Acute renal failure

Acute renal failure

Introduction Acute renal failure (ARF) is a common clinical syndrome characterised by rapid decline in glomerular filtration, perturbation of extracellular fluid volume, electrolyte and acid-base homoeostasis, and retention of nitrogenous waste from protein catabolism.1-3 ARF complicates about 5% of admissions to hospital and 30% of admissions to intensive care, is typically asymptomatic, and usually diagnosed when routine tests reveal an acute rise in blood mL per day) occurs urea and creatinine. Oliguria (<400 in about half the cases. ARF is usually reversible, the kidney being able to recover from almost complete loss of function. Nevertheless, ARF is associated with major inpatient morbidity and mortality, reflecting the severity of the causal illnesses and the high frequency of

complications. For purposes of differential diagnosis and management, ARF is conveniently subclassified as: (1) prerenal azotaemia (about 70%), a physiological response to renal hypoperfusion in which the integrity of renal tissue is preserved; (2) intrinsic renal azotaemia (about 25%) in which ARF is caused by diseases of renal parenchyma; and (3) postrenal azotaemia (5%) due to acute obstruction of the urinary tract (table 1). Most acute intrinsic renal azotaemia is induced by ischaemia and/or nephrotoxins and is classically associated with necrosis of renal tubule epithelial cells (acute tubular necrosis [ATN]). As a result, the term ATN is commonly employed in clinical practice to denote acute intrinsic renal azotaemia in these clinical settings. We will review the management of ARF and focus on ATN. Because ARF can complicate a range of diseases that require different therapies, we will also discuss briefly the pathophysiology, and differential diagnosis of ARF. We will emphasise the results of randomised controlled trials. The latter were identified by a computerised search of MEDLINE, a manual search of Index Medicus, and from review articles and textbooks of nephrology. It is difficult to draw firm conclusions about the efficacy of many treatments for ATN because most reports have been retrospective, inadequately controlled, or of limited statistical power. Indeed, there remains no effective treatment for ATN. Management is directed at prevention of ATN in high-risk individuals and control of uraemic complications in patients with established ATN until spontaneous recovery of renal function.

Renal Section, Medical Service, Brockton-West Roxbury Department of Veterans Affairs Medical Center, Boston, Massachusetts, USA; and Renal Division, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston (H R Brady FRCPI, G G Singer MD) Dr Hugh R Brady, Renal Section, West Roxbury Veterans Administration Medical Center, 1400 VFW Parkway, Boston, MA 02132, USA

Correspondence to:

Causes, pathophysiology, and differential diagnosis of ARF Prerenal azotaemia Prerenal azotaemia and ischaemic ATN are part of a spectrum of manifestations of renal hypoperfusion and can complicate any disease that reduces the "effective arterial blood volume" (eg, cardiac failure, severe systemic vasodilation, hypovolaemia). True or "effective" hypovolaemia is detected by arterial and cardiac baroreceptors that trigger neural and hormonal responses, including activation of the sympatheticnervous and renin-angiotensin-aldosterone systems and release of vasopressin. Noradrenaline, angiotensin II, and vasopressin attempt to restore the effective arterial blood volume and protect cardiac and cerebral perfusion by stimulation of vasoconstriction in musculocutaneous and splanchnic vascular beds, inhibition of salt loss through sweat glands, enhancement of thirst and salt apetite, and promotion of renal salt and water retention. Renal perfusion and glomerular filtration are maintained during mild hypoperfusion by compensatory mechanisms, including afferent arteriolar vasodilation triggered by a local myenteric reflex within the vessel wall, intrarenal biosynthesis of vasodilator prostaglandins, kallikreinkinins, and possibly nitric oxide, and selective efferent arteriolar vasoconstriction induced by angiotensin II. Autoregulation of renal blood flow and glomerular filtration rate (GFR) is overwhelmed at mean arterial blood pressures below 60-80 mm Hg and ARF ensues. GFR may be impaired at lesser degrees of hypotension in elderly patients and those with diseases of the renal microvasculature (eg, hypertensive nephrosclerosis, diabetic nephropathy). Several drugs also perturb renal adaptive responses and can precipitate or aggravate prerenal azotaemia in subjects with renal hypoperfusion. These include non-steroidal anti-inflammatory drugs and angiotensin-converting-enzyme (ACE) inhibitors, which block intrarenal biosynthesis of vasodilator prostaglandins and angiotensin II, respectively. ACE inhibitors classically induce ARF in patients with bilateral renal artery stenosis or unilateral stenosis of the artery leading to a solitary functioning kidney, particularly if there is also volume depletion (about 30% frequency). In these settings, high levels of angiotensin II help to maintain GFR distal to stenoses by increasing systemic blood pressure (via action on vascular smooth muscle) and intraglomerular pressure (via selective action on efferent arterioles). However, GFR may also be exquisitely dependent on the actions of angiotensin II in other forms of glomerular

hypoperfusion. Prerenal azotaemia should be suspected when serum creatinine rises in patients with a recent history or objective clinical evidence of "true" hypovolaemia (eg,

haemorrhage, vomiting, diarrhoea, diuresis, burns, hyperpyrexia) or decreased "effective" circulatory volume (eg, cardiac or liver failure, nephrotic syndrome, sepsis) 1533

