Tag: kidney disease

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T Cells, not B Cells, Are the Culprit of Kidney Damage in Lupus

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

Kidney damage is a serious complication affecting individuals with lupus, an autoimmune disease where immune B cells malfunction and produce antibodies that attack the body’s own cells, tissues, and organs.

B cells, when they make autoantibodies, have been blamed for the illness, prompting the development of several FDA-approved medications that target them. However, lupus nephritis is inevitable in more than half of patients with lupus and B cell depletion is often ineffective therapeutically.

Now, in a study published April 20 in Immunity, Yale scientists have found that the kidney damage culprit is actually a specific T cell – the CD8 T cell.

“People have been, to some extent, ignoring CD8 T cells because of their focus on B cells and the production of autoantibodies,” says lead author Jafar Al Souz, an MD-PhD student in the lab of Joseph Craft, MD, Paul B. Beeson Professor of Medicine (Rheumatology) and professor of immunobiology at Yale School of Medicine. “But we need to think more deeply about why current therapies fail in some patients.”

T cells drive kidney damage in lupus

Previous work in the Craft Lab has shown that blocking T cells’ activity in mouse models of lupus could spare the animals from kidney injuries. That result prompted Al Souz to look closer at this subset of the immune cells.

“What I saw was that these T cells in the sick kidney had a killer phenotype; they were very activated with the potential to cause kidney damage,” he says. Nearly all of these cells were CD8 T cells – also known as cytotoxic T lymphocytes – which are generally tasked with identifying and killing pathogens. That they are aggravated in the kidneys of mouse models of lupus shows that the cells see the kidney as a foreign invader that needs to be destroyed, Al Souz says.

He also found that when the CD8 T cells were depleted, the kidney function was maintained.

Using single-cell multiomics, a high-resolution technique to simultaneously measure the various molecular characteristics of a cell, analysing simultaneous RNA production, gene regulation, and T cell identity, the researchers pinned down the origin of the CD8 T cells to the renal lymph nodes.

“What gave us the biggest clue was that the CD8 T cells in the kidney had very strong overlap with the cells in renal lymph nodes,” Al Souz says. T cells normally undergo rapid proliferation, where one T cell multiplies and generates identical offspring that target the same antigen proteins. “We know that once a T cell is activated in renal lymph nodes, it will leave, go to the circulation and then enter kidneys. So, the fact that we saw identical T cells in renal lymph nodes, circulation, kidneys tells us that the lymph nodes were actually the site of origin.”

What is unique about these CD8 T cells is their capacity to self-renew like stem cells, a discovery that sheds light on a long-held mystery of why it’s hard to stop treatment in patients with lupus. “Constant therapy is needed because these CD8 T cells in the lymph nodes continually supply the kidney with T cells that can damage the organ,” says Craft, who is also the director of the Colton Center for Autoimmunity at Yale.

Targeting T cells for treatment

To draw parallels in humans, the researchers used single-cell RNA sequencing to analyse biopsies from 156 patients with lupus nephritis and 30 healthy individuals. Just as they found in mice, the researchers identified kidney-infiltrating CD8 T cells with the stem-like property in the patients. Unlike in healthy individuals, there was a significantly higher proportion of CD8 T cells that were always active and ready to cause damage in the patients’ kidneys.

“Generally, CD8 T cells are good at pumping the brakes and limiting damage potential upon chronic activation. But we found that in lupus, even when molecules that should stop these T cells from damaging healthy cells are present, it didn’t make the T cells lose function and the capacity for kidney injury,” Al Souz says.

The tendency for T cells to attack a person’s own cells is a typical autoimmune response. For example, in type 1 diabetes – an organ-specific autoimmune disease – T cells mistakenly recognise pancreatic beta cells as foreign and destroy them, thereby stopping insulin production. In cancer and chronic diseases, the ability for T cells to replenish could be beneficial, leading to the elimination of pathogens and tumours. However, the role of T cells in systemic autoimmune diseases like lupus has not been fully described.

“Our results show that there’s more to it than what we understand,” Al Souz says.

By identifying the real culprit, the researchers hope that future treatment of lupus nephritis will be more targeted. “The first step is knowing that it’s abnormal in the first place,” Craft says. “Now, we can think about strategies to lower the number of active CD8 T cells back to the normal range.”

By Kristel Tjandra

Source: Yale School of Medicine

Categories : Genetics UrogenitalTags :

Kidney Disease is Growing in Africa: Big New Study Casts Light on Genetic Risk Factors

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

Segun Fatumo, Queen Mary University of London

Every minute your kidneys are hard at work, filtering around 200 litres of blood, removing waste, balancing salts and fluids, and regulating blood pressure. This happens without any conscious effort on your part.

