WeeklySA_AdminDEVELOPMENT: A potential treatment for the world’s leading cause of renal failure in children has been discovered…
By WSAM Health Correspondent
The commonest cause of kidney failure in children is due to toxin producing bacteria that enters the circulation through the gut, an international team of scientists have discovered.
This intrusion results in a disease called Haemolytic Uraemic Syndrome (HUS), according to the findings. There are different types of HUS – the most common is called Shiga toxin-associated haemolytic uraemic syndrome (STEC-HUS).
As one of the most common causes of kidney problems in people of all ages, it can be particularly devastating to young children, often requiring kidney dialysis, with around one in 20 children developing life-long kidney failure or dying.
STEC-HUS commonly happens after a gut infection, associated with bloody diarrhoea. Exactly why the kidney is so susceptible to injury in STEC-HUS has, until now, remained unclear. The research, funded by the Medical Research Council and Kidney Research UK and led by scientists from Bristol Renal, wanted to identify the mechanism underpinning the disease pathway.
Using laboratory models, the team found a specific cell in the kidney called the podocyte — which plays a crucial role in renal function — is targeted by the Shiga toxin and then ‘talks’ to local blood vessels causing small blood clots to form. This is due to the activation of the ‘complement’ pathway, and can lead to an eventual loss of kidney function.
Critically, the team demonstrated in both mouse models and in human kidney cells that STEC-HUS can be successfully treated by inhibiting the complement pathway early in the disease process with a drug called Eculizumab.
Richard Coward, Professor of Renal Medicine at the University of Bristol and Consultant Paediatric Nephrologist at Bristol Royal Hospital for Sick Children, and one of the study’s lead researchers, said:
“As a children’s kidney doctor, one of the most difficult and devastating diseases we treat is STEC-HUS, which causes kidney failure and death in some children. This is normally caused by a bacteria that enters the circulation via the gut causing bloody diarrhoea.
“We have now discovered that a cell in the kidney called the podocyte is a key target cell of Shiga toxin and that it can be treated if the ‘complement’ pathway is blocked in the blood early in the disease.”
Dr Aisling McMahon, executive director of research and policy at Kidney Research UK, added: “This research has not only shown exactly how Shiga toxin is able to target the kidney and cause such devastating damage but has also discovered a way in which HUS could be stopped in its tracks using a drug that is already in clinical use. This is another great example of the importance of research in identifying new treatment options for patients, and we look forward to the next steps in this project.”
The research team has demonstrated that early use of Eculizumab can prevent Shiga-toxin driven kidney failure and the drug has therapeutic potential for this devastating disease that can result in life-long dialysis, and death, for some children.
The next steps for the researchers will be to understand how quickly Eculizumab needs to be given and carry out more early trials in children with STEC-HUS.
The international team included researchers from Bristol Renal at the University of Bristol; Bristol Royal Hospital for Sick Children, UK; Hospital for Sick Children in Toronto, Canada; MRC Harwell Institute, Oxfordshire, UK; University of Manchester, UK; School of Medicine at Cardiff University, UK and Arkana Laboratories in Arizona, USA.
Promising New Options for Treating Aggressive Prostate Cancer
PROGNOSIS: Clinical trial results released today point to two potential treatment possibilities that may improve the condition…
By WSAM Correspondent
United States medical experts have identified two promising new treatment options for men with recurrent prostate cancer—both of which helped patients live longer without their disease progressing than the current standard treatment.
The study, which was conducted experts attached to the Cedars-Sinai Cancer, involved trials in a total of 17 countries, involving more than 1 000 patients. Its results of the International Phase III clinical trial in the New England Journal of Medicine today.
“If these treatments are approved by the Food and Drug Administration, our results will be practice changing,” said Dr Stephen Freedland, associate director for training and education and Law Families Chair in Prostate Cancer at Cedars-Sinai, and lead researcher of the study. “In the study, both of these new options improved metastasis-free survival while preserving quality of life.”
Cancer of the prostate, a walnut-sized gland that helps make semen, will be diagnosed in 288 300 men in the United States in 2023, according to American Cancer Society estimates. For some, treatment may never be needed because they have a slow-growing form of the disease, but those with more aggressive prostate cancer are often first treated with surgery or radiation therapy.
“Unfortunately, in about a third of those patients, the cancer recurs within 10 years,” Freedland said.
Patients with aggressive recurrence are treated with androgen deprivation therapy (ADT), also known as hormone therapy, which reduces the patient’s production of the male sex hormone testosterone. Testosterone helps prostate cancer cells grow and spread, and the hormone therapy effectively reduces the growth-stimulating effects. But Freedland said ADT has two downsides: It doesn’t completely eliminate testosterone, and it can cause many side effects.
“When you go on ADT, the testosterone level in the blood is reduced, but not completely eliminated,” Freedland said. “And the concern is that the testosterone that remains may still be enough to stimulate tumour growth. Also, patients don’t love the idea of being on hormones.”
In this study of 1 068 prostate cancer patients from 244 sites in 17 countries, Freedland and fellow investigators tested two experimental interventions—one to address each of these issues.
In the randomised clinical trial, one-third of the patients received ADT plus a medication called enzalutamide, which blocks the effects of testosterone. Enzalutamide keeps any testosterone remaining in the blood from stimulating the growth of cancer cells.
Another third of the patients received enzalutamide alone. This option relied on the medication to block the effects of testosterone even though testosterone levels in the patients’ blood were not reduced.
“We wanted to see whether enzalutamide on its own was so effective that we didn’t need the ADT,” Freedland said. The final group of patients received ADT alone, which is the current standard treatment.
Investigators found that the combination of ADT plus enzalutamide reduced the risk of metastasis or death by 58% over ADT alone. They found that enzalutamide alone reduced the risk of metastasis or death by 37% over ADT alone. Both treatments maintained quality of life relative to the ADT alone.
“While the combination therapy offers greater risk reduction, some men might prefer enzalutamide alone. It does a good job of preventing cancer spread or death, with different side effects that may be more acceptable for some men,” Freedland said.
The next step is for the makers of enzalutamide to apply for FDA approval, so the experimental therapy can come into wide use, Freedland said.
“Optimising therapy for patients with aggressive recurrence after their prostate cancer is initially treated has been an unmet need,” said Dr Dan Theodorescu, director of Cedars-Sinai Cancer and the PHASE ONE Distinguished Chair. “The results of this trial point the way to two options which the study showed were more effective than current standard of care, giving these patients and their providers the opportunity to choose a potentially improved course of therapy that best meets their needs.”
