Acute Renal failure(Acute Kidney Injury)

Anil K. Saxena, MD; FRCP (Dublin)

Renal Physician,

Nephrology Division,

Al- Rahba Hospital - Johns Hopkins Medicine,

Abu Dhabi, UAE

Renal autoregulation, Definitions, Pathogenesis, Diagnosis & General Principles of Management

To function properly kidneys require:

• Normal renal blood flow • Functioning glomeruli and

tubules • Clear urinary outflow tract

– for drainage and elimination of formed urine from the body.

RENAL BLOOD FLOW

“Effective Circulating Volume”

Normal RBF/RPF

Intrarenal Autoregulation

GFR, FF

Renal Perfusion Pressure

Cardiac out put

Mean Arterial

Pressure

Renal Autoregulation

Autoregulation is the maintenance of a near normal intrarenal hemodynamic environment (RBF, RPF, FF and GFR) despite large changes in the systemic blood pressure

Renal autoregulation• RBF - blood perfusing the kidneys each

minute (1200 ml/min)• Renal Plasma Flow (RPF) - plasma

flowing to kidneys each minute (670 ml/min or 55-60% of RBF)

• GFR - amount of plasma filtered each minute by the glomeruli. (Normal GFR -125 ml /min for men and 100 ml/min for women)

• Filtration Fraction (FF) - the ratio of GFR to RPF (Normal - .18 - .22)

Renal autoregulation

F = P R

RAP RBF Raff + Reff~

F = Flow

P = Pressure Changes

R = Resistance

RBF = Renal blood flow

Raff = Afferent arteriolar resistance

RAP = Renal arterial pressure

Reff = Efferent arteriolar resistance

Renal blood flow (RBF)

• Major sites of renal vascular resistance -Glomerular afferent (Raff ) and efferent (Reff) arterioles

• Changes in Raff and Reff affect RBF.

Intrarenal autoregulation

Vasoconstrictors– Renin– Angiotensin II– Endothelin– ADH

Vasodilators– PGs– Kinins– NO– ANP

RBFGFR

Figure : RBF / GFR is maintained by a balance between vasodilators and vasoconstrictors of Afferent and Efferent arterioles

Intrarenal Mechanisms for Autoregulation

Afferent Arteriole

PGC

GFR.

Glomerulus

Efferent Arteriole

Tubule

Figure - shows normal conditions normal renal perfusion pressure and a normal GFR.

RBF

Reff / Raff ratio =N

N Engl J Med 357;8 August 23, 2007

RBF Afferent Arteriole

PGC

GFR.

Efferent Arteriole

PGEAng II

Figure: shows reduced perfusion pressure within the autoregulatory range. Normal glomerular capillary pressure is maintained by afferent

vasodilatation and efferent vasoconstriction.

Intrarenal Mechanisms for Autoregulation under decreased Perfusion Pressure MAP

Reff / Raff ratio =

N Engl J Med 357;8 August 23, 2007

Reff / Raff ratio

Figure: Loss of vasodilatory PGs increases afferent resistance causing drop in the glomerular capillary pressure below normal values and the fall in GFR

RBF PGC

GFR.

Ang II

Afferent Arteriole

Efferent Arteriole

PGE

NSAIDΘ

Reduced perfusion pressure with a NSAID.

N Engl J Med 357;8 August 23, 2007

Reduced perfusion pressure with an ACEI or ARB.

PGC

GFR.

Ang II

Afferent Arteriole

Efferent Arteriole

PGE

ACEI /ARB

Θ

Figure: Loss of angiotensin II action reduces efferent resistance; this causes the glomerular capillary pressure to drop below normal values

and the GFR to decrease.

Reff / Raff ratio

RBF

N Engl J Med 357;8 August 23, 2007

Renal autoregulation failure

• Renal autoregulation breaks down as MAP falls below 80 mm Hg,

• Further adjustments in intra-renal hemodynamics are unable to maintain RBF and GFR

• Hallmark of ARF

After age 30, RBF/ GFR decreases progressively with age; at 80 years it is nearly half of that at 20 years

ARF - definition

• An abrupt fall in GFR over a period of minutes to days with rapid & sustained rise in nitrogenous waste products in blood.

