http://www.a-s-t.org/ American Society of Transplant Surgeons: http://www.asts.org/ See also Selection and preparation of recipients, p. 544 This page intentionally left blank A. BARLOW AND M. NICHOLSON 552 Transplant surgery and surgical complications Introduction Renal transplantation is well-established as the best treatment for restoring quality and quantity of life to patients with ESRD. Although essentially comprising three a nastomoses, the surgery can be challenging, particularly in the case of obese patients and complex graft anatomy. The inherently poor premorbid state of the recipients and the need f or postoperative immunosuppression increases the risk of infection and bleeding. Although m ostly rare, clinicians should be aware of the potential immediate complications of renal tr ansplant surgery. A number require a high index of suspicion to identify and may result in graft loss if the diagnosis is delayed or missed. Easier control of major bleeding than LDN. Disadvantages \200 As for LDN. \200 Increased cost of consumables compared to LDN. Retroperitoneoscopic donor nephrectomy This technique involves approaching the kidney via t he retroperitoneal space. The dissection is performed via laparoscopic ports and the kidney removed through a small \202 ank incision. It can also be performed using a hand-assiste d technique. Advantages \200 \200 \200 As for LDN. Shorter operating times than LDN. The peritoneal cavity is not entered, reducin g the risk of bowel injury and adhesion formation compared to LDN. Living donor nephrectomy Over recent years, living donor renal transplantation has increasi ngly been used to offset the shortage of cadaveric kidneys. The safety of the procedure for the donor has been con \201 rmed, and the improved outcome for the recipient over cadaver ic grafts proven. However, controversy still remains about the optimal technique for removi ng the kidney. The options are as follows: \200 \200 Disadvantages \200 Technically challenging procedure with a steep learning curve. Increased warm ischemic time compared to MODN and ODN. Increased operating time compared to MODN and ODN. Smaller worki ng space than LDN. Total laparoscopic donor nephrectomy (LDN); Hand-assisted laparoscopic donor nephrectomy (H ALDN); Retroperitoneoscopic donor nephrectomy (RDN); Mini-incision open donor nephrectomy ( MODN); Open donor nephrectomy (ODN). \200 \200 Mini-incision open donor nephrectomy This is similar to the traditional open procedure, but is performed through a smaller \202 ank incision without rib resection. Total laparoscopic donor nephrectomy This involves dissection via 4 \200\2235 laparoscopic ports and removal of the kidney through a 6 cm Pfannansteil or lower midline incision. Advantages \200 \200 \200 Less painful than ODN. Better cosmesis than ODN. Shorter warm ischemic times than LDH, HALD N and RDN. Advantages \200 Reduced post-operative pain and analgesia requirements compared to MODN and ODN. Quicker re sumption of normal activities compared to MODN and ODN. Better cosmesis compared to MODN an d ODN (Fig. 14.3.1). Better post-operative respiratory function compared to MODN and ODN. Disadvantages \200 More painful and slower recovery than LDN, HALDN and RDN. Dif \201 cult access compared to ODN. May not be feasible in patients with higher BMI. \200 Disadvantages \200 Open donor nephrectomy This is performed through a \202 ank incision, with or without res ection of the 12th rib. The dissection is performed in the retroperitoneal space. Technically challenging procedure with a steep learning curve. Increased warm ischemic time compared to MODN and ODN. Increased operating time compared to MODN and ODN. Potentially i ncreased risk of bowel injury and intra- abdominal adhesions compared to retroperitoneal ap proaches. Advantages \200 \200 \200 \200 Least technically demanding of the various approaches. Allows easier control of major bleed ing. No breach of the peritoneal cavity. Shortest warm ischemic time. Disadvantages \200 Hand-assisted laparoscopic donor nephrectomy This is similar to LDN, but one port is a hand port, allowing placement of a hand within the peritoneal cavity. This allows tactile feedb ack and manual assistance with retraction and control of bleeding. More post-operative pain and analgesia requirements than other techniques. Slower return to normal activities than other techniques. Risk of signi \201 cant wound bulge due to paral ysis of \202 ank muscles. \200 Advantages \200 \200 As for LDN. Shorter learning curve than LDN. CHAPTER 14.3 Transplant surgery and surgical complications 553 Fig. 14.3.1 Comparison of incisions for open donor