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Acute Renal Failure

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Title: Acute Renal Failure


1
Acute Renal Failure
  • Fatiu .A. Arogundade FMCP, FWACP, ISN Fellow
  • Renal Unit,
  • Department of Medicine,
  • Obafemi Awolowo University,
  • Ile-Ife.

2
Acute Renal Failure
  • Definition - Traditionally, ARF can be defined as
    sudden deterioration in kidney function resulting
    in accumulation of nitrogenous waste,
    perturbation of fluid homeostasis as well as its
    metabolic and endocrine functions.
  • Consensus

3
Introduction.
  • Definition Acute renal failure (ARF) is a
    sudden decrease in GFR over a period of hours to
    days, and resulting in the failure of kidney to
    excrete nitrogenous waste products, and maintain
    fluid and electrolyte homeostasis.
  • Clinically, ? Scr and BUN.

4
Introduction.
  • ARF complicates approximately 5 of hospital
    admissions and up to 30 of admissions to
    intensive care units.
  • ARF is an independent risk factor for mortality
    and is associated with a significant prolongation
    in length of hospital stay in survivors.
  • Most ARF is reversible. Nevertheless, ARF is
    associated with major in-hospital morbidity and
    mortality. Mortality rate in ICU setting 60-80.

5
Bellomo R et al Acute Dialysis Quality Initiative
workgroup. Acute renal failure definition,
outcome measures, animal models, fluid therapy
and information technology needs the Second
International Consensus Conference of the Acute
Dialysis Quality Initiative (ADQI) Group. Crit
Care. 2004 Aug8(4)R204-12.
6
  • Acute kidney injury (AKI) is defined as abrupt
    clinical and/ or laboratory manifestation of
    abnormal kidney function within 48 hours of
    kidney injury.
  • A reduction in urine output documented as less
    than 0.5 ml/kg/hour for more than 6 hours.
  • Absolute increase in serum creatinine of more
    than or equal to 0.3 mg/di (26.4 umol/L) or a
    percentage increase in serum creatinine of more
    than or equal to 50 (1.5 fold from baseline).
  • The term AKI was introduced by the International
    Consensus Conference on Acute Dialysis Quality
    Initiative (ADQI) workgroup Critical Care 2004
    in place of the highly restrictive and commonly
    used term, acute renal failure (ARF).

Mehta R et al Acute Kidney Injury Network Report.
Crit Care. 2007 Aug11R31.
7
Epidemiology
  • Medical wards about 5 of medical admissions
  • ICU 5-30 of ICU admissions

8
n 30,000 ICU pts, 53 centres, 23 Countries AKI
2000
9
Classification
  • Urine Volume
  • Medical Specialty
  • Aetiological classification

10
ARF
Urine Volume
Specialty
Aetiological
Medical
Surgical
Obstetric or Gynae
Oliguric
Non-oliguric
ICU
Pre- renal
Renal / Intrinsic
Post - renal
11
Aetiological
Renal / Intrinsic
Pre- renal
Post - renal
  • Vascular
  • Renal infarction, RAS, RVT
  • Malignant HT, Scleroderma,
  • Atheroemboli
  • Tubular
  • Ischaemic eg Sepsis,
  • Prolonged pre renal, Hypo T
  • Nephrotoxic eg
  • Aminoglycosides,
  • myoglobin,
  • Hb, chemotherapy
  • Glomerular
  • AGN
  • Vasculitis
  • Thrombotic microangiopathy
  • Pre Eclamptic Toxaemia
  • Interstitium
  • Drug induced TIN
  • Tumour infilteration
  • Intra ureteral obstruction
  • Stones, Clots, crystals,
  • tumour, papillae etc
  • Extra ureteral obstruction
  • Tumour
  • RPF
  • Prostate
  • BPH, Ca, Prostatitis
  • Urinary Bladder
  • Ca, Stones, Clots,
  • Urethra
  • Stricture, Ca, stones
  • Hypotension
  • Hypovolaemia
  • Fluid Loss Renal loss, Extrarenal
  • Blood Loss RTA, Perforation/rupture,
  • APH, PPH
  • Poor Pump Function
  • Cadiogenic Shock
  • CCF
  • Pericardial effusion with tamponade
  • Haemodynamic
  • Contrast Neph
  • Prostaglandin Inhibition (NSAIDs)
  • Other Drugs eg CyA, Tac,
  • ACE Inhibitors
  • HRS

