Debate: Intermittent Hemodialysis versus Continuous Kidney Replacement Therapy in the Critically Ill Patient: The Choice Should Be Evidence Based

Introduction

AKI is a frequent complication of critical illness.1 It is associated with both higher mortality and long-term sequelae including CKD.1,2

Timely use of KRT is an important aspect of treatment of AKI.3 Recent data indicate that the number of patients who receive KRT in intensive care units (ICUs) has increased. This may reflect augmentation of the incidence of AKI as patient severity, age, and previous morbid conditions increased over time.4

Several KRT techniques are available in the ICU settings. The two main modalities are intermittent hemodialysis (HD) and continuous KRT (CKRT), and the comparison of those two techniques will be the subject of this review.

Background and Uncertainties

Since CKRT was introduced in practice, there has been debate as to whether this modality provides better clinical outcome (survival and kidney function recovery) than conventional intermittent HD. This has been particularly the case for hemodynamically instable patients or those with important fluid overload.3,5,6

Putative better hemodynamic tolerance with CKRT, if confirmed by adequate studies, could facilitate kidney recovery.7 As a matter of fact, some but not all studies6 reported delayed kidney function recovery with intermittent HD. Intermittent HD, if administered for 3–4 hours every session using parameters (in particular ultrafiltration rate) usually prescribed for stable end-stage kidney disease patients,8 causes rapid plasma solute clearance provoking a decrease in plasma osmolality and free water movement from the intravascular to the interstitial and intracellular compartments, which have relatively higher osmolality.7 In addition, the rate of ultrafiltration may exceed that of plasma refilling from interstitium and contribute to occurrence of hypotension.7,9 This aspect is discussed in more detail in the chapters devoted to description of techniques.8,10 By providing a more progressive equilibration, CKRT may be associated with better hemodynamic stability. Interestingly, a before-after study showed that simple interventions (inspired by KRT practices in end-stage kidney disease) such as isovolemic initiation of KRT, reduced dialysate temperature, preferential use of bicarbonate buffer, sodium profiling (i.e., dialysate [Na+] >145 mmol/L), and conservative initial ultrafiltration dramatically improved the hemodynamic tolerance of intermittent HD.11 A recent review insisted on this aspect.8

In our era of evidence-based medicine, it is noteworthy that conclusions from previous observational and even randomized controlled trials (RCTs) comparing treatment methods date back at least 15 years.12–15 Their validity can be challenged for two main reasons. First, mortality of critically ill patients diminished over time: It was 60%–70% in these RCTs12 versus 45%–55% in recent studies.16 Moreover, older studies were flawed by the inclusion of an unknown (but likely significant) number of patients who would no longer receive any KRT because of simple reduction of urine output, as in several studies including the HEMODIAF trial.17 Indeed, timing of initiation and choice of modality of KRT are strongly intertwined. The former issue is discussed elsewhere in CJASN's series on Critical Care Nephrology and Acute Kidney Injury, but it is useful to keep in mind that four large multicenter RCTs (AKIKI [2016],16 Initiation of Dialysis EArly Versus deLayed in Intensive Care Unit [2018],18 STARRT-AKI [2020],19 AKIKI 220) and an individual patient data meta-analysis of nine RCTs21 demonstrated that there is no need to initiate KRT in emergency in the absence of life-threatening complication during severe AKI. Delaying KRT initiation may allow hemodynamic stabilization of patients and initiation of KRT in better conditions. This is important concerning intermittent HD, for which hemodynamic tolerance is claimed by some to be less favorable than that of CKRT.7 Three large multicenter RCTs conducted in France18,20,21 showed a balanced use of both techniques, whereas CKRT was prevalent in a larger international RCT.19 Main participants in these four studies were academic centers, which may affect external validity of results.

Currently, French22 and Kidney Disease Improving Global Outcomes (KDIGO) recommendations23 concur on many aspects. For instance, CKRT should be preferred in patients with acute brain injury and a risk of intracranial hypertension22 (Figure 1). Rapid shifts in blood osmolality more often caused by intermittent HD may contribute to iatrogenic increases in intracranial pressure. By contrast, poisonous dialyzable substances24 (and small molecules such as potassium in case of life-threatening hyperkalemia) are removed faster with intermittent HD.25

fig1Figure 1:

KRT modality indications for severe AKI: few certitudes, many questions. CKRT, continuous KRT; IHD, intermittent hemodialysis.

