Dialysis at a Crossroads

Abstract

Engineering is the profession that is responsible for designing, constructing, and manufacturing products, systems, and structures. Csete and Doyle (1) noted that the theory and practice of complex engineering systems has progressed to the point that they often embody Arthur C. Clarke's dictum, "Any sufficiently advanced technology is indistinguishable from magic." In the 20th century, the development and implementation of dialysis as a life-sustaining therapy for kidney failure constituted a "magical" medical advance.The expansion of hemodialysis into a chronic renal replacement therapy also created a new field of medical science, sometimes termed the physiology of the artificial kidney. When the National Cooperative Dialysis Study (NCDS), the first landmark randomized trial in dialysis, demonstrated that a higher dose of delivered dialysis (measured as the time-averaged plasma concentration of urea) was associated with a lower risk for subsequent hospitalization (2), a science of dialysis had emerged (3). Gotch and Sargent (4) used NCDS data to develop the concept of Kt/V urea , a dimensionless construct that relates the clearance of urea to its volume of distribution, as a measure of dialysis dose. Nephrologists became familiar with concepts of diffusive and convective clearance, volume of distribution, and solute modeling. Quantifying the dialysis prescription became part of the parlance of clinical nephrology, thereby objectifying the "magical" early results with dialysis therapy.Urea is an attractive molecule for kinetic modeling. It is readily and accurately measurable, its volume of distribution generally reflects total body water, and it is neither lipophilic nor highly protein bound. Furthermore, urea kinetic modeling is an attractive paradigm for the physiology of the artificial kidney because urea removal is concentration dependent and high urea concentration discriminates a uremic and a nonuremic state. Therefore, as long as data clearly supported the concept that the amount of urea removal closely associated with clinical outcomes in dialysis patients, the paradigm of hemodialysis therapy as renal replacement therapy was on a sound conceptual footing.The limitations of dialysis as treatment of uremia now are becoming more apparent, bringing dialysis therapy to a crossroads. Over the past decade, there has been minimal improvement in the risk for hospitalization or mortality, even adjusting for changing demographics and comorbidities in dialysis patients and despite steady improvement in achieving identified dialysis clinical performance measures, including Kt/V urea ( Figure 1A) (5). Perhaps even more alarming, recent US Renal Data System data indicate that risk-adjusted mortality of longterm dialysis patients (vintage Ͼ 5 yr) has been increasing rather than decreasing over time ( Figure 1B). This suggests that cumulative toxicity from uremia is unabated and perhaps even exacerbated by recent changes in dialysis care. In comparison, transplantation, the current therapy of choice for ESRD, has made ...

Innovation in the Treatment of Uremia: Proceedings from the Cleveland Clinic Workshop: Uremic Toxicity, Oxidative Stress, and Hemodialysis as Renal Replacement Therapy

“…In the US, over the past two decades, there have been only limited improvements in risks for hospitalization or mortality, despite steady improvement in achieving many identified dialysis clinical performance measures such as achieving adequate urea clearance or in anemia management. This has lead to the suggestion that dialysis therapy may be at a developmental crossroads or tipping point (5).…”

The anglerfish and uremic toxins

“…With the apparent success of hemodialysis in correcting the uremic syndrome, research in uremia shifted and came to be focused largely on techniques and dialysis membranes that would allow more effective removal of small molecules capable of traversing dialysis membranes. To date, the evidence that differences in the porosity of artificial membranes, techniques of hemodialysis, dial-ysis time, or adequacy of dialysis based on assessments of urea removal, or urea kinetics significantly improve outcome is not convincing (3)(4)(5)(6).…”

Combining Dialysate and Blood Recirculation to Boost Uremic Toxin Removal: Theory and Simulation Study

“…Renal replacement therapies such as peritoneal dialysis (PD) only partially correct the symptoms experienced by the patient. HRQoL of patients during ESRD treatment is influenced by age and by many comorbid conditions such as diabetes mellitus, ischemic heart disease, congestive heart failure, liver disease, respiratory disease, and peripheral vascular disease (4).…”

“…This dimensionless parameter, called Kt/V, is advised by K/DOQI guidelines of the National Kidney Foundation to define the minimum dialysis dose needed for minimizing morbidity and mortality rates (3). Although dialysis and the underlying technologies have advanced strongly, we are now at a crossroads, because the mortality of ESRD maintenance dialysis patients is still high, and there is a lack of knowledge regarding the causal phenomena that relates mortality to the type and dose of dialysis (4).…”