Chronic kidney disease changes the composition of intestinal bacterial microbes that normally play a crucial role in staving off disease-causing pathogens and maintaining micro-nutrient balance, according to UC Irvine researchers.
This profound alteration of the gut microbial population may contribute to the production of uremic toxins, systemic and local inflammation, and nutritional abnormalities present in patients with advanced renal disease, they said.
Study leader Dr. N.D. Vaziri of the UCI School of Medicine’s Division of Nephrology & Hypertension noted that consumption of high-fibre foods and better control of uremia — a disease common in kidney failure — by diet and dialysis may improve the composition of gut microbes and the well-being of patients.
The researchers studied microbial DNA extracted from the stool samples of a group of renal failure patients and healthy control individuals. They found marked differences in the abundance of some 190 types of bacteria in the gut microbiome of those with kidney disease — and confirmed the results in a concurrent study of rats with and without chronic kidney disease.
Vaziri explained that nitrogen-rich waste products — particularly urea and uric acid, which are usually excreted by the kidneys — accumulate in the body fluids of patients with renal failure. This leads to the massive release of these waste products in the gastrointestinal tract, supporting the growth and dominance of microbial species that can utilise these compounds.
The impact of this flooding of the gut by nitrogenous waste products in patients with advanced kidney disease, Vaziri added, is compounded by dietary restrictions on fruits and vegetables, which contain the indigestible fibres that favourable gut microbes feed on. This is because fruits and vegetables contain large amounts of potassium, a mineral normally excreted by the kidneys. In cases of renal failure, potassium levels are high, increasing the risk of cardiac arrest.
One solution, Vaziri said, is to provide longer, more frequent dialysis treatments. This would let more potassium be removed by dialysis and allow for more potassium in the diet. Alternatively, packaged fibre foods that do not contain potassium could be used as a dietary supplement.
The work adds to a growing body of evidence pointing to the role of gut bacteria in disease and health. Recent research by other groups has identified changes in the composition of intestinal microbial flora in people with diabetes, colorectal cancer, obesity and inflammatory bowel disease, among other conditions. University of California, Irvine

Many patients who have genetic testing for Lynch syndrome, a hereditary predisposition to colon cancer, receive the inconclusive result ‘variants of uncertain clinical significance.’ This can be a problem, as people with Lynch syndrome have a much higher probability to develop colon cancer, and often develop colon cancer at an earlier age than is common among the general population; consequently, they need to begin screening at a much younger age.
Now, between two-thirds and three-fourths of these genetic variants can be classified into categories that indicate the most appropriate screening and treatment guidelines, according to two complementary papers recently published. The two papers, both co-authored by Sean Tavtigian, Ph.D., a Huntsman Cancer Institute (HCI) investigator and associate professor in the Department of Oncological Sciences at the University of Utah, provide a model that could help physicians as they assess their patient’s risk to develop cancer.
According to the American Cancer Society, about 143,460 new cases of colon cancer will be diagnosed in the United States this year. The National Cancer Institute estimates that two to four percent of all colon cancer is attributable to Lynch syndrome.
Mutations in mismatch repair genes, which proof-read DNA to correct genetic typos that occur during the replication process, are known to be the cause of the syndrome. ‘Some people in families with Lynch syndrome have already known mutations, and a small number of missense substitutions have also been classified as pathogenic,’ said Tavtigian. ‘But a fair number have other missense substitutions for which the clinical significance could not be determined, creating uncertainty concerning proper screening and treatment for patients and physicians alike.’
The first of the two studies reported on standardising several already available computer programs that grade the severity of missense substitutions (at the genomic level, these mutations affect only a single structural unit of DNA rather than an entire gene; at the protein level, they affect only a single amino acid rather than the entire protein). The second describes how clinical data concerning the tumours, family history, and other factors were combined with that initial information about severity. Taken together, the procedures described in the two papers allow previously unclassified genetic variations to be assessed for the level of risk they pose in colon cancer development.
‘Using these tools, we can evaluate any particular missense substitution and come up with a percentage indicating the probability that it is pathogenic,’ said Tavtigian. ‘I’m very careful to avoid saying pathogenic or neutral as an either-or statement. With missense substitutions, I don’t believe in a binary classification.’ A scale developed by his team in 2008 indicates the appropriate level of clinical action for a given percentage of risk, he adds. Huntsman Cancer Institute

Researchers at Case Western Reserve University School of Medicine have discovered a mutant form of the gene, Chk1, that when expressed in cancer cells, permanently stopped their proliferation and caused cell death without the addition of any chemotherapeutic drugs. This study illustrates an unprecedented finding, that artificially activating Chk1 alone is sufficient to kill cancer cells.
‘We have identified a new direction for cancer therapy and the new direction is leading us to a reduction in toxicity in cancer therapy, compared with chemotherapy or radiation therapy,’ said Dr. Zhang, assistant professor, Department of Pharmacology at the School of Medicine, and member of the university’s Case Comprehensive Cancer Center. ‘With this discovery, scientists could stop the proliferation of cancer cells, allowing physicians time to fix cells and genetic errors.’
While studying the basic mechanisms for genome integrity, Dr. Zhang’s team unexpectedly discovered an active mutant form of human Chk1, which is also a non-natural form of this gene. This mutation changed the protein conformation of Chk1 from the inactive form into an active form. Remarkably, the research team discovered that when expressed in cancer cells, this active mutant form of Chk1 permanently stopped cancer cell proliferation and caused cell death in petri dishes even without the addition of any chemotherapeutic drugs.
The biggest advantage of this potential strategy is that no toxic chemotherapeutic drug is needed to achieve the same cancer killing effect used with a combination of Chk1 inhibitors and chemotherapeutic drugs.
Cells respond to DNA damage by activating networks of signalling pathways, termed cell cycle checkpoints. Central to these genome pathways is the protein kinase, called Chk1. Chk1 facilitates cell survival, including cancer cells, under stressful conditions, such as those induced by chemotherapeutic agents, by placing a temporary stop on the cell cycle progression and co-ordinating repair programs to fix the DNA errors.
It has long been suggested that combining Chk1 inhibition with chemotherapy or radiotherapy should significantly enhance the anticancer effect of these therapies. This idea has serves as the basis for multiple pharmaceutical companies searching for potential Chk1 inhibitors that can effectively combine with chemotherapy in cancer therapy. To date, no Chk1 inhibitor has passed the clinical trial stage III . This led Dr. Zhang’s team to look for alternative strategies for targeting Chk1 in cancer therapy.
Future research by Dr. Zhang and his team will consider two possible approaches to artificially activating Chk1 in cancer cells. One possibility is to use the gene therapy concept to deliver the active mutant form of Chk1 that the team discovered, into cancer cells. The other is to search for small molecules that can induce the same conformational change of Chk1, so that they can be delivered into cancer cells to activate Chk1 molecules. The consequence of either would be permanent cell proliferation inhibition and cancer. EurekAlert

