Last updated: Anaemia
on 19 Aug 2012

Transplantation

Background

Renal transplantation (especially living transplantation) is the treatment of choice for most patients with ESRF

Key Point: NHS Blood and Transplant data (2009-10) show that the current deceased donor graft survival rates are 93% and 85% at one and five years after transplantation, respectively; while comparable rates for grafts from living donors are 96% and 90%. For deceased donor transplants, patient survival is 96% and 87% at one and five years. For living donor transplants, its is 99% and 96%

Successful renal transplantation allows freedom from the lifestyle restrictions and complications associated with dialysis and is therefore associated with better quality of life (Cameron, 1996)

One study of United States Renal Data System (USRDS) data compared outcomes in patients on the transplant waiting list (ie, who were continuing to receive dialysis) with those of controls who had received a kidney transplant (Wolfe, 1999). It found that, after 3 to 4 years of follow-up, transplantation reduced the risk of death overall by 68%. Transplantation conferred a survival benefit in almost all subgroups, including in elderly or obese patients or those with hepatitis C. In addition, over the long term, it is more cost-efficient than dialysis (Laupacis, 1996). Thus, transplantation remains the optimal therapy for patients with ESRF

Rejection rates have fallen over the years, and rejection is now an uncommon cause of early loss of a graft. This encouraging outcome reflects many factors, particularly a favorable shift in the balance between the efficacy and toxicity of immunosuppressive regimens. In the medium term (one to three years) after transplantation, clinical outcomes are now so good that it is difficult to improve the survival of the patients or the grafts

The focus is, therefore, increasingly directed toward the prevention and treatment of the long-term complications of renal transplantation. These include suboptimal allograft function, premature death, cardiovascular disease, and bone disease 

The shortage of donor organs, however, remains a major obstacle to successful, early transplantation. This shortage has actually worsened despite an increase in living and non-heart beating donors

 

 


Transplant, Pre and Post Theatre

The Transplant - Pre Theatre

Transplants may be deceased (heart beating or non-heart beating) or living (related or non-related). If a living transplant, it may be antibody-incompatible or part of a paired transplant

The pre-transplant evaluation of donor and recipient are carried out in outpatients and the operation is scheduled the same way as other elective surgeries, with specialist input from surgeons, nephrologists anaesthetists, transplant co-ordinator and specialist nurses in transplant/dialysis. The recipients optimisation can be planned well to minimise any peri-operative surprises or complications. In the UK, all living donors also need to be assessed by an independent third party on behalf of the Human Tissue Authority. The assessor must be satisfied that:

  • The donor understands the procedure, including the risks and is able to give valid consent
  • The donor recipient relationship is stated
  • There was no coercion or financial reward that led to the potential removal of the organ
  • There are no problems in communicating with the donor/recipient and if an interpreter is needed they have no personal involvement with the donor or recipient

Details of the surgery are beyond the scope of this chapter and best left to those who actually do the procedures. Essentially, the donor kidney is anastamosed to the iliac vessels in the recipient, and the donor ureter is implanted into the recipient bladder. It is important to know what to do in the following situations:

When a Kidney Becomes Available

Don’t panic! Transplantation should (initially) be treated the same way as any other semi-urgent operation. Transplant is truly multi-disciplinary, so ensure all staff are aware that a renal transplant is due to take place. This may include: Surgical and theatre staff; transplant co-ordinator; anaesthetist; transplant nurse and laboratory staff. If you have to ring the patient, tell them not to eat or drink anything, and to come quickly (without rushing unsafely) to hospital

When the patient arrives:

  • Patient to remain nil by mouth
  • Call the anaesthetist (request triple lumen central line and remind not to use forearm veins for cannulation)
  • Call the surgeon and tissue typist, and make sure theatres are booked
  • Locate the kidney
  • Get the patient’s notes (or read on your computer system) and ensure they include the recipients most recent clinic letters and assessment for fitness for transplant – although this may change
  • If the patient is from another unit, and you do not have adequate information, try to contact that unit, and find the consultant that knows the patient the best
  • Decide whether the patient needs dialysis – more of an issue for HD patients as PD is a continuous process. Patient will require dialysis if there is significant fluid overload or potassium is high (varies depending on unit protocol). Dialysis in this instance is often given heparin free. If the patient is on PD, then they will often require 2 exchanges over a 2 hour period, making sure fluid is drained before the operation. At the end of dialysis, the patient should be euvolaemic, as operating on ‘full’ blood vessels is easier 

Pre-op Assessment of Patient 

The patient will have had a full assessment prior to being placed on the transplant list to assess suitability. As a registrar, your job is to find out if anything has changed, and see if they remain medically fit for transplant. Unfortunately some patients will no longer be appropriate to transplant, and it is important to recognise this and not transplant inappropriately than to ‘waste’ a kidney

Key questions in the history:

  • Record their normal urine output
  • What is their dry weight (target weight if on dialysis)
  • Are they ‘well’? – Any recent infections/illnesses?
  • Is the patient on warfarin – if so why? And consider taking appropriate steps to reverse warfarin pre-op
  • Any drugs that may interact with immunosuppressive treatments (eg azathioprine and allopurinol)
  • When did the patient last dialyse (if on HD)

Key points on examination:

  • Record the patients current weight
  • Look for any signs of fluid overload
  • Examine all peripheral pulses: If they are poor, the iliac vessels may be poor and affect make the anastamoses more difficult – tell the surgeon 

Investigations (Pre-Transplant)

Most units have their own protocol, so look these up. They may include the following:

  • FBC, U&E’s, Clotting profile
  • Crossmatch (3-6 units)
  • Tissue typing crossmatch - (see below)
  • ECG and Chest X-ray
  • MSU
  • Blood Culture
  • PD fluid for analysis and culture
  • Virology (EBV, CMV, HIV, Hep B, Hep C)

Tissue typing crossmatch: In some cases the recipient will have preformed lymphocytotoxic antibodies against HLA antigens in the graft. When this happens hyperacute rejection of the graft may occur. A tissue type crossmatch is where donor lymphocytes are mixed with recipient serum – if a reaction occurs, then transplantation is unlikely to proceed. A 'negative cross-match' is a pre-requisite for most transplants to proceed 

Medication and Writing the Drug Chart 

Ordinarily you might consider this a menial task to be carried out by any qualified doctor. However the pre-op transplant patient’s drug chart needs to be checked and completed by an experienced senior nephrologist before the patient goes to theatre. This is because patients will require:

a. Induction Immunosuppression – This will vary between units, and the type of transplant, so ensure you have referred to the protocols in your hospital (see section below for details of immunosuppression)

b. Prophylaxis – Involves prescribing drugs to prevent opportunistic infections that may develop when the transplanted patient is immunosuppressed (again varies between units, so refer to hospital protocol and always discuss with a senior nephrologist experienced in managing transplant patients). The follwoing conditions may need prophylaxis

