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 Graft dysfunction Introduction Immune factors are important to both acute rejection and chr onic allo- graft dysfunction, but there are many other potential causes ( b pp. 405, 414). Consideration of their timing post-transplant can help narrow the differential diagnosis (s ee Fig. 5.18). Transplant Graft failure Hyperacute rejection Acute rejection* Subclinical rejection* Chronic rejection* Donor disease Ischaemia Acute CNI toxicity Chronic CNI toxicity Polyomavirus nephritis Recurrent disease Fig. 5.18 Timing of graft dysfunction after renal transplantation. Reproduced from Chapman et al. Kidney Int. Suppl . 99 , S108 \200\223 S112 (2005), with permission. Immediate post-transplant period Causes of graft dysfunction \200 Delayed graft function (DGF). \200 Vascular thrombosis. \200 Ureteric leak or obstruction. \200 Hyperacute r ejection. \200 Recurrent disease ( 2 FSGS, HUS). Delayed graft function (DGF) Occurs in t he immediate post-operative period and can effectively be considered as acute tubular injur y or AKI following transplantation (it is caused by an ischaemia-reperfusion injury). The r ecipient will usually be oliguric, unless they had a signi \201 cant urine output pre-tran splant (e.g. a pre-emptive transplant). DGF is unusual with living donors ( 7 3%) but affec ts 7 20% of deceased donor grafts overall ( 7 30% for ECD and 7 40% for DCD kidneys). DGF has numerous de \201 nitions but is usually described as the need for >1 dialysis post -transplantation. Of those patients with DGF: 7 50% will recover by day 10; 7 33% will reco ver between day 10 and 20; 7 10 \200\223 15% will recover subsequently, and 7 2 \200\223 15% will not recover at all (primary non-function). GRAFT DYSFUNCTION 405 DGF is associated with acute rejection (in \202 ammation l HLA upregula- tion l enhanced g raft immunogenicity). It is also associated with d graft survival and i mortality (see Tabl e 5.7). Table 5.7 Risk factors for DGF Donor DCD or ECD donor Inadequate perfusion/cold storage Long cold ischaemia time (>18h) Pr e-donation AKI i BP, vascular disease Older donor (>60) High Karpinski score on time 0 biop sy ( b p. 400) Recipient Black race Vascular disease Intra-op/post-op d BP Highly sensitized (PRA >50) Cal cineurin inhibitors Management \200 Regular USS and Doppler to ensure adequate perfusion (including immediately post-op). Maintain euvolaemia to encourage recovery. \200 Avoid d BP during dialysis. \200 Transp lant biopsy (usually day 5 \200\223 7) to con \201 rm diagnosis (histology: acute tubular injury) and exclude acute rejection. Repeat every 5 \200\223 7 d ays if no improvement. CNI-related vasoconstriction may aggravate DGF. If immunological risk allows, some centers will reduce (or even stop) CNIs \200\224 particularly if a depleting antibody has been use d for induction. Early graft dysfunction Initial transplant function, but subsequent progressive i SCr. Causes \200 Pre-transplant: Volume depletion. \200 Vascular thrombosis ( b p. 402). \200 Sepsis. Intrinsic transplant: Acute rejection ( b p. 408). \200 CNI nephrotoxicity ( b p. 416). \200 Thrombotic micro angiopathy ( b p. 412). \200 Recurrent disease ( b p. 418). Post-transplant: Obstruction ( b p. 403). \200 Urinary leak ( b p. 402). \200 Urinary infection ( b p. 4 38). CHAPTER 5 Transplantation 406 Assessment \200 Clinical assessment: Fluid balance; assess volume status. \200 Any new nephrotoxic drugs? \200 Urinary tract symptoms to suggest infection or out \202 ow obstruction? Any other evidence of infection, e.g. fever? \200 Pain over graft? Investigation FBC, SCr, U&E, bone pro \201 le, clotting. \200 If d Plt l LDH and blood \201 lm (TMA? ). \200 Review recent CNI levels. \200 Urinalysis and MSU for M,C&S. \200 Urgent tran splant USS ( l obstruction) and Doppler ( l perfusion). \200 Transplant biopsy. GRAFT DYSFUNCTION 407 Transplant biopsy See native renal biopsy ( b p. 81). The patient may no longer be an inpat ient, in which case a day case biopsy can be considered. However, if SCr is rapidly rising, rejection is deemed likely, or the patient is high-risk for any other reason (e.g. Hb <80g /L; BP requires additional treat- ment), then an inpatient biopsy, with at least an overnig ht stay, may be desirable. \200 Pre-biopsy: USS: to exclude obstruction. \200 BP <160/90mmHg, preferably <140/90mmHg. \200 Hb ideal ly >80g/L. \200 Normal clotting (PT and APTT <1.2 x control). Platelet count >100 x 10 9 /L. Send G&S. \200 Omit aspirin and prophylactic heparin on the day of biopsy and day after ( preferably 5 days for aspirin if an elective biopsy). \200 Consider DDAVP if eGFR <25mL/m in or urea >30mmol/L (780mg/dL) ( b p.80). Sterile urine. \200 Informed consent. \200 If the patient has DGF, they should be well dialysed, preferably with their last dialysis the day before biopsy. Biopsy: Performed under USS guidance. \200 Usually upper pole (further away from vasculature and ureter). \200 LA is in \201 ltrated down to the transplant. \200 Disposable TruCut needles or spring-loaded biopsy guns are generally used (e.g. 16 gauge \200\224 larger needles may i complication rate). An initial stab incision at the skin can ease passage of the needle. One core of tissue is usually adequate, although 2 are preferred (sampling of 10 glomeruli and 2 vessels is required for accurate Banff classi \201 cation). Avoid >4 passes with the biopsy needle. Call for a more experienced operator after two unsuccessful passes. \200 Pressure can be applied to the biopsy site for 10min. The patient remains on bed rest with a good \202 uid intake for 6h. Pulse and BP are monitored regularly and urine inspected f or haematuria. Complications: Haematuria (macroscopic in 7 5%). \200 Bleeding. Blood transfusion required in <2%. \200 If bleeding is severe or persistent ( 7 1 in 1,500), then angiography with embolization c an be undertaken. However, many centers would proceed directly to surgical exploration. A t ransplant nephrectomy is necessary in 7 1 in 3,000. Small AV \201 stulae complicate 7 10% of transplant biopsies. These very rarely become la rge enough to cause problems or require embolization. CHAPTER 5 Transplantation 408 Acute rejection 2 Treat suspected rejection immediately. Introduction Acute rejection is de \201 ned as a sudden deterioration in graft function, a ssociated with speci \201 c immunopathological changes which are classi- \201 ed accordi ng to agreed international criteria (Banff classi \201 cation, see Table 5.8). Acute rejection is described as either predominantly T cell-mediated or predominantly antib ody-mediated (humoral), although, in reality, there is almost certain to be a degree of pat hophysiological overlap. Key facts \200 Modern immunosuppressive regimens have reduced the incidence of early acute rejection to 7 10 \200\223 20%. <10% of patients experience rejection after 1 year ( \200\230 late \200\231 rejection is often associated with non-compliance). A single episode of rejection reduces 5-year graft survival by 7 10%. \200 The classical presentation of fever, painful graft, and oligo-anuria is now very rare. Rejection usually presents with an asymptomatic rise in SCr (or as a \201 nding on a protocol or DGF transplant biopsy). Risk factors (see also b Box 5.4, p. 381) \200 Delayed graft function ( b p. 404). \200 Sensitization with anti-HLA antibodies ( b pp. 361 \200\2233). \200 Repeat transplantati on. \200 HLA-mismatched graft ( b p. 361). \200 No induction immunosuppressive therapy ( b p. 382). \200 Non-TAC-/MMF-based immune suppression ( b p. 386). \200 Poor complian ce or other cause of inadequate immune suppression (e.g. recent vomiting). Recent CMV infection (intentional reduction in immune suppression). Recent UTI (increased graft immunogenicity). 3 Hyperacute rejection This catastrophic form of rejection occurs immediately on reperfusio n of the transplanted kidney and is due to the presence of pre-formed antibod- ies (anti-AB O or anti-HLA). These antibodies bind to donor endothelial cells where they activate comple ment and clotting cascades l vascular thrombosis. Graft loss is inevitable. Thankfully, it has been virtually eradicated by modern cross-matching techniques. T cell-mediated rejection \200 Most common form of rejection ( 7 90%). \200 Highest inc idence in the \201 rst 3 months post-transplantation. ACUTE REJECTION 409 T cell-mediated rejection may either be tubulointerstitial (more common \200\224previously known as cellular ) or vascular or both. Tubulitis is the characteristic lesion of tubulointerstitial T cell-mediated rejection: mononuclear cells in \201 ltrate the walls and lumina of the tubules. Tubulitis is scored as mild, moderate, or severe, depending on the number of mononuclear cells within the tubular basement membrane (scored t1 \200\223 3 ). In addition to T cells, in \201 ltrates often