Cystatin C A 13kDa cysteine protease inhibitor produced by all nucleated human cells and re leased into plasma at a constant rate ( b p. 36). Freely \201 ltered in glomeruli and com pletely reabsorbed in the proximal tubule. Detectable in urine 12 \200\223 24h after renal injury. Results confounded by systemic in \202 am- mation, malignancy, thyroid disorders, smoking, glucocorticoid de \201 ciency and excess. BIOMARKERS OF AKI 95 Interleukin-18 An 18kDa proin \202 ammatory cytokine. Released from proximal tubular cells . Rises 6 \200\223 24h after renal injury. Confounders: in \202 ammation, sepsis, cardiac failure. Kidney injury molecule-1 (KIM-1) A transmembrane glycoprotein, produced by proximal tubular cells after ischaemic or nephrotoxic injury (it sheds an extracellular domain that can be measured in urine). No systemic source. Rises 12 \200\223 24h after renal injury. Confound ers: renal cell carcinoma, adult polycystic kidney disease, chronic proteinuria. N-acetyl- B -D-glucosaminidase (NAG) A lysosomal enzyme (>130kDa), produced in many cells, including proxi- mal and distal tubular cells. Detectable in urine 12h after tubular injury. Retinol-binding protein (RBP) A 21kDa single-chain glycoprotein. Undergoes glomerular \201 ltration before reabsorption by proximal tubular cells. Detectable in urine within 12h . Liver-type fatty acid-binding protein (L-FABP) A 14 kDa intracellular lipid chaperone, prod uced in various organs as well as proximal tubular cells. Freely \201 ltered by glomeruli and reabsorbed in proximal tubular cells. Detectable in urine within 1h, i.e. soon after i njury. A glutathione S-transferase ( A GST) and glutathione S-transferase 47 \200\223 5 1kDa cytoplasmic enzymes, produced in distal tubular cells. Urinary levels increase within 12h. Other promising biomarkers Urinary insulin-like growth factor-binding protein 7 (IGFBP7) an d tissue inhibitor of metalloproteinases-2 (TIMP-2) are both markers of cell cycle arrest. Several microRNAs (ribonucleotides that regulate gene expres- sion) are upregulated during AKI, e.g. miR-210. Proteomic pro \201 ling and other techniques have identi \201 ed many other candidates, including the Na + /H + exchanger (NHE3), perforin, granzyme B, and monoc yte chem- oattractant protein (MCP)-1. It is hoped that combining biomarkers into an \200\230AKI panel \200\231 will further improve sensitivity and clinical utility. Idealized SCr KIM-1 s l e v e IL-18 l e v i t a l e R Fig. 2.1 Temporal relationship of studied AKI biomarkers to injury. The characteristics of an ideal biomarker are also shown. NGAL L-FABP 0 10 20 30 Time (hours) 40 CHAPTER 2 Acute kidney injury (AKI) 96 Causes and classi \201 cation Introduction \200 It is crucial to remember that AKI is neither a diagnosis nor a disease . Rather, it is a clinical syndrome that is caused by, or complicates, a wide range of diso rders. (See Fig. 2.2) The introduction of the new nomenclature has propagated a tendency for AKI to be conceptual ized as a \200\230standard \200\231 or homogenous disorder. While this may have bene \201 ts, clinical practice must always re \202 ect the heterogeneity and complexity of the syndrome and its context. The goals are to: (i) identify patients earlier \200\224 when simple interventions may make an important difference to outcome; (ii) consider the multiple possi ble causes of renal injury; (iii) anticipate complications before they arise. Three dependable clinical syndromes can be used to help categorize AKI and 6 to direct diag nosis and therapy. Pre-renal AKI \200 d renal blood \202 ow (RBF) l d GFR. \200 d RBF may be s to hypovo laemia per se, d effective RBF ( d cardiac output, vasodilatation in sepsis), or intrarenal vasomotor changes (e.g. NSAIDs and ACE-I). Potentially reversed by restoration of RBF. \200 Kidneys remain structurally normal. Intrinsic renal AKI \200 The renal parenchyma itself sustains damage through injury to th e renal vasculature, glomerular apparatus, or tubulointerstitium. The commonest cause (by far) is acute tubular necrosis (ATN), itself the end-product of an ischaemic or a nephrotoxic injury ( b p. 106). The diagnosis of ATN implies: Glomerular, vascular, and other interstitial diseases are not responsible for AKI. Be cautious; these disorders often require speci \201 c treatment, an d a delay in their diagnosis can have signi \201 cant consequences for long-term kidney fu nction. They may also coexist with ATN. 2 Seek expert help if you are uncertain. Recovery of renal function should occur if supportive measures are adequate (so make sure that they are adequate). A potentially reversible phase has passed during which ATN may have been avoided. Post-renal AKI \200 The kidneys produce urine, but there is obstruction to its \202 ow. \200 i back pressure l d tubular