But when your kidneys begin to fail, the consequences are devastating, including fatigue, fluid buildup and heart complications. Some people eventually need dialysis or a transplant to stay alive.

Kidney disease is one of the fastest-growing causes of death across the world. Around 850 million people are living with some form of it, more than the combined number of people affected by diabetes and cancer. Chronic kidney disease – when your kidneys slowly lose the ability to do their job – causes approximately 1.5 million deaths each year globally and that toll is rising.

But kidney disease develops silently, with few symptoms until it is already severe.

And the burden is not shared equally. People of African ancestry are four times more likely to develop the most severe form of kidney failure than people of European ancestry. In sub-Saharan Africa, rates of high blood pressure and type 2 diabetes are rising too. Both are leading drivers of kidney damage. Around 30% of adults in sub-Saharan Africa have high blood pressure, and 25 million (one in 20 adults) have diabetes) – mostly undiagnosed and untreated.

Sub-Saharan Africa has lower numbers of kidney specialists, dialysis facilities and transplant services per capita than the rest of the world. Africa as a whole has fewer than one nephrologist per million people. In some African countries there are no kidney specialists at all. The global median is around 10 per million. In high-income countries the figure reaches 23 per million. For most Africans who reach kidney failure, there is simply no treatment available.

Identifying who is at risk before their kidneys fail is therefore vital.

Our recently published research fills a big gap here. We are members of the KidneyGenAfrica consortium, a pan-African partnership that aims to deliver research and training excellence in genomics of kidney disease.

We found new genetic variants that point to kidney disease risk in African populations. And we uncovered differences between the genetic risks faced by people living in Africa, on one hand, and people of African descent living in the North America and Europe, on the other.

This shows how important it is for medicine to be based on relevant research.

Understanding kidney disease

Kidney disease does not appear suddenly. It often develops gradually, shaped by a combination of factors. Some people carry genetic variants, small differences in their DNA, that make their kidneys more susceptible to damage.

Others face environmental risks such as high-salt diets, uncontrolled high blood pressure or diabetes infections. The use of herbal medicines, contaminated water and environmental toxins are risks too.

In most cases, it is the combinations of these factors that determine who gets sick and how quickly. But until recently, African populations had barely featured in the scientific conversation about this. Africa, home to the most genetically diverse human populations on Earth, have been represented in only a small fraction of the world’s genomic research.

That is beginning to change.

Large genetic study of Africans

We analysed genomic data from about 26,000 individuals across eastern, western and southern Africa, and around 81,000 individuals of African ancestry living elsewhere. It’s the largest genetic study of kidney function in continental Africans ever conducted.

Our study sheds new light on the genetics of chronic kidney disease across diverse African populations. It will also support future work aimed at improving prevention, diagnosis and treatment of kidney disease among these populations and worldwide.

The team used a method called a genome-wide association study, which scans the entire human genetic code to find variants linked to a particular trait or disease. Here, the trait of interest was estimated glomerular filtration rate, a standard blood test result that measures how efficiently the kidneys are filtering waste. A lower score signals poorer kidney function and higher risk of disease.

Analysing continental African populations alone, the study identified four relevant locations on genes, including two that hadn’t been reported before.

Adding African-ancestry populations across the diaspora, the number rose to 19 locations, three of them new. Four of these genetic locations were pinpointed with high precision. This means the team was able to identify the specific genetic variant most likely driving the effect, rather than simply flagging a region of the genome where something relevant was happening.

Each newly discovered location is now a potential target for future drugs or diagnostic tools.

The study also examined polygenic scores, which are tools that estimate a person’s overall risk of developing a disease. A key finding here was that scores built using data from genetically similar African populations performed better than scores derived from larger but genetically distant datasets.

This matters enormously for medicine in Africa: the science only works if the reference data matches the population it is meant to serve.

A gene that behaves differently on either side of the Atlantic

An important finding from the study concerns a gene called APOL1. Two variants of the APOL1 gene, known as G1 and G2, increase the risk of several serious forms of kidney disease in African Americans. It was widely assumed that the same risk would apply equally to people living on the African continent.

However, the data suggests otherwise. In continental Africa, these high-risk APOL1 variants occur at lower frequencies (and vary across regions of Africa). Their association with reduced kidney function is markedly weaker than in the African diaspora.

The same gene appears to behave differently depending on where a person lives and what population they descend from.

The finding matters for drug development. Clinical trials for kidney disease treatments must include people living in Africa and not just people of African descent living elsewhere.