contain macrophages, eosinophils, and plasma cells. There is usually associated interstitial oedema. Intimal arteritis or \200\230 endothelialitis \200\231 is the characteristic lesion of vascular T cell-mediated rejection: mononuclear cells in \201 ltrate the arterial endothel ium. More severe vascular rejection will demonstrate transmural arteritis, \201 brinoid change 9 stromal hemorrhage (scored v1 \200\223 3 ). Treatment T cell-mediated rejection without vascular involvement \200 Corticosteroids: Methylprednisolone IV 500mg daily for 3 days. \200 Consider increasing oral prednisolone to 0.3mg/kg/day to a maximum 20mg, then taper by 5mg weekly to previous maintenance dose. Optimize maintenance immunosuppression: Switch CIC to TAC. Target trough concentration 10 \200\223 12 micrograms/L. Optimize MMF dose. Target dose of 2g/day, if tolerated. Response expected within 5 days ( 7 75% response rate). Re-biopsy if no improvement. Refractory ( \200\230 steroid-resistant \200\231 ) or vascular (Banff IIB, III) T cell-me diated rejection \200 Add T cell-depleting antibody (e.g. ATG) ( 7 90% response). \200 For protocol, see b p. 384. \200 If no response ( 7 5%), consider IVIg 2g/kg single dose (or 0.4g/kg for \201 ve doses). Humoral or antibody-mediated rejection Antibody-mediated rejection (AMR) refers to rejectio n caused by antibod- ies directed against donor HLA, blood group antigens, or other endothe lial cell antigens. The dominant mechanism of injury is antibody-dependent, with activation of the classical complement pathway. Although antibody-mediated, T cells are vital for the initiation and main- tenance of the B cell responses that lead to the generation of plasma cells and injurious antibody. The diagnosis of AMR requires evidence of graft dysfunction and is sup- ported by the presence of the following features: \200 Morphologic evidence of acute tiss ue injury: Acute tubular injury. \200 Neutrophils and/or mononuclear cells in peritubular capillarie s (PTC) 9 glomeruli 9 capillary thrombosis. CHAPTER 5 Transplantation 410 Fibrinoid necrosis/intramural or transmural in \202 ammation in arteries. \200 Immunopat hological evidence of antibody action (often absent, so not essential to the diagnosis of AMR): \200 C4d 9 (rarely) immunoglobulin in PTC. C4d is a c omplement degradation product, derived from classical pathway activation). Ig and complement in arterial \201 brinoid necrosis. Serologic evidence of circulating antibodies to donor HLA (DSA) or other anti-donor endothelial antigen. Cases that meet only two out of the three criteria are considered suspi- cious for AMR. Acu te T cell-mediated rejection may also be present. Treatment X Unfortunately, the evidence base is poor and mostly derived from sin- gle cente r experiences. However, the treatment of AMR is based on four concepts: \200 Suppression of T cell responses (e.g. depleting antibody, escalation in maintenance immune suppression (MMF, CNI)). Elimination of circulating antibody using plasma exchange or other immunoadsorption technique. Inhibition of residual antibody (e.g. IV immunoglobulin). \200 Suppression or depletion o f B cells (e.g. rituximab or splenectomy). In practice \200 DSA level daily during treatment course. \200 Optimize maintenance imm unosuppression: Switch CIC to TAC. Target trough concentration 10 \200\223 12 micrograms/L. Optimize MMF dose. Target dose of 2g/day, if tolerated. Corticosteroids: Methylprednisolone IV 500mg daily for 3 days. \200 Increase oral prednisolone to 0.3mg/kg /day to a maximum 20mg, then taper by 5mg weekly to previous maintenance dose. \200 EITHER: ATG if evidence of co ncomitant T cell-mediated rejection. \200 OR: plasma exchange ( b p. 950): This should be given on alternate days or daily in severe cases (e.g. high DSA titre, anuri c patient). Treatment should continue until there is clinical improvement 9 DSA titres beco me undetectable. After each PEX, give intravenous immunoglobulin (IVIg) 400mg/kg. \200 Consider rituximab as part of initial therapy if severe histological change (or ongoing AMR despite PEX and IVIg). \200 Repeat biopsy if no improvement in SCr in 7 days: Ongoing AMR: continue PEX and IVIg 9 rituximab, if not already given. Consider eculizumab ( b p. 391). Some centers would also contemplate a splenectomy. Resolution of AMR: continue oral immunosuppression at doses above. Close monitoring with weekly DSA. ACUTE REJECTION 411 Table 5.8 Revised Banff