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. Risk factors for recurrence are mutation of complement regulatory proteins (e.g. causing fa ctor H or factor I de \201 ciency). Serum factor H and I concentration should be measured and a mutation analysis under- taken in all patients with HUS if transplantation is being c ontemplated. Previously, the risk of recurrence with almost inevitable graft loss, has been so high that transplantation, particularly live donor transplantation, has been relatively contraindicated. Eculizumab shows great promise for protecting renal allografts from post-transplant HUS, al though it is unclear how long treatment should continue (particularly important, given the cost of the drug). RECURRENT DISEASE 421 CHAPTER 5 Transplantation 422 Long-term transplant follow up Introduction The purpose of long-term follow-up is to mainta in both graft and patient health. In most centers, this is undertaken in a dedicated multid isciplinary transplant clinic, but close communication with the patient \200\231s primary c are provider is crucial. In general, after 73 months the focus begins to shift from immunol ogical factors and rejection risk towards more long term concerns such as CV risk. Initial follow-up is intense; usually at least three clinic visits a week for the \201 rs t 1 \200\223 2 months, gradually reducing to 7 1 visit monthly at 6 \200\223 12 months, a nd eventually every 3 \200\223 6 months. Cardiovascular disease \200 Cardiovascular disease (CVD) is the commonest cause of death with a functioning graft in renal transplant patients. Renal transplantation is considered cardioprotective \200\224 dialysis patients have 7 10 \200\223 20 x increased risk of CVD mortality, and renal transplant patients have a 3 \200\223 5 x increased risk of CVD mortality, when compared to the general population. Pre-transplantation CVD management and screening are discussed in earlier sections. Immunosuppressive medications can exacerbate CV risk factors (see Table 5.11). The relationship between falling GFR and increasing CV risk holds true in patients with ren al allograft dysfunction. Stroke and sudden cardiac death are the main CV associations. Addressing CV risk factors should be a focus of care within the long-term management of the renal transplant recipient. Achieving optimal graft function is one of the most effective ways to reduce CVD. Table 5.11 Immune suppression and CV risk CV risk Corticosteroids CNIs MMF n n n n n mTOR inhibitor n +++ n +++ n Hypertension ++ ++ Dyslipidaemia ++ + NODAT + n n ++ n ++ Proteinuria d eGFR Hypertension \200 The rationale for controlling hypertension in transplant recipients is twofold \200\224 and the same as in patients with CKD, i.e. reduce CV risk and slow progre ssive loss of GFR. LONG-TERM TRANSPLANT FOLLOW UP 423 2 Hypertension has been identi \201 ed as a major predictor of graft survival in renal transplant recipients. BP targets for transplant patients have mostly been extrapolated from RCT studies in the CKD population (see b Chapter 3). Of note, there are no large-scale studies comparing different classes of antihypertensive d rugs with a focus on reducing CV events in transplant recipients. Hypertension is common after transplantation due to: \200 Pre-existing hypertension ( 7 9 0% of patients with ESRD have hypertension pre-transplantation). Established arterial stiffness (may improve over time but only slowly, if at all). Use of immunosuppressive drugs, particularly steroids (through i Na + retention) and CNIs ( i vasoactive and nephrotoxic effect). \200 May occur in the setting of transplant renal artery stenosis. Approach to management \200 Kidney Disease Improving Global Outcome (KDIGO) guidelines suggest a target BP of <130/80mmHg. Many centers aim for a target BP of <125/75mmHg if coexistent proteinuria (uPCR >50mg/mmol). Patients should be educated regarding the bene \201 ts of lifestyle interventions for BP control. Choice of drug class as per BHS/NICE guidelines ( b p. 488). Of note: \200 Drugs that blo ck the renin \200\223 angiotensin system may unmask a transplant renal artery stenosis. Hyperkalaemia is common in patients on CNIs and ACE-I/ARBs (CNI l acidosis and distal tubule K + retention). Dihydropyridine calcium antagonists inhibit cytochrome P450 isoenzyme l i CNI levels. Calcium antagonists reduce blood pressure effectively and, theoretically, protect