How might hypertension and hyperlipidemia protect dialysis patients?

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.


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Why might high serum creatinine and homocysteine levels be better than low levels in dialysis patients?

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.

What is the “malnutrition inflammation-cachexia syndrome” and how might it explain the existence of reverse epidemiology?

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.

You’ve said there may be other explanations for reverse epidemiology, including “survival bias,” and “time discrepancies among competitive risk factors.” How might these explain your paradoxical findings?

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.

I know your work on the theory of reverse epidemiology is still in its infancy, but if it proves to be a genu-ine phenomenon, how might it affect treatment for dialysis patients?

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.

Given what we now know, do you ad-vise your patients on dialysis to take medication to lower elevated BP and cholesterol levels, and to lose weight if they are overweight?

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.”