King Chulalongkorn Memorial Hospital

The Thai Red Cross Society Acute Kidney Injury:

Approach and Management

Sadudee Peerapornratana, MD, MS

1Department of Laboratory Medicine, Faculty of Medicine,
Chulalongkorn University
2Excellence Center for Critical Care Nephrology, Division of Nephrology,
King Chulalongkorn Memorial Hospital
Scope of Talk
• Continuum of kidney disease
• Risk assessment and early recognition of AKI
• Etiologies of AKI
• Prevention of AKI
• Management of Established AKI
• Recovery after AKI
Continuum of Kidney Disease

Insult

7 days

KDIGO consensus. Kidney Int. 2021

Risk Assessment and
Early Recognition of AKI
Risk Factors of AKI
EXPOSURES SUSCEPTIBILITIES
• Sepsis • Dehydration or volume depletion
• Critical illness • Advanced age
• Circulatory shock • Female gender
• Burns • Black race
• Trauma • CKD
• Cardiac surgery (especially with CPB) • Chronic diseases (heart, lung, liver)
• Major noncardiac surgery • Diabetes mellitus
• Nephrotoxic drugs • Cancer
• Radiocontrast agents • Anemia
• Poisonous plants and animals

KDIGO Guideline. 2012

Diagnosis and Staging of AKI
Stage Serum creatinine Urine output
Diagnosis • Increase of ≥0.3 mg/dL (26.5 μmol/L) within 48 h • <0.5 mL/kg/h for 6 h
• Increase of ≥1.5-fold above baseline, known or
assumed to have occurred within 7 days
1 • 1.5–1.9 times baseline • <0.5 mL/kg/h for 6–12 h
• ≥0.3 mg/dL increase
2 • 2.0–2.9 times baseline • <0.5 mL/kg/h for ≥12 h
3 • 3.0 times baseline • <0.3 mL/kg/h for ≥24 h
• Increase in SCr to ≥4.0 mg/dL • Anuria for ≥12 h
• Initiation of RRT
• Decrease in eGFR to <35 mL/min/1.73 m2 (<18
years old)

KDIGO Guideline. 2012

Oliguria detects AKI earlier than SCr criteria

Only 3-5 hours of consecutive oliguria (<0.5 mL/kg/h) within 12 hours

after septic shock recognition may provide a valuable measure of
AKI risk.

Leedahl et al. CJASN. 2014

Serum Cr does not reflect the real-time changes in the GFR.

Comprehensive Clinical Nephrology 5th edition, 2015

Sharma A et al. Nephron Clin Pract. 2014
 Potential Pitfalls of Using Serum Creatinine Levels in AKI
Clinical Scenario Mechanism Consequences
Liver failure Reduced creatinine production Delayed diagnosis of AKI
Muscle disease
Sepsis
Elderly / Amputee
Inhibition of tubular secretion of creatinine GFR-independent increase in Overdiagnosis of AKI
• Cimetidine serum creatinine
• Trimethoprim
• Dronedarone
• Cobicistat and dolutegravir
• Tyrosine kinase inhibitors: imatinib, bosutinib, sorafenib,
sunitinib, crizotinib, gefitinib, and pazopanib
• Pyrimethamine
Increase intake of cooked meat, creatine supplements Increased creatine availability Overdiagnosis of AKI
Muscular habitus
Severe muscle injury
Pregnancy Physiologically increased GFR Delayed diagnosis of AKI
Sepsis
Osmolar load
Fluid overload Dilution of serum creatinine Delayed diagnosis of AKI
 Subclinical AKI Clinical AKI

Increased risk /
Normal cellular stress Tubular Damage Loss GFR

Acute Kidney Stress AKI with Damage AKI with Dysfunction

Stress Markers Damage Markers Functional Markers

TIMP-2 NGAL Creatinine
IGFBP7 KIM-1 Urine output, FST
L-FABP Cystatin C
Etc. Proenkephalin A

Ronco, Bellomo, Kellum. Lancet 2019

Novel AKI Biomarkers

Ronco, Bellomo, Kellum. Lancet 2019

Use of Damage and Functional Biomarkers in AKI
No Damage Damage

KDIGO (-) KDIGO (-)

Normal Biomarker (-) Biomarker (+)
Function
‘No AKI’ ‘Subclinical AKI’

