y r a t n e m e p p u S 5 2 g n d e e f . t e d i e l b a T l a r e t n E e t u o R i l : l a r O l a r o p i s AKI MANAGEMENT: NUTRITION 143 e s o l c . g n i r o t i n o m y r o t a r o b a l . c t e s e r i u q e r . n o i t c e f n : n o i t r e s n , x a r o h t o m u e n p : i i c i l r e t e h t a C r e t e h t a C o b a t e M t s i s s a t n e m e c a l p e r ) F H V V C . g n d e e f i l a n e r . y l w o l s . g e ( f . o y r e v i l s u o u n i t n o C s e u q n h c e t d e e f e d i t r a t S e h t y g r e n e n e v g y l n a m e r a o s t n u o m a i i a . y l l a u s u e r u s a e m m r e t - t r o h s e b a v ( l l a . s n e v n u r i w o n a c i t e e m l l a m y l l a r t n e c s i l . ) e n a l a r e h p i r e p o t n d e e f d n a t s u m N P T s s t n e m e r i u q e r . e v a h y l t n e r r u c n o c t o n o d a i l , y t i l a l o m s o e b i s s o p d e t a c d e d l a r e t n e l n e v g s d p i y e h T i i i l l l e b u F V f o f I a I i d n a e h t s a / g 1 \211 y l l a u s u ( s e t y l o r t c e e , , d e d d a e s o c u l g o t n e t f o r e t t a l y r o t a r i p s e r n , ) r e v i l . ) a m e a d p i 2 O C s e s u a c l a i t n e s s e l a i t n e s s e \200\231 y l l a n o i t i d n o c d e s u i y t t a f ( e r a l s a e r a i , s t n e m e e ) n n e v g i l r e p y h r e d n a m e r d e n b m o c g n i s a e r c n i ( s d p L e h t ( s i s e n e g o p i l u s n y a d / g k / g 5 > h g u o h t l a i i i i i y l l a p c n i r p l a i t n e s s e - n o n i l s e m . ) I K A a m e a c y l g r e p y h d o v a o t i e c a r t i i i l : s d c a i t e m o s e h t n o i t c u d o r p f , ) s d n a m e d . o t x e t n o c y r a s s e c e n i \200\230 , s n m a t i V e m o c e b e d v o r p : y g r e n E y a d / g k i o n m A i d n a ( i d n a l a r e t n e r a P CHAPTER 2 Acute kidney injury (AKI) 144 AKI management: myths Loop diuretics Theory. (i) i urinary \202 ow \200\230washes out \200\231 cellular debris, casts, and nephro- toxins from tubules; (ii) blockade of active t ransportation processes l d tubular O 2 consumption and protects against ATN; (iii) vasodil ator action l i RBF. Evidence. None to suggest improved renal or patient outcome in any AKI setting. In particular, the natural history and prognosis of ATN remains unchanged. Some s tudies have suggested harm . May increase diuresis, however, assisting the management of \202 uid balance and preventing pro- gressive volume overload. 2 Given as part of the treat ment of pulmo- nary oedema ( b p. 134). 1 The only indication for diuretics is volume overl oad. Mannitol An osmotic diuretic, previously used for the prevention of ATN in high-risk CV sur gery. A lack of evidence means the practice is in decline. Can para- doxically cause pulmon ary oedema through volume expansion. Avoid. Dopamine Previously widely used for the prevention and treatment of AKI. A lack of evidence for ef \201 cacy and potential risk of harm have led most to abandon this practice. You s hould do the same. Theory. Dopamine (DA) is synthesized in the proximal tubule from cir- cu lating L-dopa and helps regulate Na + excretion and renal vasodilata- tion through speci \201 c DA1 and DA2 receptors. Exogenously administered \200\230low-dose \200\231 dopamine should l renal vasodilatation l i RBF l i natriuresis and mild i GFR. All would be of pote ntial bene \201 t in AKI, although evi- dence suggests these mechanisms may not remain int act in renal insuf- \201 ciency. (See Table 2.6.) Table 2.6 Dopamine effects Micrograms/ kg/min Effect Selective DA (mainly DA1) receptor activation l i renal (and mesenteric) blood \202 ow Bo th DA and B 1 receptors are activated, the latter l i cardiac output (mainly by i SV). B 1 effect predominates. Starts to activate A adrenoreceptors. A adrenergic (vasoconstrictive) effect takes over with i SVR. 0.5 \200\223 3 3 \200\223 10 10 \200\223 20 >20 AKI MANAGEMENT: MYTHS 145 Evidence. Largely anecdotal or from inadequate studies. Larger trials (e.g. ANZICS) have fa iled to show bene \201 t. 1 It may cause harm : tachycardia, arrhythmias, myocardial ischa emia, blunted hypoxaemic drive, splanchnic vasoconstriction ( l bacterial translocation), d igital ischaemia, impaired pituitary function, electrolyte disturbances (even at \200\230r enal \200\231 dose), impaired T cell function. Dopamine accumulates in renal failure. Other \200\230renoprotective \200\231 agents Fenoldopam \200 Dopaminergic agonist that acts through DA1 receptors (without signi \201 cant A or B adrenergic activity) to produce afferent and efferent arteriolar vasodilatatio n. Preserves renal blood \202 ow and tissue oxygenation in animal studies. \200 Human stud ies (mainly small) have yielded variable results in several clinical contexts, including AKI prevention post-cardiac surgery. Larger randomized studies are awaited. In