Five genes have been found to determine human facial shapes, as reported by researchers from the Netherlands, Germany, Canada, the United Kingdom, and Australia.
Monozygotic twins have almost identical faces and siblings usually have more similar faces than unrelated people, implying that genes play a major role in the appearance of the human face. However, almost nothing is known about the genes responsible for facial morphology in humans.
This study used head magnetic resonance images together with portrait photographs to map facial landmarks, from which facial distances were estimated. The researchers then applied a ‘Genome-wide association (GWA) approach with independent replication, to finding DNA variants involved in facial shapes in almost 10,000 individuals.
Professor Manfred Kayser from the Erasmus University Medical Center, Rotterdam, The Netherlands, the leading author of the study, said: ‘These are exciting first results that mark the beginning of the genetic understanding of human facial morphology. Perhaps some time it will be possible to draw a phantom portrait of a person solely from his or her DNA left behind, which provides interesting applications such as in forensics.’ Erasmus University Medical Center

Children with HIV have a 2.5 fold increased risk of atherosclerosis, according to research presented at EUROECHO and other Imaging Modalities 2012. Antiretroviral treatment, lipid lowering drugs and prevention with healthy lifestyles are needed to prevent early death from cardiovascular disease.
EUROECHO and other Imaging Modalities 2012 is the annual meeting of the European Association of Cardiovascular Imaging (EACVI), a registered branch of the European Society of Cardiology (ESC).
Antiretroviral treatment is prolonging the lives of HIV patients, who no longer die prematurely from the infection. But the treatment is not a cure, and the virus remains in the body.
‘The infection makes the body fight for its life, so the immune system is always activated and there is chronic inflammation,’ said Dr Talia Sainz Costa, principal investigator of the study and a paediatrician from Madrid, Spain.
In addition, many antiretroviral drugs increase bad (LDL) cholesterol and lower good (HDL) cholesterol. Dr Sainz Costa said:
‘Children with HIV will have high cholesterol for a long period and on top of that the virus causes chronic inflammation – both are bad for the arteries.’
Patients with HIV die 10 years prematurely from non-AIDS disease which includes cardiovascular diseases, cancer, liver and renal diseases.
‘This is especially important for children because they have been living with HIV since birth or even before,’ said Dr Sainz Costa. ‘By the time they are 50 years old they will have accumulated more toxicity from the treatment and more secondary effects from the infection and will be at an even greater risk of heart attacks and other complications.’
The present study aimed to discover whether children and adolescents already have early atherosclerosis damage. Carotid intima-media thickness (IMT), a marker of atherosclerosis, was measured using echocardiography in 150 children and adolescents with HIV and 150 age and sex matched healthy controls.
The researchers found that 17% of the HIV group were smokers compared to 11% of the control group. Dr Sainz Costa said:
‘Smoking levels in adolescents in Spain are known to be high. The even higher levels in the HIV group are probably related to low socio-economic status and very complex social/family backgrounds.’
After adjustment for age, sex, BMI and smoking status, HIV was independently associated with thicker IMT (p=0.005). Children and adolescents had a 2.5 fold increased risk of higher IMT due to HIV. Dr Sainz Costa said:
‘Our study shows that children and adolescents with HIV have arteries that are more rigid and less elastic, which means that the process of atherosclerosis has begun and they have increased risk of an infarct in the future.’
The researchers also found that frequencies of activated T CD4+ cells were higher among HIV-infected children and young adults (p=0.002). ‘This shows that the immune system is more active,’ said Dr Sainz Costa.
They concluded that clinicians need to take cardiovascular prevention more seriously in children and adolescents with HIV, while continuing to treat the HIV infection. Dr Sainz Costa said: ‘Cardiovascular disease has already put down roots in children and adolescents with HIV and we need to take preventive measures at this early stage. We should be more aggressive in treating their high cholesterol with medication – this practice is common in adults but rare in children.’ She added:
‘We also need to be stricter about healthy lifestyle advice. Many children and adolescents with HIV come from families with low socio-economic status and are more prone to smoking, poor diet and inactivity. This age group also struggles with adherence to medication which is another worry, but we should not let this decrease our efforts to prevent future complications.’
Dr Sainz Costa concluded: ‘HIV research is investigating ways to control the inflammation and immune activation with agents such as probiotics, aspirin and corticoids. In the meantime clinicians need to focus on ensuring their young patients with HIV take the antiretroviral treatment, take lipid lowering drugs when necessary, and adopt healthier lifestyles.’ European Society of Cardiology