response to diuretics. Volume status is an important determinant of outcome in AKI and should be afforded a high priority in this setting. The remaining indications for dialysis are urgent , rather than emergent. This can be an im portant distinction \200\224 depending on local resources, it may be preferable to delay d ialysis and perform it as a planned daytime procedure under adequate supervision and with m ultidisciplinary support. When to start RRT \200 There is limited evidence to support an earlier start to RRT in AK I, e.g. at lower values of urea (<25 \200\223 30mmol/L or 70 \200\22385mg/dL), the onset o f oliguria, and certainly well before \200\230classical \200\231 indications supervene. However, the bene \201 ts of this practice (in terms of survival, duration of AKI, and renal recovery) are not clear-cut. Clinicians have a general tendency, perhaps extrapolated from their CKD care, to wait as long as possible before dialysis initiation. \200 The recent KDIGO g uidelines sensibly recommend a pragmatic approach and to \200\230consider the broader clinical context, the presence of conditions that can be modi \201 ed with RRT, and trends of laboratory tests \200\224 rather than si ngle Ur or SCr thresholds alone \200\231 . RENAL REPLACEMENT THERAPY IN AKI 173 Relative indications \200 Acidosis (pH <7.2), especially if haemodynamically unstable, or where volume overload precludes IV bicarbonate administration. \200 There is evidence tha t myocardial enzymes are dysfunctional with pH <7.2 l higher risk of arrhythmia. Critically unwell patients (usually in an HDU/ITU setting): To maintain \202 uid balance and allow safer administration of \202 uid, feeding, blood and blood products, antimicrobials, and drugs. Uraemic complications: Rare for these to be a signi \201 cant factor in AKI. If you are waiting for these before initiating dialysis, then you are waiting too long! Uraemic pericarditis or encephalopathy. \200 Uraemic symptoms, especially once Ur >40mmol /L (112mg/dL) ( 1 there is no absolute \201 gure that equates with \200\230uraemia \200 \231 , and there is considerable interpatient variation in \200\230biochemical tolerabilit y \200\231 ). Diuretic-resistant cardiac failure. \200 Poison or toxin removal (lithium, ethylene glyco l, etc.) ( b p. 906). \200 Hyperthermia. Why delay RRT \200\224the potential complications \200 Complications of dialysis access i nsertion ( b p. 180). \200 Haemodynamic strain or overt hypotension in an already sick pa tient ( X which may then perpetuate AKI). Electrolyte imbalances, e.g. rapid reduction of K + ( 1 l arrhythmias). \200 Complication s of anticoagulation ( b p. 182). \200 Dialysis disequilibrium ( b p. 177). When to stop RRT \200 Requires regular (at least daily) assessment. \200 Average durati on of RRT in AKI is 7 12 days. \200 Assessment of underlying renal function during RRT ca n be dif \201 cult. It is often particularly uncertain for intermittent haemodialysis (IHD ) where variable rebound in Ur, SCr, and electrolytes may occur between treatments. An increase in urine output is particularly helpful, although the use of diuretics will need to be factored in (routine administration of diuretics to i UO and faci litate earlier cessation of RRT is not recommended). Trends in SCr, Ur, and electrolytes need to be carefully considered (and allowance made for non-renal confounding factors, such as the patient s catabolic state and volume status). Theoretically, serial measurements of urinary Cr excretion might be helpful but are very rarely undertaken in practice. Cessation of RRT does not have to be an absolute. It might be prudent to initially adjust the duration and frequency of treatment or to consider a modality chang e (e.g. step down from CRRT on ITU to IHD on a renal unit). On occasion, particularly in a critical care setting, more fundamental issues concerning th e futility of further treatment will need to be included in the decision-making. CHAPTER 2 Acute kidney injury (AKI) 174 RRT in AKI: modalities Introduction The ideal modality of RRT in AKI is unknown. In practic e, the choice will be based primarily upon: (i) the availability of different treatments an d (ii) a patient s haemodynamic status and overall clinical condition. PD use in AKI is inf requent, except in pediatric practice and in areas where resources are constrained ( b p. 1 88). The treatments are not mutually exclusive, with changes between them dictated by clini cal circumstances. Modalities Generally, intermittent haemodialysis (IHD) is preferred on renal units whilst c ontinuous techniques (CRRT), such as continuous veno-veno hae- mo \201 ltration (CVVHF), c ontinuous veno-venous haemodialysis (CVVHD), continuous veno-veno haemodia \201 ltration ( CVVHDF), and sustained low-ef \201 ciency dialysis (SLED), are more often encountered in h igh dependency