Resolution

Progression
Resolution KDIGO (+)
KDIGO (+)
Biomarker (+)
Biomarker (-)
Loss of
‘AKI with functional
Function ‘AKI with functional
loss and tubular
loss
damage
(prerenal)’
(intrinsic AKI)’

Progression
Proposed New Definition and Staging of AKI

Ostermann M, et al. JAMA Network Open. 2020

Subclinical AKI is also associated with adverse outcomes.
A Multicenter Pooled Analysis of Prospective
Studies (2,322 critically ill patients)
Majority of cardiorenal syndrome

Urine and plasma NGAL at ICU admission or

2-6 h after new insult

Hasse et al. JACC. 2011

Hasse et al. Nat Rev Nephro. 2012
Etiologies of AKI
Comprehensive Clinical Nephrology 5th edition, 2015
Investigation for the Causes of AKI
Urinalysis, CBC, BUN, Cr, electrolyte
Post-renal: plain KUB film, KUB U/S
Intrinsic renal parenchymal disease
◦ Glomerular disease: RBC casts, dysmorphic RBCs/acanthocytes, proteinuria,
kidney biopsy
◦ Tubulointerstitial disease: concentration ability, +/- mild proteinuria (< 2 g/d),
sediments (eosinophiluria, pyuria), kidney biopsy, damage biomarkers
◦ Vascular disease: doppler renal U/S, CTA, MRA, kidney biopsy

Pre-renal azotemia: urine indices

Specific causes from clinical context
AKI is a syndrome.
• Sepsis
• Cardiac surgery
• Acute liver failure
• Intra-abdominal hypertension
• Hepatorenal syndrome
• Malignancy-related
• Cardiorenal syndrome
• Renal hypoperfusion
• Contrast-associated
Organ Crosstalk Syndromes with AKI

Kellum JA et al. Nat Rev Nephrol 2021

Comprehensive Clinical Nephrology 5th edition, 2015
Urine Hansel stain: Eosinophiluria (AIN)
 Urine Crystals in AKI

Uric acid Calcium oxalate

Tumor lysis syndrome Ethylene glycol intoxication
AKI from Sulfadiazine Crystal (Intratubular Obstruction)
 Prerenal Azotemia VS Intrinsic Renal (ATN)
Features Prerenal AKI Acute tubular necrosis
History GI, urinary, skin volume loss, Drugs or toxin exposure,
blood loss, or third spacing hemodynamic change
Physical examination Hypotension or sign of volume No specific symptoms or signs
depletion
Laboratory investigation
Urine sediment Hyaline casts Muddy-brown casts, tubular
epithelial cell casts
Urine specific gravity >1.018 ≈ 1.010
Urine osmolality (mOsm/kg) >500 ≈ 300
Urine Na (mmol/L) <20 >40
Proteinuria None to trace Mild to moderate
BUN/creatinine ratio >20 <10-15
FENa (%) <1* >1*
FEurea (%) <35 >35
Biomarkers of tubular None NGAL, KIM-1, L-FABP,
stress/damage TIMP-2•IGFBP7
Prevention of AKI
KDIGO Bundle for Management of AKI

KDIGO Guideline. 2012


High risk defined as a urinary TIMP-2*IGFBP7 >0.3 (ng/mL)2/1000, 4 h after CPB
Standard Care (N=138)
• Restart ACEi or ARBs once hemodynamics
stabilized*
• Mean arterial pressure (MAP) > 65 mmHg
• Central venous pressure (CVP) between 8 and
10 mmHg
PrevAKI Study
Early KDIGO Bundle (N=138)
• Discontinue ACEi and ARBs for the first 48 hours after
surgery
• Avoid nephrotoxic agents
• Close monitoring of sCr and UO
• Avoid hyperglycemia for 72 h after surgery
• Consider alternatives to radiocontrast
• Close hemodynamic monitoring (PICCO catheter) and
optimization by pre-specified algorithm
Meersch et al. Intensive Care Med. 2017
KDIGO Bundle Prevents AKI in High-Risk Patients after CPB Sx
PrevAKI Study
Primary endpoint
Reduction of AKI occurring within 72 h

• All AKI (stage 1+2+3)

Absolute risk reduction 16.6%
(95% CI, 5.5-27.9%; p=0.004)
• Moderate-severe AKI (stage 2+3)
Absolute risk reduction 15.2%
(95% CI, 4.0-26.5%; p=0.009)

