AKI management: electrolytes and acidosis
Step 5: ensure volume and electrolyte content appropriate for AKI
• Low volume and low electrolyte feeds are often necessary.
• Requirements may change as renal support is initiated (and will depend on whether intermittent dialysis or CRRT).
• Consider high dose vitamin administration (e.g. Pabrinex®) if pre-existing malnutrition.
Reference
3. Schofi eld WN (1985). Predicting basal metabolic rate, new standards and review of previous work. Human Nutrition Clinical Nutrition , 39 , 5 – 41.
Table 2.5 Administration routes Route What’s in it? Notes Concerns in AKI Complications Oral: Nutrition-dense oral diet Supplementary sip feeding Modest protein and energy content. Many patients can tolerate an oral diet. Supplementation with nutrition drinks useful if appetite poor.
Observe restrictions: K + PO 4 Volume Enteral Enteral feeding formulae specifi cally for AKI are available; e.g. Nepro ® (Ross), Nova source renal ® (Novartis). Ensure correct position of NG tube (aspirate pH or CXR). Start at 30mL/h. Allow 4h bowel rest in every 24h.
Enteral feeding maintains the structural integrity of the gut and protects against translocation of Gl bacteria.
A tailored regimen (i.e. non-standard feed) may be necessary if the above restrictions apply. To prevent refeeding syndrome in a malnourished patient, K + , PO 4 , and Mg 2+ must be checked and corrected prior to commencement.
Mechanical: dislodged tube. Gastrointestinal: abdominal distension, nausea, cramps, and diarrhoea. Infectious: aspiration pneumonia. Metabolic: hyper/ hypoglycaemia, electrolyte abnormalities.
AKI MANAGEMENT: NUTRITION 143
Parenteral Amino acids: combined essential and non-essential (the latter often become ‘conditionally ’ essential in the context of AKI) Energy: principally given as glucose, although >5g/kg/day causes CO 2 production (increasing respiratory demands), lipogenesis (fatty liver), and hyperglycaemia. Lipids are used to provide the remainder (usually ≤1g/ kg/day to avoid hyperlipidaemia). Vitamins, trace elements, electrolytes (and sometimes insulin) are added, as necessary.
IV lipids have a low osmolality and can be given into peripheral veins. They do not meet all energy requirements so are mainly a short-term measure. Full TPN must usually be given centrally (via a dedicated line). If possible, a small amount of enteral feed is run concurrently.
Start feed slowly. Continuous renal replacement techniques (e.g. CVVHF) assist the delivery of feeding.
Catheter insertion: pneumothorax, etc. Catheter infection . Metabolic: requires close laboratory monitoring.
AKI management: myths
Loop diuretics
Theory. (i) i urinary fl ow ‘washes out ’ cellular debris, casts, and nephro-toxins from tubules; (ii) blockade of active transport processes l d tubular O 2 consumption and protects against ATN; (iii) vasodilator action l i RBF.
Evidence. None to suggest improved renal or patient outcome in any AKI setting. In particular, the natural history and prognosis of ATN remains unchanged. Some studies have suggested harm . May increase diuresis, however, assisting the management of fl uid balance and preventing pro-gressive volume overload. 2 Given as part of the treatment of pulmo-nary oedema ( b p. 134). 1 The only indication for diuretics is volume overload.
Mannitol
An osmotic diuretic, previously used for the prevention of ATN in high-risk CV surgery. A lack of evidence means the practice is in decline. Can para-doxically cause pulmonary oedema through volume expansion. Avoid.
Dopamine
Previously widely used for the prevention and treatment of AKI. A lack of evidence for effi cacy and potential risk of harm have led most to abandon this practice. You should do the same.
Theory. Dopamine (DA) is synthesized in the proximal tubule from cir-culating L-dopa and helps regulate Na + excretion and renal vasodilata-tion through specifi c DA1 and DA2 receptors. Exogenously administered
‘low-dose ’ dopamine should l renal vasodilatation l i RBF l i natriuresis and mild i GFR. All would be of potential benefi t in AKI, although evi-dence suggests these mechanisms may not remain intact in renal insuf-fi ciency. (See Table 2.6.)
Table 2.6 Dopamine effects Micrograms/
kg/min
Effect
0.5 – 3 Selective DA (mainly DA1) receptor activation l i renal (and mesenteric) blood fl ow
3 – 10 Both DA and B 1 receptors are activated, the latter l i cardiac output (mainly by i SV).
