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 Post-transplant UTI 2 UTI is the most common infection, following kidney transplantation, a nd has been reported in 42 \200\223 70% of patient cohorts. This relates to uri- nary trac t instrumentation, poor bladder function, other pre-existing uri- nary tract abnormalities, and immune suppression. It is most common in the \201 rst year and associated with highe r rates of hospital admission. More common in \231\200 . Prevention Patients with recurrent UTIs should undergo urological investigation prior to tr ansplantation. Those taking prophylactic antibiotics pre-transplant may need to continue th em post-transplant \200\224 co-trimoxazole for PCP prophylaxis will provide some cover. Br oad-spectrum antibiotic prophy- laxis is administered preoperatively. Ensure timely removal of urinary cath- eter (usually 5 days) and ureteric stent (usually 4 \200\223 6 weeks). Clinical features \200 Asymptomatic, with incidental detection on urinalysis/MSU more common in this group (and more likely to develop into a symptomatic infection). Irritative urinary tract symptoms \200\224 dysuria, frequency, nocturia. \200 Graft pyel onephritis: fever, graft tenderness, often systemically unwell with graft dysfunction. Systemic in \202 ammatory response syndrome l septic shock. \200 (cid:2) Note: UTI is a risk factor for rejection. Diagnosis \200 Urinalysis. \200 MSU for M,C&S. \200 Transplant (and native kidney) US S: exclude obstruction. Microbiology \200 E. coli is the most common pathogen. \200 Others: enterococci, Pseudo monas , coagulase-negative staphylococci, and Enterobacter . Treatment \200 Empirical antibiotics should be started after an MSU has been obtained in symptomatic patients. Therapy should be guided by sensitivities ( (cid:2) a signi \201 cant proportion of infect ions will be resistant to \201 rst-line antibiotics, with increasing detection of extende d-spectrum beta-lactamase organisms). Discuss complex cases with microbiology. Avoid nephrotoxic antibiotics, and adjust doses, according to renal function. Graft pyelonephritis: co-amoxiclav IV for 10 \200\223 14 days (+ gentamicin IV). Convert t o oral if clinically improving and afebrile for 24h. If penicillin-allergic, give 1 \200 \223 2 doses gentamicin, then review culture results. POST-TRANSPLANT UTI 439 Recurrent UTI \200 Clarify previous infective episodes, duration of treatment, compliance , and whether negative urine culture was obtained following treatment. Ensure adequate bladder emptying (USS). \200 Consider urodynamics. \200 Late UTIs (>6 m onths) are associated with worse graft outcomes: consider DMSA for transplant scarring if deteriorating graft function. Consider cystoscopy, particularly if recurrent graft pyelonephritis. \200 Consider prophy lactic and rotational antibiotic therapy. CHAPTER 5 Transplantation 440 Post-transplant malignancy Introduction The frequency of malignancy is increased in the pos t-transplant population, with a risk of 7 2.5 \200\223 3.0 x over an age-matched non-trans plant population (as well as over age - matched dialysis patients). There is a huge variati on between tumor types. Non-melanoma skin cancer (NMSC) has 7 100 x greater risk ( 7 200 x for squamous cell cancer); renal cell and urothelial can- cer have 7 10x risk, and breast c ancer in \231\200 has approximately equal risk. Cancer is recorded as the cause of death i n 7 10% of transplant recipients who die with a functioning graft (higher in some studies). Immune suppres- sion is the most important risk factor, but others, including smoking, vir al infections (e.g. EBV), and older age, are also relevant. Although donors (both living and deceased) are screened for malig- nancy, there are rare re ports of malignancy being transmitted from donor to recipient. Mechanisms \200 Increased risk is more a function of overall immune suppressant burden than of a particular immune suppressive agent. Most immune suppressants impair the cell cycle and cell growth across many different cell types. CNIs upregulate both TGF- B and VEGF, leading to increased angiogenesis and tumor spread in animal models. Azathioprine interrupts the repair of UV light-associated DNA damage in the skin. This may be aided by the viral-induced inhibition of the p53 tumor suppressor gene. PTLD is associated with EBV proliferation. Human herpes virus 8 (HHV-8) is associated with Kaposi \200\231s sarcoma. Sirolimus and other mTOR inhibitors reduce angiogenesis, so