Tag: kidneys

Long-term Use of RAS Inhibitor Drugs Could Damage Kidneys

Photo by Robina Weermeijer on Unsplash

New research is raising concerns that long-term use of renin-angiotensin system (RAS) inhibitor drugs such as ACE inhibitors could be contributing to kidney damage.

The researchers stress that patients should continue taking the medications. But the scientists are urging studies to better understand the drugs’ long-term effects.

“Our studies show that renin-producing cells are responsible for the damage. We are now focusing on understanding how these cells, which are so important to defend us from drops in blood pressure and maintain our well-being, undergo such transformation and induce kidney damage,” said UVA’s Dr Maria Luisa Sequeira Lopez. “What is needed is to identify what substances these cells make that lead to uncontrolled vessel growth.”

A billion people around the world are affected by chronic hypertension. In a study published in JCI Insight, University of Virginia (UVA) researchers were seeking to better understand why severe forms of the condition are often accompanied by atherosclerosis in the kidney, leading to organ damage.

They found that renin cells, which help regulate blood pressure through renin production, play an important role. Harmful changes in the renin cells can cause the cells to invade the walls of the kidney’s blood vessels. The renin cells then trigger a buildup of another cell type, smooth muscle cells, that cause the vessels to thicken and stiffen, resulting in impeded kidney blood flow.

Long-term use of RAS inhibitor drugs, such as ACE inhibitors, or angiotensin receptor blockers, have a similar effect. But the study found that long-term use of the drugs was associated with hardened kidney vessels in both lab mice and humans

The researchers note that the medications can be lifesaving for patients, so they stress the importance of continuing to take them. But they say additional studies are needed to better understand the drugs’ long-term effects on the kidneys.

“It would be important to conduct prospective, randomised controlled studies to determine the extent of functional and tissue damage in patients taking medications for blood pressure control,” said UVA’s Dr Ariel Gomez. “It is imperative to find out what molecules these cells make so that we can counteract them to prevent the damage while the hypertension is treated with the current drugs available today.”

Source: University of Virginia

Geology Helps Medicine to Understand Kidney Stones

Image by photochur from Pixabay
Geologists with the tools of their trade. Image by photochur from Pixabay 

Geology studies stones to help find minerals, predict earthquakes and more, but now their expertise has been tapped to understand kidney stones — how they form, why are some people more susceptible to them and can they be prevented?

In a new paper published in the journal Nature Reviews Urology, researchers described the geological nature of kidney stones, outlined the arc of their formation, introduced a new classification scheme and suggested possible clinical interventions.

“The process of kidney stone formation is part of the natural process of the stone formation seen throughout nature,” Illinois geology professor Bruce Fouke said. “We are bringing together geology, biology and medicine to map the entire process of kidney stone formation, step by step. With this road map in hand, more effective and targeted clinical interventions and therapies can now be developed.”

Kidney stones affect in 10 adults in their lifetime and send half a million people in the United States to emergency rooms annually, according to the National Kidney Foundation. Yet little is understood about the geology behind how kidney stones form, Fouke said.

The team’s previous  research found that kidney stones form in the same way as regular stones do: they don’t crystallise all at once, instead going through cycles of partial dissolution and reformation. Doctors had previously believed that they form suddenly and intact.

The research team described in detail the multiple phases kidney stones go through in forming, dissolving and re-forming, using high-resolution imaging technologies. Their findings defy the typical classification schemes doctors use, which are based on bulk analyses of the type of mineral and the presumed location of formation in the kidney. Instead, the researchers drew up a new classification scheme based on the phase of formation the stone is in, and the chemical processes it is undergoing.

“If we can identify these phase transformations, what makes one step to go to another and how it progresses, then perhaps we can intervene in that progression and break the chain of chemical reactions happening inside the kidney tissues before a stone becomes problematic,” said lead author Mayandi Sivaguru, assistant director of core facilities at the Carl R Woese Institute for Genomic Biology at Illinois.

One particularly revelatory finding was in the very beginnings of kidney stone formation. The stones start off as microspherules, tiny droplets of mineral, which merge to form larger crystals throughout kidney tissues. They are normally flushed out, but when they merge together and form larger stones that continue to grow, they can become excruciatingly painful and even deadly in some cases, Fouke said.

“Stone formation is part of a natural, healthy process within kidneys where these tiny mineral deposits are shuttled away and excreted from the body,” Fouke explained. “But then there is a tipping point when those same mineral deposits start to grow together too rapidly and are physically unable to leave the kidney.”

Image source: Leon Macapagal on Unsplash
An example of agate, which shows similar formation characteristics to kidney stones. Image source: Leon Macapagal on Unsplash

As the stone goes through the formation process, more microspherules merge, lose their rounded shape and transform into much larger, perfectly geometric crystals. Stones go through multiple cycles of partially dissolving—shedding up to 50% of their volume—and then growing again, creating a signature pattern of layered crystals much like those of agates, coral skeletons and hot-spring deposits seen around the world.

“Looking at a cross-section of a kidney stone, you would never guess that each of the layers was originally a bunch of little balls that lined up and coalesced. These are revolutionary new ways for us to understand how these minerals grow within the kidney and provide specific targets for stone growth prevention,” Fouke said.