and critical care environments. Intermittent haemodialysis (IHD) (see Fig. 2.16 ) \200 Solute clearance mainly by diffusi on across semi-permeable membrane. \200 Pores in the membrane allow small molecules (e.g. Ur (MW = 60Da), Cr (113Da)) and electrolytes but not larger ones (e.g. plasma proteins (al bumin 60,000Da, IgG 140,000Da) or blood cells) to pass through. Dialysate (physiological solution of electrolytes) is required. \200 Concentration differ ences across the membrane allow molecules to diffuse down a gradient. This allows waste pro ducts to be removed and desirable molecules or ions (e.g. HCO 3 \200\223 ) to be replaced. \200 Diffusion is maximized by maintaining high- \202 ow rates of blood and dialysate a nd by pumping the two through the dialyser in countercurrent or opposite directions. Usually administered intermittently (e.g. 4h, 3 x /week), although the delivery in AKI may differ from this ( b see chapter 4). Water can be driven through the membrane by hydrostatic force (ultra \201 ltration or UF). The pressure gradient across the membrane (transmembrane pres sure or TMP) can be controlled to vary the amount of water removed (but usually <3 \200 \223 4L in a 4h treatment). Haemo \201 ltration (HF) (see Fig. 2.16 ) \200 Solute clearance by convection (mainly), i.e. \202 uid shifts across the dialysis membrane also allow solutes to cross ( \200\230 solute drag \200\231 ). Achieved by generating a TMP across the membrane. \200 Large volumes need to be \201 lt ered to achieve adequate solute clearance. This would cause hypovolaemia, unless replacement \202 uid is administered \200\224 usually pre-prepared 5 \200\223 10L bags (during IHD, HF is used to remove \202 uid that has accumulated between treatments 6 no \202 uid replacement is necessary). No dialysate is required. Removes larger MW (30 \200\223 50kDa) molecules (e.g. vitamin B12 and B 2 microglobulin) m ore ef \201 ciently than dialysis. X May also remove pro- (and anti-) in \202 ammatory cy tokines. Delivered as a continuous, rather than intermittent, technique. RRT IN AKI: MODALITIES 175 IHD modi \201 cations (e.g. SLED) \200 This essentially refers to treatments using stand ard dialysis equipment but for a longer treatment than the \200\230traditional \200\231 4h. Both IHD and CRRT machines can be adapted easily for this purpose. \200 Sustained low-ef \201 ciency dialysis (SLED) uses extended (e.g. 6 \200\223 12h) treatments with blood and dialysate \202 ows of between 100 \200\223 300mL/min. The aim of SLED is to improve tolerability over IHD. \200 The \200\230low-ef \201 cienc y \200\231 tag is misleading \200\224 it is often commendably ef \201 cient. Hemofiltration Hemodialysis Predilution replacement fluid blood flow blood flow effluent dialyzate Mid-dilution replacement fluid filtrate fresh dialyzate blood flow blood flow Postdilution replacement fluid Convective blood purification Diffusive blood purification Fig. 2.16 Principles of HD and HF. For HF, replacement \202 uids can be given before, int o, or after the haemo \201 lter (pre- or post-dilution). Reproduced from Oxford Desk Refer ence: Nephrology , Jonathan Barratt, Kevin Harris, and Peter Topham (2008), with kind permi ssion of Oxford University Press. Haemodia \201 ltration \200 Combines HD and HF to get the best of both modalities (see F ig. 2.17). \200 Set up as for HD, but with a higher TMP, to produce a signi \201 cant \201 ltration. \200 Both dialysate and replacement \202 uid are required. Replacement fluid CWHDF Dialysate and ultrafiltrate Dialysate Fig. 2.17 Haemodia \201 ltration. Reproduced with permission from Levy J, Morgan J, and Br own E (2004). Oxford Handbook of Dialysis , 3rd edn.(2009), with permission form Oxford Uni versity Press. CHAPTER 2 Acute kidney injury (AKI) 176 RRT in AKI: choosing modality? Introduction One size does not \201 t all. No single modal ity of RRT is ideal for all patients in all situations. It is 6 important to be aware of th e advantages and dis- advantages of available techniques and to tailor treatment to a parti cular clinical context. The treatments should not be considered competitive but complementa ry. It should also be acknowledged that availability may in \202 uence choice to a greater or lesser extent. Advantages and disadvantages CRRT \200 Advantages: slower \202 uid removal ( l haemodyn amic stability); continuous ( 6 improved) \202 uid balance (including greater overall capacity for \202 uid removal); gentler solute control ( l slower \202 uid shifts and d risk of cerebral oe dema); adjustable as clinical circumstances evolve; relatively simple equipment. Disadvantages: continuous anticoagulation ( b p. 182); immobilized patient; risk of hypothermia; potential higher cost. IHD \200 Advantages: faster correction of electrolyte abnormalities and toxin removal ( 6 potential advantage