Renal transplantation

Renal transplantation - technical

Topics covered:

  • Summary
  • Introduction
  • Supply, demand and kidney donation
  • Recipient assessment
  • Allocation of kidneys
  • Surgical technique
  • Postoperative management
  • Complications of renal transplantation
  • Immunosuppressive regimens
  • Specific side effects of particular immunosuppressive agents
  • General side effects of immunosuppression
  • Other post-transplant complications
  • Outcome of renal transplantation
  • Other aspects of medical management of transplant recipients

Summary

Renal transplantation is the preferred option for the treatment of endstage chronic renal failure in patients for whom there are no major medical contraindications. In well-selected recipients, both life expectancy and quality of life are superior to treatment with long-term dialysis. However, as the dialysis population continues to grow, the gap between supply and demand for renal transplantation is widening. Attempts to bridge this gap have included (1) relaxation of the criteria for a suitable deceased donor (expanded/extended criteria or 'marginal donors'); (2) reversion to the procurement of kidneys from donors with cardiac death (DCD donors, previously known as non-heart beating donors); and (3) encouragement of living donation—including techniques for desensitization of recipients, also paired exchanges, both to circumvent blood group incompatibilities or preformed antibodies that would otherwise bar transplantation.

Technical aspects

Surgery—the new kidney is placed in one or other iliac fossa, usually in an extraperitoneal position that allows ease of repeated biopsy to detect cause of graft dysfunction. Typically, the renal artery is anastomosed end to side to the common iliac artery or end to end to the internal iliac artery, the renal vein to the common iliac vein, and the transplant ureter is implanted into the bladder through a submucosal tunnel. The native kidneys are left in situ unless there are particular reasons for them to be removed in a separate pretransplant operation.

Immunosuppression—excepting for transplants between HLA-identical twins, immunosuppression is required to prevent rejection, but there is no clear consensus on the best immunosuppressive regimen. Most centres use an induction antibody directed against CD25 (the IL-2 receptor), followed by what is now called standard triple therapy—comprising a calcineurin inhibitor (CNI) (ciclosporin or tacrolimus), combined with either mycophenolate mofetil or azathioprine, and steroids. Steroids are not infrequently tailed off rapidly in the early post-transplant period.

Transplant rejection

This can be classified into four main categories:

  1. hyperacute—due to preformed cytotoxic antibodies, always leads to very rapid graft failure;
  2. accelerated—a predominantly T-cell-mediated rejection crisis occurring within the first few days, cannot usually be treated satisfactorily;
  3. acute cellular—due to a primary cell-mediated response, occurs in 10% to 20% of recipients, manifests histologically as tubulitis, first-line treatment (usually successful) with intravenous steroids;
  4. humoral—antibody-mediated, manifest histologically as marked staining for the complement breakdown product C4d in peritubular capillaries, best treatment uncertain.

Complications of renal transplantation

Specific side effects of immunosuppressive agents—these are important causes of morbidity and (rarely) mortality, with steroids culpable for many of the complications of transplantation, and nephrotoxicity being the main drawback of CNIs. The desire to overcome these problems is one of the main drivers in the search for new immunosuppressants and immunosuppressive regimens.

Nonspecific side effects of immunosuppressive agents—all currently available immunosuppressive regimen are nonspecific in the sense that they suppress not only the immune response to the allograft, but also the immune response to infections and tumours.

Infective complications—transplant recipients are vulnerable to opportunistic infections including:

  1. viral infections—particularly cytomegalovirus (the main infectious complication in solid organ transplantation, with manifestation ranging from asymptomatic viraemia to life-threatening multiorgan failure), Epstein–Barr virus (EBV or HHV4), varicella zoster virus, herpes simplex, human polyomavirus (especially BK, which can lead to nephropathy and graft failure), human papillomavirus (HPV), and HIV;
  2. bacterial infections—particularly mycobacterial, nocardia, nontyphoid salmonella, listeria;
  3. fungal infections—including candidiasis and aspergillosis aspergillus and pneumocystis (a dreaded complication of transplantation before routine introduction of prophylaxis with co-trioazole or pentamidine);
  4. parasitic infections—including Strongyloides stercoralis, scabies, and toxoplasmosis.

Malignant complications—post-transplant neoplasia is an important cause of morbidity and mortality. Particular conditions include:

  1. post-transplant lymphoproliferative disorder (PTLD)—driven by EBV, first-line treatment by stepwise reduction in immunosuppression;
  2. Kaposi’s sarcoma—caused by HHV8, first-line treatment by switch of immunosuppression to sirolimus;
  3. HPV—responsible for skin, vulval, and anogenital warts, and some types are associated with carcinoma. After 20 years, most renal transplant recipients who are white will have cutaneous squamous cell carcinoma.

Other complications—these include hypertension, accelerated atherosclerosis, electrolyte, musculoskeletal, haematological, gastrointestinal, and cosmetic disorders.

Prognosis

The short-term outcome of renal transplantation has improved markedly over the last 30 years, with 1-year graft survival around 90%. However, the rate of chronic graft-loss remains at about 4% per year, with the descriptive term ‘chronic allograft nephropathy’ commonly (but unhelpfully, because it does not imply a mechanism or aid management) being applied to the failing graft. The commonest cause of insidious late graft failure is probably calcineurin toxicity, which by 10 years probably affects nearly all exposed grafts to some degree. Conversion from CNIs to either mycophenolate mofetil or sirolimus can prolong graft survival, and is being used increasingly in many centres.

Introduction

Renal transplantation is the preferred option for the treatment of endstage chronic renal failure in patients for whom there are no major medical contraindications. With improvements in immunosuppression and in the equally important general medical support of the immunocompromised patient, the age ranges and permissible comorbidities of recipients continue to be extended. In well-selected recipients, both life expectancy and quality of life are superior to long-term dialysis. The two impediments to the extension of transplantation are the shortage of donor organs and the side effects of the still crude immunosuppressive agents. Xenotransplantation may remove the first of these hurdles, but is likely to increase our dependence on potent immunosuppressive regimen. In humans, immunological tolerance to the graft with preservation of normal immunoresponsiveness to infections and tumours has not yet been achieved.

Supply, demand and kidney donation

On 31 March 2010 there were just under 7000 patients waiting for a kidney transplant in the United Kingdom. In the previous 12 months, 1482 patients had received a kidney from a deceased donor, 1058 a kidney from a living donor, and 160 a combined simultaneous pancreas and kidney transplant. In the past, the proportion of transplants performed in the UK from living donors was less than elsewhere, but this is no longer the case: in 2004/5 they accounted for 35% of all UK renal transplants, rising to 41% in 2009/10. This compares with 37% in the United States in 2008 and similar values in most European countries.

The dialysis population continues to grow, with the gap between supply and demand for renal transplantation widening and the waiting list growing by about 3% per year. Attempts to bridge this gap have included a relaxation of the criteria for a suitable deceased donor (expanded/extended criteria donors, previously termed marginal donors), increasing usage of kidneys obtained from donors after cardiac death (DCD donors, previously called non-heart beating donors), and—when histological assessment of biopsies taken from explanted kidneys shows them to have features that would make them 'borderline' for use—transplantation of both kidneys from a single donor into one recipient (dual kidney grafts).

