Ciclosporin \200 Neoral , a microemulsion preparation, has been the main CIC formulation over recent years, but several generic preparations are now available. (cid:2) There are important differences in bioavailability between formulations, so it is crucial that the patient is consistently prescribed the same brand. Dose: 7mg/kg in two divided doses (PO), with subsequent adjustment, according to levels. Target ranges (12-hour trough). (cid:2) Depends on local practice, immunological risk, and evidence of nephrotoxicity. For guidance: \200 0 \200\223 6 mont hs: 200 \200\223 250ng/mL. \200 6 \200\223 12 months: 150 \200\223 200ng/mL. \200 >1 2 months: 75 \200\223 150ng/mL. X There has been much interest in using 2h post-dose levels (C 2 ) for therapeutic monitori ng, as these provide a better estimate of drug IMMUNOSUPPRESSION: MAINTENANCE 387 exposure (and have been associated with d acute rejection in some studies). However, perhap s because it is a less practical, it has not been widely adopted. CIC is metabolized in the GI tract and liver by the cytochrome P450 system (CYP3A4) \200\224 with implications for drug interactions (see Table 5.6, Box 5.6 ) . If required IV, administer 1/3 of the oral dose. Tacrolimus \200 Prograf has been the main formulation over recent years. Advagraf i s a once-daily formulation. (cid:2) Several generic preparations are now available, with potentially signi \201 cant differences in bioavailability between brands. Dose: 0.1mg/kg in two divided doses (or as a single dose for once-daily formulations), with subsequent adjustment, according to level. Typical target ranges (12-hour trough). (cid:2) Depends on immunological risk and evidence of nephrotoxicity. Check local protocols: \200 Low immunological risk: trough level 3 \200\223 7 micrograms/L. \200 Standard immunological risk: trough level 1 0 \200\223 12 micrograms/L for \201 rst 2 months, then 8 \200\223 10 micrograms/L. High immunological risk: trough level 10 \200\223 12 micrograms/L for \201 rst 2 months, then 8 \200\223 10 micrograms/L. C 0 (trough) levels correlate well with drug exposure (a signi \201 cant advantage over CIC). Metabolized by the cytochrome P450 (CYP3A4) system \200\224 with implications for drug interactions (see Table 5.6, Box 5.6 ). If required IV, the dose is 0.03 \200\223 0.05mg/kg as an infusion over 24h. CHAPTER 5 Transplantation 388 CNI side effects \200 Nephrotoxicity: initially reversible renal vasoconstriction l d GFR, but irreversible interstitial \201 brosis supervenes. Some degree is common on trans plant biopsies (and a particular problem in recipients of other solid organ transplants, wi th 7 5% l ESRD after 10 years). i BP. \200 Headache (rarely, more severe neuropsychiatric issues). \200 Tremor. \200 Liver dysfunction. \200 Post-transplant DM \200\224 NODAT (esp. TAC) ( b p. 424). \200 May potentiate DGF. \200 i K + (similar to a type IV RTA) ( b p. 825). \200 i urate (+ gout), d Mg 2+ , d PO 4 . \200 Thrombotic microangiopathy (TMA) ( b p. 412). \200 Cosm etic: hirsutism (esp. dark-haired, darker-skinned patients), gum hypertrophy (CIC > TAC), hair loss (TAC > CIC). Dyslipidaemia (CIC > TAC). \200 Diarrhea (TAC > CIC). (cid:2) Severe diarrhea may signi \201 cantly i TAC levels (enterocytes that normally secrete TAC into the gut lumen via P-gl ycoprotein are destroyed, causing less TAC elimination via this route). Table 5.6 Induction and inhibition of CYP3A4 i CNI levels Grapefruit juice d CNI levels Rifampicin Erythromycin Caspofungin Clarithromycin Griseofulvin Fluconazole Phenobarbital Ketoconazole Phenytoin Itraconazole Carbamazepine Verapamil St John \200\231s wort Diltiazem Lercanidipine Ritonavir Nel \201 navir IMMUNOSUPPRESSION: MAINTENANCE 389 Box 5.6 CNI drug interactions \200 Statin levels are signi \201 cantly increased by CNIs (CIC > TAC). May l i CK and rhabdomyolysis. \200 Statins should be introduced at low dose and titrated cautiously. \200 The co-prescription of simvastatin and CIC is contraindicated by the MHRA in the UK. CIC inhibits the enterohepatic recirculation of MPA, meaning that higher MMF doses are requ ired in recipients treated with CIC. These drugs increase the nephrotoxicity of CNIs: NSAIDs. \200 Aminoglycosides. \200 Amphotericin. These drugs increase the incidence of i K + : ACE-I/ARB. \200 K + -sparing diuretics. Mycophenolic acid \200 Mycophenolate mofetil (MMF) and mycophenolate sodium (MPS) are the ester and sodium salt pro-drugs of the active compound mycophenolic acid (MPA). MPA is a reversible inhibitor of inosine monophosphate dehydrogenase (IMPDH), a critical en zyme for de novo purine nucleotide synthesis. \200 Lymphocytes are dependent on the de no vo pathway (other cell types have a salvage pathway), so inhibition l d proliferation of ac tivated T and B lymphocytes. MMF has been shown to d acute rejection, more than