(Rate of production of metabolic waste exceeds the rate of renal excretion)

Definitions …

• Well over 30 definitions used in published studies (Ranging from subtle increases in S. Cr. levels – requirement of dialysis)

• Multiple aetiologies

• Different outcomes

• Classification according to severity and outcome - elusive

Clinical markers of ARF

• Reduced GFR

• Raised S.Creatinine

Ser

um

Cre

atin

ine

(mg

/dl)

GFR (ml/min per 1.73m2)

1.0

0

2.0

3.0

4.0

5.0

6.0

7.0

8.0

9.0

40 60 80 100 120 140 160 180200

Relationship between GFR and serum creatinine in ARF

Relationship between GFR and serum creatinine in ARF

• S.Cr. poor marker of renal function.

• Poor correlation between S.Cr. and level of GFR related to muscle mass.

S.Cr. of 1.0 does not represent the same level of GFR in a cachectic 70-year-old as in a highly muscular 25-year-old.

Figure: The abrupt drop in GFR but the S.Cr. does not start going up for 24 or 36 hours after the acute insult .

40

80

0

GFR(mL/min)

0 7 14 21 28

4

Days

2

0

6

Serum Creatinine(mg/dL)

Acute Kidney Injury Network (AKIN- 2005)

Continuum of the renal injury

STAGE I

RISK (R)

STAGE I

RISK (R)

STAGE II

INJURY (I)

STAGE II

INJURY (I)

STAGE VESRD

(E)

STAGE VESRD

(E)

STAGE III

FAILURE (F)

STAGE III

FAILURE (F)

STAGE IVLOSS

(L)

STAGE IVLOSS

(L)

Severity Outcome

– RIFLE criteria/staging system

Definitions….

–Azotemia - silent

–Uremia - symptomatic

–Oliguria - < 400 mL/24 h

–Anuria - < 100 mL/24 h –Nonoliguric ARF - > 400 ml / 24 h

D/D of Azotemia

Acute rise in S. Creatinine• Medications that block tubular creatinine

secretion– Trimethoprim– Cimetidine

• Substances that interfere with creatinine assay – Cefoxitin– Flucytosine

D/D of Azotemia

• Acute elevation of BUN– Protein loading– Catabolic state - severe sepsis – GI bleeding– Corticosteroid therapy– Antibiotics -Tetracycline

ARF: Life threatening consequences

• Volume overload

• Hyperkalaemia• Uremia:

Pericarditis

Encephalopathy

Platelet dysfunction

• Metabolic acidosis

Epidemiology

INCIDENCE

• 1-5% of all patients

• 7-23 % in the ICU

Crit Care Med 16 (11): 1106-1109, 1998

ARF- Community vs. Hospital Acquired

Obialo, C. I. et al. Arch Intern Med 2000;160:1309-1313.

Epidemiology

MORTALITY

• 20-70% Overall

• 79% for patients requiring RRT (ICU)

Nephrol Dial Transplant. 1994:9 S179-S182

Epidemiology

MORTALITY

ARF Outcome ~ Severity of Underlying Disease

Significant Mortality difference -

Ischemic -30% vs. Nephrotoxic- 10%

MORTALITY

ARF is an independent predictor of a poor renal outcome

Vascular/ cardiac surgery – ARF increases mortality

Cardiac surgery patientsMatched illness severity / comorbidities

• 63% mortality dialysis• 4.3 % mortality intact renal function

Am J Med 1998; 104 (4) 343-348Am J Med 1998; 104 (4) 343-348

Predictors of mortality

Multisystem failure

– Mechanical ventilation

– Hypoalbuminemia

– Hyperbilirubinemia

– Severe Lactic acidosis

Dialysis requirement

Spectrum of AKI

• Prerenal : renal hypoperfusion

• Renal (Intrinsic) :– Glomerular– Tubular– Vascular – Interstitial

• Post renal: obstruction

injuryinjury

Spectrum ….

