Amount varies but serum glucose usually normal. \200 Clinical sequelae are rare, though h ypoglycaemia occurs in some forms (e.g. Fanconi \200\223 Bickel syndrome/glycogenosis). Renal tubular acidosis (RTA): Defective bicarbonate reabsorption in the proximal tubule results in systemic acidosis (a form of type II RTA, b p. 824). Na + loss: If severe l postural d BP, d Na + , and metabolic alkalosis result. \200 Salt supplementa tion occasionally necessary. Hypokalaemia: i delivery of Na + to the distal tubule l Na + reabsorption at the expense of K + excretion. CLINICAL SYNDROMES: TUBULAR SYNDROMES 77 Acidosis and RAS activation by volume depletion also l K + loss. \200 Clinical sequelae c ommon (muscle weakness, constipation, polyuria, cardiac arrhythmias) and supplementation often required. Proteinuria: LMW proteinuria is common ( B 2 microglobulin, lysozyme, and other tubular proteins), though excretion rates are usually low \200\223 moderate. Polyuria: Polyuria, polydipsia, and dehydration can be prominent. \200 Caused by d K + and impaired concentrating ability in the distal tubule. \200 Hypercalciuria: Rarely l nephrolithiasis/calcinosis (? protective effect of polyuria), although these may b e precipitated by treatment with vitamin D metabolites (further i urinary Ca 2+ ). Serum Ca 2+ usually normal. Isolated tubular defects Renal glycosuria \200 d proximal tubular glucose reabsorption l glycosuria (despite normal blood glucose). Clearance studies allow differentiation into different patterns implicating several defecti ve tubular transportation mechanisms. \200 The amount can be quite signi \201 cant (norm ally 1 \200\223 30g/24h) but generally a benign condition with no clinical sequelae. (cid:2) Always needs to be distinguished from DM. \200 Genetic mechanisms involved but in heritance unpredictable. Aminoaciduria \200 Causes: Inborn error of metabolism l i plasma levels and \200\230over \202 ow \200\231 . \200 Renal aminoaciduria secondary to defective tubular transportation mechanisms. Amino acid transportation is complex, involving transporters speci \201 c to single or chemically related groups of amino acids. The most important isolated aminoaciduria is cystinuria, an autosomal recessive cause of re current cystine stone formation ( b p. 719). Phosphaturia \200 Defective phosphate transportation l phosphaturia, hypophosphataemia, and disorders of the skeleton. Several described, including X-linked hypophosphataemic rickets (vitamin D-resistant rickets) and autosomal dominant hypophosphataemic rickets. FGF-23 excess, causing inhibition of phosphate reabsorption, is now known to underpin many of these disorders ( b p. 236). CHAPTER 1 Clinical assessment 78 Clinical syndromes: bladder out \202 ow obstruction Introduction \200 Main causes are sh own in Box 1.11. The likelihood of each is in \202 uenced by age and sex. Presentation is with: \200 Acute retention of urine. \200 Lower urinary tract symptoms (LUTS). LUTS are divided into two groups. Symptoms correlate poorly with underlying urinary patholo gy, so it is best to remain as descriptive as possible (see Table 1.15). (cid:2) Bladder out \202 ow obstruction (BOO) can be clinically silent in some patients, despite signi \201 cant residual bladder urine volumes and eventually progr essive urinary obstruction. Table 1.15 Symptoms of bladder out \202 ow obstruction Obstructive (voiding) symptoms Impaired size or force of stream Hesitancy or straining Inte rmittent or interrupted \202 ow Sensation of incomplete emptying Storage ( \201 lling) symptoms * Nocturia Daytime frequency Urgency Urge incontinence Dysu ria Also called irritative. \200\230 Prostatism \200\231 is no longer preferred to describe out \202 ow symptoms (ag e-matched \231\200 report similar symptoms). Examination Palpate for bladder enlargement; rectal examination, pelvic examination