azathioprine, as part of triple therapy with CIC. Limited evidence for additional bene \201 t in TAC-based regimens. However, ther e has been a massive shift toward MMF, such that it is now the staple at most centers. Note that AZA may remain a good option in TAC-treated patients with MMF-related GI side effects . SE: gastrointestinal side effects can be problematic. Diarrhea in 7 30%, gastritis in 7 20%, nausea, vomiting, constipation, dyspepsia. Bone marrow suppressi on is relatively common. Infective side effects (e.g. CMV) are more common than with AZA. Relatively few important drug interactions. CIC d enterohepatic recirculation of MPA, so hi gher doses of MMF are required than with TAC. MPA sodium is available as an enteric-coated, slow-release formulation, designed to d GI side effects (Myfortic ). This is not demonstrably the cas e in practice, although some patients seem to bene \201 t from a change in tablet. Initial dose: MMF 1g bd (or 500mg qds) \200\224 some centers use 1.5g bd for black recipie nts; MPA 720mg bd. Subsequent dosing will depend on local protocols, CNI levels, and side e ffects (including bone marrow tolerability). X There is very marked interpatient variability in plasma MPA levels. Therapeutic monitorin g of MPA levels is available, but its role has not CHAPTER 5 Transplantation 390 yet been established. May be measured in those with severe GI side effects. Azathioprine \200 Metabolized to a purine analog (6-thioguanine), which competitively inhibits purine synthesis (for RNA and DNA). This inhibits all cell replication, including d T cell proliferation. An old friend: in use in transplantation for >40 years. \200 Dose: usual starting dose is 1.5 \200\223 2mg/kg once daily. Reduce if WCC <4.0 x 10 9 /L and stop if <2.0 x 10 9 /L. SE: myelosuppression, hepatitis, cholestasis. \200 Interactions: (cid:2) allopurinol shou ld be used with great caution with azathioprine, as AZA is also metabolized by xanthine oxi dase ( l potentiates bone marrow toxicity). Consider transfer to MMF. \200 Patients with an inherited de \201 ciency of the enzyme thiopurine methytransferase (TPMT) metabolize AZA slowly, resulting in drug accumulation (and bone mar row suppression). If necessary, patients can be screened for TPMT levels (and the presence of the genetic abnormality). Sirolimus (rapamycin) \200 Derived from a macrolide antibiotic identi \201 ed on Rapa Nu i (Easter Island). Inhibits mammalian target of rapamycin (mTOR), a key regulatory kinase in cell division. Like TAC, it binds FKBP12, but the resulting complex binds and inhibits mTOR l d lymphocyte proliferation in response to cytokines. A long half-life allows once-daily dosing. \200 Dose: typical loading dose of 6mg for two doses, followed by maintenance dose of 2 \200\223 4mg. Trough C 0 levels correlate well with overall drug exposure. Aim level 5 \200\223 10ng/mL. SE: antiproliferative and anti-angiogenic ((cid:2) l impaired wound healing and lymphocele formation). Pneumonitis (can be severe: cough, breathlessness, in \201 ltrates on CXR/CT. Exclude infection. Resolves on withdrawal.). Also mouth ulcers, i lipids, bone marrow suppr ession, TMA, rashes. Appears to prolong DGF ( d tubular regeneration). i proteinuria. (cid:2) Intolerance is very common. Many side effects are more pronounced in those not on steroids. Because of its propensity to impair healing, it is often introduced after 3 months in selected patients. Interactions: potentiates CIC nephrotoxicity. \200 An additional mTOR inhibitor everolimu s is available in some countries. May have a role when there is progressive loss of GFR from non-immune mechanisms ( l IF/TA) ; for example, if CNI nephrotoxicity is problematic >6 months post-transplant ( b p. 416). X Associated with less malignancy. Not a strong evidence base but studies ongoing (particularly in the context of skin cancer) ( b p. 440). IMMUNOSUPPRESSION: MAINTENANCE 391 Corticosteroids \200 d cytokine gene transcription l d cytokine-regulated lymphocyte signaling, d T cell activation (via d NF- B), and d chemokine-driven lymphocyte homing t o areas of in \202 ammation. Familiar toxicity: insomnia, weight gain, i BP, i CV risk, impaired glucose tolerance and i NODAT ( b p. 424), dyslipidaemia, mood disturbance, poor wound heal ing, osteoporosis. Dose: huge center variation. Typical: pulsed steroids at the time of transplantation, follo wed by 20mg prednisolone orally for at least 4 weeks, then phased reduction to maintenance 5mg. Steroid withdrawal \200 The problems associated with steroid use have made regimens invol ving their withdrawal popular, particularly in the USA. However, RCTs involving withdrawal at 3 \200\223 4 months have shown signi \201 cantly i rejection (albeit with CIC-based regimens). Experience with TAC- and MMF-based regimens is more positive. \200 However, the bene \201 ts