Meersch et al. Intensive Care Med. 2017

Fluid Management in AKI

Kellum JA et al. Nat Rev Dis Primers. 2021

 Avoidance of Nephrotoxic Agent
Hemodynamically ACEi, ARBs, NSAIDs Acute interstitial b-Lactam drugs (penicillin and derivatives, cephalosporins)
mediated AKI SGLT2 inhibitors nephritis trimethoprim-sulfamethoxazole, sulfadiazine
Calcineurin inhibitors Fluoroquinolones
Macrolides
Acute tubular Aminoglycosides
Vancomycin (+/- piperacillin/tazobactam) Rifampin
injury
Colistin/polymyxins Proton pump inhibitors (class effect)
Histamine-2 blockers
Amphotericin B
NSAIDs, COX-2 inhibitors (class effect)
Cidofovir, tenofovir, adefovir, Foscarnet
PD-1 inhibitors (nivolumab, pembrolizumab, cemiplimab)
Cisplatin, Ifosfamide, Pemetrexed
Iodinated radiocontrast agents PD-L1 inhibitors (atezolizumab, durvalumab, avelumab)
Calcineurin inhibitors CTLA-4 inhibitors (ipilimumab, tremelimumab)
Bevacizumab, tyrosine kinase inhibitors (sorafenib, sunitanib)
Pamidronate, Zolendronic acid
Loop diuretics, thiazide
Crystalline Methotrexate Acyclovir, Abacavir, Indinavir, Atazanavir, Foscarnet
nephropathies Sulfadiazine, Sulfamethoxazole Phenobarbital, Carbamazepine, Phenytoin
Indinavir, atazanavir, darunavir Ifosfamide
Acyclovir Pemetrexed
Ciprofloxacin, levofloxacin Lithium
IV ascorbic acid, orlistat Allopurinol
Sodium phosphate purgative Mesalamine and other 5-aminosalicylates
Triamterene
Amoxicillin
Foscatnet

Perazella MA and Rosner MH. CJASN 2022

Management of Established AKI
Furosemide Stress Test (FST)
• The patients need to be well resuscitated and euvolemic before
performing the FST.

Standardized IV furosemide
• 1 mg/kg in naïve-patients
• 1.5 mg/kg if furosemide used within 7 days

• Low UO after FST (< 200 mL/2 h) à Non-responsive is predictive for

• Progression to severe AKI (stage 3) – AUC 0.87
• Need for RRT – AUC 0.86;
• In-hospital mortality – AUC 0.70

Chawla et al. Crit Care 2013

Koyner et al. J Am Soc Nephrol 2015
 Furosemide Stress Test (FST)

OAT: organic anion transporter

Test of tubular function
Furosemide mechanism of action

Chawla L. and Ronco C. Kidney Int Rep. 2016

Mori T. et al. Hepatology Research 2017
FST-Guided KRT Initiation
FST Trial

Underwent KRT
◦ 13.6% in FST-responsive
◦ 75% in FST-nonresponsive

Lumlertgul et al. Crit Care. 2018

Bicarbonate Therapy in AKI
BICAR-ICU study

• 389 ICU patients with severe

acidemia (pH ≤7.20, PaCO2 ≤45
mmHg, and bicarbonate conc
≤20 mmol/L) + SOFA ≥4 or
arterial lactate ≥2 mmol/L
• Prespecified subgroup of stage
2-3 AKI
• 60% Sepsis
• IV 4.2% sodium bicarbonate (0.5
mEq/mL) 125-250 mL in 30 min
each (max. 1000 mL within 24 h),
to maintain the arterial pH
>7.30; VS no bicarbonate