for i i K + , poisoning, tumor lysis, rhabdomyolysis); rapid \202 ui d removal; allows mobilization ( l less muscle wasting and respiratory infection) and time for other investigations and interventions to take place; fewer bleeding complications; tra nsfer to a high dependency environment is usually unnecessary; several patients can be trea ted with the same equipment each day; possible reduced cost. Disadvantages: haemodynamic instability; dialysis disequilibrium ( b p. 177); less overall control of \202 uid balance and less adaptability; technically more complicated. Hybrid treatments The aim of treatments, such as SLED, is to share the advantages whilst mi nimizing disadvantages of both CRRT and IHD. Evidence Several RCTs have compared CRRT to IHD in the context of AKI. However, a clear dem onstration of the superiority of either technique has proved elusive, e.g. a Cochrane colla boration meta-analysis analyzed 15 studies involving 7 1500 patients and concluded that out comes were similar in terms of mortality, length of hospital stay, and renal recovery. X An often debated bene \201 t of CRRT is a favorable effect on renal recovery (as a by-produc t of improved haemodynamic stability). However, whilst reduced progression to ESRD has been suggested by a few observational studies, all controlled trials and meta-analyzes to date have failed to demonstrate a consistent bene \201 t of CRRT. Comparative studies between SLED and CRRT demonstrate similar outcomes, particularly with respect to haemodynamic tolerability. RRT IN AKI: CHOOSING MODALITY? 177 General guidance \200 In the patient with haemodynamic instability, CRRT is preferred to standard IHD. CRRT is also preferred in patients with AKI who cannot tolerate \202 uct uations in \202 uid status (e.g. cardiogenic shock). In a critically ill patient with multi-organ involvement, particularly in an HDU/ITU settin g, the adaptability of CRRT means that it is generally preferred to IHD. CRRT is preferred for a patient with acute brain injury where IHD may worsen neurological s tatus ( d BP + cerebral oedema l d cerebral perfusion pressure). CRRT is preferred in combined liver-kidney failure (possible advantage for prevention of i intracranial pressure). SLED may be better tolerated than IHD, particularly if other forms of CRRT are unavailable. Dialysis disequilibrium \200 A syndrome thought to be s to cerebral oedema: blood Ur drops rapidly during dialysis but slower both in the intracellular compartment and within t he blood \200\223 brain barrier. This results in water in \202 ux into the brain and cere bral oedema ( 9 cerebral acidosis). Usually occurs in the context of AKI on a background of CKD. \200 3 Rare if \201 rst di alysis prescription/precautions observed ( b p. 178). Those with Ur >60mmol/L (168mg/dL) at particular risk. \200 Symptoms (during or shortly a fter dialysis): nausea, dizziness, headache, visual disturbance, agitation, confusion, d GC S, and seizures. 2 Exclude hypoglycaemia, d Na + , drug toxicity (has a renally excreted drug stayed at the same dose despite a dramatic reduction in kidney function, e.g. antibiotics?), and intracerebral bleeding. \200 Prophylaxis: observation of \201 rst d ialysis prescription/precautions is mandatory. Phenytoin 15mg/kg loading dose, then 200 \200\223 300mg/d, is no substitute for applying these but has been used. Treatment: stop dialysis, and supportive care (improvement should occur within 24h). Seizures: mannitol 10 \200\223 15g IV (raises plasma osmolality) and di azepam 9 phenytoin. CHAPTER 2 Acute kidney injury (AKI) 178 RRT in AKI: prescription 2 Remember: the dialysis staff have considerable expertise and are likely to know a great deal more than you can possibly learn from this book. Intermittent HD \200 Time: 1 Rapid overcorrection of uraemia may cause the syndrome of dialysis disequilibrium ( b p. 177), so initial treatment aims for partial correction of uraemia only ( d Ur \211 30%). A guide: 1st session l 2h, 2nd l 3h, and subsequent l 3 \200\223 4h. Blood \202 ow: Relatively slow, 7 150 \200\223 200mL/min ( i by 50mL/min/session to 300 \200\223 400mL/min). Frequency: Ur rebound is common, so aim to dialyse daily against symptoms and chemistry ( 1 beware i K + ) for the \201 rst 2 \200\223 4d. Catabolic patients (e.g. sepsis) may need to remain on a daily regimen for longer. Dialyser: Small dialyser ( \211 1.2m 2 ) preferable ( b p. 284). Fluid removal or ultra \201 ltration (UF): 2 Assessment of volume status is crucial. Hypovolaemia: administer saline (e.g. 1 \200\223 2L) prior to, and during, dialysis \200\224 no UF. \200 Euvolaemia: no UF. \200 Overload: up to 2 \200\223 3L c an be removed over 2h, depending on haemodynamic status, progress and stability of the pati ent. If further \202 uid removal is desirable (patient remains in pulmonary oedema with s atisfactory BP), then it can be removed through \200\230isolated UF \200\231 ( l dialysat e \202 ow is turned off, leaving \202 uid removal, rather than biochemical control, as the p treatment goal). 