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Acute Kidney Injury Patho-physiological considerations

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Title: Acute Kidney Injury Patho-physiological considerations


1
Acute Kidney Injury Patho-physiological
considerations
  • Sharma Prabhakar MD

2
Definitions
  • Abrupt (lt48 hrs) reduction of kidney function
    with Scr increase of gt0.3 mg/dl or a reduction of
    urine output lt0.5 ml/kg/hr for gt6 hrs)
  • Acute and sustained increase in Scr gt0.5 mg/dl if
    the baseline Scr is lt2.5 mg/dl or gt25 increase
    if the baseline is gt2.5 mg/dl
  • Associated often with oliguria and heavy
    mortality
  • Variable severity and outcomes

3
Incidence
  • Reported rates 100-620 /million/yr
  • 5-20 of critically ill patients (5.7 pts in
    BEST kidney study)
  • 20 of all severely septic patients
  • 50 of all patients in septic shock
  • Overall in-hospital incidence at least 0.5 up to
    13 (the PICARD study group)

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Pre-renal azotemia
  • Most common cause of ARF
  • Integrity of renal structure intact
  • Severe pre-renal state may lead to ATN (parts of
    a spectrum)
  • Intermediate renal syndrome
  • Result in ?NE, Ang II and ADH levels ? splanchnic
    and skeletal vasoconstriction
  • GFR preserved in mild hypoperfusion by
    vasodilatory renal PG, nitric oxide and Ang II,
    and kinins

10
Pre-renal azotemia
  • In moderate severe hypoperfusion, compensatory
    responses overwhelmed
  • Autoregulation fails below systolic pressure of
    80 mm/Hg
  • Lesser degrees of hypotension trigger prerenal
    azotemia in elderly, renovascular disease, DN and
    nephrosclerosis
  • High levels of Ang II (CHF) cause aff and eff
    constriction.

11
Pre-renal azotemia
  • NSAIDs COX-2 inhibitors impair adaptive renal
    responses by inhibiting renal PG synthesis only
    in hypovolemics and in CKD.
  • ACEi and ARBs cause AKI (reversible) in patients
    where renal filtration pressures are dependent on
    ANG effects such as in hypoperfused states and in
    RAS.
  • Non-oliguric pre-renal ARF is seen in pts with
    renal concentration defects (DI) and solute load
    (glucose, urea, mannitol)? Hypernatremia is a
    clue in these states.

12
Classification and Major Disease Categories
Causing Acute Renal Failure
DISEASE CATEGORY OF PATIENTS WITH ACUTE RENAL FAILURE
1. Prerenal azotemia caused by acute renal hypoperfusion 5560
2. Intrinsic renal azotemia caused by acute diseases of renal parenchyma 3540
   Diseases involving large renal vessels  
  Diseases of small renal vessels and glomeruli  
  Acute injury to renal tubules mediated by ischemia or toxins  
   Acute diseases of the tubulointerstitium  
3. Postrenal azotemia caused by acute obstruction of the urinary collecting system lt5
More than 90 of cases in the intrinsic renal azotemia category in most series are caused by ischemic or nephrotoxic acute tubule necrosis
13
Pathophysiology of ATN-Histology
  • Most severe injury in outer medulla (pars recta
    of the proximal tubule and mTAL)
  • Patchy necrosis
  • Loss of tubular cells from tubules
  • Loss of BBM in proximal tubules
  • Intratubular casts (THP and cells)
  • Peritubular congestion

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ATN-clinical-histological correlations
  • Poor structure-function correlations
  • Recent human data suggests subtle changes with
    sublethal injury and apoptosis contribute
    significantly to functional losses
  • ATN a misleading term -? AKI (Solez and
    Racussen)
  • Animal models do not fully replicate human
    disease. Animals resistant to renal hypoperfusion
    unless very severe (lt20 mm/Hg). Less severe
    pressures even if prolonged do not cause ARF
    despite PT necrosis.

