Research Updates in Kidney and Urologic Health

NIDDK Contributions to Dialysis

Dialysis as a practical treatment for kidney failure has evolved over centuries and continents. Many have played a role in developing this medical technology, starting with Thomas Graham of Glasgow, who first presented the principles of solute transport across a semipermeable membrane in 1854.¹ Almost 100 years later, the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), originally called the National Institute of Arthritis and Metabolic Diseases (NIAMD), was established as part of the National Institutes of Health (NIH). As NIDDK observes its 50th anniversary in 2000, a retrospective on the progress in dialysis seems appropriate.

Hemodialysis: Proof of Concept

The team of Abel, Rowntree, and Turner dialyzed the blood of animals at Johns Hopkins Medical School in Baltimore in 1912. The German scientist George Haas first tried hemodialysis on humans in 1924.² Then two decades passed before Willem Kolff and his colleagues at the Municipal Hospital of Kampen in the Netherlands developed an artificial kidney using cellophane tubing wrapped around a rotating drum.³ In the 1940s, Kolff's team extended the life of a patient with uremia for 26 days, until his blood vessels became too damaged for further access. At that time, hemodialysis was considered a treatment to keep patients with acute renal failure alive long enough for their kidneys to recover.

Early dialysis.	Walter Reed Hospital

Shunts and Membranes

After NIAMD was established, the first major breakthrough in hemodialysis came in 1960 at the University of Washington in Seattle, where Belding Scribner and Wayne Quinton devised a reusable vascular access in the form of a shunt made of Teflon tubing. The Scribner shunt did not react with living tissue and remained patent between treatments because of the nonstick properties of Teflon. Although the shunt would later be replaced with the arteriovenous fistula and synthetic graft, this reusable vascular access made it possible for the first time to keep patients with end-stage renal disease (ESRD) alive indefinitely. Supported in part by the U.S. Public Health Service (PHS), the Seattle Artificial Kidney Center was established in January 1962 as the first outpatient dialysis unit in the country.⁴

In the 1960s, NIAMD established the Artificial Kidney-Chronic Uremia Program (AKCUP-NIAMD), a contract program to support research that would advance dialysis technology. One of the early advances emanating from AKCUP and NIAMD-funded researchers Ben Lipps, Frank Gotch, and John Sargent was the hollow-fiber dialyzer membrane that replaced bulky plate and frame dialyzers that had to be rebuilt after each use.⁵

Peritoneal Dialysis

In 1963, Henry Tenckhoff—like Scribner, a researcher at the University of Washington—developed a catheter that made peritoneal dialysis more practical.⁴ But at that time, peritoneal dialysis was delivered in an intermittent form that was not as efficient as hemodialysis.

In the 1970s, NIAMDD (digestive diseases had been added to NIDDK's title at that time), sponsored research to make intermittent peritoneal dialysis more efficient. In 1978, teams of researchers from the University of Texas and the University of Missouri collaborated to describe a new, continuous method of delivering peritoneal dialysis.⁶ Their article coined the term continuous ambulatory peritoneal dialysis (CAPD). The Texas researchers, led by Robert Popovich and Jack Moncrief, and the Missouri team, led by Karl Nolph, received research support from NIAMDD's AKCUP program.

Congress Expands Medicare To Cover ESRD Treatment

As maintenance hemodialysis became more common during the 1960s, one major problem in the widespread transfer of this technology was that it still was not available to everyone who needed it. Facilities were forced to establish criteria for selecting their patients from among the many applicants, in effect choosing who would live. The Veterans Administration and the PHS supported the establishment of dialysis centers in several locations around the country, but availability was still far from universal. The high cost also limited the number of people who could receive regular hemodialysis treatments. By one estimate, only about 5,000 people were receiving hemodialysis in 1971, more than a decade after it became available.⁷

In 1972, Congress extended Medicare coverage to anyone with ESRD, as long as that person was eligible for or insured under Social Security, or was the spouse or dependent of someone who was. Starting on July 1, 1973, Medicare payments could be applied to hemodialysis or renal transplantation expenses. With these financial barriers lifted, the number of people receiving hemodialysis began to grow steadily. But even with advances in vascular access, many patients were unable to receive hemodialysis because vascular problems made repeated needle insertions impossible.

