Acute kidney injury
- An abrupt or rapid decline in renal function as evidenced by a rapid rise in serum creatinine or decrease in urine output.
- Creatinine clearance or filtration is dependent on the glomerular filtration rate (GFR).
- The driving force for the GFR is the gradient from the glomerulus to the Bowman space.
- GFR = Glomerular hydrostatic pressure – Bowman capsule hydrostatic pressure – glomerular oncotic pressure
- Glomerular pressure is primarily dependent on renal blood flow (RBF) and is controlled by combined resistances of renal afferent and efferent arterioles.
- Regardless of the cause of acute kidney injury (AKI), reductions in RBF represent a common pathologic pathway for decreasing GFR.
Maintenance of GFR
- Physiologically, GFR is auto-regulated very precisely with changes in the mean arterial pressure (MAP) (see figure below). Mechanisms of auto-regulation include: myogenic, tubuloglomerular, and the neuro-hormonal feedback.
- Myogenic mechanisms: Afferent arteriolar smooth muscle cell contraction in response to the stretch from the high MAP.
- Tubuloglomerular feedback: Because of the folded shape of the nephron, the macula densa in the distal convoluted tubules come into direct contact with the glomerulus, allowing GFR to be adjusted based on distal salt delivery. The macula densa responds to increased sodium chloride content (high GFR) by releasing adenosine, which causes the afferent arteriole to constrict, thus decreasing GFR. This is the tubuloglomerular feedback autoregulatory mechanism. The macula densa also responds to low salt (decreased GFR) by activating the juxtaglomerular apparatus to release renin, which activates angiotensinogen (secreted by the liver), and leads to the production of angiotensin II.
- Neuro-hormonal feedback: In states of low renal perfusion, increase release of angiotensin II (Ang II) and epinephrine takes place. Ang II increases resistance at the efferent arteriole more than at the afferent arteriole, whereas norepinephrine affects both to a similar degree. These vasoconstrictor effects are antagonized by renal-vasodilatory prostaglandins.
Etiology and pathogenesis
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AKI can be divided into pre-renal, renal or post-renal etiology.
- Pre-renal: Defined by conditions with normal tubular and glomerular function; GFR is depressed by compromised renal perfusion.
- Renal: Diseases that affect the kidney itself, predominantly affecting the renal glomeruli or the renal tubules, which is associated with release of renal afferent vasoconstrictors; ischemic renal injury is the most common cause of intrinsic renal failure
- Post-renal: Initially causes an increase in tubular pressure, decreasing the filtration driving force; this pressure gradient soon equalizes, and maintenance of a depressed GFR is then dependent on renal efferent vasoconstriction.
Aside from the total volume depletion and effective arteriolar volume depletion (from third-spacing in liver and heart failure), certain etiologies can also lead to a reduced renal perfusion state.
- Hypercalcemia: Mostly via concurrent hypovolemic states in hypercalcemia and vaso-constrictive effects of calcium.
- Non-steroidal anti-inflammatory drugs (NSAIDs): Vasodilatory prostaglandins are secreted by the renal glomeruli. NSAID-induced inhibition of cyclooxygenase leads to reduced production of prostaglandin E2 and prostacyclins.
- This class of anti-inflammatory drug has little effect on renal function of normal subjects due to the small levels of Ang II, epinephrine and prostaglandins. However, in patients with marked effective volume depletion, exaggerated renal vasoconstriction occurs as the compensatory prostaglandin response to high Ang II and norepinephrine levels is blocked.
- Renal artery stenosis (RAS):can be due to plaque development in atherosclerosis or due to fibromuscular dysplasia (FMD). FMD is a genetic condition causing thickening of the intima, media and adventitia.
- RAS is associated with low arterial pressures distal to the obstruction. Initially auto-regulation maintains GFR, but later fails as renal arterial pressures continue to drop further.
- Hepato-renal syndrome:Defined as an otherwise unexplained and progressive elevation in [plasma creatinine] in advanced liver disease.
- Due to a systemic release of vasodilators, marked splanchnic dilatation occurs in advanced liver disease leading to significant reductions in systemic vascular resistance and blood pressure.