• Hemodynamic AKI (≈30%)

• Parenchymal AKI (65%)– Acute tubular necrosis (55%)– Acute glomerulonephritis (≈5%)– Vasculopathy (3%)– Acute interstitial nephritis (≈2%)

• Obstruction (≈5%)

Generalized or localized reduction in RBF

HypovolaemiaHaemorrhageHaemorrhage

Volume depletionVolume depletion( vomiting,( vomiting,diarrhoea,diarrhoea,

inappropriate inappropriate diuresis, burns)diuresis, burns)

HypotensionCardiogenicshockCardiogenicshockDistributive Distributive shockshock

(sepsis, (sepsis, anaphylaxis)anaphylaxis)

Oedema states

Cardiac failureCardiac failureHepatic cirrhosisHepatic cirrhosis

Nephrotic syndromeNephrotic syndrome

Renal Hypoperfusion

NSAIDs NSAIDs ACEI / ARBsACEI / ARBs

AAAAAARAS /occlusionRAS /occlusion

HepatorenalHepatorenalsyndromesyndrome

Reduced GFR

PRE-RENAL (Hemodynamic) AKI

PRERENAL AKI

Prerenal AKI

• Renal hypoperfusion– Decreased RBF and GFR

– Increased Na and H2O reabsorption

– Oliguria

– High Uosm (>500), low UNa ( FeNa >1%)

– Elevated BUN / S.Cr. Ratio– Bland urinary sediments

Renal / Intrinsic AKI

TubularTubularGlomerularGlomerular VascularVascularInterstitialInterstitial

ATNATN

Ischemia (50%)Ischemia (50%)Toxins (30%)Toxins (30%)

Ac. Interstitial Ac. Interstitial nephritisnephritis

Drug inducedDrug induced - - NSAIDs,NSAIDs,

antibioticsantibioticsInfiltrative -Infiltrative -lymphomalymphoma

Granulomatous- Granulomatous- sarcoidosis, sarcoidosis, tuberculosistuberculosis

Infection relatedInfection related - - post-infective, post-infective, pyelonephritispyelonephritis

Vascular Vascular occlusionsocclusions

- - Renal artery Renal artery occlusion occlusion

- Renal vein - Renal vein thrombosisthrombosis

- Cholesterol - Cholesterol emboliemboli

Ac.GN Ac.GN

–post-infectious,post-infectious,– SLE,SLE,–ANCA associated,ANCA associated,–anti-GBM diseaseanti-GBM disease–Henoch-Schönlein Henoch-Schönlein purpurapurpura–Cryoglobulinaemia,Cryoglobulinaemia,–Thrombotic Thrombotic microangiopathy microangiopathy

•TTPTTP•HUSHUS

5%5%

85%85%

8 -12%8 -12%

< 2%< 2%

N Engl J Med 1996;334 (22):1448-60

ATN• Sepsis - 48%

• Hemodynamic (excluding sepsis) - 32%

• Toxic – 20%– NSAIDS– Radiocontrast media – ACEI– Antibiotics (Gentamicin, Amphotericin)

Crit care Med 1996; 24(2) 192-198

PaO2

50 mm of Hg

PaO2

20 mm of Hg

10 mm of Hg

PaO2

ATN

• Medullary blood flow constitutes about 10% to 15% of total RBF

• Relative hypoxia in the outer medulla predisposes to ischemic injury in – S3 segment of the proximal tubule – Thick ascending limb (more glycolytic

machinery for ATP synthesis)

Pathophysiology of ATN:Tubular Epithelial Cell Injury and Repair

Loss of polarityLoss of polarityNormal EpitheliumNormal Epithelium

Migration , Dedifferentiation of Viable CellsMigration , Dedifferentiation of Viable Cells

Differentiation & Differentiation & Reestablishment Reestablishment of polarityof polarity

Sloughing of viable and dead cells Sloughing of viable and dead cells with luminal obstructionwith luminal obstruction

Ischemia/ Ischemia/ ReperfusionReperfusion

ApoptosisApoptosisNecrosis

Cell deathCell death

Adhesion moleculesNa+/K+-ATPase

ProliferationProliferation

ATN

• Renal Tubular obstruction, Tubular back leak– Decreased GFR, Oliguria – Decreased Na reabsorption– Low Uosm (< 350), High UNa (FeNa <1%)– Elevated BUN / S.Cr. – Urinary sediments- Muddy pigmented

granular casts

Principal POST-RENAL causes of AKI

Intra-luminalIntra-luminal•Stone,Stone,•Blood clots, Blood clots, •Papillary Papillary necrosisnecrosis

