The risk of kidney failure is greater for people with chronic kidney disease who also have atrial fibrillation, one of the most common forms of irregular heart rhythm in adults, according to a new study by researchers at UCSF and the Kaiser Permanente Northern California Division of Research.
The finding opens the way for further studies into the relationship between the two factors, which could lead to new treatment approaches that would improve outcomes for people with chronic kidney disease.
Many people who suffer from chronic kidney disease progressively lose their kidney function over time and eventually develop a condition called end-stage renal disease – the complete failure of the kidneys – placing them in need of lifelong dialysis or a kidney transplant.
Doctors have known that patients with chronic kidney disease or end-stage renal disease commonly have atrial fibrillation and as a result are more likely to have a stroke or to die. However, the long-term impact of atrial fibrillation on kidney function among patients with known chronic kidney disease has been unknown.
The new study involved 206,229 adults with chronic kidney disease who were drawn from members of Kaiser Permanente Northern California, a large integrated health care delivery system.. Over the course of about five years, approximately 16,400 patients developed atrial fibrillation, and those who did were 67 percent more likely to progress to end-stage renal disease compared with patients who had chronic kidney disease but did not develop atrial fibrillation.
‘These novel findings expand on previous knowledge by highlighting that atrial fibrillation is linked to a worse kidney prognosis in patients with underlying kidney dysfunction,’ said kidney specialist Nisha Bansal, MD, an assistant professor in the Division of Nephrology at UCSF.
‘There is a knowledge gap about the long-term impact of atrial fibrillation on the risk of adverse kidney-related outcomes in patients with chronic kidney disease,’ said senior author Alan S. Go, MD, director of the Comprehensive Clinical Research Unit at the Kaiser Permanente Division of Research. ‘This study addresses that gap and may have important implications for clinical management by providing better prognostic information and leading to future work determining how to improve outcomes in this high-risk group of patients.’
UCSF is one of the world’s leading centres for kidney disease treatment, research and education. Its Division of Nephrology is ranked among the best programs in the nation by U.S. News & World Report.
People who have chronic kidney disease fall into a spectrum in terms of how severe their disease is.
At one end are those who have very minor loss of kidney function. They may not have any symptoms at all, and only by applying a simple blood test can doctors properly diagnose their disease.
At the other end of the spectrum are the people who have progressed to end-stage renal disease, which is basically complete kidney failure. They require lifelong dialysis or a kidney transplant. Some people progress rapidly to end-stage renal disease while others may live for decades without ever progressing.
Doctors are interested in understanding the factors that place patients at greater risk for end-stage renal disease, Bansal said, because it may be possible to address those factors through medications or lifestyle changes like diet or exercise.
Bansal added, however, that while the two conditions are intertwined, scientists do not know exactly which specific genes, pathways and biological mechanisms connect irregular heartbeat to declines in kidney function. Neither do they yet know the extent to which treating atrial fibrillation will improve outcomes for people with chronic kidney disease. University of California – San Francisco

