Tag: kidney disease

Categories : Diseases, Syndromes and ConditionsTags :

Kidney Damage in Lupus Comes from an Unexpected Source

On By ModernMedia
When the NKp46 receptor of the ILCs is blocked (right), the lupus nephritis recedes. Blue: cell nuclei.
Credit: Charité | Frauke Schreiber

A Berlin-led research team has uncovered critical regulators of severe kidney damage in patients with the autoimmune disorder lupus. A small, specialised population of immune cells – called innate lymphoid cells (ILCs) – trigger an avalanche of effects that cause harmful kidney inflammation, also known as lupus nephritis.

The research, published this week in Nature, upends conventional wisdom that autoantibodies are primarily responsible for lupus nephritis.

“While autoantibodies are required for tissue damage, they are by themselves not sufficient. Our work reveals that ILCs are required to amplify the organ damage,” says Dr Masatoshi Kanda, a senior paper author who was a Humboldt Fellow at Max Delbrück Center and is now at the Department of Rheumatology and Clinical Immunology, Sapporo Medical University in Japan.

Lupus, or systemic lupus erythematosus, is most often diagnosed between the ages of 15 and 45. Symptoms can range from mild to severe. But what causes kidney damage in some patients – some to the point of requiring dialysis – has been unclear.

“The role of ILCs in lupus or lupus nephritis was entirely unknown,” says Professor Antigoni Triantafyllopoulou, a senior paper author at the German Rheumatology Research Center (DRFZ), an institute of the Leibniz Association, and at the Department of Rheumatology and Clinical Immunology at Charité – Universitätsmedizin Berlin. “We have now identified most of the circuit controlled by ILCs by looking at the whole kidney at single-cell resolution.”

Unusual immune cells

ILCs are a small group of immune cells that – unlike most other immune cells that circulate throughout the body – live in a specific tissue or organ.

“They are in the tissue all the time, from the time of embryonic development, which makes them very different from other immune cells,” says Professor Andreas Diefenbach, a senior paper author and director of the Institute of Microbiology, Infectious Diseases and Immunology at Charité – Universitätsmedizin Berlin.

Diefenbach’s lab was among those that discovered ILCs in the mid-2000s. Most of his research is focused on ILCs in the gut and how they modify tissue function. In this study, Triantafyllopoulou and Kanda teamed up with his group and Dr Mir-Farzin Mashreghi at the DRFZ to find out whether ILCs were present in the kidney and what role they might play in lupus nephritis.

The whole single-cell picture

To unravel this mystery, the team turned to single-cell RNA sequencing, which identifies genes that are active, or “switched on,” in individual cells and helps researchers understand the cell’s identity and function.

Kanda, a rheumatologist who was studying bioinformatics in Professor Norbert Hübner’s lab at the Max Delbrück Center at the time, developed a specialized protocol for single-cell RNA sequencing of mouse and human kidneys. “Masatoshi’s protocol was very good at pulling out and preserving multiple types of kidney cells, which gave us a much more complete overview of how lupus affects the whole kidney,” explains Triantafyllopoulou. The team sequenced nearly 100 000 individual kidney and immune cells of various types and functions.

The key receptor

Through experiments in mice, the team learned that a subgroup of ILCs with a receptor called NKp46 must be present and activated to cause lupus nephritis. When NKp46 is activated, this subgroup of cells ramped up production of a protein called GM-CSF, which stimulates invading macrophages to multiply. In the kidney, a flood of incoming macrophages caused severe tissue damage and fibrosis.

“These ILCs are really amplifiers in this system,” Diefenbach says. “They are small in population, but they seem to fertilise the whole process.”

When the team blocked NKp46 with antibodies or the receptor was genetically removed, kidney tissue damage was minimal. They also blocked GM-CSF with similar anti-inflammatory effects.

“Critically, autoantibody levels did not change when NKp46 was inhibited, but kidney tissue damage was reduced, which shows autoantibodies are not directly responsible for kidney inflammation,” Triantafyllopoulou explains.

The team also compared the results to sequencing data from tissue taken from human patients with lupus and found ILCs present, though more work is required to fully understand how to target ILCs in human kidneys. Nevertheless, the insights gained through these detailed studies point to new antibody therapies for patients with severe forms of lupus. The hope is to prevent the need for kidney dialysis in these patients.

