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Acute Renal Failure
Mark L. Zeidel, M.D.
Herrman L. Blumgart Professor of Medicine
Harvard Medical School
Physician-in-Chief
Beth Israel Deaconess Medical Center
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Acute Renal Failure
Clinical burden of AKI
Mechanisms, Outcomes and
Prognosis
Care for the Patient
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Better to remain
silent and be
thought a fool
than to speak
out and remove
all doubt.
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Acute Renal Failure
Clinical burden of AKI
Mechanisms, Outcomes and
Prognosis
Care for the Patient
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Burden of AKI: the US
Lewington JP, Cerda J, Mehta RL.
Kidney Int 2013;84:457-467.
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AKI with Progression to CKD and Death: A
Global Problem
Lewington JP, Cerda J, Mehta RL.
Kidney Int 2013;84:457-467.
High Income Nations Middle, Low Income
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IRI
sepsis
Cisplatin
Contrast
Rhabdo
Aminoglycoside
Obstruction
Ischemia/Hemorrhage
other
OtherMedications
Causes of AKI (on Right)
As of May 8, 2014
SEARCH terms: (rat or mouse) AND “model” AND kidney
PUBMED
Rodent
AKI
NASH
Chicago Study
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Causes of Death in 3000 Patients Dialyzed
for Acute Tubular Necrosis
Percentage Cause of Death of Patients
Infections 30-70%
Cardiac failure 5-30%
Intestinal hemorrhage and other diseases 5-20%
Pulmonary emboli and insufficiency 1-10%
Central nervous system disease 1-5%
Hyperkalemia, technical dialysis problems 1-2%
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Prerenal Causes of Renal Failure
• Volume Depletion
– Intravascular: Hemorrhage, burns, internal sequestration
– Extracellular: Diuresis, GI or skin losses
• Low Cardiac Output
– CHF, cardiogenic shock
– Poor cardiac filling-Pericardial tamponade or constriction
–
• Increased Renal to Systemic Vascular Resistance
– Systemic vasodilatation-Vasodilators, sepsis, anaphylaxis
– Renal vasoconstrictors-Alpha adrenergic agonists
– Hepatorenal syndrome
– NSAIDs, ACE inhibitors, calcineurin inhibitors
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Postrenal Causes of Renal Failure
• Lower Urinary Tract Obstruction
– Urethral stricture or malpositioned catheter
– BPH or prostate cancer
– Bladder cancer, stones, blood clots, fungal ball
– Neurogenic bladder
• Upper Urinary Tract Obstruction
– Stones, blood clots, sloughed papillae
– Transitional cell carcinoma
– Retroperitoneal fibrosis or malignancy
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Intrarenal Causes of Renal Failure
• Acute Tubular Necrosis
– Ischemic
– Nephrotoxic
• Acute Interstitial Nephritis– Allergic drug-induced
– Metabolic: urate, calcium
– Infection and systemic disease related
• Cortical Necrosis
• Vascular Diseases
• Systemic Diseases, Myeloma and Malignant Infiltration
• Acute Glomerulonephritis
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Acute Renal Failure
Clinical burden of AKI
Mechanisms, Outcomes and
Prognosis
Care for the Patient
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Pathophysiology of Acute Kidney
Injury
Why do we know so much, yet so little about acute kidney injury?
What are the mechanisms of injury and how do they lead to the clinical manifestations?
Does a pathophysiologic approach lead to better management?
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Why do we know so much, yet so little
about acute kidney injury?
Multiple causes in individual patients
ischemia, sepsis, toxins
Biopsies are rarely obtained
Multiple predisposing factors
age, male sex, diabetes, hypotension,
prior azotemia, genetics
Animal models are unidimensional
homozygous strains, models of single
elements
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What affects our patients
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Why do we know so much, yet so little
about acute renal failure?
In other words, acute kidney injury is not a
disease, but a syndrome, with different
manifestations in different patients.
Pathology mirrors this heterogeneity, with
injury to proximal convoluted and proximal
straight tubules, as well as thick ascending
limb of Henle.
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Proximal Tubule:
Microanatomy
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Proximal Tubule: Ischemic
Damage
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mTAL: Microanatomy
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mTAL in ischemia
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AKI Complexity of Course
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Annual
Reviews
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Chawla LS et al. N Engl J Med 2014;371:58-66.
Pathophysiological Features of Acute Kidney Injury Leading to Chronic Kidney Disease.
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Even in Mice, AKI differs in
Form…
Ischemia-reperfusion Surgical Sepsis Cisplatin
Miyaji, et al. Kid Intl 2003
Mukhopadhyay, et al. Free Rad Biol Med 2012
Parikh Lab unpublished
Cortex and OSOM Scant Cell Death Proximal Tubule
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What have we learned about acute renal
failure?
