Acute Kidney Injury (AKI)

Background Andy Lewington ajpl1901@hotmail.com

(currently under review) Key points: 1. Acute Kidney Injury (AKI) is traditionally referred to as a rapid decrease in renal function over days to weeks, resulting in a failure to regulate fluid, electrolyte and acid-base balance. Patients are at risk of a number of complications and have an increased mortality 2. New definitions based on rises in serum creatinie or reductions in urine output have been proposed which will provide improved epidemiological data 3. The mortality associated with AKI has remained unacceptably high for the last four decades 4. The most common forms of AKI are secondary to hypoperfusion injury, sepsis and nephrotoxins. Therapy is supportive and consists of rapid correction of hypovolaemia, prompt treatment of sepsis and withdrawel of nephrotoxic medication 5. Prevention of AKI is of paramount importance and is dependent upon recognition of patients with risk factors. It has been estimated that 30% of cases of AKI could be prevented 6. The cause of AKI must always be established to ensure that rarer forms (vasculitis) are not overlooked. Specific therapies are available and must be initiated as soon as possible 7. The duration and severity of AKI predicts the development of progressive chronic kidney disease (CKD) 8. Following AKI serum creatinine may return towards the baseline value but remains a poor marker of the residual tubular and vascular damage. The ensuing CKD is associated with an increase in ardiovascular disease 9. The cost of AKI has been estimated to be 400-600M/year in the UK 10. There is renewed interest in developing specific therapies to prevent AKI and major investment from pharma

Epidemiology and Definitions

Epidemiology

The incidence of AKI is uncertain, and is determined by the definition and the study population In a whole health economy based study of AKI and ACRF, including all patients requiring RRT or not, all patients with serum creatinine concentrations ?150 mol/L (male) or ?130mol/L (female) over a 6-month period, were identified (Ali, 2007). The incidences of AKI and ACRF were 1811 and 336 per million population, respectively - ie, the incidence of AKI/ACRF is nearly 20x incidence of patients with new ESRF. Median age was 76 years for AKI and 80.5 years for ACRF. Sepsis was a precipitating factor in 47% of patients. Of the AKI patients, 8% required RRT, of which 57% died Conversely, in a hospital based study, AKI not requiring dialysis was common, being present in 5-10% of all medical and surgical admissions (Nash, 2002). In this study of 4622 consecutive medical and surgical admissions, mortality was 19.4%, but was 37.8%, if creatinine reached >250 mcmol/L. AKI develops in upto 70% of intensive care unit (ICU) patients. Approximately 95% of consultations with nephrologists are related to AKI A study from Canada showed a much higher incidence of AKI than in previous reports, 18.3% (7,856 of 43,008) in hospitalised patients (Pannu, 2011) But AKI, requiring dialysis is rare. In one study, incidence was approximately 203 patients/million/yr (nearly 2x the incidence of new ESRF). It had a very high mortality: 73.5% of patients receiving RRT for ARF died within 90 days. 23.5% became independent of RRT. The median duration of hospital admission was 19 days (>50%) (Metcalfe, 2002) In an earlier whole health economy study, Feest et al (1993) found a similar incidence of 140 ppm per year. Overall survival was 54% at three months and 34% at two years and was not significantly age related New cases of AKI are unsual but not rare, affecting approxinately 0.5% (about 1 in 200) of the UK population per year (2000 ppm/year), 20x incidence of new ESRF. AKI requiring dialysis (10% of these) is rare (200 ppm/year), 2x incidence of new ESRF An average GP with 2000 patients, will see 10 per year. 90% (9 patients), will not require RRT; 10% of these (1 patient) will die. Of the 10% that will require RRT, 50% will die, and 10% will remain on dialysis. In other words, AKI that is bad enough to require nephrology input, still has a very high mortality

Definitions

Advances in understanding the epimiology of AKI have been hampered by the lack of a universal definition. More recently there have been a variety of definitions proposed.

RIFLE (Bellomo, 2004)

The Acute Dialysis Quality Initiative (ADQI) group, proposed the RIFLE criteria. It describes five stages of AKI: Risk: 1.5x rise in creatinine, or >25% decrease in GFR (or urine output <0.5 ml/kg/h for 6 hours) Injury: 2x rise in creatinine, or >50% decrease in GFR (or urine output <0.5 ml/kg/h for 12 hours) Failure: 3x rise in creatinine or creatinine >350 ?mol/l (with an acute rise of ?45umol/L) or >75% decrease in GFR (or urine output <0.3 ml/kg/h for 24 hours) Loss: persistent AKI or complete loss of kidney function for more than 4 weeks End-stage renal disease: complete loss of kidney function for more than 3 months

AKIN (Mehta, 2007)

The Acute Kidney Injury Network (AKIN) proposed the following definition for AKI An increase in serum creatinine ?26 ?mol/L within 48 hrs or 1.5-1.9 x rise from baseline creatinine (within 1 week) or Urine output <0.5 ml/kg/h for >6 hours

If these criteria are met the cause of AKI should be ascertained and staging can be performed Stage 1: increase in serum creatinine ?26 ?mol/L or 1.5-1.9 x rise from baseline or urine output <0.5 ml/kg/h for >6 hours Stage 2: 2-2.9 x increase in serum creatinine from baseline or urine output <0.5 ml/kg/h for >12 hours Stage 3: >3x increase in serum creatinine from baseline, or serum creatinine ?350?mol/L with an acute rise of at least ?45 ?mol/L, or initiation of RRT or urine output <0.3 ml/kg/h for >24 hours, or anuria ?12 hours

KDIGO
The Kidney Disease Improving Global Outcomes (KDIGO) international guideline group has most recently harmonised the AKIN and ADQI definitions An increase in serum creatinine ?26 ?mol/L within 48 hrs or 1.5-1.9 x rise from baseline creatinine (within 1 week) or Urine output <0.5 ml/kg/h for > 6 consecutive hours