function. \200 Obstruction may occur at any level in the urinary tract. \200 AKI results when both kidneys are obstructed or when there is obstruction of a solitary kidney. Obstruction eventually causes structural (and 6 permanent) damage. CAUSES AND CLASSIFICATION 97 n o i t c u r t s b o n o i t c u r t s b o t e l t u o r e d d a l B \200 s g u r d l a n e r - t s o P l a r e t e r u t s a r t n o c o d a R \200 c x o t o r h p e N \200 i n o i t c u r t s b O s u o n e g o x E l a r e t a l i c x o t o r h p e N i i B \200 N T A c m e a h c s I i s l a t s y r c a i r u n b o l g o m e a H \200 s t s a c a i r u n b o l g o y M \200 e t u c A N T i r a l u b u t a r t n I s u o n e g o d n E i a m o e y M \200 l l a n e r I I K A c i s n i r t n e t u c A N G I . y r u n j i y e n d k s e h t a p o g n a o r c m i i e v i s n e t r e p y H \200 s e c n e g r e m e c i t o b m o r h T \200 e t u c a i i s i t i l r a l u c s a V u c s a V \200 f o s e s u a c i r o a m d n a j e m u o v n o i s u l c c o / s i s o n e t s l n o i t a c \201 i s s a l C g n i t a l u c r i c t u p t u o c a d r a c w o L n o i t e p e d l a n e r - e r P e g a h r r o m e a H \200 l s B R A r o t o m o s a V \200 i s i s o h r r i C \200 e v i t c e f f E s D A S N \200 e m u o V \200 / I - E C A \200 s i s p e S l a i r e t r A 2 2 I F C C \200 . l . g i F d CHAPTER 2 Acute kidney injury (AKI) 98 Prevention of AKI 3 Many cases of AKI can be prevented or reversed at an early stage. Who is at risk? \200 i age. \200 Pre-existing CKD: i SCr, d eGFR, or proteinuria. Surgery (esp. if with another risk factor): Trauma and burns surgery (hypovolaemia, sepsis, myoglobinuria). \200 Cardiac surgery (poo r LV function, intra-operative haemodynamic instability, cardiopulmonary bypass, use of aprotinin). Vascular surgery (e.g. suprarenal aortic cross-clamping) and endoluminal intervention (e.g. an endovascular stent occludes a renal artery ori \201 ce) can disturb renal perfusion 9 cause atheromatous emboli to kidneys). Pre or intra-operative contrast administration. Risk of emergency AAA repairs > elective (25% vs <5% AKI). Hepatic and biliary surgery (over 70% of hepatic transplants complicated by AKI); biliary surgery also high risk. Diabetes mellitus (esp. if established diabetic nephropathy with d eGFR). Volume depletion (NBM, bowel obstruction, vomiting, burns). \200 LV dysfunction and other cardiac disease. \200 Other causes of d effective arterial volume (cirrhosis). \200 Dr ugs that cause renal vasomotor changes (NSAIDs, ACE-I, ARB). \200 Hyperbilirubinaemia and frank jaundice. \200 Multiple myeloma ( X may just be that these patients are often dehy drated, with a degree of renal insuf \201 ciency to start with). Precipitation of casts wi th tubular injury is the concern ( b p. 622). Common nephrotoxins (see b p. 898) The kidneys are particularly susceptible to nephrotoxic injury because of their rich blood supply and a propensity to concentrate toxic substances within their cortex. \200 NSAIDs (including COX-2 inhibitors). \200 Diuretics, ACE-I, A RB (esp. in volume-depleted patients). \200 Antimicrobials: aminoglycosides, vancomycin, amphotericin (lipid preparation is ONLY 7 50% less nephrotoxic and may still cause AKI). Immunosuppressants (e.g. ciclosporin, tacrolimus) and chemotherapeutic agents (e.g. cisplatin). IV contrast ( b p. 148). Using nephrotoxic drugs 1 Recognizing the potential for nephrotoxi city is the critical step: \200 Is it a de \201 nite indication? \200 Is there a thera peutic alternative? \200 Have all precautions to d toxicity been undertaken (e.g. hydrati on)? \200 Have you arranged for renal function to be monitored closely? \200 Is therape utic drug monitoring necessary (e.g. gentamicin/vancomycin)? PREVENTION OF AKI 99 Reducing AKI risk perioperatively Three principles 1. Avoid dehydration. 2. Avoid nephrotoxins ( 1 contrast, NSAIDs, aminogly cosides). 3. Review clinical (esp. volume) status and renal function if at risk. Optimize volume status preoperatively: No patient should ever go to theater dehydrated. \200 Review daily weights, chart input/o utput; check postural heart rate and BP. Calculate losses, esp. in patients NBM. \200 1 CVP: intermittent measurement does not cor respond to volume status in many studies. Seek expert help prior to undertaking. IV \202 uid replacement l use balanced crystalloid solutions unless hyperkalaemic and/or anuric (seek expert help if present) (GIFTASUP guidelines). 