the meantime, fenoldopam use is not recommended in the KDIGO (2012) guideline. Atrial natriuretic peptides \200 ANP l d tubular Na + reabsorption, i afferent arteriolar vasodilatation, and d RAS activation. Tested in a post-surgical context in multiple studies, but overall quality of study evidence is variable and inconsistent. Can induce signi \201 cant, and potentially harmful, hypotension. \200 Other natriuretic peptides have been tried, e.g. brain natriuretic peptide (nesiritide) and urodilatin. Not recommended in KDIGO (2012) guideline. N-acetylcysteine \200 Most widely studied in the context of contrast-induced AKI ( b p. 150). NAC is a modi \201 ed form of the amino acid L-cysteine, a precursor of glutathione. NAC is a potent free radical scavenger and antioxidant that also possesses vasodilator prop erties (via nitric oxide availability). Shown to reduce ischaemic and nephrotoxic ATN in animal studies but clinical evidence lacking. Not recommended in KDIGO (2012) guideline. CHAPTER 2 Acute kidney injury (AKI) 146 AKI: hope for the future? Phases of ATN (see also b p. 108) There are four pathophysiologic al/temporal phases of ATN that can help to conceptualize where pharmacological intervention s might be targeted and applied. Initiation phase Characterized by aberrant vascular reactivity, diminished renal perfusion, and widespread oxidative injury. Extension phase A proin \202 ammatory state, with macrophage activation, in \202 ammatory medi- ator release, and stimulation of epithelial and endothelial cells. Maintenance phase Restoration of tubular cell integrity through the division of adjacent tu bu- lar cells and the differentiation of local (kidney) and systemic (haematopoi- etic \200\224 X ) stem cells. Repair phase Normal tubular cell function is restored. Very broadly speaking, therapeutic interventions can, therefore, attempt to decrease vascul ar reactivity, moderate in \202 ammation, preserve cell via- bility, and augment cell repa ir. Putative agents are shown in Table 2.7. Many of these are currently being studied in animal models of renal ischaemia-reperfusion injury, but bene \201 t in human AKI is yet to be d emon- strated. There are many potential reasons for this: AKI is a heterogeneous condition (both in terms of the type of patient affected and the underlying cause); study endpoints ( such as mortality) are often confounded, and, until recently, there was no agreed consensus de \201 nition of AKI. Furthermore, late detection of AKI prevents timely administration. It is hoped that novel AKI biomarkers will facilitate earlier intervention ( b p. 94). AKI: HOPE FOR THE FUTURE? 147 Table 2.7 Putative therapeutic strategies in AKI Pathogenic mechanism targeted Interventions currently of unproven bene \201 t in humans Ameliorate renal vasoconstriction Endothelin receptor antagonists (e.g. tezosentan) Leukotriene receptor antagonists PAF anta gonists iNOS antisense oligonucleotides Phosphodiesterase inhibition (e.g. milrinone) Haem- oxygenases Attenuate in \202 ammation Anti-ICAM-1 monoclonal Ab Anti-IL-18 monoclonal Ab N-acetylcysteine, desferrioxamine, and/o r other free radical scavengers A -MSH Adenosine Minocycline Corticosteroids Fibroblast gro wth factor-inducible 14 (Fn14) blockade Prevention of apoptosis and necrosis Erythropoietin (initial trials disappointing) Protease (e.g. caspase) inhibitors Guanosine Pi \201 thrin A (p53 inhibitor) PARP inhibition Prevention of tubular obstruction Diuretics RGD peptides Promoting tubular regeneration Insulin-like growth factor (IGF) Thyroxine Epidermal growth factor Hepatocyte growth factor Osteopontin Stem cell therapy (early studies with stem cells in high-risk patients undergo ing cardiac bypass surgery have been promising) PAF, platelet-activating factor; RGD peptides, peptides containing the arginine \200\223 g lycine \200\223 aspartic acid motif (involved in adhesion); ICAM-1, intercellular adhesion molecule-1; A -MSH, A -melanocyte-stimulating hormone; PARP, poly ADP-ribose polymerase. CHAPTER 2 Acute kidney injury (AKI) 148 Contrast-induced AKI (CI-AKI) Introduction CI-AKI accounts for 7 10% of in-hospital AKI and is associated with signi \201 - cant mortality ( x 5.5 odds adjusted risk of death), prol onged hospitaliza- tion, and future cardiovascular events. It may also irreversibly d GFR ( esp. in those with pre-existing CKD). These adverse outcomes are worse in those who require dialysis treatment (2-year mortality rate >80% in one study!). CI-AKI risk is low ( 7 1 \200\223 2%) in patients with normal renal function (even in the presence of diabetes) but much higher in patients with pre-existing renal impairment ( 7 25 %), particularly in the presence of additional risk factors (see Box 2.2 \200\224 these fa ctors are additive). Why is contrast toxic? \200 Direct toxicity: oxidant injury to proximal tubular cells. \200 Vasomotor effects: contrast (perhaps through its osmolality) alters afferent/efferent tone and thus glomerular perfusion. 