nephrectomy and total laparoscopic donor nephrectomy. If \202 uid is removed, the patient should be maintained above their target weight to fac ilitate adequate postoperative \202 uid \201 lling. Consideration should be made of the likelihood of primary graft function, as this may affect the decision to dialyse. Immunosu ppression is commonly commenced preopera- tively, usually in the form of an IL-2 receptor a ntibody. Complications Regardless of the surgical approach there are a number of potential complicat ions of donor nephrectomy that clinicians should be aware of. These include: \200 major post-operative bleeding, usually from the renal vessel stumps; deep vein thrombosis a nd/or pulmonary embolism; renal impairment; atelectasis and/or pneumonia. \200 \200 Incision An oblique or curvilinear incision is made from above the symphysis pubis towards the anterior superior iliac spine. The decision concerning which groin is used varies betwe en transplant centers. Arguments for the choice of groin are: \200 Post-operative management is tailored to reduce the risk of these complications and include s: \200 low molecular weight heparin; \200 IV \202 uid to maintain urine output >50 m L/h; \200 close monitoring of FBC and renal function; \200 early mobilization. a left kidney is placed in the right groin and vise versa as this places the renal pelvis a nd ureter anteriorly and facilitates the ureteric anastomosis; all kidneys are placed in th e right groin as the right iliac vessels are more accessible and convenient for anasto- mos is than the left. Follow-up Donors should be seen 4 \200\2236 weeks post-surgery for wound review and assessm ent of blood pressure and proteinuria. Some centers also repeat an isotope GFR at this stag e, but this is not mandatory. All being well, follow-up should then be on a yearly basis. T his should include measurement of blood pressure, renal func- tion and urine dipstick, part icularly looking for proteinuria. In the patient with a previous failed transplant in situ, the kidney is placed in the contr alateral groin. The muscles of the anterior abdominal wall are divided and the retroperiton eal space developed to expose the iliac vessels. Long-term sequelae Following the initial decline in GFR, the rate of loss of renal function in kidney donors is no faster than expected with normal aging. Overall, the risk of ESRD i s 0.2 \200\223-0.5%. Kidney donation does result in a small increase in urinary protein ex cretion secondary to hyperfiltration in the remaining kidney. There is an increased risk of hypertension, with a mean increase of 5 mmHg compared with control groups. The overall ris k of long-term mortality among kidney donors is infact lower than the predicted age- and se x-matched mortality. Vascular anastomoses Renal vein The renal vein is anastomosed end-to-side to the external i liac vein. If the renal vein is short this anastomosis may be facilitated by dividing the i nternal iliac vein, increasing the mobility of the external iliac vein Renal artery The renal artery is anastomosed to either the internal or external iliac artery. Cadaveric kidneys with an aortic patch are conventionally anastomosed end-to-side to the external ili ac artery (Fig. 14.3.2). Live-donor kidneys, which do not have an aortic patch, are convent ionally anastomosed end-to-end to the internal iliac artery (Fig. 14.3.3). However, an aort ic punch may be used to create a circular arteriotomy in the external iliac artery, and an end-to-side anastomosis created. The transplant operation Pre-operative preparation The need for pre-operative dialysis is d etermined by the patient \200\231s \202 uid status and serum electrolytes, particularly p otassium. A. BARLOW AND M. NICHOLSON 554 the donor \200\231s ipsilateral native ureter. This is termed an uretero-ureterostomy. Intra-operative \202 uid and drugs Central venous pressure should be maintained >10 mmHg. Mean arterial pressure should be maintained >90 mmHg. Methylprednisolone and prophylactic antibiotics (e.g. co-amoxiclav or a cephalosporin) are given at induction of anesthesia. Ma nnitol may be given immediately before clamp release to protect against renal cortical isch emia, and has been shown to reduce postoperative dialysis requirements. Loop diuretics and dopamine are commonly used, but have not been shown to have any bene \201 t on post-operat ive renal function. Surgical complications Bleeding Early postoperative bleeding usually occurs in the \201 r st 24 \200\22348 h after surgery. It is rarely due to bleeding from the vascular anastomose s, but may be from small hilar vessels damaged during the preparation