Acute Tubular Necrosis (Ischemic and Toxic)
- Prolonged ischemia of the nephrons leads to a number of vascular and tubular defects. Some of these changes include impaired autoregulation and tubuloglomerular feedback, tubular necrosis and apoptosis, endothelial injury causing defective prostaglandin synthesis and oxygen radical production.
- Fluid sequestration in the damaged muscles induces volume depletion, activation of the sympathetic nervous system, antidiuretic hormone (ADH) secretion, and RAS activation all of which favor vasoconstriction and renal salt and water preservation. Additionally, myoglobin induced stress increases vasoconstrictor proteins (endothelin) and reduces vasodialatory molecules (nitric oxide).
- Myoglobin has also been shown to induce direct tubular toxicity.
- Along with vasoconstriction, heme pigments induce direct tubular obstruction as well as cellular injury
- Aminoglycosides (AG):
- Classes of antibiotics that inhibit bacterial protein synthesis
- AGs are freely filtered through the glomeruli, and small amounts are taken up and stored in the tubular cells where they induce direct lysosomal toxicity causing cellular damage. This binding and damage is thought to be charge mediated.
- Amphotericin B:
- Along with vasoconstriction, amphotericin B is thought to insert its nephrotoxicity via insertion into the cellular membranes and creating pores that increase cellular permeability.
- Contrasts are associated with vasoconstriction in the nephrons due to increased vasoconstrictive molecular and decreased vasodilatory molecules.
- Contrasts have also been shown to induce direct tubular toxicity and ischemia.
Acute Interstitial Nephritis (AIN)
- Accounts for two-thirds of all AIN
- Sulfa drugs, β-lactam antibiotics, and proton pump inhibitors (PPIs).
- This is thought to be a hypersensitivity reaction to the drug (See Hypersensitivity and immunology) due to the presence of T-cells on biopsies.
- Immune system is activated in a susceptible individual, either due to drug acting as an external antigen, hapten, or because of molecular mimicry to one of the tubular antigen
- Humoral mechanisms are also involved where anti-glomerular basement membrane (anti-GBM) antibodies are found.
- Chemokines and cytokines secreted by the offending pathogen leads to inflammatory cell infiltration and direct damage to the interstitium.
- Infection is thought to begin with tubular cell injury which are then also involved in overexpression of chemokines
- The injury exposes the endogenous antigens to immune-mediated reaction and hence the development of interstitial nephritis.
Immune complex deposition and destruction of some glomeruli leave less total filtration area, reducing the GFR.
Microangiopathies, various forms of vasculitis and emboli lead to reduced renal blood flow due to vascular obstruction or destruction, thus lowering the GFR.
See Urology for details.
Pathophysiology and clinical features
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Hypotension accompanied by refractory tachycardia
Volume contraction: Most likely seen in pre-renal etiology, if volume deplete.
Can be present in all different levels of AKI due to various reasons.
Results from inability of the affected kidneys to excrete fluid from the body and therefore third spacing occurs. Can cause pulmonary edema.
Nephritic syndrome of hematuria, edema, and hypertension can indicate a glomerular cause.
Maculopapular rash and fever
Uremic encephalopathy, pericarditis, bleeding
Hyperkalemia due to reduced potassium excretion
Nausea, vomiting, abdominal pain, altered appetite, muscle weakness and decreased visual acuity
Very non-specific symptoms but can be a result of metabolic acidosis and accumulation and end organ affects of H+.
Lancet. 2005 Jan 29-Feb 4;365(9457):417-30
Crit Care. 2004 Aug;8(4):R204-12
- Treat underlying etiology.
- Indications of dialysis
- Metabolic acidosis, hyperkalemia and fluid overload refractory to medical therapy
- Toxins and uremic complications.
- Correction of fluid overload:
- Furosemide, a loop diuretic works to excrete excess fluid in the body reducing the volume overload.
- Furosemide blocks the NKCC (sodium-potassium-dichloride) pump in the ascending limb of loop of Henle reducing salt resorption and excreting fluid.
- Correction of acidosis:
- Bicarbonate administration: HCO3 binds the excess H+ in the blood correcting the metabolic acidosis.
- Hyperkalemia can lead to complicated arrhythmias in some patients.
- Potassium binders, to reduce absorption of potassium through the gut.
- Reducing dietary intake of potassium.
- Symptomatic patients may need insulin administration to shift potassium from the blood into the cells (via the H+-K+ pump).