against the vasoconstrictor actions of CNIs. Dyslipidaemia \200 Dyslipidaemia often results in raised total cholesterol, LDL cholester ol, and triglycerides as well as increased levels of intermediate (atherogenic) lipoproteins. Studies have shown that this dyslipidaemia, in the context of transplantation, is modi \201 able by reduction of immune suppression and the use of conve ntional lipid-lowering drugs. ALERT is the only larger RCT of statin treatment in renal transplant recipients and demonstrated a signi \201 cant reduction in non-fatal MI and cardiac death in the \202 uvastatin treatment group. SHARP was another landmark renal statin study and, although transplant patients were excluded, many patients received a transplant in the fol low-up period. Dyslipidaemia is common after transplantation due to: \200 Pre-existing dyslipidaemia (>6 0% of patients with ESRD have dyslipidaemia pre-transplant). CHAPTER 5 Transplantation 424 Use of immunosuppressive drugs, particularly steroids, CNIs and mTOR inhibitors (see Table 5.11). Change in dietary intake in the absence of restriction associated with ESRD. Approach to management \200 CV risk tables are not always helpful in this cohort of patie nts, but, in the UK, guidelines suggest any transplant patient with a 10-year CVD risk of > 20% should take a statin. Treatment should be to a target TC <4mmol/L, LDL cholesterol <2mm ol/L. However, KDIGO practice guidelines have recently moved away from such numeric targets , recommending statin treatment for all transplant recipients (b p. 205). Patients should be educated regarding the bene \201 ts of lifestyle interventions for lipid control. Review immune suppression, and moderate where possible. \200 Options regarding statin cho ice should take into consideration the following: \200 Simvastatin, lovastatin, and rosuvastatin are metabolized by microsomal enzyme cytochrome P450 3A4, which is inhibited by calcineurin inhibitors, partic ularly CIC. The resultant increased statin concentrations can cause adverse effects. The prescription of simvastatin and CIC is contraindicated by the MHRA in the UK. The others should be started at lower doses and titrated carefully. Drugs with alternative metabolism, such as pravastatin, \202 uvastatin, and atorvastatin, are reported to be safe and effective at standard doses, but should be in troduced and titrated carefully under supervision. There are no data to support \201 brates, and concerns regarding side effect pro \201 le in the presence of low eGFR, makes them a less favorable choice. New-onset diabetes after transplantation \200 New-onset diabetes after transplantation (N ODAT) is due to both impairment of insulin secretion and increased insulin resistance. Incidence of new-onset diabetes is between 5 and 20% in the \201 rst year after transplantation. 2 The presence of diabetes is an important risk factor for both poor patient and graft surv ival. This is in the context of both pre-existing diabetes and NODAT. NODAT is associated w ith a doubling in all-cause mortality and a tripling in CV events. Steroid avoidance regimens have reported that NODAT occurred less frequently \200\224 and, when it did, it was less severe. However, overall bene \201 ts w ere modest and associated with increased risk of acute rejection. Risk factors for new-onset diabetes after transplantation are: \200 Age >60. \200 Use o f certain immunosuppressive drugs, particularly steroids, CNIs, and mTOR inhibitors (impaired insulin secretion). Non-Caucasian ethnicity (particularly Afro-Caribbean and Indo-Asian patients). Deceased donor transplants. \200 BMI >30kg/m 2 . LONG-TERM TRANSPLANT FOLLOW UP 425 Family history of T2DM. \200 History of diabetes in pregnancy. \200 HCV +ve patients. \200 Predisposing genetic markers (e.g. TCF7L2 and PPARG ). Approach to management \200 Use WHO criteria for diagnosis. \200 Patients should be edu cated regarding the bene \201 ts of lifestyle interventions for diabetic control. Review medications \200\224 many would consider steroid withdrawal, although the evidence of bene \201 t is slim (despite the well-recognized risk of late ste roid withdrawal, b p. 391). In terms of hypoglycaemic agents: Refer to local guidelines for oral hypoglycaemic use. Metformin is an option if eGFR >45mL/ min (caution due to risk of lactic acidosis). (cid:2) Exercise caution with thiazolidinedio nes, acarbose, and exenatide