A certain enzyme, the CaM kinase II, keeps the cardiac muscle flexible. By transferring phosphate groups to the giant protein titin, it relaxes the muscle cells. This is reported by researchers led by Prof. Dr. Wolfgang Linke of the Institute of Physiology at the. In failing hearts, which don’t pump enough blood around the body, the scientists found an overly active CaM kinase II. ‘The phosphorylation of titin could be a new starting point for the treatment of heart failure’ Prof. Linke speculates.
Titin phosphorylation determines the mechanical tension of the muscle cell
Titin is the largest protein in the human body, and it acts like a spring which tenses or relaxes the muscle cell. The attachment of phosphate groups to specific titin sites – known as phosphorylation – relaxes the cell. It was already known that the calcium/calmodulin-dependent kinase II, CaM kinase II for short, phosphorylates several proteins in heart cells. Whether it also targets the spring protein titin, has now been examined by the researchers in Bochum.
For the study, the researchers used heart cells of ‘normal’ mice, mice that have no CaM kinase II, and mice that produce more CaM kinase II than usual. In cells without the enzyme, titin phosphorylation was reduced by more than 50 percent compared to the normal state. In cells with excess enzyme, however, titin phosphorylation was twice as strong as in normal cells. The CaM kinase II is therefore crucial for the attachment of phosphate groups to the giant protein titin. Linke’s team identified two regions within the flexible segment of the titin molecule which are phosphorylated by the enzyme, namely the PEVK and N2Bus region. These sites contain several amino acids of the type serine and threonine, which have changed little in the course of evolution.
In further analyses, the research team also showed that a lack or an excess of CaM kinase II affected the stiffness of the muscle cells. Cells without the enzyme were stiffer, cells with the enzyme more flexible. If they added CaM kinase II to cells that were not able to produce the enzyme themselves, these relaxed. In failing human hearts, the team found increased activity of CaM kinase II in comparison with healthy hearts, and thus excessive phosphorylation in the PEVK and N2Bus titin regions. ‘This seems to alter the mechanical properties of the human heart muscle’, says Wolfgang Linke. Ruhr University Bochum

Researchers at the Perelman School of Medicine at the University of Pennsylvania and the University of Massachusetts Amherst report utilising a novel statistical tool to analyse existing large databases of genetic information to mine new information about genes that modulate low density lipoprotein (LDL) cholesterol and its downstream consequences, heart attack, stroke and death. This new approach to analysing existing data suggested a dozen new LDL cholesterol genes for analysis and provides opportunities for developing new treatments and advancing approaches to identifying those at greatest risk for heart disease.
The new analytical approach, called ‘mixed modelling of meta-analysis P-values’ or MixMAP, offers new and complementary information as compared to single nucleotide polymorphism-based analysis approaches that have been used in past studies to identify novel genes linked to heart disease. The researchers say the tool is straightforward to implement and can be used with freely available computer software. The approach may also be applied broadly to advance genetic knowledge of many other diseases.

‘The MixMAP approach provides a significant advance by unlocking more information regarding the genetic basis of disease using existing large data and at little additional cost to the research community and funding agencies,’ said Muredach P. Reilly, MBBCH, MSC, associate professor of Medicine at Penn and senior study author. ‘For complex diseases such as heart attack and diabetes, this provides a real opportunity to generate substantial new knowledge and advance treatment and diagnostic opportunities.’ Perelman School of Medicine

In a new study in mice, a scientific collaboration centred at Brown University lays out in unprecedented detail a neurological signalling breakdown in Angelman syndrome, a disorder that affects thousands of children each year, characterised by developmental delay, seizures, and other problems. With the new understanding, the team demonstrated how a synthesised, peptide-like compound called CN2097 works to restore neural functions impaired by the disease.
‘I think we are really beginning to understand what’s going wrong. That’s what’s very exciting,’ said John Marshall, professor of medical science in the Department of Molecular Pharmacology, Physiology, and Biotechnology and the senior author of the study. However Marshall did caution that it is too early to predict how soon a clinical therapy might arise from the results.
In mice and people, Angelman syndrome arises from flaws in a gene called Ube3A. When it functions properly, the gene limits the amount of a protein called Arc in the brain. Left unchecked by the disease, Arc impairs the development of synapses in the hippocampus. Those neural connections may be essential for proper learning and memory function.
In the new study, Marshall and his colleagues report a series of experiments that show how the abundance of Arc creates such negative effects and how Arc might possibly be defeated and its ill-effects repaired in the lab.
Essentially, Arc interferes with the operation of a synaptic protein called PSD-95, that is required for the actions of a growth factor, known as brain-derived neurotrophic factor (BDNF). This growth factor is released at synaptic contacts and initiates a sequence of molecular interactions necessary for the strengthening of neuronal connections or synapses. In mice with the flawed Ube3A gene, the signals sent by BDNF for memory formation are disrupted.
Although the researchers were surprised by the details they discovered about how Arc hinders the signalling process, they didn’t come to the insight with complete naivete.
In other work, Marshall had been studying CN2097, designed by co-author Mark Spaller of Dartmouth College (Spaller synthesised it during earlier tenures at Wayne State University and Brown). The compound, which binds to PSD-95 was predicted to protect neurons under conditions of stroke and in disease states such as multiple sclerosis. With co-senior author Dennis Goebel of Wayne State, Marshall and Spaller found this to be the case. During the course of those studies the Marshall group learned that CN2097 enhanced the action of brain-derived neurotrophic factor (BDNF) which is known to be critically involved in long-term potentiation (LTP), a phenomenon believed by many neuroscientists to underlie learning.
Then, when University of North Carolina professor and former Brown postdoc Ben Philpot, now a leading expert on Angelman syndrome, returned to campus in 2008 to speak about Angelman syndrome, he showed how LTP is notably lacking in mice with the condition. After discussions with Philpot, Marshall and his group decided to test whether CN2097 might restore LTP in Angelman mice.
Early on, Marshall said, the team figured the defect in LTP in Angelman mice effect had to do with BDNF signalling.
‘We started studying BDNF signalling in the Angelman syndrome mouse and discovered the signalling was defective, so that really was the breakthrough,’ he said. ‘It was completely unexpected. It’s a new way of thinking about this disease.’
That led to the set of experiments now reported, in which the group found that CN2097 essentially protects PSD-95 from interference by Arc, helping to restore BDNF signaling and the formation of stronger synapses. In electrophysiological tests on hippocampal tissue of healthy and Angelman mice, the compound made obtaining LTP significantly easier, although observing LTP in Angelman mice is still more difficult than in normal mice, Marshall said. Brown University

