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The management of acute kidney injury
the same stages (risk, injury and failure) but the time frame for diagnosis of AKI is reduced to 48 hours, and a lower threshold for the rise of serum creatinine from baseline to peak value is used. Both sets of criteria have been validated for in-hospital mortality in numerous studies and have been found useful for diagnosis and prognosis.3,4 These criteria are covered in more detail elsewhere in this issue (see Assessment and Initial Management of Acute Kidney Injury on pp 390e397 of this issue). The incidence of AKI is increasing, particularly in the elderly, although reporting suffers from the lack of consensus on a precise definition. UK-based population studies have estimated the annual incidence of AKI from 486 to 620 per million population, accounting for about 1% of hospital admissions and complicating more than 7% of hospital inpatient episodes.5,6 AKI is a common finding on the critical care unit with as many as 35% of patients admitted to the intensive care unit requiring renal replacement therapy (RRT); when AKI is present as part of multiple organ failure, mortality is over 90% if four organs or more fail.7
Victoria J Ingham Lui G Forni
Abstract Acute kidney injury is a commonly encountered condition in the hospital setting. Often accurate history-taking, careful physical examination and meticulous monitoring of volume balance are enough to reverse this process. However, acute kidney injury does present a unique set of metabolic derangements that, if untreated, will result in death. We outline the initial management of acute kidney injury as well as specific treatments that may be required. Some consideration is also given to the use of renal replacement therapies.
Keywords acute kidney injury; glomerular filtration rate; haemofiltration; hyperkalaemia; metabolic acidosis; uraemic encephalopathy; uraemic pericarditis
At-risk populations The two main in-hospital patient groups at increased risk of AKI are those with pre-existing renal impairment and associated comorbidities, and those at risk of iatrogenic AKI. The first group includes elderly patients and those with underlying chronic renal impairment of any cause. Co-morbidities such as congestive cardiac failure and hepatic disease add to the increased risk of AKI following relatively mild insults. Those at risk of iatrogenic AKI include patients undergoing major surgery or radiological procedures involving intravenous contrast agents. There is considerable overlap between the two groups in the hospital setting.
There are over 30 definitions of acute renal failure found within the literature. This lack of clarity prompted collaboration between nephrologists and intensivists to decide on a uniform means of classifying acute renal failure (ARF) or, as it is now known, acute kidney injury (AKI). The introduction of this term ensures that patients with even relatively minor deteriorations in glomerular filtration rate (GFR) and kidney injury should be included in a working clinical definition of kidney damage that will allow early detection and intervention. The Acute Dialysis Quality Initiative group (ADQI) proposed the RIFLE classification encompassing two separate criteria, the calculated GFR and urine output.1 The acronym RIFLE provides diagnostic definitions for the three grades of increasing severity of ARF and the two outcome variables of loss (L) and end-stage renal disease (E). The grades of severity of injury include the stage at which injury can be prevented (risk, R), when the kidney has already been damaged (injury, I) and when renal failure has occurred (failure, F). Although the RIFLE criteria may help to define AKI, practical problems remain with this definition, including the proposed calculation of the baseline creatinine as well as the lack of consensus regarding initiation of treatment. More recently, the Acute Kidney Injury Network (AKIN) modified the RIFLE criteria.2 The AKIN criteria refer to
Prevention of AKI Simple measures may prevent AKI. These include prompt fluid resuscitation when required to provide adequate hydration and maintain blood pressure.8 Nephrotoxic drugs should be temporarily omitted, and the dosages of drugs that are eliminated via the kidney adjusted in line with the estimated GFR (eGFR). During radiological investigation in patients at risk of AKI, the risk of contrast nephropathy should be minimized by the use of non-ionic contrast agents, wherever possible, and adequate hydration before the procedure with sodium chloride 0.9% or sodium bicarbonate solutions. The value of acetylcysteine in the prevention of contrastinduced nephropathy is debatable.9 Concurrent medical conditions should always be optimized before elective surgery, paying particular attention to adequate volume replacement before, during and after the operation. The 2009 National Confidential Enquiry into Patient Outcome and Death (NCEPOD) report Adding Insult to Injury reviewed the care of patients who died in hospital with a primary diagnosis of AKI, and made recommendations about patient care. They suggested that all patients admitted as an emergency to hospital should have their electrolytes monitored regularly to prevent unrecognized AKI, and that predictable and avoidable AKI should never occur. They also recommended senior review of all
Victoria J Ingham MB BChir MRCP is a Specialist Registrar in Renal Medicine at Western Sussex Hospitals Trust, Worthing, West Sussex, UK. Competing interests: none. Lui G Forni MBBS BSc PhD MRCPI is Consultant Physician and Intensivist at Western Sussex Hospitals Trust, Worthing, West Sussex, UK, and Honorary Senior Lecturer at the Brighton and Sussex Medical School, UK. Competing interests: none.
