kidney failure in patients with diabetes, a finding that could lead to earlier diagnosis and intervention, researchers reported in the Journal of Clinical Investigation. Elevated adenine was also associated with all-cause mortality.
The study results are significant because until now, the most important marker for kidney disease has been protein (or albumin) in the urine. Up to half of diabetes patients who develop kidney failure never have much protein in their urine. As 90% of patients with diabetes remain at increased risk despite low levels of albumin in their urine, this study has widespread consequences. It is the first study to identify these patients at an early stage by measuring this new causative marker in the urine.
The finding paves the way for clinic testing to determine that a patient is at risk, five to 10 years before kidney failure, said the senior study author, Kumar Sharma, MD. The study was conducted by The University of Texas Health Science Center at San Antonio.
Importantly, the research team identified a small molecule that blocks the major pathway of endogenous adenine production in the body. This therapeutic drug reduced kidney adenine levels in mice with type 2 diabetes. “The drug protected against all the major aspects of diabetic kidney disease without affecting blood sugar,” Sharma said. “The study is remarkable as it could pave the way to precision medicine for diabetic kidney disease at an early stage of the disease.”
Findings consistent across diverse study populations
The researchers studied more than 1200 patients with diabetes across three international research cohorts. The Chronic Renal Insufficiency Cohort (CRIC) study included African American, Hispanic and Caucasian participants in the US. A separate study was in the American Indian population. The team also evaluated an Asian cohort of mostly Chinese, Asian Indians and Malay populations in a study based in Singapore.
Mapping the metabolites
UT Health San Antonio is one of few centres perfecting a technique called spatial metabolomics on kidney biopsies from human patients. This technique enables researchers to determine the locations of adenine and other small molecules in kidney tissues.
“It’s a very difficult technique, and it took us several years to develop a method where we combine high resolution of the geography of the kidney with mass spectrometry analysis to look at the metabolites,” Sharma said.
Metabolites are small molecules that the body produces based on metabolism. They make cells go in a healthy way or in a disease pattern, Sharma said.
Adenine situated around kidney blood vessels
The team found endogenous adenine around scarred blood vessels in the kidney and around tubular-shaped kidney cells that were being destroyed. Endogenous substances are those that naturally occur in the body.
The finding that high levels of adenine were also associated with all-cause mortality in the study participants suggests that the metabolite is affecting other parts of the body, as well, Sharma said.
False sense of security
Many patients with diabetes know they’re at risk of kidney disease, but if they don’t have protein in their urine, they think they are protected, he said.
“They could be feeling a false sense of security that there is no kidney disease occurring in their body,” Sharma said. “But in fact, in many cases it is progressing, and they often don’t find out until the kidney disease is pretty far advanced. And at that time, it is much harder to protect the kidneys and prevent dialysis.”
“The death rate is very high, especially in patients with diabetes,” Sharma said. “There is about 40% mortality within five years in patients with diabetes and kidney failure.”
New type of therapy is needed
Although treatments to protect against diabetes and blood pressure are improving, they only push the envelope a little bit, Sharma said, in that patients still have progressive kidney disease and kidney failure, but they are afforded more time before they reach that endpoint. The measurement of urine adenine is difficult; however, the team at the Center for Precision Medicine at UT Health San Antonio has developed a robust and sensitive method to measure urine adenine in patients.
“What we’re hoping is that by identifying patients early in their course and with new therapies targeting adenine and kidney scarring, we can block kidney disease or extend the life of the kidney much longer,” Sharma said.
The furore over claims of fraudulent account manipulation happening at Mediclinic hospitals continues to grow, as the initial whistleblower responded to a challenge for more information by providing a detailed list of of starting points for investigators, according to Daily Maverick.
Widely reported in media outlets such as News24, Radio 702, and eNCA, the initial email alleged that hospital codes were being altered to ones which drew higher remunerations from medical aid schemes and therefore which financially benefitted the hospitals. They further claimed that no action was being taken against employees who were engaging in this practice, which was supposedly happening at six hospitals.