Both recommendations agree on the theoretical equivalence of the two techniques in the vast majority of patients with AKI but differ concerning patients with hemodynamic instability. The KDIGO guidelines suggest preferential use of continuous techniques, whereas French guidelines stipulate no preference.

Finally, financial considerations are at stake when choosing a KRT technique. This particular aspect is examined below. It stems from all the preceding that preference of one technique over the other should rely more on solid data than on key opinion leaders' utterance. This article contends that data are not sufficient at present to favor any technique, except in very particular circumstances that were mentioned above.

What Is at Stake in This Debate

This must be addressed not only regarding clinical outcome but also resources and logistics. Both intermittent and continuous techniques have advantages and drawbacks. As mentioned above, hemodynamic tolerance is putatively better with CKRT than with intermittent HD according to some but not all investigators.26 On another side, use of CKRT mandates patient dependency on an extracorporal technique 24 hours a day for several days, which is less convenient for physiotherapy interventions and some aspects of care (transporting patient to the computed tomography scan suite or operating room). Physiotherapy interventions may influence and even prevent physical impairment of ICU patients.27 Anticoagulation, with its associated risks and costs, is required more frequently with CKRT than with intermittent HD25 and is another concern that will not be discussed here.

Finally, the same intermittent HD machine may be used for several patients in the same day, which may prove useful in case of shortage of extracorporeal KRT machines because it occurred during the recent coronavirus disease 2019 epidemics in a high-outcome country.28 The choice of a technique must also take the availability of resources and skilled personnel into account. They may vary among countries and ICUs.

Comparison of Clinical Outcome According to KRT Technique Mortality

Observational studies did not clarify this issue,29 and most RCTs30 did not show any difference in mortality. The latter are detailed in Table 1. The larger one (HEMODIAF trial) included 360 patients, most of them with severe hemodynamic compromise.12 Mortality at day 60 was not different according to the technique (68% versus 67%; P=0.98 for intermittent HD and CKRT, respectively). Contrasting with these negative studies, an RCT by Mehta et al. that included 166 patients reported a higher hospital mortality with CKRT than with intermittent HD (66% versus 48%; P<0.02).13 The authors of this study attributed this finding to an imbalance in some characteristics at baseline. However, randomization procedure contributes to equilibration of known and unknown factors by definition. A Cochrane systematic review and meta-analysis30 (some aspects of included studies are summarized in Table 1) concluded to the lack of mortality difference between CKRT and intermittent HD. Three more recent meta-analyses that included two additional RCTs concurred with this conclusion.34–36

Table 1 - Main characteristics of randomized controlled trials comparing KRT techniques Study Time Frame No. of Patients Initiation Criteria for KRT Survival (Intermittent HD versus CKRT) Hemodynamic Status (Intermittent HD versus CKRT) Kidney Function Recovery (Intermittent HD versus CKRT) Mehta et al. 13 1991–1995 166 At least one of the three following criteria:
BUN >40 mg/dl
SCr >2.0 mg/dl
Rise in SCr >1 mg/dl from baseline values
And judgment of the treating nephrologist ICU mortality
41.5% versus 59.5% (P<0.02)
Hospital mortality
47.6% versus 65.5% (P<0.02) NA Complete recovery
33% versus 35% (ns)
KRT dependency at hospital discharge
7% versus 14% (ns) Augustine et al. 15 1995–1999 80 Determined by the consulting nephrologist on the clinical service (no clear criteria) Hospital mortality
70% versus 67.5% (ns) The groups were not compared:
Intermittent HD: decrease in MAP from baseline during the initial treatment (77.6 versus 75.0 mm Hg, P=0.04)
CKRT: MAP remained unchanged from baseline (76.8 versus 77.4 mm Hg, P=ns) KRT dependency at hospital discharge
20% versus 20% (ns) Misset et al. 31 1993–1996 39 At least one of the two following criteria:
BUN >84 mg/dl
SCr >4.5 mg/dl
And mechanical ventilation for more than 48 h NA Mean value of MAP
81 versus 83 mm Hg (P=0.72)
Greatest change of MAP (highest-lowest MAP)
48 versus 46 mm Hg (P=0.73)
Frequency of MAP decrease >10 mm Hg
25% versus 26% (P=0.72) NA Uehlingrer et al. 14 1998–2000 125 At least one of the two following criteria:
SCr >4.0 mg/dl
UO <20 ml/h ICU mortality
38% versus 34% (P=0.71)
Hospital mortality
50.9% versus 47.1% (P=0.72) Incidence of circulatory failure (average daily MAP <65 mm Hg)
15% versus 21% (P=0.36)
Hemodynamic instability (average variability between maximum and minimum daily MAP)
40% versus 29% (P=0.13) Complete recovery
42% versus 50% (P=0.61) Vinsonneau et al. 12a 1999–2003 360 At least one of the three following criteria:
SCr >3.5 mg/dl
BUN >100 mg/dl
UO <320 ml for 16 hb
And need for KRT determined by practitioner judgment
And multiple organ dysfunction Day 60 mortality (primary end point)
31.5% versus 32.6% (P=0.98) Hypotension (systolic arterial pressure ≤80 mm Hg or a fall >50 mm Hg from the baseline value)
39% versus 35% (P=0.47) NA Gasparović et al. 32 2001–2003 104 At least two of the three following criteria:
Three-fold increase in SCr
Hyperkalemia >5.5 mmol/L
Base excess >−6
And multiple organ dysfunction Mortality (time not defined)
59.6% versus 71.1% (ns) Blood pressure instabilityc (>10 mm Hg)
(ns [values not given]) NA John et al. 17 Unclear but the article was published in 2001 33 At least one of the two following criteria:
SCr >3 mg/dl
UO <10 ml/h
And severe septic shock
And need for MV
And APACHE II between 20 and 45
And pulmonary capillary wedge pressure ≥12 and <18 mm Hg ICU mortality
70% in both groups (no more precision given) Evolution of systolic arterial pressure after 2 h:
5 versus +12 mm Hg (P<0.05)
Decline of cardiac output:
0.25 versus −1.54 L/min (P<0.01) NA Lins et al. 33 (SHARF) 2001–2004 316 Decision of the attending physician Hospital mortality
62.5% versus 58.1% (P=0.43) NA eGFR <15 ml/min at hospital discharge
25% versus 17% (ns)