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acute admissions and that all admitting hospitals should have access to specialist nephrology services.10
mainstay of volume replacement therapy. Crystalloids expand plasma volume by about 25% of the infused volume, correcting sodium depletion as well as restoring solute and water diuresis. However, large-volume infusion of sodium chloride can lead to so-called ‘hyperchloraemic acidosis’, which may be associated with renal vasoconstriction and gut hypoperfusion.13 Colloids, such as albumin, gelatins and hydroxyethyl starch, result in volume expansion approximate to the infused volume but, if administered in isolation in AKI, can lead to osmotic nephrosis (osmotic tubular damage). Hydroxyethyl starches are highly polymerized sugars characterized by their molecular weight, grade of substitution and concentration. They are degraded through hydrolytic cleavage, the remnants of which are excreted by the kidney, and should be avoided in AKI particularly when this has resulted from sepsis.
Management of AKI General management Early recognition and treatment of AKI saves nephrons and prevents further decline in GFR. It is important to remember that measured serum creatinine may not rise appreciably until GFR has fallen significantly. This is of particular relevance in individuals of small build, vegetarians and the undernourished, in whom a serum creatinine in the normal range can be misleading. Treatment in AKI is aimed at minimizing damage to surviving nephrons while providing support until the kidney recovers. This includes restoration of the circulating volume, relief of outflow obstruction, if present, removal of tubular toxins and specific treatment of glomerular disease. Early restoration of renal perfusion in precipitant AKI due to acute tubular necrosis is essential. Recovery of GFR depends on the number of remaining functional nephrons that will increase their filtration to maintain GFR. However, continued hyperfiltration may result in progressive glomerular sclerosis and nephron death, leading to end-stage renal failure. As there is no specific therapy for AKI, management should address the causes, as well as correcting metabolic and volume derangements. This should be combined with optimal nutritional support, ensuring adequate calorific intake while limiting nitrogenous waste production and potassium intake. Sepsis should be treated aggressively and ulcer prophylaxis with proton pump inhibitors initiated.
Volume overload The volume status of a patient with AKI should be assessed carefully. Although somewhat unfashionable, careful bedside examination including assessment of the venous pressure, capillary refill time, pulse and postural blood pressure changes are elementary tools for assessing volume status. Hourly urineoutput and fluid-input charts need to include all fluid losses, including estimated insensible losses, drain/stoma output and nasogastric losses where appropriate. If possible, patients should be weighed daily. Ideally, a central venous catheter and an arterial cannula are required, particularly where multiorgan failure (MOF) is imminent. In established MOF, absolute measurement of central venous pressure can be misleading, especially in the ventilated patient where high intrathoracic pressures may be present, and further invasive monitoring may be required. Where volume overload is encountered in the setting of AKI, symptoms can be alleviated by high-flow oxygen. Where pulmonary oedema is refractory to pharmacological management while preparing the patient for urgent RRT, continuous positive airway pressure ventilation (CPAP) should be considered. The use of diuretics, such as furosemide and mannitol, and ‘low-dose’ dopamine have yielded inconsistent results in AKI, when subject to rigorous scrutiny.14,15 Although loop diuretics may promote diuresis in oliguric renal failure, there is little evidence that they influence outcome,16 and the large doses of furosemide often required for diuresis in AKI can result in ototoxicity. Similarly, the use of dopamine does not reduce mortality or accelerate the recovery of renal function and, in the critically ill, dopamine use is not without risk due to peripheral vasoconstriction causing gut ischaemia, tissue necrosis and digital gangrene.