1 Note: UF without dialysis can still cause hypotension and CV insta bility. Anticoagulation ( b p. 182): Use minimal or no heparin, as necessary, to prevent clotting in the extracorporeal circuit. AKI patients are at high risk of bleeding ( b p. 138) e.g. GI hemorrhage, unintentional arterial puncture during line insertion, i BP, pericarditis (whic h may l haemorrhagic tamponade). Dialysate ( b p. 282): Bicarbonate buffer is preferred to lactate. \200 Lactate l liver metabolism l HCO 3 \200 \223 . However, lactate may accumulate in multi-organ failure, esp. in patients with liver failure ( d clearance) or sh ock ( i production) l worsening acidosis. \200 Dialysate Na + of 145mmol/L is typical. If serum Na + <125mmol/L, use a dialysate Na + \211 20mmol/L higher to avoid rapid correctio n. \200 Serum K + decides dialysate K + . 1 Overcorrection l arrhythmias. (See Table 2.11.) RRT IN AKI: PRESCRIPTION 179 Haemodynamic tolerability of IHD: Measures to help improve this: (i) prime circuit with saline; (ii) stop vasodilator therapy (if possible); (iii) dialysate Na + \211 10mmol/L above plasma Na + (up to 150mmol/L); ( iv) dialysate Ca 2+ 1.35 \200\223 1.5mmol/L; (v) dialysate K + as in Table 2.11 (use highe st possible); (vi) cooled dialysate (35 \200\223 37 C); (vii) minimum UF clinical statu s allows. Table 2.11 Serum decides dialysate Serum (mmol/L) Dialysate (mmol/L) >5.5 2.0 3.5 \200\223 4.5 4.0 <3.0 4.5 K + -free dialysate can be used if i i K + . CRRT \200 Time: Continuous. Blood \202 ow: Usually 150 \200\223 200mL/min. Filter: High- \202 ux (synthetic) membrane. Fluid removal: UF rates of 10 \200\223 45mL/kg/h are typical. Fluid removal is achieved by the UF rate ex ceeding replacement \202 uid administration per hour (e.g. net 100 or 200mL UF/h). Replacement \202 uid (usually supplied in 5L bags) contains: Buffer: bicarbonate is preferred to lactate. \200 K + : generally 0 \200\223 4mmol/L and adjusted to serum K + . \200 Also Na + (132 \200\223 140mmol/L), Ca 2+ , Mg 2+ , and Cl \200\223 . \200 Note : replacement \202 uid is not the same as dialysate. Anticoagulation: Heparin, citrate, or epoprostenol ( b pp. 182 \200\2237). SLED \200 Time: Usually 5 \200\223 12h. Blood \202 ow: Blood and dialysate \202 ows of between 100 and 300mL/min. Dialyser: Standard IHD dialyser. Fluid removal: Prolonged treatment time allows more UF than IHD. Anticoagulation: Heparin. Circuits potentially more prone to clotting than IHD. 1 Drugs: Guidelines for appropriate drug-dosing in RRT are usually for IHD or CRRT. As SLED will potentially provide more effective clearance than IHD, caution is necessary before extrapolating such recommendations. Speak to your pharmacist. CHAPTER 2 Acute kidney injury (AKI) 180 Vascular access \200 Type: An uncuffed, double-lumen dialysis catheter ( \200\230 temporary line \200\231 or vascular catheter) is acceptable for periods of <7 days. If >7 days, consider a cuffed (and tunneled) double-lumen catheter (not in ICU). Route: 1 Avoid the subclavian veins ( l more dif \201 cult insertion and i incidence of central venous stenosis). Jugular: often the route of choice, although a volume-overloaded patient may \201 nd it d if \201 cult to lie \202 at during insertion. Left-sided jugular lines are technically m ore dif \201 cult to insert. Femoral: no need to wait for a CXR post-insertion in emergent situations. However, i infection risks, reduced mobility, increased risk of DVT. Insertion: For insertion technique, see b p. 936. \200 2 The bene \201 ts of insertion under ultras ound guidance have been clearly demonstrated (fewer attempts necessary, quicker procedure, better catheter pos ition, fewer complications). Precautions: Strict adherence to infection control policies. This includes, but goes signi \201 cantly beyond, a sterile technique at insertion \200\224 catheter afterca re is just as important. CXR prior to the use of jugular (or subclavian) lines. \200 Review ongoing need for, and function of, access regularly \200\224 remove or replace, as necessary. Beware recirculation ( b p. 297) with temporary lines, particularly short catheters in the femoral vein. Optimal lengths: \200 12 \200\223 15cm right intern al jugular. \200 15 \200\223 20cm left internal jugular. \200 19 \200\223 25cm femora l. 3 Complications of central venous catheterization. These should be explained to the patient (and audited regularly): \200 Unsuccessful insertion (10 \200 \223 20%). \200 Arterial puncture (<6%). \200 Haematoma (<5%). \200 Haemothorax (<1%) . \200 Pneumothorax (<3%). RRT IN AKI: PRESCRIPTION 181 Adequacy ( \200\230dose \200\231) The optimal \200\230dose \200\231 of RRT in AKI (and