In the United Kingdom, new legislation (the Human Tissue Act 2004) has helped facilitate living donation from both related and unrelated donors, and any significant increase in kidney transplantation seems most likely to come from increased living donation. It is now safe and effective to transplant across blood group incompatibility barriers by removal and suppression of recipient blood group antibodies using various combinations of antibody removal (plasma exchange or specific immunoabsorption) and suppression of antibody formation (most commonly with rituximab, an anti-CD20 monoclonal antibody) with or without intravenous immunoglobulin (IVIG). Transplantation can go ahead once antibody titres have been suppressed, but further cycles of treatment may be needed in the early post-transplant period.

The use of paired living donation is also increasing in many countries, including the United Kingdom. The principles are straightforward: A wishes to give a kidney to B, but is prevented from doing so because they are immunologically incompatible; C wishes to give a kidney to D, but again is prevented from doing so because of immunological incompatibility; however, A is not incompatible with D, and C is not incompatible with B, hence a paired exchange can be organized such that A gives to D and C to B, hence blood group incompatibilities or preformed antibodies that would otherwise bar transplantation are circumvented. Depending on local regulatory arrangements there can be several interlinked pairs.

A further possibility is altruistic donation, in which an individual offers a nondirected kidney for transplantation. It would be possible to use this to start a series of paired donations, and this is permitted in some countries. Another proposal (not implemented) is that by donating a kidney to the national pool, a family member might secure the highest possible priority for the next suitable kidney for their relative.

Living donors

Every care must be taken to protect the interests of the donor. Informed consent is crucial. Potential donors must be aware that giving a kidney carries risks, albeit the mortality rate is only 0.01 to 0.03%, with most deaths attributable to acute pulmonary embolus. The other risks that are involved in a general anaesthetic and an abdominal operation must also be fully explained. Increasing use of laparascopic kidney retrieval in live donors has done much to improve donor acceptability and speed postoperative recovery. Needless to say, a donor should be in good general physical health and have normal kidney function and surgically acceptable renal anatomy. The assessments required are summarized in Bullet list 1. Apart from exceptional circumstances, donors outside the age limits of 18 to 70 years are not considered. It is usual to wait for a young female potential donor to complete her family.

Bullet list 1 Assessment of the potential living donor

  • Medical history
  • Psychiatric and psychosocial history—including at-risk behaviour
  • Physical examination
  • Blood group (ABO)
  • Tissue typing
  • Lymphocyte crossmatch (recipient serum against donor lymphocytes)
  • DNA testing to prove family relationship (where relevant)
  • Urine:
    • Stick testing—blood, protein, glucose, leucocytes, nitrites
    • Culture and microscopy
    • Quantify protein excretion (albumin:creatinine ratio)
    • Creatinine clearance
  • Blood:
    • Glucose—formal glucose tolerance testa
    • Electrolytes
    • Urea, creatinine, uric acid
    • Liver function tests
    • Full blood count
    • Glucose-6-phosphate dehydrogenasea
    • Haemoglobin, electrophoresisa
    • Sickle testa
    • Procoagulant screena
  • Infection screen
    • HIV
    • HTLV 1 and 2
    • Cytomegalovirus (HHV5)
    • Epstein–Barr virus (HHV4)
    • Hepatitis B virus
    • Hepatitis C virus
    • Kaposi’s sarcoma virus (HHV8)a
    • Syphilis
    • Toxoplasmosis
    • Schistosomiasisa
    • Malariaa
    • Trypanosoma cruzia
    • Strongyloides stercoralisa
  • Chest radiograph
  • ECG
  • Cardiac stress testinga
  • Glomerular filtration rate estimation by isotopic method
  • Renal imaging:
    • Ultrasound and DMSA scan
    • Donor renal arteriogram (MRA or CT)
  • Informed consent, assessment by independent assessor (Human Tissue Act) (legal requirements vary from country to country)

a Where clinically indicated, such as specific geographical or other risk.

Most studies have shown an increase in life expectancy of donors when compared with age-matched controls. A few donors will develop hypertension, but at a risk that is similar to that of the general population. A small number develop proteinuria, but this is usually less than 0.5 g/24 h and does not affect survival. Renal function usually returns to 75 to 80% of the predonation level.

The use of living kidney donors is driven not only by the shortage of cadaver organs for transplantation, but also by the fact that these kidneys do better than those from a deceased donor. This is partly due to better matching, with many related donors and recipients sharing one or two extended haplotypes, but an additional benefit—shared also by kidneys from living unrelated donors, which similarly out perform those transplanted from cadavers—is the physiological state of the organ when recovered under ideal and planned conditions, and without the necessity for prolonged cold storage.

Deceased donors

In this situation the prime responsibility is to the potential recipient. The kidney should be in as good a physiological state as possible, and there should be no obvious risk of transfer of infection or malignancy by the donor organ. The major contraindications to organ procurement are listed in Bullet list 2. Expanded/extended criteria donors are increasingly being considered, particularly for older recipients and for those with a limited life expectancy. In some situations it may be appropriate to consider organs from hepatitis C (HCV)-positive or hepatitis B (HBV)-positive donors for positive recipients.

Bullet list 2 Contraindications to cadaver organ procurement

  • Donor age:
    • <3 years (en bloc dual transplant possible)
    • >70 yearsa
  • Cancer not confined to the central nervous system (CNS), but note:
    • Nonmelanoma skin tumours and carcinoma in situ of the uterine cervix are permissible
    • Cancer confined to CNS is acceptable, excepting medulloblastoma and glioblastoma
  • Risk of transmissible infection:
    • At-risk behaviour
    • HCV
    • HBV
    • HIV
    • HTLV 1, 2
    • HHV8
    • Deep fungal infections
    • Parenchymal renal infection
    • Meningoencephalitic syndromes of unknown aetiology
    • Inadequately treated bacterial infection
    • Infection with resistant organisms (e.g. MRSA, VRE, ESBL)
  • Diabetes mellitusa
  • Acute kindey injuryb
  • Hypertensiona
  • Chronic kidney disease
  • Warm ischaemia >90 min
  • Cold ischaemia >30 ha

ESBL, extended-spectrum β-lactamase producer; HTLV, human T-cell lymphocytotrophic virus; MRSA, methicillin-resistant Staphylococcus aureus; VRE, vancomycin-resistant enterococcus.

a Relative contraindication.

b Donors with acute tubular necrosis (proven by biopsy of the explanted kidney) will often be used.

Experience in parts of the world where safe long-term dialysis is not available have shown that an acceptable quality of life can be sustained with less than perfect kidneys, and—given the shortage of organs—expanded/extended criteria donors should not be discarded out of hand without discussion with the local transplant unit. When there is doubt about the suitability of kidneys for transplantation, either because of the age and comorbidities of the donor, or the circumstances of their death, or the fact that they are a donor with cardiac death, it has become standard practice for biopsies of the explanted kidneys to be assessed histologically before a decision is made as to whether they should be used. A widely used histological scoring system enables kidneys to be classified into three groups: those that can be used, those that should not be used, and those that are 'borderline', which many transplanting centres would use for dual transplantation, when both kidneys from a single donor are given to a single recipient.

Many involved in the process of renal transplantation think that prospective recipients of expanded/extended criteria or otherwise 'borderline' kidneys should have the opportunity to discuss these possibilities with the transplant team and decide whether or not they wish to receive such organs. However, there is no time for adequate discussion and consideration when the kidney is sitting in a box of ice waiting to be transplanted (or not). Such discussions really need to occur at the time that patients go onto the renal transplant waiting list, and in some countries patients can be listed for 'standard kidneys only' or 'standard and expanded/extended criteria kidneys'. Such arrangements should be encouraged.