HD, hemodialysis; CKRT, continuous KRT; SCr, serum creatinine; ICU, intensive care unit; NA, not applicable; ns, not significant; MAP, mean arterial pressure; UO, urine output; MV, mechanical ventilation; APACHE, Acute Physiology, Age, Chronic Health Evaluation; SHARF, Stuivenberg Hospital Renal Failure; RCT, randomized controlled trial.

aIn this study, the largest RCT on this topic, median SCr was 427 μmol/L, median BUN was 30 mmol/L, and 58% of patients included were oliguric (<500 ml UO per day).

bThis inclusion criterion was added 8 months after the beginning of the study.

cNo precision whether the reported blood pressure was MAP or systolic arterial pressure.

A secondary analysis of two large multicenter recent RCTs16,18 raised the hypothesis that CKRT might actually be associated with a higher death rate.37 Using propensity scores, that study reported that the weighted Kaplan–Meier death rate at day 60 was 54% in the CKRT group and 47% in the intermittent HD group (weighted hazard ratio [HR], 1.26; 95% confidence interval [CI], 1.01 to 1.60; P=0.049). This unexpected finding was more evident in less severely ill patients (weighted HR, 1.82; 95% CI, 1.01 to –3.28; P<0.01). Caution is warranted in the interpretation of these results, which should be essentially viewed as hypothesis generating, given the marginal significance of the main finding and possible residual confounding. This is all the more true because that study suffered the pitfall evoked at the beginning of this review: Only patients allocated to the early KRT initiation group (in which many patients received KRT without real need) were included.

Hemodynamic Stability

Many clinicians choose KRT modality according to patient hemodynamic status.26 As explained above, the belief of a better hemodynamic tolerance of CKRT stems from observational studies conducted in the 1990s.38–40

If the particular status of the critically ill is not taken into account and intermittent HD is prescribed with the same settings as for patients with terminal CKD, it will likely result in severe hemodynamic compromise and potential worsening of kidney injury. Studies comparing the two modalities should mandate the implementation of adequate settings for intermittent HD, which was not always the case.

Observational studies left many uncertainties that were not fully dissipated by RCTs. The HEMODIAF trial12 showed that the number of patients with hypotensive episodes during KRT did not differ according to the technique (39% in the intermittent HD group versus 35% in the CKRT group [P=0.47]). This is all important because many patients were hemodynamically unstable on inclusion in this study (more than 85% of patients were receiving catecholamine on the day of randomization). It is, however, difficult to base a definitive opinion on a single RCT, which may suffer from potential pitfalls explained above.