it is hoped they may be associated with less malignancy than other agents. Studies are ongoing. Screening Ensure access to national screening programs, such as cervical screen- ing, mammo graphy, and FOB testing. X PSA 9 DRE in 4 recipients aged >50 (or younger if family history of prostate cancer). Some advocate annual USS screening of native kidneys for renal cell c ancer (particularly if known acquired cystic disease, i.e. cysts arising in atrophic ESRD k idneys). Prevention 2 Smoking cessation, self-examination, sun avoidance (appropriate cloth- ing; su nblock; avoid sunburn), reporting of untoward symptoms. Education should start in the pre-transplant phase and be continually reinforced during transplant follow-up. Skin cancer 7 50% of transplant recipients will develop a non-melanoma skin cancer (NMSC) a fter 20 years (SCC > BCC \200\224 a reversal of the incidence in the general population). Skin type ( (cid:2) pale skin), human papilloma virus, and POST-TRANSPLANT MALIGNANCY 441 sun exposure ( 6 older age) all appear to be risk factors. Tumors are often multiple and me tastasize more commonly ( 7 5%). 2 Advocate sun protection at all times, starting pre-trans plant. Recommend regular self-surveillance and annual dermatological review (particularly i f previous NMSC). Treatment: local excision, topical therapy, e.g. imiquimod, 5- \202 uorouracil, podophyllin. Retinoids have been used for secondary prevention. Consider reduction of immune suppression. Stop AZA/MMF, if possible. X Conversion from a CN I to sirolimus may be advantageous (proven bene \201 t in Kaposi \200\231s sarcoma). Studi es are ongoing. Malignant melanoma and Kaposi \200\231s sarcoma also occur more frequently in transplant recipients. Post-transplant lymphoproliferative disorder Second most common post-transplant malignancy after NMSC. PTLD encompasses a range of disorders, from an EBV-associated infectious mononu cleosis syndrome early after transplantation through to non-EBV- (and often non-B cell-) as sociated malignant lymphoma, occurring late after transplantation (see Table 5.15). EBV and PTLD EBV is an overwhelming risk factor for PTLD. EBV is usually acquired in childh ood. Most transplant recipients will be EBV-seropositive. However, EBV may be transmitted t o an EBV-naive recipient from a donor kidney. EBV-related lymphomas occur mainly within the \201 rst year post-transplantation (>90%). Immune suppression disrupts CD8 +ve cyto- tox ic T cell EBV surveillance, allowing latently infected cells to undergo replication l event ual B cell transformation and immortalization. 2 Recipient and donor EBV serological status should be known pre-transplant. EBV infection post-transplant: fever, malaise, pharyngitis, lymphadenop- athy, hepatospleno megaly, and lymphocytosis. Other non-PTLD manifes- tations include: hepatitis, pneumonitis, bone marrow suppression. PTLD risk factors \200 EBV-seronegative recipient. \200 Depleting antibodies and high l evels of immune suppression. \200 The development of a primary EBV infection. \200 CMV infection \200 For late PTLD: risk factors include older donor age and length of immune suppression. CHAPTER 5 Transplantation 442 Table 5.15 WHO classi \201 cation of PTLD Categories of PTLD Comment Usually EBV +ve Early Early lesions Plasmacytic hyperplasia Infectious mononucleosis-like lesion Polymorphic PTLD Most common Usually EBV positive Monomorphic PTLD B cell neoplasms Diffuse large B cell lymphoma High-grade malignancy Burkitt \200\231s lymphoma Usually EBV \200\223 ve Plasma cell myeloma Late Plasmacytoma-like lesion T cell neoplasms Peripheral T cell lymphoma Hepatosplenic T cell lymphoma Other rare types Classical Hodgkin \200\231s lymphoma-type PTLD Clinical presentation of PTLD May be asymptomatic. Weight loss, fever, night sweats, sore t hroat, malaise, anorexia, GI symptoms, and headache. Signs include: lymphadenopathy, hepatosplenomegaly, tonsillar enlarge- ment, and focal neurological signs. Disease may be nodal or extranodal, localized (more common) or dis- seminated. Localized disease may occur in the transplant kidney. Investigations \200 Anemia, i serum urate, i LDH. \200 High-risk individuals (children and seronegative adults) should undergo surveillance, using EBV-DNA PCR. If suspected, whole body CT is usually undertaken (or CT-PET). \200 Histopathology to con \201 rm diagnosis, and classify according to international criteria. Additional tests may include bone marrow examination and LP