2 AKI s to ATN results. Box 2.2 Risk factors \200 Pre-existing CKD. \200 Diabetes mellitus. \200 Hypertension . \200 Cardiac failure. \200 Volume depletion. \200 Haemodynamic instability. \200 i Age. \200 Hyperuricaemia. \200 Renal transplantation. \200 Concurrent nephrotoxic d rug administration. \200 High contrast volumes. \200 Intra-arterial contrast. Precautions \200 Speci \201 c measures are discussed on b p. 149. \200 Recognize those at risk (see Box 2.2). For ambulatory patients in whom a recent measurement of renal funct ion is not available, a simple questionnaire may identify those at increased risk. 4 , 5 \200 Dipstick proteinuria will also help identify individuals in whom measurement of renal function is desirable. 1 Many high-risk patients may not be suitable for \200\230day case \200\231 procedures. Is the procedure really necessary? Is there an alternative \200\230non-contrast \200\231 technique? Speak to your radiologist. \200 Use iso-osmolar, non-ionic contrast. \200 Mi nimize contrast volume (<100mL, if possible). \200 2 Optimize volume status pre-study. CONTRAST-INDUCED AKI (CI-AKI) 149 Stop all other nephrotoxins prior to procedure (including high doses of loop diuretics). X Although often undertaken, there is no evidence that cessation of ACE-I, ARBs, or metformin prior to contrast administration is protective. Space out multiple procedures whenever possible. \200 Inform your renal team of high-risk cases (beforehand!). Clinical features \200 d GFR begins immediately (although SCr may be unchanged initially) . \200 The earliest (and often only) sign may be oliguria ( 2 so ensure UO is being measured in high-risk hospitalized patients). i SCr at 12h is the best predictor of CI-AKI. \200 Peak SCr usually occurs at 2 \200\223 3d but can be delayed 5d in a minority of cases. In practice, CI-AKI often becomes apparent when renal function is rechecked the day after a procedure (so make sure it is checked and that you see the result ). Although rarely (if ever) measured, fractional urinary excretion of Na + often remains <1% (unlike other causes of ATN). This fact is useful for exam purposes only. Treatment \200 Once established, treat as for any other cause of ATN. \200 Ensure adequ ate hydration, and avoid additional nephrotoxins. \200 Standard indications for dialysis support apply ( b p. 172). Prognosis \200 In the majority, renal dysfunction is mild and transient (although still associated with i mortality). Recovery within a week is usual. Those with pre-existing advanced CKD are most susceptible to a permanent d GFR. Dialysis support will be necessary in 3 \200\223 4% of those with underlying CKD, and long-term renal replacement therapy will be required in the minority of these. Strategies to prevent RCN Hydration \200 IV \202 uids correct volume depletion and i RB F. They also minimize the pre-renal effects of a post-contrast diuresis. Evidence supporting their use is strong. Example regimens: 1.26% NaHCO 3 3mL/kg/h for 1h pre- and 1mL/kg/h for 6h during and post-procedure. 0.9% NaCl 1mL/kg/h for 12h pre- and 12h post-procedure. NaHCO 3 may have theoretical advantages over other IV \202 uids through an antioxidant effect (peroxynitrate scavenging), but this remains poorly de \201 ned and clinically unproven. Examine the patient \201 rst \200\224 if overtly dehydrated, then larger volumes may be required and the procedure may need to be postponed. If already volume-overloaded, then fur ther \202 uids are ill advised. Aim for a good urine output (>150mL/h). \200 In diuretic dependent patients, withholding diuretics may be suf \201 cient \200\230hydration \200\231. CHAPTER 2 Acute kidney injury (AKI) 150 X N-acetylcysteine (NAC) \200 Used for its antioxidant properties, always in conjunction with hydration. The evidence underpinning NAC use from randomized trials and meta-analyzes is inconsistent, with many actually suggesting no bene \201 t. NAC may d SCr independently of GFR through interference with tubular handling. Side effects are rare for the doses relevant to CI-AKI prevention (unlike those for paracetamol overdose); however, marginal effects on cardiac function and coagulation have been described. \200 A typical regimen is 600 \200\223 1200mg capsules PO 12h x 4 doses (generally two doses pre-contrast and two doses post). Despite the lack of compelling evidence, low cost and a favorable side effect pro \201 le have led to widespread use \200\224 as well as retention in several guidelines (although n ot KDIGO (2012)). Others \200 There has been interest in both theophylline (antagonizes adenosine-mediated d RBF) and fenoldopam (speci \201 c dopamine 1 receptor agonist), but c linical studies have been disappointing and their use is not recommended (although a recent meta-analysis has suggested there may yet be a role for theophylline. 