1 Optimize blood sugar control in diabetics ( l sliding scale). \200 Optimize nutrition (wi th par/enteral nutrition, if indicated). \200 Consider bladder catheter for those with pr ostatic disease. \200 Avoid surgery, if possible, immediately after a contrast procedure. \200 Stop antihypertensives (esp. diuretics, ACE-I/ARB) for 24 \200\223 48h, as BP allows. Find out how the procedure and patient progressed in theater. Check intraoperative records for blood loss and \202 uid and drugs administered. Review the patient early post-op. Consider need for level 2 and 3 care. There is no role for dopamine, furosemide, or other diuretics in the prevention of perioperative AKI. 1 M http://www.bapen.org.uk/pdfs/bapen_pubs/giftasup.pdf CHAPTER 2 Acute kidney injury (AKI) 100 STOP AKI checklist The London AKI network (LAKIN) is a regional collaborative that aims to collate available evidence, clinical standards, and national guidelines into accessible pra ctical advice and well-de \201 ned clinical pathways. The guidelines are designed for those managing AKI in general ward areas and aims to facili tate the interaction between general wards, local critical care teams, and regional kidney unit services. (See Fig. 2.3) LAKIN advocates the following STOP ( S epsis; T oxicity; O bstruction; P arenchymal disease ) checklist to help improve awareness of the causes of AKI. \200 Sepsis and hypotension: \200 Severe sepsis. \200 Hemorrhage. \200 Dehydration. \200 Cardiac failure. \200 Liver failure. \200 Renovascular insult. Toxicity: Nephrotoxic drugs. \200 Iodinated radiological contrast. Obstruction: Bladder out \202 ow. \200 Stones. \200 Tumor. \200 Surgical ligation of ureters. \200 Extrinsic compression (lymph nodes). \200 Retroperitoneal \201 brosis. \200 Par enchymal kidney disease: \200 Glomerulonephritis. \200 Tubulointerstitial nephritis. \200 Rhabdomyolysis. \200 Haemolytic uraemic syndrome. \200 Myeloma. \200 Malignant hypertension. PREVENTION OF AKI 101 Risk, prevention, and recognition Some AKI is predictable, preventable, and/or recognized late Risk assess for AKI The risk of AKI is contributed to by the acute insult and background mo rbidity Background Elderly CKD Cardiac failure Liver disease Diabetes Vascular disease Background n ephrotoxic medications Acute \200\230STOP \200\231 Sepsis and hypoperfusion Toxicity Obstruction Parenchymal kidn ey disease Prevent AKI \200\224the 4 \200\230M \200\231s Monitor patient (observations and EWS, regul ar blood tests, pathology alerts, fluid charts, urine volumes) Maintain circulation (hydrat ion, resuscitation, oxygenation) Minimize kidney insults (e.g. nephrotoxic medications, sur gery or high-risk interventions, iodinated contrast and prophylaxis, hospital-acquired infe ction) Manage the acute illness (e.g. sepsis, heart failure, liver failure) Recognize AKI 1.5x increase from most recent baseline creatinine or 6 hours of oliguria AKI develops INSTITUTE CARE BUNDLE Prevent AKI progression by rapid diagnosis, supportive care, specific therapy, and appropriate referral Fig. 2.3 AKI risk, prevention and recognition. Reproduced from London AKI network manual (2 012), with permission. M http://www.londonAKI.net/clinical CHAPTER 2 Acute kidney injury (AKI) 102 Pre-renal AKI Any cause of apparent volume depletion may compromise renal perfusion, as d R BF l d GFR. The kidneys are structurally intact but functionally com- promised. As a genera l rule, the metabolically susceptible proximal tubule can withstand relative underperfusion (and hypoxia) for a period of days (as many as 5) before true cellular injury supervenes ( ATN). (See Fig. 2.4 for algorithm detailing sequence of events.) Hypoperfusion Hypoperfusion is not the same as volume depletion. Renal perfusion is a produ ct of effective circulating volume, cardiac output, and peripheral vascular resistance. 1 A ny cause of a fall in effective arterial blood volume ( b p. 104) can cause pre-renal AKI, regardless of the hydration status of the patient: \200 Hypovolaemia. \200 Cardiogenic shock (or cardiac failure). \200 Systemic vasodilatation (as in sepsis). Physiological response to hypoperfusion Systemic response Systemic hypoperfusion is sensed as a d in arterial BP by carotid and arte- riolar baroreceptors. Activation of the sympathe tic nervous system (SNS) and renin \200\223 angiotensin \200\223 aldosterone system (RAAS ) as well as i vasopres- sin (ADH) release act in concert to maintain BP and preserve blood \202 ow to vital organs. This is accomplished by: \200 Vasoconstriction in \200\230di spensable \200\231 vascular beds (e.g. cutaneous). \200 i cardiac output and heart rate. \200 i thirst and d sweating. \200 i renal conservation of salt and water. Renal response (renal autoregulation) GFR is initially maintained because intraglomerular p ressure is preserved despite the fall in systemic BP through renal autoregulation. This is dependent on the balance between dilatation of the pre-glomerular affer- ent arteriole ( l prostaglandins and NO) and constriction of the efferent post-glomerular arteriole ( l mainl y angiotensin II). If perfusion continues to fall, pre-renal AKI