nephrology

1. Journal Club
04-11-2021

2. NEED FOR STUDY
Acute kidney injury is a common condition among patients in
the intensive care unit and is associated with high morbidity
and mortality.
Renal-replacement therapy is the cornerstone of the
management of severe acute kidney injury.

3. • Many studies have focused on methods of renal-
replacement therapy but the issue of when to initiate the
therapy in the absence of a potentially life- threatening
complication directly related to renal failure remains a
subject of debate.

4. • Early initiation of renal replacement therapy may allow for
better control of fluid and electrolyte status, removal of uremic
toxins, and prevention of complications such as gastric
hemorrhage and metabolic encephalopathy.
• Delaying renal-replacement therapy initiation is intuitively
unlikely to have any immediate benefit per se.
• However, a delay may allow time for the stabilization of a
patient’s condition before renal replacement therapy is initiated
and may avoid the need for such support, which is not devoid of
risk .

5. • Given such uncertainties, there is heterogeneity among criteria for
the initiation of renal- replacement therapy

9. Clinical Question
• In critically unwell patients with acute kidney injury, does early
initiation of renal replacement therapy (RRT) compared to delayed
initiation reduce all cause mortality at 90 days?

10. Design
• Randomised, single centre, 2 group, parallel-group trial
• 1:1 randomization between treatment arms

11. Setting
• University Hospital Munster, Germany
• August 2013 to December 2015

12. Inclusion
• Acute kidney Injury- KDIGO stage 2:
• 2-fold increase in serum creatinine from baseline, or urine output <0.5ml/kg/hr for ≥12 hrs
despite optimal resuscitation (PCWP>12, MAP>65)
• NGAL >150ng/dl
• At least one of the following conditions:
• Severe sepsis
• Catecholamines (noradrenaline/adrenaline) >0.1mcg/kg/min
• Refractory fluid overload (worsening pulmonary oedema, fluid balance >10% body weight)
• Development or progression of non-renal organ dysfunction (SOFA organ system score ≥2)
• Age between 18 and 90
• Intention to provide full intensive care treatment for at least 3 day

13. Exclusion
• Patients with pre-existing kidney disease not requiring RRT
• Patients who had received any previous RRT
• AKI caused by permanent occlusion/surgical lesions of the renal artery
• Obstructive AKI
• HUS/TTP
• Prior Kidney transplant
• Hepatorenal syndrome
• AIDS with CD4 count <0/05 X109/L

14. Intervention
• Initiation of RRT within 8 hours of confirmation of KDIGO stage 2
• Delivered to 100% of patients assigned to early group
• Median time to RRT was 6.0 hours (IQR 4.0–7.0)

15. Control
• Inititation of RRT within 12 hours of either
• KDIGO stage 3 criteria
• Creatinine rise >3 fold increase from baseline, or oliguria <0.3ml/kg/hr for ≥24 hours or serum
creatinine > 4mg/dl (353.6 μmol/l) with an acute increase of at least 0.5mg/dl (44.2μmol/l)
within 24 hours
• Absolute indication for RRT
• Urea >100mg/dl
• Potassium >6mmol/l and or ECG abnormalities
• Blood pH <7.15
• Urine production <200ml/12hr or anuria
• Organ oedema in the presence of AKI resistant to diuretic treatment (defined as one trial of
furosemide)
• Delivered to 91% of patients assigned to delayed group
• Median time to RRT was 25.5 hours (IQR 18.8–40.3)

16. Common to both groups
• RRT standardized
• CVVHDF
• prediction 100%
• dialysate:replacement fluid ratio 1:1
• effluent flow 30ml/kg
• minimum 110ml/min blood flow
• citrate anticoagulation
• RRT discontinued if renal recovery evident by both:
• > 400ml urine in 24hr without diuretics or > 2100ml in 24hr with diuretics
• creatinine clearance > 20ml/min occurred
• RRT could be changed to SLED after 7 days if no recovery
• Additional treatments (ventilation, nutrition) standardized
• Follow up up to 1 year post randomization

17. Primary outcome
• 90 day mortality
• Early group 39.3% vs Delayed group 54.7%
• Hazard ratio 0.66 (95% CI 0.45 to 0.97; P=0.03)
• Absolute risk reduction 15.34% (95% CI 2.62% to 28.06%; P= 0.025)
• Fragility Index is 3