Cause of acute renal failure

Suggestive clinical

Prerenal azotaemia

Evidence of volume depletion (thirst, postural hypotension and tachycardia, low JVP, dry mucous membranes, weight loss, fluid output >mput). or decreased "effective" circulatory volume (eg, heart failure, liver failure); NSAIDs or ACEI.

(-70%)

Intrinsic renal azotaemia

features

Typical urinalysis Hyaline UNa <10,

Confirmatory tests

casts, FeNa SG >1.018

<1%,

Occasionally requires invasive haemodynamic monitoring; rapid resolution of ARF on restoration of renal perfusion

(-25%)

Diseases involving large renal vessels Renal artery thrombosis

History of atrial nausea,

Usually age >50 retinal plaques,

Atheroembolism

Renal vein thrombosis

fibrillation

vomiting, flank

or

or recent

myocardial infarct,

abdominal pain

years, recent subcutaneous

Mild proteinuria,

occasionally red cells

manipulation of aorta, nodules, palpable purpura,

livedo reticularis, vasculopathy, hypertension Evidence of nephrotic syndrome or pulmonary embolism,

Often normal,

eosmophiluna, rarely

Elevated LDH with normal transammases, renal artenogram Eosinophilia, hypocomplementaemia, skin biopsy, renal biopsy

casts

Proteinuria, haematuna

flank pain

Inferior

vena

cavagram and selective renal

venogram

Diseases of small vessels and glomeruli

Glomerulonephrltis/ vasculitis

HUS/TTP Malignant hypertension Acute tubular necrosis (ATN) due to ischaemia or toxms* Ischaemia

Compatible clinical history (eg, recent infection) or evidence of multisystem diseases (sinusitis), lung haemorrhage, rash, or skin ulcers, arthralgias) Compatible clinical history (eg, recent gastrointestinal infection, cyclosporin, anovulants), fever, pallor, ecchymoses, neurological abnormalities Severe hpertension with headaches, cardiac failure, retinopathy, neurologic dysfunction, papilloedema

haemorrhage, hypotension (eg, cardiac arrest, pancreatitis), major surgery or burns Recent

Recent radiocontrast study, nephrotoxic antibiotics or anticancer agents often coexistent with volume depletion, sepsis or chronic renal insufficiency (1) History suggestive of rhabdomyolysis (seizures, coma, ethanol abuse, trauma)

Exogenous toxins Endogenous toxins

Acute diseases of the tubulointerstitium Allergic interstitial nephritis

Red cell

or

dysmorphic

granular casts, red cells,

proteinuria May be normal, red cells mild proteinuria, rarely red Red cells, red cell casts,

proteinuna "Muddy brown" granular or epithelial cell casts, FeNa >1%, UNa >20, SG 1.010 "Muddy brown" granular or tubular epithelial cell casts, FeNa >1%, UNa >20, SG 1.010 Urine supernatant tests positive for heme Unne

(3) History suggestive of (a) tumour lysis (recent chemotherapy), (b) myeloma (bone pain), or (c) ethylene glycol ingestion

Urate

crystals (a), dipsticknegative protelnuna (b), oxalate crystals (c)

ingestion of drug, and fever, rash

White cell casts, white cells (often eosinophils), red cells,

or

arthralglas

Anaemia, thrombocytopenia, schistocytes on blood smear, increased LDH, renal biopsy

cell/granular casts

(2) History suggestive of haemolysis (blood transfusion)

Recent

C3 level, ANCA, anti-GBM Ab, ANA, ASO, anti-DNAse cryoglobulins, renal biopsy

supernatant pink and positive for heme

LVH by echocardiography/ECG, resolution with control of blood pressure

Clinical assessment and sufficient for diagnosis

urinalysis usually

Clinical assessment of urinalysis sufficient for diagnosis

usually

Hyperkalaemia, hyperphosphataemia, hypocalcaemia, mcreased circulating myoglobin, CPK MM, and uric acid Hyperkalaemia, hyperphosphataemia, hypocalcaemia, hyperuricaemia, pink plasma positive for hemoglobin Hyperuricaemia, hyperkalaemia, hyperphosphataemia (a); circulating or urinary paraprotein (b); toxicology screen, acidosis, osmolal gap (c)