In any event, the Cochrane systematic review and meta-analysis30 included 15 RCTs (1550 patients) and reported that “CKRT did not differ from intermittent HD with respect to hemodynamic instability (relative risk [RR], 0.48; 95% CI, 0.10 to 2.28) or hypotension (RR, 0.92; 95% CI, 0.72 to 1.16) and need for escalation of pressor therapy (RR, 0.53; 95% CI, 0.26 to 1.08).” However, this meta-analysis showed that mean arterial pressure was higher with CKRT (mean difference 5.35 mm Hg, 95% CI, 1.41 to 9.29). The clinical significance of this modest difference may be questioned. Main characteristics of RCTs comparing KRT techniques are presented in Table 1.

Future studies may allow definitive conclusion because they should include patients for whom, in the absence of severe metabolic complication, time has been given to assert KRT indication. This may allow for hemodynamic stabilization in many instances.

Kidney Function Recovery

Some experts26 advocate CKRT because of its alleged association with more rapid recovery of kidney function. In support of this opinion, a systematic review and meta-analysis of studies comparing the two modalities concluded that intermittent HD (compared with CKRT) was associated with a higher risk of KRT dependency at the end of the follow-up (RR, 1.99; 95% CI, 1.53 to 2.59).6 This meta-analysis included both observational studies and RCTs. The superiority of CKRT was the result of observational studies only (RR, 1.99; 95% CI, 1.53 to 2.59), whereas RCTs concluded to the lack of difference (RR, 1.15; 95% CI, 0.78 to 1.68).

A major bias of observational studies, including those presented in that meta-analysis, is called competing risk by statisticians.41 It is the consequence of CKRT being more often used in severest patients for already explained reasons. Such patients may have a higher mortality rate than those receiving intermittent HD. This was the case in that meta-analysis. This artificially reduces patient dependence on KRT in the long term (death and KRT dependency are competitive events). Indeed, if KRT dependency is defined at a precise time point (day 30 or 60 for instance), patients must survive long enough for kidney recovery to be determined. Otherwise, all early deaths are classified as nondependent from KRT, leading to a substantial bias in favor of the CKRT group.42

A recent systematic review and meta-analysis36 did not find any difference on dialysis dependency between CKRT and intermittent HD (RR, 0.90; 95% CI, 0.59 to 1.38).

Two recent large retrospective studies of patients with severe AKI have attempted to overcome the bias explained above using appropriate statistical methods. One used multivariable analysis and a propensity score to balance clinical characteristics between groups in 1338 patients.43 No difference in kidney function recovery was observed at 90 and 365 days according to the technique of KRT (odds ratio [OR], 1.19; 95% CI, 0.91 to 1.55; P=0.20; OR, 0.93; 95% CI, 0.72 to 1.2; P=0.55, respectively). However, as mentioned by authors, patients with initially impaired hemodynamics were more often placed on CKRT. The other study5 examined a composite end point of death and KRT dependency at day 30 in 1360 patients. Using a marginal structural Cox model, no difference was observed according to KRT modality (RR, 1.00; 95% CI, 0.77 to 1.29). There was also no difference in persistency of kidney dysfunction at 6 months (OR, 0.70; 95% CI, 0.36 to 1.37) between the two modalities.5 However, as mentioned by authors, here also, patients with initially impaired hemodynamics were more often placed on CKRT.

In contrast with these studies, an intriguing finding was reported in a subsequent individual patient data meta-analysis assessing the effect of KRT intensity on dialysis dependence.44 A total of 3682 patients from eight prospective RCTs were included. Time to cessation of KRT was longer with high-intensity KRT (P=0.02). Among patients who received high-intensity KRT, CKRT was also associated with longer KRT dependence than intermittent HD (P=0.03).

Long term (matter of years) was not evaluated in these studies. In 2014, a retrospective population-based matched cohort was conducted in critically ill patients undergoing KRT for AKI.45 Receipt of CKRT was associated with a lower risk of progression to maintenance dialysis (HR, 0.75; 95% CI, 0.65 to 0.87; P<0.001). However, and as duly stated by the authors, this study provides evidence of association, rather than causation. An RCT addressing this issue with a comparison of CKRT versus intermittent HD with long-term follow-up (3–5 years) would then be advisable.

As a partial conclusion, it is possible to state that there is no scientific argument in favor of one over the other technique in the vast majority of patients. Some rare specific indications (Figure 1) are, however, usually accepted. In such conditions, the issue of cost-effectiveness is a major consideration that can inform the debate.