19. Secondary outcome
• Median duration of RRT: 9 days vs 25 days (P = 0.04, HR 0.69 [95% CI 0.48–1.00])
• Enhanced recovery of renal function at day 90: 53.6% vs 38.7% (P = 0.02, OR 0.55
[95% CI: 0.32–0.93])
• Median duration of mechanical ventilation: 125.5 hrs vs 181.0 hrs (P = 0.002)
• Error noted in manuscript: should be 181.0 hours not days?
• Length of hospital stay: 51 days vs 82 days (P < 0.001, HR 0.34 [95% CI 0.22–0.52])
• No significant differences seen in
• Requirement of RRT at day 90
• Length of ICU stay
• Adverse events, fluid balance, and RRT modality
• Subgroup analysis of those who reached KDIGO stage 3 vs those who achieved absolute RRT
requirement

20. • Inflammatory mediators (comparison of MIF, IL-6, IL8, IL-10, IL-18):
• No difference at randomisation
• 24 hours post randomisation: significantly lower IL-6 and IL-8 in early group
compared to delayed group (100% of early group and 21.8% of late group had
received RRT but this time point)

22. Conclusion
• Amongst critically unwell patients with AKI, early RRT compared with
delayed initiation of RRT reduced mortality over the first 90 days

23. Strengths
• Very strict definitions of AKI used and followed
• No patients lost to follow up, and very little data lost
• Clear separation achieved between groups
• Pre-specified secondary outcome analysis
• Exploratory analysis of inflammatory mediators provides a potential
mechanism by which early RRT may improve outcomes

24. Weaknesses
• Fragility Index 3: a shift of 3 patients would render it non-significant
(however, this is greater than the number lost-to-follow-up)
• Single centre study: limits its external validation
• Not all the treatments were standardised between groups. With the
groups also being unblinded, this introduces bias, challenging its
internal validity.
• External validation further challenged by skewed patient population:
• 216/231 (93.5%) were surgical of which 108 (46.75%) were cardiac surgery
patients
• 203 (88%) were mechanically ventilated at time of randomization

28. Study objective
Among ICU patients with AKI, does early renal replacement
therapy (RRT) reduce mortality as compared to delayed RRT?

29. TRIAL DESIGN

30. Multicenter, open-label, prospective, randomized trial N=620
Early RRT (N=311)
Delayed RRT (N=308)
Setting: 31 ICU in France
Enrollment: 2013-2016
Follow-up: 60 days
Analysis: Intention-to-treat
Primary outcome: Overall survival at day 60

31. INCLUSION CRITERIA
• Age ≥18 years
• Admitted to ICU with KDIGO Stage 3 AKI, with one of the following:
 Serum creatinine concentration> 4 mg/dl (354 µmol/l) or >3 times the baseline level
 Urine output ≤100 ml/day for >12 hours or <500 ml/day or <0.3 ml/kg/h for >24 hours
• ≥1 of the following:
 Mechanical ventilation
 Vasopressor support with epinephrine or norepinephrine

32. EXCLUSION CRITERIA
• BUN >112 mg/dL (40 mmol/L)
• Potassium >6 mmol/L or >5.5 mmol/L despite medical treatment pH <7.15 due to either
pure metabolic acidosis (PaCO2 <35 mm Hg) or mixed acidosis (Paco2 ≥50 mm Hg
without any capacity to increase alveolar ventilation)
• Severe hypoxemia requiring mechanical ventilation with oxygen flow rate >5L/min to
maintain SpO2 >95% or requiring a Fio2> 50% due to acute pulmonary edema despite
diuretic therapy
• Pre-existing CKD (creatinine clearance <30 ml/min)
• Patients fulfilling the inclusion criteria who have been present for >5 hours
• Poisoning due to an agent which is dialyzable

33. INTERVENTIONS
• In the early-strategy group, renal-replacement therapy was
initiated as soon as possible after randomization in order for
it to be started within 6 hours after documentation of stage
3 acute kidney injury.