10 – 20 B 1 effect predominates. Starts to activate A adrenoreceptors.
>20 A adrenergic (vasoconstrictive) effect takes over with i SVR.
AKI MANAGEMENT: MYTHS 145
Evidence. Largely anecdotal or from inadequate studies. Larger trials (e.g.
ANZICS) have failed to show benefi t.
1 It may cause harm : tachycardia, arrhythmias, myocardial ischaemia, blunted hypoxaemic drive, splanchnic vasoconstriction ( l bacterial translocation), digital ischaemia, impaired pituitary function, electrolyte disturbances (even at ‘renal ’ dose), impaired T cell function. Dopamine accumulates in renal failure.
Other ‘renoprotective’ agents Fenoldopam
• Dopaminergic agonist that acts through DA1 receptors (without signifi cant A or B adrenergic activity) to produce afferent and efferent arteriolar vasodilatation.
• Preserves renal blood fl ow and tissue oxygenation in animal studies.
• Human studies (mainly small) have yielded variable results in several clinical contexts, including AKI prevention post-cardiac surgery.
• Larger randomized studies are awaited. In the meantime, fenoldopam use is not recommended in the KDIGO (2012) guideline.
Atrial natriuretic peptides
• ANP l d tubular Na + reabsorption, i afferent arteriolar vasodilatation, and d RAS activation.
• Tested in a post-surgical context in multiple studies, but overall quality of study evidence is variable and inconsistent.
• Can induce signifi cant, and potentially harmful, hypotension.
• Other natriuretic peptides have been tried, e.g. brain natriuretic peptide (nesiritide) and urodilatin.
• Not recommended in KDIGO (2012) guideline.
N-acetylcysteine
• Most widely studied in the context of contrast-induced AKI ( b p. 150).
• NAC is a modifi ed form of the amino acid L-cysteine, a precursor of glutathione.
• NAC is a potent free radical scavenger and antioxidant that also possesses vasodilator properties (via nitric oxide availability).
• Shown to reduce ischaemic and nephrotoxic ATN in animal studies but clinical evidence lacking.
• Not recommended in KDIGO (2012) guideline.
AKI: hope for the future?
Phases of ATN (see also b p. 108)
There are four pathophysiological/temporal phases of ATN that can help to conceptualize where pharmacological interventions might be targeted and applied.
Initiation phase
Characterized by aberrant vascular reactivity, diminished renal perfusion, and widespread oxidative injury.
Extension phase
A proinfl ammatory state, with macrophage activation, infl ammatory medi-ator release, and stimulation of epithelial and endothelial cells.
Maintenance phase
Restoration of tubular cell integrity through the division of adjacent tubu-lar cells and the differentiation of local (kidney) and systemic (haematopoi-etic — X ) stem cells.
Repair phase
Normal tubular cell function is restored.
Very broadly speaking, therapeutic interventions can, therefore, attempt to decrease vascular reactivity, moderate infl ammation, preserve cell via-bility, and augment cell repair.
Putative agents are shown in Table 2.7.
Many of these are currently being studied in animal models of renal ischaemia-reperfusion injury, but benefi t in human AKI is yet to be demon-strated. There are many potential reasons for this: AKI is a heterogeneous condition (both in terms of the type of patient affected and the underlying cause); study endpoints (such as mortality) are often confounded, and, until recently, there was no agreed consensus defi nition of AKI. Furthermore, late detection of AKI prevents timely administration. It is hoped that novel AKI biomarkers will facilitate earlier intervention ( b p. 94).