Source: Max Delbrück Center for Molecular Medicine in the Helmholtz Association

Categories : UrogenitalTags :

Cutting Down on Salt Levels Stimulates Kidney Regeneration

On By ModernMedia
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

Categories : Metabolic DisordersTags :

30-year Diabetes Study Determines HbA1c Threshold for Complications

On By ModernMedia
Diabetes - person measures blood glucose
Photo by Photomix Company from Pexels

The levels of long-term blood sugar, HbA1c, can be used to accurately determine the risk of a person with type 1 diabetes developing eye- and kidney complications. A Swedish study, published in Diabetes Care, followed individuals after the onset type 1 diabetes for 30 years and showed that this level should under 53mmol/mol (7%).

People with diabetes may experience damage to the small blood vessels in various organs. The reasons for this are unclear, but it has been known since the 1990s that good control of blood sugar levels reduces the risk of complications. It has, however, not been clear what level of long-term sugar, HbA1c, people with type 1 diabetes should have in order to avoid serious damage to blood vessels in the eyes and kidneys.

“Our study determines accurately the levels of long-term sugar that can avoid complications. This knowledge can increase a person’s motivation to keep their blood sugar level under control,” said study leader Hans Arnqvist, professor emeritus at Linköping University.

Researchers in the current study, known as VISS (Vascular Diabetic Complications in Southeast Sweden), have followed all children and adults under 35 who developed type 1 diabetes during the period 1983–1987 in Southeast Sweden. All 447 newly diagnosed persons in the region during this period were included in the study. The researchers have followed the patients’ HbA1c values, which reflect their average blood sugar levels during a longer period. They have also monitored the development of eye- and kidney damage in these patients for a period of between 32 and 36 years after diagnosis.

In type 1 diabetes, the small blood vessels in the eye are particularly susceptible to damage. Nearly all patients experience small haemorrhages in the eye that do not affect their vision. In some cases, proliferative retinopathy develops, forming new blood vessels which can lead to blindness. The macula of the retina can also be damaged, leading to blurred vision.

While the kidneys are not as sensitive to high blood sugar levels as the eye, the important small blood vessels here can also be damaged, leading to albuminuria. The damage to the kidneys eventually leads to impaired kidney function and, in serious cases, kidney failure.

In healthy individuals, the blood sugar level is very closely controlled, with a maximum HbA1c level of 42mmol/mol (6.0%).

“The results of our study show that people with type 1 diabetes for at least 32 years should keep their mean long-term sugar level below 53mmol/mol (7.0%), if they are to completely avoid serious damage. The risk of eye- and kidney complications increases as the level increases. Our conclusions relate to avoiding complications arising from blood vessel damage. But if a patient has problems with low blood sugar, hypoglycaemia, it’s not possible to control the blood sugar level so strictly,” said Prof Arnqvist.

The target level for HbA1c that is suggested by the results of the VISS study agrees with the individual targets recommended by the American Diabetes Association. In Sweden, target levels are given for groups, rather than individuals.

The previous follow-up by the research group was conducted 20 years after the onset of disease. Now after 30 years, the results show that damage has arisen at lower blood sugar levels than was the case after 20 years.

More patients have experienced damage, despite having blood sugar levels that are not higher than those they have previously had. In other words, it seems that the threshold for developing complications falls gradually with time. This means that the study does not allow any conclusions for the recommended blood sugar levels of people with type 1 diabetes longer than 30 years after diagnosis.

Source: Linköping University

Categories : Diseases, Syndromes and ConditionsTags :

Methylprednisolone Halves Kidney Failure Risk in IgA Nephropathy

On By ModernMedia
Anatomic model of a kidney
Photo by Robina Weermeijer on Unsplash

A large study has found that treatment with methylprednisolone – a cheap, widely used corticosteroid – halves the risk of losing kidney function and kidney failure in IgA nephropathy. The study, published in the journal JAMA, also found that this can be effectively achieved with fewer side effects if a reduced dose is used.

Researchers say the results of the multi-country study will provide a clear treatment option with definite benefits outweighing well defined and mostly manageable risks. 