ho w best to measure it) is unknown. In addition, the actual delivered dose of RRT often falls short of that intended or prescribed (reasons: haemodynamic instability, variations in BMI , access malfunction, technical dif \201 culties, \201 lter or dialyser clotting, and pa tient disconnection, e.g. for other interventions or investigations). Measurement Although routinely used for the assessment of dialysis adequacy in CKD ( b p. 2 86), Kt/V for urea has less utility in AKI where patients are more metabolically unpredicta ble, particularly with respect to urea production. Many clinicians aim for a consistent blood Ur (post-dialysis Ur for IHD), e.g. <25mmol/L or even <15mmol/L. Overall, the goals of RRT prescription in AKI should 6 be more holis- tic, aiming to achiev e the optimum electrolyte, acid \200\223 base, and \202 uid bal- ance that are appropria te for a particular clinical circumstance. This may require continuous reassessment and adj ustment. Guidelines There is currently no evidence that increased RRT dose in AKI improves outcomes with respect to either mortality or renal recovery. However, KDIGO recommended the followin g: IHD: a cumulative weekly Kt/V of 3.9, e.g. Kt/V 1.3 for each treatment on a 3 x /week dialy sis prescription. CRRT: \201 ltration volume of 20 \200\223 25mL/kg/h. For the reasons g iven earlier, this is likely to require a prescribed dose in the range of 25 \200\223 30mL /kg/h. High-dose RRT in sepsis \200 X There has been interest in high-dose RRT in the context of AKI and septic shock. It is postulated that removal of proin \202 ammatory cytokine removal might be important. Limited data suggest potential bene \201 t, particularly in terms of the vasopressor doses required to maintain MAP in these patients. \200 In the IVOIRE trial, there was no evide nce that high volume HF at 70mL/kg/h, compared with contemporary standard volume HF at 35mL /kg/h, leads to a reduction in 28-day mortality, or contributes to early improvements in ha emodynamic pro \201 le or organ function. Cytokine removal may not only be through UF, but also via adsorption on the \201 lter membrane (potentially increasing costs, as the \201 lter be comes cytokine-saturated and requires regularly changing). It seems likely that anti-in \202 ammatory cytokines are just as likely to be removed as their proin \202 ammatory counterparts. High-dose CRRT means \201 ltration volumes in the range of 65mL/kg/h. \200 Cytokine rem oval can also be achieved with IHD and SLED, using special high- \202 ux (i.e. large pore size) membranes. CHAPTER 2 Acute kidney injury (AKI) 182 RRT in AKI: anticoagulation Introduction Contact between blood and the dialysis circuit l c oagulation pathway and platelet activation l clotting. This reduces treatment ef \201 cien cy and causes blood loss. Prevention requires concomitant anticoagulant therapy, which intr oduces a bleeding risk and increases technical complexity. (See Fig. 2.18) Patient factors \200 Anticoagulant therapy can be individualized to the patient. \200 P atients with pre-existing coagulation issues (e.g. thrombocytopenia, liver disease) will be at higher risk from therapeutic anticoagulation. \200 AKI patients may already be antico agulated for an underlying condition (e.g. ACS, AF) and 6 not require additional treatment. If anticoagulation is not possible, other measures (and nursing skill) can prevent or delay thrombosis, e.g. satisfactory vascular access, pre- \201 lter \202 uid replacement for CRRT, regular saline \202 ushes, i blood \202 ow, and immediate attention to equipment alarms. Intermittent haemodialysis Unfractionated heparin \200 Remains the most widely used antic oagulant for IHD (see also b p. 290). Dose and target ACT/APTT can/should be patient-speci \201 c. \200 Advantages: vast exper ience with use; widely available; short half-life; reversible with protamine; tests required for monitoring (APTT, ACT) are usually readily ac cessible; relatively low cost. Disadvantages: narrow therapeutic index; drug kinetics often unpredictable; HIT; heparin resistance ( s to d antithrombin levels in the critically ill), (page 184). LMW heparin \200 Use in AKI has increased, as experience has grown in chronic IHD. \200 1 LMWH relies on renal elimination, so AKI patients are at i risk of accumulation and bleeding ( b p. 138). Doses lower than those familiar from therapeutic anticoagulation, e.g. enoxaparin (0.5mg/kg) single bolus at start of IHD. 1 Caution if patient also receiving LMWH for thromboprophylaxis (consider combining at the start of dialysis to achieve two goals). \200 Intermittent measurement of anti-factor Xa activity desirable with prolonged, or daily, use. Advantages: simple regimen; more predictable drug kinetics; consistent anticoagulant effect ; less monitoring usually necessary; d risk of HIT. \200 Disadvantages: accumulation; mea surement of anti-factor Xa activity may not be available; incomplete reversal by protamine; higher cost. RRT IN AKI: ANTICOAGULATION 183 Yes Impaired coagulation? Proceed without anticoagulation No Underlying condition requires systemic anticoagulation? Use anticoagulation adapted to this condition Yes No Choose RRT modality CRRT Intermittent RRT No Contraindication to citrate? Regional citrate anticoagulation Yes No Increased bleeding risk Heparin Yes Proceed without anticoagulation No Increased bleeding risk? Heparin Yes Proceed without anticoagulation Fig. 2.18 Flow chart summary of KDIGO recommendations for anticoagulation during RRT for AK I. Reproduced from Kidney Disease: Improving Global Outcomes (KDIGO) Acute Kidney Injury Wo rk Group. KDIGO Clinical Practice Guideline for Acute Kidney Injury. Kidney Inter ., Suppl. 2012; 2: 1 \200\223 138. with permission from Nature Publishing Group. CHAPTER 2 Acute kidney injury (AKI) 184 CRRT Heparin \200 Unfractionated heparin widely used. Usually a pre- \201 lter infusion, e.g. 15 \200\223 30IU/kg, followed by maintenance 5 \200\223 15IU/kg/h ( 1 the relationship be tween dose, APTT, circuit longevity, and bleeding is complicated). \200 LMWH is less popu lar for CRRT and requires factor Xa monitoring. Heparin-induced thrombocytopenia (HIT) \200 HIT is an immune phenomenon. Antibodies react against the heparin: platelet factor 4 complex on platelets ( l clumping, activation, and thrombosis). Incidence: <3% of heparin-treated patients. \200 Consequences: severe thrombocytopenia 9 thrombosis (usually within 5 \200\223 10d of heparin use). Treatment: stop all heparin (LMWHs are not safe in this context). Usually resolves within 1 \200\223 2 weeks. In patients undergoing RRT with heparin, monitor the platelet count and suspect the diagnosis if repeated circuit clotting occurs. If ongoing anticoagulation for RRT is required, alternatives include: Citrate ( b p. 186). \200 Argatroban (direct thrombin inhibitor, hepatic elimination, sho rt half-life, continuous infusion, monitored with APTT). \200 Factor Xa inhibitors (e.g. dan aparoid, fondaparinux). \200 Epoprostenol. RRT IN AKI: ANTICOAGULATION 185 CHAPTER 2 Acute kidney injury (AKI) 186 RRT in AKI: citrate regional anticoagulation \200 Citrate regional anticoagulation is an increasingly popular means of anticoagulation for CRRT. (See Fig. 2.19) Citrate forms a complex with ionized calcium (iCa 2+ ), thereby eliminating a crucial const ituent of the coagulation cascade. Citrate reaching the systemic circulation is metabolized (liver, muscle, kidney), releasing calcium and generating bicarbonate. Low or zero calcium dialysate/replacement solutions are required, and separate calcium infusions prevent d Ca 2+ . Advantages: d bleeding; d transfusion requirement; longer circuit patency; generation of HCO 3 . Disadvantages: citrate accumulation l acidosis; d Ca 2+ (esp. liver impairment or shock); d Mg (citrate binds to Mg); risk of metabolic alkalosis; i Na + (tris odium citrate); technically much more complicated. Procedure \200 Citrate (e.g. 4% trisodium citrate) is infused into the \200\230arterial \200\231 side of the haemo \201 lter circuit, for example: \200 90mL of stock 46.7% trisodium citrate in 1L 5% dextrose. \200 Infused at 175 \200\223 350mL/h, depending on blood \202 ow. Different protocols use different concentrations of calcium, e.g. 0.75% calcium chloride infused concomitantly into central vein: \200 80mL of 10% calcium chlori de in 1L normal saline. \200 Infuse at 7 60mL/h. Circuit and systemic total and iCa 2+ are measured hourly until stable and then 4 \200\223 6h. Aim to maintain circuit iCa 2+ 0.25 \200\223 0.35mmol/L and systemic iCa 2+ 0.9 \200\223 1.23 mmol/L. Titrate citrate infusion to circuit iCa 2+ and calcium infusion to systemic iCa 2+ . Total systemic Ca 2+ (and total to ionized ratio) will rise if citrate accumulates. RRT IN AKI: CITRATE REGIONAL ANTICOAGULATION 187 Step 6 Ca2+ is infused through a separate central line to replace Ca2+ lost in dialysate Step 1 Infuse citrate \210\235 blood flow Step 2 Citrate chelates free Ca2+ as iCa2+ \206\223 to 0.2 mmol/L Bleeding time \206\221 Zero Ca2+ dialysate in Step 5 Citrate is metabolized primarily in liver and also muscle to \210\222 HCO3 bound Ca 2+ is released Effluent dialysate out Step 4 Returning blood combines with mixed venous blood, normalizing iCa2+ so preventing systemic anticoagulation Step 3 Post-filter iCa2+ is monitored and used to titrate citrate rate to assure anticoagulation Fig. 2.19 Principles of citrate anticoagulation for CRRT. iCa 2+ , ionized calcium. Reprodu ced from Oxford Desk Reference: Nephrology , Jonathan Barratt, Kevin Harris, and Peter Toph am (2008), with permission of Oxford University Press. CHAPTER 2 Acute kidney injury (AKI) 188 Peritoneal dialysis (PD) in AKI Rarely used for AKI in Europe and North America but an impo rtant treat- ment worldwide. Until recently, it was also the most popular technique for the treatment of AKI in children. Potential advantages \200 No need for a specialist renal set-up. \200 Technical aspects and apparatus are relatively straightforward. \200 Minimizes haemodynamic instability (m aking \202 uid removal easier). \200 Gentle correction of biochemical abnormalities. \200 No need for vascular access or systemic anticoagulation. \200 Glucose in PD \202 uid increases caloric intake. \200 Low cost. Potential disadvantages \200 Bowel perforation during catheter insertion (esp. if previou s surgery l adhesions). 