If these criteria are met the cause of AKI should be ascertained and staging can be performed Stage 1: increase in serum creatinine ?26 ?mol/L or 1.5-1.9 x rise from baseline or urine output <0.5 ml/kg/h for > 6 consecutive hours Stage 2: 2-2.9 x increase in serum creatinine from baseline or urine output <0.5 ml/kg/h for >12 hours Stage 3: >3x increase in serum creatinine from baseline, or rise in serum creatinine ?350?mol/L, or initiation of renal replacement therapy (RRT) or urine output <0.3 ml/kg/h for >24 hours, or anuria ?12 hours

Aetiology Classification
AKI can be simply classified into 3 groups: pre-renal, intrinsic and post-renal. Pre-renal is due to ineffective perfusion of the kidneys that are otherwise structurally normal. Intrinsic renal AKI results from structural damage to the glomeruli and renal tubules. Post-renal is due to obstruction of the urinary tract anywhere from the calyces to the urethral meatus Prerenal AKI Prerenal AKI, is caused by underperfusion of an otherwise normal kidney. The hallmark of prerenal failure is that it is quickly reversible with appropriate therapy. Thus, it can be thought of as 'a good kidney looking at a bad world' Pre-renal AKI and ischaemic acute tubular necrosis occur on a continuum of the same pathological process and together account for approximately 95% of hospital-acquired and 75% of community-acquired AKI (Lamiere, 2005) Pre-renal AKI, in which the integrity of the renal tissue is preserved, is an appropriate physiological response to renal hypoperfusion associated with sepsis, hypovolaemia or cardiac failure (Prowle, 2009). Responses of the ageing kidney leave it more vulnerable to AKI. The kidney shrinks with age and with anatomical changes including: Cortical atrophy Decreased glomeruli Proximal tubule numbers Glomerular scarring Intimal thickening of renal arterioles Functional changes include a decrease in renal blood flow and in GFR. Baseline 'normal' GFR is not known but in one study, median eGFR (using the MDRD equation) decreased from 90100 ml/min (age 1824 years) to 6065 ml/min (age 85+ years) (Wetzels, 2007) Prerenal AKI is most often caused by volume depletion; eg caused are gastrointestinal fluid loss,

haemorrhage, poor oral intake, diuretic treatment, and 'third space' losses (eg pancreatitis). All of these cause 'true hypovolaemia'. Three other mechanisms can cause reduction in effective circulating volume ('pseudo-hypovolaemia'): poor cardiac output (heart failure), systemic vasodilatation and afferent arteriolar vasoconstriction (often for haemodynamic reasons relating to drugs). Further examples are listed below. The urinalysis is bland and the urinary sodium level is low, but urine osmolality is high - ie the body is trying to retain Na and water

Prerenal Failure
Volume depletion Renal losses (diuretics, polyuria) GI losses (vomiting, diarrhoea) Cutaneous losses (burns, Stevens-Johnson syndrome) Haemorrhage Pancreatitis ('third-space' loss, ie pseudo-hypovolaemia) Decreased cardiac output Heart failure Pulmonary embolus Acute myocardial infarction Severe valvular disease Abdominal compartment syndrome (tense ascites) Systemic vasodilation Sepsis Anaphylaxis Anaesthetics Drug overdose Afferent arteriolar vasoconstriction Hypercalcemia Drugs (NSAIDs, ACEi/ARBs, amphotericin B, calcineurin inhibitors, norepinephrine, radiocontrast agents) Hepatorenal syndrome Prerenal failure is often multifactorial, eg a patient may be septic and dehydrated post-operatively, on the background of a recent anaesthetic causing hypotension, and has just been given an NSAID. Therefore treatment of pre-renal failure has to address all these factors, eg IV fluids, adrenaline and antibiotics, and withdrawal of the nephrotoxic drug (NSAID). Treatment of all causes of prerenal AKI is imperative, because continued renal hypoperfusion can progress to intrinsic renal failure Note: none of these treatments will be effective, if the underlying problem is not addressed (eg the patient needs an operation) Drug causes The kidney responds to changes in renal perfusion pressure by closely regulating renal blood flow. A decrease in perfusion leads to dilatation of afferent glomerular arterioles mediated through

prostaglandins and vasoconstriction of efferent glomerular arterioles through angiotensin II thereby maintaining hydrostatic pressure in the glomerulus and adequate filtration. Drugs that interfere with this regulatory mechanism can precipitate AKI Acute inhibition of cyclo-oxygenase (type I or II) by non-steroidal anti-inflammatory drugs (NSAIDs results in decreased prostaglandins and an inadequate dilatation of the afferent arteriole. This loss of pre-renal blood flow leads to a decreased glomerular pressure and a reduced GFR is particularly common in these clinical situations: atherosclerotic cardiovascular disease in a patient older than 60 years, pre-existing chronic renal insufficiency, and states of renal hypoperfusion such as in sodium depletion, diuretic use, hypotension, and sodium-avid states such as cirrhosis, nephrotic syndrome, and congestive heart failure Hyperkalaemia, sometimes out of proportion to the degree of renal impairment, can occur when these patients are concomitantly treated with potassium-sparing diuretics, inhibitors of angiotensin-converting enzyme (ACE), or angiotensin-II-receptor blockers. There is little evidence that NSAIDs can acutely impair renal function in otherwise healthy individuals Drugs that block the action of Angiotensin Converting Enzyme (ACE-inhibitors and Angiotensin Receptor Blockers) cause inadequate constriction of the efferent arteriole resulting in decreased hydrostatic pressure across the glomerulus and a decreased GFR - especially in patients with stenosis of the renal artery in a solitary kidney or with bilateral renal-artery stenosis. But patients with hypovolaemia, severe CCF, polycystic kidney disease, or intrarenal nephrosclerosis without renal artery stenosis are also at risk. The frequency of AKI induced by ACE inhibitors varies between 5% and 20% in patients with bilateral renal-artery stenosis and increases to 40% in patients with unilateral stenosis in a single kidney