Enormous investment in mechanisms of tubular
epithelial damage: The “MI Model.”
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New Acute Renal Failure Treatments
Older Pathways to discovery:
Novel aspects of cell injury and repair are
described in the literature.
This prompts a search to see if these pathways
are present in AKI models.
1. The pathway is measured and always found.
2. Alteration of the pathway in a selected model
of AKI attenuates the renal damage.
The resultant therapeutic strategy is tried in
humans and fails.
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Therapies Proposed for AKI
Atrial natriuretic peptide (ANP, anaritide)
Insulin-like growth factor (IGF-I)
Epidermal growth factor (EGF)
Endothelin antagonist
Nitric oxide inhibitor
Low dose dopamine
Thyroxine
Loop diuretics
Mannitol
Vasopressin or midodrine + octreotide for the
hepatorenal syndrome
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Summary Thoughts
• Mice are not the problem…we are– Better models: sepsis plus CKD (Star Lab), diabetes plus AKI– Fund a consortium to develop best practices
• All AKI is not the same– Stratification by host factors and molecular phenotypes PLUS clinical features
– Should we somehow increase the frequency of biopsies in AKI?
• Enhance access to NIH-Funded Renal Biobanks– Rapid validation à better markers and better drugs
– Aligns basic and clinical researchers to a common goal
• Rigorous science to seek safe, inexpensive therapies– AKI is a worldwide issue, fancy biologics don’t transport well– Primary prevention should not be dismissed (e.g., statins, ASA in CV dz)
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AKIN Classification and Staging of AKI
Stage 1: éSCr ≥ 0.3 mg/dl or ≥ 150-200%, UO < 0.5 ml/kg/h (>6h)
Stage 2: éSCr > 200 – 300%, UO < 0.5 ml/kg/h (>12h)
Stage 3: éSCr > 300%, Anuric or UO < 0.3 ml/kg/h (24h) or on RRT
Classification of AKI
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Chawla LS et al. N Engl J Med 2014;371:58-66.
Classifications of Acute Kidney Injury and Chronic Kidney Disease.
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Acute Renal Failure
Clinical burden of AKI
Mechanisms, Outcomes and
Prognosis
Care for the Patient
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AKI in a Longitudinal Context
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Innovative Phenotyping &
Clinical Stratification
• Compare molecular profiles across different forms of AKI
• Follow high-risk individuals sequentially, even pre-insult
• Point-of-care tools for bedside physiology
• Human Biobanks for rapid validation of emerging pathogenic
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IRInonesham
Metabolomics of renal ischemia (Parikh CRRT 2014)
Bedside real-time GFR (Molitoris CRRT 2012)
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Bonventre, Nat Biotech 2010
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Kinetics are important
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AKI in a Longitudinal Context
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AKI Prophylaxis
• Radiocontrast
– Isotonic saline infusion
– Oral acetylcysteine (600 mg bid 1 day pre-contrast X 2
days)
– Sodium bicarbonate infusion (150 mEq/L D5W at 3.5
ml/hr for 1 hr pre-contrast and 1.2 ml/hr for 6 hr post-
contrast
– Hemofiltration
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Therapy of Acute Renal Failure
• Correct life-threatening disorders
• Evaluate for reversible causes
• Avoid exacerbating factors
• Conservative management
• Renal replacement therapy
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Diagnostic Approach to Renal
Failure• History and physical exam
• Lab
– CBC, BUN, creatinine, glucose, electrolytes
– Calcium, phosphate, albumin, globulins
– Special tests as indicated – CPK, ANCA,
ANA,
complement levels, uric acid, SPEP/UPEP
• Urinalysis
• Urinary Indices
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Diagnostic Approach to Renal
Failure
• Urethral catheterization, if indicated
• Quantitate urine output
• Fluid or diuretic challenge, if indicated
• Renal radiology
• Renal biopsy
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Management of Acute Renal
Failure• Evaluate and treat reversible causes of
ARF
• Avoid factors contributing to morbidity
– Review/revise drug doses for lower GFR
– Discontinue nephrotoxins when possible
– Decrease contribution to uremia when possible,
e.g., high dose steroids, high protein or acid loads
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Conservative Management of Acute