Recipient assessment

Patients may be transplanted before the need for dialysis (pre-emptive transplantation) or from an established dialysis programme (haemodialysis or peritoneal dialysis). It is essential that all patients are fully assessed by both a transplant surgeon and transplant physician before being placed on the waiting list or offered a kidney, whether it be from a cadaver or a relative. Patients with chronic renal failure develop a multitude of complications that need assessment before surgery. Transplantation carries with it the risks of any major surgical procedure, together with the added risks of prolonged immunosuppression.

An additional consideration is that, given the shortage of organs for transplantation, it is important that the best use is made of all organs. Although everyone would agree with this in principle, making decisions in individual cases can be difficult. In some situations the general health and life expectancy of the potential recipient argue strongly against transplantation. Patients with congenitally abnormal lower urinary tracts can be difficult to transplant and ideally should be managed in centres with urological transplant expertise, some needing complex bladder augmentation or drainage procedures before transplantation.

Since the main cause of death post transplant is cardiovascular, it is important to screen at-risk patients for occult vascular disease (carotid, aortoiliac, peripheral, and cardiac). This is particularly true for patients with diabetes mellitus, for whom coronary angiography and appropriate intervention are particularly likely be required.

Recipient hepatitis (HCV or HBV) complicates transplantation. Without antiviral therapy, immunosuppression accelerates liver disease and death may occur within 5 to 10 years of transplantation, usually from sepsis or progressive liver disease, particularly in the case of HBV. The advent of effective antiviral therapy has greatly improved the outlook. Attempts should be made to clear hepatitis C prior to renal transplantation (the use of interferon after renal transplantation is contraindicated as it is likely to trigger acute allograft rejection.) There are now a number of effective oral agents for the treatment of HBV which can be used after renal transplantation particularly in combination. In the setting of advanced liver disease (cirrhosis and ascites) assessment for a combined liver and renal transplant may be appropriate.

There are an increasing number of people with HIV infection who have end stage renal disease, many of whom would wish to consider renal transplantation if this can be performed safely. A recent study showed that this is possible for carefully selected patients. The outcomes for 150 patients with HIV—all on stable highly active antiretroviral therapy (HAART), with CD4+ T-cell counts above 200/ml, and with undetectable plasma HIV-1 RNA levels—fell between those reported for all kidney transplant recipients and those of recipients aged over 65.

Allocation of kidneys

Fully matched kidneys (zero A, zero B, and zero DR mismatch—denoted 0–0–0 mismatch) and DR identical kidneys do better than less well-matched organs, hence most countries have local or national kidney sharing schemes so that more recipients can receive the benefits of a well-matched organ. Use is increasingly being made of point scoring systems to allocate kidneys fairly, patients accruing points based on the degree of match as well as the length of time they have been waiting for a transplant.

Although there is no strict upper age limit for transplantation, it is relatively unusual to transplant patients over the age of 70 years because of increasing comorbidities. Whenever possible both age and size matching are important so that an adequate nephron mass is provided, but these are not features of most organ allocation algorithms.

Surgical technique

The new kidney is placed in one or other iliac fossa, usually in an extraperitoneal position that allows ease of repeated biopsy to detect cause of graft dysfunction. The renal artery is anastomosed end to side to the common iliac artery or end to end to the internal iliac artery. The renal vein is usually anastomosed to the common iliac vein. The transplant ureter only has a short distance to run before it can be implanted into the bladder, which is usually done through a submucosal tunnel to reduce the chances of reflux of urine from the bladder into the transplant. Some surgeons routinely place a vesicoureteric stent to reduce the risks of urine leakage and to promote healing. A drain is usually placed near the renal hilum. Lymphatics in the perihilar region are tied off. A urethral catheter and/or suprapubic bladder catheter is inserted and left in situ for about 5 days. The ureteric stent is removed at cystoscopy after a few weeks. Most units use prophylactic low-molecular-weight heparin (LMWH) routinely.

Note that in the standard renal transplant operation described above the native kidneys are left in situ. In some patients one or both may need to be removed (at a separate operation) before the patient can be listed for transplantation: mandatory indications for this include suspicion of renal tumour (usually in those with cystic disease), chronic renal infection, and massive organomegaly in patients with adult polycystic kidney disease, when there is literally no space in which to put a new kidney. Some would also advocate nephrectomy as a prelude to transplantation in those with gross ureteric reflux, persistent upper tract infection, renal stone disease, or analgesic nephropathy. Pretransplant nephrectomy is also recommended in patients with persistent gross nephrotic syndrome in order to correct the procoagulant state.

Retransplantation is increasingly being undertaken as the general medical care of patients with renal failure has improved. Second transplants are now not uncommon, and even third and fourth transplants may be occasionally undertaken. Third and fourth transplants are more surgically demanding, as vessels available for anastomosis become limited. Aortic and venocaval anastomoses can be performed.

Ischaemia times

Warm ischaemia is defined as the time between circulatory arrest and renal artery cannulation for ice-cold perfusion, together with the time between the removal of the kidney from ice and release of the vascular clamps at implantation. With the beating heart donor, the first component is zero. The maximum permissible warm ischaemia time before irreversible damage occurs is 60–90 min.

Cold ischaemia time (preservation time) is defined as the time between ice-cold perfusion of the kidney and removal from the ice at the start of the implantation operation. Cold ischaemia times of up to 96 h have resulted in functioning grafts, but times in excess of 20 h are associated with a less favourable outcome. The permissible cold ischaemia time of 20 h allows for organ sharing and suitable operating times for the surgical teams.

Given the increasing use of DCD donors, there is a trend for machine perfusion after procurement to attempt both to improve the graft and also to identify which kidneys are actually unsuitable for implantation.

Postoperative management

Excepting for transplants between HLA-identical twins, immunosuppression is required to allow transplantation. The first dose of this is often given pre- or intraoperatively. Details are discussed below.

Following implantation, the function of the new kidney is assiduously monitored. The use of dopamine and/or mannitol in the immediate postimplantation period has now virtually ceased as there is no evidence of benefit. Furosemide may be given to provoke a urine output for ease of management, but again there is no convincing evidence of benefit as far as improving glomerular filtration rate is concerned.

Hourly urinary volumes are closely monitored for the first few days. Fluid balance is usually maintained by a prescription that requires 100% replacement of urinary volumes and drain losses with crystalloid, and central venous pressure is monitored and maintained in the high normal range (+10 cmH2O) with blood or colloid.

Serum creatinine is measured at least daily. A failure to fall rapidly, or a 15% rise once it has fallen to a plateau, is evidence of graft dysfunction and requires prompt investigation. A kidney that fails to function initially, despite good perfusion on the table when the vascular clamps were removed, is usually suffering from acute tubular necrosis, which is expected to recover. A sudden cessation of urine flow usually means a surgical problem, e.g. clot obstruction, urinary leak, or vascular catastrophe. A slow tailing-off of the urinary volumes is more suggestive of rejection, hypovolaemia, or developing drug nephrotoxicity. Two of the major immunosuppressive agents, ciclosporin and tacrolimus, are nephrotoxic: doses have to be carefully adjusted to maintain the therapeutic range. Blood pressure should be returned to normal, obstruction excluded, and coagulation checked before any diagnostic biopsy is undertaken. Close and careful monitoring needs to continue for the first 6 months after transplantation as the risk of rejection is at its greatest during this period.