The Council for Medical Schemes noted that hospital charges to beneficiaries had increased by nearly 19% from R7039.74 in 2020 to R8346.40. Just over 92% of the total hospital expenditure was paid to private hospitals.
Greg van Wyk, CEO of Mediclinic Southern Africa, was also emailed among the initial recipients. He responded swiftly, writing in a reply to all the cc’d recipients last week that Mediclinic had appointed Steven Powell, head of law firm ENSafrica’s forensics practice, to head its independent audit.
The Mediclinic CEO also challenged the anonymous whistleblower to come forward and reveal themselves, the whistle-blower then responded with an email cc’d to medical schemes and the media. The email contained extensive of details of the alleged fraud – plenty of information for investigators to get started with.
The whistle-blower told News24 that, for example, “When a patient died in a hospital emergency room, sometimes Mediclinic case managers were expected to change their accounts to reflect an ICU death instead. This is because of the fixed fees associated with emergency room deaths, which are lower than ICU-related fees.”
A US study found that, despite prescriptions for the antibiotic ciprofloxacin dropping by two-thirds between 2015 and 2021, the rates of ciprofloxacin-resistant E. coli bacteria circulating in the community did not decline.
In fact, a study of women over age 50 who had not taken any antibiotics for at least a year discovered that the incidence of gut-colonising ciprofloxacin-resistant E. coli actually increased. About 1 in 5 women in the study were affected.
Scientists at the University of Washington School of Medicine, Kaiser Permanente Washington Health Research Institute and Seattle Children’s Hospital conducted the study. Their findings appear in Communications Medicine.
Their results are consistent with theoretical models indicating that, once a drug-resistant form of E.coli emerges, it will continue to spread by taking up long-term residence in individuals’ gut microbiomes. E. coli is among an alarming number of disease-causing bacteria that have become resistant to several types of antibiotics. Resistance means that the antibiotics can’t kill the bacteria.
Pathogenic E. coli from the gut occasionally enters the urinary tract opening and causes infections. The female pelvic anatomy makes women more vulnerable to these mobile bacteria. Postmenopausal women are especially susceptible to severe, drug-resistant infection. Some drug-resistant E. coli infections are associated with considerable risk of hospitalization and death from sepsis.
Urinary tract infections from antibiotic-resistant E. coli can be frustrating to treat, even with third-generation cephalosporins, the newer types of antibiotics that are being prescribed more frequently for some populations of patients. Resistance to cephalosporins among ciprofloxacin-resistant E. coli also rose between 2015 and 2021.
Ciprofloxacin and similar drugs in its class were once the most prescribed antibiotic for urinary tract infections. In 2015, recommendations from the Centers for Disease Control and Prevention, Food and Drug Administration and Infectious Disease Society of America discouraged broad use of this class of drugs for uncomplicated urinary tract infections, partly due to rising resistance.
“However, it appears to be questionable whether a reduction in antibiotic use can be effective in reducing the rates of resistance in E. coli infections,” the research paper’s authors noted.
“Evidence from studies such as this one may be changing lots of paradigms on how to fight the rise in antibiotic resistance,” said physician scientist Dr. Evgeni V. Sokurenko, professor of microbiology at the University of Washington School of Medicine, who headed this latest research.
In the study, the scientists examined participants’ positive samples to determine which antibiotic-resistant strains of E. coli were present.
They found that the rate of a particularly virulent strain, ST1193, rose during the study period. Together with E. coli strain ST131-H30, these strains are the major causes of a global pandemic of multi-drug-resistant urinary tract infections among all women.
If ST1193 makes its home in more people’s guts, the situation could lead to more urinary tract infections with this more virulent strain, regardless of the curbing of fluoroquinolones prescriptions.
Another strain with a troubling increase in the participant samples was ST69, known to more frequently cause urinary tract infections in children.
tize discovering better ways to control drug-resistant E. coli’s ability to colonize the gut before it causes these infections, the authors wrote. They mentioned potential strategies of deploying probiotic bacteria and anti-bacterial viruses (bacteriophages).