Renal Failure• Fluid balance
– Achieve euvolemia and record I & O
– Replace insensible and measured losses
– Weigh daily
• Dietary control
– Protein intake 0.6-1.2 Gm/Kg BW
– Provide carbohydrate and lipid calories to maintain nutrition
– Restrict Na, K, PO4 and fluids as indicated
• Calcium-phosphate balance
– Phosphate binder Rx with either aluminum hydroxide or calcium carbonate
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Acute Renal Failure
Correction of life-threatening disorders
• Electrolyte disorders
• Uremic coagulopathy
• Pulmonary edema
• Pericarditis with tamponade
• Uremic encephalopathy
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Electrolyte Disorders in Renal
Failure
• Hyperkalemia
• Metabolic acidosis
• Hyponatremia
• Hypocalcemia
• Hyperphosphatemia
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Correction of Hyperkalemia
• Eliminate potassium intake
• Antagonize ECG effect of hyperkalemia
– CaCl2 1 gm IV or Ca gluconate 4 gm IV
• Lower serum potassium
– Insulin 10U regular + 50ml 50% dextrose IV
– Sodium bicarbonate 50-150 mEq IV
– Albuterol 2.5 mg IV or 20 mg inhaled, terbutaline 7 µg/kg
SC
– Kayexalate, oral or rectal
– Dialysis, peritoneal or hemodialysis
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Patient F.D. in Emergency
Room
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Patient F.D. after CaCl2
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Patient F.D. after
Hemodialysis
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Electrolyte Disorders in Renal
Failure
• Hyperkalemia
• Metabolic acidosis
• Hyponatremia
• Hypocalcemia
• Hyperphosphatemia
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Acute Renal Failure
Correction of life-threatening disorders
• Electrolyte disorders
• Uremic coagulopathy
• Pulmonary edema
• Pericarditis with tamponade
• Uremic encephalopathy
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Treatment of Uremic
Coagulopathy
Treatment Peak Action Duration
DDAVP, 0.3 µg/Kg IV 1 hour 4 hours
Cryoprecipitate, 10 units IV 3-4 hours 12-16 hours
Conjugated estrogens, 5-30 mg
IV or po qd for 5 days
24 hours Up to 14 days
Dialysis Days Indefinite
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Acute Renal Failure
Correction of life-threatening disorders
• Electrolyte disorders
• Uremic coagulopathy
• Pulmonary edema
• Pericarditis with tamponade
• Uremic encephalopathy
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Renal Replacement Therapy
• When to prescribe RRT?
• Which modality?
• How much of a dose?
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When to Prescribe?Acid-base disturbances
• pH < 7.1 and problems with using isotonic
bicarbonate therapy
Electrolytes
• K, Ca, Phos
Intoxications
• Only works well for selected intoxications
Overload
• Most common indication at BIDMC
Uremia
• Overt signs uncommon, often a r/o in altered patients with neuro injury
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Intoxications
• Salicylates
• Alcohol and Glycols (Iso, EtOH, MeOH)– fomepizole supplement during RRT to block osmàanion
• CNS drugs: Lithium/Valproate/Phenobarb
• Metformin: lactic acidosis with AKI
• Theophylline
• Methotrexate: glucarpidase instead?
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WHEN?
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AKIAKI
• Design: Multi-center RCT (31 sites)
• Subjects: 620, KDIGO Stage 3 AND [vent, pressor, or both]
• Intervention: early (immediate post-randomization, n=311) vs. delayed (specific criteria for K, acidosis, edema, BUN, oliguria, n=308)
• Outcome: 60d mortality post-randomization
• Result: Survival same, more catheter infxns in early arm– 49% of delayed arm AVOIDED dialysis
• average 50 hrs delay
• helpful vs. harmful: avoid RRT if destined to improve, but once RRT started, worse SOFA, more pressors, higher mortality
• DEATH: RRT avoiders 37% àearly RRT 48.5%àlate RRT 61.8%
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ELAIN
• Design: Single-center RCT
• Subjects: 231, KDIGO Stage 2 AND plasma NGAL > 150 ng/ml
• Intervention: early (8 hrs of KDIGO 2, n=112) vs. delayed (12 hrs of KIDGO 3 or none, n=119)
• Outcome: 90d mortality post-randomization
• Result: Survival, RRT duration, LOS all better in early arm
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Bagshaw, S. M. & Wald, R. (2016) Timing of renal replacement therapy in AKI
Nat. Rev. Nephrol. doi:10.1038/nrneph.2016.92
SOFA: Sequential Organ Failure Assessment
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WHICH?