One of the ‘holy grails’ of transplant medicine is a method of determining the immunological relationship between the recipient and their transplanted organ, since this would allow tailoring of immunosuppression to immunological need. However, immunological monitoring of transplant recipients is still in its infancy: lymphocyte T- and B-cell subsets and activation markers can be of value, particularly when antilymphocyte preparations are being used; serial estimation of post-transplant anti-HLA antibodies can help predict patients at risk of humoral rejection. Much work continues to look for better ways of monitoring patients, such as testing for cytokine gene polymorphisms to predict those at highest risk of rejection, and examination of graft biopsies for alterations in gene expression and the expression of adhesion molecules, HLA, cytokines, and enzymes (e.g. granzyme, perforin) to better characterize the rejection process. Protocol biopsies may demonstrate subclinical rejection, and there is limited data that treatment of these may improve outcome. However, the optimum frequency and timing of protocol biopsies is yet to be determined, their benefits (if any) have to be weighed against their risks (certainly present), and they are not routine practice in most transplant centres. What is abundantly clear is that chronic damage and interstitial scarring with tubular atrophy is present within the first few months of transplantation, and that after 5 to 10 years evidence of nephrotoxic damage from the calcineurin inhibitors (CNI) is almost universal.

Complications of renal transplantation

Surgical

Table 1 summarizes the main surgical complications of transplantation, which include those of any general anaesthetic and laparotomy. Extra risk is added because patients on dialysis are immunosuppressed by uraemia per se, and transplant patients also require immunosuppressive drugs following surgery. Wound healing is significantly delayed in the early post-transplant period by steroids, and particularly by sirolimus, which for this reason is rarely used in transplantation practice until wounds have healed.

Table 1 Complications of renal transplantation
Surgical Medical
Wound infection (<1%) Infections transmitted by graft
Wound haematoma Opportunistic infections
Perirenal: (collections → infections) Specific complications of immunosuppression
 Lymph (1–5%) Complex aetiologies:
 Haematoma  Accelerated vascular disease
 Urine  Hypertension
Vascular catastrophe: (arterial or venous)  Electrolyte disturbances
 Haemorrhage  Cosmetic
 Thrombosis (1% arterial/1–6% venous)  Thromboembolism
Segmental artery occlusions:  Erythrocytosis
 Ischaemia → hypertension (2%)  Marrow suppression
 Infarction → calyceal fistula  Liver dysfunction
Devitalization of ureter: (stripping)  Neoplasia
 Sloughing  Metabolic bone disease
 Ischaemic stricture  
Urinary leaks:  
 Cystotomy  
 Ureteric–bladder dehiscence  
Venous thromboembolism/PE (8%)  
Pancreatitis  
Urinary sepsis

On review of a patient’s predialysis and dialysis career it may be apparent that the patient has a procoagulant state (e.g. systemic lupus erythematosus, numerous thrombotic episodes involving vascular access, a past history of deep venous thombosis or pulmonary embolus). Such patients should have a full procoagulant work up before transplantation, and, if appropriate, be offered post-transplant anticoagulation. It is also of note that both the CNIs have a procoagulant effect.

Rejection

Rejection can be classified into four main categories (Table 2): these are not mutually exclusive and there is overlap in the pathological processes.

Table 2 Classification of transplant rejection
  Hyperacute Accelerated Acute cellular Humoral
Timing Minutes 1–5 days 5 days–3 months Variable
Mediators
  • Preformed antibodies
  • Complement
Sensitized cells and antibodies Primary cell-mediated response
  • Antibodies
  • Complement
Histology
  • Infarction
  • Platelets
  • Fibrinogen
  • Polymorphs
  • Tubulitis
  • Endovasculitis (acute)
Tubulitis
  • Obliterative chronic endovasculitis
  • Transplant glomerulopathy
  • Splitting at tubular basement membrane
Treatment Nephrectomy
  • Serotherapy salvage?
  • Plasma exchange
High-dose intravenous steroids
  • Upgrade to tacrolimus and MMF
  • Consider plasma exchange
  • IVIg, rituximab

NB: Cellular and humoral rejection can coexist.

Hyperacute rejection

In the presence of preformed cytotoxic antibodies the new graft infarcts within minutes of insertion. This can occur if transplantation is attempted across ABO incompatibilities without appropriate antibody removal/immunosuppressive therapy. It is a rare event, as the lymphocyte crossmatch usually identifies pre-existing anti-HLA antibodies. Transplantation is not undertaken in the presence of a positive lymphocyte crossmatch, but hyperacute rejection can rarely occur in the presence of non-HLA cytotoxic antibodies. There is no treatment except nephrectomy.

Accelerated rejection

A fierce, predominantly T-cell-mediated rejection crisis may occur within the first few days of transplantation. This is thought to be due to sensitization of the recipient by a previous pregnancy, blood transfusion, or a failed transplant. Patients present clinically with fever, an acutely swollen tender graft, and a rapidly rising serum creatinine. Salvage usually requires the combination of high-dose intravenous pulse methylprednisolone (10–15 mg/kg per day infused over 30 min on 3 successive days) and an antilymphocyte antibody such as antithymocyte (ATG) or antilymphocyte globulin (ALG), with the murine monoclonal antibody OKT3 used as an alternative. It is unusual to be able to reverse fully this type of severe rejection and long-term graft survival is compromised.

Acute cellular rejection

In most centres about 10 to 20% of patients will experience an acute cellular rejection, usually occurring between days 7 to 21, but up to 3 months after transplantation. Acute cellular rejection is often clinically silent, as the inflammatory component of the rejection is masked by immunosuppression. Fluid retention, increasing hypertension, and a sharp rise in creatinine are typical. Assessment of renal perfusion (Doppler ultrasonography or renography studies) may show a dramatic reduction in graft perfusion, but these tests are not sensitive or specific enough for a confident diagnosis of rejection. Most centres routinely take kidney biopsies for all episodes of graft dysfunction once infection, toxic levels of the CNIs and urinary obstruction have been excluded. Obtaining a histological diagnosis is very important since several processes can mimic rejection, including drug nephrotoxicity, bacterial pyelonephritis, recurrence of original disease, BK virus-induced interstitial nephritis, and post-transplant lymphoproliferative disorder (PTLD). The hallmark of acute cellular rejection is tubulitis, in which the invading lymphocytes have penetrated the tubular epithelial cell basement membrane and directly engage tubule epithelial cells. Late acute rejection episodes usually imply inadequate immunosuppression, sometimes due to poor compliance. Treatment is very effective and usually involves a bolus of intravenous steroid therapy as described above. Long-term graft survival is severely jeopardized if the rejection episode is not completely reversed. With some of the newer, very potent induction regimes, the incidence of acute rejection episodes can be reduced to less than 5 to 10%, but whether this will lead to better long term outcome, or translate into a higher rate of infection and neoplasia, awaits further follow-up.

Humoral rejection

Humoral rejection implies an antibody mediated attack on the graft. Histologically the biopsy reveals splitting and reduplication of tubular basement membrane, an hypercellular glomerulus with double basement membranes (so-called ‘transplant glomerulopathy’), and a polymorph infiltration in the peritubular capillaries and glomeruli. Blood vessels show acute endothelial damage and may sometimes appear involved in a vasculitic process. Marked staining for C4d (a complement breakdown product) in the peritubular capillaries (involving >50%) is taken as evidence of an antibody-mediated attack on the graft. In some cases the patient may also have elevated levels of anti-HLA antibodies in the circulation, sometimes donor specific, which can now be detected by sensitive techniques. About 20% of patients develop circulating anti-HLA antibodies and these patients have a threefold increased rate of graft loss. Treatment may involve plasma exchange, IVIG, increasing tacrolimus, or adding in mycophenolate mofetil, and possibly plasma exchange. Some units have used rituximab, particularly if the rejection is acute.

