3 Always consider other causes of peritonitis (e.g. perforation, stran- gulated hernia, etc .). Bacteriology \200 Gram +ve cocci: 7 45 \200\223 75% (coagulase-negative staphylococci, S . aureus ), often introduced after touch contamination of the connections or following catheter exit si te infection. Colonization of catheter bio \201 lms can lead to recurrence of peritonitis and necessitate catheter exchange. PERITONITIS 321 Gram \200\223 ve organisms: 7 15 \200\223 25% ( Pseudomonas , coliforms). Usually of bowel origin. Air in the peritoneum is common and may not indicate bowel perforation. Suspe ct perforation if mixed organisms on culture, and arrange appropriate imaging and/or explor ation. Culture negative or \200\230 no growth \200\231 : ideally, cultures should be positive in >85% cases. Higher yields may be obtained by inoculating blood culture bottles with PD \202 uid. Mycobacterial infections: 7 1%. Consider in patients with culture-negative peritonitis not responding to empiric antibiotic therapy. Smears of PD ef \202 uent are rarely positive fo r acid-fast bacilli, and diagnosis is usually made on culture (6-week) or at laparoscopy/ot omy, with con \201 rmation on peritoneal biopsy. Fungal: 7 3%. Usually Candida spp. Peritonitis is infrequent but has a poor prognosis. It often follows antibiotic therapy in at-risk (e.g. malnourished) patien ts. PD catheter removal is mandatory. Allergic peritonitis is well described and often found following prescrip- tion of icodextr in solutions (although it can occur with glucose-based solutions). In general, the elevatio n of WCC is modest, and the pro- portion of eosinophils in PD ef \202 uent may be high (>1 0%). Does not respond to antibiotics. Withdrawal of icodextrin usually helps. Complications of peritonitis \200 Relapsing peritonitis . A second episode of peritonitis with the same organism within 4 weeks of completing antibiotic therapy. Prolonged antibiotics (particular ly for relapses secondary to Staphylococcus ) are required. Recurrent peritonitis refers to a second episode of peritonitis within 4 weeks with a different organism. Antibiotic treatment failure . Consider infected, encysted \202 uid collections and frank abscess formation if no response to protocol antibiotic therapy ( l C T abdomen and pelvis). (cid:2) PD catheters will generally require removal, and a laparotom y should be considered, especially if there is a suggestion of other intra-abdominal pathol ogy. Acute and chronic UF failure . In \202 ammation l vasodilatation l i glucose absorption, d glucose gradient, and impaired UF. Repeated bouts of peritonitis can lead to long-term changes in the structure and function of the peritoneal membrane, causing chronic UF failure. \200 Malnutrition . Peritoneal protein loss through the in \202 ame d membrane can be high. Anorexia and prolonged ileus can further impact on nutritional stat us. CHAPTER 4 Dialysis 322 Peritonitis: management 2 Empiric antibiotic therapy should always be initiated in cases of de \201 nite peritonitis without waiting for the results of cultures. Many therapeutic pr otocols are available and will be in \202 uenced by local experience \200\224 discuss wit h your microbiologist. The International Society of Peritoneal Dialysis (2010) recommends: Gram +ve cover with vancomycin or a cephalosporin, plus \200 Gram \200\223 ve cover with an aminoglycoside or third-generation cephalosporin. 2 IP administration is more effective than IV. In the UK, despite concerns surrounding the development of vancomy- cin resistance, most un its utilize vancomycin-based regimens. Protocols differ from unit to unit, but, as an examp le: \200 Vancomycin 2g IP on day 1, with a further dose on days 3 \200\223 7, depending on trough vancomycin levels (aim to keep trough level >15 micrograms/mL, plus Either gentamicin 0.6mg/kg IP daily (adjusted against trough gentamicin levels on days 3 \200\223 5; (cid:2) ototoxicity) or, alternatively, to spare potential aminoglycoside toxic ity, ceftazidime 1g IP daily. Once culture result and sensitivities known: \200 If Gram +ve: continue vancomycin accord ing to levels. If S. aureus , add in rifampicin 300mg PO bd. Stop gentamicin/ceftazidime. If Gram \200\223 ve: continue ceftazidime or gentamicin. Although concerns about aminoglyc osides affecting residual renal function exist, this is not borne out by current evidence. However, if the patient still has a signi \201 cant UO (e.g. >500mL), many centers may pre fer ceftazidime over gentamicin. Stop vancomycin. If culture negative: continue both Gram +ve and Gram \200\223 ve cover, doses adjusted according to trough levels. If mixed Gram \200\223 ve growth: add in metronidazole, and consider laparotomy ( 2 suspect bowel perforation). Treat for 14 \200\223 21 days. X PD programs with a high incidence of fungal peritonitis a fter antibi- otics may consider prophylaxis with oral \202 uconazole. Mupirocin ointment administered to the catheter exit site can prevent exit site infection and, potentially, S. aureus peritonitis. 