Systemic eosinophilia, skin biopsy of rash (leukocytoclastic vasculitis), renal biopsy

proteinuria (occasionally Acute bilateral

Flank pain and tenderness, toxic, febnle

Urine and blood cultures

red cells, bactena

pyelonephntls Postrenal azotaemia

nephrotic) Leucocytes, proteinuria,

(5%)

Abdominal

or

flank pain,

palpable bladder

Frequently normal, without casts

or

haematuna

proteinuna

Plain film, renal ultrasound, IVP, retrograde or anterograde pyelography, computed tomography

*Denotes major cause of acute intrinsic renal azotaemia. NSAIDs=non-steroidal anti-inflammatory drugs, ACEI=anglotensln-convertlng-enzyme inhibitor; SG=specific gravity (mmol/kg), FeNa=fractional excretion of sodium (%), UNa=urinary sodium concentration (mmol/L), LDH=lactate dehydrogenase, ANCA=antineutrohil cytoplasmic antibody, anti-GBM Ab=antlglomerular-basement-membrane antibody, ANA=antinuclear antibody, ASO=antistreptolysm-0 antibody, LVH=left ventricular hypertrophy, ECG=electrocardiography, HUS/TTP=haemolytic-uraemic-syndrome/thrombotic-thrombocytopenic-purpura, IVP=mtravenous pyelogram, JVP=jugular venous pressure, CPK=creatme phosphokinase. Modified with permission from ref 1

Table 1: Clinical features, typical urinalysis, and confirmatory tests for diagnosis of

(table 1). The classic urinary and biochemical sequelae of prerenal azotaemia reflect the influence of noradrenaline, angiotensin II, vasopressin, and low urinary-flow-rate on salt and water reabsorption from urine and include a concentrated urine (SG > 1-018, urinary osmolality >500 mmol/L) and mmol/kg), low urinary sodium (<10 fractional excretion of sodium (<1-0%), and a benign urine sediment containing transparent hyaline casts formed by precipitation of Tamm-Horsfall protein in concentrated urine.’-’ Definitive diagnosis of prerenal azotaemia rests on rapid recovery of GFR after restoration of renal perfusion. Intrinsic renal azotaemia Clinicopathologically, it is useful to categorise the causes of acute intrinsic renal azotaemia into diseases of large 1534

major causes of acute

renal failure

renal vessels, disorders of the renal microvasculature and glomeruli, ischaemic and nephrotoxic ATN, and tubulointerstitial diseases (table 1). Ischaemic and toxic ATN account for around 90% of cases of acute intrinsic renal azotaemia. ARF due to renal artery disease is infrequent and can be caused by atheroemboli, thromboemboli, thrombosis, dissecting aortic aneurysm, or vasculitis. Atheroemboli are the most common culprits and are usually dislodged from the atheromatous aorta during arteriography, angioplasty, or aortic surgery. Diseases of the renal microvasculature that induce ARF include inflammatory (eg, glomerulonephritis/vasculitis) and non-inflammatory (eg, malignant hypertension) conditions of vessel walls, thrombotic microangiopathies thrombotic haemolytic-uraemic (eg, syndrome,

thrombocytopaenic purpura), and, rarely, hyperviscosity

Tubulointerstitial causes of ARF, other than ischaemia or toxins, include allergic interstitial nephritis, severe infections, allograft rejection and, rarely, infiltrative disorders such as sarcoid, lymphoma, or leukaemia. Prompt diagnosis relies on a high index of suspicion and astute clinical assessment, especially when the history, physical examination, urinalysis, or course of ARF are not typical of prerenal azotaemia or ATN. Ischaemic ATN differs from prerenal azotaemia in that renal hypoperfusion has been severe enough to injure renal parenchymal cells, particularly tubule epithelium, and ARF does not resolve immediately after restoration of renal blood flow. Extreme ischaemia can induce bilateral renal cortical necrosis and irreversible renal failure. The course of ischaemic ATN can be divided into initiation, maintenance, and recovery phases, the pathophysiology and management of which differ. In the initiation phase (hours to days), ischaemic injury is evolving. GFR falls because of impaired renal blood flow and glomerular ultrafiltration pressure, disrupted integrity of tubule epithelium with backleak of glomerular filtrate, and obstructed urine flow due to intratubular formation of casts comprised of detached epithelial cells and cellular debris (figure). The terminal portion of the proximal tubule (S3segment, pars recta) and the medullary portion of the thick ascending limb of the loop of Henie are the nephron segments that are most vulnerable to ischaemic injury. Both have high rates of active (ATP-dependent) solute transport and oxygen consumption. Furthermore, both are located in the outer medulla, an ischaemic zone compared with other regions, even under basal conditions by virtue of the unique counter-current arrangement of the medullary vasculature. Importantly, renal injury can be limited by restoration of renal blood flow during this period. Next comes the maintenance phase (typically 1-2 weeks) during which epithelial cell injury is established, GFR stabilises at its nadir (5-10 mUmin), urine output is lowest, and uraemic complications arise. It is unclear why

syndromes.