12
ARF
Urine Volume
Specialty
Aetiological
Medical
Surgical
Obstetric or Gynae
Oliguric
Non-oliguric
ICU
Renal or Intrinsic
  • Hypotension
  • Hypovolaemia
  • Fluid Loss
  • Blood Loss
  • Poor Pump Function
  • Cadiogenic Shock
  • CCF
  • Pericardial effusion
  • Haemodynamic
  • Contrast Neph
  • Prostaglandin Inhibition
  • CyA, Tac, ACE Inhibitors
  • HRS

Pre- renal
Post - renal
  • Vascular
  • Renal infarction, RAS, RVT
  • Malignant HT,
  • Tubular
  • Ischaemic
  • Nephrotoxic
  • Glomerular
  • AGN
  • Vasculitis
  • Thrombotic microangiopathy
  • Pre Eclamptic Toxaemia
  • Interstitium
  • Drug induced TIN
  • Tumour infilteration
  • Intra ureteral obstruction
  • Stones, Clots, crystals, t
  • umour, papillae etc
  • Extra ureteral obstruction
  • Tumour
  • RPF
  • Prostate
  • BPH, Ca, Prostatitis
  • Urinary Bladder
  • Ca, Stones, Clots,
  • Urethra
  • Stricture, Ca, stones

13
Prerenal causes
  • Hypovolaemia
  • Bleeding, Diarrhea and Vomitting, Skin loss,
    Third space loss, PPH, APH, TENS, RTA
  • Decreased cardiac output
  • CHF, Myocardial dx, pericardial dx, valvular
    dx, arrhythmias, pericardiac effusion
  • Renalsystemic vascular ratio alteration
  • Liver Disease(HRS),
  • Renal vasoconstriction Hypercalcemia NE, E,
    amphotericin B
  • Systemic vasodilatation sepsis, anti
    hypertensives, anaesthesia
  • Impairment in Renal Autoregulation
  • ACEIs, Cox inhibitors






14
Intrinsic Renal causes
  • Vascular
  • Thrombo-embolic disease, dissecting aneurysm,
    vasculitis, renal artery stenosis, malignant
    hypertension.
  • Glomerular Disease
  • GN, pre-eclampsia, DIC, vasculitis, TTP,
    SLE,
  • Tubular Necrosis (ATN)
  • Ischaemic
  • Toxins- e.g drugs like aminoglycosides, lithium,
    n platinum derivatives
  • Tubulo-interestitial Disease
  • Acute Interestitial Nephritis (AIN), Acute
    cellular allograft rejection, viral (HIV, CMV),
    infiltration (sarcoidosis, leukaemia, lymphoma)
  • Intratubular Obstruction
  • myoglobin, hemoglobin, myeloma light chains,
    uric acid, tumor lysis, drugs (oxalate in
    ethylene glycol toxicity

15
Postrenal causes
  • Ureteric obstruction
  • Prostate disease
  • Bladder obstruction
  • anatomic cancer, schistosomiasis
  • functional neurogenic bladder
  • Urethral obstruction
  • anatomic posterior valve
  • functional anticholinergics, L-DOPA

16
Peculiar aetiological factors in our environment
  • Nephrotoxins
  • Native herbs
  • Drugs
  • Cholera
  • Septicaemia
  • CuSo4 (green water)

17
Pathophysiology of ARF
  • 3 major phases
  • Initiation Phase
  • Maintenance Phase
  • Recovery Phase

18
Maintenance of renal auto-regulation
  • Renin Angiotensin Activation
  • Kinnin kinninogen
  • Renal prostaglandins
  • Sympatho-adrenal activation