6 Haemo \201 ltration/haemodialysis: \200\230prophylactic \200\231 removal of circulating contrast, particularly in those with advanced CKD. No convincing evidence of bene \201 t. Costly with signi \201 cant potential adverse effects. (See Fig. 2.14.) 2 All centers should have a locally agreed protocol, usually based on risk assessment and \202 uid 9 NAC administration. An algorithm produced by LAKIN is shown in Fig. 2.14. References 4. KDIGO. Available at: M < http://kdigo.org/home/guidelines/acute-kidney-injury / >. 5. Choyke PL, Cady J, DePollar SL, et al. (1998). Determination of serum creatinine pr ior to iodi- nated contrast media: is it necessary in all patients? Techniques in Urology , 4 , 65 \200 \223 9. 6. Dai B, Liu Y, Fu L, et al. (2012). Effect of theophylline on prevention of contrast-indu ced acute kidney injury: a meta-analysis of randomized controlled trials. American Journal of Kidney Diseases , 60 , 360 \200\223 70. CONTRAST-INDUCED AKI (CI-AKI) 151 Differential diagnosis Many patients undergoing invasive endovascular studies have diffuse ath- erosclerotic disease and are at risk of renal atheroemboli. These may occur as a disti nctive clinical syndrome ( b p. 590) but can often go unrecognized until the anticipated re covery of renal function fails to materialize. Contrast-induced nephropathy (CIN) prophylaxis Assess risk High volume (>100mL) iodinated contrast procedure and CKD with eGFR <60 (particularly diabe tic nephropathy) or AKI Other risk factors dehydration, heart failure, severe sepsis, cirrh osis, nephrotoxins (NSAIDs, aminoglycosides). Risk factors are multiplicative. Is contrast procedure necessary? Yes Resuscitate to euvolaemia Give prophylaxis if high risk Volume expansion (unless hypervolaemic) with normal saline or 1.26% bicarbonate Sample regimens IV Na bicarbonate 1.26% 3mL/kg/h for 1 hour pre-procedur e and 6 hours post-procedure or IV 0.9% normal saline 1mL/kg/h pre- and 12 hours post-proce dure Minimize contrast, use low or iso-osmolar contrast Monitor function to 72 hours in high-risk cases If oliguria or rising creatinine, early ref erral to local renal team. NB There is no proven role for N-acetylcysteine, post-contrast d ialysis/CVVH or routine cessation of metformin or ACE inbitors. Fig. 2.14 The LAKIN contrast-induced nephropathy algorithm. Reproduced from London AKI netw ork manual (2012), with permission. M http://www.londonAKI. net/clinical CHAPTER 2 Acute kidney injury (AKI) 152 Rhabdomyolysis Introduction First described as \200\230crush syndrome \200\231 during the London blitz of WWII. Rhabdomyolysis is a clinical syndrome caused by release of cellular con- tents after a signi \201 cant injury to striated muscle. Injury is caused by either energy depletion and cell death or, more commonly, during reperf usion of ischaemic muscle. In \201 ltrating leucocytes release oxidant species that cause myonecrosis. If cell death is widespread, intracellular elements and membrane products are released into the cir- culation: creatine kinase (mainly MM isoenzyme but also MB), LDH, my o- globin, purines ( l hyperuricaemia), electrolytes (esp. K + and PO 4 ), and aminotransfe rase enzymes. (See Table 2.8.) Myoglobin (Mb) The main nephrotoxin. A 19kDa weak O 2 carrier (similar to Hb but with a sin gle haem moiety), Mb is usually bound to plasma proteins. When in excess, the ferric form ( Fe 3+ ) is freely \201 ltered and concentrated l intralu- minal cast formation. Tubular d egradation generates highly toxic ferryl-Mb (Fe 4+ ), with direct oxidant tubular cell inju ry. A key feature of rhabdomy- olysis is the large quantities of \202 uid retained in in \202 amed muscle, causing profound hypovolaemia, in addition to toxic renal injury. 2 Not all rhabdomyolysis l AKI (particularly if you act quickly). Clinical presentation Variable, but the classical myalgia, weakness, and dark urine are rar e ( 7 50% have no muscle pain at presentation). Maintain high index of suspicion in relevan t clinical situation; initial clues: i ALT/AST, dipstick +ve haematu- ria, disproportionate i K + or PO 4 (see \200\230Investigations \200\231 section). 1 Examine the limbs carefull y \200\224 do not miss a compartment syndrome. Recurrent rhabdomyolysis after mild exertio n may suggest an underlying myopathy. Investigations \200 Dipstick cannot distinguish between myoglobin and hemoglobin. Classic ally, urine is dipstick +ve for blood but with no red cells on microscopy. 7 20% of patient s will have a \200\223 ve urinalysis. 