AKI: HOPE FOR THE FUTURE? 147
Table 2.7 Putative therapeutic strategies in AKI Pathogenic mechanism
targeted
Interventions currently of unproven benefi t in humans
Ameliorate renal vasoconstriction
Endothelin receptor antagonists (e.g. tezosentan) Leukotriene receptor antagonists
PAF antagonists
iNOS antisense oligonucleotides Phosphodiesterase inhibition (e.g. milrinone) Haem-oxygenases
Attenuate infl ammation Anti-ICAM-1 monoclonal Ab Anti-IL-18 monoclonal Ab
N-acetylcysteine, desferrioxamine, and/or other free radical scavengers
A -MSH Adenosine Minocycline Corticosteroids
Fibroblast growth factor-inducible 14 (Fn14) blockade
Prevention of apoptosis and necrosis
Erythropoietin (initial trials disappointing) Protease (e.g. caspase) inhibitors Guanosine
Pifi thrin A (p53 inhibitor) PARP inhibition Prevention of tubular
obstruction
Diuretics RGD peptides Promoting tubular
regeneration
Insulin-like growth factor (IGF) Thyroxine
Epidermal growth factor Hepatocyte growth factor Osteopontin
Stem cell therapy (early studies with stem cells in high-risk patients undergoing cardiac bypass surgery have been promising)
PAF, platelet-activating factor; RGD peptides, peptides containing the arginine – glycine – aspartic acid motif (involved in adhesion); ICAM-1, intercellular adhesion molecule-1; A -MSH, A -melanocyte-stimulating hormone; PARP, poly ADP-ribose polymerase.
Contrast-induced AKI (CI-AKI)
Introduction
CIAKI accounts for 7 10% of inhospital AKI and is associated with signifi -cant mortality ( x 5.5 odds adjusted risk of death), prolonged hospitaliza-tion, and future cardiovascular events. It may also irreversibly d GFR (esp.
in those with pre-existing CKD). These adverse outcomes are worse in those who require dialysis treatment (2-year mortality rate >80% in one study!).
CI-AKI risk is low ( 7 1 – 2%) in patients with normal renal function (even in the presence of diabetes) but much higher in patients with pre-existing renal impairment ( 7 25%), particularly in the presence of additional risk factors (see Box 2.2 — these factors are additive).
Why is contrast toxic?
• Direct toxicity: oxidant injury to proximal tubular cells.
• Vasomotor effects: contrast (perhaps through its osmolality) alters afferent/efferent tone and thus glomerular perfusion.
• 2 AKI s to ATN results.
Box 2.2 Risk factors
• Pre-existing CKD.
• Diabetes mellitus.
• Hypertension.
• Cardiac failure.
• Volume depletion.
• Haemodynamic instability.
• i Age.
• Hyperuricaemia.
• Renal transplantation.
• Concurrent nephrotoxic drug administration.
• High contrast volumes.
• Intra-arterial contrast.
Precautions
• Specifi c measures are discussed on b p. 149.
• Recognize those at risk (see Box 2.2). For ambulatory patients in whom a recent measurement of renal function is not available, a simple questionnaire may identify those at increased risk. 4 , 5 • Dipstick proteinuria will also help identify individuals in whom
measurement of renal function is desirable.
• 1 Many high-risk patients may not be suitable for ‘day case ’ procedures.
• Is the procedure really necessary? Is there an alternative ‘non-contrast ’ technique? Speak to your radiologist.
• Use iso-osmolar, non-ionic contrast.
• Minimize contrast volume (<100mL, if possible).
• 2 Optimize volume status pre-study.
CONTRAST-INDUCED AKI (CI-AKI) 149
• Stop all other nephrotoxins prior to procedure (including high doses of loop diuretics).
• X Although often undertaken, there is no evidence that cessation of ACE-I, ARBs, or metformin prior to contrast administration is protective.
• Space out multiple procedures whenever possible.
• Inform your renal team of high-risk cases (beforehand!).
Clinical features
• d GFR begins immediately (although SCr may be unchanged initially).
• The earliest (and often only) sign may be oliguria ( 2 so ensure UO is being measured in high-risk hospitalized patients).
• i SCr at 12h is the best predictor of CI-AKI.
• Peak SCr usually occurs at 2 – 3d but can be delayed 5d in a minority of cases.
• In practice, CI-AKI often becomes apparent when renal function is rechecked the day after a procedure (so make sure it is checked and that you see the result).
• Although rarely (if ever) measured, fractional urinary excretion of Na + often remains <1% (unlike other causes of ATN). This fact is useful for exam purposes only.
Treatment
• Once established, treat as for any other cause of ATN.
• Ensure adequate hydration, and avoid additional nephrotoxins.
• Standard indications for dialysis support apply ( b p. 172).
Prognosis
• In the majority, renal dysfunction is mild and transient (although still associated with i mortality).
• Recovery within a week is usual. Those with pre-existing advanced CKD are most susceptible to a permanent d GFR.
• Dialysis support will be necessary in 3 – 4% of those with underlying CKD, and long-term renal replacement therapy will be required in the minority of these.