will result. As RBF drops, so glomerular \201 ltration and urine output fall as well. Below a mean arterial pressure (MAP) of 7 80mm Hg, GFR d rapidly. However, lesser degrees of hypotension may provoke pre-renal AKI in susc eptible individuals: \200 The elderly. \200 Pre-existing afferent arteriolar pathology (e.g. hypertensive nephrosclerosis or diabetic nephropathy). ACE-I or ARB therapy where constriction of the efferent arteriole is blocked. Patients on NSAIDS with afferent arteriolar constriction. PRE-RENAL AKI 103 (A) dOncotic pressure and/or icapillary permeability dExtracelluar fluid volume Low-output cardiac failure, pericardial temponade, constrictive pericarditis dCARDIAC OUTPUT Activation of ventricular and arterial receptors Non-osmotic vasopressin stimulation Activation of the renin \200\223angiotensin \200\223 aldosterone system Stimulation of sympathetic nervous system iPERIPHERAL AND RENAL ARTERIAL VASCULAR RESISTANCE RENAL SODIUM RETENTION RENAL WATER RETENTION MAINTENANCE OF ARTERIAL CIRCULATORY INTEGRITY (B) High-output cardiac failure Arteriovenous fistula Arterial vasodilators Sepsis Cirrhosis Pregnancy PERIPHERAL ARTERIAL VASODILATION Activation of arterial baroreceptors SNS stimulation Activation of RAAS Non-osmotic AVP stimulation iCARDIAC OUTPUT iPERIPHERAL ARTERIAL VASCULAR AND RENAL RESISTANCE WATER RETENTION SODIUM RETENTION MAINTENANCE OF ARTERIAL CIRCULATORY INTEGRITY Fig. 2.4 (A) Sequence of events in which reduced cardiac output intiates renal sodium and w ater retention. (B) Sequence of events in which peripheral arterial vasodilatation intiates renal sodium and water retention. Reproduced from Schrier RW et al. (2004). Neuroscience , 129 , 897 \200\223 904. With permission from Elsevier. CHAPTER 2 Acute kidney injury (AKI) 104 Causes of pre-renal AKI Hypovolaemia Any cause of d intravascular volume. \200 ECF deplet ion (usually both Na + and H 2 O depletion \200\224 when losses are predominantly H 2 O, ECF volume is usually preserved until late). \200 Inadequate \202 uid intake: limited access to \202 uid (children, elderly patients with poor mobility, endurance sports), NBM, inadequate IV \202 uids (everyone on a drip is at risk). GI losses: D&V, NG drainage, GI bleeding. \200 Renal losses: diuretic therapy, uncontroll ed DM (osmotic diuresis), salt-losing nephropathy (rare \200\224 b p. 583), post-relief of urinary obstruction, diabetes insipidus. Skin losses: excessive sweating, febrile patients, burns. Hemorrhage: Trauma, surgery (and surgical drains), GI bleeding. \200\230 Third space \200\231 compartmental losses * : Intestinal obstruction, peritonitis, pancreatitis, major fractures. Impaired cardiac output \200 Cardiac pump failure l d BP l d RBF. Ischaemic heart disease l angina or MI. \200 Dysrhythmias (incl. uncontrolled AF). \200 New or established LV dysfunction (incl. myocarditis and cardiomyopathy of any cause). \200 Pericardial disease: 1 tamponade. In CCF, the ECF volume may be normal or i (with oedema and ascites), but the kidneys respon d as though it were inadequate ( d \200\230effective circulating volume \200\231 ). See b p. 102 and p. 778. Peripheral vasodilatation \200 The pathophysiology of septic shock is complex but causes failure of peripheral circulatory control ( b p. 166). Interactions between intraglomerular vaso-dilating and \200\224 constricting mediators resulting from sepsis also contribute to d GFR. Intrarenal vasomotor changes \200 NSAIDs impede prostaglandin-mediated afferent arteriola r dilatation. 2 Post-op patient prescribed NSAIDs. ACE-I and ARB oppose angiotensin II-induced efferent arteriolar constriction. 2 Dehydrated elderly patient still taking an ACE-I. Contrast administration ( b p. 148). \200 Renovascular disease ( b p. 586). \200\230Third space \200\231 was originally coined to refer to a \202 uid compartment t hat is not in equilibrium with the ECF. CAUSES OF INTRINSIC RENAL AKI 105 Causes of intrinsic renal AKI Encompasses all causes of AKI in which the renal parenchyma h as been damaged. 2 ATN accounts for 80 \200\223 90% of all intrinsic AKI. 1 Exclusion or c orrection of pre-renal 9 post-renal factors is an essential part of the diagnosis. (See Fig . 