classi \201 cation (2007) T cell-mediated rejection Potential management X None. Close surveillance Tubulitis but no signi \201 cant interstitial in \202 ammation (or vise versa). No arteri tis. Borderline changes \200\230 suspicious \200\231 for rejection IA Moderate tubulitis (>4 MC in >25% of sample) Optimize immunosuppression levels Switch to more potent drugs ( l TAC, MMF) IB Severe tubulitis (>10 MC in >25% of sample) Pulse corticosteroids If unresponsive, consider depleting antibody Mild l moderate arteritis in one or more vessels (v1) IIA Severe arteritis (>25% d in luminal area) (v2) IIB Switch to TAC Anti-lymphocyte therapy III Transmural arteritis, with \201 brinoid necrosis and perivascular in \202 ammation (v3) Antibody-mediated rejection Potential management Low threshold for switching to tacrolimus or increasing target range. Likely to need interv al biopsy C4d +ve \200\230 Indeterminate \200\231 Circulating DSA, no evidence of active rejection but borderline changes or ATN Switch to tacrolimus Consider IV immunoglobulin 9 plasma exchange Anti-lymphocyte therapy Circulating DSA, evidence of active rejection: I \200\224 ATN-like minimal in \202 ammati on II \200\224 capillary and/or glomerular in \202 ammation III \200\224 arterial lesion s C4d +ve Acute antibody-mediated rejection MC, mononuclear cells. CHAPTER 5 Transplantation 412 Thrombotic microangiopathy Occurs in two contexts post-transplantation: \200 Recurrent HU S ( b p. 420). \200 New TMA: Usually associated with CNI use but associated with other drugs (particularly sirolimus). Rejection: antibody-mediated rejection and severe T cell-mediated rejection. Antiphospholipid syndrome ( b p. 664). \200 Accelerated i BP. \200 Unsuspected compleme nt mutations (these should always be considered). \200 CMV disease. Pathogenesis Involves endothelial toxicity, d prostacyclin synthesis, vasoconstriction, i s ynthesis and release of large vWF multimers, i leucocyte adhesion to vascular endothelium, platelet aggregation, thrombosis, and ischaemia. Clinical features May occur <1 week to >5 years post-transplant. Often, an unexpected \201 nding on transplant biopsy, following i SCr (graft dysfunction may be rapidly progress ive). <50% have d Plt, d Hb, red cell fragmentation on blood \201 lm, i LDH \200\224 but may be \200\230 transplant-limited \200\231 , with none of these apparent. Consider investigation for complement mutations (usually H or I) in all patients. Histology Vessels: arteriolar wall thickening, swelling and detachment of endothelial cells , \201 brinoid necrosis. Glomeruli: capillary thrombi, attenuation of mesangial matrix an d degen- eration of mesangial cells ( \200\230 mesangiolysis \200\231 ), glomerular ischa emia. X Management \200 In less fulminant disease, more gradual changes to immune suppres sion can be undertaken \200\224 although the optimum regimen is unknown. 2 Treat rejection. \200 In more aggressive disease: Stop CNI. \200 The role of PEX (with FFP) in CNI-associated TMA is uncertain but often undertaken anyway. Eculizumab ( b p. 391) shows great promise, but its role awaits further clari \201 cation. ACUTE REJECTION 413 CHAPTER 5 Transplantation 414 Chronic allograft dysfunction Introduction Both immunological and non-immunological factors play a role in pro- gressive graft dysfunction and loss over time (see Table 5.9). Use of the previous descriptive term \200\230 chronic allograft nephropathy \200\231 (CAN) is no w discouraged, as a more pathologically speci \201 c diagnosis (or diagnoses) should alway s be sought. Chronic rejection implies an immune-mediated process, but optimum treatments a re unknown. Shared histological features are of interstitial \201 brosis and tubular atro- phy (IF/TA). At 2 years, 7 70 \200\223 90% of grafts will show features of IF/TA. Table 5.9 Contributors to chronic allograft dysfunction Alloantigen-dependent Chronic rejection Acute rejection episodes HLA mismatches Prior sensi tization Donor-speci \201 c antibodies Inadequate immunosuppression Proteinuria (transplan t glomerulopathy) Alloantigen-independent CNI toxicity Delayed graft function Prolonged cold ischaemia Reduce d nephron number Donor factors (e.g. DCD or ECD donor, pre-existing donor disease, i age, i BP) Recurrent recipient disease Recipient factors (e.g. i BP, diabetes, CV disease, obesit y) Recipient urinary tract infection or obstruction BK virus nephropathy Proteinuria Assessment The