Clinical syndromes: bladder outfl ow
CLINICAL SYNDROMES: BLADDER OUTFLOW OBSTRUCTION 79
Box 1.11 Causes of bladder outfl ow obstruction • Congenital:
• Urethral valves and strictures.
• Structural:
• Benign prostatic hyperplasia ( b p. 758).
• Carcinoma of the prostate ( b p. 766).
• Bladder neck stenosis.
• Urethral stricture.
• Functional:
• Bladder neck dyssynergia.
• Neurological disease — spinal cord lesions, MS, diabetes.
• Drugs — anticholinergics, antidepressants.
Prostatic enlargement ( b p. 758)
• Prostate size correlates poorly with degree of obstruction on urodynamic assessment.
• Impaired fl ow is a function of two separate components:
• Dynamic: i sympathetic tone of prostatic smooth muscle.
• Static: mass effect of enlargement.
Renal biopsy: introduction
Despite improvements in other diagnostic techniques, renal biopsy and examination of histology retain pivotal roles in nephrology.
Renal transplant biopsy is considered separately ( b p. 407).
Indications ( b p. 82)
• Unexplained acute or chronic kidney disease with normal renal size.
• Histology is likely to infl uence treatment.
• Histology is likely to offer prognostic information.
• Information concerning the activity (and potential reversibility) and/or chronicity of a previously identifi ed lesion is desirable.
Preparation for renal biopsy
• Renal biopsy is an invasive procedure. An evaluation of the risk-benefi t ratio is required in every case.
• Imaging: confi rm two normal-sized, unobstructed kidneys with normal parenchyma.
• BP <160/90mmHg; preferably <140/90mmHg.
• Hb ideally >100g/L.
• Normal clotting (PT and APTT <1.2 x control). Platelet count
>100 x 10 9 /L.
• Send group and save.
• Antiplatelet agents and anticoagulants stopped >5 days prior to procedure. Ideally, do not restart for 7 days post-biopsy.
• Sterile urine.
• Informed consent. Give appropriate written or visual patient information.
• If renal impairment, the risk of bleeding increases 7 2 – 3-fold.
• Most units will have their own policy, e.g. if urea ≥ 20mmol/L (55mg/
dL) or SCr ≥ 250 μ mol/L (2.8mg/dL) or bleeding time >10min, give DDAVP 0.4 micrograms/kg IV 2 – 4h pre-biopsy ( not if recent or ongoing angina).
Contraindications
• Uncorrected bleeding tendency (absolute contraindication).
• Chronic kidney disease with small kidneys.
• Multiple cysts.
• Suspected renal malignancy ( b p. 743).
• Hydronephrosis.
• Active urinary infection.
• Uncontrolled hypertension (>160/95mmHg).
• Hypotension.
• Signifi cant anaemia.
• Uncooperative patient.
• Solitary kidney (only a relative contraindication).
RENAL BIOPSY: INTRODUCTION 81
Technique
• Performed percutaneously under LA via a posterior approach.
• Sedation is generally avoided, as patient cooperation is essential.
• Patient lies prone, with a pillow under the abdomen to straighten the spine.
• USS locates the kidneys, determines their size, and identifi es cysts.
• Either kidney may be biopsied.
• A lower pole biopsy reduces the risk of piercing a major vessel.
• USS is used to directly guide the needle to the kidney ‘real time ’ . • LA is infi ltrated down to the renal capsule, using a spinal needle.
• 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.
• Disposable TruCut ® 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 needle. 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 operator after two unsuccessful passes.
• Routine processing includes light, immunofl uorescence (or immuno-histochemistry), and EM. Biopsy material is divided, as different fi xatives are required for the different techniques, e.g. glutaraldehyde for EM.
• Patient remains on bed rest, with a good fl uid intake for 6 – 8h. Pulse and BP are monitored regularly 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. These should be deemed low risk, as complications actually occur after 6 – 8h in 7 1/3 cases.
• High risk 6 not for day case: SCr >200 μ mol/L (2.2mg/dL), BP
>140/90mmHg, small renal sizes ( b p. 84).
Open renal biopsy
• 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.
• More tissue can potentially be obtained.
• The risk of a GA may actually exceed that of a percutaneous biopsy.