‘Chronic rejection’

The term ‘chronic rejection’ has been used for many years and is so poorly defined that it is of little value. Similarly, the term ‘chronic allograft nephropathy’ defines a light-microscopic appearance in the graft that has so many possible causes as to be of little practical help. Neither ‘chronic rejection’ nor ‘chronic allograft nephropathy’ represents a specific entity for which specific therapy can be prescribed. What is clearly of major importance is to define the pathological process in as much detail as possible so that appropriate therapy can be chosen.

Immunosuppressive regimens

There is no clear consensus on the best immunosuppressive regimen for renal transplantation, and for commercial reasons the large multicentre trials that the community of transplant physicians and surgeons would most like to see performed are unlikely ever to be funded. The choice of agents available is summarized in Table 5 (below).

Most centres worldwide use what is now called standard triple therapy, comprising a CNI (ciclosporin or tacrolimus), combined with either mycophenolate mofetil or azathioprine, and steroids. Steroids are not infrequently tailed off rapidly in the early post-transplant period. Most units also use an induction antibody directed against CD25 (the interleukin 2 (IL-2) receptor).

Agents of established efficacy for induction therapy include polyclonal antibodies such as antithymocyte globulin (ATG) or antilymphocyte globulin (ALG), and the murine monoclonal antibody OKT3. Two anti-CD25 antibodies, daclizumab and basiliximab, which bind to the nonsignalling α-chain of the IL-2 receptor, have largely replaced these older agents. Both are heavily engineered antibodies, comprising a murine antigen-binding site and human immunoglobulin. Both are very effective and have been shown to reduce acute rejection episodes by about 30%.

A number of newer immunosuppressive regimen are in development to lessen our dependence on the nephrotoxic CNIs and steroids, which are responsible for much post-transplant morbidity. The potent monoclonal antibody alemtuzumab (anti-CD52) has been used as an induction agent followed by low-dose tacrolimus or low-dose ciclosporin, with or without mycophenolate mofetil, and very early steroid withdrawal (or avoidance altogether). Preliminary results are very encouraging, with a low acute rejection rate (although acute rejection may be delayed), and no apparent price to pay by way of increased infection or cancer. Rituximab (directed against the CD20 antigen) may have a role as an induction agent as well as in salvage from antibody-mediated rejection.

A variety of biological agents has been tried and are in development for blockade of the costimulatory pathways involved in the initiation of the immune response, the hope being that we can reduce our dependence on the nephrotoxic CNIs and use much less steroids to avoid later side effects and complications.

Many centres are now exploring the possibility of tailoring immunosuppression to the needs of the individual recipient, but as described above we are not good at assessing immunological risk. In practice this involves giving immunosuppressants that are perceived to be more powerful to those recipients perceived at greatest risk, e.g. using tacrolimus instead of ciclosporin, mycophenolate mofetil instead of azathioprine, or adding antibody induction. These would include patients who are highly sensitized, have rejected a previous transplant, or have suffered an acute rejection episode.

The best long-term immunosuppressive therapy is equally in doubt. This is partly due to the nephrotoxicity of two of the main agents employed for the prevention of rejection: both ciclosporin and tacrolimus can produce a nodular arterioleopathy resulting in ischaemic renal damage and graft loss. It is also clear that the morbidity and mortality from long-term steroid therapy is significant, such that many centres are now attempting steroid-free immunosuppression or withdrawing steriods by day 5 to 10. Other centres are reducing or withdrawing steroids at 3 to 6 months despite the associated risk of rejection, which has been reported to be as high as 30% if background immunosuppression is inadequate. The risks of steroid withdrawal are less if induction therapy has been used and if patients are maintained on a CNI and an antiproliferative agent.

Unfortunately, it is not possible to predict who is going to reject on withdrawal of steroids, hence one of the main aims of those developing new immunosuppressive drugs and regimens is to devise agents or protocols that allow less dependence on steroids without increased rates of rejection or other unacceptable toxicities.

Specific side effects of particular immunosuppressive agents

Steroids

Steroids are responsible for many of the complications of transplantation (Bullet list 3). In recent years the dose of steroids used has been safely reduced, thanks in part to the introduction of the CNIs, but attempts to produce totally steroid-free transplantation are only successful in about two-thirds to three-quarters of cases. One of the most significant side effects of steroids is that they mask the inflammatory response so that symptoms sometimes develop late, which is particularly important in cases of intra-abdominal catastrophy such as a perforated hollow viscus.

Bullet list 3 Side effects of steroids

  • Acne
  • Hypertrichosis
  • Redistribution of body fat
  • Obesity
  • Cushingoid facies
  • Insulin resistance—diabetes mellitus
  • Hypertension
  • Hyperlipidaemia
  • Proximal myopathy
  • Osteoporosis—avascular necrosis of bone
  • Tendon ruptures
  • Poor wound healing
  • Skin atrophy/fragility/easy bruising
  • Scleromalacia
  • Growth inhibition: premature fusion of the epiphyses
  • Erythrocytosis
  • Cataracts
  • Benign intracranial hypertension
  • Psychosis
  • Peptic ulceration
  • Colonic perforation
  • Pancreatitis

Calcineurin-blocking drugs

The main drawback of both ciclosporin and tacrolimus is nephrotoxicity (Table 3), which adds another level of complexity to the differential diagnosis and management of both acute and chronic graft dysfunction. Most consider tacrolimus to be more potent than ciclosporin, but perhaps more toxic (diabetes mellitus and neurotoxicity). It does, however, have real cosmetic advantages over ciclosporin, perhaps mediated by lower levels of transforming growth factor β (TGFβ). New-onset diabetes after transplantation (NODAT) occurs in about 10% of patients on ciclosporin but 15% of patients on tacrolimus.

Table 3 Side effects of calcineurin inhibitors—relative risk
Side effect Ciclosporin Tacrolimus
Nephrotoxicity ++ ++
Hypertension/sympathetic overactivity ++ +
Hyperuricaemia ++ ++
Hyperkalaemia (type IV renal tubular acidosis) + +
Hypomagnesaemia (urine leak) + +
Haemolytic uraemic syndrome + +
Platelet hyperaggregability +
Insulin resistance → diabetes mellitus + +/++
Dislipidaemia + ±
Hepatoxicity + +
Breast fibroadenosis +
Coarsening of facial features +
Gum hypertrophy +
Hypertrichosis +
Distal limb pain/periostitis + ±
Cardiotoxicity +
Neurotoxicity: + ++
 Fits + +
 Ataxia + +
 Posterior fossa leucoencephalopathy + +
 Paraesthesiae   +
 Tremor + +
Neoplasia ++ +
Infection + +

Azathioprine and mycophenolate mofetil

Both agents block purine synthesis. The main side effects of azathioprine are hepatotoxicity and bone marrow suppression (Table 4). Mycophenolate mofetil is more potent and more specific than azathioprine, blocking purine synthesis in lymphocytes. Its most troublesome side effects are abdominal colic and diarrhoea: about 10% of patients are so badly affected that they are unable to tolerate the drug. A higher incidence of invasive cytomegalovirus (CMV) disease has been associated with mycophenolate.