of the graft. Clinica l features include a fall in hemoglobin, increased drain output, swelling at the operative site and blood seepage from the wound. Ultrasound or CT examination may reveal a hematoma a round the graft. Treatment includes correction of any clotting abnormalities, blood transfu sion and, if necessary, surgical exploration. Fig. 14.3.2 End-to-side anastomosis between the renal artery and external iliac artery. Wound infection The use of prophylactic antibiotics has reduced the inci- dence of wound in fection post-renal transplant to <1%. If a wound infection does occur, treatment is with an tibiot- ics and drainage of any collections as required. Vascular thrombosis This usually occurs within the \201 rst 48 \200\22372 h post-trans- p lant. Incidence is between 0.5 and 10%. The risk of vascular thrombosis is reduced by the a dminis- tration of post-operative aspirin, continued for 6 \200\22312 weeks post-surgery. Renal transplant arterial thrombosis Renal transplant arterial thrombosis is usually due to a technical error during procurement or transplanta- tion, such as an intimal injury to either the renal or iliac arteries. It is heralded by a sudden fall in urine output to zero. Obviously, the diagnosis is harder to make in patients with good urine output from their native kidneys, or those with nonfuncti oning grafts. For this reason patients with delayed graft function should undergo regular U SS examination with Doppler studies. The treatment of arterial thrombosis is prompt surgery , and the advantage of diagnostic USS should be weighed against the risk of delaying treatm ent. Unfortunately the majority of grafts with arterial thrombosis are lost. Fig. 14.3.3 End-to-end anastomosis between the renal artery and internal iliac artery. Ureteric anastomoses The transplant ureter is usually anastomosed directly onto the recipie nt \200\231s bladder. A JJ stent may be placed in the transplant ureter to protect the anas tomosis and prevent hydronephrosis; this is usually removed cystoscopically after 4 weeks. A urethral catheter remains in situ for \211 5 days postopera- tively. If the transplant u reter is too short to anastomose to the bladder without tension, it may be anastomosed to CHAPTER 14.3 Transplant surgery and surgical complications 555 Renal transplant venous thrombosis Renal transplant venous thrombosis is marked by: \200 \200 \200 Treatment depends on the size and presence of compres- sive complications and includes: \200 \200 \200 aspiration; percutaneous drainage; drainage into the peritoneal cavity (can be done laparo- scopically). a fall in urine output; gross hematuria; graft swelling associated with pain. Ultrasound examination shows: \200 absent \202 ow in the renal vein; \200 reversal of arterial blood \202 ow in diastole; \200 peri-transplant hematoma due to capsular rupt ure. Further reading Allen R, Chapman J. A manual of renal transplantation. London: Hodder Arnold; 1994. Danovitch GM (ed.), Handbook of kidney transplantation. Treatment is surgical and usually involves removal of the kidney and revision of the venous anastomosis. Philadelphia: Lippincott Williams & Wilkins, 2004. Kahan BD, Ponticelli C (eds), Principles and practice of renal trans- Ureteric leak This usually occurs due to necrosis of the distal transplant ureter or a tech nical problem with the ureteric anastomosis. Clinical features of a urine leak from the ure teric anasto- mosis include: \200 \200 \200 \200 plantation. London: Taylor & Francis; 2000. Kuo PC, Bollinger RR, Dafoe DC, Davis RD (eds), Comprehensive atlas of transplantation. Phi ladelphia: Lippincott Williams & Wilkins; 2004. Morris PJ. Kidney transplantation. Philadelphia: WB Saunders; 2001. Tan HP, Marcos A, Shapi ro R (eds), Living donor transplantation. New a fall in urine output; a rise or plateau in serum creatinine; pain and swelling at the ope rative site; increased drain output. York: Informa Healthcare; 2007. Internet resources British Transplantation Society: www.bts.org.uk The Kidney Patient Guide: If a drain is in situ the diagnosis can be aided by sending drain \202 uid and urine for comparative biochemical analysis. Ultrasound may show a peritransplant collection, which ca n be aspirated and sent for biochemical analysis. If there is doubt about the diagnosis, a cystogram may demonstrate the site of the leak. Treatment is prompt surgical repair of the leak. www.kidneypatientguide.org.uk/site/tran- splants.php American Society of Transplantation: http://www.a-s-t.org/ American Society of Transplant Surgeons: Urinary tract obstruction This diagnosis should be considered in grafts that initially prod