• Laparoscopic techniques have been described.
Transvenous renal biopsy
• An endovascular technique developed in hepatology and not widely 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.
Renal biopsy: indications
Clinical syndromes: when to biopsy?
2 There is no such thing as a ‘routine ’ renal biopsy.
X Microscopic haematuria ( b p. 66)
• Practice varies, but most do not biopsy, unless there is associated proteinuria and/or renal impairment (either at presentation or during the course of follow-up). Isolated microscopic haematuria generally has an excellent prognosis, and histology will not infl uence management.
• Possible exceptions: suspected systemic condition (e.g. SLE, vasculitis), potential live kidney donors, or for insurance or employment reasons.
Proteinuria
X Non-nephrotic proteinuria (<3.5g/24h)
• Many recommend a biopsy at modest levels of proteinuria to ensure potentially treatable lesions, e.g. primary FSGS and membranous 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.
• Some clinicians use an arbitrary ‘cut-off ’ level of proteinuria to guide their decision-making (e.g. biopsy if >1g/24h — 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 insuffi ciency weighs in favour of a biopsy.
Nephrotic range proteinuria
• A biopsy is generally recommended. Two exceptions:
• Minimal change disease in childhood. In this situation, an initial trial of steroids may be appropriate.
• Diabetic nephropathy ( b p. 611).
Acute nephritic syndrome
The need to confi rm diagnosis and adapt treatment, according to the type and severity of the renal lesion, mandates a biopsy in the majority of cases, even when the diagnosis is suggested by serological tests (e.g. anti-GBM disease or ANCA +ve vasculitis).
Acute kidney injury ( b p. 121)
• 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 are:
• Renal size. If <9cm, a biopsy is technically more demanding and histology is more likely to show chronic, non-specifi c, irreversible change (with the original insult not identifi 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 excretion is low (e.g. <1g/24h or uPCR <100mg/
mmol).
Systemic disease potentially involving the kidney
• Immunological or serological testing ( b p. 40) may provide important diagnostic clues (e.g. ANCA +ve vasculitis, anti-GBM disease), but renal biopsy will confi rm the diagnosis and assess the degree of activity and potential reversibility. This aids decision-making around the type and duration of treatment.
• This is particularly true of lupus nephritis where classifi cation of the renal lesion is a cornerstone of management.
• In some conditions, demonstrable renal involvement may be an important determinant of the need for systemic treatment, e.g.
myeloma.
• Other important systemic conditions that often precipitate a renal biopsy include sarcoidosis and amyloidosis.
Renal biopsy: complications
Introduction
In general, percutaneous kidney biopsy is a safe procedure, and serious complications are uncommon. However, less serious sequelae, such as pain and mild bleeding, are relatively common, so it is important to explain the potential for these to the patient pre-procedure.
Higher risk 1
• Uncorrected bleeding tendency ( 3 do not biopsy).
• i BP (>130mmHg systolic).
• d GFR, especially if SCr >177mmol/L (2.0mg/dL).
• Small renal sizes (<10cm).
• Hb <120g/L.
• Older age (>40).
• Use of larger (e.g. 14-gauge) biopsy needle.
Complications • Pain:
• Dull ache around the needle entry point and tract is almost universal once LA effect wears off.
• Simple analgesia is often necessary.
• Severe pain raises the possibility of a signifi cant perirenal bleed and should prompt assessment 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.
• Three potential sites:
• Collecting system ( l haematuria).
• Within the renal capsule ( l pain).
• Perinephric space ( l haematoma).
• A degree of capsular or perirenal bleeding accompanies almost every renal biopsy.
• A Hb drop ≤10g/L is common.
• Asymptomatic haematomas can be detected on USS in up to 30%
patients.
• A larger capsular haematoma (pain, signifi 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 ‘page ’ kidney).
• Transient microscopic haematuria is present in virtually all patients.
• Macroscopic haematuria in 7 3.5%.
• Gross haematuria may cause painful clot colic 9 ureteral obstruction.
• Transfusion required in 7 1%.
• Endovascular intervention to control bleeding in 0.6%.
• Nephrectomy to control bleeding in 0.01%.