  • Candida (Nystatin)
  • Pneumocystis jiroveci (Triemthoprim-Sulfamethoxazole)
  • Tuberculosis (in ‘at risk’ patients) (Isoniazid)
  • CMV (especially if recipient is CMV negative and the donor is CMV positive) (Valganciclovir)
  • Peptic ulcer disease (PPI)
  • (Osteoporosis)

c. Stopping 'Dialysis Drugs' - It is conventional to stop 'dialysis drugs' (eg anti-hypertensive, ESA, phosphate binders and Vitamin D). This is not entirely logical, and can cause problems. Many patienst will end up back on 1-3 drugs for hypertension

Talking to the Patient Pre-Transplant

The patient will invariably have some questions about the procedure itself, and how long they can expect to be in hospital recovering afterwards. Being able to answer some of the more common questions with general answers is of great benefit to the patient

  • The procedure itself can be expected to take 2-3hours
  • Showing them the site into which the kidney will be transplanted (iliac fossa) can help ease anxiety
  • Patients can expect to be out of bed the next day, and go home in 10-14 days if all goes well
  • Explain that after theatre they will have some ‘tubes’ in them – CVP line, wound drain(s), urinary catheter; and they will usually come back to the surgical ward
  • Surgeons often put a stent from inside the ureter to into the bladder. You may need to explain what a ‘stent’ is, and explain that this is usually removed after the operation if the graft is working well. If the patient has a PD catheter, it will usually be removed at the same time as the stent

Patients are invariably worried about the risks of rejection/the graft not functioning. There is a 30% chance the graft will not work initially ('delayed graft function'), but will start working later. It is worth warning the patient of this issue. If DGF occurs, renal transplant patients require a weekly biopsy, so that acute rejection is not missed

There is also a chance that the graft will work initially, but function will decline in the following months. However, 90-95% of all grafts are functioning 1 year post transplant. If patients have specific worries about rejection, it is fair to say that sometimes rejection does occur, but this is usually successfully treated with immunosuppressive treatments. Discussing graft and patient survival data immediately pre-op is not useful and will make them anxious. It should have been done before in the outpatients' department

 

The Transplant - Post Theatre

From the nephrologist's perspective, this when the work (and worry) really begins. Initially look at all the basic observations (simple things first), the patient have had a surgical procedure and could have any of a number of surgical complications that are not related directly to the graft, but can easily affect graft function.

Essential Post-Transplant Observations

  • Blood Pressure
  • Pulse
  • O2 saturation
  • Respiratory rate
  • Temperature
  • Central venous pressure
  • Urine output (crucial) and fluid balance (meticulous input/output chart) 

Any problems encountered in these basic parameters need to be dealt with seriously and involving senior colleagues ASAP (see below)

Different units will have their own protocols for post-transplant investigation and management, so refer to these appropriately, but other investigations that need doing when the patient returns to the ward will include:

  • FBC, repeat U&E’s (particularly for potassium), with repeat U&E’s 4 hours later
  • Chest X-ray (for CVP position and pneumothorax)
  • Wound drains

If you have any concerns about your post-op transplant patient, never be afraid to ring the oncall consultant nephrologist. They will want to know a number of things to make a proper assessment, and it is best to have these to hand before making the call:

  • They will want to know the type of transplant and when the procedure was (hours, days, weeks may alter the management)
  • They will want to know why you are worried – eg hypotension, deteriorating urine output, hyperkalaemia, and they will invariably want to know all the most recent observations and trends, as well as the latest blood tests
  • They will want to know the patients clinical state, so don’t ever forget to talk to, and examine the patient! Tip: Often useful to get an arterial blood gas
  • They will want to know what steps you have taken to stabilise the patient – eg, increased oxygen, increased speed of IV fluid – and what initial investigations you have arranged

Oliguria Post Transplant

Knowing what the patients pre-op urine output is essential to interpreting their post-transplant urine output. If output is similar or less than pre-transplant, take this seriously as it may mean graft dysfunction. Talk to a consultant early, but don’t forget to consider the simple things (and take simple steps to correct them)

  • Hypovolaemia: Correction with crystalloid is probably the best first step in fluid resuscitation, using CVP measurements to guide replacement. Transplanted kidneys are very sensitive to hypovolaemia and it is easily correctible.
  • Obstruction: Catheters get blocked. If in doubt after flushing the catheter, change it
  • Renal artery thrombosis: Is a rare, but devastating cause of graft dysfunction. Arrange Doppler studies of the kidney immediately. Do not wait until morning
  • Ureteric leak: Symptoms include pain and swelling of the graft and around the perineum. Urine may also leak from the wound or out of the wound drains. Urgent US is required

Continued reassessing of fluid status and CVP monitoring is key, and once the patient is euvolaemic you need to keep up with fluid needs: Continue to give crystalloid at a rate equal to urine output, plus 50 ml/hour


Immunosuppression

Principles

In almost all patients, immunosuppression must continue for the life of the graft. Stopping immunosuppression, even for short periods, can risk acute rejection, and permamant graft loss. Stages and types of immunosuppression include: 

A. Prevention of graft rejection, by induction (early) therapy, initial (intermediate) therapy and maintenance (late) therapy

  • Early – Intense immunosuppression to prevent rejection
  • Intermediate – Less intense to allow graft-host ‘accomodation’ and to reduce risk of side effects from immunosuppressive agents
  • Late – Reduction/replacement of immunosuppressants at a time when rejection unlikely and there are significant risks of excess immunosuppression (eg cancer, or nephrotoxic effects of calcineurin inhibitors)

Prevention of graft rejection with immunosuppression has customarily be based around three groups of drugs (so called 'triple therapy'): (1) a calcineurin inhibitor (eg ciclosporin or tacrolimus); (2) an anti-proliferative agent (eg azathioprine, or mycophenolate); and (3) a corticosteroid (eg prednisolone)

B. Treatment of Acute Rejection

Induction Therapy

This is an intensive course immunosuppression given for (roughly) 2 weeks immediately post-transplant. It is often started immediately pre-operatively and aims to ‘switch-off’ the immune system and reduce the risk of accelerated rejection/acute rejection. The humanised anti-CD25 monoclonal antibodies basiliximab or daclizumab, used as part of a calcineurin-inhibitor-based immunosuppressive regimen, are recommended by NICE as options for induction therapy in the prophylaxis of acute organ rejection in adults