uce urine and then urine output reduces or stops. A common cause is blockage of the urethra l catheter with clots, which can be solved by gentle irrigation of the catheter. Obstructio n of the transplant ureter is diagnosed by hydronephrosis on USS. Early post-transplant thi s may be caused by blood or oedema, but this is rare with a JJ stent in situ. Once the JJ s tent has been removed, obstruction is usually due to an anastomotic stricture. Initial trea tment of ureteric obstruction is percutaneous insertion of a nephrostomy tube. This is foll owed by a nephrostogram to identify the site of the obstruction. Ureteric anastomotic stric tures may be treated radiologi- cally, but long strictures often require surgery. http://www.asts.org/ Laparoscopic live donor nephrectomy at the John Hopkins Medical Instit ute: http://urology.jhu.edu/surgical_techniques/ nephrectomy/index.html See also Early management of transplant recipients, p. 556 Recurrent disease and de novo di sease post renal trans- plantation, p. 566 Drug-induced nephropathies, p. 698 Lymphocele A lymphocele is a collection of lymph at the operative site. The incidence is 1 \200\22310% and may be reduced by the use of silk ligatures when dividing the lymphatics ov erlying the iliac vessels. Presentation may be with: \200 ureteric obstruction; \200 de ep vein thrombosis or leg swelling due to obstruc- tion; swelling at the operative site. Diagnosis is by USS examination, aspiration will reveal clear \202 uid with a high protei n content. C. NEWSTEAD 556 Early management of transplant recipients The \201 rst 48 hours In the early period post surgery, frequent monitoring is critical i n order to maintain appropriate \202 uid balance. There is a small risk of hemorrhage tha t is common to all surgery. Massive diuresis resulting in hypovolemia is a risk particular to renal transplant surgery. As in any patient with ESRD there is also the signi \201 cant risk that overaggressive \202 uid replacement can result in pulmo- nary edema and/or sev ere hypertension when the patient is oligo- or anuric. Where the patient is oliguric it is important to establish the cause of graft dysfunction. A renal USS should be performed. This can usually reliably rule out signi \201 cant urinar y tract obstruction and con \201 rm renal perfusion. If the graft is obstructed then eithe r re-exploration, further investigation with an isotope renogram or the placement of a neph rostomy is necessary. Arterial thrombosis, which is usually asymptomatic, is almost never r etrievable. Venous thrombosis, which is often associated with more periwound pain than is u sual, can on occasion be treated with thrombectomy resulting in salvage of the graft. If th e USS con \201 dently con \201 rms absence or greatly compro- mised perfusion, urgent sur gical exploration is preferred to further imaging such as an MRI, as any delay will have a serious negative impact on graft survival. Monitoring and prophylaxis Frequent CVP monitoring, FBC, U+Es and monitoring of \202 uid balance is part of standard care. Routine antibiotic prophylaxis should be prescribed for 48 h. Routine heparin prophy laxis against deep vein thrombosis should be started. In the immediate postoperative period some centers also routinely use: \200 dopamine; \200 mannitol; \200 IV furosemide. Urine leak An early urinary leak is a rare complication. There will be a high volume of \202 uid in wound drains or an obvious wound leak of urine. It may be necessary to measure the potassium and urea concentration in \202 uid to establish the diagnosis. It is even r arer for a urinary leak to pass into the peritoneal cavity. The urine is then absorbed, mak ing it very dif \201 cult to diagnose early, as usually the USS is normal. If this is susp ected then an isotope scan should be performed with late \201 lms to show urine passage i nto the peritoneal cavity. The intention is to reduce the rate of delayed graft func- tion (DGF); there is no evidence base to justify the prac- tice. Blood transfusion Well-compensated patients with ESRD without access to erythropoetin will often have tolerated a hemoglobin <7.5 g/dL for many months. Transfusion may be appropriate if there is a fall in hemo- globin of >2.0 g/dL. Patients with known or high risk of ische mic heart disease should be transfused to maintain a hemoglobin of 10.0 g/dL. Rejection When there is early graft dysfunction with unremarkable USS appearances the diagn osis of rejection needs to be considered. To make this diagnosis securely requires a biopsy and then prompt analysis of the histology. Acute cellular rejection takes several days to cause graft