of late steroid withdrawal from a maintenance dose are likely to be quite marginal. What are you trying to achieve in this situation? This risk/bene \201 t ratio needs caref ul explanation to the patient. Early withdrawal (e.g. \201 rst week) or total avoidance is increasingly popular with ant ibody induction and TAC-/MMF-based regimens. Newer immune suppressants Belatacept \200 A fusion protein comprising an immunoglobulin domain and modi \201 ed CT LA4 (a T cell molecule, which forms part of the co-stimulatory signals required for T cell activation). It is designed to strongly bind the APC surface co-stimulatory ligands CD80 and CD86. Must be given IV every 4 \200\223 6 weeks. \200 Has been used in early studies to allow CNI avoidance. \200 In addition, experimental studies have suggested that the interruptio n of co-stimulatory signals could lead to donor-speci \201 c graft tolerance. Eculizumab \200 A humanized monoclonal antibody that targets complement protein C5, inhib iting its cleavage to C5a and C5b 6 preventing formation of the membrane attack complex (MA C). It has been primarily used to treat atypical HUS and antibody-mediated rejection (AMR). It may have a prophylactic role in transplants at high risk for these conditions. All patients should receive vaccination against Neisseria meningitidis prior to receiving eculizumab. Clinical trials, predominantly in antibody-incompatible renal transplantation, are ongoing to determine the optimal use. It is eye-wateringly expensive. CHAPTER 5 Transplantation 392 Perioperative care Introduction Patients listed for transplantation will have undergone com prehensive prior evaluation and have been deemed suitable ( b p. 350). However, circumstanc es may have changed physically, psychologically, or socially and require brief reassessment to ensure the recipient is \201 t to proceed with urgent surgery. The same is true of live donor, but this is elective surgery without the time pressure of attempting to minimize CIT. Transplantation is major surgery, and a full general history and examina- tion are required . Additional useful information may be gained from the full case notes (which may need to b e couriered from another site, if not available electronically). In particular, you need to establish the following. Is the patient \201 t for major vascular surgery today? \200 Is the CV work-up complete , up to date, and satisfactory? \200 Are there any new cardiorespiratory symptoms (or sig ns) which warrant further assessment? Any recent or present intercurrent illness? \200 Are the vascular history and exam satisf actory? Document femoral and more distal pulses; look for signs of ischaemia, and ask about claudication. Is the patient appropriate for immune suppression? \200 Any recent or active infections? \200 Any history of malignant disease and treatment? \200 Any concerning symptoms or si gns under, or requiring, assessment, e.g. unexplained weight loss, new or disproportionate anemia, change in bowel habit? What are the likely requirements for RRT perioperatively? \200 Is the patient pre-emptive , HD or PD? \200 What is the K + ? ( 2 urgently required) \200 Any signs of \202 uid overload? \200 Current weight vs target weight? \200 When did they last dialyse? \200 What is the current dialysis access, and how has it been functioning? \200 Is DGF antici pated (e.g. DCD, ECD, long CIT, AKI at retrieval)? What are the factors that need extra consideration for this patient? \200 What is the und erlying renal disease and residual urine output? \200 Any comorbid disease that increases operative risk 9 requires speci \201 c perioperative management, e.g. diabetes, i BP, airways disease? \200 History of dif \201 cult vascular access? Will central venous access be possible? Previous major abdominal surgery? \200 Previous urological surgery? Anticipated bladder o r bladder out \202 ow dysfunction? What is the bleeding risk? Antiplatelets or anticoagulation? PERIOPERATIVE CARE 393 What is the immunological history? Previous biological therapy (ATG, OKT3, alemtuzumab)? Current or historical HLA antibodies/PRA, previous transplants, recent potential sensitizing events (esp. blood transfusion)? Investigations \200 All patients should have their donor-speci \201 c cross-matched bloo ds sent urgently to tissue typing, as this is a rate-limiting step. In selected patients (esp. with no historical antibodies or recent sensitizing events), a \200\230 virtual cross-match \200\231 (see b p. 364) may be permitted. FBC, clotting, and G&S ( 9 cross-matched blood). \200 U&E, Ca 2+ , PO 4 , LFT, glucose, C RP. \200 ECG \200\224 compare to previous. \200 CXR \200\224 if signi \201 cant card iorespiratory disease or symptoms/signs. \200 MSU \200\224 unless anuric. \200 HIV, HB V, HCV \200\224 screened 3-monthly in HD patients but may not have been performed recently