**4. For whom and how to make the prescription?**

In view of the potential beneficial clinical effects associated with the use of HDx, most patients on chronic hemodialysis would be potential candidates for HDx treatment, especially since, to our knowledge, there is currently no specific contraindication to the use of MCO membranes in patients on chronic hemodialysis. That said, some criteria can help us to choose the patients to start with and gain experience in HDx therapy.

As HDx would optimize the clearance of middle molecules, it would ideally be prescribed in patients who have the greatest retention of large middle molecules and those who would have the greatest benefit from increased removal of these molecules. Among these patients, mention may be made of anuric patients, since serum concentrations of middle-molecules are closely correlated with residual renal function, patients with a long-expected lifespan, without kidney transplant project, patients with persistent hyperphosphatemia, and patients with chronic inflammation, erythropoietin resistance, secondary immunodeficiency, and cardiovascular disease [30, 57]. Moreover, there are some promising applications in which HDx could have an interest: pruritus, post-HD asthenia, anorexia, restless legs syndrome, myeloma, and rhabdomyolysis [50].

Compared to the OL-HDF, the HDx would be useful when an adequate convective volume (23 L) cannot be reached (elevated hemoglobin, suboptimal blood flow…), or when the OL-HDF needs to be suspended (dialysis without anticoagulation, one needle puncture, safety reasons) [7]. HDx is a simple dialysis technique, requiring no sophisticated equipment or special training for nurses. It can be delivered with any standard hemodialysis monitor. As described above, blood flow around 300 mL/ min and dialysate flow around 500 mL/min is sufficient to achieve optimal clearance, superior to HF hemodialysis and comparable to or even exceeding HDF [13]. HDx therapy requires no specific or intensified clinical monitoring. However, as with all filters with internal filtration, the quality of dialysis fluid remains a sine qua non condition to ensure the safe conduct of the dialysis session. The manufacturer recommends that the MCO membrane should not be used in convective strategies most likely due to the potential risk of significant albumin loss [30]. Thus, especially in patients who were in HDF, or when using monitors that can perform HDF, care should be taken to verify the selected treatment mode, and switch the treatment mode to hemodialysis if not.

Another factor that should probably be considered is the length of the session. In comparison to small water-soluble solutes, the clearance of middle-molecules is affected more by the inter-compartment transfer from extra to intravascular compartments during dialysis [30]. So, it would make sense that, at least in dialysis settings where time is flexible, such as home hemodialysis, MCO membranes could be used for long or more frequent dialysis treatments to increase middle-molecule removal.