Intrinsic AKI
Once prerenal and postrenal causes are ruled out, intrinsic renal failure is likely. There are a number of different causes Acute tubular necrosis (ATN) Drugs (eg aminoglycosides, contrast nephropathy) Rhabdomyolysis (recreational drugs, alcohol, long lie), tumour lysis syndrome Acute glomerulonephritis/Vasculitis (eg Lupus nephritis, ANCA positive vasculitis) Interstitial nephritis (penicillins, cephalosporins, diuretics) Myeloma (should be actively excluded in all cases of AKI) Microangiopathic haemolytic anaemia (MAHA) (eg many causes including Haemolytic Uraemic Syndrome, HUS) Intrinsic AKI, ie disease of the renal parenchyma, has many causes. Acute Tubular Necrosis (ATN) is the commonest. However, disorders may involve the glomeruli, tubules, or interstitium. Glomerular disease reduces GFR and increases glomerular capillary permeability to proteins; it may be inflammatory (glomerulonephritis) or the result of vascular damage from ischaemia or vasculitis. Tubules also may be damaged by ischaemia and may become obstructed by cellular debris, protein or crystal deposition, and cellular or interstitial edema. Tubular damage impairs reabsorption of Na, so urinary Na tends to be elevated, which is helpful diagnostically. Interstitial inflammation (nephritis)

usually involves an immunologic or allergic phenomenon There are multiple processes that combine to result in ATN. These include a vascular component (intrarenal vasoconstriction, endothelial injury, microvascular disruption, vascular congestion in the outer medulla); and a tubular component (hypoxia and obstruction). New concepts such as sublethal cell injury, apoptosis, and cell repair after injury are emerging (see Lamiere, 2005) ATN is most often the consequence of untreated prerenal AKI (renal hypoperfusion and renal ischaemia). Other causes include various endogenous nephrotoxic substances (eg myoglobin and haemoglobin after trauma; cellular products in tumour lysis syndrome; crystals of uric acid, calcium, or oxalate) and a host of exogenous substances If a patient develops ATN, all medication (prescribed and non-prescribed) must be reviewed for the possibility of nephrotoxicity. It should not be assumed that the 'usual suspects' (eg ACE are the cause). There may be more than one drug cause. If in doubt, stop most or all drugs ATN usually behaves in a particular way with 3 phases: Prodrome. This phase, with usually normal urine output, varies in duration depending on causative factors. Urea and creatinine rise acutely Oliguria. In this phase, urine output is typically between 50 and 400 mL/day. It lasts an average of 10 to 14 days but varies from 1 day to 8 weeks. However, many patients are never oliguric. Non-oliguric patients have lower mortality and morbidity and less need for dialysis Recovery. In this post-oliguric phase, urine output gradually returns to normal, but serum creatinine and urea levels may not fall for several more days. Tubular dysfunction may persist and is manifested by Na wasting, polyuria (sometimes massive) unresponsive to vasopressin, and hyperchloraemic metabolic acidosis AKI secondary to glomerulonephritis is the least common cause of AKI but beware rapidly progressive glomerulonephritis/vasculitis as this requires urgent treatment. Myeloma is more common and should be excluded with the same degree of urgency as glomerulonephritis/vasculitis

Postrenal AKI
Postrenal AKI is caused by obstruction of the urinary tract. This may occur anywhere along the the urinary tract and includes: Prostate (malignancy, benign prostatic hypertrophy) Bladder (malignancy) Ureter (calculi, extrinsic compression) Pelvic tumour Obstructive nephropathy is more common in selected populations such as older men with prostatic disease and patients with a single kidney or intra-abdominal cancer, particularly pelvic cancer. Severe ureteral obstruction is also seen with small inflammatory aortic aneurysms; this type of obstruction can be successfully treated with corticosteroids when surgery is not an option. Most causes of postrenal AKI are amenable to therapy and the prognosis is generally good, depending on the underlying disease

Important clinical sequelae of postrenal AKI are postobstructive diuresis and the presence of hyperkalaemic renal tubular acidosis. Severe diuresis can occur after the release of the obstruction, especially if both kidneys, or a single functioning kidney, are completely obstructed. The period of total obstruction is short in most cases, a few days to a maximum of a week. Once the obstruction is relieved, the urine output generally ranges from 4 L to 20 L per day. This diuresis must be closely monitored as it can precipitate pre-renal AKI due to volume depletion, delaying renal recovery The development of hyperkalaemic hyperchloraemic tubular acidosis is indolent in most cases, and the abnormality tends to persist after correction of the obstruction. Patients in whom the hyperkalaemia is not corrected as their AKI is reversed, by treatment of the obstructive lesion, should be investigated for the presence of tubular acidosis The pathophysiology of obstruction nephropathy is complicated. It affects renal blood flow, initially increasing the flow and pressure in the glomerular capillary by reducing afferent arteriolar resistance. However, within 3 to 4 hours, the renal blood flow is reduced, and by 24 hours, it has fallen to < 50% of normal because of increased resistance of renal vasculature. Renovascular resistance may take up to a week to return to normal after relief of a 24 hour obstruction Renal ultrasonography, when used to detect obstruction, has a sensitivity and specificity of 90-95%. Unfortunately, it is also highly operator-dependent, so it should be performed by a highly experienced radiologist. Further information in Investigation Key point: a 'normal' renal US does not exclude obstruction, and dilatation (hydronephrosis) can occur without obstruction Treatment should focus on removing the obstruction. Techniques vary with the type of obstruction, but may include bladder catheterisation, nephrostomy and placement of urinary stents (either retrograde or antegrade)