What must happen now

Several things must follow from this research if it is to benefit people’s health:

  • African health systems must invest in early kidney disease detection. Simple, affordable blood and urine tests can identify kidney damage when lifestyle changes and medication can still make a difference. Genetic risk tools can help identify who needs screening most urgently.
  • Pharmaceutical companies must include continental African populations in their clinical trials.
  • The global research community must continue investing in African genomic infrastructure – research cohorts and large groups of consenting participants whose genetic and health data are collected and stored for analysis.

This research is evidence that African scientists, working with African communities, can generate knowledge that shifts the global picture. The world’s understanding of one of its most urgent health challenges will be sharper for it.

Segun Fatumo, Professor and Chair of Genomic Diversity, Queen Mary University of London

This article is republished from The Conversation under a Creative Commons license. Read the original article.

Categories : Diet and NutritionTags :

Could a Dietary Supplement Radically Alter Disease Trajectory?

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Salk Institute scientists uncover key role of kidneys in clearing inflammation from body, and show amino acid supplementation boosts this effect in mice

The latest findings from Salk scientist Janelle Ayres’s lab show that a deceptively simple dietary supplement could alter disease trajectory and make the difference between life and death for patients. Credit: Salk Institute

Disease trajectory is a unique journey from injury or infection, mediated by variable symptoms toward either recovery or death. It varies from person to person based on history, sex, age, and many other factors. Salk scientist Janelle Ayres, PhD, has spent decades unravelling the ways the body directs this journey – why some get sick and die while others go unscathed, and what sorts of methods could be used to shift trajectories of disease and death to ones of health and survival.

For many, inflammation is the ultimate cause of a downward trajectory toward death. Inflammation is a double-edged sword: a powerful weapon against intruders but an equally powerful generator of bodily damage if not properly regulated.

Since infections are some of the strongest drivers of inflammation-induced damage, the Salk team used a mouse model of infection to find that dietary supplementation of the amino acid methionine protected infected mice against inflammation-related wasting, blood-brain barrier dysfunction, and death. Methionine was accomplishing all this by boosting kidney filtration, revealing an underappreciated role the kidneys play in a successful journey from infection back to health.

The findings, published in Cell Metabolism on January 22, 2026, reveal the big impact that small dietary tweaks can have on disease trajectory, lighting the way to therapeutic strategies that steer patients from death to recovery. Methionine supplementation may be a useful tool for a variety of inflammatory conditions, as well as for patients with kidney disease or failure, or those undergoing dialysis.

“Our study indicates that small biological differences, including dietary factors, can have large effects on disease outcomes,” says senior author Ayres, professor and holder of the Salk Institute Legacy Chair at Salk, as well as a Hughes Medical Institute Investigator. “Our discovery of a kidney-driven mechanism that limits inflammation, together with the protective effects of methionine supplementation in mice, points toward the potential of nutrition as a mechanistically informed medical intervention that can direct and optimise the paths people take in response to insults that cause disease.”

Shifting the focus on inflammation

Research on the balance between too much and too little inflammation has been tricky, and mainly focused on how inflammatory responses are switched on and off. Ayres’s team is shifting the focus from these binary on/off mechanisms to studying how the body toggles the immune response higher or lower through the release and accumulation of pro-inflammatory cytokines.

“Pro-inflammatory cytokines are ultimately what leads to sickness and death in a lot of cases,” says first author Katia Troha, PhD, a postdoctoral researcher in Ayres’s lab. “The immune system has to balance inflammation to attack the invader without harming healthy cells in the body. Our job is to find the mechanisms it uses to do that, so that we can target them to improve patient outcomes.”

How can kidney function help reduce inflammation?

To understand how the body regulates its cytokine levels, the researchers used a mouse model of systemic inflammation induced by the pathogen Yersinia pseudotuberculosis. The first thing they noticed was that the infected mice were not eating as much – a sign of likely metabolic changes. To look at the nutritional status, the researchers looked at the levels of circulating amino acids, which are protein building blocks that support cellular health throughout the body.

Infected mice showed depressed methionine levels – an essential amino acid found in our everyday diets. Curious, Troha decided to feed a new batch of mice with methionine-supplemented chow, and surprisingly, these mice were protected against the infection.

Further experiments showed that methionine reduced circulating cytokine levels by partnering with a surprising ally: the kidneys. Methionine increased the kidneys’ filtration capacity, improving blood flow and helping the body excrete pro-inflammatory cytokines through the urine. Importantly, this methionine-kidney effect cleared excess cytokines without hindering other key aspects of the immune response.

Curious whether methionine’s effect was present in other conditions, the researchers also looked at sepsis and kidney injury models. They found that methionine was also protective for these mice, supporting that methionine may be a useful tool in other inflammatory disease settings.