for CSF examination. Management \200 A multidisciplinary approach, involving transplant physicians, histopathologists, and haemato-oncologists is essential. Histological type is crucial to planning therapy. POST-TRANSPLANT MALIGNANCY 443 For EBV-associated PTLD, the mainstay is a stepwise reduction in immune suppression. Expect response in 2 \200\223 4 weeks. (cid:2) Rejection causing graft loss in <10%. This process can be tailored by measuring EBV-speci \201 c T cell subsets (their appearanc e with reduction of immunosuppression may herald regression of tumor). No evidence to support antiviral therapy. \200 Rituximab (anti-CD20 antibody) is usually the next step and has made a signi \201 cant difference to remission rates (B cell tumors are CD20 +ve). Treatment of late and T cell PTLD requires more conventional chemotherapy, e.g. CHOP. Prognosis \200 >80% of early EBV-associated polymorphic disease will enter remission with treatment, and relapse is rare. Worse prognosis with i age, non-EBV-associated disease, monomorphic disease, high LDH that is slow to fall with treatment. CHAPTER 5 Transplantation 444 ABO- and HLA-incompatible transplantation Introduction Many patients have live donors come forward to donate, but the trans- plant cannot proceed, as they are not ABO-compatible or b ecause they have a positive cross-match. Transplanting across blood groups Blood group O individuals are universal donors and AB uni versal recipi- ents. Until fairly recently, transplantation was only carried out in blood g roup matched pairs or according to \200\230 transfusion rules \200\231 . This is no longe r necessarily the case. Note: blood group A patients can be subgrouped as A1 and A2. Those with A2 express much low er amounts of A antigen on cell (including endothelial) surfaces and can 6 be considered as blood group O if the recipients have no (or low) levels of circulating anti-A antibodies. This means that A2 to O transplants are relatively straightforward. In addition, anti-blood group antibody removal to reduce anti-A and anti-B antibody titres to an acceptable range for transplantation (generally 1:8) is increasingly common. Technique Plasma exchange or immunoabsorption are used to remove anti-A and anti-B antibody . The number of treatments will depend on the initial antibody titre. Treatment is often co ntinued post-transplant. New anti- body production is prevented by administration of rituxi mab \200\224 usually 7 1 month prior to transplantation (previously a splenectomy was nece s- sary). Induction therapy (often with a repeat dose of rituximab) is usual. Maintenance i mmune suppression will be TAC- and MMF-based. Antibody titres are measured regularly post-t ransplant (often daily initially). Anti-A and anti-B antibody titres rise over time but do not injure the graft (thought to be an example of immune accommodation). 2 It is imperative that anti-A and anti-B antibodies are not inadvertently transfused back to the recipient i n a blood transfusion or FFP. This means that only blood group AB FFP or blood products sho uld generally be used. Packed red cells of the recipient \200\231s type are safe to use. Di scuss with your transfusion laboratory. 7 10% incidence of antibody-mediated rejection (the majority of grafts are C4d +ve but with no other evidence of antibody-mediated rejection). Graft outcomes are excellent: 1- and 3- year graft survival 96% and 94%, respectively. Transplanting across a positive cross-match \200 The aim is to remove donor-speci \201 c anti-HLA antibodies prior to transplantation. This has proved more challenging than ABO-incompatible pairs. \200 Meticulous assessment of the donor-speci \201 c cross-match is necessary. ABO- AND HLA-INCOMPATIBLE TRANSPLANTATION 445 The goal is essentially to remove DSA until the CDC-XM becomes negative ( b pp. 363 \200\2234). Unfortunately, antibody removal is often a temporary phenomenon. There is likely to be a me mory immune response with induction of, and concomitant, T cell reaction. Antibody removal protocols are often complex, involving PEX ( 9 IVIg), rituximab, depleting antibody induction, steroids, TAC, and MMF. Serial DSAs are measured both pre- and post-transplantation. \200 There is higher inciden ce of DGF and both antibody and T cell-mediated acute rejection ( 7 35%). Outcomes are generally comparable to deceased, rather than live, donor transplantation. 