Clinical Features
The differential diagnosis of AKI is extensive therefore history and examination should aim to

distinguish between pre-renal, intrinsic and post-renal causes An important skill is to recognise patients at risk of developing AKI. Consider recent events in the individuals history and highlight those that will put them at risk of AKI - especially the post-operative surgical patient who is volume depleted, potentially septic and on nephrotoxic drugs. And may have had a CT or angiogram before the operation Initially, weight gain and peripheral edema may be the only findings. Often, predominant symptoms are those of the underlying illness or those caused by the surgical complication that precipitated renal deterioration Later, as nitrogenous products accumulate, symptoms of uraemia may develop, including anorexia, nausea and vomiting, weakness, myoclonic jerks, seizures, confusion, and coma; asterixis and hyperreflexia may be present on examination Chest pain (typically worse with inspiration or when recumbent), a pericardial friction rub, and findings of pericardial tamponade may occur if uraemic pericarditis is present Symptoms of hypocalcemia are rare but may be profound in patients with rhabdomyolysis, apparently because of the combined effects of Ca deposition in necrotic muscle, reduced calcitriol production, and resistance of bone to parathyroid hormone (PTH). During recovery from ARF, hypercalcemia may supervene as renal calcitriol production increases, the bone becomes responsive to PTH, and Ca deposits are mobilized from damaged tissue Anuria Complete anuria is very rare, and has only three causes: Obstruction. Put a catheter in now Vascular catastrophe. Eg aortic dissection, or thromboembolism in a single kidney Acute severe glomerulonephritis/vasculitis Note: unless it is 1, and can be rectified simply, a consultant needs to see the patient ASAP

History
Prerenal AKI Symptoms related to hypovolaemia include increased thirst, decreased urine output and postural dizziness whilst simple causes of hypovolaemia are easy to explore diarrhoea, vomiting, haemorrhage and reduced oral intake Drug history is vital. If you are going to do ONE thing .. TAKE A DRUG HISTORY The past medical history is important, particularly looking for conditions such as ischaemic heart diasease, cerebrovascular disease, peripheral vascular disease and diabetes mellitus that would suggest renovascular disease. These risk factors are especially important for prerenal causes Intrinsic AKI

ATN is suggested by prolonged renal failure and hypotension, symptoms of sepsis, exposure to nephrotoxic drugs and situations with potential for muscle injury prolonged lying, seizures, alcohol and excessive exercise that may lead to rhabdomyolysis Ask about recent procedures such as angiography or CT scans that may have exposed the patient to nephrotoxic contrast Clues to glomerular disease include upper respiratory tract infection, rash, fever, haemoptysis and sore throat (post-streptococcal glomerulonephritis) whilst more systemic symptoms should be looked for in diseases such as Systemic Lupus Erythematous (SLE) and the vasculitides Postrenal AKI For post-renal AKI it is important to assess preceeding symptoms of prostatism (hesitancy, poor flow, dribbling and nocturia), lower abdominal pain, constipation and an inability to pass urine. Also look for symptoms suggesting covert malignancy such as weight loss and decreased appetite

Examination
A comprehensive physical examination is vital focusing on an accurate assessment of fluid status. The JVP is the most important sign in nephrology. If the patient has an obese neck, measurement of CVP should ve considered. Assess skin turgor, mucous membranes and closely monitor heart rate What is the blood pressure? A high or low temperature (>38C or <36C) with tachycardia or tachypnoea defines the systemic inflammatory response syndrome (SIRS) and evidence of infection should make you strongly consider sepsis as your underlying cause for AKI Systematically examine the different systems looking for complications of AKI such as pulmonary oedema, and causes of it (recent MI). A palpable bladder suggests a postrenal obstruction and necessitates a rectal examination looking for constipation and prostatic enlargement Remember that AKI can be a complication of many systemic conditions (or their investigation and treatment); therefore clues to aetiology will be given by thorough examination

Investigation
Urea, electrolytes and creatinine

In the early stages of AKI, serum creatinine levels may rise within the normal range despite a significant reduction in GFR - especially in an elderly patient, with poor muscle mass A progressive daily rise in serum creatinine is diagnostic of AKI. Serum creatinine can increase by as much as 200 mcmol/L/day (180 ?mol/L/day), depending on the amount of creatinine produced (which

varies with lean body mass) and total body water. A rise of >200 mcmol/L a day suggests overproduction due to catabolic causes of AKI including rhabdomyolysis and tumour lysis syndrome Estimating GFR from serum creatinine should not be done, because the rise in serum creatinine concentration is a delayed response to GFR decline Serum urea may increase by 3.5 to 7 mmol urea/L/day. But the urea level may be misleading because it is frequently elevated in response to increased protein catabolism resulting from surgery, trauma, corticosteroids, burns, transfusion reactions, parenteral nutrition or GI or internal bleeding Note: the fact that it is inappropriately raised in dehydration is useful, though, as a diagnostic tool New Biomarkers

Efforts to identify biomarkers to assist with the early diagnosis of AKI have yielded many promising candidates, such as KIM-1, NGAL, IL-18, Cys-C, clusterin, FABP, and osteopontin (Vaidya, 2010). None of these have reached clinical practice Blood Gases

Whilst sending blood samples to the laboratory, also take a sample to go through the blood gas machine. This allows rapid evaluation of pH, potassium and lactate all of which can signify the need for immediate intervention. Serum should be sent to haematology, biochemistry, immunology and microbiology. It is vital to know potassium level as soon as possible Other laboratory findings are progressive metabolic acidosis, hypernatraemia or hyponatraemia, and anaemia. Acidosis is normally moderate, with a plasma HCO3 content of 15 to 20 mmol/L. Serum K concentration increases slowly, but when catabolism is markedly accelerated, it may rise by 1 to 2 mmol/L/day. Inappropriately high or rapidly rising K suggests catabolic causes of AKI including rhabdomyolysis and tumour lysis syndrome Hyponatremia, if present, is usually moderate (Na 125-135 mmol/L) and correlates with a surplus of water. If hypernatraemic, sodium can be very high (>160 mmol/L), if dehydrated Haematology