monitoring of graft function over time is one of the fundamental roles of a transplant follow-up clinic. Most patients will be asymptomatic. Key investigations include : \200 SCr and eGFR. It is important to consider changes in these over time in a similar manner to native kidney CKD. Therapeutic drug levels, especially CNI levels. Again, these should be considered over time and in the context of an individual patient \200\231s progress. What was their immunological risk? What were the donor characteristics of their graft? Have they had any rejection episodes? Have they developed a ny infections or other complications of immune suppression? Urinalysis and uPCR. Proteinuria is a marker of renal injury, as well as risk of progressive transplant dysfunct ion, and overall CV morbidity and mortality. It may also identify recurrent native disease. CHRONIC ALLOGRAFT DYSFUNCTION 415 It is a feature of transplant glomerulopathy, the glomerular manifestation of chronic antibody-mediated rejection (see below). MSU: if abnormal urinalysis, symptoms of UTI, unexplained loss of function, and pre-biopsy. HLA antibody screen ( b p. 363). Measure monthly for the \201 rst 3 months (weekly in selected cases), then 3-monthly for the \201 rst year, then annually. BK virus screening ( b p. 436). \200 Transplant USS ( 9 renal artery Doppler). \200 Tra nsplant biopsy (the majority). Some centers perform interval \200\230 protocol biopsies \200\231 , regardless of function (e.g. at 1, 3, 6, or 12 months), to assess overall graft health and individualize management, esp. immunosuppression. X The relevance of \200\230 subclinical \200\231 rejection on such protocol biopsies is uncertain. 2 The interpretation of a transplant biopsy performed for chronic dysfunction is complex an d requires careful clinical-histological correlation, considering all the factors in Table 5.9. Histology The Banff classi \201 cation includes both \200\230 immune \200\231 and \200 \230 non-immune \200\231 chronic damage. \200 Chronic active antibody-mediated rejection . Only accepted as a distinct entity in 2005 but now the focus of a considerable amount of attention. Features: (i) circulating anti-HLA antibody (esp. DSA), (ii) peritubular capillary (PTC) C4d positivity (only present in 750% cases), and (iii) evi dence of chronic tissue damage (arterial intimal \201 brosis without elastosis, duplicati on of the glomerular basement membrane ( \200\230 double contours \200\231 ), multilayeri ng of the peritubular capillary basement membrane, IF/TA). The glomerular changes are refer red to as transplant glomerulopathy and will eventually develop into glomerulosclerosis. Chronic active T cell-mediated rejection. Chronic allograft arteriopathy is characterized by rejection-induced intimal thickening of arteries ( l arterial luminal occlusion and graft ischaemia). Characterized by arterial intimal \201 brosis with mononuclear cell in \201 ltration in \201 brosis and formation of neointima. IF/TA, with no evidence of speci \201 c etiology. \200 I: mild IF/TA (<25% of cortical a rea). \200 II: moderate IF/TA (>25 \200\22350% of cortical area). \200 III: severe IF/T A (>50% of cortical area). 2 The key structures that determine the destiny of a transplant are the vessels (mainly art eries). There is no collateral vasculature, so ves- sel narrowing and occlusion inevitably lead to downstream ischaemia, particularly in the interstitium. CHAPTER 5 Transplantation 416 Management: general measures \200 BP control ( b pp. 422 \200\2233). \200 ACE-I/ARB if proteinuria. \200 CV disease prevention ( b p. 422). \200 Avoid nephrotoxins. \200 Ma intain good \202 uid balance. Management of chronic rejection Chronic active T cell-mediated rejection Generally treated as for acute T cell-mediated rejection ( b p. 408 \200\2239). X Chronic active antibody-med iated rejection Present in 7 25% of those undergoing assessment for loss of graft func- tio n. Optimum treatment is unclear \200\224 studies are ongoing. Common strategies include op timizing general measures, switching from CIC to TAC, increasing MMF as tolerated. IVIg, PE X, and rituximab are used in some centers (as for acute antibody-mediated rejection), but b ene \201 t is unproven. Management of CNI toxicity The earliest functional change is vasoconstriction, but structur al toxicity, with histological change in arterioles, glomeruli, and tubules eventually supe rvenes. Some degree of damage is