The reasons for a clinical trial on incremental haemodialysis

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An author video to accompany this article is available at https://academic.oup.com/ndt/pages/author_videos. There is growing interest in an incremental approach to haemodialysis (HD) for incident end-stage kidney disease (ESKD) patients, starting with one or two sessions per week [1–5]. Such an approach not only seems to preserve residual kidney function (RKF) and improve health-related quality of life with similar or higher survival rates than those observed in patients receiving the standard thrice-weekly HD regimen, but also allows saving economic resources [6–10]. The term ‘incremental HD’ means that, in the presence of substantial RKF, both dialysis dose and frequency can be low at dialysis inception but should be progressively increased to compensate for any subsequent reduction in RKF [11–13]. The current principle for calculating the amount of dialysis required to compensate for RKF reduction is based on the constancy of the value of total (renal + dialytic) weekly clearance as expressed by the equivalent continuous clearance (ECC) of urea [11–13]. Two versions of ECC exist, the standard Kt/V [14] and the equivalent renal urea clearance (EKR) [15]. For the sake of simplification, only EKR will be used. The assumption of a constancy of the total EKR (renal + dialytic), the so-called fixed target model of EKR, implies the attribution of a clinical equivalence to dialytic EKR (EKRd) and renal urea clearance (Kru), which is a mistake [16]. A variable target model (VTM) has recently been introduced to correct this mistake [16]. In short, the total EKR should vary from a minimum value, provided only by the native kidneys, to a maximum value, provided only by the dialysis treatment [16] (Figure 1). The minimum value corresponds to a hypothesized threshold Kru (KruThr) for starting HD even in the absence of signs or symptoms of uraemia; at this level, by definition, there is no need for dialysis, so the target ECC is just KruThr [16] (Figure 1). The maximum value corresponds to the adequate equilibrated Kt/V (eKt/V) in anuric patients on a 3 HD/week regimen [16] (Figure 1). The mistake of attributing a clinical equivalence to dialytic urea clearance and Kru is not trivial, because it leads to overestimates of dialysis needs in the presence of substantial RKF, requiring such high values for both RKF and dialysis dose (Kt/V) that it would be difficult to prescribe less frequent treatments [1, 16]. Moreover, delivering more dialysis than really needed could accelerate the decline of RKF [17], likely due to many factors, such as more blood–membrane and blood–dialysate interactions, intradialytic arterial hypotension with cardiac and renal ischaemia, as well as disruption of the compensating mechanisms set in motion by intact nephrons in response to nephron loss [17–19]. The VTM for the prescription of incremental dialysis. Total EKR is the total equivalent renal urea clearance [15]: it expresses the total clearance (dialytic + renal), i.e. the sum of the contribution of the dialyser urea clearance (Kd) to EKR (EKRd) and of the residual renal urea clearance (Kru). According to the fixed target model, the total target EKR should remain constant: 12 mL/min/35 L = eKt/V × 3 sessions/week. This means that each mL/min of Kru should be replaced by increasing the dialysis component (EKRd) by the same amount. In contrast, according to the VTM, the total target EKR varies from a minimum value at the start of HD treatment (in this case Kru = 6 mL/min/35 L) to a maximum value when Kru = 0. This reduces the amount of dialysis dose required (red bars). The above concept [16, 20] can be applied to both versions of ECC. In fact, the concept of an increased clinical weight of Kru introduced by the VTM [16, 20] is in line with the new version of standard Kt/V, which uses Kru at 100%, instead of a ‘compressed’ Kru used with the original standard Kt/V [13, 21]. Table 1 shows a simulation study using Solute-Solver software [22] based on the double-pool urea kinetic model recommended by the 2015 Kidney Disease Outcomes Quality Initiative (KDOQI) guidelines [13]. It allows drawing two trajectories for the variable target as Kru approaches zero [20]: a low-level one with EKR increasing from 4 mL/min/35 L, corresponding to a glomerular filtration rate (GFR) of 6 mL/min/1.73 m2, in agreement with the European Renal Best Practice position statement [23], to 10 mL/min/35 L, corresponding to an eKt/V of 1.05 for anuric patients on a 3 HD/week schedule, which is the adequate dialysis dose established by the Hemodialysis (HEMO) Study [24]; and a high-level one, with EKR increasing from 6 mL/min/35 L, corresponding to a GFR of 9 mL/min/1.73 m2, to 12 mL/min/35 L, corresponding to an eKt/V of 1.29 on a 3 HD/week schedule (Table 1) [16]. A simulation study using Solute-Solver software [22] based on the double-pool urea kinetic model recommended by the 2015 KDOQI guidelines [13] The eKt/V values required to reach two different levels of target EKR (in bold) as a function of Kru and treatment schedule. The simulation was made for a patient with a urea distribution volume of 35 L and ultrafiltration volume per session of 1, 2 and 3 L, for 1, 2 and 3 HD/week regimens, respectively. The values in columns 3–5 refer to the lowest target in column 2; the values in columns 7–9 refer to the highest target in column 6. A simulation study using Solute-Solver software [22] based on the double-pool urea kinetic model recommended by the 2015 KDOQI guidelines [13] The eKt/V values required to reach two different levels of target EKR (in bold) as a function of Kru and treatment schedule. The simulation was made for a patient with a urea distribution volume of 35 L and ultrafiltration volume per session of 1, 2 and 3 L, for 1, 2 and 3 HD/week regimens, respectively. The values in columns 3–5 refer to the lowest target in column 2; the values in columns 7–9 refer to the highest target in column 6. The availability of two prescription lines, instead of a single one, allows defining a ‘prescription zone’ between the two lines. This can avoid both delivering unnecessarily high doses of dialysis, which could accelerate Kru decline, and maintaining a stable prescription in front of reductions in Kru. In particular, Table 1 shows that an eKt/V of 0.79 is adequate for a 1 HD/week schedule in the presence of Kru ≥3.0 mL/min/35 L, so that an eKt/V of 1.05 (+31%) should be largely adequate. Analogously, an eKt/V of 0.97 suffices on a 2 HD/week schedule, and even more, an eKt/V of 1.05 will be adequate because it corresponds to a single-pool Kt/V (spKt/V) of 1.2 [24]. On this basis, one could safely use a constant eKt/V of 1.05 on a 1 HD/week schedule until Kru is ≥3.0 mL/min/35 L and on a 2 HD/week schedule for Kru ≥1.5–<3.0 mL/min/35 L [20, 25]. Moreover, relying on a prescription zone with a constant Kt/V largely above the minimum value required reduces the need for a frequent Kru measurement. The above construct is apparently sound but, obviously, it should be confirmed by a randomized clinical trial (RCT) before its clinical implementation. To this end, the European Dialysis (EUDIAL) Working Group of the ERA-EDTA is ready to start the ‘RandomizEd clinicAL triaL on the effIcacy and saFety of incremental haEmodialysis’ (REAL LIFE), using VTM on incident HD patients [25]. Keystones of this study are the following concepts: (i) Incremental dialysis represents a continuum and integration of pre-dialysis care [11], with a smooth transition from conservative management of chronic kidney disease (CKD) to the full 3 HD/week regimen [2, 19, 25, 26]. Interestingly, such a smooth transition has been advocated in opposition to the ‘abrupt’ start with a full thrice-weekly schedule, which could be responsible for the exceptionally high annualized mortality rate of ~40% for the first few months after HD inception [2]. Accordingly, the patient on transition to the full HD therapy should be seen as a patient essentially on cons

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