The initial high doses of immunosuppressive therapies also means a lower dose of calcineurin inhibitors may be used in the early stages post transplant when the graft may be more vulnerable to their nephrotoxic effects

Initial Therapy

Is given to all recipients (<3 months) post transplant. The combination of immuosuppressants is usually the same ‘triple therapy’ that is used for induction, but at a lower dose. The ‘primary’ agent is usually a calcineurin inhibitor (ciclosporin or tacrolimus, but when these are not tolerated, sirolimus) in combination with a 'anti-proliferative' (eg azathioprine or mycophenolate) and a corticosteroid (usually prednisolone) . Titration of exact doses of immunosuppressants in patients at his stage is complex and depends on many factors, including graft function, drug toxicity and side effects as well as compliance and concordance issues

Maintenance Therapy

Is the long-term (>3 months) treatment to maintain (low level) immunosuppression, for the life of the allograft. Again maintenance therapy is often similar to initial therapy but at a reduced dose. One of the main reasons reducing the dose of immunosuppressants is possible is because the allograft becomes (immunologically) more stable with time and accommodation occurs between the host and the transplanted kidney. However, titration of doses in maintenance is a variable and ongoing process, requiring regular monitoring and assessment of graft function 

Although corticosteroids, azathioprine and ciclosporin still have a role in these three stages of immunosuppression, there is increasing use of newer potent immunosuppressants. Many of these drugs act on T-lymphocytes. Tacrolimus is a calcineurin inhibitor which has a similar mechanism of action to cyclosporin, reducing T-cell differentiation. Sirolimus binds to the same protein as tacrolimus, but has a different mechanism of action. As some of these drugs have a narrow therapeutic range, drug concentrations must be monitored. Mycophenolate is an inhibitor of purine synthesis. Another approach is to block the receptors on T-cells with immunosuppressant antibodies such as basiliximab and daclizumab

Episodes of Acute Rejection 

Acute rejection may occur at any time when levels of immunosuppression become inadequate, but 90% occur in the first 4 weeks post transplant, with almost all occuring in the first three months. Rejection is rare in the first 5 days (except in AIT). The acute rejection process is cell-mediated (T-cell) or antibody-related (B-cell), or both. Traditionally acute rejection was divided histopathologically into: a. a (milder) 'cellular rejection', characterised by destruction of cellular structures in the transplanted organ; and b. a rarer (more aggressive) form called 'vascular rejction', where the process is not limited to cellular structures and includes a vascular component

Pathology of Acute Rejection

These terms were never defined. In fact, until the early 1990s there was no standardised international classification of renal allograft biopsies resulting in considerable heterogeneity in reporting among the various centres. A group of dedicated renal pathologists, nephrologists, and transplant surgeons developed a schema in Banff, Canada in 1991. Subsequently there have been updates at regular intervals, the last one being in 2007 (Solez, 2007). 'Banff '07' classified rejection as follows:

Class 1 is a 'normal biopsy'

Class 2 is 'Antibody-mediated changes'. Ideally, both positive C4d staining and circulating donor-specific antibodies are present in the setting of a rising creatinine to make this diagnosis. In acute antibody-mediated rejection, there are three variants: (i) an ATN-like picture, (ii) capillary involvement, or (iii) arterial involvement. In chronic antibody-mediated rejection, there is evidence of chronic tissue injury such as glomerular double contours, peritubular capillary basement membrane multilayering, interstitial fibrosis/tubular atrophy (IFTA), or fibrous intimal thickening in arteries

Class 3 refers to 'Borderline Changes' which is essentially a mild form of T-cell-mediated rejection. This category is used when there is no intimal arteritis present, but there are foci of tubulitis or minor interstitial infiltration.

Class 4 is a more full-blown form of T-cell mediated rejection. As with humoral rejection, there are both acute & chronic forms:

The acute form of T-cell mediated rejection is furthermore subclassified as follows. Since this is the most common form of rejection, it is useful to know:

  • Class IA: there is at least 25% of parenchymal showing interestitial infiltration and foci of moderate tubulitis (defined as a certain number of immune cells present in tubular cross-sections)
  • Class IB: just like Class IA except there is more severe tubulitis
  • Class IIA: there is mild-to-moderate intimal arteritis
  • Class IIB: there is severe intimal arteritis comprising at least 25% of the lumenal area
  • Class III: there is transmural (e.g. the full vessel wall thickness) arteritis

Class 5 refers to interstitial fibrosis and tubular atrophy (IFTA), which was proposed as a new term for 'chronic allograft nephropathy'. Grade I refers to <25% and >50% of cortical area involved

Class 6 is a catch-all term describing changes not considered to be due to rejection--for example, recurrent FSGS or CNI toxicity

Investigation and Treatment of Acute Rejection

Acute rejection manifests as a deterioration in graft function; as shown by a rising (or stable) creatinine (with or without decreased urine output), and the patient may become fluid overloaded. A doppler ultrasound is needed to exclude transplant kidney obstruction and transplant artery stensois (this can come on quite quickly, even in the first 2 weeks). If these diagnoses are excluded, a renal biopsy is needed to confirm acute rejection, and differentiate it from other causes of deteriorating graft function, eg CNI toxicity, infection, ATN or HUS/TTP-like syndrome (which can be CNI related). These investigations should not delay treatment, if rejection is suspected

Treatment of these episodes is aimed at further suppressing the immune system to allow graft recovery. Short courses of high dose corticosteroids (eg daily 500mg iv methylprednisolone, or 200mg oral prednisolone, for 3 consecutive days) are the standard treatment and are usually effective. Maintenance therapy should be reviewed at the same time and either temporarily or permanently adjusted following rejection episodes

If rejection does not resolve after treatment with steroids ('steroid-resistant acute rejection’), it is usually treated with the polyclonal antibodies; eg antilymphocyte immunoglobulin (ALG), antithymocyte immunoglobulin (ATG) or the monoclonal antibody muromonab-CD3 (OKT3); and/or by switching ciclosporin to high-dose tacrolimus 
 

Maintenance Immunsuppression

Corticosteroids: Prednisolone

Corticosteroids (mainly prednisolone) remain a cornerstone of immunosuppression in most patients. They were introduced as maintenance immunosuppression by Goodwin in 1963. They have widespread effects because most mammalian cells have glucocorticoid receptors their cytosol. They have direct effects on antigen presenting cells (eg dendritic cells and macrophages) and T lymphocytes , in which they inhibit cytokine production - by inhibiting the transcription of a number of cytokine genes including IL-1, 2, 3, 6 and TNFα. They also have non-specific immunosuppressant and anti-inflammatory actions including inhibition of vasodilators and blocking monocyte migration to sites of inflammation