inevitable in all patients taking a CNI (>50% within 12 mo nths). CNI-induced arteriolar changes include swelling of the medial smooth muscle cells and occas ional endothelial or smooth muscle cell necrosis. The mature lesion demonstrates PAS-positi ve hyaline nodules in the media and adventitia of the afferent arteriole (similar to hypert ensive dam- age). TMA may also be present, and FSGS can occur in the glomeruli as a s conse quence of arteriolar injury. IF/TA is considered a non-speci \201 c secondary feature caus ed by nephron dropout. It is characteristically described as striped \201 brosis in this context. Tubuloepithelial cell vacuoliza- tion 9 microcalci \201 cation may be evident. CN I minimization \200 Either: Dose reduction to aim for a lower therapeutic level. \200 Complete withdrawal, usually wi th a switch to sirolimus. There is some evidence to suggest bene \201 t from this maneuver if undertaken early enough in selected patients ((cid:2) not those with proteinuria). Other agents, such as belatacept, may have a role in the future. CHRONIC ALLOGRAFT DYSFUNCTION 417 The failing transplant It is very easy to forget the \200\230 CKD basics \200\231 in a tr ansplant patient with deteriorating graft function. These include: \200 Explaining the si tuation to the patient, with appropriate psychosocial support. Management of the secondary complications of a falling GFR, including anemia (with IV iron and an ESA, as necessary) and CKD-MBD. Ongoing control of BP and CV risk. \200 Early discussion regarding future dialysis and po ssible retransplantation (ideally pre-emptively). The earlier this is undertaken, the greater chan ce the patient will be able to choose the most acceptable modality for them. Creation of dialysis access. In some cases, this may still be functioning from earlier in their RRT career. (cid:2) Immune suppression should not be stopped suddenly. AZA/MMF are generally stopped \201 rst, followed by slow steroid withdrawal and pro- gressive reduction of CNI (over 7 3 \200\223 6 months). Slow weaning will help to prevent in \202 ammation in a remnant graft which can make the patient feel quite unwell and provoke the development of anti-HLA antib odies that might prejudice future transplantation. Transplant nephrectomy is an operation with appreciable associated morbidity. Indications: the graft is a source of infection or in \202 ammation (presenting as pain, general malais e, haematuria, ESA resistance). Removal of the graft to prevent HLA sensitization is controversial \200\224 the patient ma y still become sensitized to antigens present in the vascular stump. CHAPTER 5 Transplantation 418 Recurrent disease Introduction Recurrence of original disease following transplantation aff ects 7 10 \200\223 20% of patients and accounts for 7 8% of graft failures at 10 years. It is an important differential in the assessment of a recipient with graft dysfunction, part icu- larly in the presence of proteinuria. With the exception of primary FSGS and atypical HUS, which can recur immediately, recurrent glomerular disease tends to manifest months, or even years, after transplantation. Even then, recurrent disease may run an incipient course; for example, although evidence of recurrent IgA is present on a signi \201 cant number of transplant biopsies, it does not lead to graft dysfunction or loss in the majority (see Table 5.10). Table 5.10 Recurrent disease post-transplantation Recurrence rate 7 40% 7 40% 7 20 \200\223 30% 7 20% >90% 7 100% 7 50% 7 80 Graft loss 7 50% 7 5 \200\223 10% 7 20% 7 33% 7 25% <5% p FSGS IgAN Membranous MCGN I MCGN II Diabetic nephropathy HUS (D \200\223) >80% Familial HUS (with complement gene mutation) >80% Primary FSGS Risk factors for recurrence include a short time between initial presenta- tio n and ESRD, recurrence in a previous transplant ( l recurrence >80% for subsequent transpla nt), younger patients (a particular problem in pae- diatric transplantation where FSGS is a common cause of ESRD), diffuse mesangial proliferation on native renal biopsy. Black patie nts appear to have a reduced risk. Familial FSGS is a different disease, and recurrence is rare. Potential recurrence is not an absolute contraindication to live donor transplantatio n but requires careful assessment and discussion, as recurrence appears more common in this context. Presentation May present immediately post-transplant, with oliguria and graft dysfunc- tion from acute