Acute Kidney Injury

By: Maryam Hami, MD

Associate Prof. of Nephrology MUMS

Objectives

Why estimation of the glomerular filtration rate is the primary test used to estimate the degree of renal function.

The major causes of acute kidney injury and the diagnostic approach used to establish the correct diagnosis.

The renal response to decreased renal perfusion.

The pathgenesis of postischemic and toxic acute tubular necrosis.

An appreciation for high risk clinical situation that can lead to acute kidney injury.

As the GFR is equal to the sum of the filtration rates in all of the functioning nephrons, the total GFR is assumed to be an index of the functioning renal mass.

Thus a fall in GFR with intrinsic renal disease usually reflects disease progression.

However, the GFR can also be reduced if there is a decline in renal perfusion (prerenal) or if there is obstruction to the flow of urine out of the kidney (postrenal).

Acute Kidney Injury

Traditionally defined as the abrupt decrease of renal function sufficient to result in:

1. retention of nitrogenous waste products

2. loss of regulation of extracellular volume

plasma electrolytes

Acid- Base composition

The simplest definition is a recent (within the past month) increase in the plasma creatinine concentration of at least 0.5 mg/dl, or an increase of>50%over baseline value of serum creatinine.

Epidemiology

AKI complicates 5–7% of acute care hospital admissions and up to 30% of admissions in ICUs

AKI is also a major medical complication in the developing world, particularly in the setting of diarrheal illnesses, infectious diseases like malaria and leptospirosis, and natural disasters such as earthquakes

AKI is associated with a markedly increased risk of death in hospitalized individuals, particularly in those admitted to the ICU where in-hospital mortality rates may exceed 50%

Acute Kidney Injury

Tubular Glomerular Vascular ATN TIN GN vasculitis

Ischemic Toxic

PRERENAL

AKI

INTRINSIC POSTRENAL

Acute Kidney Injury

PRERENAL: 40-80% ◦ Volume loss/Sequestration

◦ Impaired Cardiac Output

◦ Hypotension (and potentially hypo-oncotic states)

Net result: glomerular hypoperfusion

Acute Kidney Injury

RENAL/INTRINSIC: 10-30% ◦ Vascular disorders:

◦ small vessel ◦ large vessel

◦ Glomerulonephritis ◦ Interstitial Inflammatory disorders ◦ Tubular necrosis:

◦ Ischemia ◦ Toxin

◦ Intratubular obstraction: ◦ Exogen ◦ endogen

Acute Kidney Injury

POSTRENAL: 5-15%

◦ Urinary tract obstraction

◦Pelvis/Ureter

◦Bladder/Urethra

Diagnosis

Is begun with:

1. History (including timing the onset of the decline in renal function)

2. Physical examination

3. Careful analysis of the urine

Time of onset

In many patients, especially those who are admitted in hospitals, the date of onset of the decline in renal function can be identified.

The GFR estimates from the serum creatinine reflect total function, so processes affecting a single kidney (stone, ischemis) may not manifest a noticeable elevation in creatinine concentration.

Exclusion of urinary tract obstraction

It should be ruled out, since it is a

1. relatively common (especially in men)

2. Rapidly reversible cause

Unilateral obstruction will not manifest with a severe decline in GFR due to compensation from the unobstructed kidney.

Urinalysis May reveal findings that are suggestive of

a type of disease in patients with AKI.

Dysmorphic RBC, RBC cast and proteinuria of diagnostic of GN or vasculitis.

WBC casts are highly suggestive of interestitial nephritis or pyelonephritis.

Granular and epithelial cell casts strongly suggest ATN.

A relatively normal urinalysis is seen in prerenal disease.

It is also occurred in about 10-15% of ATN and urinary tract obstruction.

Distinction between prerenal disease and ATN

An improvement in renal function (over 1 to 2 days) back to the baseline plasma creatinine concentration is considered diagnostic of prerenal disease, while a continued elevation in the plasma creatinine concentration points toward ATN.