RENAL BIOPSY: COMPLICATIONS 85
• Arteriovenous fi stula:
• 7 18% on Doppler but rarely symptomatic; may cause persistent haematuria and (rarely) hypertension.
• Most resolve spontaneously within 12 – 24 months.
• Embolization may be an option in those that remain symptomatic.
• Incorrect tissue obtained:
• Usually muscle, fat, liver, spleen.
• Colonic perforation.
• Perirenal infection (0.2%).
• Peritoneal-calyceal fi stula.
• Death (0.02%).
3 Management of signifi cant bleeding
• Seek expert help.
• Bed rest.
• Regular pulse, BP, and O 2 saturations (every 15min).
• Ensure adequate IV access and commence fl uid resuscitation as necessary.
• Reassure the patient, and ensure adequate analgesia.
• Check Hb, and repeat after 2, 4, 8, and 12h as a minimum.
• Cross-match at least 2 units of blood, and transfuse as necessary.
• Repeat clotting studies post-biopsy. Correct coagulopathies.
• Maintain a high urine fl ow with IV fl uids to prevent ureteral obstruction and clot colic.
• Consider a 3-way urethral catheter for irrigation if clot retention and bladder outfl ow obstruction.
• Inform surgical team.
• Do not move the patient for imaging until they are stabilized. An ultrasound is unlikely to be of value beyond the identifi cation of a haematoma. A contrast CT may identify ongoing active bleeding, but the patient ’ s clinical status 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 native kidney biopsy: a systematic review and meta-analysis. American Journal of Kidney Diseases , 60 , 62 – 73.
87
Acute kidney injury (AKI)
Defi nition 88 Epidemiology 92 Biomarkers of AKI 94 Causes and classifi cation 96 Prevention 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 AKI: priorities 112
Assessing AKI: clinical clues 114 Assessing AKI: urinalysis 116 Assessing AKI: blood tests 118 Assessing AKI: imaging 120 Assessing AKI: histology 121 AKI management: a checklist 122
AKI management: volume replacement — which fl uid? 124 AKI management: volume replacement — how much? 126 AKI management: hyperkalaemia 130
AKI management: pulmonary oedema 134 AKI management: electrolytes and acidosis 136 AKI management: 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: management 154 AKI in cirrhosis 156
Management of HRS 158 Tumour 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
RRT in AKI: choosing modality? 176 RRT in AKI: prescription 178 RRT in AKI: anticoagulation 182
RRT in AKI: citrate regional anticoagulation 186 Peritoneal dialysis (PD) in AKI 188
Chapter 2
Defi nition
Introduction
Acute kidney injury (AKI) (formerly acute renal failure) is the syndrome arising from a rapid fall in GFR (over hours to days). It is characterized by retention of both nitrogenous (including Ur and Cr) and non-nitrogenous waste products of metabolism, as well as disordered electrolyte, acid – base, and fl uid homeostasis.
22 There is evidence that even relatively small acute reductions in kidney function are associated with poorer outcomes, including increased mortality, higher risk of long-term dialysis, and longer hospital stay.
Historical limitations
• Despite a relative insensitivity to acute changes in GFR, most defi nitions of acute renal dysfunction have been based on serum Cr, either as an absolute value or as a change from baseline. Other defi nitions have incorporated urine output (UO) or the need for dialysis support.
• A 2004 survey of 598 participants at a critical care nephrology conference revealed 199 different criteria to defi 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
• In response, the Acute Dialysis Quality Initiative established a multilayered defi nition of AKI called the RIFLE criteria.
• AKI is stratifi ed into fi ve stages, based on severity and duration of renal injury: 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.
• RIFLE-defi ned AKI is associated with signifi cantly reduced survival (with increasing RIFLE stage leading to greater risk of death).
Acute Kidney Injury Network (AKIN) classifi cation
• More recently, AKIN (an international network of AKI experts) modifi ed RIFLE to incorporate small changes in SCr occurring within a 48h period and to remove changes in GFR as diagnostic criteria (see Table 2.1).
KDIGO AKI defi nition (2012)
• AKI, classifi ed by either of the earlier listed criteria, may identify slightly different patients: RIFLE may not detect 7 10% of AKIN-identifi ed cases, and AKIN may miss 7 25% RIFLE cases.
