Prerenal acute kidney injury

Prerenal AKI is an adaptive response to severe volume depletion and hypotension in structurally intact nephrons. Prerenal AKI that is prolonged or inadequately treated can be followed by parenchymal renal damage. Prerenal AKI is a potentially reversible cause of ARF.

Reductions in renal blood flow (RBF) and GFR occur in the setting(s) of hypovolaemia, hypotension (cardiogenic shock, anaphylaxis, sepsis), oedematous states with a reduced ‘effective’ circulating volume (cardiac failure, hepatic cirrhosis, nephrotic syndrome) or renal hypoperfusion (renal artery stenosis, hepatorenal syndrome). Drugs that interfere with autoregulation (e.g. prostaglandin inhibitors, angiotensin converting enzyme (ACE) inhibitors or angiotensin II receptor antagonists) also reduce glomerular perfusion. The physiological responses to volume depletion and hypotension, and the link to prerenal AKI, are shown in Figure 10.1.1.

Fig. 10.1.1 Physiological response of the kidney to hypovolaemia or reduced perfusion. The normal response results in a reduced volume of concentrated urine. The presence of risk factors, impaired autoregulation or prolonged hypovolaemia can cause acute kidney injury. ADH, antidiuretic hormone; BP, blood pressure; CVP, central venous pressure; GFR, glomerular filtration rate; JGA, juxtaglomerular apparatus; PR*, renal prostaglandins; RBF, renal blood flow; TPR, total peripheral resistance.

In the early stages of hypovolaemia the serum urea concentration can increase before there is a rise in SCr concentration. An increase in the serum urea concentration or the blood urea nitrogen (BUN) concentration with a normal SCr concentration when renal perfusion is reduced is called prerenal azotaemia. If acute renal hypoperfusion is prolonged the serum urea concentration and the SCr concentration are both increased.

Renal (parenchymal) acute kidney injury

Ischaemic, cytotoxic or inflammatory processes damage the renal parenchyma. The causes of the damage are grouped according to the major structures that are damaged: vessels, glomeruli, renal tubules or renal interstitial tissue.

Vascular causes involving the larger vessels are acute thrombosis of the renal artery, embolism of the renal arteries, renal artery dissection and renal vein thrombosis. Damage to the renal microvasculature is caused by inflammatory damage (e.g. glomerulonephritis or vasculitis), malignant hypertension or thrombotic microangiopathy (TMA).

Glomerulonephritis causes proteinuria, haematuria, nephrotic syndrome, nephritic syndrome or chronic renal failure. Rapidly progressive glomerulonephritis (RPG) is a rare type of glomerulonephritis with extensive cellular crescents in the glomeruli. Patients with RPG can develop oliguric AKI that progress within weeks to end-stage renal failure.

Acute tubular necrosis (ATN) is the most common pathological process that causes ARF. While the terminology suggests that the main cause is tubular damage, the actual pathophysiology is more complex: impaired autoregulation and marked intrarenal vasoconstriction (the main mechanism for the greatly reduced GFR), tubular damage (with cytoskeleton breakdown), increased tubuloglomerular feedback, endothelial cell injury, fibrin deposition in the microcirculation, release of cytokines, activation of inflammation and activation of the immune system.^8,9

ATN is classified as ischaemic ATN or cytotoxic ATN (due to damage by toxins); both processes are present in some patients. In ischaemic ATN there is a continuum between prerenal azotaemia, the RISK and INJURY stages of AKI, and the development of ATN. ATN caused by administration of intravenous or intra-arterial contrast agents is due to renal vasoconstriction, reduced injury.¹⁰ The main mechanisms of AKI or ATN caused by drugs are vasoconstriction, altered intraglomerular haemodynamics, tubular cell toxicity, interstitial nephritis, crystal deposition, thrombotic microangiopathy and osmotic nephrosis.¹¹

Important causes of cytotoxic ATN are listed in Table 10.1.2. Non-steroidal anti-inflammatory drugs (NSAIDs), ACE inhibitors and angiotensin receptor blockers (ARBs) often cause a gradual and asymptomatic decrease in the GFR, but can cause AKI (including ATN). NSAIDs do not impair renal function in a healthy person, but can reduce the GFR in elderly persons with atherosclerotic cardiovascular disease, in persons with chronic renal failure, when chronic prerenal hypoperfusion is present (e.g. cardiac failure, cirrhosis), or in persons using diuretics and calcium channel blockers.¹²