Jaber S et al. Lancet 2018

Bicarbonate Therapy in AKI
BICAR-ICU study

Overall Stage 2-3 AKI Overall use of KRT

SSC 2021

Jaber S et al. Lancet 2018

Evans L et al. Crit Care Med 2021
 Indications for KRT in AKI
• Initiate KRT emergently when life-
threatening changes in fluid,
electrolyte, and acid-base balance
exist
• Consider the broader clinical context,
the presence of conditions that can
be modified with KRT, and trends of
laboratory tests, rather than single BUN
and creatinine thresholds alone, when
making the decision to start KRT.
Classic Urgent Indications
• Refractory hyperkalemia (K ≥6.0 mmol/L,
rapidly increasing, or cardiac toxicity)
• Refractory metabolic acidosis (pH ≤7.2 or
serum bicarbonate level ≤12 mmol/L despite
normal or low arterial PCO2)
• Refractory hypoxemia (PaO2/FiO2 ≤200 and
perception of volume overload; diuretic-
resistant pulmonary edema)
• Symptoms or complications of uremia
(bleeding, pericarditis, encephalopathy)
• Overdose/toxicity from a dialyzable drug/toxin
 AKIKI Trial

• Multicenter RCT, 31 sites in France

• Patients with KDIGO stage 3 AKI (N = 620)
• 67% septic shock
• Early initiation: start KRT within 6 h after stage 3
AKI
• Delayed initiation:
• Severe hyperkalemia (K >6 mmol/L)
• Severe pulmonary edema, refractory to diuretics
• Severe acidosis (pH <7.15)
• BUN >112 mg/dL
• Oligo-anuria >72 h
• Primary outcome: No difference in 60-day
mortality (49.7% vs 48.5%, p=0.79)
Gaudry S et al. NEJM 2016
 ELAIN Trial

• Single center RCT, Germany

• N = 231
• Inclusion: stage 2 AKI, pNGAL >150 ng/mL
• 32% septic shock
• Early KRT: start KRT within 8 h of diagnosis of 54.7%
KDIGO stage 2 AKI
• Delayed KRT: start KRT within 12 h of stage 3 39.3%
AKI or on urgent indication
• Primary outcome: Early KRT reduced
mortality over the first 90 days (↓15.4%).
• Others: early strategy conferred a greater
likelihood of kidney recovery and dialysis
independence, and shorter duration of ICU
stay and hospitalization

Zarbock A et al. JAMA 2016

• Multicenter RCT, 24 sites in France IDEAL-ICU Trial
• Patients with septic shock with AKI stage 3
• Expected N = 864
• Early initiation: start KRT within 12 h after the
onset of RIFLE-F (equivalent to KDIGO stage 3)
• Delayed initiation: delay KRT of >48 h (no
more than 60 hours)
• Terminated prematurely after N = 488 (56.5%)
• Primary outcome: no difference in 90-day
mortality (58% vs 54%, p=0.38)

Barbar SD et al. NEJM 2018

 STARRT-AKI Trial

• Multicenter RCT, 15 countries, 168 sites

• Inclusion: KDIGO stage 2-3 AKI with no urgent
indication (provisional eligibility)
• Integrating clinician equipoise into the eligibility
criteria (full eligibility)
• N = 3019
• 58% sepsis; 44% Septic shock
• Accelerated strategy: KDIGO stage 2-3 AKI
(started within 12 h)
• Standard strategy: watchful-waiting approach
until K ≥6 mmol/L, pH <7.20, HCO3- ≤ 12 mmol/L,
PaO2/FiO2 <200 (volume overload), or persistent
AKI ≥72 h
• Primary outcome: no difference in 90-day all-
cause mortality

Bagshaw SM et al. NEJM 2020

How late is too late?
AKIKI AKIKI 2
• Early strategy: start KRT within 6 h after • Delayed strategy: KDIGO stage 3 AKI
stage 3 AKI with oliguria >72 h or BUN >112 mg/dL
• Delayed strategy: (as early as possible within 12 hours)
• Severe hyperkalemia (K >6 mmol/L) • More-delayed strategy: KRT postponed
until
• Severe pulmonary edema, refractory
to diuretics • Urgent indications (hyperkalemia,
acidosis, fluid overload) or
• Severe acidosis (pH <7.15)
• BUN >140 mg/dL
• BUN >112 mg/dL
• Primary outcome: KRT-free days
• Oligo-anuria >72 h
between randomization and day 28
• Primary outcome: 60-day mortality
 AKIKI 2

• Multicenter RCT, 39 sites in France

• N = 278
• 54% Septic shock
• Delayed strategy: KDIGO stage 3 AKI with
oliguria >72 h or BUN >112 mg/dL (started
immediately after eligible)
• More-delayed strategy:
• Urgent indications (hyperkalemia,
acidosis, fluid overload) or
• BUN >140 mg/dL
• Primary outcome: no difference of KRT-free
days between randomization and day 28