Figure: Major mechanisms of impairment of glomerular filtration rate in ischaemic ATN and some drug therapies that have been tested in human or experimental disease Whereas various agents have proven beneficial in experimental animals, there is no proven therapy for established ATN in human bemgs. See text for explanation. Modified with permission from ref 1. ANP=atrial natriuretic peptide, RGD=peptides containing "argmne-glycmeaspartate" motif.

GFR remains low

during this phase despite correction of systemic haemodynamics. Putative mechanisms include persistent intrarenal vasoconstriction and medullary ischaemia triggered by dysregulated release of vasoactive mediators from injured endothelial cells (eg, decreased nitric oxide, increased endothelin), congestion of medullary blood vessels, and reperfusion injury induced by reactive oxygen species and other mediators derived from leucocytes or renal parenchymal cells. In the recovery phase, renal function is restored by repair and regeneration of renal parenchymal cells. Nephrotoxic ATN can complicate exposure to many structurally diverse drugs and poisons, and to some endogenous compounds if present in the circulation at high concentrations (eg, myoglobin, haemoglobin, uric acid, paraproteins). The kidney is especially vulnerable to nephrotoxic injury because of its rich blood supply and capacity to concentrate toxins within tubule epithelial cells and the interstitium via the actions of epithelial cell transporters and renal counter-current exchange. The kidney is also an important site of xenobiotic metabolism and can transform parent compounds into toxic metabolites. As with ischaemic ATN, nephrotoxins impair GFR by causing intrarenal vasoconstriction, direct injury to tubule epithelium, and tubule obstruction. The contribution of each pathophysiological mechanism varies For example, intrarenal among different agents. vasoconstriction dominates the initiation phase of ARF induced by cyclosporin, radiocontrast compounds, haemoglobinuria, and myoglobinuria, whereas direct epithelial cell toxicity appears to be the primary event in ATN induced by many antimicrobials (eg, aminoglycosides, amphotericin B) and anticancer agents (eg, cisplatin, ifosfamide). Intratubular obstruction is a pivotal pathophysiological event in ARF triggered by myeloma light chains (cast nephropathy), uric acid (acute urate nephropathy), and aciclovir (aciclovir crystalluria). Nephrotoxic ATN, similar to ischaemic ATN, is characterised by initiation, maintenance, and recovery phases and similar management issues apply to both syndromes. The pathognomonic urinary findings include casts composed of tubule epithelial cells and/or cellular debris, classically muddy brown in colour. The urine differs from that of prerenal azotaemia in that it is typically isosmotic with plasma (300 mmol/kg, SG 1-010), contains sodium at over 20 mmol/L, and fractional excretion of sodium is over 1-0%, even in the presence of renal hypoperfusion. These biochemical features reflect the impaired ability of injured tubule epithelium to respond to noradrenaline, angiotensin II, aldosterone, and vasopressin. Between prerenal azotaemia and ischaemic ATN, an "intermediate syndrome" is being increasingly recognised: patients present with non-oliguric ischaemic or nephrotoxic ARF, often with granular or epithelial cell casts, low urinary sodium and fractional excretion of sodium, a partial response to fluid challenge, an abbreviated maintenance phase, and improved prognosis.’-3 The intermediate syndrome probably represents a milder form of ATN and its emergence may reflect an increasing awareness by physicians and surgeons of the critical importance of intravascular volume status and judicious pharmacotherapy in high-risk patients. Postrenal azotaemia Urinary tract obstruction accounts for less than 5% of cases of ARF (table 1). Again, because one kidney has 1535

sufficient clearance to maintain creatinine balance, a rise in serum creatinine because of obstruction implies blockade of the urethra or bladder neck, bilateral ureteric obstruction, or unilateral ureteric obstruction in patients with one functioning kidney or chronic renal insufficiency. This syndrome is usually easily recognised by clinical assessment and ultrasonography of the urinary tract.