1-year graft survival 7 80%. Long-term data, particularly with respect to the incidence of chronic antibody-mediated rejection and graft outcomes, are awaited. Most pairs should be offered the paired scheme (see below) before proceeding. Live donor exchange schemes If a patient has a live donor but, for ABO or immunological rea sons, a direct transplant cannot go ahead, donors and recipients may agree to swap kidneys (see Fig. 5.22). This is coordinated centrally (e.g. by NHSBT in the UK). Very careful plan ning is required. Donor nephrectomies are carried out simultaneously in order to prevent a particular donor \200\230 backing out \200\231 after their relative has received a kidney . A large pool is required for suitable exchanges to occur. Blood group O and highly sensit ized patients are the least likely to be matched (as per the deceased donor list). Recipient A Recipient B Recipient C No Yes No Yes No Donor A Donor B Donor C Yes Fig. 5.22 Donor A is unable to donate to recipient A for immunological reasons. The same is true of the pairs B and C. Using an exchange scheme, donor A donates to recipient B, donor B to recipient C, and donor C to recipient A. CHAPTER 5 Transplantation 446 Kidney \200\223pancreas transplantation Introduction Transplantation is the treatment of ch oice for diabetic patients with ESRD. In addition to kidney transplantation alone, options are: \200 Simultanous kidney \200\223 pancreas transplantation (SPK) ( 7 80%). \200 Pa ncreas (cadaveric) after kidney (usually living donor) transplantation (PAK) ( 7 20%). Islet cell transplantation (see Box 5.7). Bene \201 ts \200 Pancreas transplantation corrects the glycaemic state (HbA1c falls to normal), leading to improved quality of life (freedom from both insulin and dialysis). Prevention of progression (and possibly partial reversal X ) of diabetic complications. Comparable survival to live donor kidney transplant alone. Selection criteria for SPK \200 T1DM and ESRD (dialysis anticipated within 6 months). \200 Usually have established diabetic compliactions. \200 Recipient age <60. \200 BMI <30. \200 Adequate cardiovascular reserve ( b pp. 352 \200\2236). \200 Note: T2DM pati ents may also be eligible if insulin-requiring, BMI is close to or <25, and who ful \201 ll the listed criteria. Selection criteria for PAK \200 Patients with stable function of a previous renal transpl ant (usually eGFR >40mL/min) who meet earlier listed criteria for SPK. Selection criteria for pancreas transplant alone (PTA) \200 Presence of T1DM. \200 Life -threatening complications: hypoglycaemic unawareness, with frequent or severe episodes of hypoglycaemia. These patients do not have ESRD. Selection criteria for islet cell transplantation \200 In combination with renal transpla ntation in a patient with T1DM and ESRD. After successful live or deceased donor transplantation in a patient with T1DM and ESRD. Hypoglycaemic unawareness, with frequent or severe episodes of hypoglycaemia. Less commonly: poor metabolic control and progressive diabetic complications, despite intensive insulin therapy. KIDNEY \200\223PANCREAS TRANSPLANTATION 447 Box 5.7 Barriers to successful islet cell transplantation Islet cell transplantation shows promise, but early excellent results have proved dif \201 cult to sustain. Supplemental in sulin is required by many recipients within 1 year and >90% by 5 years. Reasons include: \200 Immune-mediated destruction (highly immunogenic). \200 Insuf \201 cient islet cell mass (more than one donor needed). \200 Drug toxicity (CNIs and steroids are toxic to is let cells). \200 Recurrent transplantation is often necessary. Surgical technique for pancreas transplantation Two options: \200 Bladder drainage. Kidne y is transplanted into the left iliac fossa and exocrine secretions of the pancreas routed into the bladder via a duodenal cystotomy. Metabolic complications: \200 Acidosis (HCO 3 \200\223 depletion) and Na + loss ( l relative d BP requiring oral sodium bicarbonate administration (e.g. 2g qds). Calcium bladder stones (alkaline urine). \200 Chemical cystitis/urethritis. \200 Re \202 ux pancreatitis. Enteric drainage (generally preferred): exocrine secretions drain into bowel. Fewer metabolic complications. Immunosuppression. Similar to kidney alone transplantation. Depleting antibodies more commonly used at induction. Steroid withdrawal often favored, e.g. by 6 mon ths. Graft thrombosis (rarely salvageable) is the commonest early cause of graft loss (prophylaxis with heparin 9 aspirin is usual). More morbidity in the \201 rst year (length of hospital stay doubles, compared to kidney alone). 