3 Every episode of PD-related peritonitis should prompt a root cause analysis and review of aseptic technique. PERITONITIS: MANAGEMENT 323 Special considerations for APD Even in the absence of peritonitis, long day dwells may be \200\230 misty \200\231 . However, because cycling times are shorter, cloudy overnight dia lysate may not occur, even in the presence of peritonitis. Moreover, in some cases, PD ef \202 uent is drained directly into a sink. This means it is very important for APD patients to recognize poten- tial symptoms of perit onitis and to perform a dwell of at least 2 hours (for visual inspection and sampling of \202 uid for M, C+S). Treatment also requires some modi \201 cations to normal APD tech- nique. One option is to convert patients to CAPD for the duration of the episode. More preferable is to give antib iotics into the last dwell on the machine (sometimes called the \201 rst ambulatory dwell ). Indications for PD catheter removal during infection \200 2 Refractory peritonitis (cloud y bags persists after 5 days of appropriate antibiotic therapy). \200 Relapsing peritonitis ( b p. 321). \200 Fungal pe ritonitis. \200 Persistent exit site or tunnel infection. \200 Potential: Multiple episodes of peritonitis in an individual patient. \200 Mycobacterial peritonitis . \200 Peritonitis caused by multiple organisms of likely enteric origin. CHAPTER 4 Dialysis 324 Other PD complications Catheter exit site infection A purulent 9 bloody discharge from a PD catheter exit site, often associ- ated with erythema and pain. Crusting alone is not indic ative of an acute exit site infection. Scoring systems have been developed, including this one recommended by the ISPD (see Table 4.4). Table 4.4 Exit site infection scoring system 0 points 1 point 2 points Swelling No Exit only; <0.5cm >0.5cm and/or tunnel Crust No <0.5cm >0.5cm Redness No <0.5cm >0.5cm Pain No Slight Severe Drainage No Serous Purulent Reproduced from Piraino, B, Bailie, GR, Bernardini, J, et al . Peritoneal dialysis-related infections recommendations: 2005 update. Perit Dial Int 2005; 25 :107. Causes \200 Usually S. aureus , Pseudomonas . \200 The use of prophylactic topical exit site ointment (e.g. mupirocin) reduces such infections. Reducing nasal carriage of S. aure us is also helpful. Treatment \200 Swab for culture, and con \201 rm PD \202 uid is clear. \200 Empiric therapy: start \202 ucloxacillin 500mg PO qds or cipro \202 oxacin 500mg PO bd if there is a history of Gram \200\223 ve infection. Topical antibiotics are not suf \201 cient. \200 Adjust therapy once culture result and sensitivities known. \200 Gram +ve organisms: continue \202 ucloxacillin, unless sensit ivities dictate otherwise. Treat for 14 days. If S. aureus con \201 rmed, consider adding rifampicin 300mg bd. Gram \200\223 ve organisms: cipro \202 oxacin 500mg PO bd for 14 days. (cid:2) If Pseudomonas , dual treatment is often recommended (e.g. add IP gentamicin or cef tazidime), and catheter change is often required. Exit site trauma increases the likelihood of infection \200\224 it should 6 be pro- tected from this (including dressings that immo bilize the catheter, thereby preventing pulling on the exit site). Increasing the frequency of exit site care (to daily or twice daily dress- ings) is often a dvocated during infections. Crusts or scabs should not be forcibly removed. A tunnel infection is de \201 ned as erythema and/or tenderness over the subcutaneous cath eter pathway 9 intermittent discharge from the exit site. Diagnosis of tunnel infection is usually obvious clinically but can be con \201 rmed by ultrasound examination. Treatment u sually involves remov- ing the catheter, as peritonitis is a common complication. OTHER PD COMPLICATIONS 325 Drainage problems This needs to be differentiated from the more serious UF failure. Cathete r \202 ow problems can present with either slow drainage (drainage takes >15 \200\223 20 minutes under gravity) or incomplete drainage (high residual volume measured on PET or dra in volume is less than the infused volume of a \200\230 rapid \200\231 exchange). Causes include: Constipation. \200 Catheter malposition (usually migration out of the pelvis). \200 Cat heter occlusions (kinking, thrombus, \201 brin, and omental wrapping). \200 Fluid leaks into subcutaneous tissue via hernias or at the catheter insertion site. In \202 ow problems can also occur for similar reasons \200\224 and also if the cath- ete r tip is trapped in an area of intra-abdominal adhesions. Clinical assess- ment will usuall y determine the majority of causes. If necessary, plain KUB can be performed to exclude