• KDIGO have recently produced a defi nition that incorporates the key elements of both, and it is likely that this defi nition will become the accepted standard.
DEFINITION 89
Key elements of KDIGO AKI defi nition • Increase in SCr by ≥ 26.5μmol/L ( ≥ 0.3mg/dL) within 48h.
• Increase in SCr by ≥ 1.5 x baseline (known or presumed to have occurred within prior 7d).
• Urine volume <0.5mL/kg/h for 6h.
(Only one criterion needs to be present to fulfi ll the defi nition.)
Table 2.1 The evolving defi nition of AKI (a) RIFLE classifi cation 1
RIFLE category SCr/GFR criteria Urine output criteria Risk i SCr ≥ 150 – 200% (1.5 – 2-fold) OR
decrease of GFR >25%
<0.5mL/kg/h for 6h
Injury i SCr >200 – 300% (>2 – 3-fold) OR decrease of GFR >50%
<0.5mL/kg/h for 12h
Failure i SCr >300% (>3-fold) from baseline OR decrease of GFR >75% OR SCr≥350μmol/L (≥4.0mg/dL) with an acute rise of at least 45μmol/L (0.5mg/dL). Or on RRT.
<0.3mL/kg/h for 24h OR anuria for 12h
Loss Complete loss of renal function for
>4 weeks End-stage
kidney disease
Need for RRT for >3 months
(b) AKI network classifi cation 2
AKIN stage Serum creatinine criteria Urine output criteria 1 SCr ≥ 26.4μmol/L (0.3mg/dL) in ≤ 48h OR
i SCr ≥ 150 – 200% (1.5 – 2-fold) from baseline
<0.5mL/kg/h for >6h
2 SCr >200 – 300% (2 – 3-fold) from baseline <0.5mL/kg/h for >12h 3 SCr ≥ 300% (3-fold) from baseline OR SCr
≥ 354μmol/L (>4mg/dL) with an acute rise of ≥ 44μmol/L (0.5mg/dL) OR treatment with RRT
<0.3mL/kg/h for 24h OR anuria for 12h
(c) KDIGO classifi cation 3
Stage Serum creatinine criteria Urine output criteria 1 1.5 – 1.9 times baseline OR ≥ 0.3mg/dL
(>26.5μmol/L) in ≤ 48h
<0.5mL/kg/h for 6 – 12h
2 2 – 2.9 times baseline <0.5mL/kg/h for ≥ 12h 3 ≥ 3 times baseline OR increase in SCr to
≥ 4.0mg/dL (354μmol/L) OR initiation of RRT
<0.3mL/kg/h for ≥ 24h OR anuria for ≥ 12h
GFR, glomerular fi ltration rate; RRT, renal replacement therapy; SCr, serum creatinine. Only one criterion needs to be met to be classifi ed as AKI; if both are present, the criterion which places the patient in the higher stage of AKI is selected.
1 R. Bellomo, et al . Critical Care, vol. 8, no. 4, pp. R204–R212, 2004.
2 R. L. Mehta, et al . Critical 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
Reference
1. Ricci Z, Ronco C, D’Amico G, et al . (2006). Practice patterns in the management of acute renal failure in the critically ill patient: an international survey. Nephrology Dialysis Transplantation , 21 , 690 – 6.
Acute kidney disease (AKD)
• Strict adherence to defi nitions of both acute (AKI) and chronic (CKD) renal disease may miss individuals with functional or structural abnormalities present for <3 months but who may benefi t from active intervention to restore kidney 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 decrease in GFR by ≥ 35% or an increase in SCr by >50% for <3 months.
DEFINITION 91
Epidemiology
Incidence
Depends on the population studied and the defi nition used, meaning few studies historically have been able to provide accurate incidence data.
However, the more recent use of AKIN/RIFLE criteria has improved this. It remains important to recognize 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 earlier identifi cation.
Hospital
• 5 – 10% of general admissions.
• 20 – 25% of patients with sepsis and 7 50% with septic shock.
• 50% of all ITU admissions (where it acts as an independent risk factor for mortality of 20 – 60%, depending on AKI stage).
Community
• 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.
• Community-based studies in the UK (SCr >300μmol/L or 3.4mg/dL) estimate 486–620 pmp. This is age- and comorbidity-related (17 pmp aged <50 and 949 pmp aged 80–89).