Management

of prerenal azotaemia

Prerenal azotaemia is, by definition, rapidly reversible after restoration of renal blood flow and glomerular ultrafiltration pressure. Therapy is directed at the cause of hypoperfusion. The composition of replacement fluids for hypovolaemia is guided by the source of fluid loss. Hypovolaemia due to severe haemorrhage is usually corrected with packed red blood cells, whereas isotonic saline is more appropriate for plasma losses. Urine and gastrointestinal fluids vary greatly in composition, are typically hypotonic, and are replaced initially with hypotonic solutions, such as 0-45% saline in 5% dextrose. Subsequent therapy is based on measurements of the volume and tonicity of excreted or drained fluids. In general 500-1000 mL is administered intravenously over 30 min, guided subsequently by clinical variables, such as jugular venous pressure, blood pressure, heart rate, and bodyweight. Invasive haemodynamic monitoring may be necessary in complex cases, if clinical assessment of volume status is difficult. The treatment of cardiogenic and septic shock, hepatorenal and nephrotic syndromes, and other causes of decreased effective circulatory volume is reviewed elsewhere.’-3

Management of intrinsic

renal azotaemia

Strategies to prevent and treat ATN aim to restore renal perfusion, minimise epithelial cell injury, relieve tubule obstruction, and promote epithelial repair and regeneration (figure). Unfortunately, few large randomised trials have been conducted and

Adapted with *Most tnals

permission from

Conger JD (Drug therapy

m

acute renal

current

failure)

in

is based largely on the results of retrospective and case-control studies (table 2).

therapy

Prevention The frequency of ATN can be reduced dramatically by close attention to systemic haemodynamics, and careful choice and dosing of potentially nephrotoxic drugs in high-risk subjects. For example, astute clinical monitoring of intravascular volume can almost completely prevent clinically significant contrast-agent nephropathy, even in diabeties and patients with chronic renal insufficiency. 4,5 Importantly, human studies have failed to consistently demonstrate a protective effect of prophylactic vasodilators (eg, low-dose dopamine, calcium-channel blockers) or diuretics (mannitol, frusemide, bumetanide, ethacrynic acid) in either ischaemic or nephrotoxic ATN, despite encouraging results in animal models (table 2).6-38 Indeed, a randomised comparison of 0-45% saline with or without mannitol or frusemide administered before radiocontrast agent to patients with chronic renal insufficiency demonstrated superior renal function in subjects treated with saline alone.5 Monitoring of circulating drug levels may limit renal impairment in

patients

on

cyclosporin

or

aminoglycosides, although

Treatment Various agents have been tested for their ability to attenuate renal injury or hasten renal recovery in patients with ischaemic and nephrotoxic ATN (table 2). These include manoeuvres to augment renal blood flow (eg, atrial low-dose natriuretic dopamine, peptide, prostaglandins), increase urine flow and relieve tubule obstruction (mannitol, loop-blocking diuretics), reduce

ref 3.

small, retrospective, inadequately controlled, and/or of limited statistical power. tUsed prophylactically to prevent ARF. CrCI=creatlnlne clearance, GFR=glomerular filtration rate, RBF=renal blood flow, SeCr=serum creatinine. were

Table 2: Some

1536

agents that have been tested for ability to alter

as

many of 33% of cases of aminoglycoside nephrotoxicity occur in patients with "therapeutic" levels.I-3 Interestingly, aminoglycosides can be less nephrotoxic, without compromising antimicrobial activity, when administered once daily. 39 Several other strategies to prevent nephrotoxic ARF in rarer settings are outlined in table 2.

course

of clinical ischaemic

or

toxic acute renal failure*

Adapted with permission from ref 2. *These are general guidelines and must be tailored to needs of individual patients. Table 3: Supportive therapy in ischaemic and nephrotoxic ATN

epithelial cell swelling (mannitol), lower epithelial cell ATP and oxygen requirements by inhibition of active solute transport (loop-blocking diuretics), and prevent accumulation of intracellular calcium (calcium channel blockers).38 Whereas many of these compounds afford some benefit in experimental models of ischaemic or nephrotoxic ARF, consistent benefit has not been demonstrated in human beings. Most studies have evaluated small numbers of patients (usually <100) and included ARF with different causes, raising the possibility that a significant renoprotective effect was missed. Enrolment of patients into a multicentre randomised blinded placebo-controlled trial of the efficacy of intravenous atrial natriuretic peptide has just been completed. Several novel therapeutic approaches have proved effective in experimental models but remain untested in human beings. These include specific receptor antagonists of the vasoconstrictive action of endothelin, compounds that attenuate ATP depletion in tubule epithelial cells (eg, glycine, MgATPCI,), synthetic peptides ("RGD" peptides) that prevent aggregation of epithelial cells and cast formation within tubules, agents that inhibit leucocyte recruitment and activation during reperfusion (monoclonal antibodies against leucocyte adhesion molecules), and growth factors that promote regeneration of tubule epithelium (epidermal growth factor, insulin-like growth factors).’ The treatment of other causes of intrinsic azotaemia is guided by the primary diagnosis. For example, atheroembolic disease is often irreversible, whereas glomerulonephritis and vasculitis may respond to aggressive immunosuppressive therapy. Plasma exchange is useful in the management of HUS-TTP. Allergic interstitial nephritis typically resolves spontaneously after the inciting drug is stopped; however, corticosteroids can hasten recovery and may obviate the need for dialysis in patients with severe disease.