IgA nephropathy is a common form of glomerulonephritis caused by the deposition of IgA immunoglobulins in the glomerular basement membrane. Immune-mediated damage to the basement membrane results in haematuria and renal insufficiency progressing to kidney failure in some.

Joint Principal Investigator Professor Vlado Perkovic said that around 10–30% of people with the condition go on to develop kidney failure that requires dialysis or kidney transplantation to prevent death.

“There are few proven treatment options so many treatments including corticosteroids have been used in some patients for decades, despite uncertainty about their effectiveness, as well as the ideal dose. This has led to significant regional variability and clinical uncertainty about this treatment,” he said.

The Therapeutic Evaluation of Steroids in IgA Nephropathy Global (TESTING) study is a double-blinded, randomised, controlled trial that assessed the effects of oral methylprednisolone on major kidney outcomes, kidney failure and safety in patients with IgA nephropathy.

503 patients diagnosed with IgA nephropathy were recruited from centres across Australia, Canada, China (including Hong Kong), India and Malaysia between May 2012 and November 2019. Patients were randomised to receive methylprednisolone or a placebo at:

  1. full dose of 0.6-0.8mg/kg per day of methylprednisolone or placebo for 2 months reducing by 8mg per day each month (262 participants between May 2012 and November 2015), or
  2. reduced dose of 0.4mg/kg per day of methylprednisolone or placebo, also for two months, reducing to 4mg per day each month (241 participants between March 2017 and November 2019), 

for a total treatment period of 6–9 months.

“We found that that treatment with methylprednisolone for six to nine months significantly reduced the risk of losing substantial kidney function, kidney failure requiring dialysis or transplantation, or death from kidney disease compared to placebo,” said Professor Perkovic.

“However, there was an increase in serious adverse events in those who received methylprednisolone, mainly seen in the full dose regimen with fewer in the reduced dose treatment group.”

Joint Principal Investigator Professor Hong Zhang said that with IgA nephropathy being an immune-mediated condition, the benefits seen were likely due to the immune suppressing action of the steroid treatment.

“A well-known side effect of steroid treatment is an increased risk of infections, but we found that this could be mitigated to a degree by using the lower dose and giving the patients antibiotics to prevent infections,” she said. 

“This is the strongest evidence yet for the benefit of any treatment for the prevention of kidney failure in people with IgA nephropathy.

“The results provide a treatment option for clinicians and patients, especially at the lower dose, given the net benefits versus the risk of side effects,” she added.

Associate Professor Muh Geot Wong said that given that the condition develops slowly, and that there was some indication that the effects of treatment appeared to diminish over time, the research team have now extended the study.

“We are now following a significant number of patients from our original study for another five years so we will have a total of around ten years follow up,” he said.

“By then, we hope to have the most comprehensive set of evidence ever collected to help guide the treatment of people with this type of kidney disease.”

Source: EurekAlert!

Categories : TransplantsTags :

Lifestyle Changes Key for Older Kidney Transplant Recipients

On By ModernMedia
Photo by Robina Weermeijer on Unsplash

Researchers discovered that deaths among kidney transplant recipients due to factors other than organ rejection is the leading cause for transplanted kidney loss. Their findings, published in Transplantation Direct, revealed that only one in four transplanted kidney losses were caused by organ rejection.

“Immunosuppression medication to prevent rejection is often the focus when caring for patients post transplant. But this study highlights the increased risk of death from cancer and infection for transplant patients, especially those who are older and have diabetes,” said Andrew Bentall, MB, ChB, MD, the study’s co-first author.

The study involved 5752 patients who underwent a kidney transplant between 2006 and 2018. Of those, 691 died with a functioning kidney. Researchers found that 20% of these patients died from cancer; 19.7%, infection; and 12.6%, cardiac disease.

Another 553 patients lost their transplant due to the failure of a transplanted kidney. Of these patients, 38.7% of the patients’ kidneys failed due to rejection; 18.6%, glomerular diseases; and 13.9%, tubular injury.

Two types of recipients were found to be most vulnerable after transplant. The first are younger, nondiabetic patients who develop kidney failure due to organ rejection. The second group includes older, often diabetic patients who are at risk of death due to causes not associated with organ rejection, including cancer, infections and heart disease.