dysfunction. Humoral rejection due to donor-directed antibodies that develop po st grafting takes a similar inter- val to develop. Only humoral rejection due to donor-dire cted antibodies that were present prior to implantation can cause rejec- tion in the \201 rst 48 h. At the inception of transplantation and before identi \201 ca- tion of these an tibodies was possible, they were the cause of the hyperacute graft rejection that occurred very soon after reperfusion. With modern crossmatch techniques and molecular HLA typing to ensure that patients are not transplanted with a kidney to which they have a known preforme d antibody, the likelihood of humoral rejection is very small. The important exception to t his rule is when the trans- plant is performed in the presence of a known donor relevant an tibody. This is an increasingly common practice in the live donor setting when recipient pr econditioning with plasma exchange usually in tandem with other strategies can achieve a si tuation that avoids hyperacute rejection but leaves the patient at risk of early accelerate d humoral rejection. Dialysis Dialysis support is required for 1/3 of patients in the post-transplant period. H yperkalemia that cannot be controlled by medical therapy is the most common indication. If the patient is oligoanuric medical therapy will only achieve temporary control of hyperkale mia. Peritoneal dialysis conventionally using low volume exchanges may be used post surgery although sometimes wound leakage of PD \202 uid due to surgical transgression of the per itoneum makes this impractical. If urgent control of blood chemistry is required, as is oft en the case, then hemodialysis is the best treatment. Complications in the \201 rst 48 hours Oligoanuria The majority of patients pass urine po st surgery and this greatly simpli \201 es management. However, some patients are oligoanu ric from the outset. A third subgroup passes dilute urine with no or very little evidence o f clearance of urea or creatinine and this group often becomes anuric between 10 and 20 h p ost procedure. CHAPTER 14.4 Early management of transplant recipients 557 Some units advocate \200\230protocol \200\231 biopsies even in patients with good graft fu nction at, say, day 7 and at other intervals post surgery in the hope that treatment of cli nically asymp- tomatic acute cellular rejection will improve long-term outcome. Prophylactic plasma exchange is part of the routine management but it is almost never used before the third day post transplant. In practice clinicians make a judgment of the likelih ood that early graft dysfunction is due either to acute rejection or to acute tubular necro sis (ATN) based on the risk fac- tors for the two scenarios. The risk of delayed graft func tion due to ATN is more common where there is prolonged cold ischemia, a kidney from a nonh eart-beating donor, or where there was donor renal impairment. Patient education Patient education should be a major focus of care during this interval. T he patient needs to understand completely new rules about \202 uid management as well as relaxation of any dietary restrictions. It is often dif \201 cult for patients to absorb t he changes in advice. A particularly critical issue is to ensure that patients understand a nd are capable of adhering to the complex medication regimens. The importance of medication concordance on graft survival should be emphasized. Patients also need to be educated abou t the side-effect pro \201 le of drugs as well as symptoms of urinary tract infection and graft dysfunction. Education about lifestyle choices that in \202 uence cardiovascu- lar d isease as well as the risk of cutaneous squamous cell carcinomas (common) and other maligna ncies can be con- veniently made part of the predischarge education \200\230package \200 \231. Ileus Prolonged ileus is unusual but more common in patients with diabetes and if present I V medication is necessary. Two to ten days post transplant Monitoring and prophylaxis During this interval the need fo r intensive monitoring of \202 uid balance is greatly decreased and CVP, peripheral lines , urinary catheter and wound drains are removed. Daily weighing to assess changes in \202 uid status is necessary. In common with all abdominal surgical procedures there is a risk of pulmonary embolism, as well as wound and chest infections. In patients who have been tre ated with peritoneal dialysis there is also a small risk of peritonitis. During this interv al the majority of patients with delayed graft function due to presumed ATN will have a ste adily increasing urine volume but a useful clearance of 5 mL/min is rare