Addressing the cause Although widely accepted, the term AKI does not confer a diagnosis; it simply acknowledges that measured variables are deranged. As in ARF, the major causes of AKI can be grouped into three general categories: pre-renal causes, intrinsic renal disease and obstruction. Pre-renal failure is responsible for up to 60e70% of AKI and is due in most cases to hypovolaemia, relative hypotension or renal hypoperfusion.11 In the same way as in the prevention of AKI, potential nephrotoxins should be avoided and restoration of the circulation attempted using careful volume resuscitation and/or vasopressors. The management of intrinsic renal disease is beyond the scope of this review; acute tubular necrosis remains the most common cause.11,12 Although post-renal obstruction accounts for only 5e15% of cases of AKI, it is important to recognize it as prompt intervention may result in complete recovery of renal function. Clinical assessment should include percussion for an enlarged bladder and prostate examination, where applicable; if obstruction is suspected in a catheterized patient, the urinary catheter should be changed. The investigation of choice is abdominal ultrasound. Relief of obstruction may lead to a significant diuresis, with subsequent volume depletion and consequent worsening of renal function, so careful monitoring of fluid balance is mandatory.
Hyperkalaemia This life-threatening complication arises through cellular shifts of potassium or release from lysed cells, together with decreased renal excretion of potassium, and requires immediate treatment. Acidosis, hyponatraemia and hypocalcaemia all potentiate the harmful effects of hyperkalaemia on cardiac function and must also be corrected. Muscle weakness may be present, and if severe can lead to flaccid paralysis, although symptoms rarely manifest until the serum potassium exceeds 7.0 mmol/litre. The most serious effect is on cardiac conduction, which classically presents as a shortened QT interval with a tall peaked T wave on the
Specific problems Volume resuscitation In hypovolaemia, volume expansion is recommended. However, uncontrolled volume substitution may result in clinical deterioration and should be avoided. Isotonic crystalloids remain the
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allowing for CO2 removal.17,18 In clinical practice it is rarely a problem. However, if large volumes of isotonic sodium bicarbonate are employed in AKI, there is a risk of volume expansion and development of hypernatraemia.
electrocardiogram (ECG). Without treatment, progressive lengthening of QRS duration and PR interval ultimately lead to a ‘sine wave’ appearance, followed by ventricular standstill or fibrillation. A variety of other conduction disturbances may occur, including bundle-branch block (left or right), bifascicular block and advanced atrioventricular block. All patients with AKI should have continuous cardiac monitoring and be treated immediately if ECG changes or neuromuscular abnormalities occur. Asymptomatic patients with serum potassium <6.5 mmol/l, or whose ECG does not manifest signs of hyperkalemia, should be treated with a low potassium diet, and additional sources of potassium intake should be withheld and any potentiating drugs discontinued. Specific treatment of hyperkalaemia is directed at removing excess potassium, shifting extracellular potassium into the cells or antagonizing its membrane effects. Calcium directly antagonizes the actions of hyperkalaemia and, although short-lived, its effect begins within minutes. Hyperinsulinaemia, achieved by giving insulin and glucose intravenously, stimulates Na/K-ATPase activity and causes a shift of potassium into cells; effective therapy usually leads to a 0.5e1.5-mmol/l fall in the plasma potassium concentration within 15 min, and the maximal effect is observed after approximately 60 min. Sodium bicarbonate solution can correct acidosis and achieve a similar effect but concern for volume balance may limited its use in AKI. b2-adrenergic agonists, which also act directly on Na/K-ATPase activity, may also be used effectively to treat hyperkalaemia but should be avoided in patients with active coronary disease. If these conservative measures are ineffective and/or hyperkalaemia is severe, RRT should be employed. It is important to note that b2-adrenergic agonists, calcium infusions and insulin offer only temporary protection from hyperkalaemia. They do not reduce total body potassium and can lead to a false sense of security, particularly in septic, haemodynamically unstable or anuric patients. Acute measures to reduce hyperkalaemia must be accompanied by additional therapies, such as diuresis or renal replacement therapy.