2.5) Intrinsic (renal) ARF Small blood vessels and glomeruli ATN Large blood vessels Tubulointerstitium Ischaemic Toxic Fig. 2.5 Classi \201 cation of intrinsic AKI. Differential diagnosis of intrinsic AKI \200 Larger renal vessels: Renal artery occlusion due to thrombosis or dissection. \200 Cholesterol emboli ( b p. 59 0). \200 Renal vein thrombosis ( b p. 590). \200 ACE-I + bilateral renovascular disease ( b p. 586). \200 Diseases involving the small renal vessels and glomeruli: Glomerulonephritis ( b p. 536). \200 Vasculitis ( b p. 638). \200 Thrombotic microangio pathies ( b p. 574). \200 Malignant hypertension ( b p. 518). \200 Scleroderma renal cr isis ( b p. 666). Diseases of the tubulointerstitium: Acute interstitial nephritis ( b p. 580). \200 Cast nephropathy (complicating multiple my eloma) ( b p. 622). \200 Contrast nephrotoxicity ( b p. 148). \200 Tumor lysis or acute urate nephropathy ( b p. 160). Acute tubular necrosis (ATN) ( b p. 106): May complicate prolonged pre-renal AKI or accompany any of the disorders listed here. CHAPTER 2 Acute kidney injury (AKI) 106 Acute tubular necrosis (ATN) ATN is, by far, the most commonly encountered cause of intrins ic AKI. It is widely seen in hospitalized patients and is predictable in high-risk clinical scenarios (so it is often preventable). The diagnosis implies that pre-renal and post-renal factors have been excluded (or correcte d) and that other causes of intrinsic AKI, such as vasculitis or TIN, are deemed unlikely. It also suggests that recovery of renal function can be achieved \200\224 but only if the causative insult is removed and adequate supportive measures are put in place. (See Box 2.1 .) Box 2.1 ATN subdivided by cause ANY cause d renal perfusion: \200 Hypotension. \200 Shock: Ischaemic (incl. septic) Haemorrhagic. \200 Cardiogenic. \200 Septic. Devascularization (incl. aortic cross-clamping). Myoglobin. \200 Hemoglobin. \200 Aminoglycosides. \200 Contrast. \200 Amphotericin. \200 Cisplatin. \200 Many others ( b p. 7). Nephrotoxic Presentation \200 ATN presents as AKI: d GFR l uraemia and disordered salt, water, and electrolyte homeostasis. 2 ATN may be oliguric or non-oliguric. \200 It represents a continuum from pre-renal fail ure but with progression to: \200 Actual structural injury to the renal parenchyma. \200 Limited (or no) immediate resolution upon restoration of renal perfusion. Differentiation between pre-renal AKI and ATN can be dif \201 cult. \200 Helpful feature s include ( not uniformly present): Clear evidence of sepsis, hypotension, or nephrotoxin exposure. \200 Bland urine on dipst ick (or minor proteinuria). \200 Urine biochemistry (often not helpful and rarely perform ed in practice, b p. 116). ACUTE TUBULAR NECROSIS (ATN) 107 Histology 2 A kidney biopsy is rarely necessary for diagnosis. ATN is a misnomer \200\224 frankly necrotic tubular cells are uncommon. Acute tubular injury (ATI) is an increasingly popular alternative term. There may be few histological changes, even with marked functional renal impairment. Typica l features: tubular cell \202 attening, wide spac- ing of tubules s to interstitial oedem a, tubular cell vacuolation, loss of proximal tubular cell brush border, tubular cell sloug hing into the lumen ( l obstruction), mitotic \201 gures in regenerating epithelial cells 9 and leucocyte in \201 ltration. Glomeruli are normal. (See Fig. 2.6) Loss of polarity Apical surface Basolateral surface Loss of brush border Ischaemia and reperfusion Apoptotic epithelial cell Viable epithelial cell Integrin Tubular lumen Na+/K+ ATPase Epithelial cell with brush border Necrosis and cell death Luminal obstruction Fig. 2.6 Tubular changes in the pathophysiology of ischaemic acute tubular necrosis ( b p. 108). After ischaemia and reperfusion, morphological changes occur in the proximal tubules, including loss of polarity, loss of the brush border, and redistribution of integrins and sodium/potassium ATPase to the apical surface. Cell death, resulting from necrosis and apop tosis, causes cell shedding and luminal obstruction. Reproduced with permission from Schrie r RW et al . (2004). Neuroscience , 129 , 897 \200\223 904. Prognosis \200 AKI s ATN imparts a signi \201 cant in-hospital mortality ( b p. 92). \200 The renal prognosis: 50% will be left with some degree of renal impairment. \200 5 \200\223 10% will eventual ly require long-term renal replacement therapy. CHAPTER 2 Acute kidney injury (AKI) 108 Pathophysiology of ATN (See Fig. 2.7) Vessels and endothelium \200 Blood \202 ow is not uniform within the kidney \200\224 p O 2 falls progressively from cortex (6.65 \200\223 13.3kPa) to medulla (1.3 \200\223 2.9k Pa) despite higher metabolic activity in the latter. 