Reverse Epidemiology: Dialysis Paradox

In this population, high BMI, BP, and cholesterol seem to be associated with better survival

While obesity, hypertension and hypercholesterolemia are well-established harbingers of poor cardiovascular health and death, so-called reverse epidemiology holds that these physiological states actually increase the chance of survival in many people—including dialysis patients. That’s the controversial theory being put forth by a group of maverick researchers led by Kamyar Kalantar-Zadeh, MD, PhD, associate professor of medicine and pediatrics at the University of California in Los Angeles.

According to Dr. Kalantar-Zadeh, reverse epidemiology seems to apply to several populations that comprise between 20 million and 40 million Americans. Renal & Urology News recently spoke with Dr. Kalantar-Zadeh about his provocative theory.

It was the consistent and repeated observation that in some populations traditional CVD risk factors do not appear to be good predictors of death. For a long time, it was 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 blood pressure and obesity. But studies failed to show this. At the same time, research began to find high BMI and high serum albumin and lipid levels are consistently associated with better survival. All of these observations led, finally, to a unifying hypothesis.

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 interventional studies. There have, however, been a few. For example, a study performed at the University of Würzburg in Germany two years ago showed that dialysis patients who took statins received no survival benefit at four years’ follow-up compared with patients who received placebos. Many people were surprised, even shocked, by these results.

In addition to dialysis patients, obesity seems to improve survival in patients with chronic heart failure, rheumatoid arthritis, chronic obstructive pulmonary disease (COPD), cancer, and adults over age 80. All of 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 human body can store fat for the days of hardship when it needs nourishment, and it is therefore an asset for short-term survival. Until 30 or 40 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 blood pressure 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, in effect, a return to conditions that prevailed prior to the 20th century, when mankind had to focus on short-term survival. One might even say that traditional epidemiology is an emergence of a new association, and that reverse epidemiology is more natural.

They’re 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. This is called the endotoxin–lipoprotein hypothesis. Hypertension may protect dialysis and heart failure patients by giving them a kind of cushion against BP-lowering interventions, e.g., dialysis treatment per se or medications to improve heart conditions, both of which have low BP as side effects.

They, too, are markers of better nutritional status. Creatinine is a surrogate of muscle mass, not just kidney function. Anyone who has more muscle mass has higher creatinine levels. I’ve had bodybuilders ask me why their creatinine levels are high, and I assure them that people with above-average muscle mass are not at a disadvantage, al-though they are often categorized as morbidly obese. High BMI is not necessarily a bad thing, and we are hoping that reverse epidemiology may make it clear that obesity is not a black and white concept. Determination of appropriate body weight must be individualized.

Protein-energy malnutrition and inflammation are two relatively common and concurrent conditions in CKD patients, and they have been implicated as the main cause of poor short-term survival in this population. The malnutrition-inflammation-cachexia syndrome (MICS) ap-pears 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; acute inflammation helps fight against infections and bodily in- sults. When inflammation becomes chronic it becomes deleterious.

Survival bias can be looked at from two viewpoints. One is that patients with chronic diseases may be the ‘tip of iceberg’ of a much larger number of individuals. 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 in some way. People who live long enough to be octogenarians or non-agenarians, or to develop chronic heart failure, may also be ‘lucky un-lucky’ survivors. All of these are examples of survival bias.

With regard to time discrepancies among risk factors, malnutrition re-quires only a short amount of time to exert its deleterious effects on survival; people starve to death relatively quickly, while over-nutrition kills slowly, over several decades. So over-nutrition is the traditional risk factor while under-nutrition ‘wins’ the competition to kill.

Today, obese people on transplant lists are required to lose weight. The wisdom of this is being debated and questioned, though, and there may come a day when dialysis patients will be encouraged to eat more and not try to lose weight.

I currently take care of 80 dialysis patients. Some of them know my back- ground and ask about these issues. I tell them that we’re 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 re-consider 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, their mortality rates may go up."

Patients listed for transplants are usually on a waiting list for four to six years. Surgery is more challenging on patients who are obese, so 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. So it’s a dilemma and we don’t have any answer right now. We hope that we will have clearer answers in the future.

We believe that nutrition intervention is much more important than addressing traditional CVD risk factors in dialysis patients and others with chronic disease. In the future, I can see more attention being paid to nutritional interventions, including giving patients oral or IV nutritional supplements, and medication to im-prove appetite. Appetite status is actually a strong predictor of survival in dialysis patients. One might even say that "those who go to McDonald’s and Jack in the Box live longer." Going to such restaurants may be a surrogate for having a better appetite and better nutritional status.

Having a higher-than-average protein and calorie intake is important. But dialysis patients face other challenges. They must avoid high potassium and phosphorus intakes. To limit phosphorus, one must eliminate consumption of preservatives in sodas and from other non-protein sources. In other words, physicians should encourage dialysis patients to maintain a high protein intake, but to be sure this doesn’t lead to a high phosphorus and potassium intake. This is the dilemma.

I would like to look at the effects of nutritional interventions on dialysis patients to better understand why weight gain is associated with better survival. I’d like to give some patients more protein and calories, and give them different types of nutrition and different types of medications to improve appetite and mitigate inflammation, and then see which groups of patients do better.

No. Renal transplant patients exhibit a phenomenon called reversal of reverse epidemiology, which means they go back to normal. In transplant patients with successfully functioning kidneys, obesity becomes bad and is associated with worse, not better, survival. When you place a healthy organ in the patient, the entire model changes. You cure the disease and also cure the reverse association.