End stage renal disease (ESRD) is an increasingly common problem where failure of the kidneys results in patients requiring renal replacement therapy in the form of dialysis or a kidney transplant. In the UK, 888 out of every million people are on renal replacement therapy.

The best treatment for ESRD is a kidney transplant from a living donor (if available) or from a deceased organ donor. Transplantation not only improves quality and quantity of life but is extremely cost effective when compared to long-term dialysis. The key issue addressed by this new BMC Medicinepaper is whether obesity should be regarded as a barrier to kidney transplantation.

As with the general population, an increasing proportion of the renal replacement population is obese. Indeed, obesity increases the risk of developing kidney disease. One of the consequences of increasing obesity is an epidemic of type 2 (adult onset) diabetes mellitus. Diabetic kidney disease is now one of the commonest causes of ESRD.

The metabolic syndrome which accompanies obesity, causing hypertension and hyperlipidaemia, increases the risk of cardiovascular disease. Hypertension can cause or accelerate the progression of damage to kidneys and atherosclerosis (damage to blood vessels through deposition of cholesterol) can affect all organs including the kidneys.

Obesity has traditionally been regarded as a barrier to transplantation on the grounds of increased incidence of surgical complications and perceived poorer long-term outcomes.

This new meta-analysis included over 209,000 renal transplant recipients from studies where transplant outcomes were compared between patients with body mass index greater or less than 30 kg/m². While there was a clear increase in early surgical complications and metabolic problems, in particular new onset diabetes after transplantation (NODAT), there was remarkably little impact on three-year patient and transplant survival.

The traditional approach in the UK has been to hold off transplantation until obese patients achieve a target weight with body mass index less than 30 kg/m² with some leeway for patients with body mass of up to 35 kg/m², as advocated by the authors of this meta-analysis.   However, we all know that weight loss is challenging and even if patients lose weight to allow transplantation, there is a tendency to gain it all back again after the surgery.

A utility argument can be applied given the inadequate supply of deceased donor organs that these should be allocated to patients with the best long-term outcomes

A key current controversy is whether obese patients should be denied the potential benefits of transplantation based on current evidence of poorer outcomes when compared to non-obese individuals, but possibly better outcomes for these individuals than they would have on long-term dialysis. Bariatric surgery is seeing increasing use but the surgical complication rate is probably higher in patients with ESRD. Is it reasonable to insist on such an invasive approach to weight loss as a condition for renal transplantation?

A utility argument can be applied given the inadequate supply of deceased donor organs that these should be allocated to patients with the best long-term outcomes, although this does not apply in the case of live donation.

Based on the current data, a number of other factors, in particular cardiovascular comorbidity probably have a bigger impact on survival than obesity. It is probably reasonable that practice is drifting towards transplanting more obese patients. This needs to be accompanied by careful collection of outcome data, in particular for patients with BMI >35 kg/m² to ensure that transplantation is, in fact, in their best interests.

We are unlikely to see any sufficiently powered randomised controlled trials of renal transplantation in the obese and will need to rely on registry data.

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Rapamycin, a drug  used to coat coronary stents and prevent transplant rejection, reduces obesity and preserves lean body mass when given intermittently to older rats, studies conducted by  University of Florida Health researchers have found. The two rapamycin-related studies were published recently in the Journal of Gerontology as a joint effort of two research teams.

While the current findings are limited to rats, rapamycin has potential as a treatment for age-related obesity because it is already used to treat other conditions in people, said Christy S. Carter, PhD, an assistant professor in the department of aging and geriatric research in the UF College of Medicine and co-lead author of one of the studies.

"We need to be able to intervene with treatments for older adults. They're going to have health care issues, and not everyone can get up and exercise. So if you can give them a jump-start or combine rapamycin with other therapies, you could have better health outcomes," Carter said.

Obesity among older adults has increased dramatically in the United States during the last 20 years. More than one-third of people over age 65 are obese, according to a study published in 2012 by the Centers for Disease Control and Prevention.

Carter and Drake Morgan, PhD, an assistant professor in the department of psychiatry, are the co-lead authors of a paper that shows rapamycin reduced food consumption and body weight. Using 25-month-old rats, which are about equivalent to 65-year-old people, researchers found that body weight dropped by approximately 13% after the rats were treated with rapamycin.

The drug targets how the body makes leptin, a hormone produced by fat cells that affects hunger and metabolism. The researchers hypothesize that the reduction in eating is due to normalizing the typical age-related spike in leptin.

Rapamycin's ability to stabilize the rats' leptin level made them lighter, researchers found. Overall, there was a dramatic body metamorphosis: rapamycin selectively targeted the fat, allowing the animals to retain lean mass. It worked so well that the older rats ultimately developed a lean-to-fat ratio similar to that of their younger counterparts, researchers found.

"In this case, we feel like we restored the body composition to that of a young animal," Carter said.

In the second paper, researchers found that small, intermittent amounts of rapamycin produced the desired slimming effect in both young and old rats. That team included lead authors Philip J. Scarpace, Ph.D., a professor in the department of pharmacology, and Nihal Tümer, a professor in the department of pharmacology and a pharmacologist in the geriatric center at the Malcom Randall Veterans Affairs Medical Center in Gainesville. While rapamycin works best in older, obese rats, researchers were encouraged that it also had an effect on certain younger animals.

"One point that is common is that it seems to work better in animals, old or young, that have more fat," Scarpace said.

Getting the correct dose was crucial: Too little of the drug did not reduce obesity, but too much of it causes elevated glucose and fat levels in the blood.

The second paper determined that the drug works by inhibiting a signaling mechanism known as mTORC1, a protein complex that is an energy and nutrient sensor. This triggers a response in the brain that curbs eating, effectively reducing age-related fat until the older animals resemble much younger ones.

While rapamycin has yet to be tested in people, the rats were chosen carefully to resemble the aging and obesity pattern of humans, Carter said.

"We're looking at similarities in longevity, changing body composition and declining physical function -- and we're looking at the same trajectory of age-related obesity," she said.

Researchers remain unsure whether rapamycin is working in the brain or another part of the body. Next, Carter said she would like to study whether factors released by muscles play a role in fat metabolism.
 

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