New research provides direct evidence that genetic variations in some African Americans with chronic kidney disease contribute to a more rapid decline in kidney function compared with white Americans. The research, led by investigators from the University of Maryland School of Medicine and Johns Hopkins University, may help explain, in part, why even after accounting for differences in socio-economic background, end-stage kidney disease is twice as prevalent among blacks as whites.
‘What we found is pretty remarkable — that variations in a single gene account for a large part of the racial disparity in kidney disease progression and risk for end-stage kidney disease,’ says co-lead author and nephrologist Afshin Parsa, M.D., M.P.H., assistant professor of medicine and member of the Program in Personalized and Genomic Medicine at the University of Maryland School of Medicine. ‘If it were possible to reduce the effect of this gene, there could be a very meaningful decrease in progressive kidney and end-stage kidney disease within blacks.’
Previous landmark discoveries revealed that two common variants within a gene called apolipoprotein L1 (APOL1) were strongly associated with non-diabetic end-stage renal disease in blacks. Having only one copy of the variant APOL1 gene variant is associated with a health benefit – protection against African sleeping sickness, a potentially lethal parasitic infection transmitted by the tsetse fly, found only in sub-Saharan Africa. However, people with two copies of the variant are at a higher risk for kidney disease.
The current research expands on these prior findings and demonstrates the effect of these variants on the progression of established kidney disease and development of end-stage renal disease; analyses their role in black-versus-white renal disease disparities; investigates their effect in patients with diabetes and observes the impact of blood pressure control on APOL1-associated disease progression.
According to Dr. Parsa, approximately 13 percent of the African American population has two copies of the risk variants. Fortunately, most of those at risk do not develop kidney disease. The researchers analysed the role of APOL1 gene variants in two longitudinal studies of patients with kidney disease: the Chronic Renal Insufficiency Cohort (CRIC) and the African American Study of Kidney Disease and Hypertension (AASK), both sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), part of the National Institutes of Health (NIH). Dr. Parsa examined the CRIC study data, while co-lead author and Johns Hopkins epidemiologist W.H. Linda Kao, Ph.D., M.H.S., analysed the AASK data. University of Maryland Medical Center

Harvard stem cell scientists have identified a mutation in human cases of acute lymphoblastic leukaemia that likely drives relapse. The research could translate into improved patient care strategies for this particular blood cancer, which typically affects children but is more deadly in adults.

In recent years, a trend toward single-cell analysis has shown that individual cells within a tumour are capable of amassing mutations to make them more aggressive and treatment resistant. So while 99% of a tumour may be destroyed by the initial treatment, a particularly aggressive cell can survive and then cause a cancer patient with the ‘all clear’ to relapse six months later.

Harvard Stem Cell Institute Principal Faculty member David Langenau, PhD, and his lab members in the Department of Pathology at Massachusetts General Hospital used zebrafish to search for these rare, relapse-driving leukaemia cells and then designed therapies that could kill these cells.

The researchers found that at least half of relapse-driving leukemic cells had a mutation that activated the Akt pathway, which rendered cells resistant to common chemotherapy and increased growth. From that insight, Langenau’s lab next examined human acute lymphoblastic leukaemia and discovered that inhibition of the Akt pathway restored leukemic cell responses to front-line chemotherapy.

‘The Akt pathway appears to be a major driver of treatment resistance,’ Langenau said. ‘We also show that this same pathway increases overall growth of leukemic cells and increases the fraction of cells capable of driving relapse.’

Jessica Blackburn, PhD, the study’s first author adds, ‘Our work will likely help in identifying patients that are prone to relapse and would benefit from co-treatment with inhibitors of the Akt pathway and typical front-line cancer therapy.’

In addition to determining how best to translate this finding into the clinic, Langenau hopes to identify other mutations that lead to relapse. The work should identify a host of other potential drug targets for patients with aggressive leukaemia. Harvard Stem Cell Institute

The team headed by Angel Rodríguez Nebreda, ICREA researcher at IRB, identifies for the first time in mice that the p38 MAPK protein is required for the survival and proliferation of colon cancer cells.

In the same study the scientists demonstrate that a p38 inhibitor that has been used in clinical trials for inflammatory diseases shrinks the tumours in mice.
A team headed by Angel R. Nebreda at the Institute for Research in Biomedicine (IRB) identifies a dual role of the p38 MAPK protein in colon cancer. The study demonstrates that, on the one hand, p38 is important for the optimal maintenance of the epithelial barrier that protects the intestine against toxic agents, thus contributing to decreased tumour development. Intriguingly, on the other hand, once a tumour has formed, p38 is required for the survival and proliferation of colon cancer cells, thus favouring tumour growth.

The protein p38 is a member of the MAPK family—molecules that transmit signals from outside the cell inside, thus allowing an appropriate and dynamic cell response. This protein is expressed in all cells of the body and it performs highly diverse functions depending on the context and tissue involved.

Nebreda’s group at IRB focuses on the function of p38 in cancer. Their work describes the essential role of p38 in tumour progression for the first time in vivo. Furthermore, the scientists demonstrate that the treatment of mice with a p38 inhibitor previously used in clinical assays causes a considerable reduction in tumour size. The study provides useful information for clinicians and pharmaceutical companies about the role of p38 in the context of colon cancer. Colorectal cancer is now the second leading cause of cancer-related death in the world.

‘p38 inhibitors may have clinical applications, but probably—and this forms part of the medicine of the future—these will be in combination with other drugs. We are trying to find out what p38 inhibitors should be combined with to make the tumour, which is now smaller, finally disappear,’ explains the Spanish scientist Nebreda, head of the Signalling and Cell Cycle Lab at IRB, BBVA Foundation Cancer Research Professor and ICREA research professor.