20 \200\223 30% chance of laparotomy during early post-transplant period (peripancreatic collections are common). Fungal infection more common than after kidney alone; prophylaxis is common practice. Rejection essentially causes pancreatitis, with i serum amylase and lipase. If bladder drai ned, urinary lipase and amylase will d during rejection. (cid:2) Hyperglycaemia implies the majority of islet cells have been destroyed and is 6 a worrying sign. Rejection in the pancreas is often diagnosed by biopsy of the kidney transplant (pancreas biopsies are possible but are technically challenging \200\224 there is a Banff classi \201 cation of pancreas allograft rejection). However, asynchrono us rejection (when one of the organs rejects without a simultanous process in the other) ma y occur. 85% and 70% 1- and 5-year pancreas survival after SPK (higher kidney survival); 95% 1-year patient survival. Causes of post-transplant hyperglycaemia: graft dysfunction, NODAT ( (cid:2) steroids and CNI). CHAPTER 5 Transplantation 448 Indications for simultanous liver and kidney transplantation \200 Primary hyperoxaluria. \200 Hereditary amyloidosis. \200 HUS s to hereditary complement mutations. \200 ADPK D: ESRD with large, symptomatic polycystic liver disease. \200 Hepatorenal syndrome with irreversible renal failure. 449 Chapter 6 Hypertension Hypertension facts and \201 gures 450 What is hypertension? 451 Pathogenesis: general 452 Pathogenesis: genetics, arterial stiffness, and SNS 454 Pathogenesis: RAS and other factor s 456 BP measurement 458 Clinical assessment 462 Classi \201 cation and treatment threshol ds 464 Cardiovascular risk assessment 470 Lifestyle measures 472 Secondary hypertension 474 Primary hyperaldosteronism 476 Speci \201 c causes of hyperaldosteronism 478 Other \200 \230 hyperaldosteronism \200\231 syndromes 480 Other causes of secondary hypertension 482 Drug management of hypertension 484 Guidelines for drug treatment 488 BP treatment: special situations 490 Clinical trials in hypertension 492 Diuretics 1 498 Diuretics 2 500 B -bloc kers 502 A -blockers 504 Calcium channel blockers 506 ACE inhibitors (ACE-I) 508 A2 recepto r blockers (ARB) 510 Other antihypertensive agents 512 Non-pharmacological strategies 514 R esistant hypertension 516 Hypertensive urgencies and emergencies 518 Assessing urgencies an d emergencies 520 Management of urgencies and emergencies 522 Orthostatic hypotension 526 CHAPTER 6 Hypertension 450 Hypertension facts and \201 gures Epidemiology The WHO identi \201 es hypertension as th e single most important prevent- able cause of premature death in developed countries. It i s the most com- mon indication for prescription drug therapy (in 2009, the NHS in the UK fu nded 140 million primary care prescriptions for antihypertensive drugs at a cost of 700 m illion). \200 The 2010 Health Survey for England (sample size 12,000) found a prevalence of hypertension ( \211 140/90 or on antihypertensive medication) of 32% for \231\202 and 27% for \231\200 . This increases to 73% \231\202 and 64% \231\200 in the >75 age group . In England, only 13.6% are registered on their GPs \200\231 hypertension register. It is often found in association with other CV risk factors, rather than in isolation. It is responsible for a signi \201 cant burden to both individuals and society through cor onary heart disease, stroke, and other vascular disease. \200 Signi \201 cant underdiagn osis and treatment remain common; the \200\230 rule of halves \200\231 still applies: \200 1/2 those with i BP have not been diagnosed. \200 1/2 of those who have been diagnosed are not on treatment. \200 1/2 of those receiving tr eatment do not have adequate control. Classifying hypertension \200 Essential hypertension is a heterogeneous genetic and envir onmental condition. Secondary hypertension implies i BP is s to an underlying disorder and accounts for 75 \200\223 10% of cases ( b p. 474). Hypertension facts and \201 gures \200 Systolic BP (SBP) increases with age until the 8 th decade. \200 Diastolic BP (DBP) increases up to age 50, after which it plateaus or i slightly. DBP is the best indicator of CV risk < 50 years. With i age, there is a shift to SBP as the principal risk predictor. Reduction in SBP of 20mmHg systolic or DBP of 10mmHg is associated with reductions in death from stroke and IHD of 7 50% (slightly more in younger patients, slightly less in older). This is consistent down to 115/75mmHg in at least one large meta-analysis. X However, the q uestion of \200\230how low to go? \200\231 remains an important one. It is unclear if ther e is a threshold below which further reduction in BP is no longer bene \201 cial; the so-c alled \200\230J-curve \200\231 phenomenon (see b p. 468). \200 Non-pharmacological strat egies (i.e. lifestyle measures) have been shown to d BP. Antihypertensive drug treatment not only d BP, but also d complications. Patient education is paramount: i BP is an asymptomatic condition, and bene \201 ts of tre atment may not be immediately apparent to the patient. WHAT IS HYPERTENSION? 