Peritoneal dialysis was not initially included in the Medicare ESRD program, although it had been used for several years. In 1978, the Food and Drug Administration approved CAPD for the treatment of ESRD. Medicare began reimbursing for CAPD in 1979,⁸ and a National CAPD Registry was started and supported by NIH from 1981 to 1988.

National Cooperative Dialysis Study

In 1974, AKCUP sponsored the Conference on Adequacy of Dialysis to explore methods for quantifying the dialysis process.⁹ The National Cooperative Dialysis Study resulted from participant recommendations that a clinical trial be launched to focus on a variety of dialysis prescription factors, such as length and frequency of treatment, dialyzer membrane characteristics, and ways to measure outcomes. This study considered a theory that undiscovered "middle molecules," molecules larger than urea, were responsible for the uremic syndrome. Ultimately, researchers found that patients did best when a certain level of urea reduction took place during dialysis, although it took several years for the lesson to become a standard of practice.¹⁰

U.S. Renal Data System

In 1977, the Health Care Financing Administration (HCFA) was established, and management of the ESRD program was included in its mandate. HCFA kept statistics on patients with ESRD for administrative purposes, but more epidemiologic and demographic information was needed for scientific purposes. In 1988, NIDDK awarded a contract to establish and manage the U.S. Renal Data System (USRDS) to the Urban Institute of Washington, DC, with a subcontract to the University of Michigan.

The mandate of the USRDS included four goals: (1) characterize the total population of renal patients and describe their distribution by sociodemographic variables across treatment modalities; (2) report on incidence, prevalence, and mortality rates and trends over time; (3) develop and analyze data on the effect of various treatment modalities by disease and patient group; and (4) identify problems and opportunities for more focused special studies of renal concerns. In 1992, two more goals were added: (5) conduct cost-effectiveness studies and other economic studies of ESRD and (6) support investigator-initiated projects to conduct biomedical and economic analyses of patients with ESRD.¹¹ USRDS has published an Annual Data Report every year since 1989 and has conducted a large series of special studies.

Beyond invaluable trend data, USRDS has had practical clinical implications, such as comparisons of outcomes of hemodialysis vs. peritoneal dialysis patients, peritonitis incidence by CAPD connection technique, the role of dialysis efficiency on mortality risk in hemodialysis patients, and the role of histocompatibility antigen matching on kidney graft survival, to name only a few examples.⁷

NIH Consensus Conference on the Morbidity and Mortality of Dialysis

The establishment of the USRDS, however, did not mark the end of NIDDK's commitment to advancing ESRD knowledge. In 1993, NIDDK sponsored a consensus conference on the morbidity and mortality of dialysis.¹² Experts in general medicine, nephrology, pediatrics, biostatistics, and nutrition reviewed the available scientific data to develop a series of recommendations addressing several issues, specifically predialysis therapy, quality of life for patients with ESRD, quantitative evaluation of dialysis dose and adequacy, reasons for underdialyzing, cardiovascular complications, malnutrition, and research opportunities. The recommendations included a call for a minimum Kt/V of 1.2 for a delivered dose (a recommendation that would be repeated a few years later by the National Kidney Foundation's Dialysis Outcomes Quality Initiative) and clinical trials to explore whether a higher Kt/V would result in even more favorable outcomes.