cat heter malposition and constipation. The majority of drainage problems can be improved without surgical intervention: \200 Laxatives (most PD patients require regular laxatives, e.g. senna and lactulose, but a short course of a stronger aperient, such as sodium picosulfate, may be re quired). Intracatheter heparin locks (e.g. 500 units as a lock or 500 units/L in exchanges), particu larly if visible \201 brin in catheter or drainage \202 uid. Thrombolytics, such as urokinase, may be instilled in the catheter lumen. Endoluminal brushing ( (cid:2) infection!). If surgical repositioning of the PD catheter is required, a concomitant adhesiolysis and omentectomy should be considered. Peritoneal leaks Dialysate may leak down the catheter tunnel and spread into the subcu- tan eous tissues (or leak around the exit site). A patent processus vaginalis may allow PD \202 uid to track into the scrotum, mimicking a hernia or hydro- cele. Small diaphragmatic hernias may permit PD \202 uid to enter the pleural space (usually on the right side). Clinically, local oedema 9 peau d \200\231 orange skin appearance may signify a subcutaneo us leak. Pleural taps or aspirates from hydroceles can be tested for glucose concentration to con \201 rm it is dialysis \202 uid. If in doubt, perform CT peritoneogram, e.g. infu se 100mL of non-ionic contrast into a 2L PD bag, and drain in 1L. Perform CT 1 \200\223 2 hours thereafter. Leaks around the catheter often heal with temporary (2 \200\223 4 weeks) discontinuation o f PD (temporary HD will usually be required). PD can be restarted, using smaller exchange v olumes to reduce intra-abdominal pressure. If leaks recur, the PD catheter can be repositio ned with a new insertion site. Hernias should be repaired in a standard manner. APD with a dry day (NIPD) can be particularly successful to minimize recurrence. CHAPTER 4 Dialysis 326 Sclerosing encapsulating peritonitis (SEP) SEP is a feared complication of long-term PD the rapy, with a poor prog- nosis. It is extremely rare before 3 years and has an incidence aro und 5% at 5 years. The peritoneal cavity becomes encased in \201 brous tissue, with bowel wall thickening an d peritoneal calci \201 cation. It is thought to be multifacto- rial in origin, with prior severe/recurrent peritonitis, foreign body reac- tions to plasticizers on catheters, and l ong-term PD exposure to high concentration glucose-containing solutions all suggested to be pathogenic. Clinically \200 Symptoms of intermittent bowel obstruction (abdominal pain, nausea, vomiting). Poor UF or UF failure ( b p. 332). \200 Malnutrition is frequent and may be severe. \200 Symptoms may occur after peritonitis and often after stopping PD (e.g. post-transplantation). Investigation \200 CT abdomen is the investigation of choice, demonstrating peritoneal thickening and calci \201 cation with entrapped bowel loops. Laparoscopy and peritoneal biopsy is diagnostic. Management \200 Evidence is limited: Stop PD (symptoms may paradoxically worsen). \200 Early specialist dietetic input. Nasoga stric feeding or TPN may be required. X Drug therapy: immunosuppression (steroids, CNIs, azathioprine) and tamoxifen (anti \201 brotic) have all been tried, but evidence of ef \201 cacy is anecdotal at best. Surgery (enterolysis) is an option but only in specialist centers. \200 Renal transplanta tion \200\224 some reported cases of improvement. Prevention \200 There are no effective screening tests, and onset may be rapid. \200 Cu rrently, there is no optimal duration of PD therapy, and decisions should be tailored to the individual. Switching to HD may be advisable, based upon episodes of peritonitis and/or deteriorating membrane function/UF failure. OTHER PD COMPLICATIONS 327 CHAPTER 4 Dialysis 328 PD adequacy Introduction Although the term dialysis adequacy is often restricted to the for mal cal- culation of delivered dialysis dose in terms of weekly clearance of urea (Kt/V) an d creatinine (CrCl) ( b p. 286), the measurement of dialysis adequacy should mandate a more global assessment of health, including: \200 Absence of uraemic symptoms. \200 Nutriti onal status, appetite, weight, serum albumin. \200 Fluid status. \200 Quality of life ( e.g. by subjective global assessment scoring). \200 Improved biochemistry and correction of the complications of uraemia, such as anemia. Delivered dialysis dose can be formally measured by calculating weekly clearance for urea ( Kt/V) and creatinine (CrCl) ( b p. 286). The utility of Kt/V, a kinetic measure derived fro m HD practice, remains contentious in PD. Commercially available computer programs will hel pfully calculate urea and creatinine clearances, based on dialysate and plasma urea and cre atinine values obtained during a PET ( b p. 330) or other standardized regimen. The current US and UK PD adequacy targets are very similar: US KDOQI: Measure after 1 month, then 4-monthly. \200 If residual urine output >100mL/day: combined urine and peritoneal weekly Kt/V should be >1.7. If residual urine output <100mL/day: peritoneal weekly Kt/V should be >1.7. UK Renal Association: Measure 6-monthly (or more frequently, if indicated). \200 Combined urinary and peritonea l Kt/V \211 1.7/week or CrCl \211 50L/ week/1.73m 2 . X Although there is no evidence that increasing the dose above these tar- gets improve surv ival, it is generally accepted that they should be viewed as minimum treatment standards an d that the dialysis dose should be increased as clinical circumstances dictate. 