451 What is hypertension? BP variation in a given population follows a skewed normal distributi on (see Fig. 6.1). Any cut-off point used to de \201 ne abnormal will be arbitrary. Normal BP varies with race, sex, and age, so, even if an arbitrary de \201 nition of i BP could be agreed, it would need to be adapted, according to the population in question. 2 In addition, an individual whose BP is just below the de \201 ned cut-off has a virtuall y identical CV risk to one just above it. n o i t a l u p o p n i y c n e u q e r F Blood pressure Fig. 6.1 Distribution of BP in any population: the cut-off for de \201 ning \200\230 high \200\231 BP is arbitrary. De \201 nition Perhaps the most useful de \201 nition is: Hypertension is a level of blood pressure which places an individual at increased risk of c ardiovascular events and, when treated, results in more bene \201 t than harm. SBP, pulse pressure, and CV risk SBP \200 Historically, DBP was thought the best predictor of CV disease. \200 It is now clear that SBP has a continuous independent relationship with stroke and IHD risk. It can be dif \201 cult to get SBP to target, particularly in the elderly. Pulse pressure (PP) and risk \200 PP is SBP minus DBP. \200 A wide PP more accurately p redicts adverse CV outcome than SBP or DBP. PP appears to be a marker of arterial stiffness. \200 PP may identify those with SBP at p articularly high CV risk. \200 At present, the majority of outcome data from clinical tri als is for SBP and DBP, so the major guidelines are based on these, rather than on PP. CHAPTER 6 Hypertension 452 Pathogenesis: general Introduction The great apes do not get i BP, nor do present-day hunte r-gatherer popu- lations (with a similar diet and lifestyle to that of our ancestors). It a ppears that there are important factors within our environment and diet that pre- dispose t o hypertension. Genetic in \202 uences are important but insuf \201 cient in isolation. The \201 nal common pathway in chronic i BP is i OH systemic vascular resistance (SVR). T he earliest event in the development of i BP is usually a rise in cardiac output (CO). i CO causes an increase in wall:lumen ratio in resistance vessels (to normalize wall stress). T his leads to a sustained rise in SVR and causes chronic i BP. CO is usually normal in those with established hypertension. BP = cardiac output (CO) x systemic vascular resistance (SVR) Central role of the kidney \200 Sodium excretion depends on renal perfusion pressure (the Guyton hypothesis). So i renal perfusion l pressure natriuresis. In i BP, the curve descri bing this relationship is pushed to the right (see Fig. 6.2). \200 In most people, the re nal pressure natriuresis curve is steep (a small increase in BP l large i in salt excretion). If this curve is shallower, BP will vary more widely with salt intake. This \200\230 salt-sensitive \200\231 i BP occurs more commonly in black patients and in CKD. Monogenic forms of i BP (rare!) suggest tubular ion transportation mechanisms are important mediators of blood pressure control. n o i t e r c x e m u d o S i Afferent arteriolar pressure Fig. 6.2 In the normotensive individual, salt balance is maintained at a normal BP. The slo pe of the curve is very steep such that dietary salt loading does not signi \201 cantly al ter BP. In hypertensive individuals, the curve is shifted to the right, though it remains p arallel. Thus, on a normal sodium diet, salt balance is maintained but at a higher BP. In s alt-sensitive individuals, the rightward shift is accompanied by a depression of the slope (not shown). Thus, not only is the BP set point on a normal diet elevated, but the BP also increases in response to dietary salt loading. PATHOGENESIS: GENERAL 453 Salt intake and blood pressure \200 There is a large body of evidence supporting the role of high salt