2 Urinary myoglobin (u-Mb) is +ve (not present in normal urine). d u-Mb can be used to monitor treatment. U&E (SCr:Ur ratio often very high), i Alb if volume-deplete, or hypoalbuminaemia if capillary leak. i CK (better indicator of amount of muscle damage than likelihood of AKI). i ALT, AST, LDH. i K + ( 1 often i i ), i i PO 4 , i urate, i lactate, and i anion gap acidosis (organic acids). d d Ca 2+ , often with avid calcium sequestration in injured muscle. \200 Mild DIC freque nt ( d Plt, i D-dimers). \200 Consider toxicology screen for drugs, viral screen, TSH if cause not apparent. RHABDOMYOLYSIS 153 Table 2.8 Causes of rhabdomyolysis Physical causes Trauma (crush injury) Prolonged immobility Compartment syndrome Muscle vess el occlusion Sickle cell disease Shock and sepsis Excessive exertion Delirium tremens Elect ric shock Status epilepticus or asthmaticus Neuroleptic malignant syndrome Malignant hypert hermia Myopathies: Polymyositis/dermatomyositis McArdle s disease and other inherited myopa thies Drugs and toxins Alcohol, heroin, amphetamines, cocaine, and ecstasy Statins and \201 bra tes Antimalarials Zidovudine Snake and insect venoms Infections Pyomyositis and gas gangren e Tetanus, Legionella , Salmonella Malaria HIV, in \202 uenza, and Coxsackie Electrolyte a bnormalities: d K + , d Ca 2+ , d PO 4 , d Na + , i Na + Endocrine disorders: Hypothyroidis m Hyperglycaemic emergencies CHAPTER 2 Acute kidney injury (AKI) 154 Rhabdomyolysis: management Prevention of AKI In the early phase of the disorder, vigorous r esuscitation may protect patients from many of the subsequent complications. \200 Aim to resuscitate to euvolaemia: As much as 12L may be required/day (and more if severe injury). \200 Alternate 1L 0.9% Na Cl (or balanced crystalloid) with 1L 1.26 \200\223 1.4% NaHCO 3 . If the Na + load l i Na + , use 1L 5% dextrose or 1L 0.45% NaCl containing 50mL 8.4% NaHCO 3 to d total Na + load. Aim to maintain a UO \211 150mL/h or \211 300mL/h with traumatic injuries. \200 Conti nue therapy until disappearance of urinary myoglobin. Urinary alkalinization and mannitol X The role of urinary alkalinization (stabilizes oxidiz ing form of myoglo- bin) and forced diuresis ( i urine \202 ow l d tubular precipitation) remains controversial. 2 The priority is to volume-resuscitate the patient. \200 Aim for a target u-pH >6.5 by using alternating NaCl and NaHCO 3 , as described in previous sectio n, but increasing the frequency of NaHCO 3 as necessary. Evidence for a meaningful clinical impact is weak, and volume overload is a risk unless good UO. In addition, urinary alkalin ization can cause a signi \201 cant systemic alkalosis and 6 symptomatic d Ca 2+ . Loop diuretics acidify the urine and should be avoided. Mannitol, an osmotic diuretic, is preferred: give as a bolus (e.g. 12.5 \200\223 25g as a bolus (= 6 2.5 \200\223 125mL of 20% (200mg/mL) mannitol solution)) or as an infusion (10mL/h of 15 \200\223 20% mannitol). 1 Mannitol l i osmolar gap and may potentially worsen AKI. Supportive care \200 Standard indications for dialysis apply ( b p. 172), although i K + may occur early. Physiotherapy to debilitated muscles is essential. Prognosis \200 The prognosis is good if the causative insult is removed, and renal functi on will return to normal in the majority \200\224 even in those who require an extended pe riod of dialysis support. RHABDOMYOLYSIS: MANAGEMENT 155 Compartment syndrome in rhabdomyolysis \200 May occur in two circumstances: If the blood supply to particular limb has been compromised (immobility after drug overdose, seizures, etc.). Generalized muscle injury and in \202 ammation (toxic, viral). In \202 ammation and oedema within a closed muscle compartment l i intracompartment pressure l d O 2 delivery l myonecrosis. 2 Always examine the major muscle groups for the characteristic \200\230woody \200\231 consistency of an evolving/established compartment syndrome. Timel y fasciotomy in these circumstances may save limb function. If in doubt, compartmental pressure can be measured via the insertion of a needle with an a ttached tonometer. An intracompartment pressure >50mmHg with a normal BP, or 30 \200\223 5 0mmHg in hypotensive patients, is suggestive. If necessary, recheck every 6h. Hypocalcaemia Do not attempt to correct d Ca 2+ , unless it is symptomatic (tetany, arrhyth mias) \200\224 there is a risk the administered calcium will precipitate in injured muscle . Rebound hypercalcaemia is common during the recovery phase. 1 Symptomatic d Ca 2+ may com plicate NaHCO 3 administration. Haemoglobinuric AKI \200 Occurs in the context of massive intravascular haemolysis: Transfusion reactions (ABO incompatibility). \200 Falciparum malaria (blackwater fever, b p. 702). \200 Haemolytic anaemias (glucose-6-phosphate de \201 ciency (G6PD), drug-induced, autoimmune). Mycoplasma infection. \200 Snake, insect, and spider venoms. Free Hb does not enter the urine as freely as myoglobin, so AKI is relatively rare. Investigations d Hb, d haptoglobins, i bilirubin, i LDH, i K + ; urine is dipstick +ve for blood; plasma appears dark. Management Treat underlying disorder; volume resuscitation to establish a diuresis. CHAPTER 2 Acute kidney injury (AKI) 156 AKI in cirrhosis Introduction 7 25% patients presenting with AKI cirrhosis-associated ascit es will develop AKI within 1 year. The presence of AKI at the time of an admission increase s mortality 7 8 - fold, and >50% of patients will develop AKI during an inpatient episode. is common in cirrhosis. 