Mild normochromic-normocytic anemia with an Haematocrit of 25 to 30% is typical. A rapidly falling or severe anaemia has three main causes: haemorrhage, myeloma and haemolytic uraemic syndrome (HUS)/thrombotic thrombocytopenia purpura (TTP). In the latter case, a blood film should also be sent Raised inflammatory markers, ESR or CRP, imply infection or an underlying systemic disorder whilst in Black patients a sickle cell screen should be performed Bone

Hypercalcaemia suggests myeloma, sarcoidosis (or TB) or malignancy Hypocalcemia is common and may be profound in patients with rhabdomyolysis, apparently because of the combined effects of Ca deposition in necrotic muscle, reduced calcitriol production, and resistance of bone to parathyroid hormone (PTH). During recovery from AKI hypercalcemia may supervene as renal calcitriol production increases, the bone becomes responsive to PTH, and Ca deposits are mobilised from damaged tissue Amylase, and Other 'False Positive' Tests Mild hyperamylasemia commonly is seen in AKI (2-3 times controls). Elevation of baseline amylase can complicate diagnosis of pancreatitis in patients with AKI. Lipase, which commonly is not elevated in AKI, often is necessary to make the diagnosis of pancreatitis. Pancreatitis has been reported as a concurrent illness with AKI in patients with atheroemboli, vasculitis, and sepsis from ascending cholangitis. Troponin T can also be falsely raised in AKI, complicating the diagnosis of myocardial disease Urine Tests

Urine dipstick should be done early. The presence of blood and protein is highly suggestive of glomerulonephritis or vasculitis whereas their absence almost excludes it. This sample should be sent for microscopy, culture and sensitivity. The presence of red cell casts is diagnostic of glomerulonephritis. Pyuria (the presence of white cells) is suggestive of urinary tract infection or tubulointerstitial nephritis Urine osmolality and electrolytes are helpful in distinguishing between pre-renal and intrinsic AKI. In intrinsic renal injury, there is an inability to concentrate urine. Therefore urine will be dilute (<300mOsm/kg) with a urinary sodium of <40 mmol/L. This compares to the concentrated urine of pre-renal kidney injury (>500mOsm/kg) (with increased sodium reabsorption), with a urinary Na of <10 mmol/L in a healthy adult, and <20 in the elderly. A urinary Na of 20-40 mmol/L is harder to interpret Other Tests

An ECG is important to look for changes of hyperkalaemia (absent p-wave, tall tented T-wave, wide QRS complex becoming sinusoidal) and those of pericarditis (diffuse saddle-shaped ST segments) A CXR is also important, looking for pulmonary oedema, pericardial effusion and pulmonary haemorrhage Renal Imaging After immediate investigation and initial management has been implemented, a renal ultrasound is indicated. Early identification of AKI secondary to obstruction is essential. Dilatation of any part of the renal tract will indicate obstruction whilst bilateral small kidneys suggest chronic renal disease Renal ultrasonography, when used to detect obstruction, has a sensitivity and specificity of 90-95%. Unfortunately, it is also highly operator-dependent, so it should be performed by a highly experienced radiologist

Note: the result of renal US should be known in no more than 24 hours ftom referral, preferably that day Furthermore, false positives and negative occur. For example, false-negative result can occur if the obstruction is caused by retroperitoneal fibrosis or certain malignancies that encase the entire system. It might also fail to detect an obstruction in extremely volume-depleted patients who do not have enough fluid buildup to reveal the obstruction. Conversely dilatation of the urinary can occur without obstruction (eg pregnancy, and in a transplant ureter) Key point: a 'normal' renal US does not exclude obstruction, and dilatation (hydronephrosis) can occur without obstruction In other words, non-dilated obstruction and non-obstructed dilatation, can occur. For thess reasons, specialist imaging techniques (eg cystoscopy and retrograde pyelograms) may be necessary. Then, if the diagnosis is still unclear, relieving the obstruction and seeing if renal function improves may be necessary Summary of Investigations

Haematology Full Blood Count - Eosinophilia (cholesterol emboli, vasculitis) - Thrombocytopenia (with normal clotting, HUS/TTP; with deranged clotting, DIC) ESR, CRP Clotting Venous/arterial (if ?hypoxic) blood gas Note: if you are going to do ONE test, do the VBG Biochemistry Urea and electrolytes LFTs (bilirubin raised in liver disease, and leptospirosis; low albumin in nephrotic syndrome, cirrhosis) Bone (hypercalcaemia in myeloma, sarcoidosis and malignancy) Glucose Creatinine kinase (rhabdomyolysis) Urine Dipstick (proteinuria suggestive of glomerular disease? infection?) Microscopy (infection?) Culture and sensitivity Other Chest xray (pulmonary oedema or haemorrhage) ECG (hyperkalaemia) Summary of Specialist Investigations (Selected Patients) Haematology Blood film (fragments in HUS/TTP and DIC; malarial parasites)

