Dr. Saad Mustafa

Acute Kidney Injury ( AKI )

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 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

Intrarenal Mechanisms for Autoregulation

Afferent

Arteriole

PGC

GFR.

Glomerulus

Efferent

Arteriole

Tubule

Reff / Raff ratio =N

RBF

RBF Afferent

Arteriole PGC

GFR.

Efferent

Arteriole

PGE Ang 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

NSAID

Θ

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

Acute Kidney Injury

Acute kidney injury (AKI) refers to:

An abrupt decrease in kidney function, resulting in the

retention of urea and other nitrogenous waste

products and in the dysregulation of extracellular

volume and electrolytes

Acute Kidney Injury

It is a syndrome that rarely has a sole and distinct pathophysiology. Many patients with AKI have a mixed aetiology where the presence of

sepsis, ischaemia and nephrotoxicity often co-exist and complicate recognition and treatment

Of these, only ‘intrinsic’ AKI represents true kidney disease, while pre-renal and post-renal AKI are the consequence of extra-renal diseases leading to the decreased glomerular filtration rate (GFR).

If these pre- and/or post-renal conditions persist, they will eventually evolve to renal cellular damage and hence intrinsic renal disease

History

The first description of ARF, then termed ischuria renalis,was by William Heberden in 1802

At the beginning of the twentieth century, ARF, then named Acute Bright’s disease,was described in William Osler’s Textbook for Medicine (1909).

During the First World War the syndrome was named war nephritis

During Second World War Bywaters and Beall published their classical paper on crush syndrome.

Acute tubular necrosis (ATN) was the term that was used to describe this clinical entity

Homer W. Smith introduced the term acute renal failure in his 1951 textbook The kidney-structure and Function in Health and Disease

definitions

Several consensus definitions of AKI have been developed in order to provide a uniform definition of AKI.

These definitions are based exclusively on the serum

creatinine and urine output

used primarily to identify patients with AKI in epidemiologic and outcome studies.

They are of limited utility in the clinical assessment and management of patients with AKI.

The KDIGO guidelines definition AKI

●Increase in serum creatinine by ≥0.3 mg/dL within 48

hours, or

●Increase in serum creatinine to ≥1.5 times baseline, which is known or presumed to have occurred within the prior seven days, or

●Urine volume <0.5 mL/kg/hour for six hours

The KDIGO criteria allow for correction of volume status and obstructive causes of AKI prior to classification.

Before diagnosing and classifying AKI, one should assess and optimize volume status and exclude obstruction

The timeframe for an absolute increase in serum creatinine of ≥0.3 mg/dL is retained from the AKIN definition (48 hours), while the timeframe for a ≥50 percent increase in serum creatinine reverted to the seven days originally included in the Acute Dialysis Quality Initiative (ADQI) RIFLE criteria.

STAGING CRITERIA — Using the Kidney Disease: Improving Global Outcomes (KDIGO) criteria

Stage 1 – Increase in serum creatinine to 1.5 to 1.9 times baseline, or increase in serum creatinine by ≥0.3 mg/dL , or reduction in urine output to <0.5 mL/kg/hour for 6 to 12 hours.

Stage 2 – Increase in serum creatinine to 2.0 to 2.9 times baseline, or reduction in urine output to <0.5 mL/kg/hour for ≥12 hours.

Stage 3 – Increase in serum creatinine to 3.0 times baseline, or increase in serum creatinine to ≥4.0 mg/dL or reduction in urine output to <0.3 mL/kg/hour for ≥24 hours, or anuria for ≥12 hours, or the initiation of renal replacement therapy, or, in patients <18 years, decrease in estimated glomerular filtration rate (eGFR) to <35 mL/min/1.73 m2.

LIMITATIONS

Many etiologies cause AKI

The criteria do not distinguish between the multiple etiologies that cause AKI. It is incorrect to treat AKI as a single disease

different causes of AKI are associated with different long-term outcomes and prognoses

Use of urine output to define AKI using urine output to define or stage AKI is not based on robust

evidence

Determination of baseline creatinine

It is impossible to calculate the change in serum creatinine in patients who present with AKI but who do not have a baseline measurement of serum creatinine.

However,

KDIGO criteria have greatest utility in epidemiologic studies and in defining consistent inclusion criteria and/or endpoints for clinical studies

The severity of AKI stage is correlated with mortality risk and intensive care unit (ICU) and hospital length of stay

Examples of application of AKI definitions

Estimating baseline SCr

Many patients will present with AKI without a reliable baseline SCr on record.

Baseline SCr can be estimated using the Modification of Diet in Renal Disease (MDRD) Study equation assuming that baseline eGFR is 75 ml/min per 1.73 m2

Hence, most current data concerning AKI defined by RIFLE criteria are based on estimated baseline SCr for a large proportion of patients.

Incidence of AKI depends on definition

1% if > 2 mg/dl increase in SCr

12% if > 0.5 mg/dl increase in SCr

This paper was based on 9200 admissions to the Brigham in patients who had at least 2 serum creatinines during that admission.

Chertow GM et al. J Am Soc Nephrol. 2005 Nov;16(11):3365-70.

