Are you urging elderly people and those with lung disease, heart failure, arthritis, and kidney disease to eat less? Maybe you shouldn’t.
While obesity, hypertension, and hypercholesterolemia are well-known harbingers of poor cardiovascular health and death, “reverse epidemiology” holds that these physiologic states actually increase the chance of survival in many people. That is the theory being put forth by a group of researchers led by Kamyar Kalantar-Zadeh, MD, associate professor of medicine and pediatrics at the University of California, Los Angeles. The Clinical Advisor spoke with Dr. Kalantar-Zadeh about his provocative theory.
Q: What made you think that obesity, elevated cholesterol, and hypertension might be protective in some patients?
A: The consistent and repeated observation that in some populations, traditional CVD risk factors do not appear to be good predictors of death. It has long been taken for granted that the poor survival rates seen in dialysis patients were based on the presence of traditional CVD risk factors, such as high BP and obesity. But studies failed to show this. At the same time, research has begun to find that among some groups, high BMI, serum albumin, and lipid levels are consistently associated with better survival. All of these observations led, finally, to a unifying hypothesis.
Q: What is the evidence in favor of reverse epidemiology?
A: The studies are mostly observational. This doesn’t mean that interventional studies would show the opposite, it’s just that there is a paucity of clinical trials. There have, however, been a few. For example, a study performed at the University of Würzburg in Germany showed that dialysis patients who took statins derived no survival benefit at four years’ follow-up compared with patients who received placebos. Many were shocked by these results.
Q: You’ve said there may be distinct populations in which obesity is an advantage. Which populations are these—and how might extra fat tissue be helpful?
A: In addition to dialysis patients, those with chronic heart failure, rheumatoid arthritis, chronic obstructive pulmonary disease, and cancer—as well as adults older than 80—seem to have improved survival if they are obese.
These populations have some important commonalities: In all of them, wasting syndrome and malnutrition become more important markers for mortality than conventional risk factors. Fat is a natural protective mechanism; the body can store fat for days of hardship when it needs nourishment, and it is therefore an asset for short-term survival. Until 30 years ago, being “chubby” was a surrogate for being considered healthy; in the past, some cargo ships selected staff by seeking out obese men because people with more fat tissue can better overcome infectious diseases.
In short-term survival, long-term risk factors become irrelevant; most people with end-stage renal disease, heart failure, cancer, and so on won’t live long enough to succumb to the consequences of obesity, high BP, and high cholesterol. Looking at populations in which reverse epidemiology applies, we can better understand why humanity tends toward obesity; we are genetically programmed in a way that protects us against short-term threats, such as famine. Chronic disease states are a return to conditions that prevailed prior to the 20th century, when mankind had to focus on short-term survival. One might say that traditional epidemiology is an emergence of a new association, and that reverse epidemiology is more natural.
Q: How might hypertension and hyperlipidemia protect dialysis patients?
A: These conditions are markers of better nutritional status. Circulating blood lipids may contain important defense mechanisms against infection, and cholesterol can neutralize bacteria circulating in the body. This hypothesis springs from the fact that patients with genetic diseases linked to very low cholesterol levels are prone to infection. Hypertension may protect dialysis and heart failure patients by giving them a kind of cushion against BP-lowering interventions, such as dialysis treatment per se or medications to improve heart condition, both of which have low BP as side effects.
Q: Why might high serum creatinine and homocysteine levels be better than low levels in dialysis patients?
A: They, too, are markers of better nutritional status. Creatinine is a surrogate for muscle mass—not just kidney function. Anyone who has more muscle mass has higher creatinine levels. People with above-average muscle mass are not at a disadvantage, although they are often categorized as morbidly obese. High BMI is not necessarily a bad thing, and we are hoping that reverse epidemiology will help make it clear that obesity is not a black-and-white concept. Determination of appropriate body weight must be individualized.
Q: What is the “malnutrition inflammation-cachexia syndrome,” and how might it explain the existence of reverse epidemiology?
A: Protein-energy malnutrition (inadequate intake of protein and calories) and inflammation are relatively common and concurrent conditions in chronic kidney disease (CKD) patients and have been implicated as the main causes of poor short-term survival in this population. Malnutrition-inflammation-cachexia syndrome seems to be the main cause of worsening atherosclerotic CVD in the CKD population. Inflammation plays a very important role in wasting-disease states, and what used to be considered wasting cachexia is now believed to be a combination of dietary components and inflammatory processes in the body. Inflammation is one of the human body’s defense mechanisms; when inflammation becomes chronic, however, it becomes deleterious.