2 The most powerful predictor of patient survival on PD is not dialysis adequacy, but the p resence of residual renal function. Preserving residual function is extremely important: \200 Control BP, with preferential use of ACE-I or ARB. \200 Avoid nephrotoxins, e.g. NS AIDs, aminoglycosides, contrast, etc. \200 Avoid dehydration and hypercalcaemia. PD ADEQUACY 329 How to improve a low Kt/V 9 CrCl Tailor changes, according to transporter status ( b p. 318 ) Increasing dialysate osmolality to increase UF and drain volumes will also improve total clearance. CAPD \200 If high or high average transporter: The osmotic gradient is lost quickly, so reduce dwell times (possibly allowing an additional exchange). Consider converting to APD to allow rapid cycling overnight. \200 Increasing dwell volume s is unlikely to help, as it will slow down exchanges and may reduce UF. \200 If low or low average transporter: More time is required, as solute clearance is slower. \200 Increasing dwell volumes and d well times may help. \200 Consider an overnight dwell. APD \200 Optimize cycle duration in accordance to patient transportation status, as descr ibed in \200\230CAPD \200\231 section (short cycles for high transporter). This might nece ssitate increasing total duration of APD. Consider the use of additional daytime exchanges. CHAPTER 4 Dialysis 330 The peritoneal equilibration test (PET) The test \200 The evening prior to PET, the patient performs a standard CAPD exchange. The exchange should dwell for 8 \200\223 12h. \200 Drain overnight dwell over 20min, and note volume. \200 Prepare a 2L 2.27%/2.5% dialysate solution bag at body tempe rature, and infuse over 10min, with the patient in a supine position. After 10min, dialysate samples are collected as follows: drain 200mL dialysate back into th e \201 ll bag, and mix sample by inverting bag 2 \200\223 3 times. Using aseptic techniq ue, withdraw 10mL dialysate sample, and send for determination of creatinine and glucose. Repeat at 2h. \200 At 4h, completely drain the exchange over 20min. Weigh drain bag, and record volume drained. Invert bag 2 \200\223 3 times; send samples for creatinine and glucose. \200 PET calcula tions: D cr /P cr = dialysate concentration of creatinine at 0, 2, and 4h, divided by serum concen tration of corrected creatinine. D/D 0 = dialysate glucose concentration at 2h and 4h, divided by dialysate glucose concentration at 0h. Residual renal function is estimated on 24h urine collection. Interpretation \200 If protocols are strictly followed, this is a highly reproducible assessment of peritoneal membrane transportation function. The ratio of dialysate and plasma creatinine concentrations (D cr /P cr ratio) after a 4h dwell is a measure of solute equilibration. High transporters are de \201 ned by a D cr /P cr >0.8 and low transporters <0.5. In between these are high average (0.65 \200\223 0.8) and low average (0.5 \200\223 0.64). Since glucose absorbed from the dialysate is very quickly metabolized, D/P ratio for glucos e is meaningless. Instead, the fraction of glucose absorbed from the dialysate at 4h is com pared with the initial dialysis solution (D/D 0 ). This is also a useful indicator of trans portation status. A PET is also a useful objective assessment of ultra \201 ltration. However, a UF volume < 400mL after modi \201 ed PET, utilizing a 3.86% glucose dwell, is more speci \201 c for U F failure ( b p. 332). PD ADEQUACY 331 CHAPTER 4 Dialysis 332 Ultra \201 ltration (UF) failure PD patients with \202 uid overload are either strugglin g to be compliant with a realistic \202 uid restriction or have inadequate UF. Inadequate UF might be the result of an inappropriate dialysis prescription or the failure of an appr opriate prescription to remove adequate \202 uid volumes; the latter is termed UF failure . PD patients are asked to achieve an ideal dry weight through a \202 uid restriction and t he use of hyperosmolar PD bags to produce UF. Residual urine output (which may be stimulate d with diuretics) is also very important. As a general rule, a patient should be able to UF \211 1L/day. If they are anuric, (de \201 ned as UO <100mL/day), then minimum daily UF should be 750mL. Approach (See Fig. 4.10) \200 Consider modi \201 ed PET (sometimes called standardized p ermeability analysis) to differentiate UF failure from other cases of \202 uid overload. 