Dialysis at a crossroads: reverse engineering renal replacement therapy.

E ngineering 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/Vurea, 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/Vurea (Figure 1A) (5). Perhaps even more alarming, recent US Renal Data System data indicate that risk-adjusted mortality of longterm dialysis patients (vintage 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 strides in improving patient and graft survival. Data from three recently published randomized, clinical trials are particularly challenging. The HEMO Study used a 2 2 factorial design to examine whether a high dose of dialysis (as measured by Kt/Vurea) or use of high-flux dialysis membranes could improve morbidity and mortality for hemodialysis patients. The results supported the null hypothesis in both treatment arms (Figure 1C) (6). The ADEMEX Trial, another wellconducted clinical trial, similarly did not demonstrate a relationship between peritoneal dialysis dose and patient outcomes (Figure 1D) (7). These studies suggest that there may be a threshold dialysis dose above which there is a significant plateauing of augmented benefit. Recently, an eagerly awaited study did not support the hypothesis that the use of statins would significantly lower the rate of cardiovascular complications in dialysis patients with diabetes (8). Given the lack of recent progress, a reexamination of the engineering principles that are at the root of dialysis therapy, and a comparison with kidney physiology is timely.