Dosage is progressively decreased in the first 3 to 6 months after transplantation, eg  to 5-10 mg/d of prednisone. The adverse effects of steroids are well known; of particular importance in transplant recipients are: delayed wound healing, easy bruising and thin skin; hyperlipidaemia; hypertension; weight gain; cataracts, diabetes (NODAT), and osteoporosis. Osteoporosis is particularly associated with vertebral crush fractures, and avascular necrosis of the femoral head. This latter problem can occur early (within first 3 months) and be bilateral. It may require MRI to diagnose, and require unilateral or bilateral hip replacements. Unfortunately, complete withdrawal of steroids has traditionally been associated with rejection, and with both short- and long-term graft dysfunction in a subset of recipients (Hricik, 2002)

However, 'newer' immunosuppressants such as mycophenolate and tacrolimus should allow the safe use of much lower doses of steroids or their avoidance altogether. Certainly, nonsteroid or low-dose protocols should now be considered in patients at risk for significant toxicity (eg those with pretransplantation osteoporosis). And steroid withdrawal should be considered in patients who have developed significant post-transplantation toxicity (eg new onset of diabetes mellitus). Recipients treated without steroids must be followed up closely for possible rejection

Anti-proliferative Drugs: Azathioprine and Mycophenolate

Azathioprine was first introduced into clinical practice by Sir Roy Calne in 1962 (Calne, 1962). Following the work done by Sir Peter Medawar and Gertrude Elion in discovering the immunological basis of rejection of transplanted tissues and organs, and the synthesis of 6-mercaptopurine by Elion and George Hitchings (in 1952); the drug was used by Rene Kuss in Paris, for the first time after a renal transplant, in 1960. When Azathioprine was discovered, Calne introduced it as a less toxic replacement for 6-mercaptopurine. For many years, 'dual therapy' with azathioprine and steroids was the standard anti-rejection regime, until ciclosporin was introduced into clinical practice (also by Calne) in 1978

Azathioprine, and mycophenolate function principally by inhibiting mitosis and thus proliferation of lymphocytes. Azathioprine is a purine analogue and a prodrug which is converted to 6-mercaptopurine and metabolised to cytotoxic thioguanine nucleotides which inhibit DNA and RNA synthesis. The antiproliferative effects are not lymphocyte-specific, however; with both cell-mediated and antibody-mediated immune reactions being depressed. Bone marrow suppression is the most common adverse effect. Hepatotoxicity is another important side effect. So regular monitoring of FBC and LFTs are mandatory

Patients with an inherited deficiency of the enzyme thiopurine methyltransferase (TPMT) metabolise azathioprine slowly. This results in rapid drug accumulation and pronounced marow depression with standard doses. Azathioprine is also metabolised by xanthine oxidase, which is inhibited by allopurinol. This drug combination should be avoided or used with great caution (eg cut dose of azathioprine to 25% of standard dose)

Thus, in recent years, mycophenolate has replaced azathioprine for patients with new transplants in many centres. Mycophenolate is the more powerful immunosuppressant, probably associated with better short-term - and probably better long-term - outcomes (Ojo, 2000). It was first used in renal transplantation by Takahasi in 1995

In 1893, Bartolomeo Gosio, an Italian physician, discovered Mycophenolic acid (MPA), a fermentation product (metabolite) of Penicillium Brevicompactum and related fungi (Gosio, 1893). He also discovered that mycophenolic acid inhibited the growth of anthrax bacillus, Bacillus anthracis; making it, according to some, the first ever discovered antibiotic

A variety of biological properties of mycophenolic acid, such as antibacterial, antiviral, antifungal, anti-tumor and immunosuppressant effects has been reported. Mycophenolic acid has been used as treatment for psoriasis, but unfortunately displays low bioavailability due to metabolism in the liver. To increase the bioavailability of
mycophenolic acid, the prodrug mycophenolate mofetil was invented

MPA is a reversible inhibitor of the enzyme inosine monophosphate dehydrogenase (IMPDH) a critical, rate-limiting enzyme in the de novo synthesis of purines (eg guanine nucleotides). Its anti-proliferative effects are relatively specific for activated lymphocytes. This is because T lymphocytes lack the ability to scavenge guanine nucleotides; so they must produce their own. MPA inhibits this ability; so inhibiting T-lymphoctye proliferation by preventing DNA synthesis

The combination of mycophenolate and tacrolimus is very effective in preventing acute rejection. But mycophenolate is associated with a high incidence of adverse gastrointestinal effects such as nausea, oesophagitis and gastritis (20%), and diarrhoea (30%) - especially when used with tacrolimus. This probably reflects both intrinsic effects of tacrolimus and the higher mycophenolate plasma concentrations obtained when the drug is prescribed with tacrolimus rather than ciclosporin (Hubner, 1999). Like azathioprine, bone marrow suppression also occurs. Therapeutic drug monitoring is not required with either anti-proliferative drug

There are few important drug interactiosn but MPA may increase aciclivor or ganciclovir levels by inhibiting reanl tubular secretion. Unlike azathioprine, it can be used safely with allopurinol, and no dose reduction is required

Calcineurin Inhibitors: Ciclosporin and Tacrolimus

Ciclosporin (CsA) is a small polypeptide of fungal (Tolypocladium inflatum) origin. Its immunosuppressive effect was discovered on 31 January 1972 by employees of Sandoz (now Novartis) in Basel, Switzerland, in a screening test on immune suppression designed and implemented by Hartmann F Stähelin. It was introduced in to the clinical arena in 1978 (Calne, 1978). It revolutionised medical management after transplantation, and improved early graft survival significantly

Tacrolimus (FK506) is a macrolide antibiotic, discovered in 1984, derived from a fermentation broth of a Japanese soil sample that contained the bacteria Streptomyces tsukubaensis. The first publication was in 1987 (Kino, 1987). It was first used in liver transplantation in 1994, and in kidney transplantation in 1996 (Woodle, 1996; Laskow, 1996

CsA and Tacrolimus, though chemically distinct and acting through different intarcellular proteins, exert their immunosuppressive effect by binding to the intracellular phosphatase calcineurin. As calcineurin is a pivotal enzyme in T-cell–receptor signalling. Inhibiting it leads to the disruption of the signal from the T cell receptor to the nucleus of the cell, thus preventing T cell activation - and thereby reducing the synthesis of several critical T-cell growth factors, including IL-2. Their actions, unfortunately, are not limited to T lymphocytes, and so are associated with various side-effects

Both have narrow therapeutic indices; too little results in under-immunosuppression (risking rejection) and too much leads to side effects, especially nephrotoxicity. In other words, either too much or too little can worsen renal function. So drug monitoring is required