2 Net UF <40 0mL at 4h with 3.86% glucose de \201 nes UF failure. Determining transporter status can also help diagnose the cause of UF failure; in particular, is the patient a high transporter ( b p. 318)? Evaluate the residual peritoneal volume during PET: a \200\230 normal \200\231 residual volume is up to 200 \200\223 250mL. Higher volumes might suggest catheter-related drainage problems, rather than UF failure (i.e. the patient may be removing \202 uid thr ough UF, but it does not drain out adequately from their peritoneal cavity). Also check dra in time during the PET. Exclude \200\230 mechanical \200\231 catheter or APD equipment problems ( b p. 325). Avoid long dwells (>4h) with low glucose concentrations. \200 Use icodextrin, instead of glucose, for the longest dwell. \200 If on APD, consider additional short day exchange. Causes \200 High transporter status (often seen in long-standing PD patients). \200 If not high transporter, consider: Leaks ( b p. 325). \200 Reduced effective peritoneal surface area from peritoneal adhesions. Increased lymphatic absorption. \200 Aquaporin de \201 ciency or failure (indicated by l oss of sodium sieving during modi \201 ed PET/standardized permeability analysis). Patients with ultra \201 ltration failure will usually need to be switched to HD permanently. However, peritoneal membrane function can sometimes be improved by resting PD (for 4 \200\223 12 weeks) and might be considered where quality of life on long-term HD will be poor (e.g. excessive travel times). ULTRAFILTRATION (UF) FAILURE 333 Modified PET (4h dwell of 2L 3.86/4.5% glucose) UF <400mL? Yes No Consider: - Loss of residual renal function - Non-compliance to salt and water Transportation status: LA or HA (or unchanged) Low High Sclerosing peritonitis (late stages) - Adhesions Increased lymphatics - Aquaporin deficiency - Leakages UF failure Fig. 4.10 Algorithm for diagnosing the cause of hypervolaemia in PD. LA = low average. HA = high average. CHAPTER 4 Dialysis 334 The well PD patient Introduction Adequate dialysis: maintain residual renal and peritoneal membrane function. \200 Dialysis adequacy should be measured in terms of clearance of sma ll solute clearance (including Kt/V and CrCl) and nutritional parameters. Aim for normotension by good salt and water removal \200\224 generally, achieving minimum daily \202 uid removal of >750mL. Preserving residual renal function (basically, UO) makes these goals easier to achieve and may improve outcomes (making an argument for use of ACE-I for ongoing renoprotection and avoiding nephrotoxins in PD patients; 2 residual urine matters). Changes in patients \200\231 transportation status over time ( b p. 318) may make the main tenance of satisfactory UF and small solute clearance dif \201 cult without imposing onero us dialysis regimens and unrealistic \202 uid restrictions on them. High intraperitoneal glucose concentrations, with consequent expo- sure to GDP or AGE, is suggested to accelerat e peritoneal membrane changes, so the use of low GDP solutions, such as twin-bag \200\230 physiological \200\231 solutions, icodextrin, or amino acid solutions, may be desirable ( X ). Complications Minimize peritonitis episodes and exit site infections through education and good technique. This includes teaching the patients to identify perito- nitis at an early s tage. Monitor nutritional status closely. The initial stages of sclerosing encapsulating pe ritonitis (SEP) may be reversible; early diag- nosis relies on high index of suspicion. Social rehabilitation PD is a home-based treatment that allows patients to retain their ind e- pendence. It is important to grant individual PD patients a degree of \202 ex- ibility , e.g. adapting the timing of PD exchanges to work environments (perhaps negotiating a dedi cated area and delivery of \202 uids to the work place). Travel (either within the same c ountry or abroad) improves patients \200\231 sense of well-being and should be encouraged. Support for the other family members, including children and spouse, must never be overloo ked. 335 Chapter 5 Transplantation Transplantation: bene \201 ts and challenges 336 Transplantation outcomes 340 Basic transp lant immunology 346 Pre-transplant work-up 350 Compatibility: matching donor and recipient 360 Live donor transplantation 372 Immunosuppression: overview 380 Immunosuppression: induc tion 382 Immunosuppression: maintenance 386 Perioperative care 392 The transplant operation 400 Surgical complications 402 Graft dysfunction 404 Acute rejection 408 Chronic allograft dysfunction 414 Recurrent disease 418 Long-term transplant follow up 422 