Uraemic pericarditis Uraemic pericarditis is observed in 6e10% of patients with advanced renal failure, resulting from inflammation of both the visceral and parietal membranes of the pericardial sac. Pericarditis in AKI presents with fever and pleuritic chest pain, characteristically worse in the recumbent position, and a pericardial rub may be heard on auscultation, although the ECG does not show the typical diffuse ST and T wave elevations observed with other causes of acute pericarditis. The development of pericarditis in a patient with AKI is an indication to institute RRT, unless there are signs of cardiac tamponade due to a pericardial effusion. Under such conditions, heparin-free haemodialysis or haemofiltration should be used because of the risk of increased bleeding into the pericardial sac with anticoagulation. Uraemic encephalopathy Like uraemic pericarditis, uraemic encephalopathy tends to be related to the degree of uraemia. Early clinical features include rambling speech, disorientation, lethargy, irritability, hallucinations and, more rarely, coma. Commonly encountered signs include tremor, myoclonus, and asterixis, which tend to occur with deterioration in mental status. Transient focal signs, such as hemiparesis or reflex asymmetry, occur rarely but resolve with treatment, although mental state may not improve for up to 48 hours. If the signs do not resolve, other pathologies need to be excluded. Renal replacement therapy Renal replacement therapy (RRT) does not cure acute kidney injury but it is a safe and efficient way of replacing renal function while the kidneys recover from disease or injury. Historically, single-organ AKI has been treated with either peritoneal or haemodialysis, which are the mainstay of chronic renal replacement therapy. Hospitals with acute nephrology services will perform haemodialysis in haemodynamically stable patients, although RRT is most commonly performed acutely in a level 2 or 3 facility employing either haemodialysis or more commonly haemofiltration. Although superficially similar, the mechanisms by which the composition of the blood is altered, differ markedly.19,20 In haemodialysis, blood flows along one side of a semipermeable membrane as a solution of crystalloids, the dialysis fluid, is pumped against the direction of the blood flow along the other side of the membrane. Molecules diffuse across the membrane from higher to lower concentrations driven by the law of mass action. The composition of the dialysis fluid allows as near normalization of the plasma as possible. The dialysis-fluid compartment is under lower pressure and this generates a transmembrane pressure gradient enabling the removal of salt and water. Haemofiltration in its simplest form involves the passage of blood under pressure passing down one side of a highly permeable membrane, allowing water and other molecules up to a size of about 20 kDa to pass through the membrane by convection. Thus, filtrate is discarded and replaced by an idealized buffered replacement fluid, the crystalloid components of which are at physiological concentration. Indications for renal replacement depend on the clinical and biochemical derangements outlined above and,
Acidosis Metabolic acidosis in AKI results from increased acid production, increased acid retention and decreased renal reabsorption of bicarbonate. Acidosis is exacerbated by sepsis, malnutrition and some drugs, and is very common among sick patients and those admitted acutely. Metabolic acidosis is easily detected by measuring venous serum bicarbonate in the above patient groups when requesting routine blood tests. Mild acidosis (pH >7.2) can usually be reversed by adequate volume resuscitation. Sodium bicarbonate, either intravenously or orally, may be used if the acidosis is severe (pH <7.2 or HCO3 10e15 mmol/l). There is a theoretical risk of ‘paradoxical acidosis’ on bicarbonate administration; the argument stems from the observation that CO2 is generated when sodium bicarbonate is added to a weakly acidified solution. Since there is no significant gradient between intracellular and extracellular CO2, it is argued that this results in an increase in intracellular CO2, thereby worsening the acidosis. The evidence for this comes from in vitro work far removed from the physiological, as well as animal work where predetermined ventilatory restraints were imposed. In effect, these studies have used a ‘closed’ system whereas in a spontaneously breathing patient, or indeed one being adequately mechanically ventilated, the system is ‘open’