Care providers need to treat these two populations differently to minimise risks, according to Dr Bentall. For younger patients, that includes focusing on immunosuppression medication to prevent rejection. For older, often diabetic patients, it is critical to address chronic health issues, such as obesity, high blood pressure and diabetes. Focusing on these lifestyle changes is critical for improving long-term outcomes for kidney transplant recipients.

“It is important for these older patients that care providers emphasise the need for ongoing lifestyle changes that address obesity, high blood pressure and diabetes. Those include losing weight, exercising and new strategies for managing diabetes,” he said. “Making those changes could potentially impact the patient’s life and kidney outcomes more than immunosuppression therapies.”

Source: Mayo Clinic

Categories : Metabolic DisordersTags :

Enzyme’s Role in Kidney Disease Could Unlock New Therapies

On By ModernMedia
Anatomic model of a kidney. Photo by Robina Weermeijer on Unsplash

University of South Australia (UniSA) researchers have discovered that a certain enzyme may help to curb chronic kidney disease, which affects nearly 10% of the world’s population.

This enzyme, known as NEDD4-2, is critical for kidney health, said UniSA Centre for Cancer Biology scientist Dr Jantina Manning.

Chronic kidney disease (CKD) is defined as the presence of kidney damage or reduced filtration rate, persisting for three months or more. It is a state of progressive loss of kidney function ultimately resulting in the need for dialysis or transplantation. 

Dr Manning and her colleagues, including Professor Sharad Kumar, Chair of the UniSA Centre for Cancer Biology, have shown in an animal study that there is a link between a high salt diet, low levels of NEDD4-2 and advanced kidney disease.

While a high salt diet can worsen some forms of kidney disease, it was not previously known that NEDD4-2 is involved in promoting this salt-induced kidney damage.

“We now know that both a high sodium diet and low NEDD4-2 levels promote renal disease progression, even in the absence of high blood pressure, which normally goes hand in hand with increased sodium,” says Dr. Manning.

The NEDD4-2 enzyme regulates the pathway required for sodium reabsorption in the kidneys to ensure correct levels of salt are maintained. If this enzyme is reduced or inhibited, increased salt absorption can result in kidney damage.

Even if people are on a low salt diet, they can get kidney damage if their levels of NEDD4-2 are low due to genetic causes.

Prof Kumar said the goal is to eventually to develop a drug that can raise NEDD4-2 levels in people who have CKD.

“We are now testing different strategies to make sure this protein is maintained at a normal level all the time for overall kidney health,” Prof Kumar said. “In diabetic nephropathy—a common cause of kidney disease—levels of NEDD4-2 are severely reduced. This is the case even when salt is not a factor.”

The study also revealed one other unexpected finding: that kidney disease induced by high salt diets is not always the result of high blood pressure.

“In a lot of cases, kidney disease is exacerbated by hypertension, so we wanted to investigate that link in our study. In fact, we found the complete opposite—that a high salt diet caused excessive water loss and low blood pressure. This is significant because it means that kidney disease can also happen in people who don’t have high blood pressure,” Dr Manning said.

A Lancet paper from 2020 estimated that about 700 million people—about 10% of the world’s population—suffer from chronic kidney disease, and has seen a 29% increase in the past 30 years. This massive surge in CKD is mainly due to the global obesity epidemic. Overweight and obesity lead to diabetes, one of the leading causes of CKD, along with high blood pressure. Between 1980 and 2014 there was a 300% increase in diabetes, according to World Health Organization statistics. This makes it one of the top 10 causes of death worldwide.

“Obesity and lifestyle are two main factors driving chronic kidney disease but there are other things at play as well,” said Dr Manning. “Acute kidney injuries, drugs taken for other conditions, high blood pressure and a genetic predisposition can also cause it.”

Source: Medical Xpress

Journal information: Jantina A. Manning et al. The ubiquitin ligase NEDD4-2/NEDD4L regulates both sodium homeostasis and fibrotic signaling to prevent end-stage renal disease, Cell Death & Disease (2021). DOI: 10.1038/s41419-021-03688-7

Categories : AgeingTags :

Telomere Lengthening May Treat Renal Fibrosis

On By ModernMedia

A new study has shown that it may be possible to treat renal fibrosis, an age-related disease, by lengthening telomeres.

