Dr.
Garabed Eknoyan
President National Kidney Foundation.
Professor of Medicine,
Baylor College of Medicine,
Houston, TX.
USA
Zoccali: Dr Eknoyan the HEMO study was conceived to see whether a dose of dialysis above that currently recommended can reduce mortality. Do the substantially negative results of this landmark study imply that we have already achieved maximum benefit from dialysis technology as it is now?
Eknoyan: It is fair to say that the HEMO Study convincingly showed that the current U.S. recommended minimum dose for small molecule (urea) clearance, factored for the patients volume of urea distribution, is a sufficient dialysis dose and that giving more does not seem to benefit the average patient. These results should not be construed to justify reducing the dose of dialysis. However, they do indicate that for patients receiving thrice weekly treatments lasting 2.5 to 4.5 hours each we have reached or neared the maximum benefit that can be attained when the benefit is viewed in the traditional dose-response sigmoid curve. This is not to say that future technological advances in dialysis may not provide new solutions or that either longer sessions or more frequent dialysis will not improve outcomes.
Zoccali: Results suggest a benefit of high flux membranes in
patients treated longer than 3.7 years. You have been very cautious in interpreting
this finding. Then what can be said about this subgroup analysis? Do we need
a new study?
Eknoyan: The benefit of high flux membranes observed in the HEMO Study in patients who had been on dialysis longer than 3.7 years prior to being randomized into the two flux arms of the study must be interpreted with caution. The difference was found when the number of years before randomization was analyzed as a dichotomous variable. The strength of the interaction was reduced when the number of years of dialysis was treated as a continuous variable, and different statistical methods and analysis of different dialysis periods yielded inconsistent results. As such, the reported results must be considered as hypothesis generating and are deserving of study. Perhaps the results of the multi-center Italian flux study, now nearing completion, will yield some of the answers.
Zoccali: The HEMO study was enriched with several interesting
subprojects on disparate issues from seasonal variation of clinical and laboratory
parameters to inflammation markers and nutrition. How did you manage to create
the study infrastructure and to embed proposals of subprojects in the main study
?
Eknoyan: A large data-base was generated by the HEMO Study, which has just began to be analyzed. What has been published to-date are the primary results and some of the analysis of the baseline data collected prior to randomization of subjects into the study. Over the coming months and years there will be a wealth of additional information that will be forthcoming. The credit for these belongs to the creativity and inquisitiveness of the investigators at the fifteen clinical centers of the study, and to the input and support of the statisticians of the Data Coordinating Center at the Cleveland Clinic Foundation. To illustrate, as the study was nearing completion the principal investigators were queried about questions they would like to address or explore from the collected data-base. There were over seventy questions posed. These have been prioritized and will be addressed systematically.
Zoccali: Is it possible that the HEMO study subliminally instils
a sort of pessimism on dialysis technology in the nephrology community?
Eknoyan: The HEMO Study examined only two variables in dialysis delivery. A number of others, such as duration, frequency, reuse and individualization of treatment, remain to be examined. Moreover, it would be an under-estimation of human creativity or capability to resolve problems to assume that dialysis technology has no new solutions to offer. There is no room for pessimism. Dialysis has saved and continues to save the lives of millions. There is just more work to be done.
Zoccali: The HEMO study did not assess the effect of treatment
time. In this respect daily dialysis seems to be a promising treatment. This
treatment may be costly and difficult to deploy on a large scale and (in a previous
interview) dr. Shaldon was sceptical on the future of the daily option. Do you
believe that a large scale study exploring the benefits of daily dialysis is
worth doing ?
Eknoyan: Absolutely. Answer to the benefits, cost and feasibility of daily dialysis must come from larger controlled clinical trials. A request for application for such a study has already been issued by the NIDDK. I should add that what is most impressive from the preliminary reports of daily dialysis is not only the outcomes, but also that of patient compliance.
Zoccali: An indirect implication of the negative results of
the HEMO study may be that we ought to concentrate our efforts in bettering
nephrology care in early phases of chronic renal diseases. Also in view of the
high frequency of mild and moderate degrees of renal dysfunction in the general
population, do you think that the Scientific Societies and Research Institutions
should make a strong case for focusing clinical research in prevention?