2 The proximal tubular S3 segment and the medullary thick ascending loop of Henle are found in the medulla. Any cause of d RBF or endothelial injury may d delivered O 2 , rendering vulnerable segments of the nephron relatively hypoxic. As a result of endothelial cell injury: i afferent arteriolar cytosolic Ca 2+ l i sensitivity to vasoconstrictor and sympathetic st imulation l impaired glomerular autoregulation. Endothelial cell swelling compounds d \202 ow l d O 2 delivery. \200 Injured endotheliu m (or endothelium under the in \202 uence of proin \202 ammatory mediators (TNF- A , IL-18) l d endothelial adhesion molecules (ICAM-1, VCAM, P-selectin) l d leucocyte-endothelial interaction l medullary vascular congestion l medullary hypoxia. Activated leucocytes l local in \202 ammation and local injury. \200 d endothelial nitri c oxide production + i endothelin and prostaglandin synthesis l enhanced vasoconstriction, further d RBF. The net result is impeded blood \202 ow and d O 2 delivery to metabolically active and relatively hypoxic tubular segments. In effect, demand exceeds sup ply. Tubular cells \200 Hypoxic proximal tubular cells (PTC) now become i energy-deplete. \200 Injured PTC generate proin \202 ammatory mediators l recruitment of leucocytes into the interstitium, with subsequent in \202 ammation. \200 d O 2 delivery leads to i Ca 2+ entry into energy-depleted cells. \200 i Ca 2+ -dependent cysteine protease activity l a ctin breakdown l cytoskeletal disruption l loss of cell polarity. Loss of polarity l d basolateral Na + /K + ATPase pumps and 6 d proximal Na + absorption. More Na + is delivered to the distal nephron and sensed at the macula densa. This triggers tubuloglomerular feedback ( b p. 920) l d GFR. \200 Apical relocation of integrins l loss of cell \200\223 cell adhesion l tubular cell desquamation and cast formation l tubular obstruction l d GFR. \200 Desquamation of PTC e xposes the basement membrane and provides a route for misdirected \201 ltrate, with furth er i interstitial congestion. Necrosis 9 apoptosis ( both are present \200\224 ATN is a misnomer): ATP depletion + i reactive O 2 species + intracellular acidosis + i cytosolic Ca 2+ + i phospholipase activity l cell necrosis. \200 Apoptotic stimuli l casp ase activation l cell apoptosis. Nitric oxide: Hypoxia l i PTC iNOS expression l NO release l cell death. \200 NO scavenged by O 2 radic als l toxic peroxynitrite generation. \200 (eNOS in the afferent arteriole protects again st ischaemic injury). PATHOPHYSIOLOGY OF ATN 109 Repair \200 Post-reperfusion, sublethally injured cells l repair and proliferation. \200 Non-viable cells die (necrosis and apoptosis) and exfoliate. \200 Poorly differentiated epithelial cells appear (? a population of renal stem cells). Viable cells enter the cell cycle under regulation of cyclin-dependent kinase inhibitors (especially p21). Growth factors (IGF-1, EGF, HGF, TGF- B ) l proliferation and differentiation of tubular cells, restoring the epithelium to health. Endothelial injury Activation Dysfunction Detachment Apoptosis Necrosis Epithelial cell injury Inflammation WBC recruitment Neutrophils Macrophages Lymphocytes Dendritic cell activation Lethal injury \200 Necrosis \200 Apoptosis Sub-lethal injury \200 Cytoskeleton disruption Cellular shedding Cellular debris Loss of polarity Loss of tight junctions Cytokine release Vasoconstriction Cytokine release \206\221Permeability \206\221Leucocyte adhesion molecul es Rouleaux formation Reduced flow Leucocyte activation Cytokine release Margination Tissue migration Reduced flow Tubular obstruction Backleak TGF- Defective function Reduced GFR High FENa Concentrating defect Fig. 2.7 Pathophysiology of ATN. Reproduced from Asif A. Sharfuddin & Bruce A. Molitoris, P athophysiology of ischemic acute kidney injury. Nature Reviews Nephrology 7:189 \200\223 2 00 (2011), with permission from Nature Publishing Group. Organ cross-talk in ischaemic AKI Distant organ dysfunction has long been recognized as par t of the AKI syndrome. Mechanisms underpinning this apparent systemic proin \202 am- mator y state include altered expression of cellular adhesion molecules, abnormal lymphocyte traf \201 cking, cytokine and chemokine release, and the dysregulation of immune responses. \200 Heart: LV dysfunction associated with myocyte apoptosis, neutrophil in \201 ltration , and i local cytokine expression (TNF- A , IL-1, ICAM-1). Lung: acute lung injury ( 2 high mortality) with i microvascular permeability resulting from various proin \202 ammatory and pro-apoptotic pathways ( l dow nregulation of alveolar epithelial transporters, e.g. ENaC and aquaporins). Liver: in \202 ammation, hepatocyte apoptosis, lipid peroxidation, decreased antioxidant activity l tissue injury. CNS: confusion and encephalopathy. Neutrophil recruitment and several mediators (e.g. G-CSF and glial \201 brillary acidic protein) have been implicate d in neuronal injury. CHAPTER 2 Acute kidney injury (AKI) 110 AKI: recognition Introduction There is a lot to get to grips with in a patient with AKI. It occurs in the context of a wide range of underlying conditions, and the patient can be any where on a clinical spectrum from asymptomatic to critically unwell. You are not alone, how ever. 2 Consult locally agreed AKI protocols; seek specialist help early, and make use of h elpful aids, such as the free smartphone app designed by London AKI network (LAKIN), or int ernet resources, e.g. M http://www.londonAKI.net/clinical . Recognize the problem Patients may be asymptomatic during the early stages of AKI, despite nearly non-functioning kidneys, and may be very unwell by the time the diagnosis is apparen t ( 2 emphasizing why it is so important to be familiar with high-risk patients and high-ri sk situations ( b p. 98)). Presenting features of AKI Usually \200 i Ur and i SCr. \200 d UO (UO <400mL/d is frequent ( 7 50%) but not invariable). Frequently \200 Volume deple tion OR \200 Volume overload l pulmonary oedema. \200 Hyperkalaemia ( l arrhythmias or cardiac arrest). \200 Non-speci \201 cally sick, often deteriorating, patient. Rarely \200 Uraemic symptoms ( b p. 213). 