Post-transplant i nfections 426 Cytomegalovirus (CMV) 430 BK virus nephropathy 436 Post-transplant UTI 438 Po st-transplant malignancy 440 ABO- and HLA-incompatible transplantation 444 Kidney \200\223 pancreas transplantation 446 CHAPTER 5 Transplantation 336 Transplantation: bene \201 ts and challenges Introduction For many patients with ESRD, tra nsplantation is undoubtedly the treat- ment of choice. However, for some, the risks of tran splantation (the surgery itself plus subsequent immune suppression) will outweigh potential bene \201 ts. Suitability for transplantation has no set criteria but should re \202 ect the recipient \200\231s physical status ( \200\230 \201 tness \200\231 ), likely quali ty of life post-transplantation, and, wherever possible, the patient \200\231s wishes (whic h assumes adequate education). Bene \201 ts of transplantation \200 Improved patient survival: It is not fair to make a straight comparison between the survival of dialysis patients and the survival of transplanted patients, as many dialysis patients are elderly 9 have comorbi dities that preclude transplantation. However, if the playing \201 eld is leveled and patient \200\231s survival post-transplan t is compared to a matched transplant-listed dialysis cohort, there remains a signi \201 c ant survival advantage, once the initial risk of surgery is overcome (Fig. 5.1). Much of this improvement appears to stem from a reduction in CV mortality. Improved quality of life: Freedom from the constraints of dialysis treatment, including the time commitment and both dietary and \202 uid restrictions. Improved overall sense of well-being. \200 Improved exercise capacity. \200 Improved qu ality of life for close family. More complete and physiological correction of the uraemic milieu, including complications, such as anemia and CKD-MBD. Improved sexual function and fertility, including the potential for successful pregnancy in \231\200 ( b p. 864). Better for the health economics: transplantation is less expensive than dialysis (after the \201 rst year). X The risk-bene \201 t ratio of renal transplantation is changing, although much of the cu rrently available data may not adequately re \202 ect this. There is a signi \201 cant di fference between transplanting a 70-year-old dialysis patient from a live donor and with an organ from a marginal deceased donor, particularly if the recipient is thriving on a state -of- the-art daily home dialysis therapy. Preliminary outcome data suggest satisfactory, al beit less good, early outcomes, but patients must be very carefully selected, given appropr iate (and realistic) information and edu- cation and longer-term outcomes, including qualit y of life, need further evaluation. TRANSPLANTATION: BENEFITS AND CHALLENGES 337 4.00 Survival equal Risk equal h t a e d 2.84 f o k s i r 1.00 e v i t a l e R 0.32 0.25 0 106 183 244 365 548 Days since transplantation Fig. 5.1 This much reproduced graph shows survival in transplanted patients, compared to th ose remaining on the waiting list. Reproduced with permission from R. Wolfe et al. NEJM; 34 1, 1725 \200\2231730. Challenges \200 The number of patients listed for transplantation globaly has plateaued i n recent years after an extended period of relentless growth. Demand continues to outstrip the supply of organs (see Figs 5.2 to 5.4). \200 This inevitably leads to longer waiting times for deceased donor transplantation (mean 73 years in the UK). 10 500 s r a e y n o i t a l u p o p n o Incident rate t p D R S E 8 400 6 300 0 0 1 i l l i Transplant rate m r e p r e p D R S E 4 200 e t a r t n a l p s n a r T 2 100 f o e t a R 0 0 90 94 98 02 06 10 Fig. 5.2 The number of candidates awaiting transplant continues to increase, but transplant rates per 100 dialysis patient years continue to decline (despite a progressive increase i n the number of transplants; see Fig. 5.5). Reproduced from USRDS 2012 annual report, used with permission. CHAPTER 5 Transplantation 338 8000 7000 7190 7183 6980 6871 6633 6481 6000 5863 5425 5000 5074 5020 Donors Transplants Transplant list r e b m u N 4000 3000 1792 2000 1667 1657 1570 1453 1440 1399 1388 1326 1308 1031 957 931 859 789 765 743 734 712 722 1000 0 2003 \200\2232004 2004 \200\2232005 2005 \200\2232006 2006 \200\2232007 2007 \200\2232008 2002 \200\2232003 2008 \200\2232009 2009 \200\2232010 2010 \200\2232010 2011 \200\2232012 Year Fig. 5.3 Number of deceased donors and all solid organ transplants in the UK, 2002 \200 \223 2012 and patients active on the transplant list. Reproduced from UK Blood and Transpla nt Annual Report 2012, with permission. Still waiting Transplanted Died Removed 2 1 100 6 6 8 90 10 80 17 70 39 e 60 76 g a t n e c r e P 50 40 65 30 49 20 10 21 0 1 year 3 years 5 yearss Time since listing Fig. 5.4 Post-registration outcome for 3,055 new adult kidney only