19
Mechanism of RAAS Activation
Salt water ret.
Angiotensinogen
Vasoconstriction
RENIN
aldost
ACE, Chymase, Cathepsins, Peptidases
Angiotensin I
Angiotensin II
Intra renal Events
20
Intra renal events after RAS Activation
Angiotensin II
TNFR1 TNFR2
AT recep

Angiotensinogen
NF-kB
TNF-a
Profibrotic cytokines
Tubular cells
Chem attr Adhes Prot
Prolifer. Different.
Matrix synth
FIBROSIS
Inflammatn.
21
Pathways Leading to AKI
Nephrotoxins
Hypovolaemia
Structural Proteins
Renal Growth factor and cytokine activation
Renal Perf
Proteinuria
Tubular damage
Influx of Infl cells
Lipid peroxidation
Transdifferentiation of Renal Cells to
fibroblast phenotype
GFR
Obstructive Uropathy
Renal Microvascular Injury
Acute Kidney Injury / Failure
Inflammation
Uraemia
Oedema
Acidosis
Others eg Anaemia, Ca X PO bal
22
Morphology of Acute Tubule Necrosis
  • ATN is usually most severe within the outer
    medulla of the kidney, involving both the pars
    recta (S3 segments) of the proximal tubule and
    the medullary thick ascending limb of the distal
    nephron.
  • The microvilli of the brush border are diffusely
    shortened and, in some areas, are completely
    effaced.
  • Intratubule casts Tamm-Horsfall glycoprotein as
    well as exfoliated tubule cells, remnants of shed
    brush border and other cellular debris.

23
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24
  • Vascular abnormality in ATN is congestion of
    peritubule capillaries, especially those in the
    outer medulla and corticomedullary region of the
    kidney.
  • Regenerative changes and signs of fresh
    epithelial injury are often observed in biopsy
    specimen, suggesting that recurrent episodes of
    tubule ischemia continue to occur during the
    maintenance phase of ARF.

25
Pathology
De Broe M.E. Renal injury due to environmental
toxins, drugs, and contrast agents. In Atlas of
Diseases of the Kidney. Schrier, Berl
Bonventre Current Medicine, Philadelphia 1999,
p. 11.1-11.16.
26
Pathophysiology of intrinsic ARF
  • Intrinsic Renal ARF
  • Most intrinsic ARF is triggered by ischemic
    insults that classically induce acute tubular
    necrosis (ATN).
  • Severe ischemia leads to bilateral renal cortical
    necrosis and irreversible renal failure.
  • It is believed that hypotensive event is far more
    likely to cause ATN if superimposed on a
    preexisting intrarenal vasoconstriction caused by
    "prerenal factors" such as congestive heart
    failure, cirrhosis, or NSAID ingestion.

27
  • 3 major factors contribute to the profound
    reduction in GFR
  • 1 Tubule injury back leakage and
  • intratubule
    obstruction.
  • 2 Haemodynamic abnormalities
  • reduction in perfusion
    and
  • vasoconstriction
  • 3 Intra renal inflammation

28
Tubular Injury
  • The major target of injury in ARF is the renal
    tubule epithelial cell.
  • Tubule injury ?GFR by two major mechanisms
    back-leakage of glomerular filtrate and
    intratubule obstruction.
  • Back-leakage refers to the unregulated and
    passive movement of glomerular filtrate from the
    tubule lumen into the interstitium of the kidney
    and then into the systemic circulation via renal
    capillaries and veins.

29
  • Micropuncture studies showed that back-leak
    occurs in ischemic and toxic models of ARF in
    animals and there is evidence to support the role
    of back-leakage in the pathophysiology of ATN in
    humans.
  • The presence of areas of tubule cell loss and
    denudation of basement membrane in biopsy
    specimens of ATN provides a morphologic
    explanation for back-leakage.
  • Myers et al demonstrated back-leakage of
    glomerular filtrate to contribute to renal
    insufficiency in patients with ischemic ATN.