Table 10.1.2 Causes of toxic acute tubular necrosis

Renal damage is uncommon after administration of intravenous or intra-arterial radiocontrast agents if renal function is normal, but the likelihood is increased by chronic renal impairment, diabetes, heart failure, hypertension, hypovolaemia, hyperuricaemia, proteinuria or multiple myeloma. Patients usually develop renal injury (with a rise in SCr concentration that returns to baseline within 3 to 5 days, and no reduction in the urine output) rather than ATN. Drugs that alter angiotensin levels (ACE inhibitors and ARBs) reduce renal perfusion by their antihypertensive effects, or by impairing vasoconstriction of the efferent arteriole when renal perfusion is reduced by renal artery stenosis.

The haem pigments that damage the kidney are haemoglobin and myoglobin. The clinical spectrum of AKI due to rhabdomyolysis ranges from a biochemical dominated presentation (elevated serum concentrations of muscle enzymes, a rapidly reversible increase in SCr concentration and no clinical features of muscle damage) to a presentation where the skeletal muscles are often swollen and painful, the muscle enzymes are very elevated and the patient rapidly develops ATN. The nephrotoxicity of haem pigments is enhanced by volume depletion, low urine flow rates and low urine pH.

Once ATN is established there is a persistent and marked reduction in RBF and in GFR that lasts for 1 to 2 weeks. During this time the patient is usually oliguric, and cannot excrete concentrated urine. Renal autoregulation is impaired, and renal perfusion depends directly on the systemic blood pressure. A fall in systemic blood pressure during the ATN phase causes more renal damage. Recovery from ATN is associated with increased renal blood flow (reperfusion), an increase in GFR and (often) a large volume urine output because the concentrating ability of the regenerating nephrons is impaired.

Abnormalities of renal interstitial structure and function are present in ATN. However, AKI and ATN can be caused by a primary abnormality of the interstitial tissues: acute tubulointerstitial nephritis (ATIN). The damage in ATIN is due to immunological mechanisms, the most important involving cell-mediated immunity. ATIN is usually due to a drug reaction, but can also be caused by infections (e.g. infection with hantavirus, a RNA virus that causes haemorrhagic fever with renal syndrome.¹³ Drugs that cause ATIN include antibiotics (β-lactam antibiotics, sulphonamides, fluoroquinolones), NSAIDs, cyclooxygenase-2 inhibitors, proton pump inhibitors, diuretics, phenytoin, carbamazepine and allopurinol.

Postrenal (obstructive) acute kidney injury

Obstructive uropathy refers to the functional or structural processes in the urinary tract that impede the normal flow of urine, and obstructive nephropathy is the renal damage caused by the obstruction. Hydronephrosis is a dilatation of the ureter(s); it can occur in the absence of obstruction, and some persons with obstruction do not have a dilated urinary collecting system.^14–16

Casts or crystals within the renal tubular lumen can cause intrarenal obstruction. Extrarenal obstruction can develop in the urethra, bladder, ureter or the pelvicureteric junction. Obstructive uropathy in adults is commonly caused by prostate disease or retroperitoneal neoplasm (cancer of the cervix, uterus, bladder, ovary or colon). Metastatic cancer, lymphomas or inflammatory processes in the retroperitoneum (appendicitis, diverticulitis, Crohn’s disease) or a neurogenic bladder can also cause obstructive uropathy. Renal stones passing through the ureter(s) cause pain, haematuria and varying degrees of (usually unilateral) obstructive uropathy.

Obstructive nephropathy usually develops gradually and can cause chronic renal failure if the obstruction involves the urethra, the bladder or both ureters. Unilateral ureteric obstruction will cause ARF if it involves a single kidney, or if the obstructed kidney is the only functioning kidney.

Maintaining intravascular volume and renal perfusion

The rate and volume of intravenous fluid given to hypovolaemic persons depends on the nature of the intravascular depletion, the blood pressure and heart rate, the (estimated) volume of fluid lost, cardiac function and ongoing circulatory losses. The response to treatment is evaluated by simple bedside measurements (heart rate, blood pressure, urine output). Fluid replacement that is predominately determined by formulas (e.g. in burns) often underestimates the magnitude of the fluid loss.