•Pelvic Pelvic malignanciesmalignancies•Prolapsed Prolapsed

uterusuterus•RetroperitoneaRetroperitonea

l fibrosisl fibrosis

IntrinsicIntrinsic

Intra-mural Intra-mural •Urethral stricture, Urethral stricture, •BPH, BPH, •Carcinoma prostate,Carcinoma prostate,• Bladder tumour,Bladder tumour,• Radiation fibrosisRadiation fibrosis

ExtrinsicExtrinsic

Post-renal Urinary outflow tract obstruction

How do we assess a patient with AKI?

• Is this acute or chronic renal failure?– History and examination– Previous Serum creatinine measurements– Small kidneys on ultrasound (except for in -

Diabetes, PCKD, Urinary Tract Obstruction)

Hilton et al, BMJ 2006;333;786-790

• Distinguishing between acute and chronic renal failure is important, as – – The approach to these patients differs

greatly.– This may, save a great deal of

unnecessary investigation.

• Factors that suggest chronicity include – – Long duration of symptoms,– Nocturia,– Absence of acute illness, anaemia,

hyperphosphatemia, and hypocalcaemia,

• Has obstruction been excluded?–Complete anuria

–Palpable bladder

–Renal ultrasound

Hilton et al, BMJ 2006;333;786-790

• Careful urological evaluation – P/H Renal stones,– H/O Symptoms of bladder outflow

obstruction- Prostate enlargement – Prolapsed uterus– A palpable bladder. – Catheterization

• Complete anuria suggests renal tract obstruction – X-ray KUB– Renal ultrasonography – detect dilatation

of the renal pelvis and calyces,– CT Scan

• Is the patient euvolaemic?– Pulse, JVP/CVP, postural blood pressure,

daily weights, fluid balance– Disproportional increase in urea /creatinine

ratio– Urinary sodium concentration (unless on

diuretics)– Fluid challenge

• Does evidence of renal parenchymal disease exist (other than ATN)? – History and examination (systemic

features)– Urine dipstick and microscopy (red cells,

red cell casts, eosinophils, proteinuria)

• Has a major vascular occlusion occurred?– Atherosclerotic vascular disease– Renal asymmetry– Loin pain– Macroscopic haematuria– Complete anuria

What investigations are most useful in ARF?

• Urinalysis:– Dipstick for blood, protein, or both -

Suggests a renal inflammatory process– Microscopy for cells, casts, crystals - Red

cell casts diagnostic in glomerulonephritis

Hilton et al, BMJ 2006;333;786-790

RBCs

•Dysmorphic red blood cells suggest glomerular injury.

Red blood cell cast

Marker of glomerular injury

Granular cast

Pigmented granular (“muddy brown”) casts

Marker of acute tubular necrosis

May- Grünwald - Giemsa staining

Marker of acute interstitial nephritis.

Biochemistry

• Serial blood urea, creatinine, electrolytes, Blood gas analysis, serum bicarbonate – – Important metabolic consequences of ARF

include hyperkalaemia, metabolic acidosis, hypocalcaemia, hyperphosphataemia

Biochem….

• Creatine kinase, myoglobinuria – – Markedly elevated CK and myoglobinuria

suggests rhabdomyolysis

• Serum immunoglobulins, serum protein electrophoresis, Bence Jones proteinuria – – Immune paresis, monoclonal band on serum

protein electrophoresis, and Bence Jones proteinuria suggest multiple myeloma

Haematology

• Full blood count, blood film:– Eosinophilia may be present in acute interstitial nephritis,

cholesterol embolization, or vasculitis (CSS)– Thrombocytopenia and red cell fragments suggest

thrombotic microangiopathy –TTP, HUS

Haem….

• Coagulation studies – Disseminated intravascular coagulation

associated with sepsis

Immunology• Antinuclear antibody (ANA) , Anti-double stranded

(ds) antibody - – ANA positive in SLE and other autoimmune

disorders;DNA antibodies anti-ds DNA antibodies more specific for SLE

• C3 & C4 complement concentrations-– Low in SLE, acute post infectious glomerulonephritis,

Cryoglobulinemia

• ASO and anti-DNAse B titres – High after streptococcal infection

Hilton et al, BMJ 2006;333;786-790

Immunology

• ANCA • p-ANCA - Anti PR3 antibodies

• c-ANCA - Anti MPO antibodies

– Associated with systemic vasculitis - Wegener’s granulomatosis; CSS, Microscopic polyangiitis.