Table 4 Side effects of azathioprine and mycophenolate mofetil
Side effect Azathioprine Mycophenolate mofetil
Hepatotoxicity ++ +
Marrow suppression: ++ ±
 Platelets ± ±
 Red cells ±
 Granulocytes ++ ±
Megaloblastic anaemia +
Gut toxicity ± ++
Pancreatitis +
Hypogammaglobulinaemia ± +
Lung fibrosis + ±
Alopecia +
Infection + +/++
Cancer + ±

Serotherapy

A range of antibodies to lymphocytes is available for clinical use (see Table 5). Side effects vary with the preparation used, but it is important to remember that the consequences of augmenting immunosuppression with serological agents may last many months, even though administration is usually limited to 10 to 14 days.

Table 5 The immunosuppressive agents in transplantation
Calcineurin inhibitors Ciclosporin
Tacrolimus
Purine antagonists Azathioprine
Mycophenolate mofetil
Antibodies ALG
ATG
OKT3: muromonab
Anti-CD20: rituximab
Anti-CD52: alemtuzumab
Anti-CD25 (IL2-receptor): basiliximab, daclizumab
Miscellaneous Prednisolone
Sirolimus

ALG, anti-lymphocyte globulin; ATG, anti-thymocyte globulin.

Polyclonal antilymphocyte preparations can cause a marked first-dose effect in which lymphocytes are activated and secrete cytokines. High fever, rigors, and muscle and back pains are common, and hypotension may occur. With successive doses this reaction subsides. The murine anti-CD3 antibody (OKT3) is particularly prone to produce a first-dose effect that can lead to a widespread capillary leak syndrome with noncardiogenic pulmonary oedema, hypotension, and shock. It should not be given to patients who are fluid overloaded. Aseptic meningitis and encephalitis are also seen occasionally. The toxicity profile of OKT3 has led to a dramatic reduction in its use.

By contrast, the humanized and chimeric anti-CD25 (anti-IL2 receptor) antibodies that have recently been introduced do not appear to have any short-term side effects. Although rituximab may cause a first-dose effect from cytokine release it appears remarkably safe: its place in transplantation is not yet clear, but it may have a role in the prevention and treatment of antibody mediated rejection. The recent introduction of alemtuzumab has enabled patients to be maintained on very low-dose tacrolimus, and in many cases also steroid free. Late rejections may be a problem, although with this sort of regimen early acute rejection rates are of the order of 5%, but long-term outcome data is not yet available.

General side effects of immunosuppression

It is important to remember that all currently available immunosuppressive regimen are nonspecific in the sense that they suppress not only the immune response to the allograft, but also the immune response to infections and tumours. All the agents used have significant side effects and toxicities, and to a very large extent the long-term complications of renal transplantation are those of the immunosuppressive agents used. Some side effects are more related to the total burden of immunosuppression rather than to any specific single agent, e.g. infections and cancer.

Opportunistic infections

The CNIs used for immunosuppression act to inhibit the T-helper cell (CD4) and prevent the elaboration of IL-2 and other cytokines. In some respects this is akin to the effects of HIV infection and it is therefore not surprising that the renal transplant recipient may develop the same range of opportunistic infections and tumours as is seen in patients with AIDS (see Chapter 7.5.23). Clinical features are often dramatic and rapidly evolving, hence prompt and precise microbiological diagnosis is essential. This requires early recourse to invasive techniques, e.g. biopsy, node aspiration, node excision, bronchoalveolar lavage, and even lung biopsy. Neurological symptoms and signs may herald CNS infection and require urgent CT or MRI and the examination of cerebrospinal fluid whenever possible. A brain biopsy may be the only route to a specific diagnosis. Any pyrexial episode in a transplant recipient should prompt a search for infection. Blood and urine cultures should be undertaken routinely.

Figure 1 summarizes the timetable of infections. In the first month, before immunosuppression is fully established, renal transplant recipients may develop the same sort of infection as seen after any general anaesthetic, abdominal operation, or urological procedure. From months 1 to 6, immunosuppression is maximal and the risk of opportunistic infections greatest. Thereafter, the risk of infection declines but remains greater than the general population, particularly in the patient with a poorly functioning graft.

Timetable of infections following kidney transplant.

Figure 1: Timetable of infections. Reproduced from Rubin R.H. and Young L.S. (eds) 1994, Clinical approach to infection in the compromised host, 3rd edn. Plenum Medical Book Co., New York

Table 6 Opportunistic infections in transplant recipients
Viruses
  • Human herpes viruses (HHV):
  •  Herpes simplex (HHV1, HHV2)
  •  Varicella zoster (HHV3)
  •  Epstein–Barr virus (HHV4)
  •  Cytomegalovirus (HHV5)
  •  Kaposi sarcoma virus (HHV8)
  • Hepatitis viruses:
  •  Hepatitis B virus (HBV)
  •  Hepatitis C virus (HCV)
  • Papovaviruses:
  •  Human papillomavirus (HPV)
  •  Polyomavirus (BK/JC)
Human immunodeficiency virus (HIV)
Bacteria
  • Mycobacteria:
  •  Tuberculosis
  •  Atypicals
Nocardia
Listeria
Nontyphoid salmonella
Legionella
Fungi
  • Hospital acquired e.g.:
  •  Aspergillosis
  • Community acquired e.g.:
  •  Candida
  •  Torulopsis
  •  Cryptococcus
  •  Mucormycosis
  • Pneumocystis jiroveci
  • Reactivation (geographically restricted) e.g.:
  •  Histoplasmosis
  •  Coccidioidomycosis
Parasites Toxoplasmosis
Cryptosporidium
  • Geographically restricted:
  • Strongyloides stercoralis
  • Trypanosoma cruzi
  •  Malaria
  •  Leishmaniasis
  •  Schistosomiasis 
Viral infections

Not all virus infections prove dangerous to the immunosuppressed renal transplant recipient. Those with particularly important clinical sequelae are summarized in Table 6. The most important group are the DNA viruses of the herpes group: infection with these is immunomodulating in its own right and further immunosuppresses the patient, hence they are not infrequently associated with superinfections, e.g. Pneumocystis jiroveci, listeria, and bacterial sepsis. Several of the viruses have proven oncogenic potential and are considered later. There has been a steady and dramatic fall in deaths from infection in the post-transplant period. This is due to many factors including better use of immunosuppressive agents, effective control of CMV, and major advances in the diagnosis and treatment of some infections.

Cytomegalovirus (CMV)

CMV is the main infectious complication in solid organ transplantation (Bullet list 4), with a primary infection more likely to produce serious disease than either reinfection or reactivation. Viral load and the total burden of immunosuppression are the main determinants of disease. Use of potent serological agents, for either induction or rescue, is strongly associated with CMV disease, and as would be expected the total number of treated rejection episodes is an important risk factor. Diagnosis is usually by quantitative polymerase chain reaction (PCR) for viral DNA, or by an antigen assay (pp65) on peripheral blood leucocytes. Monitoring the serological response for diagnostic purposes is obsolete as it is far too insensitive, and routine cultures are too slow. A range of effective prophylactic regimen is available: oral valaciclovir or oral valganciclovir is effective. When employed, these are typically given to patients deemed at risk of CMV infection (certainly CMV-negative recipients of CMV-positive grafts, and in many centres any patient in whom recipient and/or donor are CMV-positive) for 90-180 days. Another equally valid approach is careful monitoring by quantitative CMV PCR, combined with pre-emptive treatment of infection if the CMV count rises above a threshold value, and before clinical disease becomes apparent. In this situation 2 or 3 weeks of oral valganciclovir is usually effective. With this expectant approach only 40 to 50% of patients develop significant viraemia and need pre-emptive therapy. Foscarnet is a more toxic (nephrotoxic) alternative that can be used in resistant CMV.