Cost-Effectiveness and the Influence of ICU Organization

This issue was insufficiently evaluated. At first glance, CKRT may be more expensive because of the usually higher number of circuits compared with intermittent HD and because of more frequent need for anticoagulation among others. In a recent study, lifespan of the filter was comprised between 27 and 47 hours according to anticoagulation technique (longer duration with citrate anticoagulation than with heparin). Cost of solutes for CKRT and that of water purification systems for intermittent HD must also be taken into account. The salaries of specialized personnel, in jurisdiction where different teams (ICU and nephrology teams) concur in the treatment of the same patient, are an important determinant of cost. If a given technique is theoretically more costly than another one, this may be balanced with possible effects on length of stay in both ICU and hospital and kidney function recovery. Dialysis dependence rate (including long-term dependence) is indeed probably a major driver of cost-effectiveness.46

The cost-effectiveness of intermittent HD versus CKRT has been studied mostly by modeling studies. They were either investigator-initiated or industry-sponsored in a variety of settings (Europe, North America, and Latin America). The results, which have been summarized in a systematic review and health technology assessment report,46 show a vast heterogeneity with conflicting findings, explained in part by the uncertainty in the model inputs. In short, industry-sponsored models run for Latin American countries show CKRT to be dominant (i.e., less expensive and more effective), while investigator-initiated studies in North America and Europe tend to show noninferiority and lower costs for intermittent HD.46,47 Of the seven studies included, three that favored CKRT were conference abstracts and were funded by industry. A more recent study included in that work48 used a model-based cost utility to evaluate long-term costs and health outcomes for a hypothetical cohort of patients with AKI in ICU settings using an adapted Markov model. That study reported that CKRT dominated intermittent HD with more cost-saving and higher quality-adjusted life year gains over the modeled time horizon of 10 years.48 However, these results should be interpreted with caution because they are derived from a model.

Finally, a post hoc analysis of an epidemiological prospective study of AKI in ICU patients (Beginning and Ending Supportive Therapy for the Kidney study) included 1260 patients from 23 countries worldwide who received KRT and is particularly instructive on the factors that affect the cost of KRT.49 Extracorporeal circuit costs and costs associated with dialysate and replacement fluids were generally higher for CKRT ($3629.80/d) than for intermittent HD ($378.60/d). By contrast, that study reported higher nursing expenses with intermittent HD (from $25.70/d to $681.40/d, according to region).

Substantial differences in KRT procedures may influence cost-effectiveness. For example, the respective role of the nephrologist and of the ICU physician influences both choice of modality and cost of KRT.50–52 In the Beginning and Ending Supportive Therapy for the Kidney post hoc analysis mentioned earlier, intensivists were more likely to prescribe CKRT than nephrologists. In most regions, specialized dialysis nurses provided intermittent HD, which is likely to increase cost, whereas usual ICU nurses provided CKRT.49

Finally, no prospective study precisely evaluated the comparative cost of techniques, taking all parameters affecting cost into account, in particular outcome at 3–5 years.

No definitive argument definitely pleads in favor of one over the other technique. As explained in this review, although uncertainties persist, it seems likely that no short-term outcome (mortality, hemodynamic tolerance, kidney function recovery) differs between techniques provided they are delivered in an appropriate manner. Most of the studies, including RCTs,12–15 that compared techniques were conducted more than 15 years ago. Important progresses were eventually made leading to much lower mortality rates in recent studies of KRT for AKI16,18,19 than in these previous ones.12,13 This simple observation would justify a reassessment of the issue with the taking of present indications for KRT into account.

Research recommendations of KDIGO guidelines, and most if not all conclusions from meta-analyses, insist on the importance for future RCTs on KRT modalities to assess long-term kidney sequelae along with mortality.23 This would be best achieved by an RCT with sufficient power to draw undisputable conclusions and with a design that takes lessons from recent studies into account. Pending such study, enthusiasm of certain key opinion leaders for one technique over the other should be tempered.

Disclosures

S. Gaudry reports consultancy agreements with ZAMBON. S. Gaudry reports that Artificial Kidney Initiation in Kidney Injury (AKIKI) and AKIKI 2 trials were funded by the French Ministry of Health. All remaining authors have nothing to disclose.

Funding

None.

Author Contributions

Writing – original draft: Khalil Chaïbi.

Writing – review & editing: Didier Dreyfuss, Stéphane Gaudry.

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