• AntiGBM antibodies – Present in Goodpasture’s disease

serology

• Hepatitis B and C, HIV serology– – Important implications for infection control

within dialysis area

• Radiology

• Renal ultrasonography – For renal size, symmetry, evidence of

obstruction

Management principles in ARF• Identify and correct pre-renal and post-

renal factors

• Optimise cardiac output and RBF-

• Review drugs: – Stop ACEI, ARBs, NSAIDs – Adjust doses / monitor drug concentrations

(where appropriate)

Avoid

• Aminoglycosides– 33 % of nephrotoxicity “therapeutic levels”

• Amphotericin – hydration,– Liposomal formulation

• Radiocontrast media - – Hydration– N-acetyl cysteine

Management principles..

• Accurately monitor fluid balance and daily body weight

• Identify and treat acute complications– Hyperkalaemia,– Acidosis,– Pulmonary oedema

Optimise nutritional support

• Maintaining calories enhances patient survival

• Maintaining protein intake MAY enhance recovery & outcome

• protein intakes of > 1.2- 1.4 g/kg/ day can dramatically increase urea production WITHOUT evidence of outcome benefit

Management principles…

• Identify and aggressively treat infection;– Minimise indwelling lines– Remove bladder catheter if anuric.

• Identify and treat bleeding tendency: – Prophylaxis - proton pump inhibitor or H2

antagonist, avoid aspirin– transfuse if required

• Initiate dialysis before uraemic complications set in.

Radiocontrast induced nephropathy (RCIN)

• Less than 1% in patients with normal renal function

• Increases significantly with renal insufficiency

• Dialysis - rarely needed

Risk FactorsPatient Related

– Elderly– Dehydration– Underlying CKD– Diabetes mellitus– Urgent procedure– Multiple myeloma

– CHF ( LVEF < 40%)

– Hypertension– Low hematocrit– Intra-aortic

balloon pump

Contrast properties

– High osmolar contrast

– Ionic contrast

– High viscosity

– Large volume

Clinical Characteristics

• Onset - 24 to 48 hrs after exposure• Duration - 5 to 7 days• Non-oliguric (majority)• Urinary sediment – May contain the

“muddy-brown” pigmented casts and renal tubular cells typical of ATN or may be quite bland.

• Low fractional excretion of Na

Mechanism

• Hemodynamic- reduce RBF

• Direct tubulotoxicity

• Cytokine release

• Osmolar injury

• Tubular obstruction

Patients who are administered contrast media through an arterial vessel, are at the risk of developing Atheroembolic (cholesterol) AKI

Prophylactic Strategies

• Use I.V. contrast only when necessary• Hydration with normal saline (1-1.5 mL/Kg/ h)

6 -12 h before and after the procedure. • Use Low/ iso osmolar (nonionic) contrast

media• Minimize contrast volume• N-acetylcysteine - 600-1200 mg BID for two

doses before and 2 doses after the procedure

Conclusions.

• ARF is common worldwide • Occurs in all clinical & community

settings• It carries a high morbidity and

mortality risks.• Involves high cost of management.

Conclusions..

• The most common cause of in-hospital ARF is ATN that results from multiple acute insults e.g. sepsis, Hypotension, and use of nephrotoxic drugs or Radiocontrast media

Conclusions

• ARF is increasingly common, particularly among hospital inpatients, elderly people, and critically ill patients.

• It carries a high mortality

Conclusions..

• Patients at risk are - elderly people; patients with diabetes, hypertension, or vascular disease; and those with pre -existing renal impairment

Conclusions..

• ARF is often preventable.

• Rapid recognition of incipient ARF and early treatment of established ARF may prevent irreversible loss of nephrons.

Conclusions..

• No drug treatment has been shown to limit the progression of, or speed up recovery from, ARF.

• Advice from a nephrologist should be sought for all cases of ARF.