if eGFR <30mL/min. Refer to local guidelines for insulin choice. Standard screening for diabetic complications apply for patients with NODAT, monitoring for neuropathy, retinopathy, and vigilant foot care (due to infection risk in patients on immu ne suppression). Bone and mineral metabolism \200 Transplant recipients are at increased risk of fracture. This risk is higher than in dialysis patients. Risk factors: steroid use, CNIs, previous renal osteodystrophy, persistent hyperparathyroidism, metabolic acidosis, hypophosphataemia, lack of physical act ivity, post-menopausal \231\200 , smoking. Almost all patients will enter transplantation with a degree of renal osteodystrophy \200\224 and this will persist post-transplant. Patients who have an impaired post-transplant function (e.g. eGFR <30mL/min) are best viewe d using a CKD-MBD paradigm, i.e. they are more accurately described as having osteodystroph y than osteoporosis. This may explain why DEXA scanning does not accurately predict fractur e risk in transplant recipients (even though BMD rapidly decreases in the \201 rst year). Management: control of serum phosphate and PTH, according to familiar CKD targets ( b p. 24 4); correct nutritional vitamin D de \201 ciency (e.g. if 25-OH vitamin D <30 micrograms/L ). \200 Those with persistent tertiary hyperparathyroidism should be observed for a year to see if spontaneous involution occurs prior to proceeding with parath yroidectomy. Cinacalcet can be a useful means of ameliorating hypercalcaemia during this pe riod. Those patients with a GFR >30mL/min can be generally be managed as osteoporosis. \200 Management: oral calcium and vitamin D preparations, correction of acidosis, oral bisphosphonates, steroid minimization. CHAPTER 5 Transplantation 426 Post-transplant infections Introduction Transplant recipients are susceptible to a wide var iety of infectious patho- gens (see Fig. 5.19). The general principles of management in thi s group are: (i) to prevent certain common infections (particularly in the \201 rst few m onths after transplantation or during periods of heavier immune sup- pression); (ii) to be aware of the spectrum of infectious disease to which recipients are vulnerable at particula r times post-transplantation; and (iii) to rapidly assess and treat transplant patients pre senting with suspected infectious disease. Strategies for prevention might include: \200 Perioperative broad-spectrum antibiotics. \200 Co-trimoxazole (PCP, UTI). \200 Isoniazid for TB in high-risk recipients ( b p. 395 ). \200 Valganciclovir for CMV in at-risk recipients ( b p. 432). \200 Screening of dia lysis patients for MRSA (nose, throat, and perineal swabs), with eradication therapy if +ve. VZV vaccination for non-immune patients pre-transplantation (see Table 5.12). Pneumococcal and in \202 uenza vaccinations. \200 HBV vaccination for all those with adv anced CKD (see Table 5.12). Timing of infection Infections in the \201 rst month \200 Standard post-operative infec tions related to the procedure itself \200\224 see Surgical complications ( b p. 402). Including wound, chest, and infected haematomas or lymp hoceles. Urinary tract infection: common. Anuric dialysis patients often have small-capacity dysfunctional bladders, and indwelling urinary catheters or ureteric stents further increase risk. If recurrent, USS transplant, and assess bladder emptying. Is there a relevant abnormality of the native kidneys that may be contributing? Ureteric stent may r equire early removal. Infected lines: remove all cannulae (central and peripheral) as quickly as possible. Are dialysis lines (or PD catheters) still in situ ? Clostridium dif \201 cile: the most important cause of hospital-acquired diarrhea. Incidence of 3.5 \200\223 16% in transplant recipients. Antibiotic use is the mo st signi \201 cant risk factor, but there are others, including i age, ICU admission, i le ngth of stay. Graft l recipient bacterial infections. It is common practice to culture a sample of the pr eservation \202 uid that is used to transplant the organ and to treat according to the re sult. Rarely, a recipient bacterial infection will recrudesce in the recipient (usually S. aureus or Gram \200\223 ve organism). POST-TRANSPLANT INFECTIONS 427 1 \200\2236 months \200 Viral infections (often reactivation of latent disease): CMV, HSV , VZV, EBV, BK virus. TB. \200 Opportunistic infections: Listeria , Aspergillus , pneumocystis pneumonia. Beyond 6 months \200 Conventional community-acquired pathogens. \200 Chronic viral infe ction : BK nephropathy, EBV-driven PTLD. General management issues 2 When treating: \200 Appropriate dose reductions for d GFR: wa tch SCr carefully. \200 Drug interactions, particularly antimicrobials, that may induce/i nhibit cytochrome P450 and thus modify CNI levels: monitor CNI trough levels carefully ( b p. 388). The transplant patient with a fever \200 Fever may represent: Infection. \200 Acute rejection (less common with modern immune suppression). Systemic in \202 ammatory response. \200 May occur during treatment with biological agen ts ( b pp. 383 \200\2235). Take a full history. \200 Full examination: Including palpation of transplant. \200 Look under all dressings! \200 What was the pat ient \200\231s dialysis modality and access? Investigations: Urinalysis and MSU. \200 i WCC (or neutropenia \200\224 stop myelosuppressive drugs: MMF / AZA/co-trimoxazole/valganciclovir). i CRP. \200 Blood cultures. \200 Culture wound discharge, if present, and drain \202 uids. \200 CXR. \200 USS transplant. \200 Imaging for collections in the post-op peri od (usually USS or CT abdomen and pelvis). Aspirate for \202 uid culture. \200 Remove lines, catheters, and u reteric stents, if relevant. \200 Consider broad-spectrum empiric treatment prior to resu lts of the investigations. Seek microbiological input ASAP. \200 Immune suppression may require reduction. Seek spec ialist advice. \200 PO paracetamol to reduce fever. \200 Fluid resuscitation. CHAPTER 5 Transplantation 428 Table 5.12 Vaccination in transplant recipients 1 Vaccines that are not safe Oral polio vaccine Vaccines that are safe In \202 uenza vaccine Pneumococcal vaccine MMR or MR vaccine Inactivated polio vaccine Mumps vaccine Pertussis vaccine Rubella vaccine Adsorbed tetanus vaccine BCG vaccine Adsorbed diphtheria vaccine Yellow fever vaccine Haemophilus in \202 uenza type B vaccine Smallpox vaccine Hep A vaccine Oral typhoid vaccine Hep B vaccine Cholera vaccine Meningococcal polysaccharide vaccine Meningococcal C conjugate vaccine Typhoid vaccine Pneumocystis pneumonia (PCP) \200 Pneumocystis jiroveci , previously known as Pneumocysti s carinii , is a signi \201 cant opportunistic pathogen in organ transplantation. Before routine PCP prophylaxis, the overall incidence among kidney transplant recipients was 2 \200\223 15%. Risk factors: more intense immune suppression, particularly corticosteroids and depleting antibodies. Also pre-existing or co-infection with CMV (an im munomodulatory virus). Clinical features: develops over several days. Dyspnoea and hypoxaemia out of proportion to physical and radiological \201 ndings. CXR: normal or bilateral pulmonary in \201 ltrates. \200 CT: more sensitive. Ground glas s opaci \201 cation (but multiple different appearances are described). Con \201 rmation by demonstration of organisms in lung tissue or respiratory secretions. Usually requires induced sputum or bronchoscopy for BAL (stain w ith antibodies to PCP). \200 Treatment: co-trimoxazole. Minimum 14 days (SE: bone marrow suppression, rash, hepatitis, interstitial nephritis). Second-line: pentamidine (SE: pancreatitis \200\224 avoid in kidney \200\223 pancreas recipients, disturbed glucose me tabolism, bone marrow suppression, nephrotoxic). Adjunctive high-dose steroid if hypoxic (e.g. 40 \200\223 60mg prednisolone bd for 5 \200 \223 7 days, then taper). Respiratory support, as necessary. \200 Prophylaxis: co-trimoxa zole for 6 \200\223 12 months (also suppresses toxoplasma and Listeria ). Dapsone (SE: haemolytic anemia) and monthly nebulized pentamidin e are alternatives, if intolerant. POST-TRANSPLANT INFECTIONS 429 . s s e r P , S J n o r e m a C y t i s r e v n U d r o f x O i , A M A n o s d v a D m o r f : d r o f x O i s i t i l D L T P r o d e r i u q c a - y t i n u m m o C . n d e o c s n o i t c e f n r o s i t i n i t e r V M C n o i s s i d r 3 , y g o o r h p e N , s u r i v a m o i m r e p t n e t s i s r e p l l l i p a P h t i w d e t p a d A 6 l a c n s u c c o c o t p y r C i s u r i v o n e d a n o i t a t n a l p s n a r t i l s n o i t c e f n C f o 5 . n o i t c e f n k o o b t x e T s i s o u c r e b u t i , V S R c i t s i n u t r o p p o r o l , i a z n e u l f n s i t s y c o m u e n P 4 r e t f a t n a l p s n a r t - t s o