AKI and Mortality Based on analysis of postoperative patients from the Cleveland Clinic,

Δ serum creatinine Multivariable Odds Ratio for Death

>0.3 mg/dl 4.1 (3.1 to 5-5 )

> 0.5 mg/dl 6.5 (5.0 to 8.5 )

> 1.0 mg/dl 9.7 (7.1 to 13.2)

> 2.0 mg/dl 16.4 (10.3 to 26.0)

Spectrum of AKI

Prerenal : renal hypoperfusion

Renal (Intrinsic) :

Glomerular

Tubular

Vascular

Interstitial

Post renal: obstruction

injury

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

Hypovolaemia Haemorrhage

Volume depletion

( vomiting,

diarrhoea,

inappropriate

diuresis, burns)

Hypotension Cardiogenicshock

Distributive shock

(sepsis, anaphylaxis)

Oedema

states Cardiac failure Hepatic cirrhosis

Nephrotic syndrome

Renal

Hypoperfusion

NSAIDs

ACEI / ARBs

RAS /occlusion

Hepatorenal

syndrome

Reduced GFR

PRE-RENAL (Hemodynamic) AKI

PRERENAL AKI

Renal / Intrinsic AKI

Tubular Glomerular Vascular Interstitial

ATN

Ischemia (50%)

Toxins (30%)

Ac. Interstitial

nephritis

Drug induced -

NSAIDs,

antibiotics

Infiltrative -

lymphoma

Granulomatous-

sarcoidosis,

tuberculosis

Infection related -

post-infective,

pyelonephritis

Vascular

occlusions

- Renal artery

occlusion

- Renal vein

thrombosis

- Cholesterol

emboli

Ac.GN

–post-infectious,

– SLE,

–ANCA associated,

–anti-GBM disease

–Henoch-Schönlein purpura

–Cryoglobulinaemia,

–Thrombotic microangiopathy

•TTP

•HUS

5%

85%

8 -12%

< 2%

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

Pathophsiology of ATN

Nephron, Corticomedullary Oxygen Gradient

PO2 =

50 mmHg

Outer

Medulla

10 – 20

Inner Medulla

Vessels of the Outer Medulla

Immune Response in AKI

Endothelial Injury and AKI

Normal repair in ischemic AKI

Abnormal repair in ischemic AKI

Repair after AKI can result in incomplete repair and fibrotic lesions, which may result in progressive renal dysfunction.

Factors including

long-term hypoxia and hypertension.

Sustained production of profibrotic cytokines such as IL-13, arginase, and Transforming growth factor beta

(TGF-β1) from the chronically activated macrophages

Abnormal repair in ischemic AKI ,cont…

Renal tubular epithelial cells also play a critical role in the development of fibrosis through fundamental changes in their proliferation processes, including :-

cell cycle arrest in the G2/M phase.

This results in a secretory phenotype that facilitates the production by the epithelial cells of profibrotic growth factors (including TGF-β1 and Connective Tissue Growth Factor CTGF). Fibrogenesis is stimulated, and progression to chronic renal failure is accelerated

Management

Prediction (at risk individuals)

Risk Factors for Acute Kidney Injury

Exposures Critical illness Sepsis Circulatory shock Burns Trauma Cardiac surgery (especially with cardiopulmonary bypass) Major noncardiac surgery Nephrotoxic drugs Iodinated radiocontrast agents Poisonous plants and animal

Risk Factors for Acute Kidney Injury

Susceptibility factors

Volume depletion Older age Female sex Black race Chronic kidney disease Other chronic diseases (heart, lung, liver) Diabetes mellitus Cancer Anemia

RISK SCORE FOR PREDICTION

Chronic kidney disease (CKD) – 2 points

●Chronic liver disease – 2 points

●Heart failure – 2 points

●Hypertension – 2 points

●Coronary heart disease – 2 points

●pH <7.3 – 3 points

●Nephrotoxin exposure – 3 points

●Severe infection/sepsis – 2 points

●Mechanical ventilation – 2 points

●Anemia – 1 point

The positive and negative predictive values in the validation cohort were 32 and 95, respectively.

RISK SCORE FOR PREDICTION

The operating characteristics of this risk score are similar to others in that the positive predictive

capability is low to moderate while the negative

predictive value is very high.

32 percent of patients with score ≥5 points are likely to develop AKI within 48 hours; 95 percent of patients with score <5 percent are unlikely to develop AKI.

Prerenal AKI diagnostics

Renal hypoperfusion

Decreased RBF and GFR

Increased Na and H2O reabsorption

Oliguria

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

Elevated BUN / S.Cr. Ratio (20 :1)

Bland urinary sediments

Fractional Excretion of Sodium

FENa = Filtered Sodium

Excreted Sodium

FENa = PNa x GFR

UNa x V

FENa = UCr / PCr

UNa / PNa

Keep in mind…

Keep in mind that when pre renal patients are receiving diuretics or have bicarbonaturia all bets are off.

Also salt wasting states such and adrenal insufficiency will also alter results.

In 15% if patients with ATN FeNa can be < 1 % : reflecting patchy injury with partially preserved function.