Trough blood concentrations are used to guide dosing but recent studies have shown that lower C2 concentrations (ie, blood concentrations 2 hours after ingestion) of ciclosporin correlate better with the risk of acute rejection (Internation study, 2002). There are no published studies to date showing better long-term outcomes with C2 monitoring of ciclosporin metabolism

Side-effects of both include neuropsychiatric problems, liver dysfunction, diabetes, microangiopathic anaemia (producing an HUS/TTP-like syndrome), hypertension and nephrotoxicity. Futhermore ciclosporin causes hirsutes and gingival hyperplasia; tacrolimus causes hair loss. Hyperlipidaemis is more common with ciclosporin

Although some brands of cyclosporin are bioequivalent on a population basis and therefore interchangeable, cyclosporin has a narrow therapeutic range. There is therefore a potential that individual variations in pharmacokinetics could lead to significant alterations in blood concentrations if the patient is prescribed a different preparation. Unplanned generic substitution should not occur. If patients are switched from one brand to another brand of cyclosporin, increased monitoring is indicated

Tacrolimus is an alternative to ciclosporin when a calcineurin inhibitor is indicated as part of an initial or a maintenance immunosuppressive regimen in renal transplantation for adults. Tacrolimus is more effective than ciclosporin in preventing acute rejection at doses currently used, and there is some evidence that medium-term outcomes are better with tacrolimus (Vincenti, 2002). For these reasons and because its adverse effects profile is perceived to be better in some ways, tacrolimus is becoming the CNI of choice in kidney transplant recipients in many centres. There is still concern that its 'benefits' (eg less rejection) outweighs its less desirable side-effects (eg a greater tendencey to induce diabetes than ciclosporin)

Both drugs are metabolised by the intestinal and hepatic cytochrome P450 system (Pichard, 1990). Inducers or inhibitors of this system should be prescribed with caution and more frequent monitoring of ciclosporin and tacrolimus concentrations should be performed, if the patient on these drugs:

Drugs that Induce CNI Metabolism (possible requiring a dose increase)

  • Anti-TB drugs (rifampicin, isoniazid)
  • Anti-epileptics and barbituates (phenobarbital, phenytoin, carbamazepine)
  • Other (phenylbutazone, sulfadimidine, sulfinpyrazone, dexamethasone, and St Johns Wort)

Drugs that Inhibit CNI Metabolism (possibly requiring a dose decrease)

  • Macrolide antibiotics (erythromycin and clarithromycin)
  • Antifungals (fluconazole, ketoconazole and miconazole)
  • Calcium antagonists (nifedipine, diltiazem, verapamil, nicardipine)
  • Ergots (ergotamine, dihydroergotamine)
  • HMG CoA reductase inhibitors (atorvastatin and simvastatin)
  • Other (midazolam, protease inhibitors, glibenclamide, bromocriptine, ethynylestradiol, progesterone, and most glucocorticoids (prednisolone and methylprednisolone))

Certain groups of patients (eg black people, or patients with diabetes) absorb these drugs poorly, and are thus vulnerable to rejection. Higher doses may be required. Although both drugs cause acute nephrotoxicity, their role in causing significant chronic allograft dysfunction is unclear 

mTOR Inhibitor: Sirolimus

Sirolimus is the most recent maintenance immunosuppressive agent to be used in renal transplantation (Murgia, 1996). It is derived from a macrolide antibiotic first identified on Rapa Nui (Easter Island) and was originally called rapamycin

It exerts its effects on T lymphocytes, and to a lesser extent B lymophocytes. Like tacrolimus, it binds to FK-binding protein (FKBP), but it has no effect on calcineurin. Instead, the complex inhibits a protein kinase that is critical for cell cycle progression. This kinase is known as the mammalian target of rapamycin (mTOR). Inhibition of mTOR suppresses cytokine (IL-2) driven T-lymphocyte proliferation resulting in immunosuppression at the G1-S phase of the cell cycle (Halloran, 2004) - thus allowing cells to become activated but preventing them from proliferating

It was orginally developed as combination therapy with ciclosporin but was shown to potentiate the nephrotoxicty of ciclosporin. Sirolimus is also metabolised via the cytochrome P450 system, and therefore has a large number of drug interactions. Therapeutic monitoring requiring a 24h trough level is required

Two properties of sirolimus may benefit transplant recipients. First, its anti-proliferative effects could prevent graft atherosclerosis (a beneficial effect analogous to that of sirolimus-coated stents in coronary artery disease); second, its anti-neoplastic (anti-angiogenic; inhibits VEGF) effects could reduce the high incidence of post-transplantation tumours. It has also been used for this reason, to successfully manage Kaposi's Sarcoma, when subsituted for a CNI

Its main claimed advantage is that it is not a calcineurin inhibitor, and therefore not nephrotoxic. Therefore, potentially graft survival should be better. But data on long-term outcomes with sirolimus are still not available. And, its side-effects are significant; including severe hyperlipidaemia, hypertension, poor wound healing, interstitial pneumonitis, lymphocoele and pancytopenia

Poor wound healing has largely precluded its use as an initial therapy. Instead, its main use has been as a 'switch therapy' after 3 months; or to replace CNIs for proven intolerance (including nephrotoxicity) necessitating complete withdrawal of these drugs. Its role in routine maintenance therapy remains to be defined

Summary of Mechanisms of Action of Maintenance Immunosuppressive Agents

CNIs (ciclosporin and tacrolimus) bind to their respective immunophilins, and inhibit calcineurin. Calcineurin is then unable to dephosphorylate NFAT, which will prevent translocation of NFAT to the nucleus and thereby production of IL-2. Sirolimus is an mTOR inhibitor. It binds to FKBP and inhibits mTOR, which in turn inhibits transition of the cell cycle from G1 to S phase. MPA and LFL are also cell-cycle inhibitors, and act via inhibition of nucleotide synthesis. Abbreviations: CNI, calcineurin inhibitor; FKBP, FK506-binding protein; IL-2, interleukin-2; LFL, leflunomide; MHC, major histocompatibility complex; MPA, mycophenolic acid; mTOR, mammalian target of rapamycin; NFAT, nuclear factor of activated T cells; TCR, T cell receptor
 

Biological Agents 

Antithymocyte (ATG) and Antilymphocyte (ALG) Globulins

These are polyclonal IgG antibodies derived from horses or rabbits (ATG) or mice (ALG) immunised with human thymocytes. They have activity against human lymphocytes, especially a number of T cell markers. Administration results in deplection of peripheral lymphocytes that are lysed or cleared by the immune system. So, infusions of ATG/ALG cause profound T-cell depletion and the lymphopenia typically persists beyond one year