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3 Bellomo R, Kellum JA, Ronco C. Defining and classifying acute renal failure: from advocacy to consensus and validation of the RIFLE criteria. Intensive Care Med 2007; 33: 409e13. 4 Haase M, Bellomo R, Matalanis G, Calzavacca P, Dragun D, Haase-Fielitz A. A comparison of the RIFLE and acute kidney injury, network classifications for cardiac surgery-associated acute kidney injury: a prospective cohort study. J Thorac Cardiovasc Surg 2009; 138: 1370e6. 5 Hegarty J, Middleton RJ, Krebs M, et al. Severe acute renal failure in adults: place of care, incidence, and outcomes. QJM 2005; 98: 661e6. 6 Nash K, Hafeez A, Hou S. Hospital-acquired renal insufficiency. Am J Kidney Dis 2002; 39: 930e6. 7 Abosaif NY, Tolba YA, Heap M, Russell J, El Nahas AM. The outcome, of acute renal failure in the intensive care unit according to RIFLE: model application, sensitivity, and predictability. Am J Kidney Dis 2005; 46: 1038e48. 8 Joannidis M, Druml W, Forni LG, et al. Prevention of acute kidney injury and protection of, renal function in the intensive care unit: expert opinion of the working group for nephrology, ESICM. Intensive Care Med 2010; 36: 392e411. 9 Goldenberg I, Matetzky S. Nephropathy induced by contrast media: pathogenesis, risk factors and preventive strategies. CMAJ 2005; 172: 1461e71. 10 Smith N, Stewart J, Findlay G. Acute kidney injury: adding insult to injury NCEPOD Report, London 2009. 11 Rahman TM, Treacher DF. Management of acute renal failure on the intensive care unit. Clin Med JRCPL 2002; 2: 108e13. 12 Hilton R. Acute renal failure. Br Med J 2006; 333: 786e90. 13 Wilkes NJ, Woolf R, Mutch M, et al. The effects of balanced versus saline-based hetastarch and crystalloid solutions on acidebase and electrolyte status and gastric mucosal perfusion in elderly surgical patients. Anesth Analg 2001; 93: 811e6. 14 Uchino S, Doig GS, Bellomo R, et al. Diuretics and mortality in acute renal failure. Crit Care Med 2004; 32: 1669e77. 15 Kellum JA, Decker M. Use of dopamine in acute renal failure: a metaanalysis. Crit Care Med 2001; 29: 1526e31. 16 Mehta RL, Chertow GM. Diuretics in critically ill patients with acute renal failure. JAMA 2003; 289: 1379e81. 17 Goldsmith DJ, Forni LG, Hilton PJ. Bicarbonate therapy and intracellular acidosis. Clin Sci 1997; 93: 593e8. 18 Hilton PJ, Taylor J, Forni LG, Treacher DF. Bicarbonate-based haemofiltration in the management of acute renal failure with lactic acidosis. QJM 1998; 91: 279e83. 19 Forni LG, Hilton PJ. Continuous hemofiltration in the treatment of acute renal failure. N Engl J Med 1997; 336: 1303e9. 20 D’Intini V, Ronco C, Bonello M, Bellomo R. Renal replacement therapy in acute renal failure. Best Pract Res Clin Anaesthesiol 2004; 18: 145e57. 21 Mehta RL, McDonald B, Gabbai FB, et al. A randomized clinical trial of continuous versus intermittent dialysis for acute renal failure. Kidney Int 2001; 60: 1154e63. 22 Vinsonneau C, Camus C, Combes A, et al. Continuous venovenous haemofiltration versus intermittent haemodialysis for acute renal failure in patients with multiple-organ dysfunction syndrome: a multicentre randomized trial. Lancet 2006; 368: 379e85.
Indications for commencing renal replacement therapy Clinical
Biochemical
Fluid overload with increasing O2 requirement Uraemic encephalopathy Uraemic pericarditis
Hyperkalaemia resistant to medical therapy Acidosis resistant to medical therapy Drug overdosage (e.g. lithium)
Table 1
although these are general indications, use will be guided by the clinical situation (Table 1). In the intensive care unit, for example, treatment may begin before the absolute indications are reached, as there is uncertainty surrounding the optimal timing of the initiation of renal support. There is some evidence that, in the critically ill intensively managed patient, early treatment may result in improved outcome but to date no randomized clinical trials have specifically addressed this question. Practical aspects of renal replacement therapy Haemodialysis and haemofiltration require access to the circulation. Various double-lumen vascular catheters are commercially available, allowing blood flow rates up to 200 ml/minute. Adequate venous access is critical in preventing technical difficulties with blood flow from the patient and potential problems with clotting, leading to a loss of the extracorporeal circuit. In most cases anticoagulation is required, with unfractionated heparin being commonly used to prime the circuits, and a continuous infusion is maintained through the inflow side of the circuit. If the patient is thrombocytopenic, alternative anticoagulants can be used, including sodium chloride, citrate or prostacyclin, but care must be taken with the latter given its vasodilator effects. Continuous haemofiltration is a highly effective system for the replacement of renal function in patients with AKI. Although only a few trials have compared continuous versus intermittent techniques, as yet no evidence exists to favour one technique over the other. Those studies that have been performed have not supplied the answer because of problems in study design.21,22 The relative ease of continuous veno-venous haemofiltration (CVVH), together with its minimal haemodynamic effects, makes it the treatment of choice in acute renal failure especially when complicated by other organ failure. A
REFERENCES 1 Bellomo R, Ronco C, Kellum JA, Mehta R, Palevsky P, and the ADQI workgroup. Acute renal failureedefinition, outcome measures, animal models, fluid therapy and information technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group. Crit Care 2004; 8: R204e12. 2 Mehta RL, Kellum JA, Shah SV, et al. Acute Kidney Injury Network: report of an initiative to improve outcomes in acute kidney injury. Crit Care 2007; 11: R31.
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