34. • In delayed strategy group renal replacement therapy was initiated if

35. IN BOTH GROUPS, DISCONTINUATION OF RENAL- REPLACEMENT
THERAPY WAS CONSIDERED
• If the spontaneous urine output was 500 ml or higher per 24 hours
• If urine output was higher than 2000 ml per 24 hours in patients who
were receiving diuretic therapy.
• Discontinuation of renal replacement therapy was mandatory if
diuresis was sufficient to allow for spontaneous decrease in serum
creatinine concentration.

36. PRIMARY OUTCOME
• The duration of follow-up for each patient was 60 days from
randomization.
• The primary outcome was overall survival measured from the date of
randomization until death or day 60
• Data from patients who were alive at day 60 were censored, and data
from patients who were lost to follow-up before day 60 were censored
at their last follow-up assessment.

37. SECONDARY OUTCOME
• Receipt of renal replacement therapy at least once with the delayed strategy;
• The numbers of renal replacement therapy free days, dialysis catheter free days,
• Mechanical ventilation free days, and
• Vasopressor therapy free days
• The vital status at day 28;
• The length of stay in the intensive care unit and in the hospital;
• The occurrence of nosocomial infections and
• Complications potentially related to acute kidney injury or renal-replacement therapy

38. • The patients in the early-strategy group underwent their
first renal-replacement therapy session within a median of 2
hours after randomization and within a median of 4.3
hours after documentation of stage 3 acute kidney injury
and of the fulfillment of other inclusion criteria.

39. • A total of 157 patients (51%) received renal replacement
therapy in the delayed-strategy group
• The median interval between the occurrence of at least
one criterion mandating renal-replacement therapy and its
initiation was 4.7 hours

40. RRT IN DELAYED GROUP
• Persistence of oliguria or anuria for more than 72 hours
after randomization and a blood urea nitrogen level higher
than 112 mg per deciliter (40 mmol per liter) were the two
most common reasons for renal replacement therapy.

41. RESULTS
• Mortality did not differ significantly between the two study groups:
48.5% in the early-strategy group and 49.7% in the delayed- strategy
group

42. • Mortality at day 28, numbers of mechanical ventilation–free
and vasopressor-free days, length of stay in intensive care
unit and in the hospital, and dependence on renal-
replacement therapy at day 28 and 60 did not differ
significantly between the two study groups

43. • However the number of days free from renal-replacement
therapy was significantly higher, and the rate of catheter-
related bloodstream infections was significantly lower, in the
delayed-strategy group than in the early- strategy group

44. DISCUSSION
• Mortality at day 60 did not differ significantly between the
early-strategy group and the delayed-strategy group.

45. • Patients in the current study received renal-replacement therapy at a
median of 2 hours after randomization with the early strategy and at
a median of 57 hours with the delayed strategy.
• Contrary to hypothesis, no survival benefit was observed with the
delayed strategy of renal replacement therapy.

46. • Although the survival curves were similar in the two groups,
the recovery of renal function, as marked by diuresis, was
more rapid and catheter-related infections occurred less
frequently in the delayed-strategy group than in the early-
strategy group.

47. • Finally, the lengths of stay in the intensive care unit and in
the hospital were similar in the two groups, which indicates
that allowing time for renal function recovery did not lead
to prolongation of the stay in the intensive care unit.

48. LIMITATIONS
• The patients in the trial population had advanced acute
kidney injury, and therefore our results may not be
generalizable to patients with different KDIGO stages of
acute kidney injury.

49. • No use of Kt/V (a measure of the clearance of urea in which K
represents the rate of urea clearance by the dialyzer, t is the duration
of dialysis, and V is the volume of distribu- tion of urea in the patient)
to evaluate the dose of renal-replacement therapy.
• Limited generalizability as ~50% of patients received intermittent HD
and only 30% received continuous RRT

52. Background
• Acute kidney injury is a common occurrence in patients with septic
shock. The decision as to when to start renal replacement therapy is
controversial
• The AKIKI trial reported no difference in mortality with an early vs. a
delayed approach, whereas the ELAIN trial found a significant
mortality benefit with the early approach

53. Design
• Randomised controlled trial
• Open-label / non-blinded
• Stopped early due to futility
• Setting
• 29 ICUs in France (22 university teaching hospital and 7 general
hospitals)
• Data collected July 2012 – October 2016