p d r o f x O C s i t i t a p e h a n o m u e n p i , a i r e t s i L s h t n o M i , V Z V . ) 5 0 0 2 ( 3 l a n o i t n e v n o c n U r o B s i t i t a p e h a d r a c o N V M C , s n o i t c e f n i , V B E s u ) s d e ( f f l l i g r e p s A o e c n e u q e S o t e s n O 2 i r e t e h t a c . l a f o t e s n O t e a d d n a C , l a n o i t n e v n o C P - J i V S H r o d n u o W l a i m o c o s o n 1 s n o i t c e f n 9 1 5 l a i r e t c a B d e f n u r G l a r i V l l a g n u F . . g i F i 0 CHAPTER 5 Transplantation 430 Cytomegalovirus (CMV) Introduction 2 The most important infectious complication of transpla ntation. CMV is a DNA (herpes type) virus that infects 7 50% of the normal population. Following p C MV infection (usually asymptomatic in immuno- competent individuals), CMV persists in the h ost, and reactivation usually results in asymptomatic viral shedding. The presence of CMV I gG in serum identi \201 es past infection ( 7 50% of adults). CMV is transmitted in saliva and other body \202 uids (including blood) as well as in transplanted organs (CMV infect ion via blood products is now rare, as leucocyte-depleted products are usually supplied). CMV in transplant recipients Immunosuppression promotes reactivation of latent CMV in the t rans- planted organ and/or tissues of the recipient. The resultant active CMV infection may be asymptomatic or result in CMV disease. 2 Donor/recipient pre-transplant CMV serological status is important in determining the risk of CMV infection/disease (see Table 5.13). Symptomatic CMV disease is largely con \201 ned to the \201 rst 6 months post-transplant but may present later, especially in high-risk recipients who cease prophylaxis. CMV disease CMV disease is manifested by fever (>38 * C for 2 days over a 4-day period), d WCC, d Plt. Malaise, fatigue, fever, myalgia, and night sweats are also common. (cid:2) CMV causes further host immunosuppression (predisposing to s invasion \200\224 esp. PCP and f ungi). CMV end-organ disease \200 Hepatitis. \200 Pneumonitis. \200 GI: diarrhea (col itis), abdominal pain, nausea, dysphagia. \200 Transplant dysfunction: Due to invasive CMV disease (cid:2) OR due to rejection (CMV increases the expression of graft HLA antigens). CMV retinitis is unusual and occurs late (usually >6 months). CYTOMEGALOVIRUS (CMV) 431 Table 5.13 Risk of CMV according to serological status Donor CMV status Recipient CMV status Risk \200\223 ve \200\223 ve Low +ve \200\223 ve High \200\223 ve +ve Medium +ve +ve Medium Either donor and/or recipient CMV +ve and treatment with depleting antibody High CMV presents the greatest threat to D+ R \200\223 transplant recipients and those requirin g additional immunosuppressive therapy for rejection (e.g. following a depleting agent). Antiviral prophylaxis is currently administered to those at greatest risk but does not guar antee protection (and may delay presentation) (see Fig. 5.20). CMV serostatus D+R \200\223 D+R+ or D \200\223R+ D \200\223R \200\223 Oral prophylaxis with valganciclovir months 0 \200\2233 No survelliance or prophylaxis required PCR survelliance months 1 \200\22312 PCR surveillance months 4 \200\22312 Fig. 5.20 CMV prophylaxis and surveillance strategy by CMV serostatus. Some centers give pr ophylaxis to all recipients, except D \200\223 R \200\223 . Diagnosis and monitoring \200 Ascertain CMV IgG status pre-transplantation: test prospect ive recipient at the time of listing. Recheck recipient CMV IgG on admission for transplant if previously seronegative. Donor status is provided with transplant organ. CHAPTER 5 Transplantation 432 CMV prophylaxis \200 Indicated for CMV donor +ve/recipient \200\223 ve patients (D+ R \200\223 ). \200 Valganciclovir 900mg PO od, adjusted for renal function, for 90 days post-transplant (see Table 5.14). Routine surveillance of asymptomatic patients \200 CMV viral load is measured in whole bl ood by PCR. \200 Routine surveillance should commence at 2 weeks post-transplant and cont inue for 12 months (weekly for the \201 rst 3 months and monthly thereafter). It is unnecessary to perform viral surveillance in D \200\223 R \200\223 patients or in D + R \200\223 patients receiving prophylactic valganciclovir. Some centers issue prophylaxi s to all, but D+ R \200\223 , recipients. Interpretation of CMV viral load results \200 Rapid increases in CMV viral load (the tren d), rather than isolated