Bullet list 4 Clinical features of post-transplant viral infections

Cytomegalovirus (CMV)

  • Asymptomatic
  • CMV syndrome:
    • Fever
    • Wasting
    • Malaise
  • Leucopenia
  • Transaminitis
  • Hepatitis
  • Pseudolymphoma
  • Retinitis
  • Pneumonitis
  • Colitis
  • Gastroduodenitis
  • Pancreatitis
  • Myocarditis
  • Superinfection, e.g. Pneumocystis jeiruveci pneumonia

Epstein–Barr virus (EBV)

  • Asymptomatic
  • Classic glandular fever
  • Hairy leucoplakia
  • Hepatitis
  • Post-transplant lymphoproliferative disorder

Herpes simplex virus (HSV)

  • Stomatitis
  • Oesophagitis
  • Anogenital ulcers
  • Corneal ulcers
  • Kaposi’s varicelliform eruption
  • Haemhorrhagic skin blisters
  • Paronychia
  • Pneumonitis
  • Hepatitis
  • Pancreatitis
  • Meningoencephalitis

Varicella zoster virus (VZV)

  • Reactivation:
    • Shingles
  • Primary infection:
    • Pneumonitis
    • Hepatitis
    • Encephalitis
    • Pancreatitis
  • Disseminated intravascular coagulation

Human papilloma virus (HPV)

  • Cutaneous warts
  • Condyloma acuminatum
  • Bowen’s disease
  • Squamous cell carcinoma
  • Anogenital carcinoma (e.g. cervical invasive neoplasia, vulvovaginal invasive neoplasia)

CMV may play a role in triggering or augmenting both acute and chronic rejection. If this is confirmed then more prolonged and universal prophylaxis may be indicated.

Epstein–Barr virus (EBV)

EBV-related syndromes (see Bullet list 4) are an important cause of morbidity and mortality in renal transplant recipients, the most serious problem being so-called post-transplant lymphoproliferative disorder (PTLD), which is considered later.

Varicella zoster virus

Reactivation of latent varicella zoster virus (VZV) produces shingles, which is a common and unpleasant complication of transplantation. Immediate treatment with oral valaciclovir can limit spread and reduce postherpetic pain.

Much more dangerous is a primary VZV infection in an immunocompromised individual: this can cause a fulminating disease with hepatitis, pneumonitis, and disseminated intravascular coagulation (DIC) occurring within a few days. Mortality is high. All patients who are to receive immunosuppression should have their VZV antibody status established. Those who are seronegative should be warned about exposure to chickenpox or shingles and should report any contact immediately. Vaccination is available, but being a live attenuated vaccine this can only be given pretransplant. If exposed, susceptible individuals should be given zoster immune globulin (ZIG) and monitored closely. High-dose intravenous aciclovir should be given at the first suggestion of disease.

Herpes simplex

Although the classic herpetic cold sore is common after transplantation, herpes simplex virus (HSV), particularly if a primary infection can produce a variety of serious clinical sequelae in the immunocompromised patient (see Box 21.7.3.4). Use of prophylactic valaciclovir or valganciclovir (primarily for CMV prophylaxis) dramatically reduces the risks of HSV infection. Treatment with valaciclovir is very effective.

Human polyomavirus (BK and JC)

Most adult recipients are already seropositive for these viruses, indicating childhood infection that is usually asymptomatic. Primary infection can occur from the allograft, and in most cases this is also asymptomatic. BK virus reactivation occurs in 20%, with urinary excretion of so-called decoy cells. Nephropathy occurs in 20% of patients excreting virus, with about one-half of the patients who develop BK nephropathy losing their graft despite reduction in immunosuppression, which is the main treatment strategy. The JC virus has been reported to cause a progressive multifocal leucoencephalopathy in renal transplant recipients, but this is very rare.

Human papillomaviruses (HPV)

HPV can cause an extensive range of viral warts in renal transplant recipients. Some types have been implicated in the pathogenesis of anogenital carcinomas and squamous cell carcinomas of the skin (see below). The management of viral warts in the immunocompromised patient is difficult when they are very extensive and consideration should be given to reducing immunosuppression. Localized lesions can be treated conventionally with topical agents such as glutaraldehyde or laser therapy, but widespread surgical excision is sometimes required. Local recurrence in scar tissue is common. A combination of oral isotretinoin (50 mg daily) and topical tretinoin cream (0.05%) can control the lesions in severe cases. Topical imiquimod can be useful, and cidofovir ointment is of value in anogenital disease.

HIV

Before the advent of highly active retroviral therapy (HAART), infection with HIV was considered an absolute contraindication to transplantation because the time to AIDS and death was very significantly shortened, particularly if HIV was acquired at or shortly after transplantation. However, as discussed earlier in this chapter, intensive antiretroviral therapy for HIV infection has allowed safe transplantation, but, somewhat counterintuitively, HIV-positive patients have a higher incidence of rejection than might otherwise have been anticipated. It is important to remember that HIV infection, or behaviour considered to be at risk of contracting HIV or other viruses (lifestyle assessment), excludes such individuals from organ donation.

Bacterial infections

There are a limited number of bacterial infections that are significantly more common and more severe in the transplant population (see Table 6). However, there is little doubt that bacteraemias are more common in transplant recipients, usually as a result of urinary tract infections, and metastatic abscesses in joints, skin, muscles and the brain are also more frequent.

Mycobacterial infections

Reactivation of mycobacterial infection following transplantation is very common in the ‘at risk’ population, and most United Kingdom units recommend prophylaxis with isoniazid (with pyridoxine to prevent neuropathy) in these groups, although some debate the need for this. Isioniazid should not be given to patients with underlying liver disease.

Experience in the Indian subcontinent suggests that pretransplant bacillus Calmette–Guérin (BCG) vaccination is not effective. Mycobacterial infections (both atypical and tuberculous) can present in many different guises, e.g. pneumonia, lymphadenopathy, intracranial space-occupying lesions, discharging sinus, pyrexia of unknown origin, and skin ulcers. Tissue biopsy, cultures, and smears employing special stains are essential. PCR, particularly of cerebrospinal fluid, is proving helpful. Gallium scanning may identify nodes that can be aspirated under CT guidance. Skin testing is unreliable in the immunocompromised patient.

Treatment is compromised by serious drug interactions between rifampicin and both the CNIs, prednisolone and sirolimus. Rifampicin is such a potent inducer of cytochrome P450 that subtherapeutic levels of the CNIs and steroids can develop within weeks. Graft loss from rejection will occur unless doses are increased: that of prednisolone is usually doubled, and the calcineurin blockers may have to be increased still further and given three times daily. Monitoring of drug levels is essential.

In many units a four-drug antituberculous regimen is recommended, comprising rifampicin, ethambutol, isoniazid, and pyrazinamide. This can be reduced when sensitivities become available. Treatment should be continued for at least a year, particularly in the case of atypical mycobacterial infections. Therapy may be further complicated by hepatotoxicity, for which the differential diagnosis is complex as many other factors can cause deranged liver function tests in renal transplant recipients (e.g. viral infections—HBV, HCV, CMV—and other drugs).

Nocardia

Nocardia typically produces either a pseudotuberculosis or a pseudostaphylococcal syndrome. CNS infections can occur. Dissemination is common, occurring in 25 to 30%. Diagnosis often requires a biopsy or aspiration, with cultures needing to be prolonged for at least 3 weeks. Prolonged treatment (at least 6 months) with co-trimoxazole is usually effective, following which long-term co-trimoxazole should continue indefinitely.