3 Not all concomitant hepatic and renal impairment is due to the hepa- torenal syndrome (HR S); it is not even top of the list. Alternative diagno- ses may imply a better prognosis. A lways consider: \200 Sepsis l ATN (40% of AKI in cirrhotic patients). \200 Hypovolaemia (e.g. GI hemorrhage, diuretics) l ATN (30% AKI in cirrhotic patients). Nephrotoxins (drugs and i bilirubin l ATN). \200 Glomerulonephritis (e.g. MCGN 2 to hep atitis C). Hepatorenal syndrome HRS occurs in advanced liver dysfunction, usually cirrhosis, in conjun ction with ascites and portal hypertension. Often split into two types, based on: (i) rapid ity of onset, (ii) severity of AKI, and (iii) prognosis (see Table 2.9). Table 2.9 Classi \201 cation of HRS Type I AKI is the dominant clinical feature Rapid d GFR (SCr >221 mol/L (2.5mg/dL)) or CrCl fall ing to <20mL/min in less than 2 weeks) Progressive oligo-anuria (often profound) Median sur vival 2 weeks Type II Ascites (often refractory) the dominant clinical feature Protracted clinical course Renal i mpairment less acute and severe Can convert to type I Median survival 6 months Pathophysiology of HRS Liver disease is associated with marked splanchnic (and systemic) va sodilata- tion ( l arterial under \201 lling and d SVR), in part s to local excess NO and other vasodilator (e.g. adrenomedullin) production (caused by i shear stress in portal hype rtension). Also i bacterial translocation ( l peritoneal in \202 am- matory response) and i vasoactive gut peptides (e.g. glucagons, prostacyclin). As a result, the effective arteri al blood volume is sensed to have fallen, lead- ing to intense A adrenergic activity, s hyp eraldosteronism, ANP synthesis, and non-osmotic ADH release (hence salt and water overload) . Tubular V2 receptor activation causes a dilutional hyponatraemia. An increase in cardiac output attempts to compensate, but LV dysfunction eventually results. Excess catecholamine, angiotensin II, adenosine, thromboxane A2, and endothelin l profound and intense renal vas oconstriction ( l d RBF). AKI IN CIRRHOSIS 157 The kidneys remain structurally normal, and the renal impairment is entirely pre-renal in n ature \200\224 tubular integrity and function are preserved. Renal biopsies are normal (in practice, unnecessary and hazardous), and kidneys from HRS patients have been used success fully for transplantation. Clinical features \200 2 The diagnosis of HRS depends on exclusion of other causes of AKI . \200 Recognition can be dif \201 cult, as cirrhotic patients are usually malnourished, with signi \201 cantly d muscle mass ( 6 SCr may overestimate GFR). Urea may also be unhelpful (GI bleeding, low hepatic production 9 variable dietary protein intake). Cystatin C ( b p. 36) has 6 been used as an alternative. Other biomarkers ( b p. 94) are a waited. Signs of advanced liver disease: ascites (practically universal in HRS), stigmata of chronic liver disease, portal hypertension (beware GI bleeding!), encephalopath y, jaundice (degree variable), and coagulopathy. Cardiovascular: oedema (Na + and water retention) and d BP ( d SVR and effective circulating volume). 3 Infection: look carefully and regularly for evidence of sepsis ( 1 pneumonia, line infections, and spontaneous bacterial peritonitis). Electrolyte disorders: dilutional d Na + is almost universal. \200 Nutritional state: usu ally poor and deteriorating. \200 Urine output: oligo-anuria the norm in type I HRS, with urine volumes decreasing as the condition progresses. Anuria is an ominous sign. Urinalysis bland, with no proteinuria/haematuria. \200 Tubular function is preserved, so the kidneys excrete concentrated urine that is low in Na + (<10mmol/L) (i.e. indistinguishable from other pre-renal AKI). He avily emphasized in the past but no longer included in diagnostic criteria. Normal renal ultrasound/imaging. Renal Doppler can detect i vascular resistance (elevations predict HRS in cirrhotic patients). Box 2.3 HRS: diagnostic criteria \200 Acute or chronic liver disease with advanced hepati c failure and portal hypertension. Renal impairment: serum SCr \211 133 mol/L (1.5mg/dL). \200 Absence of hypovolaemia: no improvement in renal function after diuretic withdrawal and appropriate volume expansio n with IV albumin (1g/kg/d). Absence of other alternative explanations for d GFR, particularly nephrotoxic drugs and sepsis ( 2 spontaneous bacterial