Two ongoing studies presented at the 33rd Annual Meeting of the American Society of Nephrology could lead to revolutionary changes in the way end-stage renal disease (ESRD) patients receive hemodialysis (HD). The end result of these changes could enable patients to live longer, healthier lives.

Interrelated, but very different in design, the two studies employ biostatistical analyses to ascertain the types of treatment that are most beneficial for ESRD patients in terms of survival outcomes. The first of these investigations is the Dialysis Outcomes and Practice Patterns Study (DOPPS), a large international trial that collects data on hemodialysis practices and patient outcomes in seven geographic areas-France, Germany, Italy, Japan, Spain, the United Kingdom, and the United States. Supported by a grant from Amgen and Kirin-Amgen in Japan, which are major suppliers of HD products, DOPPS is officially defined as a "longitudinal, observational, patient, and facility data study."

According to the study's coordinator, Dr. Philip Held, Epidemiologist and Biostatistician, Head, University Renal Research & Education Association (URREA), Ann Arbor, Michigan, the study is best described as unprecedented in size and scope, at least in the field of HD.

"In operation for 27 months in Europe, 18 months in Japan, and 52 months in the US, DOPPS now encompasses 80 percent of the world population of HD patients [10,000 plus individuals] and is already providing tantalizing clues as to how ESRD management might be improved," Dr. Held said.

Key among the emerging trends is a relationship between the HD dose patients receive and the incidence of mortality, he added. "Specifically, DOPPS data to date suggest a substantial fraction of HD patients would likely have better outcomes if doses were higher both in the US and in the six other countries participating in the study," he explained.

"Dose," in HD parlance, does not refer to medications, Dr. Held explained, but to the amount of HD treatment patients receive. In simple terms, dialysis is a mechanical "scrubbing" procedure that removes toxins from the blood, thereby compensating for renal insufficiency. During dialysis, blood is run through a hollow fiber consisting of a semi-permeable membrane. On one side of the membrane is a dialysate solution, which, because of its chemical properties, draws various toxic molecules from the blood into itself by a process of diffusion. Via this same process, beneficial ingredients contained in the dialysate-electrolytes, for example-flow across the membrane into the blood. Hence, "dose" is actually a combination of the length of time patients are on dialysis, the size of the dialysis machine, the speed of blood flow through the machine, and a host of other factors that must be correlated to ascertain how much cleaning takes place during a treatment session. Clinicians ascertain whether sufficient cleaning has taken place by measuring the removal of certain markers from the blood-notably, the crude parameter urea, a small, molecular bi-product within a person's body that is normally dispensed as waste material when protein is consumed and metabolized.

"At present," added Dr. Held, "HD patients typically have their blood cleaned by dialysis three times a week in the US. However, there is an ongoing debate over how much HD is enough for effective treatment. Removal of urea, for instance, can be measured by a formula called the urea reduction ratio (URR). Typically, nephrologists have strived for a URR of 65 percent from baseline urea values as the treatment goal, believing that was enough.

"However, DOPPS data now suggest patients do significantly better in terms of mortality if a URR of 75 percent is attained, which requires a substantial increase in the dose level to achieve. This is a surprising and dramatic finding, since it was previously believed that the benefits curve of HD flattened out at a URR of 65 percent and that real improvement in patient outcomes at higher levels [i.e., at 75 percent] would be marginal."

Like the Hypertension Optimal Treatment (HOT) study on cholesterol, he added, where researchers found that maintaining cholesterol levels below what had been previously recommended had a beneficial effect on reducing the risk of heart disease, DOPPS may prove to be a study that will change the way HD is conducted in Europe, the US, and Japan.

At the same time, Dr. Held stressed that as an observational trial, DOPPS is not designed to establish "cause-and-effect" (i.e., compare and define which treatments should be considered the 'gold' standards of care).

It can, however, reveal practice patterns and trends that are worthy of further investigation in a full-protocol clinical trial, he pointed out, which does have the power to establish standards of care, typically by comparing one treatment to another to show which intervention provides the best results.