The HEMO Study

Following the consensus conference, NIDDK initiated a multicenter clinical trial testing whether a higher hemodialysis dose or high-flux membranes or both would reduce mortality and morbidity. The full-scale phase of the trial began in July 1994 with a data center and 15 participating clinical centers. Although final results of the trial will not be available for a few more years, one lesson already learned is a refinement of the Kt/V formula that provides more consistent measurements. The equilibrated dialysis dose (eKt/V) is based on the traditional single-pool Kt/V with an adjustment for time on dialysis.¹³

The Hemodialysis Vascular Access Clinical Trials Consortium

In 1998, NIDDK sponsored a workshop on Critical Issues in the Care of the Dialysis Patient. The workshop focused on nutrition and vascular access, which is often called the Achilles heel of hemodialysis because vascular access problems can lead to treatment failure. One recommendation that emerged from the workshop was to support basic investigations and clinical trials that explore ways to prolong the life of grafts and fistulas. In September 2000, NIDDK awarded grants to a consortium of institutions to conduct vascular access clinical trials. The consortium will conduct a series of multicenter, randomized, placebo-controlled clinical trials of drug therapies to reduce the failure and complication rate of arteriovenous grafts and fistulas in hemodialysis. Recently developed antithrombotic agents and drugs to inhibit cytokines will be rigorously evaluated in these large clinical trials.

Advances in the treatment of kidney failure have come from many sectors, including private industry, educational institutions, and hospitals. In its first 50 years, NIDDK has provided support and direction for much of the research that has led to incremental improvements and major breakthroughs in dialysis. At the start of its sixth decade, NIDDK continues to look for ways to improve treatment and enhance quality of life for people with chronic kidney failure.

References

1. Graham T. The Bakerian lecture: on osmotic force. Philosophical Transactions of the Royal Society in London. 1854;144:177–228.

2. Vienken J, Diamantoglou M, Henne W, Nederlof B. Artificial dialysis membranes: from concept to large scale production. American Journal of Nephrology. 1999;19:355–362.

3. Kolff WJ, Berk HT, ter Welle M, van der Ley AJ, van Dijk EC, van Noordwijk J. Artificial kidney: a dialyzer with a great area. Acta Medica Scandinavica. 1944;117:121–134. Reprinted in Journal of the American Society of Nephrology. 1997;8(12):1959–1965.

4. Blagg CR. The early years of chronic dialysis: the Seattle contribution. American Journal of Nephrology. 1999;19:350–354.

5. Lysaght MJ. Turning points: hemodialysis membrane. Dialysis & Transplantation. 1996;25(10):657–662.

6. Popovich RP, Moncrief JW, Nolph KD, Ghods AJ, Twardowski ZJ, Pyle WK. Continuous ambulatory peritoneal dialysis. Annals of Internal Medicine. 1978;88:449–456. Reprinted in Journal of the American Society of Nephrology. 1999;10:901–910.

7. Lundin AP, Port FK. Adequacy of treatment for end-stage renal disease in the United States. In: Schrier RW, ed. Advances in Internal Medicine. Vol. 41. St. Louis: Mosby-Year Book, Inc.; 1996: 323–363.

8. Institute of Medicine (U.S.). Committee for the Study of the Medicare ESRD Program. Kidney Failure and the Federal Government. Rettig RA, Levinsky NG, eds. Washington, DC: National Academy Press, 1991.

9. Wineman RJ. Artificial Kidney-Chronic Uremia Program: plans for cooperative clinical trials. Kidney International. 1975;7(suppl 2):S243-S245.

10. Depner TA. Optimizing the treatment of the dialysis patient: a painful lesson. Seminars in Nephrology. 1997;17(4):285–297.

11. United States Renal Data System. 1994 Annual Data Report. Bethesda, MD: National Institute of Diabetes and Digestive and Kidney Diseases; 1994.

12. Morbidity and Mortality of Dialysis. NIH Consensus Statement. 1993 Nov. 1–3;11(2):1–33.

13. Depner T, Beck G, Daugirdas J, Kusek J, Eknoyan G. Lessons from the Hemodialysis (HEMO) Study: an improved measure of the actual hemodialysis dose. American Journal of Kidney Diseases. 1999;33(1):142–149.

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