2 Check renal function and K + in all acutely unwell patients, esp. if: \200 Falling or l ow UO, or anuria. \200 Persistent nausea and vomiting, or prolonged NBM. \200 Drowsines s or impaired conscious level. \200 Signs of systemic sepsis. \200 Hypertension or hypo tension, particularly if severe. \200 Pulmonary 9 peripheral oedema. \200 Puzzling ECG abnormalities ( 2 T wave changes and conduction delays). Metabolic acidosis. AKI: RECOGNITION 111 AKI or CKD? Patients are often found to have i SCr or d eGFR 9 oliguria at the time of thei r presentation, with unrelated medical or surgical condi- tions. Differentiating true AKI f rom stable (long-standing) CKD, or even an acute deterioration of pre-existing renal impair ment, is clearly very important. Much has traditionally been made of the ability to distinguish the two after initial clinic al assessment and blood tests. However, many of these features \200\224 even if present \200\224 are, at best, suggestive and, at worst, misleading. The only two consistently useful discriminators are: 1. Previous measurements of renal function: Where might this be documented? Can the patient remember previous blood tests? Previous hospital admissions? \200 Search your pathology system, and pull hospital notes. \200 Ask the patient s GP to check their records. 2. Ultrasound: Long-standing renal disease leads to loss of renal parenchyma and d renal size. Small (< 9 \200\223 10cm length), echo bright, often cystic kidneys are characteristic of CKD. 2 Normal-sized kidneys should arouse suspicion of AKI. A common exception is diabetic nephr opathy ( b p. 604). Lab \201 ndings suggesting AKI, rather than CKD These are rarely as h elpful as textbooks imply. Err on the side of caution (i.e. assume AKI until proven otherwi se). \200 Anemia might suggest chronic undersynthesis of erythropoietin by scarred kidney s: a normal Hb 6 argues against CKD, but anemia occurs in both AKI and CKD. d Ca 2+ and i PO 4 suggest established CKD-MBD ( b p. 232). Not so: disturbances of mineral metabolism can occur rapidly in AKI. \200 In many situations, particularly when renal si ze is normal, a kidney biopsy may be necessary to determine the nature of the renal lesion and the extent of rever sibility ( b p. 121). CHAPTER 2 Acute kidney injury (AKI) 112 AKI: priorities Make the patient safe Evaluate as for any critically unwell patient: airway , breathing, and circu- lation. The standard priorities of resuscitation initially override thoughts regarding underlying cause. 2 Does the patient require urgent level 2 or 3 care? Two additional speci \201 c questions must be addressed urgently: 2 How high is the K + ? \200 2 What is the volume status? Hyperkalaemia ( b p. 130) and p ulmonary oedema ( b p. 134) may prove rapidly lethal, if untreated. 3 Call for expert help. Care bundles and protocols, such as that provided by LAKIN (see Fig. 2.8), provide a helpful framework for prioritizing management. Look for a reversible cause Once the patient is stabilized, consider the following question s, as they may identify situations where relatively straightforward interventions can have a signi \201 cant impact. \200 Is it pre-renal ( b p. 114)? \200 Is the patient septic ? \200 Are there predisposing factors in the history? \200 Carefully assess the patient s volume and haemodynamic status. \200 Is invasive monitoring needed? Involve your criti cal care team if it is. Is it post-renal ( b p. 115)? Are there predisposing factors in the history? \200 Is there a palpable bladder or signi \201 cant urinary tract symptoms? \200 What does the urine look like \200\224 any haema turia? \200 Arrange an urgent USS. What is on the drug chart ( b p. 7)? \200 Stop all nephrotoxins, if possible. \200 Has any radiocontrast been administered? \200 Have you dipsticked the urine ( b p. 116)? \200 2 Do it now \200\224 you may forget later. AKI: PRIORITIES 113 AKI care bundle Institute in all patients with a 1.5 \227 rise in creatinine or oliguria (0.5 mL/kg/h) for >6 hours This is a medical emergency Full set of physiological observations Assess for signs of shock/hypoperfusion If MEWS trig gering, give oxygen, begin