54. Population
• Inclusion: Adult patients with septic shock and acute renal failure
• Septic shock defined as severe sepsis with >=2 SIRS criteria and need for
vasopressors despite adequate vascular filling
• Within 48 hours of starting vasopressors
• Acute renal failure defined as “failure” stage of RIFLE classification i.e. the
presence of >=1 of the following:
• Increased creatinine
• x3 baseline value, or
• >4 mg/dl
• Oliguria <0.3ml/kg/hr for 12 hours
• Anuria: diuresis <100ml for 12 hours

55. Exclusion:
• Chronic renal failure requiring dialysis, obstructive renal failure,
emergency criteria for immediate haemodialysis (K > 6.5, pH <7.15 or
pulmonary oedema by fluid overload), moribund or unlikely to
survive to 28 days because of uncontrolled co-morbitiies.

56. • 488 patients randomised out of 1728 who were assessed for eligibility
• Comparing intervention vs. control group – no significant differences
in baseline characteristics

57. Intervention
• Early initiation of RRT
• Start of RRT within 12 hours of documentation of ‘failure-stage’ acute kidney injury
• 97% of patients received RRT
• Control
• Deferred initiation of RRT
• RRT initiated after a delay of 48 hours post-diagnosis of ‘failure-stage’ of acute
kidney injury, if renal function had not spontaneously recovered or criteria for
emergency RRT had been met
• 62% of patients received RRT at any time
• 17% of patients received RRT earlier than 48 hours due to criteria for emergent RRT
being met
• 29% did not receive RRT because renal function spontaneously recovered
• 8% died before RRT initiated

58. Management common to both groups
• Choice of RRT (intermittent vs. continuous) was at discretion of
clinician, but had to adhere to protocol instructions for setting
• In cases of life threatening conditions (K >6.5mmol, metabolic
acidosis with pH < 7.15, pulmonary oedema that was refractory to
diuretics) within the 48 hours after randomisation, RRT initiated as
soon as possible
• In case of improvement of renal function within the 48 hours post
randomisation (return of spontaneous urine output >1000ml/24hr or
>2000ml/hr with diuretics), RRT is not mandatory

59. Outcome
• Primary outcome: All cause 90 day mortality – no significant difference
• 58% in early strategy vs. 54% in delayed, p=0.38
• Secondary outcomes – comparing early vs. delayed strategy
• Significantly lower:
• Median time from diagnosis of AKI to RRT
• 7.6 vs. 51.5 hours, p<0.001
• Days free of RRT
• 12 vs. 16, p=0.0006
• Episodes of hyperkalaemia
• 0% vs. 4%, p=0.03
• No significant differences in:
• Median days free of mechanical ventilation: 2 vs. 3
• Median days free of vasopressors: 16 vs. 17
• Median length of hospital stay: 23 vs. 23 days
• Dependence on RRT amongst survivors at day 90: 2% vs. 3%
• Fluid overload: <1% vs. 4%
• Severe bleeding event: 5% vs. 6%

60. Conclusion
• In patients with septic shock and severe acute kidney injury there was
no difference in mortality for patients assigned to an early compared
with a late strategy for renal replacement therapy

61. • Strengths
• Randomised controlled trial
• Patient centered outcome
• Intention to treat analysis
• Registered on clinical trials.gov
• Minimal loss to follow up
• Weaknesses
• Non-blinded – unrealistic to blind clinicians but authors could have
been blinded during data collection and analysis
• Stopped early due to futility with resultant decrease in power
• Use of both continuous and intermittent RRT allowed which is not
consistent with practice

66. • AKIKI was primarily studying medical patients in multiple centres with
sepsis (SOFA scores ~11) whilst ELAIN was studying surgical patients
in one centre (SOFA scores ~16). Segun pointed out that the
pathophysiology between these two cohorts is probably different.
• Surgical patients: possibly reduced renal blood flow related
with stress response pathophysiology
• Medical patients: possibly increased renal blood flow with significant
immune complex / toxaemia

67. Timing of RRT
• Both trials defined criteria for the early intervention: these differed
slightly such that ELAIN was really early (KDIGO stage 2)
and AKIKI was just early (KDIGO stage 3).
• The control groups were slightly different too: the ELAIN trial used
KDIGO stage 3 (85% patients) or metabolic derangement (15%
patients) as the indication for RRT, but the AKIKI trial used metabolic
derangement only. This means that the control group in ELAIN was
actually a very similar treatment to the AKIKI intervention group.
• So ELAIN was really
early vs early and AKIKI was early vs conventional.