registrations in the UK, 2006 \200\223 2007. Reproduced from UK Blood and Transplant Annual Report 2012, with perm ission. TRANSPLANTATION: BENEFITS AND CHALLENGES 339 This disparity has encouraged the use of organs from more marginal donors, e.g. donation af ter cardiac death (DCD) and elderly donors with acknowledged comorbidity ( b pp. 366 \200 \2238). (See Fig. 5.5) \200 Other efforts to expand the donor pool include the growth of live donor programs (including altruistic donation), dual transplants ( b p. 401), ABO- and HLA-incompatible grafts, and paired schemes ( b pp. 444 \200\2235). The CKD population is ageing. The median age of prevalent dialysis patients in the UK is 7 65. This more elderly population is also more comorbid, making selection for successful tra nsplantation (and appropriate matching of organs) more challenging. The ultimate goal is to prolong both patient and graft survival post-transplantation. This requires: \200 More effective and less toxic immune suppressio n. \200 d morbidity and mortality from infection, malignancy, and CV disease ( 2 better t ransplant function l lower CV mortality). Total transplants 20 Total 15 ) s 0 0 0 1 , Deceased donor n i ( 10 s t n a l p s n a r T Living donor 5 0 90 94 98 02 06 10 Fig. 5.5 The number of both live and deceased donor transplants has increased signi \201 c antly over the last two decades and plateaued in recent years. Increases in deceased donor transplantation re \202 ect higher rates of donation after cardiac death (DCD) and the use of extended criteria donors (ECD) \200\224 a trend that is likely to see further increase s over the next decade. Reproduced from USRDS 2012 annual report, with permission. CHAPTER 5 Transplantation 340 Transplantation outcomes Renal transplant outcomes are traditionally measured in terms of: \200 Graft survival (see Fig. 5.6). \200 Patient survival. \200 Graft function (e.g. SCr 9 eGFR at 1, 3, or 5 years). Data come from large national and international registries . The most important of these are: \200 US Renal Database System (USRDS). \200 The Coll aborative Transplant Study (CTS). \200 United Network of Organ Sharing (UNOS). \200 The Australia and New Zealand Dialysis and Transplant Registry (ANZDATA). UK National Transplant Database (maintained by NHS Blood and Transplant). Box 5.1 Key facts \200 The 1-year survival for deceased donor renal transplants is 7 91%. Patient survival is >95%. The 1-year survival for live donor renal transplants is 7 97%. Patient survival is >98%. This has steadily improved over the last two decades. \200 The 5-year survival for deceas ed donor renal transplants is 7 70%. Patient survival is 7 80%. The 5-year survival for live donor renal transplants is 7 82%. Patient survival is 7 90%. The 10-year survival for deceased donor renal transplants is 7 45%. Patient survival is 7 60%. The 10-year survival for live donor renal transplants is >55%. Patient survival is 7 75%. TRANSPLANTATION OUTCOMES 341 t f a r g 10 g n n o i t c n u f / All-cause graft failure 8 i Return to dialysis or retransplant 6 w s r a e y 4 Death with function t p 0 0 1 / e t a R 2 0 92 94 96 98 00 02 04 06 08 10 Transplant year Fig. 5.6 The overall graft failure rate among adult (age >18) transplant recipients per 100 patient years is falling year on year, although the percentage that die with a functioning graft remains unchanged. Reproduced from USRDS 2012 annual report, with permission. Patient survival The principal causes of death post-transplantation are CV disease, infec- tion, and malignancy (see Fig. 5.7). 35 30 s t n e i t a p 25 20 f o e g a t n e c r e P 15 10 5 0 Infection CVD Unknown Malignancy Other Fig. 5.7 Causes of death in patients with a functioning graft. Reproduced from USRDS 2012 a nnual report, with permission. Factors in \202 uencing graft survival \200 Delayed graft function (DGF): Variably de \201 ned ( b p. 404). \200 7 3% in live donor and 7 20% in deceased donor ki dneys (the rate will vary signi \201 cantly, e.g. 7 30% for ECD kidneys and 7 40% for DCD kidneys). CHAPTER 5 Transplantation 342 DGF is itself a function of i donor age, i cold ischaemic time, and the presence of signi \201 cant anti-HLA antibodies ( b p. 405). DGF is associated with d graft survival, i mortality, i rejection ( l probably enhanced graft immunogenicity post-reperfusion). HLA matching: For deceased donor kidneys, better HLA matching is associated with improved graft survival. This falls progressively with increasing mismatch (see Fig. 5.8). \200 The effect is much less pronounced for live donor kidneys, whether related or unrelated. Timing of transplantation: Pre-emptive transplantation provides a survival bene \201 t for both graft and recipient. Graft survival deteriorates, with longer times on dialysis pre-transplantation. Reasons: more recipient CV disease, higher incidence of DGF, socio-eco nomic factors. In the UK, 7 35% of adult live donor and just 7 10% of deceased donor transplants are pre-emptive. 