Management of complications ARF impairs the ability of the kidney to excrete sodium, potassium, and water, perturbs divalent cation homoeostasis, and limits urinary acidification. Therefore, ARF is often complicated by hypervolaemia, hyperkalaemia, hyponatraemia, hyperphosphataemia, hypocalcaemia, hypermagnesaemia, and metabolic acidosis (table 3). In addition, patients cannot excrete the nitrogenous waste products of protein metabolism and can develop the uraemic syndrome. The severity of these metabolic sequelae generally correlates with the degree of renal injury and the patient’s catabolic state. For optimum management, these complications must be anticipated and preventive measures are instituted from the time of diagnosis. Expansion of extracellular fluid volume is an almost inevitable consequence of oliguric ARF and manifests as elevated jugular venous pressure, pulmonary and dependent oedema, ascites, and pleural and pericardialI effusions. Hypertension, if present, is usually mild. Hypervolaemia is often avoided by tailoring salt and water intake to match losses, and is treated by salt and water restriction and diuretics. Ultrafiltration of plasma, with standard dialysis equipment, may be required when conservative measures fail. Mild hyponatraemia and hypoosmolality frequently complicate the ingestion or administration of hypotonic or dextrose-containing solutions and is usually controlled by restriction of water intake. Serum potassium typically rises by 0-5 mmol/L per day in oligo-anuric patients because of impaired excretion of potassium derived from the diet, potassiumcontaining solutions, and potassium released from injured tubular epithelium or other cells (eg, rhabdomyolysis, tumour lysis). Hyperkalaemia may be compounded by metabolic acidosis which triggers potassium efflux from cells. Oral or intravenous potassium supplements and potassium-sparing diuretics should be stopped at 1537

-

diagnosis, unless patients are hypokalaemic. Mild hyperkalaemia is managed by dietary restriction, potassiumbinding ion-exchange resins and, in non-oliguric ARF, by loop-blocking diuretics. Emergency measures, namely insulin and glucose, bicarbonate, calcium gluconate, and dialysis, are used in patients with serum potassium over 6-5 mmol/L and in all patients with electrocardiographic abnormalities or clinical features of hyperkalaemia. Metabolism of dietary protein yields 50-100 mmol per day of fixed non-volatile acids which must be excreted by the kidneys to preserve acid-base homoeostasis. Predictably, ARF is often complicated by metabolic acidosis with widening of the serum anion gap. Most physicians administer oral or intravenous bicarbonate to patients with metabolic acidosis and a serum bicarbonate below 15 mol/L or arterial pH under 7-2 (table 3). Mild hyperphosphataemia (1-6-3-2 mmol/L, 5-10 mg/dL) is common in ARF, but can be severe (3-2-6-4 mmol/L, 10-20 mg/dL) in catabolic patients, rhabdomyolysis, or tumour lysis syndrome. Metastatic deposition of calcium phosphate can trigger hypocalcaemia, particularly when the product of serum calcium and phosphate concentrations exceeds 5-65 (when both expressed in mmol/L) or 70 (both in mg/dL). Other factors that potentially contribute to hypocalcaemia include skeletal resistance to parathyroid hormone, reduced levels of 1,25dihydroxyvitamin D, and calcium sequestration in injured tissues. Hyperphosphataemia is usually controlled by restriction of dietary phosphate and administration of aluminium hydroxide or calcium carbonate which inhibit gastrointestinal absorption of phosphate. Hypocalcaemia is typically asymptomatic, possibly due to the opposing influence of acidosis on neuromuscular excitability, and rarely requires treatment unless it is a complication of rhabdomyolysis, pancreatitis, or over-zealous bicarbonate therapy. Mild hyperuricaemia (<890 umol/L, < 15 mg/dL) and hypermagnesaemia (1-2 mmol/L, 2-4 mEq/L) are much the norm in ARF and rarely necessitate treatment. High levels of uric acid raise the possibility of acute urate nephropathy. Malnutrition remains one of the most troublesome complications of ARF and should be managed as a collaborative venture with dieticians, pharmacists, and nursing staff.’-3 Most patients have net protein breakdown which can exceed 200 g per day in catabolic subjects. Malnutrition is usually multifactoral in origin and may reflect anorexia or restricted access to food, the catabolic nature of the underlying medical disorder (eg, sepsis, rhabdomyolysis, trauma), nutrient losses in drainage fluids or dialysate, increased breakdown and reduced synthesis of muscle protein, and increased hepatic gluconeogenesis, probably mediated through the actions of toxins, hormones (eg, glucagon, parathyroid hormone) or other substances (eg, proteases) that are accumulated in ARF. Unfortunately, this scenario is usually compounded by inadequate nutritional support. The aim of dietary therapy in ARF is to provide sufficient calories (30-50 kcal/kg per day) to avoid catabolism and starvation ketoacidosis, while minimising production of nitrogenous waste. This is best achieved by restricting dietary protein to approximately 0-6-0-8 g/kg per day of protein of high biological value and by providing most calories in the form of carbohydrate (approximately 100 g daily) (table 3). Higher protein intake is advisable in catabolic patients or those with a prolonged maintenance phase, even if it precipitates the need for dialysis. Indeed, 1538