30
  • The pathophysiology of ATN can be conveniently
    divided into initiation, maintenance, and
    recovery phases.
  • Initiation phase the initial period of renal
    hypoperfusion during which ischemic injury is
    evolving.
  • Renal perfusion is compromised to the extent that
    it precipitates a complex array of intrarenal
    events that are responsible for persistence of
    renal dysfunction long after the initiating cause
    has been resolved.

31
  • The maintenance phase refers to the period of
    ongoing renal failure (lasting days to weeks).
  • The maintenance phase is usually followed by a
    recovery phase, during which the renal injury is
    repaired and relatively normal or baseline renal
    function is reestablished.
  • May be complicated by marked diuresis.

32
Intrinsic Renal ARF
  • Ischemic injury is most prominent in the terminal
    medullary portion of the proximal tubule and the
    medullary portion of the thick ascending limb of
    the loop of Henle.
  • Both segments have high rates of active
    (ATP-dependent) solute transport and oxygen
    consumption and are located in the outer medulla
    that is relatively ischemic, even under basal
    conditions.

33
Pathogenesis of Intrinsic ARF.
  • Cellular ischemia results in a series of
    alterations in energetics, ion transport, and
    membrane integrity that ultimately lead to cell
    injury and, if severe, cell apoptosis or
    necrosis.
  • These alterations include depletion of ATP.
  • Inhibition of active sodium transport and
    transport of other solutes
  • Impairment of cell volume regulation and cell
    swelling

34
Depletion of Extracellular ATP stores
  • ATP depletion plays a central role in necrosis
    after ischemic cell injury.
  • Hypoxia results in the rapid degradation of
    ATP?ADP and? AMP. If the period of ischemia is
    relatively brief, resynthesis of ATP can occur on
    reoxygenation.
  • However, if ischemia is prolonged, AMP is
    metabolized further to adenosine and inosine and
    then to hypoxanthine.
  • Inhibition of Na /K -ATPase activity
    potentiates calcium entry into the cell via the
    sodium-calcium exchange.

35
Increased intracellular calcium.
  • Increase in intracellular calcium damages the
    epithelial cells by activating proteases and
    phospholipases and can further disrupt cellular
    integrity.
  • These include exacerbation of mitochondrial
    injury, increased generation of reactive oxygen
    species, disruption of the cytoskeleton, and
    activation of injurious enzymes, including
    calcium-dependent enzymes such as phospholipase
    A2 and calpain.

36
PHOSPHOLIPASE ACTIVATION
  • Ischemia-reperfusion results in the stable
    activation of soluble and membrane-bound forms of
    these calcium-dependent PLA2.
  • PLA2 results in the release of fatty acids and
    lysophospholipids, both of which have been shown
    by some investigators to injure lipid membranes.

37
ACTIVATION OF PROTEASES
  • calpain, a cysteine protease, appear to
    contribute to ischemia-induced necrosis of tubule
    cells.
  • Pharmacologic inhibitors of calpain have been
    shown to inhibit activation of calpain and to
    protect cells from injury induced by hypoxia.
  • Caspases, a distinct family of cysteine
    proteases, have been demonstrated to play an
    important and specific role in apoptotic cell
    death.

38
ENDONUCLEASE ACTIVATION AND DNA FRAGMENTATION
  • Endonucleases generally cleave dsDNA only at
    sites that are "unprotected" by histones.
  • In apoptosis, histones remain intact, and
    activation of a specific caspase-activated
    deoxyribonuclease (CAD) results in cleavage of
    dsDNA only at the "linking" regions between
    nucleosomes

39
OXIDANT STRESS AND NECROSIS
  • Reactive oxygen species (ROS) have been
    implicated as important effectors of tubule cell
    injury in both ischemic and toxic ATN.
  • ROS have numerous deleterious effects on cells,
    including lipid peroxidation, oxidation of cell
    proteins, and damage to DNA

40
  • severe oxidant stress results in early loss of
    plasma membrane and mitochondrial membrane
    integrity and cell necrosis.
  • Milder oxidant stress can cause apoptosis

41
THE HYDROXYL RADICAL
  • It is formed from superoxide?hydrogen peroxide
    ?hydroxyl radical, which requires ferrous iron as
    a catalyst.
  • Superoxide and hydrogen peroxide are
    constantly being produce by normal cells, and
    their production is increase in pathophysiologic
    states.

