Summary

Mayo Clinic researchers are peering into the kidney’s black box to discover how to diagnose atherosclerotic renal vascular disease, a condition that leads to a hard-to-treat form of high blood pressure, before it wrecks havoc on the organ tissue. They also hope to learn how the disease process takes place and acts differently from other causes of hypertension.

“It is really great to be able to discuss my research with a partner who understands what I am talking about.” Lilach Lerman, M.D., Ph.D., with husband Amir Lerman, M.D.

Kidney physiologist Lilach Lerman, M.D., Ph.D., became intrigued early in her career by the idea that the human body is like a black box that can give clues about how systems fail. In 1987, after completing medical training in Israel, she arrived at Mayo to a ripe research landscape where imaging technology was becoming increasingly sophisticated. The innovative environment, which was developing more non-invasive tools to research and diagnose disease, helped nurture her interest in research and she decided to pursue a doctorate in physiology and imaging from Mayo Graduate School.

Dr. Lerman is now a lead investigator on a National Institutes of Health (NIH) 5-year grant administered by NIH’s National Heart, Lung and Blood Institute. Her research looks at the domino effects started by atherosclerosis, the disease that causes malfunction and thickening of arterial walls - how it contributes to irreversible kidney damage by amplifying oxidative stress, which then instigates endothelial and epithelial cell injury and blocks cellular repair, aggravating kidney damage while impairing its recovery.

J. Carlos Romero, M.D.; Stephen Textor, M.D.; and Joseph Grande, M.D., Ph.D.

J. Carlos Romero, M.D., leads the entire research team for the grant. He is also principal investigator to define the oxidation processes and how those processes can be used to predict renal recovery potential. Joseph Grande, M.D., Ph.D., is leading an effort to study how the disease causes structural cellular changes and what new therapies could target renal hypertension, and Stephen Textor, M.D. heads up an investigation of tissue oxidation processes and treatment options in patients, including the efficacy of balloon angioplasty. The studies also involve collaboration with experts in physiology and biomedical engineering, renal patho-physiology, transplantation biology, radiology, and vascular interventional radiology.

Dr. Lerman also has an ally for this grant at her dinner table – her husband Amir Lerman, M.D., a Mayo Clinic cardiology researcher and expert in vascular biology and physiology. The couple, who met in medical school, understand each other’s research because Dr. Amir Lerman’s team is exploring evidence for the early effects of atherosclerosis on the function of blood vessels in the heart and kidney, a condition called endothelial dysfunction that precedes the formation of plaque.

“We sometimes talk shop over dinner, but not when our children are home,” says Dr. Lilach Lerman. “It is really great to be able to discuss my research with a partner who understands what I am talking about.”

Assessing kidney function with state-of-the-art scanning techniques

The kidney on the left shows loss of tissue and function above a blocked artery, and small aneurysm.

“Because we have two kidneys and one often takes over when the other fails to perform optimally, it usually takes longer to detect impairment or to diagnose a developing renal artery condition that affects one kidney more than the other,” says Dr. Lerman. “And, because people may have underlying essential hypertension as a result of other genetic or environmental factors, it may be hard to ascribe the cause of the hypertension to an arterial narrowing. The diagnostic delay can lead to permanent and irreversible kidney damage and even to their failure – a life threatening situation.”

Traditionally, blood tests are used to measure kidney function but this method often uncovers problems when it’s too late to correct or reverse damage to kidney tissue.

“This is especially true when severe damage occurs in only one of the two kidneys and there are no immediate physical symptoms,” explains Dr. Lerman. “That’s why I developed an interest in Dr. Romero and Dr. Ritman’s work.”

J. Carlos Romero, M.D., and Erik Ritman, M.D., Ph.D., have distinguished careers in the development of non-invasive scanning tools and techniques. Tomographic scanners (derived from the Greek word tomos which means "a section" or "a slice", and "graphe", meaning "drawing" or “document”) produce images that can examine the anatomy and function of each kidney individually.

A solitary functioning kidney with a stent inserted to keep the artery open. The other kidney’s artery has completely blocked circulation.

Drs. Romero and Ritman were also instrumental in developing methods to study blood flow and filtration function in the kidney, as well as ways to apply these methods in humans. When results of some carefully designed protocols proved successful, and the spectacular scanning images came out, they were able to unravel the function of the kidney. This gave Dr. Lerman a rush of excitement because their results confirmed her team was on the right track.