management of nutrition is easier after institution of dialysis when patients are generally prescribed 1-0-1-4 g protein per kg per day, 50% of which should be of high biological value. Vigorous parenteral hyperalimentation has been claimed to improve prognosis in ARF; however, consistent benefit has yet to be demonstrated in controlled trials. Infection is the most serious complication of ARF, occurs in 50-90% of cases, and accounts for as many as 75% of deaths. Whether this high frequency reflects defective host immunity or repeated breaches of mucocutaneous barriers cannulae, (intravenous mechanical ventilation, bladder catheterisation) is unclear. Anaemia, prolongation of bleeding time, and leukocytosis are common haematological complications of ARF and are usually multifactorial in origin. Factors that contribute to anaemia include haemodilution, inhibition of erythropoiesis, haemolysis, bleeding, reduced red-cell survival time, and, probably, frequent phlebotomy. A diathesis reflects mild bleeding usually thrombocytopenia, platelet dysfunction, and/or clotting factor abnormalities. Anaemia may require transfusion in patients with symptoms or with active bleeding. The bleeding diathesis is typically mild and, if problematic, can usually be controlled by correction of packed cell volume and treatment with desmopressin, oestrogen, cryoprecipitate, and/or intensive dialysis. Cardiac complications include arrhythmias, myocardial infarction, and pulmonary embolism. Primary abnormalities in myocardial contractility and excitability can be ’

compounded by hypervolaemia, acidosis, hyperkalaemia, and other metabolic sequelae of ARF. Pulmonary embolism probably occurs because of prolonged immobilisation. Interestingly, whereas gastrointestinal bleeding complicates 10-30% of cases of ARF, bleeding is rarely severe, perhaps because of widespread use of

H2-antihistamines in intensive care units. Protracted periods of anuric or catabolic ARF often lead to the development of the uraemic syndrome. Clinical include manifestations pericarditis and pericardial effusion, anorexia, nausea, vomiting and ileus, and neuropsychiatric disturbances, including lethargy, confusion, stupor, coma, agitation, psychosis, asterixis, myoclonus, hyperreflexia, restless leg syndrome, focal neurological deficit, and seizures. The uraemic toxin(s) that trigger these abnormalities are still being defined and probably include urea and other compounds derived from protein metabolism, bacterial-derived products, such as aromatic amines and skatoles, and other molecules that are inadequately cleared from the circulation. The onset of the uraemic syndrome is ominous and mandates emergency

dialysis.

Indications and types of dialysis Although dialysis has been used to treat ARF for over a quarter of a century, several key questions have yet to be answered in prospective controlled trials: (a) which type of dialysis is best (haemodialysis or peritoneal dialysis, intermittent or continuous haemodialysis; choice of haemodialysis membrane); (b) when should dialysis be started, and (c) how intensively should patients be dialysed. 1-3,411-7 There is no compelling evidence that either haemodialysis or peritoneal dialysis is superior for the management of ARF. The technique is chosen according to the specific needs of individual patients (eg, peritoneal dialysis may be preferable if haemodynamically unstable,

haemodialysis after abdominal surgery), the expertise of the nephrologist, and the facilities of the institution. Peritoneal dialysis is performed through a temporary intraperitoneal catheter, whereas vascular access for haemodialysis is usually achieved through a double-lumen catheter in the internal jugular vein. The jugular vein is

this in mind, every effort should be made to preserve the veins (ie, avoid venipuncture) of the non-dominant arm of patients with ARF, because these vessels may be required later to fashion an arteriovenous fistula for chronic