until urinary vol ume >1 L in 24 h. During this period, antimicrobial prophylaxis against Pneumocysitis jirov eci as well as cytomegalovirus should be started (if not already in place). Two weeks to six months post transplantation Monitoring Outpatient follow-up during the ear ly postdischarge period should be frequent because of the need to promptly diag- nose acute graft dysfunction. It is rare for acute graft dysfunction to be symptomatic so there is no substitute for regular measurement of serum creatinine and immunosuppressive drug levels. Figure 14.4.1 shows the risk of acute rejection and how that changes with time. It is notab le that: \200 Immunosuppressants During this time immunosuppressive dose adjustment is usually required, typically guided by thrice-weekly meas- urement of calcineurin levels. Dose adjustment of a ntimetabolites and antilympho cyte preparations may be necessary, principally dictated by t he leu- kocyte count, and sometimes anemia or thrombocytopenia. Measurement of therapeutic drug levels apart from tacrolimus, ciclosporin and sirolimus is not routine but used princi pally in the research setting, in some units. rejection is almost never diagnosed before 5 days post transplantation; virtually all episo des of acute rejection occur within the \201 rst 3 months; 93% of episodes of acute rejec tion occur within 1 month. Therefore follow-up for the purpose of diagnosing occult acute r ejection needs to be frequent in the \201 rst month (thrice weekly in many units) but can be much less frequent once the recipient is >3 months post surgery. Complications Delayed graft function If the patient has protracted DGF it is important not to miss: \200 \200 \200 \200 d e m Tacrolimus Ciclosporin microemulsion 100 90 80 70 60 50 40 30 20 10 0 r i f n o c - y s p o b m o r f ) % ( occult acute rejection; urinary obstruction; urinary leak; renal arterial or venous comprom ise. n o i t c e e r i j p<0-0001 e e r f e t u c a Although there are factors which predict ATN it is impor- tant to appreciate that acute cel lular rejection is more common in grafts with ATN than in those with primary function. A gr aft biopsy is the only way to make a con \201 dent diagno- sis of rejection and to discrim inate between the types of rejection. When there is DGF, renal transplant biopsies at 5 \200\2237 day intervals are usual practice in order to ensure that acute cellular rejection is not missed. n o i t r o p o r P 7 91 28 Time since transplantation (days) 61 183 0 Number at risk Tacrolimus Ciclosporin 286 271 259 227 229 164 220 152 214 415 204 141 Fig. 14.4.1 Timing of acute rejection post renal transplantation. (From: Margreiter et al., 2002.) C. NEWSTEAD 558 Immunosuppressants Frequent follow-up also allows adjustment of immunosup- pressive medicat ion which is often necessary in the early period. During this period there is usually adjus tment to reduce the level of immunosuppressive therapy, in part because the risk of acute r ejection decreases markedly with time but also to reduce that component of the risk of prem ature cardiovascular and late malignant disease that is attributable to drug therapy. Table 14.4.1 Approximate timetable of infections after renal transplantation Time scale Site of infection and common organisms 0 \200\2237 days Chest infection Wound infection Line-associated sepsis 7 \200\22330 days Urinary tract Infection Peritoneal dialysis peritonitis Herpes simplex (cutaneous and encep halitis) Clostridium dif \201 cile Candidiasis Complications Acute graft dysfunction Acute graft dysfunction should be investigated \201 rst by measurement of immunosuppressive drug levels as these drugs can be nephrotoxic. A r enal USS should be performed to rule out urinary obstruction. This can be secondary to the development of a signi \201 cant perirenal lymphocele. Further radiology such as as nephro stomy, isotope scans or arterial imaging for suspected renal artery stenosis may be directe d by the USS appearances. Most commonly, however, a renal biopsy needs to be performed. In some cases staining for Simian BK virus/CMV or C4d antibodies will be indicated. In the rel atively rare situation where early recurrent glomer- ulonephritis is in the differential di agnosis then immunohisto- chemistry and electron microscopy need to be performed. 