Eknoyan: Correct, except that I would like to differ in characterizing the results of the HEMO Study as negative. In fact one of the positive results of the HEMO Study is the documentation of the heavy burden of co-morbid conditions (average ICED score of 2.7) with which the patients entered the study. It would be simplistic to assume that technical advances in dialysis can alter significantly the outcome of existing co-morbidities. Actually, in the course of developing the Dialysis Outcomes Quality Initiative (DOQI) guidelines it became evident that in order to improve dialysis outcomes, it was necessary to improve the health status of patients entering a dialysis program, and that therein existed an even grater opportunity to improve outcomes for all individuals with chronic kidney disease (CKD), beginning at the earliest stages of kidney injury through the entire course of CKD, well before the final stages of kidney failure when replacement therapy becomes necessary. This is now feasible because of the increasing evidence that: 1) the adverse outcomes of CKD (kidney failure, cardiovascular disease, premature death) can be prevented or delayed; 2) treatment of earlier stages of CKD is effective in reducing progression to kidney failure and in preventing the systemic complications that develop in the course of progressive loss of kidney function; and 3) initiation of treatment for cardiovascular risk factors (anemia, hypertension, dyslipidemia, bone mineral metabolism) at earlier stages of CKD can be effective in reducing the very high and leading cause of morbidity and mortality of these patients. This is what prompted the expansion of the scope of DOQI to encompass the entire spectrum of CKD, and the change of its acronym to K/DOQI for Kidney Disease Outcomes Quality Initiative.
Zoccali: Recent observations by Collins show that DOQI guidelines
have produced tangible benefits in dialysis care in the USA. You have been a
strong advocate of the need of developing nephrology guidelines. Do you feel
that now the positive experience in your country can be taken as a basis for
developing International Guidelines?
Eknoyan: It is now evident that rigorously developed evidence-based clinical practice guidelines, coupled with an implementation plan, do in fact reduce variability of care, improve patient outcomes and benefit the efficiency of care. It is the practical specificity of focused guideline statements which allows their easy incorporation in an implementation plan and translation into clinical practice. This is what differentiates them from other evidence-based approaches (meta-analysis, systematic reviews), which distill and analyze the literature, but leave it to chance for the practitioner to peruse them or determine their integration into clinical practice. It is this approach that determined the documented success of DOQI and constitutes the basis of K/DOQI. The translation of the original guidelines or their modification to be applicable to conditions unique to a given local is what provided the impetus of developing globally applicable guidelines. This should be feasible since guidelines are evidence- based and centered on optimal patient care. Given that science and patient problems are universal and have no geopolitical boundaries, it should be possible to cull resources and develop globally applicable core guidelines, that allows for their subsequent regional adaptation taking into consideration the practical and unique conditions of any given country. To this end, an international coordinating board has been convened to determine the feasibility of globally applicable guidelines in nephrology. This should place our discipline at the forefront of clinical practice guideline development, and hopefully pave the way for wider cooperation in other endeavors.
Zoccali: Which are the most important changes that you foresee
during the next 20 years in the treatment of renal diseases?
Eknoyan: The most important changes will likely come from genetic studies and that of the integration of the now mushrooming massive but fragmented experimental information of changes at the molecular level into a unified pathophysiological interpretation applicable to the entire organism. This would provide identifiable, and therefore potentially manageable, determinants of the variations we now see in all the interventional clinical trials. Another source would be epidemiologic studies that better define the course of progressive loss of kidney function and document the applicable interventions that can retard its progression to end-stage kidney failure.
Zoccali: Which advise would you give a young doctor entering
a career in nephrology?
Eknoyan: Congratulations for a wise choice of a career in a most stimulating and still growing specialty in medicine. Chose either genetics or outcomes research for areas to work in.
Zoccali: You have a deep interest in History of Nephrology.
Who is the most inspiring and fascinating scientist-doctor of the past?
Eknoyan:
This is an impossible question to answer fairly for two major reasons. First,
because the scientific endeavor is a cumulative one in which each new generation
forges its advances using the hypothesis and tools developed by the preceding
generations. Second, as deconstructionist analysis has shown, even the most
inspiring and fascinating figures in any discipline, when subjected to critical
analysis, had weaknesses, faults, deficiencies and a host of undesirable traits.
This preamble notwithstanding it is possible to list some physicians, whose
seminal work could be argued to have been a milestone in the evolution of nephrology:
Rufus of Ephesus, who wrote the first monograph on diseases of the kidneys;
Galen, who proved the kidney as the source of urine; Morgagni, who provided
the first classification showing the kidney as a site of disease; Richard Bright,
who described and gave his name to what is now end-stage kidney disease; and
Homer Smith; who shaped renal physiology. And of course, Willem Kolff and Belding
Scribner, who changed kidney failure from a fatal to a treatable disease and
thereby provided the catalyst for the emergence of nephrology as a discipline;
and Joseph Murray, the 1990 Nobel laureate, who with John Merrill pioneered
kidney transplantation. On a broader sense, one would have to include William
Harvey and Claude Bernard.