the subclavian vein because of the lower frequency of venous stenosis on long-term follow-up. The femoral vein is an alternative when only one or two dialyses are anticipated (eg, treatment of poisoning), but should not be used for longer periods because of the risk of infection and the need to immobilise patients in bed. Absolute indications for dialysis include symptoms or signs of uraemia (eg, changes in mental status, asterixis, pericardial rub or effusion, hiccoughs), and management of volume overload, hyperkalaemia, or acidosis that is refractory to medical therapy. Many nephrologists also initiate dialysis empirically if blood urea rises above 100 mg/dL (about 35 mmol/L), even in the absence of clinical uraemia; however, the results of the initial studies which suggested that such "prophylactic" dialysis improves outcome have not been confirmed in later trials.1-3,40-42 Nor is it clear whether increasing the intensity of dialysis to maintain blood urea and creatinine below a certain level favourably affects outcome.42,44 The issues of timing and intensity of haemodialysis are important, complex, and warrant further study. In addition to the complications of vascular access, unnecessary haemodialysis may exacerbate ATN and delay recovery by triggering hypotension and renal hypoperfusion. Furthermore, some activation of complement and circulating leucocytes almost invariably occurs when blood is exposed to conventional cellulosic or dialysis cupraphane mediators that then membranes, may aggravate ischaemic renal injury.46,47 Along these lines, two randomised controlled trials demonstrated a trend towards improved survival and renal recovery in patients with oliguric ATN who were dialysed with more biocompatible dialysis membranes (polymethyl methacrylate, polysulphone) compared with those dialysed with conventional materials.48,49 Continuous arteriovenous and venovenous haemodiafiltration (CAVH and CVVH) are alternative haemodialysis techniques for treatment of ARF.45 They are generally reserved for patients in whom intermittent haemodialysis fails to control hypervolaemia or uraemia, and for those who do not tolerate intermittent haemodialysis and in whom peritoneal dialysis is not possible. CAVH requires arterial and venous access and the patients’s blood pressure generates an ultrafiltrate of plasma across a porous and biocompatible dialysis membrane. A physiological crystalloid solution, usually peritoneal dialysis fluid, is passed along the other side of the membrane to achieve diffusive clearance. CVVH requires only a double-lumen venous catheter; however, a blood pump is needed to generate ultrafiltration pressure across the dialysis membrane. These new haemodialysis techniques have not been compared with conventional intermittent haemodialysis in prospective, adequately controlled trials. Such evaluations are needed given that continuous haemodialysis techniques require immobilisation in bed, systemic anticoagulation, arterial cannulation in CAVH, and prolonged exposure of blood to synthetic, albeit biocompatible, dialysis membranes. Although most patients recover from ARF, a few (<5%) will require long-term renal replacement therapy. With

Management of postrenal azotaemia Management of postrenal azotaemia usually involves a multidisplinary approach and requires collaboration between nephrologist, urologist, and radiologist. Urethral or bladder neck obstruction are usually relieved temporarily by transurethral or suprapubic placement of a

preferred

to

haemodialysis.

bladder catheter. Ureteric obstruction may be treated initially by percutaneous catheterisation of the dilated ureteric pelvis or ureter, and obstructing lesions are often removed percutaneously (eg, calculus, sloughed papilla) or bypassed by insertion of a ureteric stent (eg, carcinoma). Most patients experience appropriate diuresis for several days after relief of obstruction; however, approximately 5% develop a transient salt-wasting syndrome that may require administration of intravenous fluids to maintain blood pressure and glomerular filtration rate.

Outcome and the future

mortality rate from ATN is around 50% and has changed little over the past three decades, despite significant advances in supportive care.1-3,50 Mortality rates differ, however, depending on the cause of ARF, being about 15% in obstetric patients, about 30% in toxinrelated ARF, and around 60% after trauma or major mL per day) at presentation, a surgery. Oliguria (<400 rise in serum creatinine of greater than 3 mg/dL (265 mol/L), old age, and multiorgan failure portend a grave prognosis. Most patients who survive begin renal recovery within 10-21 days and regain sufficient renal function to live normal lives. The recovery phase is occasionally complicated by vigorous diuresis because of excretion of salt and water accumulated during the maintenance phase, osmotic diuresis induced by retained urea and other waste products, and delayed recovery of tubule function relative to glomerular filtration. 50% of survivors The

have subclinical abnormalities of renal function or structure. Patients should be observed for signs of intravascular volume depletion during this period which may retard renal recovery or even trigger a secondary rise in blood urea and creatinine. ARF is irreversible in about 5% of patients, probably because of complete cortical necrosis, and an additional 5% of patients have slow progressive deterioration in renal function over years after an initial recovery phase. It is likely that ARF will remain a major therapeutic challenge into the next millenium. Hopefully, recent advances in our understanding of the cellular and molecular basis for ischaemic and nephrotoxic renal injury and renal regeneration will herald the development of novel and effective strategies for treatment of this devastating clinical syndrome. References 1

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