In the current research project, explains Dr. Lerman, “Our multi-detector CT scanning technology is providing important data on the status of renal function."

Investigators are also employing a new technique of blood oxygen level-dependent magnetic resonance imaging (BOLD MRI) which measures the level of deoxyhemoglobin in the kidneys (a form of hemoglobin without oxygen) to determine how hard the kidneys are working. The harder the kidneys work, the more oxygen they use.

Dr. Lerman’s research also has roots in collaborations she had with Mayo radiologists Patrick F. Sheedy M.D., and Anthony Stanson M.D., and Mayo nephrologists Stephen Textor, M.D. and Sandra Taler, M.D. This team reported in 1996 that atherosclerosis caused a greater degree of damage on the kidneys of hypertensive patients with obstructed renal arteries than other causes of renal artery narrowing. “From this I speculated that atherosclerosis had a direct effect on the kidney,” said Dr. Lerman. With the thrill of discovery pushing her forward, she returned to animal models to study the phenomenon.

Connecting the historical dots
Dr. Lerman describes how an early 20th century scientist named Harry Goldblatt created a hypertensive state in an animal model by constricting the renal arteries without knowing such an abnormality could actually occur in humans.

“Its not so common to discover through experimentation a disease state that hasn’t been previously recognized as a clinical entity,” says Dr. Lerman. “That’s kind of a backwards process.”

This discovery, presented to the scientific world in 1934, demonstrated a connection between high blood pressure (hypertension) and renal function. Subsequent research proved that renal vascular stenosis (constriction of the renal artery) is indeed a human condition. Estimates say it causes five to 10 percent of all hypertension cases and the incidence of the disease is increasing with our aging population. Dr. Lerman’s research looks specifically at how atherosclerosis causes increased damage on the kidney tissue and how it decreases the effectiveness of traditional therapies that mitigate high blood pressure and renal damage due to constricted arteries.

Ineffective treatment options
Traditional surgical treatments for vascular constriction include bypass surgery, or performing balloon angioplasty and implanting stents in the part of the artery that is constricted. But these treatments have had unexpectedly poor results when applied to patients with atherosclerotic renal vascular disease. Some 75 percent of these patients have either little effect from the surgical remedies or poor outcomes. (Mayo is currently participating in a major clinical trial, called the Cardiovascular Outcomes in Renal Artery Lesions (CORAL), led locally by Dr. Textor, to determine the best treatment for patients who have high blood pressure caused by atherosclerotic blockage of the renal artery that supplies blood to the kidney.)

The fact that traditional surgical treatments improve only 25 to 30 percent of atherosclerotic patients makes earlier diagnosis imperative. The research team is searching for ways to predict which kidneys are likely to respond to therapy, in order to avoid performing procedures where they might fail.

Preliminary research results
Preliminary results of the NIH research have produced clear evidence that atherosclerosis accelerates fibrosis, the development of excess fibrous connective tissue as opposed to normal organ tissue, leading to irreversible scarring of the kidney. On the other hand, although renal disease is often associated with increased blood pressure, Dr. Lerman’s group was intrigued to find that atherosclerosis did not aggravate development of hypertension when compared to other causes of renal artery narrowing. They suspect this is because atherosclerosis injures not only blood vessels in the kidney, but also the renal tubules, causing them not to reabsorb as much salt as would have been anticipated.

The research has also produced promising results for treating the diseased kidney cells by what Dr. Lerman calls progenitor cells (a derivation of stem cells). Studies by Mayo researcher Robert Simari, M.D., suggest that injured blood vessels improve in animal models injected with these progenitor cells, which can be isolated and expanded from peripheral blood. Implementing similar techniques, Dr. Lerman’s team is observing these same types of cells seem to be beneficial within the injured kidney, and may hold promise of improving renal function and the success of interventional techniques in this disease.

The research team is a good example of Mayo Clinic’s interdisciplinary approach that is recognized for its speedy delivery of diagnostic and treatment options to patients at the bedside.

“Find, monitor and treat the disease before it severely damages the kidney tissue,” says Dr. Lerman. “That is our mission.”