68. Delivery of RRT
• AKIKI allowed unblinded clinicians to go ahead with whatever mode of RRT
they wanted, at whatever dosage. This was mixed intermittent and /
or continuous RRT for a median of 4 days. Given that intermittent mode
RRT was used extensively, it may be difficult to extrapolate the findings to
some Intensive Care Units where continuous mode RRT is used almost
exclusively. The exact modalities and dosages delivered were not
published. Only 51% of the delayed group actually received RRT.
• In contrast, ELAIN defined the RRT modality and dose: continuous vena-
venous haemodiafiltration (CVVHDF) at 30 ml/kg/hr with 100% pre-dilution
and 1:1 dialysate to replacement fluid. 91% of the delayed group received
RRT – a much higher proportion than the AKIKI trial’s delayed group.

69. • Both trials provided appropriate screening, selection, randomisation
and allocation concealment – these all minimise bias and increase the
internal validity of the results.
• The lack of defined RRT modality in AKIKI and the lack of blinding
(which is unavoidable for pragmatic reasons) may have introduced
ascertainment bias: clinicians may have treated one group more
favourably in unmeasured ways. This usually exaggerates the
measured effect in favour of the primary hypothesis.

70. Result
• The AKIKI trial failed to reject their null hypothesis.
• The ELAIN trial did demonstrate a statistical difference such that the
authors rejected their null hypothesis.
• Although the ELAIN trial demonstrated a statistically significant
outcome, given the fragility index is just 3 and it is a single centre
trial, it is quite likely that a repeat of the trial at another or multiple
sites may not find an effect size of the same magnitude.

71. • AKIKI: In sick patients that are medical or surgical with sepsis, then
early or delayed RRT is the right therapy is a ?
• ELAIN: In really sick patients on a surgical intensive care unit,
then very early CVVHDF is the right therapy.

74. Clinical Question
• In critically ill patients with severe acute kidney injury, does
accelerated initiation of renal replacement therapy compared to
standard initiation improve 90 day survival?

75. Design
• Open-labeled
• Randomised controlled trial. Participants were randomised 1:1 to
accelerated versus standard initiation of RRT
• Pre-specified subgroups were patient sex, eGFR, surgical patients,
geographical region, septic patients, SAP II score
• Setting
• Multi-national: 15 countries Australia, Austria, Belgium, Brazil, Canada,
China, France, Germany, Ireland, Italy, Finland, New Zealand, Switzerland,
the United Kingdom, and the United States.
• Multi-centre: 168 sites
• Patients were randomised from October 2015 to September 2019

76. Population
• Inclusion:
• >18 years
• Admission to an ICU
• AKI defined as Cr>100umol/L in women and Cr>130umol/L in men and had
not declined by >27umol/l in 48 hours
• Evidence of severe AKI with at least 1 of the following 3:
• > 2-fold increase in creatinine from baseline
• Cr >354umol/L and >27umol/L above baseline creatinine
• Urine output <6ml/kg in 12 hours

77. Exclusion:
• K >5.5mmol/L
• HCO3 <15mmol/L
• A drug overdose that necessitated dialysis
• Lack of commitment to provide RRT due to treatment limitations
• Any RRT in last 2 months
• Kidney transplant in last year
• Known pre-hospital ESRF with eGRF <20ml/min/1.73m2
• Presence of renal obstruction, rapidly progressive GN, vasculitis, thrombotic
microangiopathy or AIN

78. • Once all inclusion and no exclusion criteria were met the patient
could be randomised to the trial providing there was true clinician
equipoise, ie it was not felt that immediate RRT was mandated or that
deferred RRT was mandated. More than 7000 patients were excluded
at this point due to lack of equipoise
• 2927 patients; 1465 and 1462 patients were analysed for the primary
outcome (modified intention-to-treat-analysis) as a total of 42
patients were either lost to follow up or withdrew consent.
• The baseline characteristics were similar between groups with 75% of
patients mechanically ventilated and the mean Creatinine at
randomisation 300umol/L