Strategies to prevent RCN Hydration
• IV fl uids correct volume depletion and i RBF. They also minimize the pre-renal effects of a post-contrast diuresis.
• Evidence supporting their use is strong. Example regimens:
• 1.26% NaHCO 3 3mL/kg/h for 1h pre- and 1mL/kg/h for 6h during and post-procedure.
• 0.9% NaCl 1mL/kg/h for 12h pre- and 12h post-procedure.
• NaHCO 3 may have theoretical advantages over other IV fl uids through an antioxidant effect (peroxynitrate scavenging), but this remains poorly defi ned and clinically unproven.
• Examine the patient fi rst — if overtly dehydrated, then larger volumes may be required and the procedure may need to be postponed. If already volume-overloaded, then further fl uids are ill advised.
• Aim for a good urine output (>150mL/h).
• In diuretic dependent patients, withholding diuretics may be suffi cient
‘hydration’.
Others
• There has been interest in both theophylline (antagonizes adenosine-mediated d RBF) and fenoldopam (specifi c dopamine 1 receptor agonist), but clinical studies have been disappointing and their use is not recommended (although a recent meta-analysis has suggested there may yet be a role for theophylline. 6
• Haemofi ltration/haemodialysis: ‘prophylactic ’ removal of circulating contrast, particularly in those with advanced CKD. No convincing evidence of benefi t. Costly with signifi cant potential adverse effects.
(See Fig. 2.14.)
2 All centres should have a locally agreed protocol, usually based on risk assessment and fl uid 9 NAC administration. An algorithm produced by LAKIN is shown in Fig. 2.14.
References
4. KDIGO. Available at: M < http://kdigo.org/home/guidelines/acute-kidney-injury/ >.
5. Choyke PL, Cady J, DePollar SL, et al. (1998). Determination of serum creatinine prior to iodi-nated contrast media: is it necessary in all patients? Techniques in Urology , 4 , 65 – 9.
6. Dai B, Liu Y, Fu L, et al. (2012). Effect of theophylline on prevention of contrast-induced acute kidney injury: a meta-analysis of randomized controlled trials. American Journal of Kidney Diseases , 60 , 360 – 70.
X N-acetylcysteine (NAC)
• Used for its antioxidant properties, always in conjunction with hydration.
• The evidence underpinning NAC use from randomized trials and meta-analyses is inconsistent, with many actually suggesting no benefi t.
• NAC may d SCr independently of GFR through interference with tubular handling.
• Side effects are rare for the doses relevant to CI-AKI prevention (unlike those for paracetamol overdose); however, marginal effects on cardiac function and coagulation have been described.
• A typical regimen is 600 – 1200mg capsules PO 12h x 4 doses (generally two doses pre-contrast and two doses post).
• Despite the lack of compelling evidence, low cost and a favourable side effect profi le have led to widespread use — as well as retention in several guidelines (although not KDIGO (2012)).
CONTRAST-INDUCED AKI (CI-AKI) 151
Differential diagnosis
Many patients undergoing invasive endovascular studies have diffuse ath-erosclerotic disease and are at risk of renal atheroemboli. These may occur as a distinctive clinical syndrome ( b p. 590) but can often go unrecognized until the anticipated recovery of renal function fails to materialize.
Monitor function to 72 hours in high-risk cases If oliguria or rising creatinine, early referral to local renal team.
NB There is no proven role for N-acetylcysteine, post-contrast dialysis/CVVH or routine cessation of metformin or ACE inbitors.
High volume (>100mL) iodinated contrast procedure and
CKD with eGFR <60 (particularly diabetic nephropathy) or AKI
Other risk factors dehydration, heart failure, severe sepsis, cirrhosis, nephrotoxins (NSAIDs, aminoglycosides).
Risk factors are multiplicative.
Give prophylaxis if high risk
Volume expansion (unless hypervolaemic) with normal saline or 1.26% bicarbonate Sample regimens
IV Na bicarbonate 1.26% 3mL/kg/h for 1 hour pre-procedure and 6 hours post-procedure or
IV 0.9% normal saline 1mL/kg/h pre- and 12 hours post-procedure Contrast-induced nephropathy (CIN) prophylaxis
Assess risk
Is contrast procedure necessary?