42
  • Cells are normally protected from the injurious
    effects of hydroxyl radical formation by a number
    of scavenging systems.
  • Catalase and glutathione peroxidase catalyze the
    conversion of hydrogen peroxide to water.
  • Oxidant stress occurs when these defenses are
    either deficient or overwhelmed by excessive ROS
    production.

43
EVIDENCE FOR A ROLE OF OXIDANT STRESS IN ACUTE
RENAL FAILURE.
  • Cellular markers suggesting ROS generation and
    lipid peroxidation have been detected during
    ischemia-reperfusion injury e.g malondialdehyde
    (MDA) and ethane.
  • Interventions designed to scavenge ROS after
    ischemic ARF have been demonstrated by many
    investigators to be protective. Antioxidants
    shown to be successful in ameliorating ARF
    include superoxide dismutase, catalase,
    inhibitors of xanthine oxidase, scavengers of the
    hydroxyl radical.

44
Inflammation
  • There is exptal evidence that iNOS may contribute
    to tubular injury during ARF.
  • Hypoxia increases NO release.
  • Western blot analysis in ischemic kidney has
    demonstrated increased iNOS protein expression.
  • An antisense oligonucleotide block the
    upregulation of iNOS and afford functional
    protection against acute renal ischemia.

45
  • when isolated proximal tubules from iNOS, eNOS,
    and nNOS knockout mice were exposed to hypoxia,
    only the tubules from the iNOS knockout mice were
    protected against hypoxia.
  • a-melanocytestimulating hormone (aMSH) affords
    protection against ischemic/reperfusion renal
    injury by blocking both the induction of iNOS and
    leukocyte infiltration into the kidney during
    ischemia.
  • Oxygen radical scavengers, such as superoxide
    dismutase, have also been shown to protect
    against acute renal injury associated with
    endotoxemia. Caspase inhibitors, IL-18
    antibodies, and caspase-1 knockout mice have also
    been shown to be protective against
    ischemia/reperfusion injury

46
Alterations in Gene Expression in Acute Renal
Failure
  • ARF is associated with a complex pattern of
    changes in the expression of many genes within
    the kidney.
  • The role of these gene expression in acute renal
    injury remains incompletely understood.
  • Some of the genes play an important role in
    modulating events such as cell proliferation and
    differentiation, determination of cell fate that
    are associated with recovery from ARF.

47
  • Increased expression of genes that encode
    proinflammatory cytokines exacerbates ARF.
  • Another maladaptive response in ARF is the
    increased expression of the gene encoding
    pre-pro-ET-1.
  • Growth factors potentially modulate renal failure
    by stimulating proliferation or by suppressing
    apoptosis of RTCs, or both.

48
  • Number of studies have shown that ARI is
    associated with an increase in renal expression
    of the receptors for many renal growth factors
    such as EGF, IGF-1, and fibroblast growth
    factor-7.
  • There is also a large body of evidence showing
    that the exogenous administration of a number of
    tubule growth factors, including EGF, IGF-1, FGF,
    ameliorates injury or accelerates recovery from
    ischemic or toxic ARF in animals, or both.

49
REGULATORS OF THE CELL CYCLE.
  • The protein p21 is a member of the family of
    cyclin kinase inhibitors that regulate cell
    proliferation by inhibiting the cell cycle.
  • Safirstein et al, demonstrated that expression of
    p21 is induced in murine kidneys subjected to ARF
    caused by ischemia, cisplatin, or acute
    obstruction.
  • The same group also reported that p21 -/-
    knockout mice subjected to ARI demonstrated more
    RTC proliferation, worse renal functional
    impairment, and a higher mortality rate than
    wild-type controls.
  • They postulated that increased p21 expression
    protects kidneys from injury.