Can dietary changes boost kidney performance?

By supplementing their diets with methionine, Salk scientists were able to give infected mice entirely different disease trajectories. The amino acid boosted the animals’ kidney function and protected them against wasting, blood-brain barrier dysfunction, and death without hindering their bodies’ ability to fight and kill Yersinia pseudotuberculosis.

And the sepsis and kidney injury models show these effects extend to other infections and inflammatory conditions, too, making methionine a potentially useful tool for the treatment of infectious diseases, particularly in cases of kidney disease or failure, or for patients undergoing dialysis.

“Our findings add to a growing body of evidence that common dietary elements can be used as medicine,” says Ayres. “By studying these basic protective mechanisms, we reveal surprising new ways to shift individuals that are fated to develop disease and die onto trajectories of health and survival. It may one day be possible for something as simple as a supplement with dinner to make the difference between life and death for a patient.”

While the results are promising, the researchers note that efficacy in humans is yet to be tested. Follow-up studies will explore the mechanisms by which methionine acts, whether other amino acids have similar or complementary effects, and how this may all translate to humans.

Source: Salk Institute

Categories : Metabolic Disorders Surgeries & ProceduresTags :

Study Shows Greater Long-Term Benefits of Bariatric Surgery Compared to GLP-1 RAs

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Sleeve gastrectomy. Credit: Scientific Animations CC4.0

A large Cleveland Clinic study has found that people with obesity and type 2 diabetes who undergo weight-loss surgery live longer and face fewer serious health problems compared with those treated with GLP-1 receptor agonist medicines alone.

Patients who had weight-loss surgery (also known as bariatric or metabolic surgery) lost more weight, achieved better blood sugar control, and relied less on diabetes and heart medications over 10 years. The research is published in Nature Medicine.

“Even with today’s best medicines, metabolic surgery offers unique and lasting benefits for people with obesity and diabetes,” said Ali Aminian, MD, director of Cleveland Clinic’s Bariatric & Metabolic Institute and primary investigator of the study. “The benefits we observed went beyond weight loss. Surgery was linked to fewer heart problems, less kidney disease, and even lower rates of diabetes-related eye damage.”

GLP-1 (glucagon-like peptide-1) receptor agonists are a class of medications widely used to treat type 2 diabetes and obesity and to reduce health risks. Both metabolic surgery and GLP-1 medicines improve cardiovascular health and metabolism.

The M6 study (Macrovascular and Microvascular Morbidity and Mortality after Metabolic Surgery versus Medicines) followed 3932 adults with diabetes and obesity who received care at Cleveland Clinic for up to 10 years. Among them, 1657 underwent metabolic surgery (including gastric bypass or sleeve gastrectomy), while 2275 were treated with GLP-1 medicines (including liraglutide, dulaglutide, exenatide, semaglutide, and tirzepatide).

At the end of the study, patients who had metabolic surgery had a:

  • 32% lower risk of death
  • 35% lower risk of major heart problems (such as heart attack, heart failure, or stroke)
  • 47% lower risk of serious kidney disease
  • 54% lower risk of diabetes-related eye damage (retinopathy)

On average, people who had metabolic surgery lost 21.6% of their body weight over 10 years, compared with 6.8% weight loss in people who took GLP-1 medicines. Hemoglobin A1c, a marker of average blood sugar, improved more with surgery (-0.86%) than with GLP-1 medicines (-0.23%). Patients in the surgery group also required fewer prescriptions for diabetes, blood pressure, and cholesterol.

“Even in the era of these powerful new drugs to treat obesity and diabetes, metabolic surgery may provide additional benefits, including a survival advantage,” said Steven Nissen, MD, Chief Academic Officer of the Heart, Vascular & Thoracic Institute at Cleveland Clinic and senior author of the study.

“Our findings indicate that surgery should remain an important treatment option for obesity and diabetes,” said Dr Aminian. “These long-term benefits are harder to achieve with GLP-1 medicines alone, as many patients stop using the medications over time.”

According to the authors, the study has some limitations. It was observational rather than a randomized comparison of drugs and surgery, and it did not focus exclusively on the newest and most effective GLP-1 medicines. The researchers note that future studies should directly compare surgery with newer GLP-1 therapies, such as semaglutide and tirzepatide, to further guide treatment decisions.

Source: Cleveland Clinic

Categories : Diseases, Syndromes and ConditionsTags :

Kidney Damage in Lupus Comes from an Unexpected Source

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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

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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

Categories : Metabolic DisordersTags :

30-year Diabetes Study Determines HbA1c Threshold for Complications

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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

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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