tubular injury. This can mimic DGF. Urine should be tested daily for proteinuri a, and nephrotic range proteinuria may develop within days to weeks of transplantation (ass ociated with a fall in serum albumin). Urinary protein excretion (e.g. uPCR) should be docu mented RECURRENT DISEASE 419 pre-transplant for later comparison. Recurrence after 1 year is unusual. Early transplant b iopsy is likely to be normal on light microscopy (besides ATN/ATI), as it takes several mon ths for the typical FSGS lesions to develop. However, EM will be abnormal, with podocyte fo ot process effacement. Treatment \200 Dif \201 cult! \200 Plasma exchange or immunoabsorption. Start as soon as proteinuria develops. Response in 7 50% but relapse common (long-term \200\230 maintenance \200\231 P EX is not an uncommon situation). PEX may be started pre-emptively in live donor and as col d ischaemic time allows in deceased donor transplantation. High-dose CIC (given IV in some protocols) is favored. \200 Steroids and cyclophosphamide (esp. children). \200 Rituximab has been bene \201 cial in some case series. \200 ACE -I/ARB for proteinuria. De novo FSGS post-transplantation s FSGS lesions are reported, with chronic allograft dysfu nction from both immune (transplant glomerulopathy) and non-immune (e.g. hypertension) mech anisms. It may also be apparent with other recurrent diseases, e.g. IgAN. However, presenta tion with the nephrotic syndrome is unusual. IgA nephropathy Overall, long-term graft outcomes are the same as other recipients. Some se ries have suggested a recurrence in the majority ( 7 60%) but clinically signi \201 cant d isease in a minority only. Younger patients appear at greatest risk, as do those with aggre ssive disease in their native kidneys \200\224 crescentic IgAN appears to carry a particul arly high risk. No speci \201 c treatment, but BP control should be meticulous, with regim ens including ACE-I/ARB. Membranous GN Recurrence risk of 7 20 \200\223 30% and also the commonest de novo form of GN post-transplant. It is not yet known if those with anti-PLA2 antibodies are at higher ri sk. Graft outcomes are relatively poor. In common with native disease, some patients will s pontaneously remit, whilst others will have more progressive disease. Treatments have large ly been extrapolated from native disease (where CNIs are commonly used!). A potential role for rituximab is under investigation. MCGN Bears more than a passing resemblance to transplant glomerulopathy, but clinical conte xt, immuno \202 uorescence, and EM should distinguish them. Younger age of onset and aggre ssive native disease appear to be more important risk factors for recurrent disease than hi stological subtype. Type I MCGN often has an underlying cause, so recurrence (and indeed th e feasibility of transplantation) will be linked to this. Type II MCGN has a very high recu rrence rate, a poor response to treatment, and a signi \201 cant rate of graft loss. CHAPTER 5 Transplantation 420 Alport syndrome Transplanted Alport \200\231s patients may rarely develop de novo anti-GBM anti- bodies and a rapidly progressive crescentic glomerulonephritis (donor A 5 type IV col lagen is recognized as non-self). This is extremely dif \201 cult to treat and has virtual ly 100% recurrence in subsequent transplants. Diabetic nephropathy Histological recurrence occurs eventually in 100% recipients (usually within 5 years) \200\224 unless simultanous kidney \200\223 pancreas transplantation has been undertaken ( b p. 446). A reported cause of graft loss in <2%. Has an important implic ation for CV disease progression and patient survival. Transplantation in other systemic diseases, such as SLE, vasculitis, HBV, and HCV, is cover ed in the relevant section elsewhere in the book. Haemolytic uraemic syndrome (HUS) It is important to try and discriminate between de novo p ost-transplant HUS and recurrence of D+ HUS or D \200\223 HUS (a subset of the latter will be familial HUS, with a genetic basis). The rate of recurrence of D + HUS is <1%. D \200\223 HUS recurs in 7 50%, usually within a month of transplantation. De novo HUS arises after transplantation and is discussed separa tely ( b p. 412). Presentation is usually with i SCr, d Plt, and microangiopathic haemolytic anemia (MAHA). Renal biopsy will reveal typical HUS changes of endothelial cell swell- ing, widened subend othelial spaces, and glomerular capillary \201 brin deposits.