50
HEME-OXYGENASE-1
  • Heme-oxygenase-1 (HO-1) is a microsomal enzyme
    that degrades heme, a reaction that results in
    the generation of biliverdin, iron, and carbon
    monoxide.
  • Induction of HO-1 occurs as an adaptive and
    protective response to a wide variety of acute
    forms of injury induced by heme, cytokines,
    growth factors, heavy metals, NO, and oxidized
    low-density lipoprotein.

51
KIDNEY INJURY MOLECULE-1
  • Bonventre and co-workers reported that the
    expression of a novel protein KIM-1, is markedly
    up-regulated after acute ischemic or toxic renal
    injury and is expressed predominantly in
    proliferating and dedifferentiated proximal
    tubule cells undergoing regeneration.

52
  • Bonventre's group also reported that urinary
    levels of KIM-1 were approximately fivefold
    higher in patients with ARF than in normal
    subjects or patients with chronic renal failure.
  • They suggested that measurement of KIM-1 in the
    urine of patients with ATN may serve as a useful
    early biomarker for renal proximal tubule injury
    and may be useful in facilitating the early
    diagnosis of ATN.

53
  • The diagnosis of acute kidney injury
    (AKIformally known as acute renal failure) is
    usually based on either an elevation of serum
    creatinine or the detection of oliguria.
  • In AKI, because the patients are not in steady
    state hence, serum creatinine lags far behind
    renal injury. Thus, substantial rises in serum
    creatinine are often not witnessed until
    4872 h after the initial insult to the kidney.

54
  • In addition, significant renal disease can exist
    with minimal or no change in creatinine because
    of renal reserve, enhanced tubular secretion of
    creatinine, or other factors.
  • Several biomarkers of AKI have been identified
    over the past few years that are elevated in
    ischemic renal injury in experimental animals,
    and also in humans with clinical AKI, in some
    cases prior to a gold standard diagnostic
    threshold (for example, rise in serum creatinine
    by 50).
  • These biomarkers include cystatin C, IL-18 and
    neutrophil gelatinase-associated lipocalin (NGAL).

55
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56
Clinical features
  • Oliguria
  • Uraemia
  • GIT
  • Heart
  • CNS
  • Haematological
  • Dermatology
  • Oedema

57
Investigations
  • Urine volume / microscopy
  • Urinalysis
  • Urinary electrolytes
  • Serum chemistry eg creatinine, urea, K
  • Haematology including serology
  • Imaging eg USS, IVU, RUCG etc
  • Renal biopsy