These drugs may be given for treatment of rejection episodes in steroid resistant rejection (persistent biopsy proven rejection despite two courses of methylprednisolone). Sometimes (eg in antibody incompatible transplants, AITs), they are used as first line agents when acute rejection is suspected

ATG/ALG are usually given over a 10 day period, with daily FBC monitoring. CNIs are usually stopped for this time period. They should be given by a central vein (or fast flowing vein such as an AVF) to avoid thrombophlebitis. Prophylaxis against CMV and Pneumocystis jiroveci (carinii) should be given

Side effects relate largely to allergic reactions including rigors, arthralgia (ie flu-like syndrome) and hypotensions due to release of cytokines (a 'cytokine release syndrome') and rarely anaphylaxis. These reactions can be minimised by giving IV methylprednisolone and an anti-histamine 30 mins before administration

A test dose is needed to identify those patients who will develop anaphylaxis. Signs of anaphylaxis are tingling in the extremities and around the mouth, swelling of the lips and larynx, bronchospasm, tenesmus and hypotension. Any reaction will normally respond to IV hydrocortisone 100 mg and IV chlorphenaramine 10 mg; although IM 0.5 ml adrenaline 1:1000 may be necessary

The use of ATG/ALG is associated with an increased incidence of post-transplant lymphoproliferative disease (PTLD)

Muromonab-CD3 (OKT3)

This is a mouse-derived monoclonal antibody which binds to the CD3 component of the human T-cell receptor complex leading to T-cell depletion. Binding to CD3 causes its removal from the cell surface and renders the T-cell receptor (for antigen) incapable of transmitting an activating signal to the cell. Nearly all patients will develop a 'cytokine release syndrome' which can range from a mild self-limiting flu-like illness to more serious manifestations including pulmonary oedema and neuropsychiatric adverse reactions (including headache, aseptic meningitis, and encephalopathy)

Because of these side-effects, IV methylprednisolone, an anti-histamine and oral paracetamol are given 30 mins before administration on the first and second doses. Again, prophylaxis against CMV and Pneumocystis jiroveci (carinii) should be given

In the UK, OKT3 use tends to be restricted to the treatment of steroid resistant rejection that has failed ATG or ALG or these drugs are contra-indicated. In the USA, it has been used as an induction agent

Because the epitope-recognising region of OKT3 is of mouse origin and directed at only one target, antibodies can form against it and render it ineffective, as they block binding to the cell surface of the CD3 molecule. These anti-mouse neutralising antibodies can block the effect of the drug and limit its re-use. Therefore, before a second course of therapy, the recipients serum is tested for the presence of anti-OKT3 antibodies. A longer-term concern is the increased incidence of PTLD

Humanised anti-CD25 Monoclonal Antibodies

Basiliximab and daclizumab are humanised (genetically engineered to resemble human immnoglobulins)monoclonal antibodies against CD25, a receptor on the surface of T-lymphocytes. They are indicated for prophylaxis of acute rejection in renal transplantation. The antibodies bind to and block the interleukin-2 receptor α-chain (CD25 antigen) expressed exclusively on activated T-cells. This results in inhibition of interleukin-2 induced T-cell activation

Although derivde from mouse, both are monoclonal antibodies that have been genetically engineered such that a large proportion of the antibody is replaced by human IgG. They are associated with few, if any, side effects, because they are humanised and generate little human anti-mouse response (low immunogenicity). Thus they are relatively well tolerated and hypersensitivity reactions are uncommon. First dose reactions are rare and both have long half lives. No monitoring is required


Graft Dysfunction

In the early period post-transplant, acute graft dysfunction may be due to acute rejection, but the differential diagnosis is wide. In the immediate post-op period if the creatinine is rising (or the creatinine levels out at an unexpectedly high level), rapid investigation (and treatment) is required. A renal biopsy is almost always indicated, after a 'surgical’ problem (eg obstruction) and transplant artery stenosis have been excluded with a Doppler US

Clinically the patient’s urine output may or may not decrease, they may become ‘unwell’ (febrile, tachycardic, fluid overloaded), inflammatory markers may rise or they may develop pain over the graft site. Or, there may be very little systemic upset, even in severe rejection. Treatment (eg high dose IV methylprednisolone, or oral prednisolone) should be started as soon as rejection is considered a possibility - ie do not wait for a biopsy

Possible Causes for Early Graft Dysfunction

There are four common causes, with quite different treatments

  • Acute rejection
  • Calcineurin inhibitor toxicity
  • Acute tubular necrosis (ATN)
  • Delayed graft function (normal biopsy); 30% of patients

Other causes (that need to be excluded) include:

  • Obstruction
  • BK virus nephropathy
  • Recurrence of original disease (FSGS can recur almost immediately after a transplant)
  • Transplant artery stenosis (can also occur early, through a non-atherosclerotic pathology)
  • Bacterial pyelonephritis
  • Hypovolaemia

Investigations to organise for a patient with poorly functioning renal transplant include:

  • Routine observations (never forget the basics); crucially including urine output
  • Blood tests – FBC, U&E’s, Inflammatory markers
  • Doppler US
  • Renal Biopsy – putting plenty of information on the pathology request (you will get a better report), and request SV40 (BK nephropathy) and Cd4 staining (for antibody mediated rejection)

Senior nephrologists and transplant surgeons like to be heavily involved in this early transplant period. If in doubt, ring them


Complications

The complications of transplantation can be divided into 5 categories:

  • Cardiovascular (and Atherosclerotic) Disease
  • Cancer
  • Infection
  • Bone Disorders
  • Renal (Chronic Allograft Nephropathy, and Recurrent Renal Disease)

Cardiovascular (and Atherosclerotic) Disease

Cardiovascular disease is the leading known cause of death following renal transplantation (25-30%;  Kahwaji, 2011). Death with a functioning graft caused by cardiovascular disease also represents a substantial cause of graft loss. Death rates from cardiovascular disease, although lower than in dialysis patients, still greatly exceed those of the general population. The cumulative incidence of coronary heart disease, cerebrovascular disease, and peripheral vascular disease 15 years after transplantation has been estimated at 23%, 15%, and 15% (Kasiske, 2000). Addressing risk factors for these conditions must now be an important component of routine posttransplant management. Cessation of cigarette smoking is essential, not only to reduce the risk of cardiovascular disease but also because continued smoking after transplantation is associated with poorer renal allograft survival, even after censoring for death. REF 80