17
Experimental models- Strengths and weaknesses
18
AKI- Overview of pathophysiology
19
AKI- fate of tubular cells
20
Table 27-9   -- Morphologic Differences between
Apoptosis and Necrosis
MORPHOLOGIC FEATURE APOPTOSIS NECROSIS
Cell size Decreased Increased ("oncosis")
Plasma membrane integrity Relatively normal Absent
Plasma membrane "blebbing" Characteristic Absent
Mitochondria Normal appearance Swollen, distorted cristae
Cell-cell adhesion Lost early Remains relatively intact
Cell-matrix adhesion Lost early Lost late
Exfoliation Early (as single cells) Late (as sheets of cells)
Chromatin condensation Characteristic Absent
Nuclear fragmentation Characteristic Absent
Release of cytosolic contents Absent Characteristic
Pattern of cell death in tissue Individual scattered cells dying asynchronously Groups of contiguous cells dying together
Tissue inflammation Absent Characteristic
Apoptotic bodies Characteristic Absent
Phagocytosis of dying cells Characteristic Absent
21
AKI Oxidative Stress
22
Sublethal tubular injury
23
Endothelial injury in ATN
24
Sepsis and ATN
25
Organ cross talk in AKI
26
Major Causes of Acute Intrinsic Renal Azotemia
Diseases Involving Large Renal Vessels
Renal arteries thrombosis, atheroembolism, thromboembolism, dissection, vasculitis (e.g., Takayasu)
Renal veins thrombosis, compression
Diseases of Glomeruli and the Renal Microvasculature
Inflammatory acute or rapidly progressive glomerulonephritis, vasculitis, allograft rejection, radiation
Vasospastic malignant hypertension, toxemia of pregnancy, scleroderma, hypercalcemia, drugs, radiocontrast agents
Hematologic hemolytic-uremic syndrome or thrombotic thrombocytopenic purpura, disseminated intravascular coagulation, hyperviscosity syndromes
Diseases Characterized by Prominent Injury to Renal Tubules Often with Acute Tubule Necrosis
Ischemia caused by renal hypoperfusion
Exogenous toxins (e.g., antibiotics, anticancer agents, radiocontrast agents, poisons
Endogenous toxins (e.g., myoglobin, hemoglobin, myeloma light chains, uric acid, tumor lysis
Acute Diseases of the Tubulointerstitium
Allergic interstitial nephritis (e.g., antibiotics, nonsteroidal anti-inflammatory drugs)
Infectious (viral, bacterial, fungal)
Acute cellular allograft rejection
Infiltration (e.g., lymphoma, leukemia, sarcoid)
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Clinical Course of ATN
  • Initiation Phase exposure to ischemia/toxin
  • Maintenance Phase Oliguria/azotemia 1-2 wks
  • Recovery (diuretic) Phase Increasing urine
    output and decrease in Scr

29
Evaluation
  • Obstructive causes must be considered and
    excluded especially in the elderly
  • Assessment of volume status is often very
    difficult
  • Complete pelvic examination in women and a rectal
    in men is mandatory.
  • Elicit h/o nephrotoxins, consider other renal
    parenchymal pathology .

30
Evaluation of the progress
  • Scr depends on not only renal clearance , but
    also production and vol of distribution.
  • Most ATN cases increase is 0.3-0.5 mg/day but
    slower in pre-renal AKI
  • BUN/cr gt20 in prerenal, (unreliable)-exceptions
  • BUN/cr increased with low muscle mass, elderly
    without change in GFR.

31
AKI and Cancer
  • Pre-renal Volume depletion ( nausea, vomiting)
    is the most common cause of AKI. Others
    hypercalcemia, NSAIDs
  • Intrinsic renal renal infiltration by solid and
    hematological cancers( 5-10) but clinically
    important in only a few. Responds to chemotherapy

32
AKI and Cancer Tumor lysis syndrome
  • Following initiation of therapy for
    lympho-proliferative malignancies and solid organ
    tumors. Rarely spontaneous
  • Hyperuricemia, hyperphosphatemia, hypocalcemia
  • Tubular injury/obstruction by uric acid, calcium
    phosphate crystals.