 Haemoglobin electrophoresis (sickle cell disease) Biochemistry LDH (raised in haemolysis, malignancy) Haptoglobins (reduced in haemolysis) Uric acid (raised in tumour lysis syndrome) Immunology Immunoglobulins (A, G, M) (IgA nephropathy, myeloma) Protein electrophoresis (myeloma) Serum free light chains (myeloma) ANA and dsDNA (SLE) Complement factors (C3 and C4): - Low C3 and/or C4 (SLE) - Low C4 (cryoglobulinaemia) - Low serum complement activity (CH50) (post-infectious GN, Type II mesangiocapillary glomerulonephritis, cryoglobulinaemia, infective endocarditis, 'shunt' nephritis) Anti-neutrophil cytoplasmic antibodies MPO and PR3 (ANCA) (vasculitis) Anti-glomerular basement membrane antibodies (AGBM) (Goodpastures Syndrome) Anti-streptolysin O titre (ASOT) (post-infectious glomerulonephritis). This is done to test for exposure to streptococci. It has poor specificity Angiotensin converting enzyme (ACE) (raised in sarcoidosis) Cryoglobulins Microbiology and virology Blood cultures Throat swab (post-infectious glomerulonephritis) Hepatitis B, C (cryoglobulinaemia, and transmission risk on haemodialysis), HIV (FSGS and increased risk of AKI on HAART) Urine Bence-Jones protein (myeloma) Sodium and osmolality Microscopy (sediment (red cell casts indicate glomerulonephritis); eosinophiluria (interstitial nephritis)) Leptospirosis, legionella Radiology Renal ultrasound Consultant decisions (minority of patients) Renal biopsy Renal angiogram Cystoscopy and retrograde pyelogram Occasionally CT-KUB (stones or sloughed papillae), CT abdomen or CT angiogram

Management
Principles of Management

Prerenal failure is often multifactorial, eg a patient may be septic and dehydrated post-operatively, on the background of a recent anaesthetic causing hypotension, and has just been given a NSAID. Therefore treatment of pre-renal failure has to address all these factors, eg IV fluids, adrenaline and antibiotics, and withdrawal of the nephrotoxic drug (NSAID). Treatment of all causes of prerenal AKI is imperative, because continued renal hypoperfusion can progress to intrinsic renal failure. None of these treatments will be effective, if the underlying problem is not addressed (eg the patient needs an operation) Key point: in terms of treatment, removing the nephrotoxic event or agent(s) - whether it a bleeding source, or drug - is often the most important intervention. This may be a drug, incorrect IV therapy, untreated trauma, bleeding or sepsis. If there is an abscess, does the patient need an operation? 'Where there is pus, let it out'

General Measures
Nephrotoxic drugs should be stopped. The dose of all drugs excreted by the kidneys (eg digoxin, some antibiotics) should be adjusted; serum levels are useful. Patients that need, or may need dialysis, should be transferred without delay to a renal ward (or ITU if unstable)

Fluid Balance If the patient is fluid overloaded, daily water intake is restricted to a volume equal to the previous day's urine output plus measured extrarenal losses (eg vomit) plus 500 mL/day for insensible loss. Water intake may need to be increased in a dry patient, especially if hypernatraemic Nutrition Na and K intake should be minimised in most patients with. Dont forget the importance of nutritional support to patients with AKI. They will often be hypercatabolic with high nutritional requirements. Elderly patients are at particular risk of malnutrition. An adequate diet should be provided, including daily protein intake of about 0.8-1 g/kg If oral or enteral nutrition is impossible, parenteral nutrition should be used. But it should be remembered in AKI, risks of fluid overload, hyperosmolality, and infection are increased by IV nutrition Calcium and Phosphate Calcium salts (carbonate, acetate) before meals help maintain serum phosphate at < 1.8 mmol/L

Urinary Catheter An indwelling bladder catheter is often needed, accepting the risks of UTI and urosepsis. It should be removed as soon as possible Treatment of Pulmonary Oedema Pulmonary oedema must be managed very carefully. It can be directly due to AKI but is often present because of over-zealous fluid resuscitation. Initially give supplemental oxygen therapy and sit the patient upright. Pharmacological therapy including loop diuretics (furosemide), opiates (morphine) and nitrates is the next stage of management. If the patient is refractory to these treatments then they will need dialysis Treatment of Hyperkalaemia Hyperkalaemia should be teated as needed with an IV infusion of 10 ml of 10% Ca gluconate (to stabilise the heart), and 50 mls of IV 50% dextrose, containing 10 units of insulin. Nebulised salbutamol 10mg is also used These drugs do not reduce total body K. They move K back into the cells. So further (but slower acting) treatment with 15-30g of oral or rectal Calcium resonium, to remove K from the body, is also needed If K is not controlled (<6.5 mmol/L) by two rounds of insulin/dextrose, dialysis should be considered Treatment of Metabolic Acidosis Metabolic acidosis is common in AKI. Correction of an anion gap metabolic acidosis with NaHCO3 is controversial. But small amounts of sodium bicarbonate can be given if serum bicarbonate falls below 15mmol/L but this should only be done under close supervision. When metabolic acidosis is not controlled by medical therapy, this is another indication for dialysis - especially if they are oligo-/anuric or fluid overloaded Treatment Aligorthym Once venous access is established, if the patient is dry, an intravenous fluid challenge should be commenced to increase renal perfusion. A measured approach to initial fluid replacement should be taken depending on the patients heart rate, blood pressure, capillary refill time and venous filling. Overzealous fluid replacement can lead to pulmonary oedema especially in those with a cardiac history Aggressive fluid replacement (over-zealous fluid replacement)? In a post hoc analysis of the Fluid and Catheter Treatment Trial (FACTT), which examined liberal versus conservative fluid management in intubated ICU patients, fluid balance and diuretic use were identified as prognostic factors for mortality in individuals with AKI (Grams, 2011). Specifically, greater cumulative fluid accumulation over an average of 6 days was associated with a higher mortality (10.2L vs 3.7L in the liberal vs conservative group), and higher furosemide use was associated with a lower mortality (cumulatively 562 mg vs 159 mg) Of note, more than one half of the individuals had Stage 1 AKI (AKIN criteria) CKD, so whether these results apply to more severe stages of AKI is not clear. One interpretation of this study is that patients who can be stabilised with less volume resuscitation fare better. From a practical standpoint, one conclusion is that aggressive prolonged volume resuscitation does not improve prognosis in AKI in