results, are predictive of development of CMV disease. Routine surveillance forms the basis for pre-emptive therapy. The goal is to detect active CMV viraemia in order to facilitate prevention of symptomatic CMV infection/end-organ disea se. Both international units (IU) and logs are often reported. A change of one log or more in t he space of 3 or 4 days is likely to be signi \201 cant. Pre-emptive treatment \200 This strategy includes both reduction of immunosuppression, wh ere possible, and the institution of treatment doses of valganciclovir to prevent or amelio rate clinical CMV disease. Valganciclovir 900mg PO bd, adjusted for renal function, for a minimum of 2 weeks or until CMV viral load is undetectable (see Table 5.14). For patients who are CMV-negative pre-transplant, detection of CMV viraemia is consistent w ith primary CMV infection. The patient should be clinically reviewed ASAP. Immediate reduction of immunosuppression and initiation of pre-emptive antiviral therapy should be considered. If the patient was seropositive pre-transplant and is asymptomatic and the viral loads dete cted are low and not rapidly increasing, it may be appropriate to either retest in 1 week o r to reduce immune suppression and then retest. In contrast, a rapidly increasing viral load, with or without symptoms, would suggest the need to commence antiviral therapy, with additional reduction of immunosu ppression. Management of CMV disease Reduction of immunosuppression \200 Review immunosuppressive th erapy, and stop/reduce one agent, usually MMF (or AZA). Do not recommence the discontinued drug for a minimum of 1 month, unless rejection occurs. CYTOMEGALOVIRUS (CMV) 433 CMV relapse is common, usually presenting 1 \200\223 4 weeks after completion of treatment, and is more likely if immunosuppressive therapy is reinstated duri ng this period. Antiviral therapy \200 Oral valganciclovir 900mg PO bd, adjusted for renal function. 2 No te the higher dose frequency required for pre-emptive therapy and for treatment of CMV synd rome/disease vs prophylaxis. \200 IV ganciclovir 5mg/kg IV bd, adjusted for renal functio n. IV therapy is generally reserved for patients unable to tolerate oral treatment. Intravenous immunoglobulin (IVIg) is used as an adjunct for pneumonitis (IVIg 500mg/kg every other day for a total of 10 doses). Duration of therapy \200 Treatment should be given for a minimum of 2 weeks and continued until the CMV viral load in whole blood is undetectable on at least one occasion. Treatment of end-organ CMV disease should be continued for a minimum of 3 weeks and continued until the CMV viral load in whole blood is undetectable on at least one occasion. Table 5.14 Dosing of valganciclovir in renal impairment (based on Cockcroft \200\223 Gault GFR) CrCl (mL/min) Prophylaxis dose Treatment dose >60 900mg once daily 900mg twice daily 40 \200\223 59 450mg once daily 450mg twice daily 25 \200\223 39 450mg every 48h 450mg once daily 10 \200\223 24 450mg twice weekly 450mg every 48h <10 100mg three times a week after dialysis * 200mg three times a week after dialysis * 50mg/mL oral suspension available for doses less than 450mg. CHAPTER 5 Transplantation 434 Herpes simplex virus infection Herpes simplex virus seroprevalence is 7 50% in the renal tr ansplant population. Post-transplant infection may be primary, following reactiva- tion, or secondary as a result of person-to-person contact or allograft transmission. Clinical features \200 Oral or genital mucocutaneous lesions are most common; however, patients may present with: \200 Pneumonitis. \200 Tracheobronchitis. \200 Oesophagiti s. \200 Hepatitis. \200 Disseminated infection. \200 CNS infection. Diagnosis \200 Direct \202 uorescence antibody for HSV from vesicles. \200 PCR \200 \224 quantifying viral copy number from CSF, blood, etc. \200 Serology is rarely helpful in distinguishing active infection. Treatment \200 Oral aciclovir for mucocutaneous manifestations. \200 IV aciclovir for d isseminated or solid organ infection. \200 Ganciclovir and foscarnet are also effective. \200 Renal function should be carefully monitored throughout treatment with antivirals. CYTOMEGALOVIRUS (CMV) 435 CHAPTER 5 Transplantation 436 BK virus nephropathy Introduction Polyomaviruses are ubiquitous but rarely cause clinical i llness. Only two virus strains are known to be pathogenic in humans: Polyomavirus hominis 1 (BK) and