33
AKI and Cancer
  • Other causes of AKI in cancer
  • - tumor associated GN
  • - TMA (drugs/irradiation)
  • Multiple Myeloma
  • Hypovolemia, myeloma kidney, sepsis,
    hypercalemia, ATN (drugs/TLS), infiltration,
    amyloidosis.

34
AKI in Chronic liver disease
  • Hypovolemia
  • Sepsis
  • Nephrotoxins ( contrast/antibiotics)
  • GI hemorrhage
  • Hepatorenal syndrome

35
Hepato-renal syndrome
  • Irreversible AKI seen in the context of advanced
    cirrhosis but also seen in acute fulminant
    viral/alcoholic hepatitis
  • Oliguric renal failure
  • Dys-regulation of circulation intense renal
    vasoconstriction associated systemic vasodilation
    ? ?ECBV despite anasarca
  • RAS and SNS activation in early disease
  • Role of splanchnic NO in the circulatory
    dysregulation

36
Hepato-renal syndrome
  • Two forms of HRS
  • Type I- rapidly progressive form (Scrlt2.5 mg/dl
    in 2 wks). Fulminant course- severe
    hyperbilirubinemia, death in ltmonth
  • Type II- indolent course, resistant ascitis
  • Diagnosis of exclusion (r/o, pre-renal, ATN)
  • Address precipitating factors (SBP, drugs)

37
Management of prerenal azotemia
  • Fluid resuscitation Type of fluid depends on the
    nature of fluid lost (blood, isotonic saline)
  • Fluid resuscitation with saline or albumin gave
    same results in critically ill patients (SAFE
    study)
  • Once established, fluid admn must be judicious
    since pulmonary edema could be precipitated in
    patients with oliguria/anuria.

38
Contrast nephropathy-prevention
  • Hydration with isotonic saline is superior to the
    routinely recommended half isotonic saline
    (Mueller et al, 2002)
  • Oral N-acetylcysteine lowers the risk of CN in
    CKD ( 3 meta analyses, Birck 2003, Pannu et al
    2004, Alonso 2004, Isenbarger 2003)
  • However the role of N-AC without hydration is
    questionable ( Lin et al 2005)

39
Diuretics
  • Once euvolemic, loop diuretics promote diuresis
    in some forms of AKI. (Uchino et al 2004). No
    increased mortality although some smaller studies
    showed increased death and worsening renal
    function (Chertow et al 2004).
  • Mannitol is renoprotective only in the setting of
    renal transplantation (Reddy 2002)

40
Dopamine
  • Renal dose (1-3 mcg/kg/min) of dopamine dilates
    renal arteries.
  • Often used alone or with furosemide in ICU
    patients to increase urine output
  • Meta-analysis and prospective trials do not
    support any reno-protective role (Kellum 2001,
    Bellamo 2000)
  • Fenoldopam a DA-1 receptor agonist has not proven
    to be useful ( Bove 2005) in AKI after post
    cardiac surgery

41
Calcium Channel Blockers
  • Prophylaxis with calcium channel blockers
    protects against post transplant ATN (Lamiere et
    al 2001)
  • Meta-analysis- benefit unclear (Dishart et al
    2000)
  • Post-surgical AKI- data more convincing (Piper et
    al 2002)
  • No role in established ATN

42
ANP
  • In patients with established AKI, ANP given iv or
    intrarenally along with furosemide increased GFR
    acutely with lasting effects but without survival
    benefit (Allegren 1997)
  • Decreased need for dialysis
  • However no benefit in oliguric ATN patients.
    (Sward 2004)
  • Benefits inconclusive

43
IGF-1
  • IGF-1 given post-op in surgical patients with
    renal ischemia prevented the decline in GFR
    (Franklin 1997) Incidence of AKI was too low to
    validate the conclusion
  • However IGF did not accelerate the renal recovery
    in ICU pts with AKI when IGF was given within 6
    days (Hirschberg 1999)
  • Effects unclear