Resuscitate to euvolaemia
Minimize contrast, use low or iso-osmolar contrast Yes
Fig. 2.14 The LAKIN contrast-induced nephropathy algorithm. Reproduced from London AKI network manual (2012), with permission. M http://www.londonAKI.
net/clinical
Rhabdomyolysis
Introduction
First described as ‘crush syndrome ’ during the London blitz of WWII.
Rhabdomyolysis is a clinical syndrome caused by release of cellular con-tents after a signifi cant injury to striated muscle.
Injury is caused by either energy depletion and cell death or, more commonly, during reperfusion of ischaemic muscle. Infi ltrating leucocytes release oxidant species that cause myonecrosis. If cell death is widespread, intracellular elements and membrane products are released into the cir-culation: creatine kinase (mainly MM isoenzyme but also MB), LDH, myo-globin, purines ( l hyperuricaemia), electrolytes (esp. K + and PO 4 ), and aminotransferase enzymes. (See Table 2.8.)
Myoglobin (Mb)
The main nephrotoxin. A 19kDa weak O 2 carrier (similar to Hb but with a single haem moiety), Mb is usually bound to plasma proteins. When in excess, the ferric form (Fe 3+ ) is freely fi ltered and concentrated l intralu-minal cast formation. Tubular degradation generates highly toxic ferryl-Mb (Fe 4+ ), with direct oxidant tubular cell injury. A key feature of rhabdomy-olysis is the large quantities of fl uid retained in infl amed muscle, causing profound hypovolaemia, in addition to toxic renal injury.
2 Not all rhabdomyolysis l AKI (particularly if you act quickly).
Clinical presentation
Variable, but the classical myalgia, weakness, and dark urine are rare ( 7 50%
have no muscle pain at presentation). Maintain high index of suspicion in relevant clinical situation; initial clues: i ALT/AST, dipstick +ve haematu-ria, disproportionate i K + or PO 4 (see ‘Investigations’ section).
1 Examine the limbs carefully — do not miss a compartment syndrome.
Recurrent rhabdomyolysis after mild exertion may suggest an underlying myopathy.
Investigations
• Dipstick cannot distinguish between myoglobin and haemoglobin.
Classically, urine is dipstick +ve for blood but with no red cells on microscopy. 7 20% of patients will have a – ve urinalysis.
• 2 Urinary myoglobin (u-Mb) is +ve (not present in normal urine).
d u-Mb can be used to monitor treatment.
• U&E (SCr:Ur ratio often very high), i Alb if volume-deplete, or hypoalbuminaemia if capillary leak.
• i CK (better indicator of amount of muscle damage than likelihood of AKI). i ALT, AST, LDH.
• i K + ( 1 often i i ), i i PO 4 , i urate, i lactate, and i anion gap acidosis (organic acids).
• d d Ca 2+ , often with avid calcium sequestration in injured muscle.
• Mild DIC frequent ( d Plt, i D-dimers).
• Consider toxicology screen for drugs, viral screen, TSH if cause not apparent.
RHABDOMYOLYSIS 153
Table 2.8 Causes of rhabdomyolysis
Physical causes Drugs and toxins
Trauma (crush injury) Prolonged immobility Compartment syndrome Muscle vessel occlusion Sickle cell disease Shock and sepsis Excessive exertion Delirium tremens Electric shock
Status epilepticus or asthmaticus Neuroleptic malignant syndrome Malignant hyperthermia Myopathies:
Polymyositis/dermatomyositis McArdle's disease and other inherited myopathies
Alcohol, heroin, amphetamines, cocaine, and ecstasy Statins and fi brates Antimalarials Zidovudine
Snake and insect venoms Infections
Pyomyositis and gas gangrene Tetanus, Legionella , Salmonella Malaria
HIV, infl uenza, and Coxsackie Electrolyte abnormalities:
d K + , d Ca 2+ , d PO 4 , d Na + , i Na + Endocrine disorders:
Hypothyroidism
Hyperglycaemic emergencies
Rhabdomyolysis: management
Prevention of AKI
In the early phase of the disorder, vigorous resuscitation may protect patients from many of the subsequent complications.
• Aim to resuscitate to euvolaemia:
• As much as 12L may be required/day (and more if severe injury).
• Alternate 1L 0.9% NaCl (or balanced crystalloid) with 1L 1.26 – 1.4%
NaHCO 3 .
• If the Na + load l i Na + , use 1L 5% dextrose or 1L 0.45% NaCl containing 50mL 8.4% NaHCO 3 to d total Na + load.