peritonitis). \200 Absence of intr insic renal disease: proteinuria <500mg/d, urine RBCs <50 cells per hpf (with no urinary catheter), normal renal USS. After Arroyo V, et al . (1996). De \201 nition and diagnostic criteria of refractory ascit es and hepatorenal syndrome in cirrhosis. International Ascites Club. Hepatology , 23 , 164 ; and Salerno F, et al (2007). Diagnosis, prevention and treatment of hepatorenal syndrome in cirrhosis. Gut, 56 , 1310. CHAPTER 2 Acute kidney injury (AKI) 158 Management of HRS Risk factors \200 Cirrhosis + ascites = 40% 5-year probability of HRS. \200 Large volume (>5L) paracentesis without concurrent plasma expansion. ( X Give 100mL 20% human albumin per 1.5L ascites removed.) GI bleeding (variceal bleeding is a common precipitant). \200 Overdiuresis (possibly \200\224 see Box 2.3). \200 Sepsis: especially spontaneous bacterial peritonitis (SBP) ( 7 20% will develop HRS). 2 Any cirrhotic patient with ascites should be assumed to have SBP until proven otherwise. The administration of IV albumin 1.5g/kg at diagnosis of SBP and 1g/kg 4 8h later, in addition to antibiotics, appears to decrease HRS risk. Surgery. Managing established HRS 2 Seek expert help early. \200 Volume assessment: IV 20% albumin (salt-poor) for volume expansion (e.g. 0.5 \200\223 1g/kg/day or aiming for CVP of 5 \200\223 10cmH 2 O). Na + restrict (80mmol/24h) and \202 uid restrict (<1L/24h) if overloaded. Culture blood, urine, and ascites. Empirical IVI cefotaxime 2g tds for suspected SBP ( 1 ad justed for renal function). Discuss with microbiology. Consider therapeutic paracentesis if tense ascites with intravesical pressure >30cmH 2 O ( i intra-abdominal pressure transmitted to kidneys ( i renin release, d GFR) and ureters (re lative obstruction)) ( b p. 162). Speci \201 c rescue therapies \200 Vasoconstrictors l constrict the splanchnic bed l imp rove circulatory (and 6 renal) function. Given in combination with IV albumin. Aim for MAP >75mmHg. \200 Vasopressin analogs (act via splanchnic V1 receptors), e.g. terlipressin (initially 0.5 \200\223 1mg/4 \200\223 6h IVI). Bene \201 ts: d SCr, i UO, i MAP, and improved early survival. Physiological bene \201 ts seen early and often persis t. Repeat courses can be effective. 1 Side effects: ischaemia, e.g. digital, cardiac, mesen tery. Terlipressin is not available in the USA. Noradrenaline (0.5 \200\223 3mg/kg/h) is an alternative. \200 Midodrine (7.5 \200\223 1 2.5mg PO tds), a selective A 1 agonist, may be given in combination with the somatostatin a nalog octreotide (100 \200\223 200 micrograms SC tds). Aim to i MAP by 15mmHg. Bene \201 ts include improved survival although probably less effective than vasopressin analogs. MANAGEMENT OF HRS 159 Transjugular intrahepatic portosystemic shunts (TIPS) may improve SCr in selected patients (esp. those with refractory ascites and variceal bleeding). Howeve r, there is a 5% incidence of de novo AKI post-TIPS. N-acetylcysteine may have additional bene \201 ts and remains under study. Renal replacement therapy \200 1 RRT does not improve outcome in HRS and should be viewed as a bridge to liver transplantation in this context. 2 However, AKI in a cirrhotic patient is not always s to HRS and may 6 be reversible. Dialy sis treatment should not be withheld in these circumstances. Standard indications apply ( b p. 172), although volume overload is the usual precipitant in this group. Continuous RRT techniques ( b p. 174) may be better tolerated (less haemodynamic instability, slower correction of d Na + , and less \202 uctuation in intracranial pressure) than intermittent HD. It has been hoped that arti \201 cial hepatic assist devices can be developed, following t he same general principles as dialysis for renal failure; for exam- ple, the molecular adso rbent recirculating system (MARS) is an extracor- poreal technique in which dialysate is ci rculated through charcoal and anion exchanger columns (removing potential HRS mediators, e. g. TNF, IL-6, and NO). Unfortunately, the diverse metabolic functions of the liver have pro ved dif \201 cult to replicate, and results have been disappointing. Technologies under cu rrent development are based on the use of various hepatocyte cell lines to deliver syntheti c liver capacity. Liver transplantation The most (only?) effective therapy of HRS, although many patients die before transplantation is possible. Organ allocation differs between countries, but, in ma ny scoring systems (e.g. MELD), HRS patients are afforded high priority. 