in others. CMV, EBV, toxoplasma, VZV, and syphilis serology. These will have been performed during wor k-up. They only need repeating if IgG previously negative. Pregnancy test, if relevant. Although pregnancy is rare in advanced CKD/dialysis patients, it is a possibility and generally considered a contra-indication to transplantation. A urin ary pregnancy test is reliable if the patient passes urine, serum beta-HCG if not. Preoperative RRT \200 It is important to ensure that patients are safe for the \202 uid loading, tissue injury, and transfusion ( l i K + ) that may occur during a long transplan t operation. However, dialysis may delay the operation, potentially i DGF (especially if excess UF is performed), and i bleeding if heparin is used. Dialysis is advisable if: \200 K + \211 5.5mmol/L. \200 Signs of \202 uid overload (pulmonary oedema > peripheral oedema). \200 A long delay is anticipated before the organ arrives. A suitable strategy would be a short session (2 \200\223 3 hours is adequate for K + remov al), minimal or zero heparin, and the minimum necessary UF (often leaving the patient 7 1kg above their target weight). Pre-dialysis patients It is unusual for these patients to requ ire HD pre-op. Minor electrolyte/ \202 uid disturbances may be managed conservatively, wi th blood sugar con- trol, isotonic sodium bicarbonate, diuretics, etc., as appropriate. If there is no pre-existing vascular access, the bene \201 ts of dialysis cath- eter inser tion need to be weighed against the risks of time delay, DVT (femoral), pneumothorax (inter nal jugular), etc. If DGF is anticipated, ask the anesthetist to site an internal jugular dialy- sis catheter intraoperatively. PD patients Similar considerations as for pre-dialysis patients tend to apply. Additionally , rapid exchanges can be used preoperatively. PD may be used CHAPTER 5 Transplantation 394 post-operatively if the peritoneum has not been breached (talk to the operating surgeon). Writing the drug chart It is good practice for transplant units to have their own clear gui delines for perioperative transplant prescribing, including sample drug charts for the immu nosuppression protocols used. The general principles include: Diabetes medications \200 Stop all regular medications, including oral hypoglycaemics and SC insulin. Commence an IV short-acting insulin \200\230 sliding scale \200\231 unless d iet-controlled only. Regular medications will need careful retitration post-operatively once eating normally \200\224 requirements may have changed due to improved renal function. Antihypertensives \200 Fluid shifts, general anesthesia, and opiate analgesia can all con tribute to d BP post-op. i BP is preferred to d BP post-op, as autoregulation is impaired and graft perfusion is 6 m ore BP-dependent. All antihypertensives are generally stopped preoperatively. (cid:2) Excep tions are beta-blockers (re \202 ex tachycardia/myocardial ischaemia) and other drugs used as anti-anginals or anti-arrhythmic, e.g. diltiazem, verapamil. Antiplatelets and anticoagulants \200 The antiplatelet effects of aspirin and clopidogrel last at least 7 days. \200 Monotherapy is not considered a contraindication to transplan tation, and many routinely initiate low-dose aspirin as prophylaxis against graft thrombosis. Dual antiplatelet therapy is generally considered a contraindication. As such, patients sho uld not be transplant-listed until they have reverted to monotherapy (e.g. after 6 \200\223 12 months for a drug-eluting stent). Warfarin: The INR should be corrected to at least <1.5 prior to surgery (discuss with your surgeon). For live donor recipients, this can be achieved by omitting it from 5 days pre-op. The decision to admit for therapeutic IV heparin infusion pre-op depends on the indication (absolute, e.g. metallic MVR, recurrent VTE vs relative, e.g. AF). Reversal depends on the time available. If >6h, give 2mg vitamin K IV, and recheck in 4h. If surgery is imminent, reversal can reliably be achieved with concentrated vitamin K-dependent clotting factors (e.g. Beriplex 20 \200\223 50IU/kg, d epending on INR; discuss with hematology) or FFP 15mL/kg. You should not need to recheck IN R prior to proceeding. (cid:2) Effects only last 7 4 \200\223 6h though. The effect of warfarin can be prolonged \200\224 ensure adequate vitamin K loading, and re check INR post-op, and then 12-hourly for 48h. PERIOPERATIVE CARE 395 CKD-related drugs Stop: \200 Phosphate binders. \200 Vitamin D analogs, e.g. alfacalcid ol (unless previous parathyroidectomy). Cinacalcet. Rebound hypercalcaemia can occur, so monitor closely. \200 Iron. \200 ESA \200\224 often stopped. Should continue if DGF to reduce the potential need for transfusion. Immunosuppression \200 Prescribe accurately, according to local protocols. \200 Inducti on agents are prescribed on the \200\230 