30 \200\223180 days Cytomegalovirus Primary CMV: in absence of prophylaxis: 6 weeks \200 2 \200\2238 weeks after completion of prophylaxis CMV reinfection/reactivation: 12 weeks Legionella pneumoniae Mycobacterium tuberculosis Pne umocystis jiroveci Nocardia spp.a Cryptococcus spp.a Toxoplasma spp.a Strongyloides spp.a L isteria spp.a >180 days In \202 uenza/pneumococcus and other community-acquired viral and bacterial infections Var icella zoster virus reactivation Pneumocystis jiroveci Psitticosis spp. Listeria spp. Mycob acterium tuberculosis Infectious complications Infectious complications of renal transplantation approxi- mately follow the timetable as shown in Table 14.4.1. This information allows the initial diagnost ic tests to be directed towards the most likely pathogens. When managing an immunosuppresse d patient who is unwell with what is probably an infection it is standard practice to take all appropriate specimens but then insti- gate treatment directed at the most likely pathog ens while awaiting the results of the investigations. a Less common or geographically limited infections. Thaunat O, et al. To biopsy or not to biopsy? Should we screen the histology of stable rena l grafts? Transplantation 2007; 84: 671 \200\223676. Patient education As well as lifestyle advice, especially smoking cessation and control of hyperlipidemia, the most important cardiovas- cular risk factor to control is hypertension. Hypertension also signi \201 cantly in \202 uences renal transplant survival. Internet resources British Transplantation Society: http://www.bts.org American Society of Transplantation: Further reading Amend WJC, Vincenti F, Tomlanovich. The \201 rst three posttransplant mon ths. In: Danovitch G.M (ed.), Handbook of kidney transplanta- tion, 4th edn. Philadelphia: Lippincott Willliams & Wilkins; 2005. pp. 212 \200\223233. http://www.a-s-t.org/ American Society of Transplant Surgeons: http://www.asts.org/ See also Transplant surgery and surgical complications, p. 552 Immunosuppression for renal transplantation, p. 560 Recurrent disease and de novo disease post renal trans- plantation, p. 566 Drug-induced nephropathies, p. XXX Clinical approach to acute kidney injury, p. 318 Renal replacement therapies in acute kidney injury, p. 328 Kauffmann HM. Post-transplant de novo malignancies in renal transplant recipients: the past and present. Transplant Int 2006; 19: 607 \200\223620. Kotton CN, Fishman JA. Viral infection in the renal transplant recip- ient. J Am Soc Nephrol 2005; 16: 1758 \200\2231774. Margreiter R; European Tacrolimus vs Ciclosporin Microemulsion Renal Transplantation Study Group. Ef \201 cacy and safety of tac- rolimus compared with ciclosporin microemulsion in renal trans- plantation: a randomized multicentre study. Lancet 2002; 359(9308): 741 \200 \223746. Singer J, Gritsh HA, Rosenthal KR. The transplant operation and its surgical complications. In: Danovitch G.M (ed.), Handbook of kidney transplantation, 4th edn. Philadelphia: Lippin cott Willliams & Wilkins; 2005. pp. 193 \200\223211. This page intentionally left blank C. DUDLEY 560 Immunosuppression for renal transplantation Introduction The number of immunosuppressive agents available for use in renal transplantat ion has increased in the last 20 years. In September 2004, the National Institute for Healt h and Clinical Excellence (NICE) published its guidance on the use of immunosuppressive the rapy in adults following renal transplantation (NICE Technology Appraisal 85). Randomized c ontrolled trials (RCTs) comparing different agents have nearly all been funded by pharmaceu tical com- panies with commercial interests and have had a number of shortcomings. These ha ve included: \200 \200 \200 minimized by giving IV methylprednisolone and an antihis- tamine 30 min before use. Thrombo cytopenia and leukopenia are common. Although \201 xed daily dosing regimens may be used, many clinicians dose according to total lymphocyte or CD3 count to avoid over-immunosuppre ssion. CMV and Pneumocystis jiroveci (carinii) prophylaxis should be considered mandatory, because of the increased risk of infections. The use of ATG is associated with an increased incidence of post-transplant lymphoproliferative disease (PTLD). OKT3 (Muromonab \200\223CD3) OKT3 is a mouse monoclonal IgG2a antibody that reacts with the T-cell receptor \200\223CD3 complex chain of the T-lymphocyte on the surface of circulatin g human T-cells. Deactivation of the CD3 complex causes the T-cell receptor to undergo endo cytosis and the ineffectual T-cell is cleared by the reticuloendothelial system. In the UK, OKT3 use tends to be restricted to the treat- ment of steroid-resistant rejection when ATG has failed or is contraindicated. In the USA it has been used as induction therapy. Potent ially life-threatening side-effects including noncar- diogenic pulmonary edema may occur du ring the \201 rst few days of treatment due to release of T-cell-derived cytokines (cytok ine release