the ICU setting Note: careful rather than aggressive fluid replacement may be preferable. This contradicts standard renal dogma (give alot of fluids to a patient with prerenal failure) The failure of a response in urine output (minimum 0.5 ml/kg/hour) to the correction of hypovolaemia should make you consider an intrinsic or post-renal problem. If unsure, in the oliguric/anuric patient, pass a urinary catheter. If this produces a large residual volume then the patient has a post-renal problem. If the urinary catheter does not drain a significant volume of urine, then the diagnosis is either a pre-renal problem (that you have insufficiently corrected) or an intrinsic renal problem. Leave the catheter in-situ as accurate monitoring of urine output is vital Note: high dose loop diuretics have no effect on outcome (dialysis or death), but can 'buy time' my maintaining urine output and controlling pulmonary oedema) (Bennett-Jones D, 2006) (Bagshaw, 2007) If the patient does not improve with this approach, and life-threatening complications of AKI are still present (eg fluid overload and hyperkalaemia) dialysis should be started, either in the form of haemodialysis or haemofiltration (which is usually carried out on ITU). There is no evidence that one form of RRT leads to better results than another REF Urea and creatinine levels alone are not the best guides for initiating dialysis in AKI. In asymptomatic patients who are not seriously ill, particularly those in whom return of renal function is considered likely, dialysis can be deferred until symptoms occur (or K uncontrolled), thus avoiding placement of a dialysis catheter with its attendant complications. In these patients, daily bloods and senior review is necessary

Summary
Treat underlying cause Oxygenation Maintain BP Correct hyperkalaemia and metabolic acidosis Urinary catheter exclude obstruction and monitor urine output Does this patient need dialysis? Indications for Dialysis Pulmonary oedema unresponsive to medical treatment Hyperkalaemia (>6.5 mmol/L) unresponsive to treatment Metabolic acidosis (pH <7.2) unresponsive to treatment Pericarditis Encephalopathy Diuresis in Recovery Phase of ATN and Obstruction In many patients, a brisk and even dramatic diuresis after relief of obstruction or recovery of ATN, is a physiologic response to the expansion of ECF during early stage of AKI. In some patients, polyuria accompanied by the excretion of large amounts of Na, K, Mg, and other solutes may cause hypokalemia, hyponatraemia, hypernatraemia, hypomagnesaemia, or marked contraction of ECF volume with peripheral vascular collapse In this postoliguric phase, close attention to fluid and electrolyte balance is mandatory. When postoliguric diuresis occurs, replacement of urine output (with the correct fluid for the patient, eg

0.45% saline) at about 75% of the previous day's urine output prevents volume depletion Sepsis The prognosis of Sepsis-related AKI in the critically ill, is worse than non-sepsis related (Bagshaw, 2007). So, specific therapies should be considered in patients with sepsis-related AKI (Ronco C, 2008) Prevention (Lameire, 2003) AKI can often be prevented by maintaining normal fluid balance, blood volume, and BP in patients with trauma, burns, or major hemorrhage and in those undergoing major surgery. Infusion of isotonic saline and blood may be helpful. Use of contrast agents should be minimised, particularly in at-risk groups (eg the elderly and those with preexisting CKD, volume depletion, diabetes, myeloma or heart failure). However Katzberg (2010) has questioned the risk of AKI associated with contrast media If contrast agents are necessary, risk can be lowered by minimising volume of the IV contrast agent, using nonionic and low osmolar or iso-osmolar contrast agents, avoiding NSAIDs, and pretreating with normal saline at 1 ml/kg/h IV for 12 hours before the test. Isotonic NaHCO3 is used instead of normal saline in some patients. PO N-acetylcysteine 600 mg bd the day before and the day of IV contrast administration has been used to prevent contrast nephropathy, but reports of its efficacy are conflicting Before cytotoxic therapy is initiated in patients with certain neoplastic diseases (eg lymphoma, leukaemia), treatment with allopurinonol should be considered along with increasing urine flow by increasing oral or IV fluids to reduce urate crystalluria. Making the urine more alkaline (by giving oral or IV NaHCO3 or acetazolamide) has been recommended by some but is controversial because it may also induce urinary Ca phosphate precipitation and crystalluria, which may cause AKI The renal vasculature is very sensitive to endothelin, a potent vasoconstrictor that reduces renal blood flow and GFR. Endothelin is implicated in progressive renal damage, and endothelin receptor antagonists have successfully slowed or even halted experimental renal disease. Antiendothelin antibodies and endothelin-receptor antagonists are being studied to protect the kidney against ischaemic AKI

Prognosis and Follow-up

Although many causes are reversible if diagnosed and treated early, the overall survival rate of dialysis-requiring AKI remains high about 50%; perhaps because many patients with AKI have significant underlying disorders (eg sepsis, respiratory failure). Mortality may exceed 75% in patients with sepsis and critical illness. Conversely, the mortality of AKI that does not require dialysis is approximately 10%. Death in all these patient groups, is usually the result of these disorders rather than the renal failure itself Factors affecting prognosis Older age Pre-existing CKD Cause of AKI (eg sepsis)

 Multiorgan failure (ie, the more organs that fail, the worse the prognosis) Oliguria Hypotension Vasopressor support Number of transfusions Noncavitary surgery Studies suggest that of patients who have suffered AKI, approximately half will return to normal renal function, a third will have mild to moderate renal failure and about 10% do not recover and require dialysis (or transplantation), in the longterm All cases of AKI that are accepted by a renal service will require follow-up, within 4 weeks of discharge, by a nephrologist (or in some cases by the GP)