Acute haemorrhage causes prerenal azotaemia, but the incidence of ARF is low (1.5% in major gastrointestinal bleeding²⁹) if the hypovolaemia is treated promptly and there are no other risk factors. In severe trauma the incidence of ARF needing dialysis is about 0.1%.³⁰ Severe progressive ARF after cardiopulmonary resuscitation is rare, and pre-existing and post resuscitation haemodynamics are more important risk factors for AKI than the degree of hypoperfusion during resuscitation.³¹

Choice of resuscitation fluid

Hypovolaemia is initially treated with crystalloid rather than colloid, with colloid being added in specific clinical settings (e.g. burns, anaphylaxis) or if there is no initial improvement in vital signs or urine output following crystalloid administration (e.g. in sepsis). The liberal use of crystalloid and colloid in high-output sepsis with AKI may increase the incidence of ARF or need for dialysis.³²

Use of derived GFR in drug administration

Formulas are available to calculate the estimated creatinine clearance or estimated GFR from the measured SCr concentration.^33,34

Rhabdomyolysis

Most studies on the prevention of ATN after rhabdomyolysis have been in persons with crush injury after earthquakes, where the incidence of AKI is about 50%. In this situation fluid resuscitation should, if possible, begin before the crush is relieved. These patients may require massive amounts of fluid because of fluid sequestration in the injured muscles. The goal of intravenous fluid treatment is to produce a urine output of 200–300 mL/h while myoglobinuria (discoloured urine) persists. There is no evidence to support this rate of fluid replacement in persons who have rhabdomyolysis and AKI without crush injury, although a urine output of 100 mL/h would be reasonable while the urine is discoloured. The intravenous administration of mannitol and sodium bicarbonate to produce an alkaline diuresis as a means of preventing ATN in severe rhabdomyolysis has not been shown to be effective.³⁵

Radiocontrast nephropathy

The incidence of radiocontrast nephropathy can be reduced by saline infusion to produce intravascular volume expansion, by using low osmolar contrast agents and by N-acetyl cysteine administration before and after radiocontrast administration.

Envenomation and poisoning

Specific antidotes, if available, should be used to treat persons who develop AKI after envenomation or poisoning.

Evaluation of prerenal (intravascular volume) status

Imprecise or lazy terminology such as ‘dry’ or ‘dehydrated’ should be avoided. ‘Dehydration’ refers to situations where more water than electrolyte(s) has been lost, shrinking body cells and increasing the serum sodium concentration and osmolality.³⁶ In other words, ‘dehydration’ means water depletion. Hypovolaemia is a decrease in the intravascular volume due to loss of blood (haemorrhage, trauma) or loss of sodium and water (e.g. vomiting, diarrhoea, sequestration of fluid in the bowel, etc.).

The (bedside) assessment of the (extracellular) volume status determines the initial resuscitation strategy. This involves evaluation of heart rate and blood pressure, the state of the skin and mucous membranes, and the jugular venous pulse. The examination also includes auscultation of the lungs (for pulmonary crackles), abdominal examination (for ascites or masses) and examination of the legs (for peripheral oedema).

The ‘typical’ features of intravascular volume depletion (tachycardia or hypotension or both in the supine position, or postural hypotension) are not as consistent or reliable as implied by textbook descriptions. About one-third of persons with hypovolaemia due to trauma have bradycardia rather than tachycardia.^37,38 The presence of (supine) tachycardia has low sensitivity as a diagnostic feature of increasing acute blood loss in healthy persons.³⁹ An increase in the pulse rate of 30 beats per minute or more between the supine value and the standing values is a highly sensitive and highly specific sign of hypovolaemia after phlebotomy of large volumes (600–1100 mL) of blood, but the sensitivity is much less after phlebotomy of smaller volumes.³⁹ The inability to stand long enough for vital signs to be measured because of severe dizziness is a sensitive and specific feature of acute large blood loss.³⁹ The persistence of tachycardia after intravenous administration of fluids in clinical conditions causing hypovolaemia suggests that hypovolaemia is still present, but tachycardia due to other causes (pain, fever) will persist after correction of hypovolaemia.