in \231\200 ; examine the legs neurologically, and test anal tone/sensation. Investigations \200 Urine M,C+S, U&E, and PSA (in males >40 years, b p. 772). \200 Imag ing. Bladder USS to measure residual volume post-micturition (correlation to out \202 ow obstruction is poor). Uro \202 owmetry. Full bladder emptied into a \202 ow meter to generate a \202 ow curv e (rate vs time). Normal max \202 ow >20mL/s. Further urodynamic assessment will distingu ish non-obstructive causes of low \202 ow (e.g. detrusor failure). Pressure - \202 ow studies (cystometrography). More sensitive and speci \201 c but invas ive. Bladder and rectal catheters record \201 lling and voiding bladder pressures (normog rams relate pressure to \202 ow). Videocystometrography. Fluoroscopic screening of the ureters, bladder, and urethra. Useful in the investigation of neurological bladder dysfunction. Retrograde urethrography. ? urethral stricture. CLINICAL SYNDROMES: BLADDER OUTFLOW OBSTRUCTION 79 Box 1.11 Causes of bladder out \202 ow obstruction \200 Congenital: Urethral valves and strictures. Structural: Benign prostatic hyperplasia ( b p. 758). \200 Carcinoma of the prostate ( b p. 766). \200 Bladder neck stenosis. \200 Urethral stricture. Functional: Bladder neck dyssynergia. \200 Neurological disease \200\224 spinal cord lesions, MS, di abetes. \200 Drugs \200\224 anticholinergics, antidepressants. Prostatic enlargement ( b p. 758) \200 Prostate size correlates poorly with degree of obs truction on urodynamic assessment. Impaired \202 ow is a function of two separate components: Dynamic: i sympathetic tone of prostatic smooth muscle. \200 Static: mass effect of enlar gement. CHAPTER 1 Clinical assessment 80 Renal biopsy: introduction Despite improvements in other diagnostic techniques, renal biops y and examination of histology retain pivotal roles in nephrology. Renal transplant biopsy is considered separately ( b p. 407). Indications ( b p. 82) \200 Unexplained acute or chronic kidney disease with normal renal size. \200 Histology is likely to in \202 uence treatment. \200 Histology is likely t o offer prognostic information. \200 Information concerning the activity (and potential r eversibility) and/or chronicity of a previously identi \201 ed lesion is desirable. Preparation for renal biopsy \200 (cid:2) Renal biopsy is an invasive procedure. An evalu ation of the risk-bene \201 t ratio is required in every case. Imaging: con \201 rm two normal-sized, unobstructed kidneys with normal parenchyma. BP <160/90mmHg; preferably <140/90mmHg. \200 Hb ideally >100g/L. \200 Normal clotting ( PT and APTT <1.2 x control). Platelet count >100 x 10 9 /L. Send group and save. \200 Antiplatelet agents and anticoagulants stopped >5 days prior to procedure. Ideally, do not restart for 7 days post-biopsy. Sterile urine. \200 Informed consent. Give appropriate written or visual patient information. If renal impairment, the risk of bleeding increases 7 2 \200\223 3-fold. \200 Most units will have their own policy, e.g. if urea \211 20mmol/L (55mg/ dL) or SCr \211 250 m ol/L (2.8mg/dL) or bleeding time >10min, give DDAVP 0.4 micrograms/kg IV 2 \200\223 4h pre -biopsy ( (cid:2) not if recent or ongoing angina). Contraindications \200 Uncorrected bleeding tendency (absolute contraindication). \200 Chronic kidney disease with small kidneys. \200 Multiple cysts. \200 Suspected renal ma lignancy ( b p. 743). \200 Hydronephrosis. \200 Active urinary infection. \200 Uncont rolled hypertension (>160/95mmHg). \200 Hypotension. \200 Signi \201 cant anemia. \200 Uncooperative patient. \200 Solitary kidney (only a relative contraindication). RENAL BIOPSY: INTRODUCTION 81 Technique \200 Performed percutaneously under LA via a posterior approach. \200 Sedatio n is generally avoided, as patient cooperation is essential. \200 Patient lies prone, wit h a pillow under the