stat \200\231 side and not given until the cross-match is con \201 rmed negative. Ensure the anesthetist is aware of intraoperative drugs, e.g. methylprednisolone. VTE prophylaxis \200 VTE risks are present as with any major surgery. \200 Use anti-emb olism stockings (unless contraindication). \200 Consider SC heparin or LMWH prophylaxis ( discuss with your surgeon). GI prophylaxis \200 If on H2 antagonist or PPI, then continue. \200 If on neither, star t ranitidine 150mg PO bd until steroids are weaned. Anti-infective prophylaxis \200 Infections are a common cause of morbidity and mortality in transplant recipients, especially in the \201 rst 6 months. \200 PCP: co-trimoxazole 480mg od (als o covers UTI, toxoplasma). Alternatives include dapsone 50 \200\223 100mg od or monthly pentamidine nebs. Oropharyngeal candidiasis: nystatin 1mL PO qds or amphotericin lozenges. CMV: valganciclovir (unless CMV D \200\223/R \200\223), dose according to GFR (see b p. 432) TB: local guidelines vary. Prophylaxis is essentially treatment of potential latent TB with isoniazid 300mg od (+ pyridoxine 25mg od to prevent neuropathy). Indicated where the TB risk is deemed greater than the risk of severe isoniazid toxicity, e.g. hepatitis (278/100,000). Risk factors include prior infection without evidence of cure, ethnic origin, or close contacts affected. General surgical prophylaxis is often given at induction, e.g. cefuroxime 1.5g IV and/or am ikacin 500mg IV. For DD transplant, further regular prophylaxis may be continued until cult ure of the graft transportation medium is available. Analgesia \200 Give paracetamol 1g qds regularly PO/PR/IV unless contraindicated (reduce IV dose if <50kg). CHAPTER 5 Transplantation 396 Patients will require opiate/opioid analgesia initially for comfort and to help them take deep breaths and cough. Patient-controlled analgesia (PCA) is preferred immediately post-op. Morphine (1mg bolus, 5min lock-out) is an option, but its metabolite morphine-6-glucuronide is active and renally excreted. Fentanyl (10 \200\223 15 micrograms bolus, 5min lock-out) does not accumulate. It has a shorter half-life so is more patient-responsive. Once patients are ready for oral analgesia, a moderately strong opioid can be used, e.g. ox ycodone 2.5 \200\223 5mg qds or tramadol 50 \200\223 100mg qds. (cid:2) Do not forget to prescribe laxatives in conjunction with opiate analgesia. Post-operative assessment It is good practice for the patient to have a detailed clinical a ssessment in recovery prior to transfer back to the ward to ensure they have recovered safe ly from anesthesia, are haemodynamically stable, have appropriate \202 uids and analgesia , and show no signs of hemorrhage or graft thrombo- sis necessitating immediate re-explorat ion. \200 Talk to the surgeon \200\224 the op note does not always tell the full story! \200 Read the op note thoroughly \200\224 any complications? Special instructions? \200 Examine the anesthetic chart \200\224 stable haemodynamics? (look for vasopressor administration, e.g. metaraminol/ephedrine, and boluses of furosemide). What was the \202 uid balance? Patients can be very \202 uid-loaded. Was there immediate urine output? Estimated blood loss? Examine the drug chart \200\224 was all induction immunosuppression given as planned? Careful clinical examination \200\224 ideally, the patient should be: \200 Alert, orient ated, and comfortable. Able to cough. \200 Well perfused \200\224 warm peripherally. Nor mal lactate. \200 Haemodynamically stable \200\224 not tachycardic, good BP (MAP >80mmHg). On no, or minimal, supplemental O 2 , with good air entry to the lung bases. Passing urine \200\224 unless DGF is anticipated. Additionally examine: Drain outputs and contents. \200 Distal lower limb pulses \200\224 compare to pre-op. Abdomen (some post-op tenderness to be expected \200\224 but is it proportionate?). Check that full post-op bloods have been sent, particularly Hb and K + . \200 Review the CXR: CVC position? Pneumothorax? Pulmonary oedema? \200 2 Doppler USS \200\224 this shou ld ideally be performed in recovery. It helps to exclude an immediate technical complicatio n. Additionally, baseline perfusion, resistive indices, and diastolic \202 ow patterns ar e very helpful for future comparative scans. PERIOPERATIVE CARE 397 Post-operative care Attention to detail is key. Always consider: what am I expecting from t his graft, in this patient, at this time? Any deviations require urgent assess- ment, inves tigation, and intervention. Monitoring \200 HR, BP, RR, O 2 saturation hourly for at least 24h, then 4h. \200 Accur ate \202 uid balance charts, including hourly urine and drain outputs for at least 48h, then 4h. Daily weights. \200 Bloods: FBC and U&E 6-hourly for 24h. Expect a modest fall in Hb (blood loss/haemodilution). Daily FBC, U&E, CRP, glucose (bone and liver pro \201 le may be 3 x /weekly). 