1 Infection: peritonitis and catheter exit site. \200 Poor clearance: relatively slow cor rection of uraemia and i K + , particularly in catabolic patients. Unpredictable UF rate (interpatient variability). \200 Protein and amino acids lost in di alysate. \200 Catheter problems: migration, poor in \202 ow/out \202 ow, leakage. \200 Abdominal distension l diaphragmatic splinting l respiratory compromise. Hyperglycaemia (PD \202 uid uses glucose to generate hypertonicity). \200 Contraindicat ed by recent abdominal surgery. \200 Diaphragmatic splinting with respiratory compromise. Catheter placement Semi-rigid ( \200\230stab PD \200\231) Pros: inserted at the bedside und er LA (usually via a Seldinger technique). Cons: non-cuffed, therefore, high infection rate s. Uncomfortable and easy to dislodge. Higher incidence of bowel perforation. Usually requi res removal after 48 \200\223 72h ( l repeated insertions often necessary). Cuffed catheter (similar to those used in chronic PD) Pros: cuff prevents bacterial migrati on 6 d infection rates. Softer catheter so more comfortable with less risk of bowel perfora tion. More compatible with automated cyclers. Cons: insertion requires more expertise (alth ough LA still possible). PERITONEAL DIALYSIS (PD) IN AKI 189 PD vs IHD or CRRT for AKI? Studies are limited. Comparisons have suggested a worse outcome for PD than for CVVHF \200\224 though second-rate PD equipment (rigid cath- eters, home-ma de \202 uids, acetate buffer, no automated cyclers) are often judged against \201 rst-r ate CVVHF technology in highly catabolic patients. However, PD cannot be considered a front -line treatment for AKI in most settings but may be lifesaving if HD/CRRT unavailable. Prescribing acute PD \200 Commercially available dialysate solutions preferable. Warm to body temperature prior to infusion. A correctly positioned catheter should allow in \202 ow and out \202 ow times of <10 \200\223 15min. Both proceed under gravity. Ensure complete drainage (remembe r: more drains out than in if UF has occurred). \200 Dwell times of 1h are typical (<30mi n a waste of time and effort). \200 With non-cuffed rigid catheters, peritonitis risk i d ramatically after 72h. Cuffed catheters offer uninterrupted treatment. Aim for 20 \200\223 24 exchanges/day (although often logistically dif \201 cult). \200 Record the number of exchanges and \202 uid input:output. \200 Continuous equilibrium P D (CEPD), which is similar to standard CAPD, is an alternative. Dwell times are 4 \200\223 6h, allowing more time for solute equi libration between blood and dialysate. Less time \200\230hands on \200\231 the catheter l d risk of infection. Dialysate volume: most patients tolerate 2L exchanges. Larger volumes (up to 3L) can l catheter leaks, hernias, and diaphragmatic splinting. Dialysis dose is increased by i dialysate volume 9 i exchange frequency. Fluid balance. If the patient is euvolaemic, mildly \202 uid-overloaded, or haemodynamica lly unstable, a 1.5% dextrose concentration ( \200\230 light bag \200\231 ) is appropriat e. Check the subsequent drainage volume to assess UF. Use this \201 gure, in combination with repeated clinical assessment, to direct the need for higher dextrose concentrations (u sually 2.5% or 4.25%). Heparin (200 \200\223 500U/L) can be added to the dialysate to prevent plugging of the cat heter with \201 brin clots. It is not absorbed systemically. Commercial PD solutions do not usually contain K + , so if the patient is hypokalaemic or t he serum K + is rapidly falling, potassium chloride may be added (usually 2 \200\223 4mmol /L). 191 Chapter 3 Chronic kidney disease (CKD) What is chronic kidney disease (CKD)? 