Pathology of Acute Renal Failure
1. Define acute renal failure (ARF)
Refers to a sudden and usually reversible loss of renal function. It can develop over days-weeks and
during this time patients are usually oligouric (urine volume <500mL daily). Disturbances of water,
electrolyte and acid-base balance are evident, and the patient is closely monitered until these are
stabilised.
ARF is divided into three broad categories:
Pre-renal: Hypoperfusion: ARF is precipitated from vascular problems leading to the kidneys:
hypovolemia, cardiogenic shock etc.
Renal: Intrinsic renal damage: ARF is caused by some influence within the kidney: nephrotoxicity,
glomerular disease etc.
Post-renal: Obstruction: Reduction in renal function is secondary to problems in the urinary tract “after”
the kidney: Tumours, stones etc.
2. List various causes (e.g. vascular, glomerular, toxic) of pre-renal, renal, and post-renal forms of
acute renal failure.
Many possible causes exist, and can compound each other. Hence clinicians look to symptoms of the
underlying condition – eg blood loss, septic shock – to assist restoration. Rapid identification of the
cause and subsequent correction is vital, or the patient may need temporary renal replacement therapy.
ARF is classified into Pre-Renal, Renal, or Post-Renal dysfunctions.
Pre-Renal
The kidney can regulate its own blood flow and GFR over a wide range of perfusion pressures. When
the perfusion pressure falls (a result of hypovolemia, shock, heart failure or narrowing of renal arteries)
the resistance of the vessels going into the kidney increases to increase pressure. Prostaglandins are
important mediators of this regulation. If this mechanism fails, blood flow can still be maintained by
selectively dilating the afferent (pre-glomerular) arteriole & constricting the efferent (post-glomerular)
arteriole, creating a back-pressure in the glomerulus. This reaction is regulated by rennin and
angiotensin II.
Prolonged (or severe) under-perfusion of the kidneys may lead to failure of these compensatory
mechanisms & resultant decline in GFR. The tubules that are intact continue to reabsorb sodium &
water, forming low volume concentrated urine (osmolality > 600 mOsm/kg).
Clinical signs will include those of hypotension (eg reduced capillary return) – except where the cause
is not systemic hypotension (patients taking NSAIDS, ACE inhibitors – which impair regulation of
arteriole tone). Blood loss may also cause hypotension, though this may be concealed through leakage
into GIT/pregnant uterus etc. Burns, severe skin inflammations and sepsis all cause hypovolemia.
Metabolic acidosis and hyperkalaemia symptoms may also show.
Renal
Severe or prolonged under-perfusion of the kidney may develop into a histological pattern known as
acute tubular necrosis (ATN). The necrosis is classified as either ischaemic or nephrotoxic (chemical,
bacterial toxins).
Ischaemic
After fluid resusitation and restoration of haemodynamics in a hypovolemic patient, renal blood flow
can remain low (20% of normal) due to swelling of glomeruli endothelial cells & peritubular capillaries,
interstitial oedema, and constricted artieioles. Tubular cells have a high oxygen consumption so as to
generate energy for solute reabsorption (esp thick ascending section of Loop of Henle). Structural
changes occur to epithelial cells, such as cellular swelling, loss of brush-border and polarity, blebbing,
and cell detachment. Biochemically there is depletion of ATP, accumulation of intracellular calcium,
activation of proteases & phospholipases, reactive oxygen species, and caspases. In time, breaks occur
in the tubular BM, allowing contents to leak into the interstitial tissue. If tubular cells die, they may
shed into the tubular lumen and cause partial obstruction. There is no specific treatment for ATN other
than restoring renal perfusion, and allowing time for tubular cellular recovery.
Renal vascular disease is another form of ischaemia that may cause ARF. Causes include renal artery
stenosis, repeated episodes of pulmonary oedema (causing severe hypotension), or sudden occlusion
(infarction) of renal arteries.
Nephrotoxic
Here the sequence is similar, but initiated by a toxic agent acting directly at the tubular cell. Several
factors predispose the tubules to toxic injury, including a vast charged surface area, active transport
systems for ions/organic acids, and a high metabolic rate. Most commonly the cause is allergic,
particularily to drugs (gentomycin and other antibiotics), but may be due to chemicals and systemic
diseases.
Glomerulonephritis, a term for immune mediated damage to renal corpuscle, is the most common cause
of a second mechanism for acute (& chronic) renal failure; inflammation injury. In this condition, renal
biopsies show intense inflammation, which results in inability of the kidney to function. Damage results
from aggregation of inflammation cells , metabolic stress (diabetes) or cellular deposits (e.g. amyloid).
The function of the glomerulus is affected, and haematuria symptomatic.
Post-Renal Failure:
Caused by obstruction to the ureter, bladder or urethra. Overflow of urine back up into kidney occurs
causing tubular damage. Treatment is relieving urinary pressure via cathetisation, locating the
obstruction through die injection, removal of the obstruction, and then treating the underlying cause.
Causes of obstruction can be Calculi, Clots, malignant growth of or around either structure, BPH, uretal
trauma, urethral strictures or valves, neurogenic malfunction, anticholinergics. For obstruction to
precipitate ARF, both kidneys must be affected or the non-obstructed kidney must be already diseased.
Consequently, most postrenal ARF is secondary to lower urinary tract disease
3. Describe briefly the gross pathology, histology and ultrastructure of renal tissue and cellular
changes in acute renal failure.
Pathologic changes to glomeruli include:
 Decreased glomerular perfusion (further decreasing perfusion pressure).
 Vasoconstriction of the afferent arteriole (further decreasing perfusion pressure).
 Vasodilation of the efferent arteriole (further decreasing perfusion pressure).
 Decreased permeability of the capillary wall.
Gross Pathology:
An enlarged kidney (shown on ultrasound) is the most obvious sign of reduced tubular function. If
ischaemia is prolonged, infarcts and intravascular thrombi will occur, and can lead to a blackened
appearance of the kidney - in these infarcts, all renal cells become necrotic and only 'ghosts' of
nephrons and their cells will be seen. Tubular damage with cell shedding causes toxins to remain in the
kidney, and further infection can result.
Histology:
The proximal tubule and the thick ascending Loop of Henle in the outer medulla are most sensitive to
ischaemic insult and becoming necrotic. The ischaemic injury is normally patchy & in segments, and
hence acute tubular necrosis has the following histological features:
Breaks in the tubular BM, swelling, vacuolation, apoptosis & necrosis of tubular cells & endothelium of
the glomerulus, with cell debris in the lumen. Increased tubular mitotic activity due to regenerating
tissue. The interstitium is enlarged (oedema) & infiltrated with cells of inflammation.
4. Recognise that the pathology of acute renal failure may be similar in all forms (pre-renal,
renal, post-renal) of acute renal failure, and that tubular injury often dominates the
histopathology.
Whilst in pre-renal ARF, the decrease in renal function is a consequence of systemic conditions that
subsequently decrease renal perfusion (e.g. ECF volume depletion, low cardiac output, low systemic
vascular resistance, increased renal vascular resistance), the impact on renal systems is similar to intrarenal failure.
Kidney hypoperfusion, along with toxic damage & haemolysis, all create ATN, and therefore the
primary pattern of pathology is similar.
Key Symptoms shared across Patients with Acute Renal Failure:
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Anorexia
Fatigue
Mental status changes
Nausea and vomiting
Pruritus
Seizures (if blood urea nitrogen level is very high)
Shortness of breath (if volume overload is present)