abdomen to straighten the spine. USS locates the kidneys, determines their size, and identi \201 es cysts. \200 Either ki dney may be biopsied. \200 A lower pole biopsy reduces the risk of piercing a major vesse l. \200 USS is used to directly guide the needle to the kidney \200\230real time \200 \231 . \200 LA is in \201 ltrated down to the renal capsule, using a spinal needle. \200 Non-real-time techniques, after the kidneys have been marked on the surface, also remain in use. CT guidance is an alternative when USS visualization is inadequate. \200 Disposable TruCu t needles or spring-loaded biopsy guns are generally used (e.g. 16-gauge; larger needles may i complication rate). An initial stab incision at the skin can ease passage of the nee dle. The patient is required to hold their breath when the needle enters the kidney. Where possible, two cores of tissue are obtained to increase diagnostic yield. Avoid >4 passes with the biopsy needle. Call for a more experienced opera tor after two unsuccessful passes. Routine processing includes light, immuno \202 uorescence (or immuno- histochemistry), and EM. Biopsy material is divided, as different \201 xatives are requir ed for the different techniques, e.g. glutaraldehyde for EM. \200 Patient remains on bed rest, with a good \202 uid intake for 6 \200\223 8h. Pulse and BP are monitored regularl y and urine inspected for haematuria. The patient is advised not to undertake heavy lifting or strenuous exercise for 4 weeks. Day case biopsy is now common. (cid:2) These should be deemed low risk, as complications actually occur after 6 \200\223 8h in 7 1/3 cases. \200 High risk 6 not for day case: SCr >200 mol/L (2.2mg/dL), BP >140/90mmHg, small renal sizes ( b p. 84). Open renal biopsy \200 May be considered if the percutaneous approach carries an unacceptable risk or has been unsuccessful. Allows direct visualization of the kidney and easier control of bleeding. \200 More tissu e can potentially be obtained. \200 The risk of a GA may actually exceed that of a percut aneous biopsy. \200 Laparoscopic techniques have been described. Transvenous renal biopsy \200 An endovascular technique developed in hepatology and not w idely available. The kidney is approached via a transjugular or transfemoral route. Usually performed by interventional radiologists. The renal capsule is not punctured, and the risk of perinephric bleeding is reduced. High success rates demonstrated (i.e. renal tissue obtained), but complication rates appear similar. Potential uses: morbid obesity, comatose patient, uncorrected coagulopathy, failed percutaneous approach. CHAPTER 1 Clinical assessment 82 Renal biopsy: indications Clinical syndromes: when to biopsy? 2 There is no such thing as a \200\230routine \200\231 renal biopsy. X Microscopic haematuria ( b p. 66) \200 Practi ce varies, but most do not biopsy, unless there is associated proteinuria and/or renal impa irment (either at presentation or during the course of follow-up). Isolated microscopic hae maturia generally has an excellent prognosis, and histology will not in \202 uence managem ent. Possible exceptions: suspected systemic condition (e.g. SLE, vasculitis), potential live ki dney donors, or for insurance or employment reasons. Proteinuria X Non-nephrotic proteinuria (<3.5g/24h) \200 Many recommend a biopsy at modes t levels of proteinuria to ensure potentially treatable lesions, e.g. primary FSGS and memb ranous GN, are not overlooked. Others argue that the benign prognosis of these conditions, when urinary protein excretion is low, means that a biopsy is unnecessary. \200 Some clinician s use an arbitrary \200\230cut-off \200\231 level of proteinuria to guide their decision- making (e.g. biopsy if >1g/24h \200\224 uPCR >100mg/mmol), particularly if treatment with an ACE-I or ARB does not reduce the proteinuria below this threshold ( b