• Aim to maintain a UO ≥ 150mL/h or ≥ 300mL/h with traumatic injuries.
• Continue therapy until disappearance of urinary myoglobin.
Urinary alkalinization and mannitol
X The role of urinary alkalinization (stabilizes oxidizing form of myoglo-bin) and forced diuresis ( i urine fl ow l d tubular precipitation) remains controversial. 2 The priority is to volume-resuscitate the patient.
• Aim for a target u-pH >6.5 by using alternating NaCl and NaHCO 3 , as described in previous section, but increasing the frequency of NaHCO 3 as necessary. Evidence for a meaningful clinical impact is weak, and volume overload is a risk unless good UO. In addition, urinary alkalinization can cause a signifi cant systemic alkalosis and 6 symptomatic d Ca 2+ .
• Loop diuretics acidify the urine and should be avoided. Mannitol, an osmotic diuretic, is preferred: give as a bolus (e.g. 12.5 – 25g as a bolus (= 62.5 – 125mL of 20% (200mg/mL) mannitol solution)) or as an infusion (10mL/h of 15 – 20% mannitol). 1 Mannitol l i osmolar gap and may potentially worsen AKI.
Supportive care
• Standard indications for dialysis apply ( b p. 172), although i K + may occur early.
• Physiotherapy to debilitated muscles is essential.
Prognosis
• The prognosis is good if the causative insult is removed, and renal function will return to normal in the majority — even in those who require an extended period of dialysis support.
RHABDOMYOLYSIS: MANAGEMENT 155
Compartment syndrome in rhabdomyolysis
• May occur in two circumstances:
• If the blood supply to particular limb has been compromised (immobility after drug overdose, seizures, etc.).
• Generalized muscle injury and infl ammation (toxic, viral).
• Infl ammation and oedema within a closed muscle compartment l i intracompartment pressure l d O 2 delivery l myonecrosis.
• 2 Always examine the major muscle groups for the characteristic
‘woody ’ consistency of an evolving/established compartment syndrome. Timely fasciotomy in these circumstances may save limb function.
• If in doubt, compartmental pressure can be measured via the insertion of a needle with an attached tonometer. An intracompartment pressure >50mmHg with a normal BP, or 30 – 50mmHg in hypotensive patients, is suggestive. If necessary, recheck every 6h.
Hypocalcaemia
Do not attempt to correct d Ca 2+ , unless it is symptomatic (tetany, arrhythmias) — there is a risk the administered calcium will precipitate in injured muscle. Rebound hypercalcaemia is common during the recovery phase.
1 Symptomatic d Ca 2+ may complicate NaHCO 3 administration.
Haemoglobinuric AKI
• Occurs in the context of massive intravascular haemolysis:
• Transfusion reactions (ABO incompatibility).
• Falciparum malaria (blackwater fever, b p. 702).
• Haemolytic anaemias (glucose-6-phosphate defi ciency (G6PD), drug-induced, autoimmune).
• Mycoplasma infection.
• Snake, insect, and spider venoms.
• Free Hb does not enter the urine as freely as myoglobin, so AKI is relatively rare.
Investigations
d Hb, d haptoglobins, i bilirubin, i LDH, i K + ; urine is dipstick +ve for blood; plasma appears dark.
Management
Treat underlying disorder; volume resuscitation to establish a diuresis.
AKI in cirrhosis
Introduction
AKI is common in cirrhosis. 7 25% patients presenting with cirrhosis-associated ascites will develop AKI within 1 year. The presence of AKI at the time of an admission increases mortality 7 8 - fold, and >50%
of patients will develop AKI during an inpatient episode.
3 Not all concomitant hepatic and renal impairment is due to the hepa-torenal syndrome (HRS); it is not even top of the list. Alternative diagno-ses may imply a better prognosis. Always consider:
• Sepsis l ATN (40% of AKI in cirrhotic patients).
• Hypovolaemia (e.g. GI haemorrhage, diuretics) l ATN (30% AKI in cirrhotic patients).
• Nephrotoxins (drugs and i bilirubin l ATN).
• Glomerulonephritis (e.g. MCGN 2° to hepatitis C).
Hepatorenal syndrome
HRS occurs in advanced liver dysfunction, usually cirrhosis, in conjunction with ascites and portal hypertension. Often split into two types, based on: (i) rapidity of onset, (ii) severity of AKI, and (iii) prognosis (see Table 2.9).