intake in the development of i BP. Genetic disorders associated with i BP often affect salt regulation. \200 A high habitual salt intake is important for the development of the increase in BP with age. The effects of salt appear dose-dependent. \200 A key study, the Intersalt study, found t hat populations with a low intake of dietary sodium have a low prevalence of i BP. i BP is seen mainly in societies with a salt intake > 6g per day. Modest reduction in salt intake for people on a typical western diet results in a BP drop o f 5.3/3.7mmHg in hypertensive patients and 1.9/1.1mmHg in normotensives. Were salt intake to be reduced over many years, the population bene \201 ts would be substantial. The recommended intake is <6g/day salt. \200 The UK has led the way in reducing the salt content of food through public health programs and engagement with food manufacturers. The major challenge for consumers is to be aware of the amount of \200\230 hidden \200\231 salt in food. New labeling will hopefully go some way to help them to identify healthier food options. Endothelial dysfunction and nitric oxide i BP is associated with impaired endothelium-depen dent relaxation of the vessel wall. A number of factors in \202 uence endothelial function : \200 Nitric oxide (NO): NO l relaxation of vascular smooth muscle. Released by endothelium in response to shear str ess (i.e. blood \202 ow). Endogenous NO synthase (eNOS) l continuous normal basal release. Inducible iNOS l high concentrations of NO in response to in \202 ammatory cytoki nes. d NO has been reported in hypertensive patients (+ their offspring). Oxidative stress: free radicals scavenge NO, forming potentially toxic by-products. Radical s themselves (such as superoxide, O 2 \200\223 ) are potent vasoconstrictors. Prostaglandins: prostacyclin (PGI 2 ) is released by endothelial cells in response to shear stress and has a synergistic effect on tone with NO. Angiotensin II: a vasoconstrictor, also contributes to free radical generation and to endothelin release. Endothelins: potent vasoconstrictors, opposing the actions of NO. Also cause renal Na + ret ention, i aldosterone, vascular smooth muscle cell proliferation, cardiac hypertrophy, and \201 brosis. Their role in the pathogenesis of i BP is unclear. CHAPTER 6 Hypertension 454 Pathogenesis: genetics, arterial stiffness, and SNS Genetics Inheritance is not Mendelian. No one gene is responsible. Larger collabo- rative studies are providing information on sus ceptibility genes. Blood pressure levels are similar amongst close relatives (even those with \200\230 normal \200\231 range BP), suggesting alleles on several different genes may have an effect on B P. Rare monogenic causes of i BP have been identi \201 ed, using linkage analysis in affected families (see Box 6.1). Defects in these genes may also be important in essential hyperten sion (gene defects coding the B and G subunits of the epithelial Na + channel (linked to Li ddle \200\231 s syndrome) are associated with BP variations in the general population). Research focus has been on likely culprit genes (esp. the angiotensino- gen gene) and is now looking at genome-wide associations. Genes that have been associated with essential i BP include: ACE polymorphisms (I/I and I/D phenotypes associate with salt-sensitive hypertension). A -adducin polymorphisms \200\224 a cytoskeletal protein which regulates ion transportatio n in the renal tubule. Polymorphisms may relate to salt sensitivity, diuretic sensitivity, and essential hypertension. 11 B -hydroxysteroid dehydrogenase (GG phenotype correlates with salt sensitivity). AT-1 receptor gene \200\224 in experimental studies, AT-1a +/+ mice have higher blood pres sures than \200\223 / \200\223 mice. Clinical relevance unknown. Box 6.1 Rare single-gene causes of hypertension \200 Liddle \200\231 s syndrome: mutatio ns affect the epithelial sodium channel (ENaC). Autosomal dominant, with i BP characterized by d renin, d aldosterone, and d K + ( b p. 801). Glucocorticoid-remediable aldosteronism ( b p. 478). \200 Syndrome of apparent mineraloco rticoid excess ( b p. 480). \200 Pregnancy-associated hypertension: a gene defect l parti al activation of the mineralocorticoid receptor by progesterone (rare). \200 Phaeochromocytoma: may occ ur with one of the following: Multiple endocrine neoplasia type 2A: mutations in the RET proto-oncogene. Autosomal dominant. Phaeochromocytoma, medullary thyroid carcinoma, and hyp erparathyroidism.