7 40% patients admitted for liver transplantation have AKI by RIFLE criteria, and 7 70% dev elop AKI post-operatively (the majority of these will require renal replacement therapy). improves outcomes post-transplantation, although patients with pre-transplant renal impairm ent have d long-term survival, compared with those with a normal GFR. Treatment of HRS pre-transplantation Most patients will have improved renal function after they have recov- ered from surgery, a lthough the majority do not regain a normal GFR ( 7 10% incidence of ESRD at 11 years). Combined liver kidney transplantation is an option in selected patients. CHAPTER 2 Acute kidney injury (AKI) 160 Tumor lysis syndrome Tumor lysis syndrome (TLS) usually occurs at initiation of treatment ( chemo- or radiotherapy, or even corticosteroids) of lymphoproliferative (and, less commonly , solid) malignancies but may occur spontaneously, with a large tumor burden, or at later s tages of treatment. Classically, it is a complication after chemotherapy for high-blast cou nt acute lymphocytic leukaemias, lymphoma, myeloma, or germ cell tumors. It results from treatment-induced necrosis of large numbers of purine-rich (actively prolif erating) malignant cells, with intracellular and membrane products released abruptly into t he circulation. Uric acid, in particular, causes AKI. (See Table 2.10.) Table 2.10 Criteria for laboratory and clinical diagnosis The Cairo \200\223Bishop de \201 nition (2004) \211 476 mol/L (8mg/dL) or 25% increase Uric acid \211 6.0mmol/L or 25% increase Potassium \211 1.45mmol/L or 25% increase Phosphate Calcium <1.75mmol/L or 25% decrease \211 2 of these features between 3 days pre- and 7 days post-tumor treatment encompasses the laboratory de \201 nition. A clinical diagnosis of TLS can be made if AKI, arrhythmias, or seizures occur in conjuncti on with the laboratory features. Cairo MS, Bishop M (2004). British Journal of Hematology , 127 (1), 3 \200\223 11. Acute uric acid nephropathy Uric acid is freely \201 ltered and, in excess, precipitates in the tubular lumen to form obstructing crystalline casts. This is more likely in volume-d eplete patients with low urinary \202 ow rates or if u-pH d . Clinical \201 ndings In the context of recent cancer therapy, symptoms and signs are due to electrolyte abnormalities ( 3 i K + and dysrhythmias) and AKI. TLS usu- ally occurs with in 24 \200\223 48h of treatment. Nausea, vomiting, anorexia, mus- cle cramps, and \202 a nk pain may also be present. Investigations Measure the following pre- and 4 \200\223 6h post-therapy and serially 6 \200\223 12h. \200 i K + : often rapid i to >7mmol/L. \200 i PO 4 and d Ca 2+ : phospha te avidly binds calcium, precipitating hypocalcaemia and calcium phosphate deposition in the vasculature, myocardium, and kidney. d Mg 2+ . \200 i uric acid: purine nucleotides are metabolized to hypoxanthine, xanthine, and then uric acid, often rising to >1000 mol/L ( 18mg/dL). i SCr. \200 i LDH. \200 Urinary urate measurement and microscopy for crystals rarely ne eded. tumor LYSIS SYNDROME 161 Prevention \200 Identify at-risk patients. Algorithms to assist this risk assessment have been developed. These are based on tumor type, disease burden, and presence or absence of r enal impairment. They stratify patients to low, intermediate, or high risk. Local protocols may vary. Pre-hydration: 0.9% NaCl or glucose saline 2 \200\223 3L/m 2 ( 7 4 \200\223 5L/d) for 48h pre- and post-therapy. Aim for UO >3L/d (preferably >2mL/kg/h). 1 Beware volume overload i f renal or cardiac impairment. Diuretics may be used cautiously to maintain urine \202 ow unless persistent hypovolaemia. Prevent uric acid formation: If risk low to moderate: allopurinol PO 100mg/m 2 8-hourly (max 800mg/d) from 2 days prior to therapy ( 1 reduce dose by 50% if renal impairment). Inhibits xanthine oxidase and preve nts the metabolism of hypoxanthine to xanthine (and then uric acid and its salt urate). IV allopurinol is available if oral medication not possible (200 \200\223 400mg/m 2 /day in 1 \200\223 3 divided doses \200\224 maximum 600mg/day). If high-risk for TLS, pre-emptive rasburicase (see below). Treatment of established tumor lysis \200 Laboratory tests every 4 \200\223 6h. Cardiac monitor. Consider ITU transfer. \200 2 Beware i K + . \200 2 Beware d Ca 2+ induced by i PO 4 . Correct i PO 4 \201 rst to avoid systemic calcium phosphate precipitation. Parenteral calcium should only be administered if evidence of neuromuscular instability and then with extreme caution. Continue volume expansion with 0.9% NaCl, and maintain high UO. \200 Continue allopurinol . \200 X Alkalinize the urine: 50mL 8.4% NaHCO 3 in 1L 0.45% NaCl or 5% glucose (dependin g on sodium load and serum Na + ), aiming for u-pH >7.0. i u-pH converts uric acid l more s oluble urate salt, although simply maintaining adequate UO may be as effective. 1 In additi on, alkalosis may promote systemic calcium phosphate deposition (shifts ionized calcium to non-ionized form), so many have abandoned this practice (unless severe concomitant metaboli c acidosis). Rasburicase: A recombinant form of the enzyme urase oxidase that occurs in