resuscitation, and contact critical care outreach team Fluid therapy in AKI Assess heart rate, blood pressure, jugular venous pressure, capillary refill (should be <3 s), conscious level. If hypovolaemic, give bolus fluids (e.g. 250 \200 \223500 mL) until volume replete with regular review of response. Middle grade review if >2 litres filling in oliguria. If the patient is euvolaemic, give maintenenance fluids (estim ated output plus 500 mL) and set daily fluid target. Monitoring in AKI Do arterial blood gas and lactate if venous bicarbonate is low or evidenc e of severe sepsis or hypoperfusion. Consider insertion of urinary catheter and measurement of hourly urine volumes. Measure urea, creatinine, bone, other electrolytes, and venous bi carbonate at least daily while creatinine rising. Measure daily weights, keep a fluid chart , and perform a minimum of 4-hourly observations. Perform regular fluid assessments and che ck for signs of uraemia. Investigation of AKI Investigate the cause of all AKI unless multi-organ failure or obvious precipitant Urine dipstick. If proteinuria is present, perform urgent spot urine protein c reatinine ratio (PCR). USS should be performed within 24 hours unless AKI cause is obvious or AKI is recovering or within 6 hours if obstruction with infection (pyonephrosis) is susp ected. Check liver function (hepatorenal), CRP, and CK (rhabdomyolysis). If platelets low, do blood movie/LDH/Bili/retics (HUS/TTP). If PCR high, consider urgent Bence \200\223Jones protein and serum free light chains. Supportive AKI care Treat sepsis \200\224in severe sepsis, intravenous antibiotics should b e administered within 1 hour of recognition. Stop NSAID/ACE/ARB/metformin/K-sparing diureti cs, and review all drug dosages. Give proton pump inhibitor and perform dietetic assessment . Stop antihypertensives if relative hypotension. If hypovolaemic, consider stopping diuret ics. Avoid radiological contrast if possible. If given, follow prophylaxis protocol. Causes Think \200\230STOP AKI \200\231 Sepsis and hypoperfusion, Toxicity (drugs/contrast) , Obstruction, Parenchymal kidney disease (acute GN) Fig. 2.8 The LAKIN AKI care bundle. Reproduced from London AKI network manual (2012), with permission. M http://www.londonAKI.net/clinical CHAPTER 2 Acute kidney injury (AKI) 114 Assessing AKI: clinical clues Pre-renal AKI History ( b p. 104) \200 Any cause of d intra vascular volume? Inadequate \202 uid intake, hemorrhage, GI losses, renal losses, skin losses, third-space losses. \200 Any cause of cardiac pump failure? \200 Any evidence f or sepsis? Clinical examination ( b p. 12) \200 Assessment of volume status is fundamenta l to diagnosis: BP: check lying and standing, if possible. \200 Heart rate: check lying and standing, if possible. \200 Peripheral perfusion: Warm with bounding pulse l vasodilatation (? sepsis). Cold and shut down with d capillary r e \201 ll l volume \200\224 \200\224 depletion or low cardiac output. d JVP: hypovolaemia or vasodilatation (may be i with pump failure). \200 Peripheral and p ulmonary oedema. \200 Urine output. Poor signs of volume depletion Dry mucous membranes (most sick patients mouth-breathe). \200 d skin turgor (better sign in children). Classically 1. Volume depletion (hypovolaemic or haemorrhagic shock): \200 (Postural) hyp otension. \200 May be peripherally shut down. \200 JVP d . 2. Poor cardiac output (card iogenic shock): \200 Hypotension with narrow pulse pressure. \200 Peripherally shut dow n (often very). \200 JVP i . 3. Systemic vasodilatation (septic shock): \200 Hypotensio n with i pulse pressure. \200 Peripherally warm. \200 JVP d . Intrinsic renal AKI Large renal vessels History \200 Cardiovascular: CV risk: smoking, diabetes, lipids, i BP, age. \200 CV disease: claudication and PVD, str oke, IHD. \200 CV intervention: invasive/endovascular radiological procedures, vascular surgery. ASSESSING AKI: CLINICAL CLUES 115 Source of emboli: AF, prosthetic valve, cardiomyopathy, thrombophilia tendency. Nephrotic syndrome: renal vein thrombosis ( b p. 590). Examination AF, missing pulses, dila ted heart, bruits, aortic aneurysm, ischaemic toes, i BP (though very non-speci \201 c), o edema (? nephrotic). Small renal vessels and glomeruli History No other cause evident; recent infection, particu larly skin or throat (post-streptococcal GN); symptoms suggesting a deep-seated infection ( fevers, night sweats); known systemic disorder, e.g. SLE, scleroderma, vasculitis; symptoms suggesting an underlying connective tissue disorder or vasculitis ( b p. 5). Examination R ash, i BP, oedema, synovitis, arthropathy, uveitis, mouth ulcers, epistaxis, hearing loss, stigmata of endocarditis, evidence of scleroderma or other connective tissue disorder, abno rmal respiratory \201 ndings (pulmonary-renal syndrome).