Gaudry et al. Lancet 2021

 AKIKI 2
Risk factors for 60-day mortality Laboratory at The Time of KRT Initiation

Delayed More-Delayed
Characteristic P Value
(N=134) † (N=111)*

Serum creatinine (mg/dL) 4.81 ± 2.12 6.15 ± 2.51 <0.001

BUN (mg/dL) 89 ± 33 123 ± 36 <0.001
Serum potassium (mmol/L) 4.4 ± 0.8 4.6 ± 0.9 0.03
Serum bicarbonate (mmol/L) 20.8 ± 5.7 18.8 ± 5.2 0.004
Arterial pH 7.33 ± 0.09 7.30 ± 0.12 0.08
Serum sodium (mmol/L) 136 ± 7 136 ± 6 0.40

No difference found in adverse events between groups.

Gaudry et al. Lancet 2021

Clinical trial AKIKI ELAIN IDEAL-ICU STARRT-AKI AKIKI 2
(NEJM 2016) (JAMA 2016) (NEJM 2018) (NEJM 2020) (Lancet 2021)
Country / center(s) France / 31 Germany / 1 France / 24 International / 168 France / 39
Total N 620 231 488 3,019 278
Setting 80% Medical patients 95% Surgical patients 100% Septic shock 67% Medical patients Critically ill patients with stage 3 AKI
(47% cardiac surgery)
Inclusion criteria KDIGO stage 3 AKI with MV/ KDIGO stage 2 AKI with pNGAL RIFLE-F AKI, within 48 h of KDIGO stage 2–3 AKI KDIGO stage 3 AKI with MV/
vasopressors >150 ng/mL with one of: sepsis, vasopressor initiation for sepsis vasopressors with oliguria >72 h
vasopressors, fluid overload (<0.3 mL/kg/h, <500 mL/d) or
BUN >112 mg/dL
Exclusion criteria Emergency indications for RRT. Emergency indications for RRT. Emergency indications for RRT. Emergency indications for RRT. Emergency indications for RRT,
Preexisting CrCl <30 mL/min Preexisting eGFR <30 Receipt of RRT for ESKD Previous RRT, preexisting eGFR BUN >140 mg/dL, CrCl <30 mL/min,
mL/min/1.73m2 <20 mL/min/1.73m2. Clinician previous dialysis, KT
perception of mandated need for
RRT or imminent kidney recovery
Early initiation KDIGO stage 3 AKI KDIGO stage 2 RIFLE-F AKI KDIGO stage 2-3 AKI KDIGO stage 3 AKI with oliguria
(started within 6 h) (started within 8 h) (started within 12 h) (started within 12 h) >72 h or BUN >112 mg/dL
(started immediately after eligible)
Delayed initiation BUN >112 mg/dL, K >6 mmol/L, KDIGO stage 3 (started within 12 h) 48 h after inclusion, unless recovery K ≥6 mmol/L, pH <7.20, HCO3- ≤ 12 Urgent indications (hyperkalemia,
pH <7.1, oliguria >72 h, or BUN >100 mg/dL, K >6 mmol/L, of kidney function, or K >6 mmol/L, mmol/L, PaO2/FiO2 <200 (volume acidosis, fluid overload) or
pulmonary edema edema resistant to diuretics pH <7.1, fluid overload overload), or persistent AKI ≥72 h BUN >140 mg/dL
Median time difference (h) 55 (2 vs 57) 21 (6 vs 25.5) 43.9 (7.6 vs 51.5) 25 (6.1 vs 31.1) 30 (3 vs 33)
after randomization after met KDIGO stage 2 after met RIFLE-F following full eligibility after randomization
Patients received RRT (%) 98 vs 51 100 vs 91 97 vs 62 97 vs 62 98 vs 79
RRT modality IHD/CRRT (45%) CRRT (CVVHDF) IHD/CRRT (56%) IHD/SLED/CRRT (70%) IHD/CRRT (40%)
Septic shock (%) 67 32 100 44 54
CKD (%) 9.7 40 15.6 43.9 10
SOFA score 10.9 16 12 11.7 11
MV (%) 87 88 88 77 76
Vasopressors (%) 85 88 100 70 79
Primary outcome 60-d mortality: 90-d mortality: 90-d mortality: 90-d mortality: RRT-free day:
48.5% vs 49.7% (p=0.79) 39.3% vs 54.7% (p=0.03) 58% vs 54% (p=0.38) 43.9% vs 43.7% (p=0.92) 12 days vs 10 days (p=0.93)
Other outcomes / Hypophosphatemia and CRBSI Renal recovery by day 90 more Higher incidence of hyperkalemia in RRT dependent at 90 days, 28-d mortality: 38% vs 45% (p=0.26)
adverse events more common in early gr. common in early gr. (54% vs 39%). delayed gr. hypotension, hypophosphatemia 60-d mortality: 44% vs 55% (p=0.07)
Shorter time to renal recovery in 9% of patients died during the delay were more common in accelerated- No difference in AE
delayed gr. of 48 h. strategy gr.
17% required emergent RRT.
KDIGO 2020: Decisions for KRT in AKI