In GN, acute urinary post renal obstruction, and vascular diseases the FeNa will often be < 1%.

Urine sodium, specific gravity, urine osm, BUN : Cr ratio are less sensitive and of limited value in differentiating this differential.

Pre-renal

A European Renal Best Practice (ERBP)

Haemodynamic monitoring and support for prevention and

management of AKI

In the absence of haemorrhagic shock, we recommend using isotonic crystalloids rather than colloids (albumin or starches) as initial management for expansion of intravascular volume in patients at risk for AKI.

We recommend the use of vasopressors to maintain perfusion pressure in volume-resuscitated patients with vasomotor shock with, or at risk for, AKI.

If volume status is not clear, an early therapeutic trial of withholding diuretics and administering an IV fluid bolus of 500 mL isotonic saline over 4–6 hours with assessment of

- volume status,

- urine output, and SCC and eGFR within 8–12 hours.

Improved urine output, SCC, and eGFR suggests AKI due to volume depletion, whereas no improvement suggests some other cause

Vasopressors are recommended if hypotension is severe, to augment BP while optimising the patient's volume status.

A common goal of vasopressors in this setting is to keep the mean arterial pressure (MAP) >60 mmHg.

(MAP is the diastolic pressure plus one third of the pulse pressure, where

the pulse pressure is the systolic pressure minus the diastolic pressure).

Pre-renal A European Renal Best Practice (ERBP)

Vasopressors dose

dopamine: 1 microgram/kg/min intravenously initially, increase by 5-10 μ/kg/min increments until response, maximum 50 μ/kg/min

adrenaline (epinephrine): 1 microgram/min intravenously initially, increase dose maximum 20 μ

noradrenaline (norepinephrine): 1 microgram/min intravenously initially, increase dose according to response, maximum 30 micrograms/min

impaired cardiac function;

management is often difficult, but requires optimising

cardiac output and volume status by use of :-

inotropes, diuretics, or

renal replacement therapy as indicated by the clinical scenario along with close following of renal function and urine production during therapy. Vasopressors and inotropic agents should be used only

with appropriate haemodynamic monitoring in place.

Management of AKI complications

Overload;

- furosemide: 40-80 mg intravenously initially, increase by 20 mg/dose increments every 2 hours as necessary until clinical response.

-torasemide: 20 mg intravenously once daily initially, increase gradually according to response, maximum 200 mg/day

- metolazone: 5-20 mg orally once daily

- combination of loop diuretic with metolazon is often effective

Life threatining overload not responding to medical therapy needs RRT

Management of AKI complications

Metabolic Acidosis

In general, patients with AKI and organic acidosis (ie, lactic or ketoacidosis) and pH <7.1, even if they are not volume overloaded and especially if they are oliguric or anuric are treated with RRT since such patients are at risk for becoming volume overloaded with bicarbonate therapy.

Among patients with AKI who are not volume overloaded and have no other indication for acute dialysis, bicarbonate may be used in the setting of a non-anion gap acidosis related to diarrhea or in patients with a severe organic acidosis while awaiting dialysis.

Management of AKI complications

Hyperkalemia

patients with mild hyperkalemia and AKI that is from a known reversible cause (such as volume depletion or an ACE inhibitor/angiotensin receptor blocker [ARB]), treated by a low-potassium diet and volume administration and/or discontinuation of the ACE inhibitor or ARB

Patients who have severe hyperkalemia (defined as K >6.5 mEq/L) or rapidly rising serum potassium should not receive any dietary potassium until hyperkalemia can be addressed (either by dialysis or medical therapy).

Contrast induced nephropathy (CIN)

Increase in SCr by more than 25% in the 3 days following intravascular administration of contrast medium (CM) in the absence of an alternative aetiology.

Contrast nephropathy prevention

Patients at risk

(eGFR) <60 mL/min/1.73 m2, who also have proteinuria

diabetes, or other comorbidities including heart failure, liver failure, or multiple myeloma .

eGFR <45 mL/min/1.73 m2, even in the absence of proteinuria , diabetes, or other comorbidities.

Patients who have eGFR <45 mL/min/1.73 m2 and have proteinuria and diabetes or other comorbidities

Contrast nephropathy prevention

Use of nonionic low-osmolal agents

Use lower doses of contrast

Avoid volume depletion and nonsteroidal anti-inflammatory drugs (NSAIDs)

Volume expansion with isotonic sodium chloride

prophylactic intermittent haemodialysis (IHD) or haemofiltration (HF) for the purpose of prevention is not recommended.

N-acetyl cystein is not proven of benefit as shown in recent studies

The use of renal replacement therapy (RRT) for severe acute kidney injury (AKI) is often necessary to sustain life but may also be applied unnecessarily. Intradialytic hypotension and other complications of RRT provide a plausible explanation for why RRT may contribute harm

Which dialysis modality is most effective in reducing mortality in patients in the ICU with acute kidney injury ?

1. Continuous hemodialysis. 2. Intermittent hemodialysis - 3 times per week. 3. Intermittent hemodialysis - 6 times per week. 4. Slow extended daily but intermittent hemodialysis. 5. None of the above

THANKS FOR YOUR ATTENTION