Prerenal Disease

Autoregulation of GFR

Is result of three major factors that modulate either afferent or efferent arteriolar tone:

1- Miogenic reflex in afferent arteriole

2- Tubuloglomerular feedback

3- Angiotensin II mediated vasoconstriction of the efferent arteriole

Miogenic reflex is a first line of defense against fluctuations in RBF. Acute changes in renal perfusion pressure evoke reflex constriction or dilatation of the afferent arteriole

BP constrict afferent arteriole, dilate efferent

BP dilate afferent arteriole, constrict efferent

Stable for BP range of 80 to 170 mmHg (systolic)

Cannot compensate for extreme BP

Intrarenal biosynthesis of vasodilator prostaglandins (prostacyclin, prostaglandin E2), kallikrein and kinins, and possibly nitric oxide (NO) also increase in response to low renal perfusion pressure.

Tubuloglomerular feedback changes the rate of filtration and tubular flow by reflex vasconstriction or dilatation of the afferent arteriole. It is mediated by Macula densa that act as sensors of solute concentration and flow of tubular fluid. This mechanism mediated, in part, by NO.

Atherosclerosis, long-standing hypertension, and older age can lead to hyalinosis and myointimal hyperplasia, causing structural narrowing of the intrarenal arterioles and impaired capacity for renal afferent vasodilation

The combined use of nonsteroidal anti-inflammatory agents with ACE inhibitors or ARBs poses a particularly high risk for developing prerenal azotemia.

Hepatorenal syndrome

Advanced cirrhosis may lead to prerenal azotemia despite total body volume overload, as reduction in Systemic vascular resistance due to primary arterial vasodilation in the splanchnic circulation lead to effective volume depletion.

Hypotension in hepatic cirrhosis is associated with progressive elevation in Angiotensin II and norepinephrine release, resulting in an increasing renal ischemia. This is manifested by a gradual reduction in GFR as the hepatic disease becomes more severe.

Renal Artery stenosis

Is associated with a reduction in arterial pressure distal to obstruction. Despite this fall in pressure perfusing the glomeruli, the GFR can initially be maintained by autoregulation.

Angiotensin II plays an important role in the autoregulation of GFR by preferentially constricting the efferent glomerular arteriole, thereby maintaining the intraglomerular pressure.

NSAIDs

Effective volume depletion of any cause leads to enhanced secretion of Angiotensin II and Norepinephrine (vasoconstrictors).

These two also stimulate the renal production of vasodilator prostaglandins by glomeruli.

NSAIDs reduce prostaglandin synthesis by inhibiting the enzyme cyclooxygenase. They can lead to AKI when given to patients with true volume depletion, congestive heart failure, or hepatic cirrhosis.

Acute Tubular Necrosis

There are two major types of ATN 1. Postischemic 2. Toxic ATN is associated with two major

histologic changes and normal glomeruli 1. Tubular necrosis with denuding of the

epithelial cells (mostly proximal tubules and ascending limb of loop of Henle).

2. Occlusion of the tubular lumens by cellular debries and casts.

Ischemia-Associated Aki The outer medulla is particularly vulnerable to

ischemic damage because of the architecture of the blood vessels that supply oxygen and nutrients to the tubules and also active S3 segment of the proximal tubule.

Although the kidneys receive 20% of cardiac output, the renal medulla normaly exists on hypoxia. The hairpin configuration of the vasa recta capillaries results PO2 bathing the cells of the TAL is normally 10-20 mmHg. Then TAL is most sensitive to ischemic injury.

Other contributors to low GFR include backleak of filtrate across ischemic and denuded tubular epithelium and mechanical obstruction of tubules from necrotic debris.

Ischemia can lead to activation of cysteine proteases that results translocation of the Na-K ATPase from the basolateral to the apical membrane. It could explain the decrease in tubular sodium reabsorption.

The resulting elevation in intraluminal tubular pressure can disrupt epithelial cell tight junctions causing back leak of glomerular filtration into the circulation.

The decrease in proximal tubule NaCl

reabsorption will lead to increased delivery to the macula densa and activate tubuloglomerular feedback to reduce GFR. Since the afferent arteriole is vasoconstricted with ischemic injury, this may be sufficient to explain the very low GFR.

Inflammation:

Hypoxia induces release of inflammatory cytokines including TNFα and IL-18 resulting in increased neutrophil adhesion and increased free oxygen radicals.

Nephrotoxin-Associated Aki risk factors for nephrotoxicity include

1. older age

2. chronic kidney disease (CKD)

3. prerenal azotemia

4. Hypoalbuminemia may increase the risk of some forms of nephrotoxin-associated AKI due to increased free circulating drug concentrations.