192 Prevalence of CKD 194 Diagnosis of CKD 196 Cardio vascular disease in CKD 198 Pathogenesis of CKD 200 Progression of CKD: general 202 Progres sion of CKD: antihypertensives in CKD 204 Progression of CKD: miscellaneous 208 Advanced CK D: the uraemic syndrome 212 Complications of advanced CKD 214 Anemia and CKD 216 EPO and th e kidney 218 Erythropoiesis-stimulating agents (ESAs) 220 Prescribing ESAs 222 ESAs: additi onal bene \201 ts 224 ESAs: target hemoglobin 226 Iron 1: metabolism and markers 228 Iron 2: therapy and targets 230 CKD-mineral and bone disorder (CKD-MBD) 232 CKD-MBD: bone diseas e 234 CKD-MBD: physiology 236 CKD-MBD: clinical features 240 CKD-MBD: vascular calci \201 cation 242 CKD-MBD: treatment 244 CKD-MBD: hyperphosphataemia 246 CKD-MBD: vitamin D treatm ent 250 CKD-MBD: calcimimetics 252 CKD-MBD: parathyroidectomy 254 Calci \201 c uraemic art eriolopathy (calciphylaxis) 256 Diet and nutrition in CKD 258 Malnutrition in CKD 260 Endoc rine problems in CKD 262 CKD management overview 264 Advanced CKD care 266 Conservative tre atment of CKD: symptomatic management of ESRD 268 Conservative treatment of CKD: general 27 0 CHAPTER 3 Chronic kidney disease (CKD) 192 What is chronic kidney disease (CKD)? De \201 nition The NKF KDOQI (National Kidney Founda tion Kidney Dialysis Outcomes Quality Initiative) classi \201 cation of chronic kidney dis ease (CKD) has been rapidly adopted internationally. 1 It is simple and useful and has help to raise awareness of kidney disease. CKD is divided into \201 ve stages, according to e stimated GFR. (See Table 3.1.) Table 3.1 NKF KDOQI classi \201 cation of CKD GFR (mL/min/1.73m 2 ) CKD stage Description >90 \200 Normal or increased GFR but other evidence of kidney damage 1 60 \200\223 89 \200 2 Mild reduction in GFR, with other evidence of kidney damage 3A * 3B * 45 \200\223 59 * 30 \200\223 44 * Moderately reduced GFR, with or without other evidence of kidney damage 3 30 \200\223 59 4 15 \200\223 29 Severely reduced GFR 5 <15 End-stage, or approaching end-stage, kidney failure 5D <15 On dialysis \200 Early CKD is not diagnosed on eGFR alone. There must also be evidence of kidney dama ge (see rest of table). Patients with an eGFR of 60 \200\223 89mL/min without kidney damag e do not have CKD. * The subdivision of stage 3 into 3A and 3B is not part of the original KDOQI classi \201 cation but has been advocated by other organizations (e.g. NICE in the U K). It re \202 ects the higher incidence of cardiovascular disease and complications (e.g. anemia) that are more prevalent, as eGFR falls below 45mL/min. Patients with a GFR >60mL/min should not be considered to have CKD, unless there is concomi tant evidence of kidney damage: \200 Urinary abnormalities (proteinuria, haematuria). \200 Structural abnormalities (e.g. abnormal renal imaging). \200 Genetic disease (e.g. APKD). \200 Histologically established disease. The reduced eGFR and/or urinary abnormalities should ideally be present on at least two occasions \211 3 months apart. It has been suggested that the suf \201 x (p) is added to the CKD stage to indicate the pr esence of proteinuria (uACR \211 30mg/mmol or uPCR \211 45mg/mmol). This helps to highl ight the i risk of both progression and CV disease (e.g. stage 3p). Chronic renal failure (CRF) is now an outmoded term that indicates an irreversible decline in GFR. WHAT IS CHRONIC KIDNEY DISEASE (CKD)? 193 3 The majority of patients with CKD stages 1 \200\223 3 do not progress to kidney failure. The risk of death from CV disease is far higher than the risk of progression ( b p. 198). Causes of CKD Accurate data on the causes of early CKD are scarce. Registry data focuses on causes of end-stage renal disease (ESRD). As only a relatively small number progress (and live long enough) to reach dialysis or trans- plantation, it is dif \201 cult to extrapola te back to early CKD. Recent UK and US causes are shown in Table 3.2, but there is consider able variation worldwide. Table 3.2 Causes of CKD \200\224 the US and UK Renal disease UK Renal Registry US Renal Data System (USRDS) Cystic or congenital disorder 7 7 Diabetes mellitus 13 37 Glomerulonephritis a 15 18 Hypertension/atherosclerotic 9 24 Infective or obstructive (including re \202 ux) 12 3 Miscellaneous b 18 7 Unknown 26 4 a May not be histologically proven. b Includes analgesic nephropathy, TB, HIV-related, sick le cell disease, sarcoidosis, acute interstitial nephritis, trauma. Reference 1. National Kidney Foundation (2002). KDOQI clinical practice guidelines for chro nic kidney dis- ease: evaluation, classi \201 cation and strati \201 cation. American Jou rnal of Kidney Diseases , 1 , S1 \200\223 S266. CHAPTER 3 Chronic kidney disease (CKD) 194 Prevalence of CKD \200 The exact prevalence of CKD in the general population remains unknown. \200 A large UK study in primary care suggested an age-standardized prevalence of stages 3 \200\223 5 CKD of 8.5% (10.6% in 5 and 5.8% in 4 ). Over 19 million of the US adult population are thought to have some form of CKD. The most common associations are i BP, diabetes, and vascular disease. \200 In the UK stu dy just mentioned, the age- and gender-adjusted odds ratios were 2.1 for i BP, 1.33 for dia betes, and 1.69 for CV disease. \200 CKD prevalence rises dramatically with age \200\224 from 78 pmp age <40 to 5,900 pmp age >80.