2 Trough CNI levels: 3 x /weekly, starting day 3 (unless live donor with pre-loading). Managing \202 uid balance There is a broad spectrum of outcomes from the graft immediatel y post-transplant \200\224 from a brisk diuresis >20L in 24 hours to complete anuria. Addi tionally, the recipient \200\231s native UO may range from normal to anuric. \200 As a ge neral rule, daily \202 uid balance should be 7 +500mL (for insensible losses). This can be achieved by 100% replacement of the previous hour \200\231s losses + 40mL. This must be combined with regular careful clinical examination to detect hyper-/hypovolaemia and adjusted accordingly. If the patient is still polyuric after 48 \200\223 72h, it may be being \200\230 driven \200\231 by this regimen. Try reducing to 75% replacement, and monitor for signs of hypovolaemia. Fluid choice \200 Due to the electrolytes losses that can occur, it is best to use a bala nced electrolyte solution, e.g. Hartmann \200\231s or Ringer \200\231s lactate (especially if polyuria). The risk of them contributing to i K + is low, as they only contain 4 \200\223 5mmol/L. 0.9% NaCl should be avoided in high volume, as excess salt-loading and hyperchloraemic metabolic acidosis may develop. Responding to low urine output \200 Oliguria may be de \201 ned as UO <0.5mL/kg/h. \200 Remember, what are you expecting? DGF and oliguria are unusual in live donor kidneys or a DBD kidney with a short CIT. (cid:2) The most worrying sign is oliguria (or anuria!) developing in a patient previously passing good urine volumes. Causes include: \200 Hypovolaemia (beware inaccurate charts, undocumented loose stools, etc.). Catheter problems (obstruction, bypassing). \200 Relative hypotension (esp. if the donor was hypertensive). CHAPTER 5 Transplantation 398 Ureteric obstruction. \200 Urinary leak (high drain volumes?). \200 CNI toxicity. \200 Arterial or venous thrombosis. \200 Hyperacute rejection (graft pain, swelling, tendern ess) is rare but should be checked for. Action \200 Unless there are de \201 nite signs of \202 uid overload, give a \202 ui d challenge: Rate of delivery is more important than choice of \202 uid. \200 Administer a rapid bol us of 250mL. \200 Use additional variables to assess response, e.g. HR, BP, JVP, CVP. \200 Do not give repeated \202 uid challenges for oliguria, unless there are signs of a positive impact, e.g. improved BP or low CVP rising to 8 \200\223 12cmH 2 O, otherwise the re is a danger of pulmonary oedema. Flush the catheter, and replace, if necessary. \200 Send a drain creatinine if volumes ar e high ( b p. 402). \200 Check/review CNI levels. \200 Arrange an urgent Doppler USS to assess vascular patency and \202 ow, RI, and signs of obstruction or collections. If all these factors are in order, the most likely diagnosis is DGF ( b p. 404). If DGF persists to day 5 \200\223 7 post-op, then a surveillance transplant biopsy is usually undertaken. There is no role for the use of furosemide or \200\230 renal dose \200\231 dopamine to augment urine output. RRT post-transplant \200 Unless immediate graft function occurs, dialysis may be required . \200 Patients should be reassured that this is not uncommon. \200 (cid:2) Haemodialys is post-transplant can actually increase/prolong DGF. \200 Standard indications apply in the presence of oliguria: \200 Hyperkalaemia: >6.5mmol/L and/or ECG changes. \200 Pulmo nary oedema. \200 Symptomatic uraemia. If patients are passing good volumes of urine, medical therapies may be more appropriate. Avoid calcium/K + exchange resins. In addition, RRT may be required for: Safe transfusion of blood products, e.g. if Hb <70g/L. \200 Reducing risk of uraemic blee ding for planned procedures, e.g. transplant biopsy. Aim to minimize UF, and avoid intradialytic hypotension as much as possible. PD may be used if the peritoneum has not been breached. General measures \200 Remove IV lines, including CVC, as soon as practical to avoid infec tion. \200 Early oral intake, as advised by the surgical team. \200 Encourage deep brea thing exercises and early mobilization. \200 Urinary catheter to stay until at least day 5 (protects the vesicoureteric anastomosis). PERIOPERATIVE CARE 399 Watch phosphate levels. Urinary phosphate excretion often precedes a falling creatinine. Frank hypophosphataemia is relatively common. Encourage high phosphate foods; may require oral or IV supplementation. Remove drains when volume <50mL/24h (with surgical approval). \200 Watch blood sugars clo sely for the development of NODAT ( b p. 424). Encourage self-administration of medications prior to discharge. \200 Do not forget subse quent induction immune suppression doses, e.g. day 4 basiliximab. CHAPTER 5 Transplantation 400 The transplant operation Organ retrieval \200 Retrieval of multiple organs is the norm (i .e. heart \200\223 lung, liver, renal, pancreas), and several retrieval teams are often present. Both kidneys are harvested and may be sent to different centers. \200 The kidneys are per fused with a cooled balanced physiological solution in situ (e.g. with Marshall \200\231s o r University of Wisconsin solution) prior to removal. Along with the kidney, the renal artery (on a cuff of aorta), the renal vein(s) (with a cuf f of IVC), and as much ureter as possible (with periureteral tissue \200\224 to preserve i ts vascular supply) are removed. The kidneys are placed on ice for transportation. Machine perfusion techniques are an alter native \200\224 several types of apparatus are commercially available. Splenic tissue and mesenteric lymph nodes are also retrieved for cytotoxic cross-matching. Recipient operation \200 The kidney is carefully examined \200\230 on the bench \200 \231 , paying particular attention to the arterial anatomy (accessory arteries cannot be sa cri \201 ced, as there is no collateral supply). Small veins may be more expendable, as th ere is some overlap in venous drainage. Vascular reconstruction may be necessary prior to i mplantation. \200 The left renal vein is longer, making it easier to implant. \200 Graf t implantation is heterotopic, usually into the right iliac fossa (the right iliac vessels are generally more accessible), although some surgeons favor placi ng a right donor kidney on the left side and vise versa (as kidney orientation is easier). If a previous transplant remains in situ , the contralateral side will be favored. An implantation biopsy may be taken (esp. if the donor is considered marginal) to help pred ict graft function in the post-operative period. Scoring systems are applied to these \200 \230 time zero \200\231 biopsies in an attempt to predict subsequent graft outcomes, e.g. the Karpinski score is based on summation of damage to glomerular, tubular, interstitial, a nd vascular compartments. An oblique incision is made from above the symphysis pubis towards the anterior superior iliac spine. The operation is largely extra-/retroperitoneal. \200 Note: the native kidneys are not re moved. \200 Vascular anastomoses are usually end-to-side to the iliac vessels (preferably the external iliac artery \200\224 use of the internal may lead to erectile dy sfunction in 4 ). The ureter is joined to the recipient bladder. A submucosal tunnel (or oversew of bladder muscle) helps to prevent urine re \202 ux. A JJ stent is usually placed to protect this anastomosis (removed cystoscopically at 7 4 we eks). A urethral catheter is left in situ for 5 days. A drain is usually left in the perirenal space. THE TRANSPLANT OPERATION 401 Intraoperative CVP is maintained at >10cmH 2 O and MAP >90mmHg using crystalloid ( 9 albumin). Mannitol (or furosemide) may be administered as the vascular clamps are released. Methylprednisolone (0.5 \200\223 1g) is also given intraoperatively. \200 See Fig. 5.17. Dual transplants \200 Double transplants represent an attempt to increase the transplanted nephron mass. Dual transplants are increasing, as more ECD kidneys are accepted for transplantation. There are no universally agreed criteria: some centers will be guided by a pre-implant biop sy, some by donor characteristics alone, and some by both donor and recipient characteristi cs. Both kidneys are usually placed in the same iliac fossa, but one can be placed on each side in some circumstances. It is a signi \201 cantly longer operation than a single kidney transplant, so intraoperative risks are higher. En bloc transplantation refers to a technique wherein both kidneys are retrieved together, with donor aorta and IVC still attached. They are then transplanted en bloc into the recipi ent. This is usually performed in the context of pediatric donation (age <5): it increases the transplanted nephron mass and helps make the surgical anastomoses less technically dema nding. Fig. 5.17 Renal transplant surgery with an end-to-side anastomosis between the renal artery and external iliac artery. Reproduced from Oxford Desk Reference: Nephrology, Jonathan Bar ratt, Kevin Harris, and Peter Topham (2008), with permission of Oxford University Press. CHAPTER 5 Transplantation 402 Surgical complications Early Bleeding Rarely from the vascular anastomoses ( l haemorrhagic shock), more likely from dam age to a smaller vessel. May present with i HR, d BP, i drain output, blood loss from the s urgical wound, d Hb. USS or CT may reveal a haematoma around the graft. Resuscitation, then urgent re-exploration is usually indicated. Wound infection The incidence has reduced with the use of perioperative antibiotics. Contri buting factors include uraemia, steroids, sirolimus, diabetes mellitus, older age, and obes ity. Causative organisms are usually Gram +ve. Vascular thrombosis/occlusion \200 