• 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, signifi cant complication rates (including infection), risk of CKD (including ESRD), development of CV disease, and higher mortality.
Mortality
• Outcomes for the new AKIN criteria by stage are shown in Table 2.2.
• 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 replacement therapy), overall mortality in AKI requiring RRT remains >50% (refl ecting a high 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 ≥ 27 μ mol/L (0.3mg/dL) 4.1
≥ 45 μ mol/L (0.5mg/dL) 6.5 ≥ 90 μ mol/L (1.0mg/dL) 9.7 ≥ 180 μ mol/L (2.0mg/dL) 16.4
Chertow G M, Burdick E, Honour M, et al . (2005). Acute kidney injury, mortality, length of stay, and costs in hospitalized patients. Journal of American Society of Nephrology , 16 , 3365 – 70.
Renal recovery
Recovery of renal function will depend on underlying diagnosis. For ATN, 7 50% 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 CKD 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 signifi 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 – 85.
Biomarkers of AKI
Introduction
Driven by the recognition that even relatively small increases in SCr were associated with a poor outcome and increased healthcare costs, the 2005 American 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 populations and clinical settings.
SCr is a suboptimal biomarker of AKI. i SCr is delayed, making it insen-sitive for early diagnosis ( l missed therapeutic opportunities). It is also unable to differentiate pre-renal AKI from ATN.
Novel biomarkers include: (i) LMW proteins that undergo glomerular fi 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) infl ammatory mediators released by renal cells or infi ltrating infl 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 available from clinical evaluation and traditional tests. The main problem to date is that studies have been performed either in defi ned clinical settings (where the timing of the renal insult is understood, e.g. after cardiopulmonary bypass, coronary angiography, or following renal transplantation) or in children (where there are no confounding comorbidities, such as CKD, diabetes mellitus, and chronic infl ammatory disease). As a result, currently available data cannot necessarily be generalized to more heterogeneous populations, such as critically ill patients in ICU. However, it is hoped that ongoing studies will demonstrate the utility of novel biomarkers to improve recognition, management, and outcomes for AKI.
Putative biomarkers under study Neutrophil gelatinase-associated lipocalin (NGAL)
A 25kDa glycoprotein produced by epithelial tissues in several organs.
Excreted via glomerular fi ltration and completely reabsorbed by tubular cells. Also produced in distal tubular cells (renal ischaemia l i NGAL expression). Appears to be anti-apoptotic and to upregulate heme oxygenase-1. Urinary NGAL is sensitive and specifi c for early ATN (no i in pre-renal AKI). Rises 2 – 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 released into plasma at a constant rate ( b p. 36). Freely fi ltered in glomeruli and completely reabsorbed in the proximal tubule. Detectable in urine 12 – 24h after renal injury. Results confounded by systemic infl am-mation, malignancy, thyroid disorders, smoking, glucocorticoid defi ciency and excess.
BIOMARKERS OF AKI 95
Interleukin-18
An 18kDa proinfl ammatory cytokine. Released from proximal tubular cells. Rises 6 – 24h after renal injury. Confounders: infl 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 – 24h after renal injury.
Confounders: 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 fi 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, produced in various organs as well as proximal tubular cells. Freely fi ltered by glomeruli and reabsorbed in proximal tubular cells. Detectable in urine within 1h, i.e. soon after injury.
A glutathione S-transferase ( A GST) and η glutathione S-transferase 47 – 51kDa cytoplasmic enzymes, produced in distal tubular cells. Urinary levels increase within 12h.
Other promising biomarkers
Urinary insulin-like growth factor-binding protein 7 (IGFBP7) and 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 profi ling and other techniques have identifi ed many other candidates, including the Na + /H + exchanger (NHE3), perforin, granzyme B, and monocyte chem-oattractant protein (MCP)-1.
It is hoped that combining biomarkers into an ‘AKI panel ’ will further improve sensitivity and clinical utility.
0 10 20 30 40
L-FABP NGAL IL-18 SCr Idealized
KIM-1
Time (hours)
Relative levels
Fig. 2.1 Temporal relationship of studied AKI biomarkers to injury.
The characteristics of an ideal biomarker are also shown.