A systolic blood pressure of 95 mmHg or less in the supine position has high specificity but low sensitivity after acute blood loss.³⁹ Postural hypotension is present in 10% of normovolaemic person younger than 65 years, and in up to 30% of normovolaemic person older than 65 years. Postural hypotension in persons who can stand without developing severe dizziness is of no diagnostic value after blood loss due to acute phlebotomy.³⁹

The textbook descriptions of the signs of saline depletion in adults (dry mucous membranes, shrivelled tongue, sunken eyes, decreased skin turgor, weakness, confusion) are neither specific nor sensitive compared to laboratory tests for hypovolaemia. The presence of a dry axilla argues somewhat for the presence of saline depletion; the absence of tongue furrows and the presence of moist mucous membranes argue against the presence of saline depletion.³⁹

The central venous pressure (CVP) is an indicator of the vena caval or right atrial pressure. A vertical distance greater than 3 cm between the top of the jugular venous pulsation (using the external jugular vein or internal jugular vein) and the sternal angle indicates that the CVP is elevated. An elevated venous pressure in persons with pulmonary crackles or peripheral oedema means that the intravascular volume is greater than normal. A markedly elevated CVP is the cardinal finding of cardiac tamponade and constrictive pericarditis.

The absence of visible venous pulsation in the neck veins when the patient is supine or in a head down position indicates significant intravascular volume depletion. The presence of visible venous pulsations in the neck at or below the level of the sternal angle that is seen only when the patient is supine indicates that the intravascular volume is below normal.

Evaluation of the renovascular state

Acute renal infarction is caused by dissection of the aorta or renal artery, embolism, renal artery thrombosis, renal vein thrombosis or renal artery aneurysm. Acute arterial occlusion is usually symptomatic, with the development of pain (loin, abdominal or back pain), haematuria, proteinuria, nausea or vomiting. Vascular occlusion of a single functioning kidney produces anuria.

Atherosclerosis can cause abdominal aortic aneurysms that may be palpable on abdominal examination. Inflammation of the adventitia of some abdominal aortic aneurysms can cause ureteric obstruction. There is an increased incidence of dissection of the thoracic aorta in persons with autosomal dominant polycystic kidney disease.

Atheromatous disease of the renal arteries is common in persons older than 50 years with widespread atherosclerosis. There is a 7% prevalence of renal artery stenosis in persons older than 65 years, and one-third of elderly persons with heart failure have renovascular disease.^40,41 Persons with stenosis or occlusion of one or both renal arteries can develop an elevation in SCr concentration after starting treatment with ACE or ARB drugs, or develop acute on chronic renal failure.

Exclusion of thrombotic microangiopathy

TMA is a syndrome of microangiopathic haemolytic anaemia, thrombocytopenia and varying degrees of organ injury caused by platelet thrombosis in the microcirculation. There are two clinically distinct entities: haemolytic uraemic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP). HUS affects young children and causes ARF with absent or minimal neurological abnormalities. TTP occurs in adults and causes severe neurological involvement in most cases, and variable degrees of renal damage.

Pre-existing renal disease or chronic renal failure

It can be difficult to distinguish between chronic and acute renal impairment. The following features suggest the presence of chronic renal failure: documented renal impairment in the past, family history of renal disease, polyuria or nocturia, uraemic pigmentation, normochromic and normocytic anaemia, or small kidneys on ultrasound or computed tomography (CT) scans. Renal size may be normal or increased in chronic renal failure associated with diabetes, polycystic kidney disease or amyloidosis.

Infection and sepsis⁴²

Infection with virulent organisms or spread of organisms into the blood releases toxins and cytokines that produce a systemic inflammatory response. This causes systemic vasodilatation and increased permeability of capillaries. Compensatory physiological responses produce a secondary increase in the cardiac output, but this is not maximal because of the myocardial depressant effect of cytokines. Renal vasoconstriction occurs (even in the absence of hypotension), compensatory renal vasodilatation responses are impaired and the renal endothelium is injured. One half of all patients with septic shock develop ARF, and the combination of ARF and sepsis is associated with a greater than 80% mortality.

Exclusion of urinary obstruction

The symptoms and signs of urinary tract obstruction depend upon the site and cause, and the rapidity with which it develops. Pain is more common in acute obstruction and is felt in the lower back, flank or suprapubic region, depending on the level of the obstruction. Chronic obstruction is usually painless. Symptoms of prostatic obstruction include frequency, nocturia, hesitancy, post-void dribbling, poor urinary stream and incontinence. Bladder neck obstruction usually results in an enlarged (and palpable) bladder.

Recognition of rhabdomyolysis

Muscle necrosis releases intracellular contents into the circulation. This causes red-brown urine (that tests positive for haem in the absence of visible red cells on microscopy, or tests positive for myoglobin with specific tests), pigmented granular casts in the urine, elevated serum creatine kinase (CK) levels that are five times or more above the upper limit of normal and clear serum (serum is reddish in haemolysis). The severity of the rhabdomyolysis ranges from asymptomatic elevations of muscle enzymes in the serum to AKI and life-threatening electrolyte imbalances.