References
Articles Ali et al. Incidence and Outcomes in Acute Kidney Injury: A Comprehensive Population-Based Study. J Am Soc Nephrol 2007; 18: 1292-1298 Bagshaw SM et al. Loop diuretics in the management of acute renal failure: a systematic review and meta-analysis. Crit Care Resusc 2007; 9(1): 60-8 Bagshaw SM et al. Septic Acute Kidney Injury in Critically Ill Patients: Clinical Characteristics and Outcomes. CJASN 2007; 2 (3): 431-439 Bywaters EGI, Beall D. Crush injuries with impairment of renal function. BMJ 1941;1: 427-32 Bywaters EGL, Joekes AM. The Artificial Kidney: Its Clinical Application in the Treatment of Traumatic Anuria. Proc R Soc Med 1948; 41(7): 420426 Bellomo R et al (RIFLE). Acute renal failure definition, outcome measures, animal models, fluid therapy and information technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group. Critical Care 2004; 8: R204-R212 Bennett-Jones D. Early intervention in acute renal failure: Give intravenous fluids, not loop diuretics. BMJ. 2006; 333(7565): 406407 Cameron JS. Nephrologist extraordinaryMichael Darmady (19061989). Nephrol Dial Transplant 2007; 22 (3): 715-721

Cheung AK, Lysaght M, Bergstrom J. The Career of Lee W. Henderson. JASN 2002; 13 (Suppl 1, S1-S2) A description of the career of Lee Henderson Cheung MC, Ponnusamy A and Anderton JG. Management of Acute Renal Failure in the Elderly Patient: A Clinician's Guide. Drugs Aging 2008; 25(6) :455-76 Feest TG, Round A, Hamad S. Incidence of severe acute renal failure in adults: results of a community based study. BMJ 1993; 306(6876): 481-3 Grams ME, Estrella MM, Coresh J, Brower RG, Liu KD. Fluid Balance, Diuretic Use, and Mortality in Acute Kidney Injury. Clin J Am Soc Nephrol 2011; 6(5): 966-973 Henderson L, Besarab A, Michaels A, Bluemle LW Jr. Blood purification by ultrafiltra- tion and fluid replacement (diafiltration). Trans Am Soc Artif Int Organs 1967; 13: 216 Henderson L et al. Hemofiltration (1986) A long article/short book with a good historical section regarding the history of haemofiltration Hilton R. Acute renal failure. BMJ 2006; 333: 786 Katzberg RW, Jeffrey HN. Intravenous Contrast Mediuminduced Nephrotoxicity: Is the Medical Risk Really as Great as We Have Come to Believe? Radiology 2010; 256: 21-28 Kramer P, Kaufhold C, Grone HJ, Wigger W, Rieger D. Management of anuric intensive-care patients with arteriovenous hemofiltration. Int J Artif Organs 1980; 3: 225-230 Lameire et al. Prevention and nondialytic treatment of acute renal failure. Current Opinion in Critical Care 2003; 9: 481490 Lameire N, Wim Van Biesen W, Vanholder R. Acute renal failure. Lancet 2005; 365: 41730. This is a good review article Mehta RL et al (AKIN). Acute Kidney Injury Network: report of an initiative to improve outcomes in acute kidney injury. Critical Care 2007; 11: R31 Metcalfe et al. Acute renal failure requiring renal replacement therapy: incidence and outcome. QJM 2002; 95 (9): 579-583 Nash K, Hafeez A, Hou S. Hospital-acquired renal insufficiency. Am J Kidney Dis. 2002; 39(5): 930-6 Joslin J, Ostermann M. Care of the Critically Ill Emergency Department Patient with Acute Kidney Injury. Emerg Med Int 2012; 2012 Pannu N, James M, Hemmelgarn BR, Dong J, Tonelli M, Klarenbach S. Modification of Outcomes After Acute Kidney Injury by the Presence of CKD. Am J Kidney Dis 2011; 58(2) :206-13 Phu NH et al. Hemofiltration and peritoneal dialysis in infection-associated acute renal failure in Vietnam. N Engl J Med 2002;19; 347(12): 895-902

Prowle JR et al. Fluid balance and acute kidney injury. Nature Reviews Nephrology 2009; 6: 107-115 Ricci Z et al (RIFLE and AKIN). Classification and staging of acute kidney injury: beyond the RIFLE and AKIN criteria. Nature Reviews Nephrology 2011; 7: 201-208 Ronco C et al. Potential Interventions in Sepsis-Related Acute Kidney Injury. CJASN March 2008; (3, 2): 531-544 Schiffl H. Renal recovery from acute tubular necrosis requiring renal replacement therapy: a prospective study in critically ill patients. Nephrol Dial Transplant 2006; 21 (5): 1248-1252 Silverstein ME, Ford CA, Lysaght MJ, Henderson LW. The treatment of intractable fluid overload. N Engl J Med 1974; 291: 747 Smith HW. The Kidney: Structure and Function in Health and Disease. New York: Oxford University Press, 1951 Srisawat N, Kellum JA. Acute Kidney InjuryDefinition and Classification. 2009 A good review of definition and classification of AKI Vaidya et al. Biomarkers of acute kidney injury. Annu Rev Pharmacol Toxicol. 2008; 48: 463-93 Waikar SS and Bonventre JV. Creatinine Kinetics and the Definition of Acute Kidney Injury. JASN 2009, 20 (3): 672-679 Wetzels JFM et al. Age- and gender-specific reference values of estimated GFR in Caucasians: The Nijmegen Biomedical Study. Kidney Int 2007; 72(5): 6327 Guidelines Global/KDIGO. Acute Kidney Injury (AKI). March 2012 UK/GAIN. Northern Ireland Guidelines for Acute Kidney Injury (AKI). 2010 UK/NCEPOD. National Confidential Enquiry into Patient Outcome and Death (NCEPOD) Acute Kidney Injury: Adding Insult to Injury. 2009 UK/Renal Association. Acute Kidney Injury (AKI). Lewington A, Kanagasundaram S. 8.3.11 Websites Acute Dialysis Quality Initiative (ADQI) Acute Kidney Injury Network (AKIN) An account of AKI for junior doctors can be found in AcuteMed

The information provided in this pdf is only a guideline. It should not be used as a basis for the diagnosis or treatment of any medical condition. Your patient may be different

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