58
Distinguishing the different causes of AKI
Type Urinalysis Urine SG Urine Micro U Na (Mmol/L) FE Na () Fe UN () BUN/Cr ratio
Pre-Renal Normal High hyaline lt 20 lt 1 35 gt201
A.T.N Normal Low Muddy brown gt 40 gt 1 gt 50 201
Vascular Normal Normal Haematuria gt 20 Variable
G.N Proteinuria Normal Haemat / RBC casts lt 20 lt 1
TIN Mild prot WBCs / casts / Eosino. gt 20 gt 1
Post Renal Normal Normal WBcs, RBcs, granular casts gt 20 Variable 201
59
Distinguishing Acute KI from Chronic KD
Parameters AKI CKD
Duration Short Prolonged
BP Normal High
PCV or Hb Low Low
Urine Vol Low / Nil Normal or Increased
Serum K Normal / High Normal / High
Serum Urea Very high High
Serum Creatinine High High
Carbamylate Hb Low High
Fingernail Creatinine Low High
Kidney Size Normal or Increased Reduced
- Could not distinguish between the 2 conditions
Sanusi AA, Arogundade FA et al AJNT 2008 121-26.
60
ed
GRADING AKI
Bellomo R et al Acute Dialysis Quality Initiative
workgroup. Acute renal failure definition,
outcome measures, animal models, fluid therapy
and information technology needs the Second
International Consensus Conference of the Acute
Dialysis Quality Initiative (ADQI) Group. Crit
Care. 2004 Aug8(4)R204-12.
61
RIFLE Criteria for Acute Renal Dysfunction
Category GFR Criteria Urine Output (UO) Criteria  
Risk Increased creatinine x1.5 or GFR decrease gt 25 UO lt 0.5ml/kg/h x 6 hr High Sensitivity     High Specificity
Injury Increased creatinine x2 or GFR decrease gt 50 UO lt 0.5ml/kg/h x 12 hr High Sensitivity     High Specificity
Failure Increase creatinine x3 or GFR decrease gt 75 UO lt 0.3ml/kg/h x 24 hr or Anuria x 12 hrs High Sensitivity     High Specificity
Loss Persistent ARF complete loss of kidney function gt 4 weeks Persistent ARF complete loss of kidney function gt 4 weeks  
ESKD End Stage Kidney Disease (gt 3 months) End Stage Kidney Disease (gt 3 months)
62
AKIN STAGING
  • Stage 1 rise in serum creatinine (Scr) by gt0.3
    mg/dL (26.4 µmol/L) or an increase of gt150-200
    (1.5-to 2-fold increase) from baseline. OR Less
    than 0.5ml/kg/hr for more than 6 Hours.
  • Stage 2 rise in serum creatinine by gt200-300
    (2-to 3-fold increase) from baseline OR Less than
    0.5ml/kg/hr for more than 12 Hours.
  • Stage 3 rise in serum creatinine to gt300 (gt
    3-fold) from baseline or serum creatinine 4.0
    mg/dL (354 µmol/L) with an acute rise of at
    least 0.5 mg/dL (44 µmol/L) OR Less than
    0.3ml/kg/hr for 24 Hours or anuria.

Only one criterion (creatinine or urine output)
needs to be fulfilled to qualify for a
stage.aPatients who receive renal replacement
therapy are considered to have met the criteria
for Stage 3, irrespective of the stage that they
are in at the time of commencement of renal
replacement therapy. Mehta RL et al. (2007)
Crit Care 11 R31.
63
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64
Biomarkers
  • Creatinine
  • high molecular weight proteins
  • tubular proteins or enzymes
  • lack specificity and no standardized assays.
  • Neutrophil Gelatinase-Associated Lipocalin (NGAL,
    also known as lcn2)
  • Very promising

65
Management of AKI
  • Treat precipitating event / condition
  • Conservative Management
  • RRT

66
Management
  • Principles
  • Maintenance of fluid homeostasis
  • Control of biochemical abnormalities
  • Maintenance of nutrition
  • Address the underlying cause
  • Dialysis where indicated

67
AKI Management
Conservative
Treat Primary Condition
RRT
Fluid Balance
Electrolytes
Diet
Acute
Intermittent
Continuous
  • CAPD
  • CCPD
  • SCUF
  • CAVH
  • CVVH
  • CAVHD
  • CVVHD
  • CAVHDF
  • CVVHDF
  • APD
  • AHD
  • Intermittent PD
  • Intermittent HD
  • Intermittent HF
  • SLED
  • EDD

68
Treatment Modalities for ARF on the ICU
Urea clearance ml/min
IHD
SLED
CRRT
time h
69
Fluid Management
  • Limit fluid intake to insensible loss
    (500-1200mls/day)
  • Replace volume of urine / other documented losses
    in the previous 24 hours
  • Avoid Potassium containing fluids
  • Diuretics may be useful in pre-renal ARF

70
Electrolyte management
  • Hyperkalaemia
  • Biochemical confirmation
  • ECG appearance
  • Force K into cells
  • Glucose-Insulin Infusion
  • Glucose Infusion
  • Antagonise K Effects on heart
  • 10 Calcium gluconate
  • Remove K from circulation
  • Dialysis
  • Ion exchange resin

71
Diet and Calorie
  • High calorie low protein in acute phase
  • High calorie normal protein in recovery phase
  • Parenteral hyperalimentation may become necessary
    in prolonged cases