The role of p38 in cancer is not clear cut. In this same study, Indian-born Jalaj Gupta who recently obtained his PhD in Nebreda’s lab and is first author of the work, demonstrates that this same protein in a pre-tumoral context, favoured by inflammation of the colon—also known as colitis—impedes tumour development.

It is well-known that patients with chronic inflammation of the intestine, such as that caused by Crohn’s disease, have a greater incidence of colon tumours that the healthy population. In order to study the relationship between inflammation and cancer, Nebreda’s team use mouse models that reproduce this inflammatory context.

‘Given that p38 regulates inflammation and also functions as a tumour suppressor in some mouse models, our study addressed how these two functions are integrated during the colon tumorigenesis associated with inflammation’, says Gupta.

An important finding of the present study is related to the contribution of p38 to the maintenance of an intact epithelial barrier, a structure that protects the intestine from toxic agents and pathogens. Mice genetically depleted of p38 in the epithelial cells that form the intestinal barrier were subjected to a cancer-inducing protocol that causes mutations and inflammation.

These animals developed twice as many tumours as a group of p38-expressing mice subjected to the same protocol. The tumour-suppressing capacity of p38 has also been described in cancer of the liver and lung.

‘Our study highlights the complexity of p38 functions, both in cancer and in the normal maintenance of tissues, and shows why an inhibitor of this molecule could effectively have undesirable side effects. This is why it is necessary to study in depth the patients and contexts in which treatment with such inhibitors would be suitable,’ explains Gupta.

‘All drugs currently used to treat cancer have side effects,’ states Nebreda, ‘and in this regard p38 inhibitors would be no exception. However, the administration of such inhibitors to colon cancer patients may be a useful strategy to shrink the tumour in a few days before its surgical removal’.

Nebreda goes on to explain that the basic research performed in his lab seeks to understand better the biology of tumour cells, the roles of the molecules involved and the mechanisms that allow tumour progression. ‘We try to take this basic information a step further so that it becomes clinically useful when designing new treatments,’ says the researcher, who joined IRB, in Barcelona, in 2010, after working in USA, UK, Germany and the CNIO in Madrid. IRB Barcelona

The research of physician-scientist Katalin Susztak, MD, PhD, associate professor of Medicine in the Renal Electrolyte and Hypertension Division, at the Perelman School of Medicine, University of Pennsylvania, strives to understand the molecular roots and genetic predisposition of chronic kidney disease. In a recent Genome Biology paper, Susztak, and her co-corresponding author John Greally from the Albert Einstein College of Medicine, Bronx, NY, found, in a genome-wide survey, significant differences in the pattern of chemical modifications on DNA that affect gene expression in kidney cells from patients with chronic kidney disease versus healthy controls. This is the first study to show that changes in these modifications – the cornerstone of the field of epigenetics – might explain chronic kidney disease.
Epigenetics is the science of how gene activity can be altered without actual changes in the DNA sequence. DNA can be modified by different chemical groups. In the case of this study, these are methyl groups that, like using sticky notes as reminders, open or close up regions of the genome to make these areas more or less available to be ‘read’ as a gene.

Chronic kidney disease is a condition in which the kidneys are damaged and cannot adequately filter blood. This damage can cause wastes to build up, which leads to other health problems, including cardiovascular disease, anaemia, and bone disease. More than 10% of people, or more than 20 million, aged 20 years or older in the United States have chronic kidney disease, according to the Centers for Disease Control.
Past epidemiological studies have shown that adverse intrauterine and postnatal conditions have a long-lasting, over-a-lifetime role in the development of chronic kidney disease. Adverse intrauterine factors include small size of babies for gestational age due to a lack of nutrients, or conversely, a large size for gestational age, for example if mom had pregnancy-related diabetes.
Studies from the Diabetes Control and Complications trial also indicate that patients with diabetes who had poor diabetes control 25 years earlier still have an increased risk of kidney disease despite having a decade of excellent glucose control. ‘This is called the metabolic memory effect,’ says Susztak. ‘Kidney cells remember the past bad metabolic environment.’
Susztak’s lab used human kidney cells that looked almost the same under a microscope, but the way each cell type is affected by the methyl groups was very different. In general, an increase in the number of methyl groups on a gene turns off expression, and a decrease of methyl groups turns on a gene’s expression.
Specifically, they found that the differences in the methyl groups were not on promoter regions in the diseased kidney cells, but mostly on enhancer regions, and were also near sequences for important kidney transcription factors. ‘This all speaks to the importance of these regions in regulating gene expression,’ says Susztak.

Promoter regions are in front of genes and near the gene they influence. Enhancer regions are farther away from the gene of influence. This difference indicates that the two cell types would likely respond differently to stress.
‘The difference in methylation related to kidney fibrosis — genes encoding collagen and growth factors — at core kidney development sites in the genome raises the possibility that these differences are established early on in a person’s development because the genes Pax2 and Pax8 are active in the developing kidney in the fetus,’ explains Susztak.
‘Most of the research on kidney epigenetics so far has been on promoter regions on kidney cancer cells,’ says Susztak. ‘The difference we found in dysregulation between the two cell populations may indicate that dysregulation in cancer is different from dysregulation in chronic kidney disease. Five years ago there was no epigenetic information outside of cancer,’ says Susztak.

Overall, the findings raise the possibility that dysregulation of epigenetic marks plays a role in chronic kidney disease by affecting pathways that lead to more fibrosis. Identifying the genes and proteins associated with this system gone awry may help identify new biomarkers and targets for new drugs. Perelman School of Medicine