p. 61). The presence of renal insuf \201 ciency weighs in favor of a biopsy. Nephrotic range proteinuria \200 A biopsy is generally recommended. Two exceptions: Minimal change disease in childhood. In this situation, an initial trial of steroids may be appropriate. \200 Diabetic nephropathy ( b p. 611). Acute nephritic syndrome The need to con \201 rm diagnosis and adapt treatment, according to the type and severity of the renal lesion, mandates a biopsy in the majority of cases, e ven when the diagnosis is suggested by serological tests (e.g. anti-GBM disease or ANCA +ve vasculitis). Acute kidney injury ( b p. 121) \200 Unexplained AKI, particularly with an active urinary sediment (i.e. possible RPGN), or AKI that does not behave as expected, e.g. failing to recover. Chronic kidney disease The most important determinants of the appropriateness of a biopsy a re: \200 Renal size. If <9cm, a biopsy is technically more demanding and histology is more likely to show chronic, non-speci \201 c, irreversible change (with the original insult not identi \201 able). Clinical context. A high pre-test probability may circumvent the need to obtain histology, e.g. diabetic nephropathy. RENAL BIOPSY: INDICATIONS 83 Degree of proteinuria. A treatable glomerular lesion is less likely if urinary protein excr etion is low (e.g. <1g/24h or uPCR <100mg/ mmol). Systemic disease potentially involving the kidney \200 Immunological or serological testi ng ( b p. 40) may provide important diagnostic clues (e.g. ANCA +ve vasculitis, anti-GBM di sease), but renal biopsy will con \201 rm the diagnosis and assess the degree of activity and potential reversibility. This aids decision-making around the type and duration of trea tment. This is particularly true of lupus nephritis where classi \201 cation of the renal lesion is a cornerstone of management. In some conditions, demonstrable renal involvement may be an important determinant of the n eed for systemic treatment, e.g. myeloma. Other important systemic conditions that often precipitate a renal biopsy include sarcoidosis and amyloidosis. CHAPTER 1 Clinical assessment 84 Renal biopsy: complications Introduction In general, percutaneous kidney biopsy is a safe p rocedure, and serious complications are uncommon. However, less serious sequelae, such as p ain and mild bleeding, are relatively common, so it is important to explain the potential f or these to the patient pre-procedure. Higher risk 1 \200 Uncorrected bleeding tendency ( 3 do not biopsy). \200 i BP (>130mmH g systolic). \200 d GFR, especially if SCr >177mmol/L (2.0mg/dL). \200 Small renal size s (<10cm). \200 Hb <120g/L. \200 Older age (>40). \200 Use of larger (e.g. 14-gauge) biopsy needle. Complications \200 Pain: Dull ache around the needle entry point and tract is almost universal once LA effect wears off. \200 Simple analgesia is often necessary. \200 Seve re pain raises the possibility of a signi \201 cant perirenal bleed and should prompt asse ssment to determine the extent of the problem (as well as additional analgesia). Pain is usually short-lived but may be persistent >12h in <5%, meriting further investigation for a haematoma. Bleeding: Bleeding is the main complication of renal biopsy. \200 Three potential sites: Collecting system ( l haematuria). \200 Within the renal capsule ( l pain). \200 Perine phric space ( l haematoma). A degree of capsular or perirenal bleeding accompanies almost every renal biopsy. A Hb drop \211 10g/L is common. \200 Asymptomatic haematomas can be detected on USS in u p to 30% patients. A larger capsular haematoma (pain, signi \201 cant drop in Hb) occurs in 7 2%. A large capsular haematoma may tamponade and compress the kidney, causing high renin hypertension (known as a \200\230page \200\231 kidney). \200 Transient microscopic haematuria is present in virtually all patients. \200 