79. Intervention
• Patients randomised to the accelerated arm needed to commence
continuous renal replacement therapy within 12 hours of
randomisation
• 96.8% received dialysis
• The average time to commencement was 6 hours
• The average creatinine at time of commencement was 327umol/L and fluid
balance positive 2714ml

80. • Control
• Clinicians caring for patients randomised to the standard group were discouraged from
commencing RRT unless:
• Persistent AKI, with Cr >50% the value recorded at randomisation
• AND one or more of:
• K+>6mmol/L
• pH < 7.2 or HCO3 <12mmol/L
• Fluid overload causing respiratory compromise (PaO2/FiO2<200)
• Persistent AKI for >72 hours from randomisation
• There was no obligation to commence RRT in the standard group arm even if the above criteria
were met, eg if K is 6.3mmol/L, the clinician could manage it with medical therapy. Conversely,
RRT could be commenced at any time deemed suitable based on the judgement of the attending
clinician
• 61.8% of patients in the standard group received dialysis
• The average creatinine at the time of RRT commencement was 433umol/L and fluid balance
positive 5893ml

81. Management common to both groups
• The modality of RRT was at the discretion of the treating physician
(there were guidelines provided): Comparing the accelerated vs
standard groups, most received continuous RRT (68.4% vs 70.6%),
then IHD (27% vs 25.3%), then SLED (4.6% vs 4.1%)
• Citrate was the most common form of circuit anticoagulation
• RRT would continue until one of the following was encountered
• Death
• Withdrawal of life-support
• Kidney Function Recovered

82. • Outcome
• Primary outcome: 90 Day Mortality (Accelerated vs Standard)
• NO SIGNIFICANT DIFFERENCE 643/1465 (43.9%) vs 639/1462 (43.7%) RR= 1, (95% CI 0.93-
1.09), p=0.92 (modified ITT analysis)
• Adjusted OR 1.05 (95% CI 0.9-1.23) [This took into account baseline characteristics of the
patients]
• Secondary outcome: (Accelerated vs Standard) included:
• Significant difference in:
• Dependence on RRT at Day 90 after randomisation (10.4% vs 6%), RR 1.74 (95% CI 1.24-2.43)
• Patients in the accelerated group had a shorter ICU stay than the standard group (9 days vs 10 days)
• No significant difference in:
• Composite of all cause mortality and RRT dependence at D90
• Major adverse kidney event (composite of death, RRT dependence or sustained reduction in kidney
function)
• eGFR at D90
• Albuminuria at D90
• Mortality in ICU, D28, hospital
• RRT free days at D90
• Mechanical ventilation free days at D28
• Vasoactive therapy-free days through D28

83. • Sub-groups: there was no significant difference in any of the pre-
specified subgroups
• Adverse events were more common in the accelerated arm (23% v
16.5%), particularly hypotension and hypophosphataemia
• Serious adverse events were not significantly different (1% vs 0.5%)

84. Strengths
• Allocation concealment, intention to treat analysis, blinding of outcome assessors, near-complete follow-up (internal validity)
• Stratification by centre and allocation in variable block size (allowing the clinician to have little chance of predicting the allocation
prior to randomisation)
• Patients were analysed by the group they were allocated to even thought there was a 7.5% cross-over in therapies between groups
• Pragmatic design which reflects the real world: if the clinician did not have absolute equipoise regarding providing accelerated or
standard provision of RRT then they were not included in the trial
• Clinically meaningful outcomes
• The funding organisations and partners were not involved in the design, implementation, management of the trial, analysis of data
or publication
• The trial results are widely applicable as patients were recruited from many different ICUs in many different countries (external
validity)
• There was a clear differentiation between groups in term of creatinine and fluid balance at the time of RRT commencement
• There were 3 interim analyses conducted to confirm that continuation of the trial was safe

85. • There appears to be no benefit in starting renal replacement in an
accelerated fashion
• In addition early dialysis appears to increase the risk of dependence
on long term renal replacement therapy raising the possibility these
patients are of risk of dialysis induced kidney injury

88. • Thank You