The researchers listed a number of possible clinical interventions and treatment targets derived from this extra knowledge on kidney stone formation. They hope that these options can be tried out, from drug targets to changes in diet or supplements that could disrupt the cascade of kidney stone formation, Sivaguru said.

To aid in this testing, Fouke’s group developed the GeoBioCell, a microfluidic cartridge that mimics the intricate internal structures of the kidney. The team hopes the device can contribute to research as well as clinical diagnostic testing and the evaluation of potential therapies, particularly for the more than 70% of kidney stone patients with recurring stones.

“Ultimately, our vision is that every operating room would have a small geology lab attached. In that lab, you could do a very rapid diagnostic on a stone or stone fragment in a matter of minutes, and have informed and individualized treatment targets,” Fouke said.

Source: University of Illinois

Journal information: Mayandi Sivaguru et al, Human kidney stones: a natural record of universal biomineralization, Nature Reviews Urology (2021). DOI: 10.1038/s41585-021-00469-x

Cells in the Centres of Kidney Tumours are The Most Aggressive

Researchers have found that cells from different parts of kidney tumours behave differently, and cells within the centre of a tumour are the most aggressive and most likely to spread around the body.

Metastasis, where cancer cells from tumours spread to other parts of the body, is the main cause of death in cancer patients. 

In this multidisciplinary study published in Nature Ecology and Evolution, scientists analysed 756 cancer biopsy samples from different regions within tumours from the TRACERx Renal study.

They discovered that, in contrast to the cells at the outside of tumours, the cells in the centres of tumours have more unstable genomes, and a higher potential for metastasis. The cells on the outside had lower growth rates and had less genetic damage.

“Cancer cells in the central zone of the tumour face harsh environmental conditions, as there’s a lack of blood supply and oxygen. They have to adapt to survive, which makes them stronger and more aggressive. This also means they are more likely to successfully evolve into cells that can disseminate and take hold in distant organs,” explained Kevin Litchfield, paper author and group leader at the UCL Cancer Institute.

These findings show that it is important to focus on the tumour centre for a better understanding of how cancer spreads, and identify the most dangerous cells. Also, in order to wipe out the most aggressive tumour cells, treatment development must target the unique environmental conditions found within the tumour core.

The scientists also examined how genetically different populations of cancer cells grow within a tumour. With a unique mapping tall that reconstructed the growth of tumour cells, they discovered that, while tumours tend to follow a pattern where populations of cells grow in the local area, in two cases, cells took hold in a new region of the tumour by seemingly ‘jumping’ over other populations of tumour cells.

For their next steps, the researchers aim to reconstruct 3D tumour maps, providing even better visualisation of the tumours’ internal structure.

Samra Turajlic, head of the Crick’s Cancer Dynamics Laboratory, Consultant Medical Oncologist at the Royal Marsden NHS Foundation Trust and the Chief Investigator of TRACERx Renal, said: “Cancer spread is one of the biggest barriers to improving survival rates. In the context of the TRACERx Renal study we previously resolved the genetic make up of different tumour areas, but until now, there has been no understanding of how these differences relate spatially. The most critical question is the part of the tumour from which cancer cells break away and migrate making cancer incurable.

“Using this unique clinical cohort and a multidisciplinary approach, including mathematical modeling, we identified with precision the place in the tumour where genetic chaos emerges to give rise to metastases. Our observations shed light on the sort of environmental conditions that would foster emergence of aggressive behaviour. These findings are a critical foundation for considering how we target or even prevent distinct populations of cells that pose the biggest threat.”

Source: Francis Crick Institute

Cutting Edge Bio-printing Fabricates Tiny Kidneys

Researchers from the Murdoch Children’s Research Institute (MCRI) and biotech company Organovo have successfully bio-printed miniature human kidneys with unparalleled speed and quality to be used for toxicity screening of medications known to cause kidney damage. 

A world leader in modeling the kidney, Professor Melissa Little of the MRCI said, “Drug-induced injury to the kidney is a major side effect and difficult to predict using animal studies. Bioprinting human kidneys are a practical approach to testing for toxicity before use.”

The new study involved testing the toxicity of aminoglycosides, a class of antibiotics that commonly damage the kidney. The study revealed deaths of certain types of kidney cells when exposed to aminoglycosides.

Organovo first began bio-printing kidneys in 2015, but their new processes are much faster, allowing 200 mini-kidneys to be produced in 10 minutes. The improvement in speed and quality has opened the doorway for bioprinting entire organs for transplant. “3-D bioprinting can generate larger amounts of kidney tissue but with precise manipulation of biophysical properties, including cell number and conformation, improving the outcome.”

Professor Little said that prior to this study, the possibility of using such technology for transplantation was too complicated to consider. “The pathway to renal replacement therapy using stem cell-derived kidney tissue will need a massive increase in the number of nephron structures present in the tissue to be transplanted,” she said.

“By using extrusion bioprinting, we improved the final nephron count, which will ultimately determine whether we can transplant these tissues into people.”

Source: Medical Xpress