72
Newer Treatment modalities
  • Modulating Vasoconstriction
  • Calcium channel antagonists
  • eg Transplant, CyA exposure, Radiocontrast
    Nephropathy
  • Dopamine Not effective from studies
  • ANP may initiate diuresis in oliguric patients
  • Endothelin blockade
  • Nitric oxide modulation
  • N acetyl cysteine use

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Newer Treatment modalities
  • Limiting Inflammation
  • Inhibition of chemokine production eg a-MSH
  • Anti Adhesion strategies
  • Anti ICAM
  • Anti Integrins
  • PPAR ligands eg etomoxir
  • Biocompatible membranes
  • Cytokine absorbing membranes

74
Newer trends
  • atrial natriuretic factor, adenosine-receptor
    antagonists,and phosphodiesterase inhibitors
    target inappropriate vasoreactivity.
  • Lazaroids and antioxidants decrease the
    generation or action of free radicals.
  • Insulin-like growth factor I, epidermal growth
    factor, and hepatocyte growth factor facilitate
    the regeneration of tubular cells.

75
ctd.
  • The use of Anaritide - Regeneration of damage
    epithelial tubular cells in the lab setting.
  • Boosting /mobilization and acceleration of
    maturation of circulating endothelial progenitor
    cells Statins, VEGF, Adenosine, EPO
  • Transplantation of Haemopoetic and circulating
    stem cells
  • Angioblast Transplantation of endothelial cells
  • Reduction of intratubular obstruction-Anti
    integrin Anti ICAM-1
  • Endogenous anti inflammatory Alpha Melanocyte
    hormone
  • Calcium Antagonists- Nitrendipine SOD
  • Endothelium Antagonists Dual ETA/ETB (L754142)
  • Gene therapy
  • Free Radical Scanvengers-SOD, Allupurinol, NO
    inhibitors, Dimethylthiourea
  • High Dose EPO therapy

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Indications for RRT
  • Clinical
  • Biochemical
  • Features of hypercatabolism

77
Dialysis
  • 20 60 of ARF patients will require dialysis
  • Indications
  • Hyperkalemia gt 6.5mmol/l or rate of rise gt
    1mmol/day
  • Bicarbonate lt 12mmol/l
  • Urea gt 30mmol/l or rate of rise gt 8mmol/day
  • Creatinine gt 600micromol/l or rate of rise
    gt100micromol/day
  • Dysnatraemia
  • Pulmonary edema unresponsive to diuretics
  • Uraemic encephalopathy
  • Uraemic pericarditis

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Choice of RRT in ARF
Indication Clinical condition Suggested modality
Uncomplicated ARF Stable, non-catabolic Stable, catabolic IHD,PD IHD
ARF fluid overload Stable Unstable IHD, CRRT, SLED CRRT, SLED
ARF raised intracranial pressure Stable and unstable CRRT
ARF respiratory failure Stable Unstable SLED, CRRT SLED, CRRT
Septic shock SLED, CRRT
ARDS Stable and Unstable SLED, CRRT
Electrolyte abnormalities IHD, SLED, CRRT
Drug overdose/poisoning IHD and/or CRRT
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complications
  • CCF
  • Pulmonary edema
  • Arrythmias
  • Pericarditis
  • Uraemic encephalopathy
  • Infections gt60
  • GI haemorrhage- 10-20
  • Seizures
  • Paralytic ileus

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Prognosis
  • The prognosis of patients with ARF is directly
    related to the cause of renal failure and, to a
    great extent, to the duration of renal failure
    prior to therapeutic intervention.
  • Patients need dialytic therapy, the mortality
    rate is 50-90.

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Determinants of Mortality or Survival
  • Age
  • Aetiology
  • Severity
  • Other co-morbidities
  • Pulmonary Oedema
  • Use of RRT
  • Dose of RRT

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Number of Organ Failure (s) in the 2 groups of
patients
Number of Organ failure(s) Group I Group II P-value
1 8 34 Fishers exact test 0.0007
2 19 3 Fishers exact test 0.0007
3 or more 13 - Fishers exact test 0.0007
Total 40 37
83
Arogundade FA et al. Central African Journal of
Medicine 2009 (In Press)
84
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