Scientists at The University of Manchester have made important advances in understanding why our immune system can attack our own tissues resulting in eye and kidney diseases. It is hoped the research will pave the way for the development of new treatments for the eye condition age-related macular degeneration (AMD) and the kidney condition atypical Haemolytic Uremic Syndrome (aHUS).
Both AMD, which affects around 50 million people worldwide, and aHUS, a rare kidney disease that affects children, are associated with incorrectly controlled immune systems. A protein called complement factor H (CFH) is responsible for regulating part of our immune system called the complement cascade. Genetic alterations in CFH have been shown to increase a person’s risk of developing either AMD or aHUS, but rarely both. Why this is the case has never been explained until now.
Researchers from the Wellcome Trust Centre for Cell Matrix Research and the Ophthalmology and Vision Research Group in The University of Manchester’s Institute of Human Development have been expanding on their previous work that demonstrated a single common genetic alteration in CFH prevents it from fully protecting the back of the human eye. The research teams of Professor Tony Day and Professor Paul Bishop found that a common genetically altered form of CFH associated with AMD couldn’t bind properly to a layer under the retina called Bruch’s membrane. Having a reduced amount of CFH in this part of the eye leads to low-level inflammation and tissue damage, eventually resulting in AMD.
However, this mutation that changes CFH function in the eye has no affect on the protein’s ability to regulate the immune system in the kidney. A cluster of genetic mutations in a completely different part of CFH are associated with the kidney disease aHUS, but these have no affect on the eyes.
In their most recent study, which was funded by the Medical Research, the Manchester researchers have identified why these mutations in CFH result in diseases in very specific tissues. Professor Day explains: ‘For the first time we’ve been able to identify why these protein mutations are so tissue specific. We’re hoping our discovery will open the door to the development of tissue specific treatments to help the millions of people diagnosed with AMD every year.’
The research team looked at the two parts of CFH affected by the mutations. Both regions are capable of recognising host tissues, through interacting with sugars called glycosaminoglycans (GAGs). Successfully recognising these GAGs lets CFH build up a protective layer on the surface of our tissues that prevents our own immune system from attacking them.
It had always been believed that the region with mutations associated with aHUS was the most important for host recognition and for years people have been researching how to readdress immune dysregulation based on this belief. However, the recent discovery of a single common genetic alteration in the other part of CFH that is associated with eye disease raised the possibility that this previous opinion was not fully accurate. The University of Manchester