The researchers added that these approaches might be offered to high-risk patients or deployed against the most clinically relevant strains. More investigation is needed on the epidemiology and ecology of antibiotic-resistant gut E. coli, they said, to help determine how these bacteria skillfully colonize human guts and how to target them most effectively to reduce antibiotic-resistant infections.
The prevalence of microplastics in the environment is well known, along with their harm to marine organisms, but few studies have examined the potential health impacts on mammals. Now, a new study published in the International Journal of Molecular Sciences has found that in mice, the infiltration of microplastics was as widespread in the body as it is in the environment, leading to behavioural changes, especially in older test subjects.
Study leader University of Rhode Island Professor Jaime Ross and her team focused on neurobehavioural effects and inflammatory response to exposure to microplastics, as well as the accumulation of microplastics in tissues, including the brain.
“Current research suggests that these microplastics are transported throughout the environment and can accumulate in human tissues; however, research on the health effects of microplastics, especially in mammals, is still very limited,” said Ross, an assistant professor of biomedical and pharmaceutical sciences at the Ryan Institute for Neuroscience and the College of Pharmacy. “This has led our group to explore the biological and cognitive consequences of exposure to microplastics.”
Behavioural changes detected
Ross’ team exposed young and old mice to varying levels of microplastics in drinking water over the course of three weeks. They found that microplastic exposure induces both behavioural changes and alterations in immune markers in liver and brain tissues. The study mice began to exhibit behaviours akin to dementia in humans. The results were even more profound in older animals.
“To us, this was striking. These were not high doses of microplastics, but in only a short period of time, we saw these changes,” Ross said. “Nobody really understands the life cycle of these microplastics in the body, so part of what we want to address is the question of what happens as you get older. Are you more susceptible to systemic inflammation from these microplastics as you age? Can your body get rid of them as easily? Do your cells respond differently to these toxins?”
To understand the physiological systems that may be contributing to these changes in behaviour, Ross’ team investigated how widespread the microplastic exposure was in the body, dissecting several major tissues including the brain, liver, kidney, gastrointestinal tract, heart, spleen and lungs. The researchers found that the particles had begun to bioaccumulate in every organ, including the brain, as well as in bodily waste.
“Given that in this study the microplastics were delivered orally via drinking water, detection in tissues such as the gastrointestinal tract, which is a major part of the digestive system, or in the liver and kidneys was always probable,” Ross said. “The detection of microplastics in tissues such as the heart and lungs, however, suggests that the microplastics are going beyond the digestive system and likely undergoing systemic circulation. The brain blood barrier is supposed to be very difficult to permeate. It is a protective mechanism against viruses and bacteria, yet these particles were able to get in there. It was actually deep in the brain tissue.”
Possible mechanism
That brain infiltration also may cause a decrease in glial fibrillary acidic protein (called “GFAP”), a protein that supports many cell processes in the brain, results have shown. “A decrease in GFAP has been associated with early stages of some neurodegenerative diseases, including mouse models of Alzheimer’s disease, as well as depression,” Ross said. “We were very surprised to see that the microplastics could induce altered GFAP signalling.”
She intends to investigate this finding further in future work. “We want to understand how plastics may change the ability for the brain to maintain its homeostasis or how exposure may lead to neurological disorders and diseases, such as Alzheimer’s disease,” she said.
I walked into a store in Cape Town and I bought a gram of cannabis for R100. With GroundUp’s money. I had my editor’s consent.
The store was small, dimly lit, and lined with a variety of cannabis products in glass jars.
On the table was a stack of medical forms used by a doctor to prescribe cannabis to people for health reasons.
I did not have a doctor’s note. So I complimented the salesman on his luscious black curls. I think it worked because he became very chatty. Let’s call him Bob.
We discussed how the store works and the current laws. He said they’re working in a “grey area”.
There are two ways the store sells cannabis to people, Bob explained.
Method one: the membership system. Bob said that members pay a monthly fee and receive a certain amount of cannabis over a month. He says this gets around the legal problem, which is, he says, that “buying and selling” are not allowed. With the membership system, Bob said, you’re not doing either.
Method two: the medical method. The store uses section 21 of the Medicines Act to facilitate medical sales.