Indeed, that is precisely the goal of the hemodialysis (HEMO) study, which was presented in concert with the DOPPS trial during the Toronto meeting by lead investigator, Dr. Tom Greene, Biostatistician, Cleveland Clinic Foundation, Ohio.

According to Dr. Greene, the HEMO study is a randomized, single-blind, clinical study that will follow about 1,780 US HD patients for up to 6.5 years once enrollment is completed this December. To be eligible for the study, patients must be currently receiving dialysis at a hospital center, on treatment for at least three months, between 18 and 80 years of age, and have a very low level of residual kidney function (ESRD).

Designed as a "two-by-two factorial trial," the study will mount two investigative arms, Dr. Greene added. One intervention will compare a standard dialysis dose-an equilibrated level of 1.05 kt/v is the target, which meets national guidelines-to a high dose-kt/v target = 1.45. "Basically, by comparing results, we hope to establish whether providing longer dialysis sessions or providing dialysis at a higher blood flow will cause more toxins to be removed from the blood and thereby provide better patient outcomes," he explained.

The other arm of the study, referred to by researchers as "the flux arm," will examine the effectiveness of the equipment being used to perform HD. Specifically, the researchers will compare currently approved HD "low flux" membranes to a more porous, more permeable "high flux" membrane to determine if the latter improves patient outcomes.

"Basically, low-flux membranes remove small molecular waste by-products such as urea from the blood," Dr. Greene explained. "By comparison, high flux membranes remove both small waste particles and what researchers refer to as 'middle-sized' waste molecules. We want to see what, if any, beneficial effects this has on patient outcomes."

Primary outcomes of the trial will focus on survival, he added, while secondary outcomes will track composite events that correlate death with certain types of hospitalizations and co-morbidities-for instance, the occurrence of either a hospitalization or death due to a cardiovascular event. Diabetic endpoints will also be investigated, Dr. Greene said, since about 40 percent of patients in the HEMO study will have this condition.

"Many types of renal disease lead to ESRD," Dr. Greene added, "so we designed this study to be open to all of the major patient groups, including those with diabetes, a condition that can lead to diabetic nephropathy and kidney failure, glomerular nephritis, hypertension-which can result in hypertensive nephrosclerosis, particularly among Afro-Americans-and polycystic kidney disease, a genetic anomaly that accounts for about ten percent of all ESRD patients."

Although the trial obtains its comparative power by being randomized and "blinded," meaning trial results are not revealed to the investigators until the study ends, the HEMO study will not be "double-blinded," a more strict design where no one knows the effects treatments are having until codes are broken at the end of the trial, Dr. Greene said.

Instead, the investigation will have adjudicators in the background that will perform interim analyses of the outcomes data on a yearly basis to make sure no clear result has emerged.

"This is for ethical reasons," Dr. Greene explained. "For instance, if we were to discover very early on that a bigger and better treatment effect occurs with either the high flux membrane or the higher dialysis dose, quite simply, it would no longer be ethical to continue to randomize people to the standard treatment, since it would be inferior medicine."

While results are still a time away, Dr. Greene explained that the study has the potential to change and improve HD treatment protocols worldwide.

"Suppose we do find high dose HD is better than a standard dose," he said. "It would no doubt spur manufacturers to make dialysers more efficient. It could also lead to daily dialysis instead of the thrice-weekly standard currently used in the US.

"Further, such findings could also provide dialysis equipment manufacturers with important insights into how their membrane technology could be improved. Perhaps increased membrane porosity may indeed benefit patients more than the current technology. By the same token, we also have to establish that no negative effects occur. We could see useful components of the blood being taken out, for instance, in which case the benefits of a more porous membrane might be negated. Most people involved with the HEMO doubt this will be the case," he added. Rather, a measurable benefit is expected.

Should that prove the case, Dr. Greene concluded, it would immediately affect how HD membranes are manufactured. "You would probably see low flux membranes rapidly disappear in favor of the high-flux alternatives, and even though their manufacture would be more expensive, you would have significantly improved outcomes for patients with ESRD."

Still, be that the goal, the future awaits the results of the trial. The earliest Dr. Greene expects any data to become available from the HEMO study is early 2001, with final results published sometime in 2002.