100 80 60 0 MM 1 MM 2 MM 3 MM 4 MM 6 MM 5 MM ) g o l ( 40 l a v v r u s i 20-year estimate 43 % 37 % 36 % 35 % 33 % 28 % 28 % Half-life (years) 17.4 15.4 14.6 14.2 13.8 12.0 12.3 t f a r g % 0 MM 1 MM 2 MM 3 MM 4 MM 5 MM 6 MM 20 10 0 2 4 6 8 10 Years 12 14 16 18 20 Fig. 5.8 Percentage survival HLA A + B + DR mismatches: \201 rst cadaver kidney transplan ts, 1985 \200\223 2011. Reproduced from the Collaborative Transplant Study ( M http://www. ctstransplant.org ), with permission. TRANSPLANTATION OUTCOMES 343 Donor factors: Age: 5-year survival of a deceased donor kidney from a donor age 18 \200\223 34 is 7 80%, compared to 7 55% for donor age >65. (cid:2) This is a very important issue, as the average donor age is progressively increasing. Living donor grafts last longer than deceased donor grafts (less cold ischaemia, better health of donor, often less time on dialysis accruing CV disease and other complications, higher nephron mass, better recipient compliance). See Box 5.1 on b p . 340. Donation after brain death (DBD) kidneys have better outcomes than those donated after card iac death (DCD) ( b pp. 365 \200\2238). \200 ECD kidneys have poorer, if acceptable, outc omes overall (although this can be dif \201 cult to predict at the time of transplantation). i cold ischaemic time (CIT) l i DGF l d graft survival. This risk is particularly high when CIT >18h. The time it will take to transportation a kidney is usually taken into account i n organ allocation schemes ( b p. 365). \200 Recipient factors: Age. The commonest cause of graft loss beyond age 65 is death with a functioning transplant. Race. In the USA, black recipients of deceased donor transplants have poorer outcomes than Caucasian recipients. This is partly due to i DGF in black recipi ents as well as inferior HLA matching (the donor pool is predominantly Caucasian). Obesity and other comorbidities ( i BP, CV disease) ( b pp. 370 \200\2231). \200 The natu re of the recipient \200\231s original native kidney disease and the risk of this disease recurring in the transplant. Rejection episodes ( b p. 408): 2 A single episode of rejection reduces 5-year graft survival by 7 10%. The greater the number of episodes, the worse the outcome. HLA antibodies ( b p. 361 \200\2234): About 7 20% recipients develop anti-HLA antibodies post-transplantation. The development of such antibodies trebles the risk of graft failure (whether or not they are donor-speci \201 c). Donor-speci \201 c anti-HLA antibodies (DSA) are associated with chronic antibody-mediated rejection ( b p. 414 \200\2236). Proteinuria: As in native kidneys, a marker of renal injury, the risk of progressive renal dysfunction, and overall CV morbidity and mortality. May also herald recurrent native disease. Number of previous transplants (see Fig. 5.9). CHAPTER 5 Transplantation 344 100 90 80 70 ) g o l ( 60 l a v v r u s 1. TX 2. TX 3. TX > 3. TX i 50 t f a r g % 40 30 20 10 0 0 2 4 6 8 10 Years Fig. 5.9 Graft survival over time, according to number of previous transplants in an indivi dual. Reproduced from the Collaborative Transplant Study ( M http://www. ctstransplant.org ), with permission. TRANSPLANTATION OUTCOMES 345 CHAPTER 5 Transplantation 346 Basic transplant immunology Introduction A transplanted kidney will be antigenically distin ct from its new host and recognized as foreign and initiate an immune response, unless it i s from a genetically identical individual (essentially, an identical twin). In the context of transplantation, these antigens are known as alloantigens (and the donor kidney is often referred to as an allograft). The most relevant alloantigens to transplantation are a grou p of histocompatibility genes known as the major histocompatibility complex (MHC). Minor hi stocompatibility anti- gens are also relevant although less important. Alloantigen recognit ion triggers immune cell activity and the activation of multiple potent effectors of the im mune response. Histocompatibility and allorecognition The MHC presents fragments of \200\230 non-self \200\231 proteins to T cells in order to initiate an immune response. In humans, the MHC ge nes on chromosome 6 encode a polymorphic group of proteins called human leucocyte anti- gen s (HLA). Their main function is to present antigens to T cells. There are two classes: \200 Class I HLA includes HLA-A, HLA-B, and HLA-C and is present on all nucleated cells, i ncluding vascular endothelium. They exist as a heterodimer with B 2 microglobulin. Class I molecules present non-self peptides to cytotoxic CD8+ T cells, leading to their activation. Self-antigens are not recognized, as immunological tolerance, to them, has developed durin g T cell maturation.