Macroscopic haematuria in 7 3.5%. \200 Gross haematuria may cause painful clot colic 9 ureteral obstruction. Transfusion required in 7 1%. \200 Endovascular intervention to control bleeding in 0.6%. \200 Nephrectomy to control bleeding in 0.01%. RENAL BIOPSY: COMPLICATIONS 85 Arteriovenous \201 stula: 7 18% on Doppler but rarely symptomatic; may cause persistent haematuria and (rarely) hypertension. Most resolve spontaneously within 12 \200\223 24 months. \200 Embolization may be an opt ion in those that remain symptomatic. Incorrect tissue obtained: Usually muscle, fat, liver, spleen. Colonic perforation. \200 Perirenal infection (0.2%). \200 Peritoneal-calyceal \201 s tula. \200 Death (0.02%). 3 Management of signi \201 cant bleeding \200 Seek expert help. \200 Bed rest. \200 Regular pulse, BP, and O 2 saturations (every 15min). \200 Ensure adequate IV access and commence \202 uid resuscitation as necessary. Reassure the patient, and ensure adequate analgesia. \200 Check Hb, and repeat after 2, 4 , 8, and 12h as a minimum. \200 Cross-match at least 2 units of blood, and transfuse as n ecessary. \200 Repeat clotting studies post-biopsy. Correct coagulopathies. \200 Mainta in a high urine \202 ow with IV \202 uids to prevent ureteral obstruction and clot colic. Consider a 3-way urethral catheter for irrigation if clot retention and bladder out \202 ow obstruction. Inform surgical team. \200 Do not move the patient for imaging until they are stabilized. An ultrasound is unlikely to be of value beyond the identi \201 cation of a haematoma. A contrast CT may identify ongoing active bleeding, but the patient \200\231 s clinical stat us may already imply this. If severe or persistent, consider arteriography to localize source of bleeding 9 embolization to stop it. Surgical intervention may allow control of the bleeding point, but an emergency nephrectomy may be necessary. Reference 1. Corapi KM , Chen JL , Balk EM , Gordon CE (2012). Bleeding complications of na tive kidney biopsy: a systematic review and meta-analysis. American Journal of Kidney Disea ses , 60 , 62 \200\223 73. 87 Chapter 2 Acute kidney injury (AKI) De \201 nition 88 Epidemiology 92 Biomarkers of AKI 94 Causes and classi \201 cation 96 P revention of AKI 98 Pre-renal AKI 102 Causes of pre-renal AKI 104 Causes of intrinsic renal AKI 105 Acute tubular necrosis (ATN) 106 Pathophysiology of ATN 108 AKI: recognition 110 A KI: priorities 112 Assessing AKI: clinical clues 114 Assessing AKI: urinalysis 116 Assessin g AKI: blood tests 118 Assessing AKI: imaging 120 Assessing AKI: histology 121 AKI manageme nt: a checklist 122 AKI management: volume replacement \200\224 which \202 uid? 124 AKI management: volume replacement \200\224 how much? 126 AKI management: hyperkalaemia 130 AK I management: pulmonary oedema 134 AKI management: electrolytes and acidosis 136 AKI manage ment: other strategies 138 AKI management: nutrition 140 AKI management myths 144 AKI: hope for the future? 146 Contrast-induced AKI (CI-AKI) 148 Rhabdomyolysis 152 Rhabdomyolysis: m anagement 154 AKI in cirrhosis 156 Management of HRS 158 Tumor lysis syndrome 160 Abdominal compartment syndrome (ACS) 162 AKI in the developing world 164 AKI in sepsis 166 Managing septic shock and AKI 168 Renal replacement therapy in AKI 172 RRT in AKI: modalities 174 RR T in AKI: choosing modality? 176 RRT in AKI: prescription 178 RRT in AKI: anticoagulation 1 82 RRT in AKI: citrate regional anticoagulation 186 Peritoneal dialysis (PD) in AKI 188 CHAPTER 2 Acute kidney injury (AKI) 88 De \201 nition Introduction Acute kidney injury (AKI) (formerly acute renal failure) is th e syndrome arising from a rapid fall in GFR (over hours to days). It is characterized by re tention of both nitrogenous (including Ur and Cr) and non-nitrogenous waste products of met abolism, as well as disordered electrolyte, acid \200\223 base, and \202 uid homeostasis . 