Table 2.9 Classifi cation of HRS Type I AKI is the dominant clinical feature
Rapid d GFR (SCr >221 μmol/L (2.5mg/dL)) or CrCl falling to
<20mL/min in less than 2 weeks) Progressive oligo-anuria (often profound) Median survival 2 weeks
Type II Ascites (often refractory) the dominant clinical feature Protracted clinical course
Renal impairment less acute and severe Can convert to type I
Median survival 6 months
Pathophysiology of HRS
Liver disease is associated with marked splanchnic (and systemic) vasodilata-tion ( l arterial underfi lling and d SVR), in part s to local excess NO and other vasodilator (e.g. adrenomedullin) production (caused by i shear stress in portal hypertension). Also i bacterial translocation ( l peritoneal infl am-matory response) and i vasoactive gut peptides (e.g. glucagons, prostacyclin).
As a result, the effective arterial blood volume is sensed to have fallen, lead-ing to intense A adrenergic activity, s hyperaldosteronism, ANP synthesis, and non-osmotic ADH release (hence salt and water overload). Tubular V2 receptor activation causes a dilutional hyponatraemia. An increase in cardiac output attempts to compensate, but LV dysfunction eventually results. Excess catecholamine, angiotensin II, adenosine, thromboxane A2, and endothelin l profound and intense renal vasoconstriction ( l d RBF).
AKI IN CIRRHOSIS 157
The kidneys remain structurally normal, and the renal impairment is entirely pre-renal in nature — tubular integrity and function are preserved.
Renal biopsies are normal (in practice, unnecessary and hazardous), and kidneys from HRS patients have been used successfully for transplantation.
Clinical features
• 2 The diagnosis of HRS depends on exclusion of other causes of AKI.
• Recognition can be diffi cult, as cirrhotic patients are usually
malnourished, with signifi cantly d muscle mass ( 6 SCr may overestimate GFR). Urea may also be unhelpful (GI bleeding, low hepatic production 9 variable dietary protein intake). Cystatin C ( b p. 36) has 6 been used as an alternative. Other biomarkers ( b p. 94) are awaited.
• Signs of advanced liver disease: ascites (practically universal in HRS), stigmata of chronic liver disease, portal hypertension (beware GI bleeding!), encephalopathy, jaundice (degree variable), and coagulopathy.
• Cardiovascular: oedema (Na + and water retention) and d BP ( d SVR and effective circulating volume).
• 3 Infection: look carefully and regularly for evidence of sepsis ( 1 pneumonia, line infections, and spontaneous bacterial peritonitis).
• Electrolyte disorders: dilutional d Na + is almost universal.
• Nutritional state: usually poor and deteriorating.
• Urine output: oligo-anuria the norm in type I HRS, with urine volumes decreasing as the condition progresses. Anuria is an ominous sign.
• Urinalysis bland, with no proteinuria/haematuria.
• Tubular function is preserved, so the kidneys excrete concentrated urine that is low in Na + (<10mmol/L) (i.e. indistinguishable from other pre-renal AKI). Heavily emphasized in the past but no longer included in diagnostic criteria.
• Normal renal ultrasound/imaging. Renal Doppler can detect i vascular resistance (elevations predict HRS in cirrhotic patients).
Box 2.3 HRS: diagnostic criteria
• Acute or chronic liver disease with advanced hepatic failure and portal hypertension.
• Renal impairment: serum SCr ≥ 133 μ mol/L (1.5mg/dL).
• Absence of hypovolaemia: no improvement in renal function after diuretic withdrawal and appropriate volume expansion with IV albumin (1g/kg/d).
• Absence of other alternative explanations for d GFR, particularly nephrotoxic drugs and sepsis ( 2 spontaneous bacterial peritonitis).
• Absence of intrinsic renal disease: proteinuria <500mg/d, urine RBCs
<50 cells per hpf (with no urinary catheter), normal renal USS.
After Arroyo V, et al . (1996). Defi nition and diagnostic criteria of refractory ascites and hepatorenal syndrome in cirrhosis. International Ascites Club. Hepatology , 23 , 164; and Salerno F, et al (2007).
Diagnosis, prevention and treatment of hepatorenal syndrome in cirrhosis. Gut, 56 , 1310.