Previous research had shown it was that lengthening telomeres successfully treated pulmonary fibrosis and infarctions in mice.

Renal fibrosis is the leading cause of kidney failure, treatable only with dialysis. Moderate renal fibrosis is present in some 11% of people over 65, and is a predictor of the severity of renal failure. Telomeres are proteins at the end of chromosomes that maintain genetic integrity during cellular division. They shorten over time, eventually to the point where they are too short for cells to divide, becoming senescent. Telomere lengthening, eg through hyperbaric oxygen therapy, has been suggested as a way to reverse many age-related declines.

While short telomeres were by themselves not enough to cause renal fibrosis, the researchers found that mice with short telomeres developed it when they were exposed to small amounts of toxin, mimicking the environmental toxins people are exposed to over their lives. Mice that also lacked a certain protein needed for telomere function, Trf1, developed renal fibrosis, showing that telomeres are indeed involved in proper kidney function.

Since genes involved in epithelial-to-mesenchymal transition are overexpressed in patients with kidney failure, the researchers looked for this in mice with short telomeres. And “we found that short telomeres induce changes in the expression of genes involved in EMT.”

As a final demonstration of the importance of telomeres in kidney fibrosis, the authors cultured kidney cells in which they expressed the gene for the telomerase enzyme, which elongates telomeres. In these cells with restored telomeres, the epithelial-to-mesenchymal transition program returned to normal, and the cells regained their healthy, pre-fibrosis appearance.

“As short telomeres accumulate with ageing in the organism, it is tempting to speculate that pathological EMT programmes associated with ageing, such as cancer and different types of tissue fibrosis, may be originated at least in part by the presence of short telomeres,” the authors conclude.

Source: News-Medical.Net

Categories : General Interest TransplantsTags :

Teen Embraces Chance to ‘Live Well’ With Kidney Disease

On By ModernMedia

Thanks to a young organ donor, Bronwen Fredericks has a new kidney that she and her mother Bridget are deeply thankful for.
The 15-year-old was one of two patients at Red Cross War Memorial Children’s Hospital who received their new kidneys last month. With a new chance at their childhoods, they have a chance to embrace the spirit of “Living Well with Kidney Disease”, the 2021 theme for World Kidney Day tomorrow. 

Bronwen said: “I’m really grateful to my donor and excited for my new life. I’m really looking forward to being able to dance again.”

According to her mother, a blood pressure test had alerted them to the problem.

“I would like to encourage everyone, especially parents, to do a regular general check-up with their children at a clinic or GP. A simple blood pressure test could show us that there was a serious problem and we were able to take action that saved my daughter,” she said.

“Irrespective of age, being diagnosed with kidney disease can pose a huge challenge for the patient and their family. It remains draining on those involved, be it emotional, financial, physical or a combination of these – but imagine the impact on a young child,” the Red Cross War Memorial Children’s Hospital said in a statement on Wednesday.  The hospital conducts around 10 to 12 kidney transplants a year.

The Red Cross Hospital said it is aiming to reduce stress factors through education, empowerment and by building a partnership with patients and their families.

“The diagnosis and management, particularly in the advanced stages of kidney disease, impacts severely upon the lives of our young patients by reducing their ability to participate in everyday activities like attending school, participating in extra-curricular activities and socialising, whilst the whole family’s ability to travel and parents ability to work is also affected,” said Dr Deveshni Reddy, ‎paediatric nephrologist at the hospital.

Current management includes dialysis to take the strain off of kidneys, and in more extreme cases, donor transplants.
Professor Mignon McCulloch, the hospital’s head of paediatric nephrology and solid organ transplantation, said: “While we always try our best to treat chronic kidney disease and other kidney disorders through medical intervention, sometimes a surgical intervention, or dialysis and resultant kidney transplant, is the only option.

“The Red Cross War Memorial Children’s Hospital conducts around 10-12 kidney transplants per year, making it one of the most active paediatric transplant services in South Africa, which is only possible due to the close collaboration with the multi-disciplinary role-players from Groote Schuur Hospital and Red Cross.”

Source: IOL News