Q: You’ve said there may be other explanations for reverse epidemiology, including “survival bias” and “time discrepancies among competitive risk factors.” How might these concepts explain your paradoxical findings?
A: Survival bias can be looked at from two viewpoints. One is that patients with chronic diseases may be the tip of the iceberg. Most CKD patients die before they undergo dialysis; dialysis patients are the 5% who survive. These survivors, then, are the “lucky unlucky” individuals. On the other hand, perhaps people who survive long enough to undergo dialysis are physiologically different from other CKD patients. Octogenarians, nonagenarians, and people who live long enough to develop chronic heart failure may also be “lucky unlucky” survivors. All of these are examples of survival bias.
Malnutrition requires only a short amount of time to exert its deleterious effects on survival. People starve to death relatively quickly, while overnutrition kills slowly, over several decades. So overnutrition is the traditional risk factor while undernutrition wins the competition to kill.
Q: If reverse epidemiology proves to be a genuine phenomenon, how might it affect treatment for hypertensive patients older than 80 years of age?
A: Hypertension and its treatment as it relates to reverse epidemiology is controversial. It is still too early to say there is a causal relationship for the hypertension paradox observed in certain populations, such as dialysis and heart failure patients. At this point, most elderly patients should adhere to current BP guidelines until and unless clinical trial results suggest otherwise. However, it’s prudent to avoid overtreatment of hypertension in the geriatric population.
Q: Are traditional CVD risk factors relevant to patients with chronic obstructive pulmonary disease, cancer, and rheumatoid arthritis?
A: Perhaps not. In an as-yet unpublished review article about survival paradoxes, we have examined studies of 30 million to 40 million Americans that have reported an “obesity paradox” in these populations. It appears that the paradoxical association between higher BMI and better survival is a common hallmark in these groups, which are prone to wasting disease.
Q: Given what we now know, do you advise your patients on dialysis to take medication to lower elevated BP and cholesterol levels and to lose weight if they are overweight?
A: I take care of 80 dialysis patients—some of them know my background and ask about these issues. I tell them that we are still advancing our hypotheses about reverse epidemiology and suggest they follow their BP and cholesterol-lowering regimens. However, I discourage my dialysis patients from losing weight even if they are overweight. I ask those patients to reconsider the decision. I say, “Are you sure you want to lose weight now? We’re not sure what direction we’re going in yet, but studies have shown that when patients lose weight, mortality may go up.”
Q: Obese patients are less likely to be selected for kidney transplants. Given that excess weight may be protective in these patients, what should they and their physicians do?
A: Patients listed for transplants usually wait four to six years. Surgery is more challenging in patients who are obese. Therefore, they are asked to lose weight so the surgery can be done with fewer problems. But studies have shown that except for the technical surgical issues, the outcomes are similar. It’s a dilemma, and we don’t have any answer right now. We hope that we will have clearer answers in the future.
Q: What roles might protein-energy malnutrition and inflammation play in reverse epidemiology?
A: Nutritional intervention is much more important than addressing traditional CVD risk factors in dialysis patients and others with chronic disease. In the future, more attention will be paid to nutritional interventions, including giving patients oral or IV nutritional supplements and medication to improve appetite. Appetite status is a strong predictor of survival in dialysis patients. One might say that “those who go to Burger King live longer.” Eating at such restaurants may be a surrogate for having a better appetite and better nutritional status.
Q: Which foods and beverages do you think dialysis patients should consume—and avoid?
A: Having a higher-than-average protein and calorie intake is important. But dialysis patients must avoid high potassium and phosphorus intake. To limit phosphorus, one must eliminate consumption of preservatives in sodas and from other non-protein sources. Encourage dialysis patients to maintain a high protein intake, but be sure this doesn’t lead to a high phosphorus and potassium intake. This is the dilemma.
Q: If you had enough money for just one study on reverse epidemiology, what aspect would you choose to examine?
A: I would look at the effects of nutritional interventions on dialysis patients to better understand why weight gain is associated with better survival. I’d give some patients more protein and calories as well as different types of nutrition and medications to improve appetite and mitigate inflammation. And then I would see which groups of patients do better.