syndrome). Its use therefore, is contrain- dicated in volume-overloaded patient s. A sensible precau- tion is to dialyze/ultra \201 lter all patients to their target weig ht (or below) before its use. Intravenous methylprednisolone, an antihistamine and oral par acetamol are given 15 \200\22360 min before the \201 rst and sec- ond doses. Nearly all p atients develop fever and rigors which usually abate after the third dose and can be treate d with oral paracetamol. Neurological side-effects are also common and self-limiting and ra nge in severity from a mild headache to aseptic meningitis and encephalopathy. Once again, CMV and Pneumocystis jiroveci (carinii) prophy- laxis should be considered mandatory. The u se of OKT3 is associated with an increased incidence of post-transplant lymphoproliferative disease (PTLD). With repeated use, antimouse antibodies may develop. For this reason, when a second course of OKT3 is used, monitoring of CD3+ cells is recommended to ensure that ad equate depletion is being achieved. use of licensed rather than real-life dosing regimens; short-term follow-up only; inadequat e power to detect statistical differences in patient and graft survival; until recently the use of acute rejection rates as the primary endpoint rather than allograft function. Immunosuppressive regimens therefore have evolved within transplant centers based on local experience and need. Although there is no consensus on the best regimen to use, the general principles are: \200 to match the amount of immunosuppression with the perceived immunological risk; to use high doses in the early part of transplantation (induction) with phased reduction and even with drawal of some agents thereafter (maintenance); to \200\230tailor \200\231 the type of age nt with the patient \200\231s speci \201 c needs, e.g. cosmetic considerations. All regimens are still based around the use of calcineurin inhibitors. Individual drugs can be considered under two broad headings: \200 \200\230Biological \200\231 agents: monoclonal or polyclonal antibodies used as induction therapy or to treat severe acute rejection. Agents used for maintenance immunosuppression: \200 \200 \200 calcineurin inhibitors (CNIs); anti-proliferative agents; corticosteroids. Biological agents Antithymocyte globulin (ATG) A polyclonal antibody derived from rabbits w ith activity against human lymphocytes, particularly a number of T-cell markers. Administra tion results in depletion of peripheral blood lymphocytes that are either lysed or cleared by the reticu- loendothelial system. In most UK centers its use is reserved for the treatme nt of steroid-resistant acute rejection although in the USA it is also used as induction th erapy at the time of transplanta- tion to prevent rejection. It should be administered into a central vein (or fast- \202 owing vein such as an AVF) to avoid thrombophlebitis. Side- effects relate largely to allergic reactions including chills, fevers, arthralgia and rarel y anaphylaxis. These can be Humanized anti-CD25 monoclonal antibodies Basiliximab (Simulect) Daclizumab (Zenapax) These monoclonal antibodies are directed against the A chain (CD25) of the IL-2 receptor on acti vated T-cells. As such they are used together with CNIs to prevent (but not treat) acute re jection. Although derived from mouse, both monoclonal antibodies have been genetically engi neered such that a large proportion of the antibody is replaced by human IgG. CHAPTER 14.5 Immunosuppression for renal transplantation 561 Strictly speaking, basiliximab is a chimeric (xi) antibody (75% human, 25% mouse) whereas b aclizumab is a human- ized (zu) antibody (90% human, 10% mouse). Both are of low immunogeni city and do not induce a significant human antimouse antibody response when administered. T herefore \201 rst-dose reactions are rare and both have long half-lives. Because basilixi mab has a greater af \201 nity for the IL-2 recep- tor, a less intense dosing regimen is r equired compared with daclizumab. Despite increasing the early immunosuppressive burden, an increased incidence of opportunistic infections or PTLD over the control groups was not ob served in the phase 3 studies which led to their clinical introduction. Short-term phase 2 studies have shown that belatacept when used in combination with basilix imab, mycopheno- late mofetil (MMF) and corticosteroids, allows CNI avoid- ance with improv ed renal function when compared with ciclosporin-treated patients, although the incidence o f acute rejection, graft and patient survival was similar between groups. Histological feat ures of chronic allograft nephropathy were less common.