44
Thyroxine
  • Thyroxine speeds up recovery of renal function in
    many animal models of AKI
  • Human studies no benefit ( prospective randomized
    controlled study of 60 patients). In addition
    there was increased morbidity and mortality in
    critically ill patients ( Acker 2000)

45
Anti-inflammatory agents
  • Administration of ICAM-1 antibody and synthetic
    peptides that inhibit integrins reduce AKI
    (Goligorsky 1998) by decreasing intratubular
    obstruction via inhibition of cell-cell adhesion
    in the tubule. No human studies.
  • In renal ischemia model of AKI in rats, ?-MSH
    given in multiple doses even after 6 hours,
    prevented structural and functional damage
    through inhibition of IL-8, ICAM-1 and iNOS.
    (Star 2001)

46
 Supportive Management of Intrinsic Acute Renal
Failure
COMPLICATION TREATMENT
Intravascular volume overload Restriction of salt (lt11.5 g/day) and water (lt1 L/day)
  Consider diuretics (usually loops thiazide) 200 mg bolus or 20 mg/hr infusion
  Ultrafiltration
Hyponatremia Restriction of oral and intravenous free water
Hyperkalemia Restriction of dietary potassium
  Discontinue K supplements or K-sparing diuretics
  K-binding resin
  Loop diuretic
  Glucose (50 mL of 50 dextrose) insulin (1015 U regular insulin) IV
  Sodium bicarbonate (50100 mEq IV)
  Calcium gluconate (10 mL of 10 solution over 5 min)
  Dialysis/hemofiltration
Metabolic acidosis Restriction of dietary protein
  Sodium bicarbonate (if HCO3- lt15 mEq/L)
  Dialysis/hemofiltration
47
 Supportive Management of Intinsic Acute Renal
Failure
Hyperphosphatemia Restriction of dietary phosphate intake
  Phosphate-binding agents (calcium carbonate, calcium acetate, sevelamer)
Hypocalcemia Calcium carbonate (if symptomatic or sodium bicarbonate is to be administered)
Hypermagnesemia Discontinue magnesium-containing antacids
Nutrition Restriction of dietary protein (lt0.8 g/kg/day up to 1.5 g/kg/day on continuous venovenous hemodialysis) 2530 kcal/day
  Enteral route of nutrition preferred
Drug dosage Adjust all doses for glomerular filtration rate and renal replacement modality
Absolute indications for renal replacement therapy Clinical evidence of uremia, Intractable volume overload Hyperkalemia or severe acidosis resistant to conservative management
48
Dilaysis for AKI
  • Does not hasten recovery, in fact may delay if
    bio-incompatible membranes are employed
  • Early/prophylactic/intensive dialysis not shown
    to have significant benefit (Bonventre NEJM 2002)
  • Indications for initiation are evidence based
  • Effect of choice of dialytic modality or
    intensity on outcomes unclear.
  • Choice usually depends on resources available,
    expertise of physician and patients profile.

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Dialysis dosing in AKI
  • Dialysis to give a Ccr of 10 is reasonable
    initial target (12 hrs/wk) but more dosing needed
    for hypercatabolic states.
  • Kinetic urea models predict 4.4 sessions/wk
    needed to maintain BUNof 60 mg/dl in a 50 kg pt.
    More aggressive goals are associated with better
    survival (Schiffl, NEJM 2002).