Occurs in 0.5 \200\223 5% of transplants. \200 Risk factors: complex vascular anastomoses, d BP, donor vascular disease, recipient thrombotic tendency (e.g. APS), recipient sickle cell disease ( l pre-tr ansplant exchange transfusion to d sickle Hb + warm graft prior to reperfusion). Arterial Arterial thrombosis is usually secondary to a technical error (either dur- ing ret rieval or during transplantation \200\224 usually intimal injury). Usually presents with o liguria and deteriorating graft function ( 9 pain). Requires urgent surgery, but graft loss is the usual outcome. Regular USS with Doppler is required to con \201 rm perfusion in th ose with DGF. Venous Suspect if sudden d UO, graft tenderness and swelling, macroscopic haematuria, pain (often severe). Doppler USS will show thrombosis and reversed diastolic arterial \202 ow. Management: surgical exploration. The kidney will usually be removed (and reperfused) whil st the venous anasto- mosis is completely revised. Urinary leak Most commonly a technical problem with the vesicoureteric anastomo- sis or nec rosis of the distal transplant ureter due to poor blood supply. Rarely, a complication of t ransplant biopsy. Often silent but may be pain- ful (as the collection of irritant urine ex pands), scrotal/labial swelling, d UO, i SCr (resorbed urinary creatinine), i drain volumes , wound leak, collection of \202 uid on imaging. Investigation: biochemical analysis of d rain (or aspirate) will reveal a high Cr \200\224 higher than serum (lymphocele \202 uid has the same Cr as serum). Na + and K + are also high. Cystography/retro- grade pyelograph y will demonstrate the source of the leak. Management: re-catheterize the bladder. If the u reteric stent has been removed, it may be reinserted (usually antegrade insertion) and left in situ until the leak has sealed (may take weeks to months). If this conservative approac h fails, then surgery is necessary. SURGICAL COMPLICATIONS 403 Lymphocele Graft implantation interrupts the pelvic lymphatics. This may result in a collec tion of lymph around the transplant ( 7 10% of transplants). Usually small and uncomplicate d. May become large enough to obstruct the kid- ney or iliac veins ( l thrombosis). Can cau se leg swelling and DVT and may become infected. More common in those treated with sirolimu s ( b p. 390). Diagnosis is on USS (or CT). Indications for intervention: discom- fort, obs truction, or infection. Aspiration or drainage is usually carried out percutaneously. Recur rent lymphoceles may need fenestration to allow drainage into the peritoneal cavity. Early obstruction Early obstruction is usually caused by urethral catheter blockage by clot s. Ureteral blockage from clot or oedema is rare if a JJ stent has been left in situ ( (cid :2) but suspect if i SCr when it is removed). Extrinsic compression from a lymphocele may o ccur. USS will demonstrate hydronephrosis (but is often normal in early obstruction). Late Renal artery stenosis Transplant renal artery stenosis may occur early (either a techn ical com- plication due to vessel injury or s to neointimal hyperplasia) or late (often ath eromatous build-up at the transplant artery origin). Presents with i SCr ( 9 ACE-I/ARB-rela ted transplant dysfunction), increasing BP, salt and water retention. Rarely, a transplant bruit. Should also be suspected if progressive transplant dysfunction with unexplained scar ring on biopsy. Investigation: Doppler USS, CT angiography, MRA, formal angiography (accord ing to local expertise). Percutaneous angioplasty can be under- taken, although recurrence is common ( l repeat angioplasty 9 stenting). If required, surgical correction is technical ly challenging. Ureteric stenosis Occurs in 1 \200\223 5% of transplants. Almost always in the distal uret er and s to ischaemia (the ureter is supplied by the transplant renal artery; ischae- mia l \201 brosis). Other causes include: lymphoceles, BK virus ( b p. 436), urothelial tumors , and renal calculi. Investigation: USS will show hydro- nephrosis and allow nephrostomy pl acement. A nephrostogram will show the level of the obstruction. CT and cystoscopy may be n eeded to deter- mine the cause in some cases. Management: JJ stenting. Small strictures may be amenable to endourological dilatation, but surgical re-implantation is often required. Occasionally, a native ureter is mobilized and anastomo- sed to transplant pelvis. Bladder dysfunction Transplantation may uncover pre-existing bladder out \202 ow obstructi on or bladder dysfunction. Examine for a palpable bladder, DRE, USS bladder pre-/post-voidi ng and consider urodynamic studies. Bladder training may be required in patients who have u ndergone long-term dialysis, as their bladders may have reduced capacity and muscle tone, r esulting in signi \201 - cant urinary frequency. CHAPTER 5 Transplantation 404