A high prevalence of cardiomyopathy (presenting clinically as congestive heart failure or as left ventricular enlargement on echocardiography) has been noted in renal transplant recipients (Rigatto, 2002). One retrospective analysis found that the development of congestive heart failure after transplantation was as common as the development of coronary heart disease; furthermore, it was associated with the same risk of death. The authors thus proposed the interesting concept that transplant recipients are in a state of 'accelerated heart failure'. It is debatable whether this state is any different from the 'normal' cardiovascular state of patients on dialysis

Hypertension

The prevalence of hypertension after transplantation is at least 60% to 80%. Causes include steroid use, CNIs, weight gain, allograft dysfunction, native kidney disease, and, less commonly, transplant renal artery stenosis. The complications of post-transplant hypertension are presumed to be a heightened risk of cardiovascular disease and of allograft failure (Opeltz, 1998) although distinguishing cause and effect is difficult

Key Point: Hypertension should thus be aggressively managed in all transplant recipients; including a target blood pressure of less than 130/80 mm Hg

Non-pharmacological measures such as weight loss, moderation of sodium intake, moderation of alcohol intake, and increased exercise have traditionally not been emphasised in transplant clinics. The dosage of steroids and CNIs should be minimised, where possible. More than 1 antihypertensive drug therapy will still be required in many cases. Diuretics, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers should be used with caution in the first 3 months after transplantation as they may elevate plasma creatinine levels and thus complicate management

Although thiazide diuretics have the advantages of being well proven to reduce the cardiovascular complications of hypertension, of being inexpensive, and of enhancing the antihypertensive effects of other drugs, they are probably underused, as has been documented in the general hypertensive population.While studies have shown that angiotensin-converting enzyme inhibitors and angiotensin receptor blockers are safe and effective in treating posttransplant hypertension and in reducing proteinuria in the short-term, no long-term randomized studies have been published to date confirming specific renoprotective effects of these drugs in renal transplant recipients. Nevertheless, it seems reasonable to apply the same indications for their use as in the general hypertensive population

Hyperlipidaemia

Key Point: The prevalence of hypercholesterolaemia and hypertriglyceridemia after transplantation has been estimated as 60% and 35%, respectively (Kasiske, 2000) mostly because of steroid, CNI (ciclosporin more than tacrolimus), and sirolimus use

Because cardiovascular disease is so prevalent in these patients, it is reasonable to consider the renal transplant recipient status a 'coronary heart disease risk equivalent' when applying the guidelines. This implies targeting plasma low-density lipoprotein cholesterol levels less than 5.6 mmol/L via a combination of therapeutic lifestyle changes and drug therapy. Reduction in steroid dose and switching from ciclosporin to tacrolimus therapy will also aid in the treatment of dyslipidaemia

Statins are the cholesterol-lowering drug of choice in transplant recipients. A recently published trial of statin use in renal transplant recipients showed them to be safe and effective in lowering plasma low-density lipoprotein cholesterol concentrations (Holdaas, 2003). Cardiac deaths and nonfatal myocardial infarcts, although not overall mortality, were reduced. Because the metabolism of many statins is partly inhibited by the CNIs, blood concentrations of statins may be increased in transplant recipients, thereby increasing their risk for adverse effects such as rhabdomyolysis. This interaction is further enhanced if additional inhibitors of cytochrome P450 (eg diltiazem), are administered (Bae, 2002)

Measures to minimise the risk of statin toxicity include the following: starting with low statin doses; using pravastatin or fluvastatin (which appear to have the least interaction with CNIs); avoiding other inhibitors of the cytochrome P450 system; avoiding fibrates; and periodically checking plasma creatine kinase levels and liver function.89 Rarely, nonstatin drugs are used to lower plasma lipids in transplant patients. Bile acid sequestrants, if used, should be taken separately from CNIs as they impair absorption of these drugs. Fibrates should be prescribed with extreme caution to patients taking statins and CNIs

Hyperhomocystinaemia

Plasma homocysteine concentrations, which are elevated in patients receiving dialysis, typically fall after transplantation but do not normalise. One prospective study found hyperhomocystinemia in 70% of renal transplant patients, and hyperhomocystinemia was an independent risk factor for cardiovascular events (Ducloux, 2000). Until clinical trial results are available, no firm recommendations can be made regarding B vitamin therapies for lowering hyperhomocystinemia in transplant recipients. The effects of immunosuppressive drugs on plasma homocysteine concentrations, if there are any, remain to be determined

Anaemia

Post-transplant anemia is a common problem

Key Point: In one study, a cross-sectional analysis of transplant recipients, the prevalence of anaemia was 40% REF 91

This high prevalence reflects: (1) suboptimal graft function; (2) effects of medications that impair erythropoiesis (MMF, trimethoprim-sulfamethoxazole (septrin), and angiotensin-converting enzyme inhibitors); (3) chronic inflammatory state; and, (4) infections (eg parvovirus). Observational studies have shown a strong association between post-transplant anaemia and post-transplant development of congestive heart failure (Rigatto, 2003). Pending the results of studies of the treatment of post-transplantation anaemia, it is reasonable to manage anaemia according to guidelines developed for patients with chronic (native) kidney disease, ie focussing on iron repletion and using ESAs, for example

Diabetes, and New Onset Diabetes Mellitus after Transplantation (NODAT)

Although the survival of diabetic transplant recipients is less than that of their nondiabetic counterparts, transplantation still confers them a survival advantage compared with diabetic patients receiving dialysis as they remain on the waiting list (Wolfe, 1999)

In a patient with pre-transplant diabetes, glucose control worsens after transplantation because of corticosteroid, CNI and sirolimus use, increased food intake, weight gain, and restoration of kidney function

Furthermore, NODAT develops after transplantation in up to 25% of adults at 3 years. Risk factors for post-transplantation diabetes include greater recipient age, nonwhite ethnicity, steroid treatment for rejection, rejection episodes, high BMI, and high doses of CNIs. High-dose tacrolimus is particularly diabetogenic (causing diabetes in 30% patients), and more so in recipients with hepatitis C infection (Baid, 2002)

Rates of preventive care testing (eg, of eyes, plasma lipids, and blood hemoglobin A1c) in transplant recipients with diabetes, is poor - although higher than in dialysis patients. The major benefits of intensified multifactorial intervention in type 2 diabetes are clear (Gaede, 2003)

A subset of diabetic patients with ESRD are candidates for kidney-pancreas transplantation. The organs can be transplanted simultaneously (SPK) or as a staged procedure (pancreas after kidney (PAK)). Pancreatic allograft survival with the PAK procedure has been poorer than with simultaneous transplantation but this difference is narrowing. Furthermore, PAK affords the advantages of pre-emptive living donor kidney transplantation, better renal transplant outcomes, and fewer surgical complications (Hariharan, 2002). A benefit of reversing or halting the microvascular complications of diabetes is likely but randomised controlled trials have not been conducted and would be difficult to perform