Bob said he was keen for the store to use the medical route for customers during the day and to run a club in the evenings where members come and smoke in a chilled environment.
I explained to Bob that I get quite anxious when I smoke. I can hear myself think with an echo of my thoughts swirling in my brain. (Boring truth be told, I haven’t smoked cannabis in years, and I didn’t smoke what I bought either. I won’t reveal who did.) Bob recommended a specific cannabis for me.
I asked him if he could recommend a doctor so I could get a prescription. Laughing, he said that he was a doctor. I think he was only half-joking, because it seemed like we then used method two: the medical route. He took out a scale and some bright green cannabis. He weighed it, and sold me 1 gram of OG Kush for R100.
Nope, that’s not how the law works
Was Ashraf’s transaction legal? No, according to a lawyer with expertise in the cannabis industry whom we spoke to.
First, the lawyer explained, cannabis can only be produced in a facility licensed by the South African Health Products Regulatory Authority (SAHPRA). It’s unlikely that the store obtained its cannabis from such a licensed facility. In fact there is a view that even weighing out a small amount of weed from a bag obtained from a licensed cultivator, and then packaging it, is manufacturing.
Second, if Section 21 of the Medicines Act is to be used, the sale of the cannabis can only take place after the doctor has prescribed it and SAHPRA has authorised the sale of weed to that particular patient. (Ashraf didn’t even give Bob his name.)
Even if these two conditions are met, no sale of cannabis to a patient can take place outside of a retail or community pharmacy.
There’s nothing unique about Ashraf’s experience. Dozens of stores across the country are selling cannabis using the same approach. We got the impression that in Durban there isn’t even a pretence of trying to be legal as there is in some of the Cape Town and Johannesburg stores. Our experience in Durban is that you can pretty much walk into stores and simply buy cannabis over the counter without any fuss.
How it got this way
South Africa’s cannabis sector is in limbo five years after the Constitutional Court ruled that cultivation and possession of the plant for private use is legal.
In 1997, Gareth Prince, a practising Rastafarian, applied to the Law Society of the Cape of Good Hope to be admitted as an attorney. The Society rejected his application because he had two criminal convictions for possession of cannabis and he continued to smoke cannabis. Prince argued that the use of cannabis was part of his religion, and that the Law Society’s decision violated his right to religious freedom.
Prince took the decision to court in 1998. But the High Court, Supreme Court of Appeal and Constitutional Court ruled in favour of the Law Society. The Constitutional Court’s 2002 decision was close: five versus four.
After the Constitutional Court’s judgment, Prince and two cannabis activists – Jeremy Acton and Jonathan Ruben – approached the courts again. Instead of focussing solely on religious freedom, their applications challenged provisions of the Drugs Act and Medicines Act that criminalised the use of cannabis on the basis that these provisions violated the right to privacy in section 14 of the Constitution. As these challenges were related, the High Court consolidated the cases.
In 2017, the Western Cape High Court declared the provisions in the Drugs Act and Medicines Act that criminalise private adult use of cannabis unconstitutional. This decision was upheld by the Constitutional Court in 2018. This judgment has become known as Prince 3. But the Constitutional Court did not confirm the High Court order that decriminalised the dealing of cannabis. Parliament was given 24 months to deal with the offending legislation.
In the event that Parliament didn’t fix things within the two-year deadline, the court ruled that its reading-in remedy (which permits the narrow exception for personal use) would become permanent, at least until Parliament amended the law.
Five years later, the slow pace of drafting legislation following the Prince 3 judgment has resulted in a proliferation of businesses using “grey areas” in the wording.
“People are looking for gaps, so these so-called dispensaries are stepping into the market claiming to sell something legal,” explained Andy Gray, chair of the Cannabis Working Group at SAHPRA and a pharmacy lecturer at the University of KwaZulu Natal (UKZN).
Substances that you can ingest are scheduled by SAHPRA from 0 to 8. A schedule 0 substance has very few controls; anyone can sell it without any licence required. At the other end of the scale, a schedule 8 substance is very strictly controlled, it may have some medicinal benefits but also has extremely high potential for abuse. Medical practitioners have to get special permission from SAHRPA for use and prescription of any of these substances.