22 There is evidence that even relatively small acute reductions in kidney function are a ssociated with poorer outcomes, including increased mortality, higher risk of long-term dia lysis, and longer hospital stay. Historical limitations \200 Despite a relative insensitivity to acute changes in GFR, mos t de \201 nitions of acute renal dysfunction have been based on serum Cr, either as an absol ute value or as a change from baseline. Other de \201 nitions have incorporated urine outp ut (UO) or the need for dialysis support. A 2004 survey of 598 participants at a critical care nephrology conference revealed 199 different criteria to de \201 ne AKI and 90 for the initiation of renal replacement therapy. 1 This lack of consensus had implications for collection and comparison of epidemiological data, and consistency of clinical practice. The RIFLE criteria for AKI \200 In response, the Acute Dialysis Quality Initiative establ ished a multilayered de \201 nition of AKI called the RIFLE criteria. AKI is strati \201 ed into \201 ve stages, based on severity and duration of renal injur y: R isk, I njury, F ailure, L oss, and E nd-stage disease (see Table 2.1). Many studies (>0.5 million patients) have validated these criteria. \200 RIFLE-de \201 n ed AKI is associated with signi \201 cantly reduced survival (with increasing RIFLE stage leading to greater risk of death). Acute Kidney Injury Network (AKIN) classi \201 cation \200 More recently, AKIN (an inter national network of AKI experts) modi \201 ed RIFLE to incorporate small changes in SCr occurring within a 48h period and t o remove changes in GFR as diagnostic criteria (see Table 2.1). KDIGO AKI de \201 nition (2012) \200 AKI, classi \201 ed by either of the earlier liste d criteria, may identify slightly different patients: RIFLE may not detect 7 10% of AKIN-identi \201 ed ca ses, and AKIN may miss 7 25% RIFLE cases. KDIGO have recently produced a de \201 nition that incorporates the key elements of both, and it is likely that this de \201 nition will become the accepted standard. DEFINITION 89 Key elements of KDIGO AKI de \201 nition \200 Increase in SCr by \211 26.5 mol/L ( \211 0.3mg/dL) within 48h. \200 Increase in SCr by \211 1.5 x baseline (known or presu med to have occurred within prior 7d). Urine volume <0.5mL/kg/h for 6h. (Only one criterion needs to be present to ful \201 ll th e de \201 nition.) Table 2.1 The evolving de \201 nition of AKI (a) RIFLE classi \201 cation 1 RIFLE category SCr/GFR criteria Urine output criteria i SCr \211 150 \200\223 200% (1.5 \200\223 2-fold) OR decrease of GFR >25% Risk <0.5mL/kg/h for 6h i SCr >200 \200\223 300% (>2 \200\223 3-fold) OR decrease of GFR >50% Injury <0.5mL/kg/h for 12h i SCr >300% (>3-fold) from baseline OR decrease of GFR >75% OR SCr \211 350 mol/L ( \211 4 .0mg/dL) with an acute rise of at least 45 mol/L (0.5mg/dL). Or on RRT. <0.3mL/kg/h for 24h OR anuria for 12h Failure Loss Complete loss of renal function for >4 weeks End-stage kidney disease Need for RRT for >3 months (b) AKI network classi \201 cation 2 AKIN stage Serum creatinine criteria Urine output criteria SCr \211 26.4 mol/L (0.3mg/dL) in \211 48h OR i SCr \211 150 \200\223 200% (1.5 \200\223 2-fold) from baseline 1 <0.5mL/kg/h for >6h 2 SCr >200 \200\223 300% (2 \200\223 3-fold) from baseline <0.5mL/kg/h for >12h SCr \211 300% (3-fold) from baseline OR SCr \211 354 mol/L (>4mg/dL) with an acute ris e of \211 44 mol/L (0.5mg/dL) OR treatment with RRT <0.3mL/kg/h for 24h OR anuria for 12h 3 (c) KDIGO classi \201 cation 3 Stage Serum creatinine criteria Urine output criteria 1.5 \200\223 1.9 times baseline OR \211 0.3mg/dL (>26.5 mol/L) in \211 48h 1 <0.5mL/kg/h for 6 \200\223 12h <0.5mL/kg/h for \211 12h 2 2 \200\223 2.9 times baseline \211 3 times baseline OR increase in SCr to \211 4.0mg/dL (354 mol/L) OR initiation of RRT 3 <0.3mL/kg/h for \211 24h OR anuria for \211 12h GFR, glomerular \201 ltration rate; RRT, renal replacement therapy; SCr, serum creatinine . Only one criterion needs to be met to be classi \201 ed as AKI; if both are present, the criterion which places the patient in the higher stage of AKI is selected. 