• Initiation of KRT should be considered by

evaluation of the demand and renal
capacity relationship – based on the
dynamic nature of acute illness and stress.
• The exact methods for determining
demand and capacity are unknown.

Ostermann et al. Kidney Int. 2020

Demand-Capacity Balance and RRT Initiation

Demand Capacity Example Timing of RRT

High catabolic state in

High Normal patients with normal renal Watchful waiting
function

High catabolic state in patient Consider for early

High Low
with AKI or CKD initiation

Normal catabolic state in

Normal Low Watchful waiting
patient with AKI or CKD

Malnutrition in patient with AKI

Low Low Watchful waiting
or CKD

ADQI Consensus. Blood Purif. 2016


Modalities of RRT in AKI
Intracorporeal therapy
CRRT is preferred in:
• Unstable hemodynamics
• AKI with acute brain injury
• Increased intracranial pressure
• Generalized brain edema
• Control fluid balance

Peritoneal dialysis

Extracorporeal therapy

Intermittent Continuous
• IHD • SCUF
• PIRRT or SLED • CVVH
• SLEDf • CVVHD
• CVVHDF

ADQI 2016
When to discontinue KRT in AKI?
VA/NIH ATN (NEJM, 2008)
“When RRT is no longer required either
• CrCl >20 mL/min (6-h urine CrCl, UO >30 mL/h)
because intrinsic kidney function has
recovered to the point that it is adequate to
AKIKI (NEJM, 2016) meet patient needs, or because RRT is no
longer consistent with the goals of care”.
• Urine output >500 mL/day (considered)
• Urine output >1,000 mL/day (highly suggested)
• Urine output >2,000 mL/day (with diuretic)

ELAIN (JAMA, 2016)

• Urine output >400 mL/day
+ CrCl >20 mL/min
• Urine output >2,100 mL/day (with diuretic)

Able to Stop KRT ≠ Kidney Recovery

Recovery after AKI
 Repair after AKI

Normal Structure AKI Repair Resolution

Ferenbach and Bonventre. Nat Rev Nephrol 2015

Trajectories after AKI

Relapse 1
Progression
?Partial recovery
2
3

ADQI 16 Workgroup, 2017

 Approach to Patients with Persistent AKI
Kidney DAMAGE
• Determine etiology – evaluate for ongoing drivers of injury; consider less common
causes of AKI; consider kidney biopsy; nephrology consultation

• Avoid further injury – avoid nephrotoxic drugs/radiocontrast agent, fluid overload,

hemodynamic instability

• Monitor – SCr, urine output, hemodynamics

• Adverse drug events – adjust medication selection and dosing
• Goals of treatment – assess treatment goals with respect to dialysis and other therapy
• Ensure follow-up – assess renal function within 30 days; assess cardiovascular risk;
monitor/treat hypertension

Kellum JA. Crit Care Med. 2015

AKI-CKD as an Interconnected Disease

Chawla et al. NEJM 2014

Long-Term Consequences of AKI
1-year absolute risk after AKI
AKI associated with an increased risk of
• All-cause mortality
• CV event (heart failure, CAD)
• AKI rehospitalization
• CKD
• ESKD

James MT, et al. Nat Rev Nephrol. 2020.

AKI/AKD Follow-Up Candidate for Post-AKI clinic

ADQI 22 Consensus. 2019

Ostermann M et al. Kidney Int. 2020
Thank you for your kind attention.