52
Dialysis dosing in AKI
  • Higher Kt/V associated with improved survival in
    AKI except when critically ill ( Himmelfarb 1998
    )
  • Daily dialysis was associated with reduced
    mortality in AKI than with qod therapy ( Schiffl
    NEJM 2002) in intermediate severity of illness

53
Dialysis dosing in AKI
  • Reasonable targets
  • spKt/V of 1.2 or eKt/V of 1.0
  • Steady state BUN of 70 mg/dl
  • Prescribed and delivered doses are different
  • VA-NIH AKI trial Intensive therapy (6/wk) with
    target Kt/V 1.2-1.4 /tx CRRT 35 ml/kg/h
  • vs. conventional therapy ( 3/wk) CRRT 20
    ml/kg/h

54
 Dialytic Modalities in Acute Renal Failure
MODALITY MODALITY DIALYZER DIALYZER PHYSICAL PRINCIPLE UREA CLEARANCE (mL/min) MIDDLE MOLECULE CLEARANCE MIDDLE MOLECULE CLEARANCE
Hemodialysis Hemodialysis Hemodialysis Hemodialysis Hemodialysis Hemodialysis Hemodialysis Hemodialysis
Conventional Hemodialyzer Hemodialyzer Intermittent diffusive clearance and ultrafiltration (UF) concurrently Intermittent diffusive clearance and ultrafiltration (UF) concurrently 160 160
Sustained low-efficiency dialysis (SLED) Hemodialyzer Hemodialyzer Intermittent, but prolonged diffusive clearance and UF concurrently Intermittent, but prolonged diffusive clearance and UF concurrently 40 40
Sequential ultrafiltration and clearance Hemodialyzer Hemodialyzer Intermittent UF followed by diffusive clearance Intermittent UF followed by diffusive clearance 160 160
Continuous arteriovenous hemodialysis (CAVHD) Hemofilter Hemofilter Slow diffusive clearance and UF concurrently without a blood pump Slow diffusive clearance and UF concurrently without a blood pump 1721 1721
Continuous venovenous hemodialysis (CVVHD) Hemofilter Hemofilter Slow diffusive clearance and UF concurrently with a blood pump Slow diffusive clearance and UF concurrently with a blood pump 1721 1721
55
Dialytic Modalities in Acute Renal Failure
MODALITY DIALYZER PHYSICAL PRINCIPLE UREA CLEARANCE (mL/min) MIDDLE MOLECULE CLEARANCE
Hemofiltration Hemofiltration Hemofiltration Hemofiltration Hemofiltration
Continuous arteriovenous hemofiltration (CAVHF) Hemofilter Continuous convective clearance without a blood pump 710
Continuous venovenous hemofiltration (CVVHF) Hemofilter Continuous convective clearance with a blood pump 1517
Continuous venovenous hemodialysis plus hemofiltration (CVVHDF) Hemofilter Continuous convective clearance plus diffusive clearance with a blood pump 2526
56
Dialytic Modalities in Acute Renal Failure
MODALITY DIALYZER PHYSICAL PRINCIPLE UREA CLEARANCE (mL/min) MIDDLE MOLECULE CLEARANCE
Ultrafiltration Ultrafiltration Ultrafiltration Ultrafiltration Ultrafiltration
Isolated UF Hemodialyzer Intermittent UF alone - -
Slow continuous UF (SCUF) Hemofilter Continuous arteriovenous or venovenous hemofiltration UF alone without convective or diffusive clearance 13  
57
Dialytic Modalities in Acute Renal Failure
MODALITY DIALYZER PHYSICAL PRINCIPLE UREA CLEARANCE (mL/min) MIDDLE MOLECULE CLEARANCE
Peritoneal Dialysis Peritoneal Dialysis Peritoneal Dialysis Peritoneal Dialysis Peritoneal Dialysis
Continuous Peritoneum Continuous clearance and UF via exchanges performed at varying intervals lt15
Intermittent Peritoneum Intermittent clearance and UF via exchanges performed at varying intervals lt15
, minimal , modest , substantial -, little to none. , minimal , modest , substantial -, little to none. , minimal , modest , substantial -, little to none. , minimal , modest , substantial -, little to none. , minimal , modest , substantial -, little to none.
58
Dialytic modality and survival
  • Conflicting reports
  • CVVHD vs. HD No evidence of survival benefit (
    Mehta RL 2001) but significant differences
    between the groups
  • Meta-analysis of 6 studies similar results
    (Tonelli 2002)
  • CRRT is safer in unstable pts but not shown to
    give renal and patient survival benefit.
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