Aminglycoside-induced ATN

Elevation in plasma creatinine concentration more than 0.5 to 1 mg/dl occurs in 10 to 20% of patients, even if drug level is controlled, although it is common in high peak drug level.

The AGs are freely filtered across the Glomeruli, most of them excreted and small amount being taken up and stored in the tubular cell, especially in proximal tubule.

The number of cationic amino groups bind to anionic phopholipids promote drug entry into the tubular cell.

Within the cell, Ags accumulates within the lysosomes then it is responsible for the associated cellular injury.

Contrast Nephropathy

The mechanism of injury is thought to be a combination of direct vasoconstrictive effects of the contrast agent with tubular toxicity mediated by generation of free radicals.

Contrast Agents The risk of AKI, or "contrast nephropathy," is

negligible in those with normal renal function but increases markedly in the setting of chronic kidney disease, particularly diabetic nephropathy, advanced heart failure, hypovolemia, MM, hypocalemia.

The most common clinical course of contrast nephropathy is characterized by a rise in SCr beginning 24–48 hours following exposure, peaking within 3–5 days, and resolving within 1 week.

Toxic Ingestions

Ethylene glycol

Diethylene glycol

Melamine contamination

Aristolochic acid was found to be the cause of "Chinese herb nephropathy”

"Balkan nephropathy" due to contamination of medicinal herbs or farming.

Endogenous Toxins

Myoglobin

hemoglobin

uric acid

myeloma light chains

Rhabdomyolysis

may result from

1. traumatic crush injuries

2. muscle ischemia during vascular or orthopedic surgery,

3. Immobilization

4. prolonged seizure activity

5. excessive exercise

6. heat stroke or malignant hyperthermia

7. infections

8. metabolic disorders (e.g., hypophosphatemia, severe hypothyroidism)

Allergic Acute Tubulointerstitial Disease

Many drugs are associated with the development of an allergic response characterized by an inflammatory infiltrate and often peripheral and urinary eosinophilia.

Severe infections and infiltrative diseases

Glomerulonephritis or vasculitis are relatively uncommon but potentially severe causes of AKI that may necessitate timely treatment with immunosuppressive agents or therapeutic plasma exchange

Postrenal Acute Kidney Injury Postrenal AKI occurs when the normally

unidirectional flow of urine is acutely blocked either partially or totally, leading to increased retrograde hydrostatic pressure and interference with glomerular filtration.

Normal urinary flow rate does not rule out the presence of partial obstruction, since the GFR is normally two orders of magnitude higher than the urinary flow rate.

Unilateral obstruction may cause AKI in the setting of significant underlying CKD or in rare cases from reflex vasospasm of the contralateral kidney.

Bladder neck obstruction is a common cause of postrenal AKI and can be due to prostate disease, neurogenic bladder, or therapy with anticholinergic drugs, Obstructed Foley catheters, blood clots, calculi, and urethral strictures.

Ureteric obstruction can occur from:

1. intraluminal obstruction (e.g., calculi, blood clots, sloughed renal papillae)

2. infiltration of the ureteric wall (e.g., neoplasia)

3. external compression (e.g., retroperitoneal fibrosis, neoplasia, abscess, or inadvertent surgical damage).

The pathophysiology of postrenal AKI involves :

1. Abrupt increase in intratubular pressures

2. Afferent arteriolar dilation

3. Intrarenal vasoconstriction from the generation of angiotensin II, thromboxane A2, and vasopressin, and a reduction in NO production.

4. Reduced GFR

Clues suggestive of chronic kidney disease:

small, shrunken kidneys with cortical thinning

renal osteodystrophy

Serial blood tests showing continued substantial rise of SCr is clear evidence of AKI.

History and Physical Examination Prerenal azotemia should be suspected in

:

• orthostatic hypotension

• tachycardia

• reduced jugular venous pressure

• decreased skin turgor

• dry mucous membranes.

Postrenal AKI suspected if:

• history of prostatic disease

• history of nephrolithiasis

• pelvic or paraaortic malignancy

• Colicky flank pain radiating to the groin

• Nocturia and urinary frequency or hesitancy

• Abdominal fullness and suprapubic pain