Polyomavirus hominis 2 (JC) (named with the initials of the indi- viduals from wh om they were \201 rst isolated), and these only cause disease in immunocompromised patien ts. BK virus causes viral nephropathy (polyomavirus-associated nephropa- thy, PVAN) as well as haemorrhagic cystitis and ureteric ulceration and stenosis ( 9 obstruction). JC virus cause s a viral encephalopathy. Primary BK virus infection occurs in early life, resulting in almost univer- sal seropositi vity. The virus persists in the urinary tract (including latency in tubular cells), and vir al shedding into the urine is relatively common (particularly older patients, patients with diabetes, HIV-infected and trans- plant patients). There are several genotypes, so, althou gh a recipient may have acquired partial immunity to one genotype, the allograft may expo- sure them to another. Over the last 20 years, PVAN has emerged as an important cause of allograft dysfunction (pe rhaps re \202 ecting the more potent immune sup- pression introduced during that era). Ris k factors appear to include: donor seropositive and recipient seronegative (usually pediatr ic recipient), sig- ni \201 cant HLA mismatch, graft injury of other cause, acute rejectio n, and potency of immune suppression. PVAN occurs in 7 5% of kidney transplant recipients. Viraemia occurs in a greater proportio n ( 7 10%), and BK viruria is even more common. The risk of graft failure is high, with 3- and 5-year graft survival rates of 7 65% and 7 55%, respectively. Clinical features Often an asymptomatic transplantation). ( 7 9 \200\223 18 months after increase in SCr Diagnosis \200 Urine cytology. Infected tubular cells are shed into the urine \200\224 t hese so-called \200\230 decoy cells \200\231 (with ground glass intranuclear inclusions) are present in 90% of infected patients (>10 decoy cells/hpf suggests disease). This \201 nding precedes viraemia by weeks and nephropathy by months. \200 PCR quanti \201 cation of virus in urine or blood is now widely available. These are very sensitive but less speci \201 c. Some advocate monitoring for BK viraemia (e.g. screen monthly for the post-transplant year) so that pre-emptive changes can be made to immune suppression bef ore BK nephropathy supervenes. Renal biopsy is necessary to con \201 rm the diagnosis (although PVAN is unlikely if blood and urine PCR are normal). Histology. The characteristic \201 nding is tubulointerstitial nephritis with a mononucle ar cell in \201 ltrate, along with viral cytopathic changes, such as inclusions in tubular cells. Immunohistochemistry will con \201 rm BK virus. (cid:2) These \201 ndings are focal and easy to miss. They may also be confused with rejection. BK VIRUS NEPHROPATHY 437 Treatment (See Fig. 5.21) \200 2 Reduction of immunosuppression. There is no good evidenc e to guide this, but many protocols start with reduction or withdrawal of antiproliferative agents (MMF/AZA). Aim for lower CNI levels, e.g. TAC 3 \200\223 6ng/mL. (cid:2) The risk is precipitating rejection, the treatment of which, with concomitant PVAN, is extremely challenging. Many continue with immune suppression redu ction and treat rejection with IV and oral steroids. IVIg is an alternative (e.g. 2g/kg), a s it has the theoretical ability to \200\230 neutralize \200\231 BK virus as well as havi ng recognized anti-rejection ef \201 cacy. The anti-arthritic drug le \202 unomide has both immunosuppressive and antiviral propertie s (acts through inhibition of tyrosine kinase activity and depletion of pyrimidine). (cid:2 ) SE: haemolytic anemia, thrombocytopenia, and TMA. No clear evidence to support the use of antivirals. Cidofovir for 1 \200\223 4 fortnightly doses has been the most popular ( (cid:2) nephrotoxic). \200 Quinolones, incl uding cipro \202 oxacin, may be of some bene \201 t (inhibit DNA topoisomerase and polyomavirus-associated helicase). Loss of graft function, ureteric stenosis, and macroscopic haematuria Decoy cells in urine? No Not BK nephropathy Yes \200\223ve Urine or serum BK PCR? Not BK nephropathy +ve Viral inclusions or immunohistochemistry for BK? No Not BK nephropathy Yes Consider immunosuppression reduction cidofivir Fig. 5.21 BK investigation and treatment algorithm. Reproduced from Nicholas Torpey et al. (Oxford Specialist Handbook) Renal Transplantation (2010), with permission from Oxford Univ ersity Press. CHAPTER 5 Transplantation 438