1 R. Bellomo, e t al . Critical Care, vol. 8, no. 4, pp. R204 \200\223R212, 2004. 2 R. L. Mehta, et al . Cr itical Care, vol. 11, article R31, 2007. 3 http://www.kdigo.org/ Table adapted from Joslin and Ostermann. Emergency Medicine International Volume 2012, Article ID 760623 CHAPTER 2 Acute kidney injury (AKI) 90 Acute kidney disease (AKD) \200 Strict adherence to de \201 nitions of both acute (AKI) and chronic (CKD) renal disease may miss individuals with functional or structural abnormal ities present for <3 months but who may bene \201 t from active intervention to restore ki dney function (6 avoiding permanent damage and adverse outcomes). For this reason, KDIGO have proposed the term AKD to include not only those with AKI, but also those with GFR <60mL/min/1.73m 2 for <3 months or a decre ase in GFR by \211 35% or an increase in SCr by >50% for <3 months. Reference 1. Ricci Z, Ronco C, D \200\231Amico G, et al . (2006). Practice patterns in the management of acute renal failure in the critically ill patient: an international survey. N ephrology Dialysis Transplantation , 21 , 690 \200\223 6. DEFINITION 91 CHAPTER 2 Acute kidney injury (AKI) 92 Epidemiology Incidence Depends on the population studied and the de \201 nition used, mean ing few studies historically have been able to provide accurate incidence data. However, th e more recent use of AKIN/RIFLE criteria has improved this. It remains important to recogni ze the limitations imposed by the use of SCr and urine output for the detection of AKI. It is hoped that, in the future, sensitive biomarkers of renal cell injury will improve earlie r identi \201 cation. Hospital \200 5 \200\223 10% of general admissions. \200 20 \200\223 25% of patients with sepsis and 7 50% with septic shock. \200 50% of all ITU admissions (where it acts as an independent risk factor for mortality of 20 \200\223 60%, depending on AKI stage). Community \200 KDIGO estimate a worldwide AKI prevalence of 7 2,100 pmp, the majority of which are community-acquired. The burden of AKI may be highest in developing countries. \200 Community-based studies in the UK (SCr >300 mol/L or 3.4mg/dL) estimate 486 \200\223620 pmp. This is age- and comorb idity-related (17 pmp aged <50 and 949 pmp aged 80 \200\22389). Restricting the evaluation to changes in SCr, particularly large changes, will miss many cases. Individuals with CKD are at increased risk of AKI (and AKI is a risk factor for progression of CKD). Incidence of dialysis-dependent AKI: 7 200 pmp annually. Prognosis 2 There is increasing evidence for the adverse outcomes associated with AKI (even after apparent resolution), including longer hospital length of stay, signi \201 cant com plication rates (including infection), risk of CKD (including ESRD), development of CV dise ase, and higher mortality. Mortality \200 Outcomes for the new AKIN criteria by stage are shown in Table 2.2. \200 Prompt improvement (<24h) in renal, cardiovascular, or respiratory function is associated with a better chance of survival. Outcomes for patients with sepsis in an ICU setting are linked to timely AKI resolution ( 2 indicating a therapeutic window where outcomes for these patients may be improved). Despite improvements in many aspects of clinical care (particularly nutrition and renal rep lacement therapy), overall mortality in AKI requiring RRT remains >50% (re \202 ecting a h igh incidence in the elderly and those with multi-organ failure). The underlying cause will play a role, e.g. lower for nephrotoxin-driven AKI (<30%) vs higher