Urine dipstick findings may be normal because myoglobin is cleared from the serum more rapidly than CK, so serum CK levels can be elevated in the absence of myoglobinuria. Myoglobinuria may be absent in patients with renal failure or those who present later in the illness. Muscle pain is absent in about 50% of cases, and muscle swelling is an uncommon finding. Muscle weakness occurs in those with severe muscle damage. Fluid sequestration in muscles can cause hypovolaemia. Marked muscle swelling can cause a compartment syndrome.

Other blood test abnormalities include hyperkalaemia, AKI with rapid and marked elevation in SCr (e.g. 220 μmol/L per day), hypocalcaemia (which occurs early, and is usually asymptomatic), hyperuricaemia, hyperphosphataemia, metabolic acidosis and disseminated intravascular coagulopathy. About one-third of persons with ATN due to rhabdomyolysis develop hypercalcaemia during the recovery phase.

Acute kidney injury and acute renal failure

The early stages of AKI are usually asymptomatic, and the diagnosis is based on an elevated SCr concentration. It may take 24 h or more for an initially normal SCr concentration to show a definite increase, and up to 48 h after the event(s) that caused the AKI to distinguish between the early stages of AKI (risk and injury) and the development of renal failure.

The urine output usually decreases, and the patient may be oliguric (urine output less than 400 mL per day) or anuric (urine output less than 100 mL per day). Persons with AKI and oliguria have more severe kidney impairment than those without oliguria. Only a few conditions cause complete anuria: total obstruction, vascular lesions, severe ATN or rapidly progressive glomerulonephritis. The clinical features caused by ARF are shown in Table 10.1.5.

Table 10.1.5 Clinical features of acute renal failure

Serum biochemistry

The following are measured: serum concentration of electrolytes (sodium, potassium, bicarbonate, chloride, calcium, phosphate), serum urea and SCr concentrations, random blood glucose, liver function tests, coagulation tests and CK concentration.

AKI causes acute elevation in the SCr concentration or serum urea concentrations or both. In prerenal AKI the low urine flow rate favours urea reabsorption out of proportion to decreases in GFR, resulting in a disproportionate rise of serum urea concentration or BUN concentration relative to the SCr concentration. However, serum urea concentrations depend on nitrogen balance, liver function and renal function. Severe liver disease and protein malnutrition reduce urea production, resulting in a low serum urea concentration. Increased dietary protein, gastrointestinal haemorrhage, catabolic states (e.g. infection, trauma), and some medications (corticosteroids) increase urea production and increase serum urea concentration without any change in GFR.

The SCr concentration is the best available guide to the GFR. Acute reductions in GFR produce an increase in the SCr concentration. The changes in SCr concentration lag behind the change in GFR, and can be affected by the dilution effect of intravenous fluid. Correct interpretation of the SCr concentration extends beyond just knowing the normal values (Fig. 10.1.3). Creatinine is a metabolic product of creatine and phosphocreatine, which are found almost exclusively in skeletal muscle. The SCr concentration is affected by the muscle mass, meat intake, GFR, tubular secretion (which can vary in the same individual and increases as the GFR decreases) and breakdown of creatinine in the bowel (which increases in chronic renal failure). The GFR decreases by 1% per year after 40 years of age, yet the SCr concentration remains unchanged because the decrease in muscle mass with age reduces the production of creatinine. The GFR (corrected for body surface area) is 10% greater in males than females, but men have a higher muscle mass per kilogram of body weight. The SCr concentration in men is thus greater than in women.

Fig. 10.1.3 Factors that determine the serum creatinine (SCr) concentration.

The creatinine clearance (CCr) or GFR are estimated indirectly using formulae (Cockcroft–Gault formula or the Modification of Diet in Renal Disease (MDRD) Study Equation) based on the SCr concentration^33,34 (Fig. 10.1.4). These equations assume a steady-state SCr concentration, and are inaccurate if the GFR is changing rapidly. They will also be less accurate in amputees, very small or very large persons, or persons with muscle-wasting diseases.

Fig. 10.1.4 Formulae for calculating the creatinine clearance (CCr) or the glomerular filtration rate (GFR) from the serum creatinine concentration (SCr). MDRD, modified diet renal disease.

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