Nontyphoid salmonella

Nontyphoid salmonella infections are noteworthy because of their tendency to produce metastatic abscesses following bacteraemia. With control of the acute illness, the continued excretion of the organism may occur in stool or urine. Relapse is common, hence treatment needs to be prolonged. Suitable antimicrobials include ciprofloxacin, co-trimoxazole, and ampicillin.

Listeria

Listeria has a tendency to localize in the CNS following a bacteraemic phase. Neurological syndromes vary from meningitis and meningoencephalitis to space-occupying lesions, and listeria is the commonest cause of post-transplant meningitis. In the absence of evidence of raised intracranial pressure, all patients will require lumbar puncture and examination of cerebrospinal fluid. Delayed or inadequate treatment may result in permanent neurological deficit. Treatment usually includes high-dose ampicillin for at least 6 weeks, combined with gentamicin for the first week. The source of listeria is usually contaminated dairy products, chicken, or uncooked vegetables contaminated by manure.

Fungal infections

Oral candidiasis is a common post-transplant infection. Spread to the oropharynx and lungs may occur. All patients should receive prophylaxis (nystatin mouthwashes or amphotericin lozenges) for at least 6 weeks, but some practitioners would recommend longer courses, or even indefinite treatment in patients with diabetes. Intercurrent courses of antibiotics may need to be covered with oral prophylaxis against candida.

The spectrum of diseases produced by fungal infections is wide, ranging from mucocutaneous syndromes, severe pneumonias, and CNS syndromes, to skin or muscle abscesses. This variation in clinical presentation again highlights the need for aggressive invasive investigation. Outbreaks of aspergillus are usually related to hospital building projects and should prompt a search for the source. Deep-seated fungal infections carry a very high mortality. Dissemination is common. Specialist microbiological advice is usually required, but if the fungus is sensitive, then liposomal amphotericin is the drug of choice. The newer antifungals, e.g. posaconazole, voriconazole, and caspofungin, have made a valuable contribution to the therapy of deep tissue or disseminated fungal infection in addition to amphotericin-B.

Pneumocystis jirovecii

Until the widespread introduction of prophylactic low-dose co-trimoxazole, Pneumocystis jirovecii pneumonia was a dreaded complication of solid organ transplantation. Oral co-trimoxazole (480mg or 960mg, once daily or three times per week) or inhaled pentamidine (300 mg monthly) is effective prophylaxis. Pneumocystis jirovecii pneumonia is now most commonly seen in the setting of augmented immunosuppression (additional serotherapy) and in patients who already have developed CMV disease. Presentation is with fever, dry cough, and profound shortness of breath, occurring in the context of few added sounds in the chest and a remarkably clear chest radiograph. By the time the chest radiograph has altered, pulmonary fibrosis is occurring. Successful treatment demands on early diagnosis, such that the renal transplant recipient who complains of shortness of breath on exercise and who desaturates on exercise should be admitted and investigated as a medical emergency. Bronchoalveolar lavage is virtually mandatory under these circumstances. The diagnosis is made by seeing the organism by classic (Gomori Grocott) or immunofluorescence staining, or by detecting it in lavage fluid by flow cytometry or (increasingly commonly) PCR.

Overall immunosuppression should be reduced in patients with Pneumocystis jiroveci pneumonia, but steroids may need to be increased to cover a stress response (e.g. prednisolone at 20–25 mg daily) and to limit pulmonary fibrosis. High-dose intravenous co-trimoxazole is given: 15 to 20 mg of trimethoprim and 75 to 100 mg of sulphamethoxazole per kg body weight per day, although these doses may need to be reduced in severe renal failure. Treatment should be continued for at least 2 weeks. It is essential to monitor respiratory effort carefully in the renal transplant recipient with an interstitial pneumonitis and intervene with continuous positive airways pressure or full ventilation if the patient tires or cannot protect his airways. Nutrition should be ensured, using total parenteral nutrition if necessary.

Parasitic infections

Some of the parasitic infections listed in Table 6 are geographically restricted and therefore only of specific relevance in those areas. Schistosomiasis, for example, can cause ureteric strictures and leaks following transplantation.

Strongyloides stercoralis

This is usually found in patients from the West Indies or East Asia: in the immunocompromised it can reactivate, complete its life cycle in the patient without need for an intermediate host, and produce a hyperinfestation syndrome. A pretransplant eosinophilia is sometimes present. Clinical presentation is with recurrent bouts of Gram-negative septicaemia as the worm penetrates the gut mucosa. Other clinical features include pruritus ani, haemorrhagic enteritis, larva currens, cough, wheeze, and a haemorrhaging bronchopneumonia. Meningitis may also occur. Diagnosis usually requires a duodenal aspirate. Treatment is with thiabendazole, which should be given pretransplant to patients at risk. Several courses of treatment may be needed to eradicate the infestation.

Scabies

This may occur in transplant recipients and can produce so-called ‘Norwegian scabies’ in which there may be many parasitic mites per burrow. In the immunocompromised patient, skin organisms are readily carried into the bloodstream, hence cellulitis and septicaemia are common.

Toxoplasma gondii

The transplant organ, particularly the heart, can transmit toxoplasmosis. The organism becomes widely disseminated, including into the CNS. Other clinical features may include low-grade fever, lymphadenopathy, pneumonia, myocarditis, retinopathy, and myositis, producing a picture that can mimic cytomegalovirus. Treatment is with pyrimethamine and sulphadiazine for at least 4 weeks. Prophylaxis with co-trimoxazole has greatly reduced the incidence of toxoplasmosis following solid organ transplantation.

Specific infective problems

Pulmonary disease

Recurrent chest infections are common. Many are viral and will be self-limiting, even in the immunosuppressed transplant recipient. An abrupt clinical onset with fever and a lobar pattern of lung infiltrates is likely to be due to a bacterial infection. A more insidious onset with scattered or diffuse pulmonary infiltrates is more likely to be due to an opportunistic infection. Blood and sputum should be cultured urgently. Sputum samples need careful microscopy, and cultures should be set up for mycobacteria, fungi, and legionella. PCR is available for Mycobacterium tuberculosis, Pneumocystis jirovecii, CMV, and most respiratory viruses. Antibiotics may be started pending culture results. A regimen that will cover most of the common organisms is penicillin V, clarithromycin (NB: drug interactions), and a third-generation cephalosporin.

Failure to respond promptly to therapy or a nonlobar pattern of infiltration is an indication for bronchoscopy and bronchoalveolar lavage, the diagnostic accuracy of which is about 80 to 90%. It is essential to examine the fluid thoroughly, which will involve viral and bacterial cultures, special stains, and PCR where available. In clinical practice it is often necessary to start therapy blindly in seriously ill patients. Sometimes this will involve the addition of high-dose co-trimoxazole and valganciclovir to conventional antibiotics. When the results of culture and sensitivity testing become available it may be possible to reduce the antimicrobial regimen or change to specific antituberculous or antifungal therapy.

The greatest mimic of a chest infection is pulmonary oedema: measurement of an elevated pulmonary capillary wedge pressure is diagnostic, and a therapeutic test of a potent diuretic sometimes produces a dramatic clearing of the chest radiograph. Other noninfectious causes of acute pulmonary syndromes that may occur in the renal transplant recipient are shown in Bulet list 5.

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