for sepsis- and trauma-related AKI ( 7 60%). EPIDEMIOLOGY 93 Table 2.2 AKI mortality by AKIN stage Rise in SCr Odds ratio for hospital mortality \211 27 mol/L (0.3mg/dL) 4.1 \211 45 mol/L (0.5mg/dL) 6.5 \211 90 mol/L (1.0mg/dL) 9.7 \211 180 mol/L (2.0mg/dL) 16.4 Chertow G M, Burdick E, Honor M, et al . (2005). Acute kidney injury, mortality, length of stay, and costs in hospitalized patients. Journal of American Society of Nephrology , 16 , 3365 \200\223 70. Renal recovery Recovery of renal function will depend on underlying diagnosis. For ATN, 7 5 0% will have some degree of residual renal impairment. This will be irreversible, dialysis- dependent renal failure in 7 5% ( 7 10% in the elderly). The risk of worsening or de novo C KD and death following an episode of AKI (even if function appears to return to normal) is high. 2 The future healthcare impact of this is currently uncertain but could be signi \201 cant, as more patients survive to hospital discharge following serious illness. Reference 2. Bucaloiu ID, Kirchner HL, Norfolk ER, et al . (2012). Increased risk of death and de novo chronic kidney disease following reversible acute kidney injury. Kidney International , 81 , 477 \200\223 85. CHAPTER 2 Acute kidney injury (AKI) 94 Biomarkers of AKI Introduction Driven by the recognition that even relatively small increas es in SCr were associated with a poor outcome and increased healthcare costs, the 2005 Amer ican Society of Nephrology Renal Research Report assigned the highest research priority to the discovery of new biomarkers of AKI and their validation in different patient population s and clinical settings. SCr is a suboptimal biomarker of AKI. i SCr is delayed, making it insen- sitive for early d iagnosis ( l missed therapeutic opportunities). It is also unable to differentiate pre-rena l AKI from ATN. Novel biomarkers include: (i) LMW proteins that undergo glomerular \201 ltration prior to reabsorption in the proximal tubule (damaged tubules l i urinary excretion); (ii) enzymes that are released into the urine after tubular cell injury ( l markers of tubular damage); and (iii) in \202 ammatory mediators released by renal cells or in \201 ltrating in \202 ammatory cells ( l markers of site and degree of injury) (see Fig. 2.1). Use in clinical practice The ideal biomarker should provide additional information not avai lable from clinical evaluation and traditional tests. The main problem to date is that stud ies have been performed either in de \201 ned clinical settings (where the timing of the r enal insult is understood, e.g. after cardiopulmonary bypass, coronary angiography, or foll owing renal transplantation) or in children (where there are no confounding comorbidities, such as CKD, diabetes mellitus, and chronic in \202 ammatory disease). As a result, curren tly available data cannot necessarily be generalized to more heterogeneous populations, suc h as critically ill patients in ICU. However, it is hoped that ongoing studies will demonst rate the utility of novel biomarkers to improve recognition, management, and outcomes for A KI. Putative biomarkers under study Neutrophil gelatinase-associated lipocalin (NGAL) A 25kDa g lycoprotein produced by epithelial tissues in several organs. Excreted via glomerular \201 ltration and completely reabsorbed by tubular cells. Also produced in distal tubular c ells (renal ischaemia l i NGAL expression). Appears to be anti-apoptotic and to upregulate heme oxygenase-1. Urinary NGAL is sensitive and speci \201 c for early ATN (no i in pre-re nal AKI). Rises 2 \200\223 4h post-AKI; common confounders: sepsis, malignancy, CKD, COPD, pancreatitis. Clinical utility now tested in many scenarios, including cardiac surgery and contrast toxicity. Plasma NGAL may also help to predict likelihood of renal recovery. 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).