10: Genitourinary

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Section 10 Genitourinary

10.1 Acute kidney injury

ESSENTIALS

Introduction

The first recognition of illness caused by a sudden decline in renal function (‘ischuria renalis’) was by William Heberden in 1802.1 In 1888 Delafield described a form of ‘acute Bright’s disease’ that was caused by toxins, various infectious diseases and extensive injuries, and where there was degeneration or death of tubule cells.2 Impaired renal function in injured soldiers was described in World War I (‘war nephritis’) and in World War II.3,4 The term ‘acute renal failure’ (ARF) was first used in 1951.5

The basic process in ARF is a rapid (hours to days) reduction in the glomerular filtration rate (GFR) due to renal hypoperfusion (prerenal causes), damage to glomeruli, tubules, interstitium or blood vessels (renal causes), or obstruction to urine flow (postrenal causes). The GFR is inversely related to the serum creatinine (SCr) concentration. The diagnosis of ARF is made when there is an increase in the SCr concentration, with or without a decrease in the urine output. A simple definition of ARF is an acute and sustained (lasting for 48 h or more) increase in the SCr of 44 μmol/L if the baseline is less than 221 μmol/L, or an increase in the SCr of more than 20% if the baseline is more than 221 μmol/L.6 A more comprehensive definition (the RIFLE system) is used to classify persons with acute impairment of renal function7 (Table 10.1.1).

Table 10.1.1 RIFLE classification of acute renal failure

Stage Serum creatinine (SCr) concentration Urine output
RISK Increase of 1.5 times the baseline <0.5 mL/kg/h for 6 h
INJURY Increase of 2.0 times the baseline <0.5 mL/kg/h for 12 h
FAILURE Increase of 3.0 times the baseline or SCr is 355 μmol/L or more when there has been an acute rise of greater than 44 μmol/L for 24 h or anuria for 12 h <0.3 mL/kg/h
LOSS Persistent acute renal failure; complete loss of kidney function for longer than 4 weeks  
END-STAGE RENAL DISEASE End-stage renal disease for longer than 3 months  

The term ‘acute kidney injury’ (AKI) includes the spectrum of functional and structural changes seen in renal failure. AKI includes prerenal azotaemia, and the RISK, INJURY and FAILURE stages of the RIFLE system. ARF is applied to the FAILURE stage of the RIFLE system.

Aetiology and pathogenesis

The causes of AKI are grouped according to the probable source of renal injury: prerenal, renal (parenchymal) and postrenal. More than one cause can be present in AKI.

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.

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

Exogenous agents
Radiocontrast
Non-steroidal anti-inflammatory drugs
Antibiotics: aminoglycosides, amphotericin B
Antiviral drugs: aciclovir, foscarnet
Immunosuppressive drugs: ciclosporin
Organic solvents: ethylene glycol
Poisons: snake venom, paraquat, paracetamol
Chemotherapeutic drugs: cisplatin
Herbal remedies
Heavy metals
Endogenous agents
Haem pigments: haemoglobin, myoglobin
Uric acid
Myeloma proteins Correct intravascular volume depletion
Maintain perfusion pressure
Choice of resuscitation fluid
Diuresis in rhabdomyolysis
Avoid nephrotoxins
Use derived GFR or creatinine clearance when calculating drug doses

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.

Epidemiology

The annual incidence of ARF in European communities is between 209 and 620 cases per million per year, with an incidence of severe acute renal failure (SCr greater than 500 μmol/L) of 172 cases per million per year.1720 About 1% of patients in the USA have ARF on admission to hospital, and ARF develops in 5–7% of all hospitalized patients.2123 The frequency of ARF in hospitalized patients is about 19 per 1000 admissions.24

Studies of the pathogenesis of community acquired ARF have produced conflicting results. In one study the major processes were identified as prerenal in 70% of cases, renal in 11% of cases and postrenal in 17% of cases.21 Other studies found a lower incidence of prerenal factors (present in 21–48% of cases) and a higher incidence of renal factors (present in 34–56% of cases, most commonly due to ATN).19,25 Acute on chronic renal failure was present in 13% of persons in one study.19 The basic processes in hospital acquired ARF are prerenal in 35–40% of cases, renal in 55–60% of cases and post-renal in 2–5% of cases.6

Using the RIFLE criteria the community incidence of AKI is 1811 per million of population, and AKI occurs in 18% of hospitalized patients (9% had changes in SCr concentration and urine output consistent with RISK, 5% had renal INJURY and 4% developed FAILURE).26,27

There are geographical differences in the causes of ATN. In Africa, India, Asia and Latin America ATN is usually caused by infections (e.g. diarrhoeal illnesses, malaria, leptospirosis), ingestion of plants or medicinal herbs, envenomation, intravascular haemolysis due to glucose-6-phosphate dehydrogenase deficiency or poisoning.28 The incidence of ATN due to crushing injuries is increased in earthquake-prone areas.

Prevention

The processes involved in the prevention of AKI are shown in Table 10.1.3.

Table 10.1.3 Use derived GFR or creatinine clearance when calculating drug doses

Correct intravascular volume depletion
Maintain perfusion pressure
Choice of resuscitation fluid
Diuresis in rhabdomyolysis
Avoid nephrotoxins

Clinical features

The diagnosis of AKI should be considered when there is a decrease in urine output, an elevated SCr concentration or increases in SCr concentration. The clinical features depend on the pre-existing conditions that increase the risk of developing AKI, the initiating factor(s), and the effects of AKI (Fig. 10.1.2). The history should include a detailed drug history, enquiry about recent invasive vascular or radiological procedures, and any family history of renal disease. This is followed by clinical examination and evaluation of investigations. A number of key issues then need to be resolved (Table 10.1.4).

Table 10.1.4 Evaluation of acute kidney injury

Assess the intravascular volume
Look for renovascular disease
Look for symptoms or signs of obstruction to urine flow
Systematic search for presence of infection or sepsis
Evaluate for pre-existing renal disease or chronic renal failure
Obtain a detailed history of medication or drug use
Consider possibility of glomerulonephritis

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.

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.

Criteria for diagnosis

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.

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 concentration33,34 (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.