• Intermittent hemodialysis
• Continuous therapies
• Continuous hemofiltration
• Continuous hemodialysis
• Continuous hemodiafiltration
• Prolonged intermittent RRT
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IHD vs. CRRT
Bagshaw SM, et al. Crit Care Med 2008; 36: 610-617
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Prolonged Int. RRT vs. CRRT
Zhang L, et al. Am J Kidney Dis 2015; 66:322-330
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It doesn’t matter, except…
• Settings in which high removal rate is important
• Electrolyte excess
• Intoxication
• Pulmonary edema
• Settings in which low removal rate is more desirable
• Increased ICP
• Fragile cardiovascular status
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Intensity of CVVHDF: ANZICS
Outcome at 90 days
Treatment ArmOdds Ratio
(95% CI)40 mL/kg/hr(N=747)
25 mL/kg/hr(N=761)
Mortality 322/72144.7%
332/74344.7%
1.00 (0.81-1.23)
p=0.99
Dialysis dependence
27/3996.8%
18/4114.4%
1.59(0.86-2.93)
p=0.14
Bellomo R, et al. N Engl J Med 2009; 361 1627-1638
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Intensity of CVVHDF: ANZICS
Bellomo R, et al. N Engl J Med 2009; 361 1627-1638
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ATN Study
Palevsky PM, et al. N Engl J Med 2008; 359:7-20
Intensive – 53.6%
Less-Intensive – 51.5%
Odds Ratio: 1.09
95% CI: 0.86-1.40P=0.47
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HOW MUCH?
Dose IndependentDose
Dependent
Su
rviv
al
RRT Dose
RRT Dose and Survival
5.8.3: We recommend delivering a Kt/V of 3.9 per week when using intermittent
or extended RRT in AKI (1A).
5.8.4: We recommend delivering an effluent volume of 20-25 ml/kg/h for CRRT
in AKI (1A). This will usually require a higher prescription of effluent volume
(Not Graded)
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Long Term Care After AKI
AKI begets/unveils CKD
Amdur etal,KI2009
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Even Recovered AKI associated
with CKD and ESRD
Bucaloiu etal,KI2012 Waldetal,JAMA2009
CKD ESRD
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CV outcomes after AKI in the
ICUaHR (95% CI)
No AKI 1.00
AKI-Stage 1 1.33 (1.06–1.66)
AKI-Stage 2/3 1.45 (1.14–1.84)
Gammelager et al Crit Care 2014
cohort study among ICU-admitted patients in Northern Denmark 2005-2010
21,556 patients who survived to hospital discharge
4,792 (22%) had AKI
Follow-up 3 years
Outcomes were admissions for HF, MI, stroke Patients with prior HF, MI, stroke excluded
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CV outcomes after AKI in the
ICU
aHR (95% CI)
No AKI 1.00
AKI-Stage 1 1.10 (0.75–1.62)
AKI-Stage 2/3 1.07 (0.70–1.65)
Gammelager et al Crit Care 2014
cohort study among ICU-admitted patients in Northern Denmark 2005-2010
21,556 patients who survived to hospital discharge
4,792 (22%) had AKI
Follow-up 3 years
Outcomes were admissions for HF, MI, stroke Patients with prior HF, MI, stroke excluded
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CV outcomes after AKI in the
ICU
aHR (95% CI)
No AKI 1.00
AKI-Stage 1 1.04 (0.71–1.51)
AKI-Stage 2/3 1.51 (1.05–2.18)
cohort study among ICU-admitted patients in Northern Denmark 2005-2010
21,556 patients who survived to hospital discharge
4,792 (22%) had AKI
Follow-up 3 years
Outcomes were admissions for HF, MI, stroke Patients with prior HF, MI, stroke excluded
Gammelager et al Crit Care 2014
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Late MI risk higher with AKI
Wu et al JASN 2014
AKI (n=4869) No AKI (n= 4869) p-value
Coronary events 299 (6.1%) 177(3.6%)
AKI Severity
Adjusted* OR Ratio (95% CI) for elevated BP post discharge
180 days(n=40,861)
365 days(42,845)
540 days(43,407)
730 days(43,611)
AKI[vs. noAKI]
1.40 (1.28 - 1.54)
1.36 (1.25 - 1.49)
1.27 (1.17 - 1.39)
1.22 (1.12 - 1.33)
Stage 1 AKI
1.23 (1.10-1.37)
1.21 (1.09-1.34)
1.13 (1.02-1.26)
1.09 (0.98-1.21)
Stage 2 AKI
1.66
(1.33-2.08)
1.53 (1.23-1.90)
1.51 (1.22-1.87)
1.45 (1.17-1.79)
Stage 3 AKI
2.18 (1.74-2.74)
2.17 (1.73-2.71)
1.89 (1.51-2.37)
1.82 (1.45-2.29)
Raymond Hsu Kidney Wk 2015
Increased Hypertension after AKI
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Recommended post-AKI care
• No recommendations exist
• Common Sense approach (chicken or
egg)
– Follow-up with nephrologist
– Monitoring of SCr, proteinuria (#1,2 AKI
RFs)
– CV optimization (CKD is #1 CVD RF)
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Acute Renal Failure
Clinical burden of AKI
Mechanisms, Outcomes and
Prognosis
Care for the Patient
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