After the Constitutional Court ruling, SAHPRA lowered the schedules of some of the substances found in cannabis. Low doses of Cannabidiol (CBD), a component of cannabis that isn’t psychoactive, were lowered to schedule 0 in complementary medicine products. But it is unclear if CBD in products such as drinks and gummies, with their varying dosages, manufacturing processes and contents – found in nearly every major shopping outlet – qualify as “complementary medicines”.
Tetrahydrocannabinol (THC), the key psychoactive component of cannabis, was lowered from schedule 7 to schedule 6. But schedule 6 substances are still highly restricted: According to SAHPRA these are medical substances that have “a moderate to high potential for abuse” which necessitates strict control and management of supply, including restrictions on repeat prescriptions and a supply limit of 30 days’ worth.
Danmari Duguid is head of the cannabis department at Schindlers Attorneys who represented Julian Stobbs and Myrtle Clarke, intervening parties in the 2018 Constitutional Court case, Prince 3. She says that the only way you can legally buy cannabis containing THC is through the medical route. This is done using section 21 of the Medicines Act.
Why section 21 of the Medicines Act is important
In a nutshell, this clause is a way for people with particular needs to legally obtain medicines that have not been registered by SAHPRA, but contain scheduled substances. For example, patients with serious cases of lung or skin cancer use Section 21 authorisation to access a medication called nivolumab (branded as Opdivo). SAHPRA has registered a lung and skin cancer medicine called pembrolizumab (branded as Keytruda) but this may not work with every patient.
In the 2000s, the Treatment Action Campaign (TAC) famously imported a generic version of a drug called fluconazole to treat an illness that particularly affects people with advanced HIV disease. A patented version of the medicine was available in the country but it was extremely expensive. The much more affordable version of the medicine that the TAC imported was not registered in South Africa, so the then Medicines Control Council allowed a doctor working with the TAC to import the medicine for patients using section 21 of the Medicines Act.
But section 21 authorisations are far from a straightforward legal route to using cannabis as explained above.
Hardly any of the cannabis retailers that claim to use the section 21 process are adhering to what’s legally required. It is in theory possible but in practice very hard for small cannabis retailers to do so.
Also, the Cannabis for Private Purposes Bill, currently before Parliament, does not provide for a recreational or adult market.
Gray told GroundUp that he fears people who want to buy and sell recreational cannabis in private will continue to abuse the medical route.
This happened in California in the United States, where the state legalised cannabis through the medicinal route and this led to extensive abuse of the process by patients, doctors and retailers.
The most direct way to combat this abuse is through the introduction of an adult use market, said Gray. This would mean cannabis products would be highly regulated and taxed, similar to alcohol and tobacco. This model could include the “legacy” or “peasant cultivators” who grow cannabis in rural parts of the country, and cannot meet the strict conditions for growing medical grade cannabis, said Gray.
Duguid agrees that the adult use model would work best for the legalisation of recreational cannabis sale and use in the future.
“At the moment you are allowed to brew beer for your own consumption, similar to how you are now allowed to grow cannabis for your own consumption after the 2018 judgement; but the moment you want to retail the product you should need a licence like you do to sell alcohol. This would ensure you meet certain safety standards,” said Duguid.
The Department of Agriculture and Land Reform and the Presidency recently hosted the Phakisa Action Lab in June 2023, which brought together 130 representatives of government and business, religious leaders and legal experts to discuss the legalisation of cannabis and hemp.
The final report from Phakisa emphasised that the government is taking a “science-based and human rights approach” approach to creating and regulating an adult use market, but that the “supply and trade of cannabis to consumers remains illegal”.
The report suggests adding a clause to the Cannabis for Private Purposes Bill which would remove cannabis from the Drugs Act “subject to parliamentary process and approval”.
The report highlights that adult use legalisation must include “the existing historical cultivation of cannabis by indigenous communities and black rural farmers”.
But it does not provide a timeline for doing this.