Transplant Artery Stenosis

The incidence is 1-3%. It typically occurs 2 months to 2 years after transplantation, either from atherosclerosis of the donor vessels, clamp-cannulation injury or poor surgical technique. Immunological injury has been proposed but not proven. It may present as

  • Graft dysfunction (especially with ACE/ARB use)
  • Difficult to control hypertension
  • Diuretic resistant water and salt retention (fluid overload)
  • Erythrocytosis

There may be an associated bruit over the transplant kidney; or, if there has been a bruit, it diminishes. Diagnosis may be confirmed by Doppler US (operator dependent), CT angiography or conventional angiography. Treatment is with angioplasty and stenting, and in recurrent cases, operative revascularisation

 

Cancer

Data from tumour registries clearly demonstrate that the overall incidence of cancer in renal transplant recipients is greater than in patients receiving dialysis and in the general population. This increase in incidence applies to most cancers (at least in the Australian/New Zealand ANZDATA Registry; Stewart, 2009), but the risks for certain transplant-associated cancers such as lymphomas and skin cancers (10% prevalence) are dramatically increased (see table below; from Vadjic, 2006). Interestingly, the incidence of some common non–skin cancers (ie, breast and prostate cancers) is not increased

                                       Risk of Cancer in Australian Patients With ESKD (Vadjic, 2006)

As can be seen from the table above, after transplantation, there is a significant excess for melanoma, Kaposi sarcoma, non-Hodgkin lymphoma, Hodgkin disease, leukemia, and cancer of the lip, tongue, mouth, salivary gland, esophagus, stomach, colon, anus, liver, gallbladder, lung, connective and other soft tissue, vulva, cervix, penis, eye, thyroid, and unspecified site. A significant excess, based on less than 5 cases, was also observed for nasal cavity and vaginal cancer

Key Point: In this study, there was a 3-fold risk for 18 of these 25 sites. No cancer occurred at significantly decreased incidence after transplantation. The average time to cancer after transplantation was 9.4 years, and exceeded 10 years for 15 sites

The reported cancer incidence may be increased for several reasons. First, immunosuppression allows uncontrolled proliferation of oncogenic viruses and probably inhibits normal tumuor surveillance mechanisms. There is experimental evidence that CNIs may have tumour-promoting effects mediated by their effects on transforming growth factor production (Hojo, 1999). Second, recipient factors related to the primary renal disease (eg, analgesic use, hepatitis B infection, and hepatitis C infection) may also promote neoplasia. Finally, ascertainment bias may occur because of assiduous monitoring and reporting of transplantation patients

The cumulative amount of immunosuppression, rather than a specific drug, is the most important factor increasing the cancer risk. Thus, the single most important measure to prevent cancers is to minimise excessive immunosuppression. Primary and secondary preventive strategies for breast, lung, bowel, and urogenital cancers (eg, mammography, smoking cessation, endoscopy, and pelvic examination in women) should be similar to those recommended for the general population and should be more rigorous for cancers of the skin. Transplant recipients should be specifically counselled to minimise exposure to sun, wear protective clothing, and apply sunscreen to exposed areas. Premalignant skin lesions should be treated with cryotherapy or surgical excision

The long-term impact of the newer immunosuppression regimens on predisposition to cancer is unknown but it is certainly of some concern. A general rule is that when cancer occurs, immunosuppression should be greatly decreased. In PTLD, CNI and anti-proliferative agent stopped, and the patient left on low dose steroid. In some cases, rejection of the graft will result but the risks and benefits of continuing immunosuppression must be judged on a case-by-case basis. Unlike for lung and cardiac allografts, the loss of a renal allograft is not fatal, as dialysis is always an option. The potential antitumour effect of sirolimus has been discussed above

Post-Transplant Lymphoproliferative Disease (PTLD) 

Key Point: The cumulative incidence of post-transplant lymphoproliferative disease (PTLD) in renal transplant recipients is between 1% and 5%

More than 90% of PTLD cases are non-Hodgkin lymphomas. Immunophenotypically it is a CD20+ B-cell lymphoma, and most (ALL?) are of recipient B-cell origin. It is associated with EBV infection. Seronegative recipients of an organ from a seroposituve donor are at higherm risk. Most cases occur in the first 24 months after transplantation. PTLD usually presents with lymphadenopathy but extra-nodal involvement is common (CNS, kdimney, GI tract, liver, lungs) and mutiple sites are often affected. Risk factors include :

     • Demographic:
          o Age:
                highest prevalence in paediatric age group (0-18 yrs)
                Relative risk (RR): 2.8 compared to adult recipients
          o Race:
                RR: 2.2 for Caucasians
     • Infection:
          o EBV serostatus:
                25-50% prevalence in seronegative recipients
                1-2% for seropositive recipients
          o CMV infection: 
                Up to 6-fold higher in CMV-seronegative, CMV-positive allograft receipients
     • Immunosuppression:
         o PTLD extremely rare with steroids and azathioprine
         o Cyclosporine: RR 2.2
         o Muromonab-Cd3 (OKT3): 5-6 fold increase in risk; also ATG/ALG, Campath-1H TRUE?)
         o Synergism: OKT3 + Tacrolimus
         o Risk higher for Tacrolimus at higher levels
         o Mycophenolate mofetil: no increase in relative risk
         o Sirolimus may be assocaited with a decreased relative risk 

Infection and transformation of B cells by EBV is important in the pathogenesis of many cases of PTLD: the proliferation that transformed B cells is initially polyclonal, but a malignant clone may evolve

The prognosis of PTLD has traditionally been poor but may improve with better understanding of the management of the disease. In one study of 230 cases of PTLD referred to the French Registry (Caillard, 2006), cumulative incidence was 2% after 5 years. Patients with PTLD had a survival rate of 60% at 5 years. Graft PTLD had the best prognosis with an 80% survival rate after 5 years. Poor prognostic factors include increasing age, raised LDH levels, mutiple organ involvement, constitutional symtoms, and late presentation (>1 year) 

Optimism regarding prognosis is based on two areas. First, techniques for monitoring EBV load after transplantation are being developed. These may prove useful in identifying patients who are at high risk for developing PTLD or who have early disease, and ultimately facilitate pre-emptive therapy for such patients

Second, confidence with 'bolder' treatment is occuring. This involves reduction or cessation of immunosuppression and various combinations of antiviral therapy, radiotherapy, chemotherapy, and surgery. As stated above, CNI and anti-proliferative agent stopped, and the patient left on low dose steroid. Furthermore, several relatively non-toxic immunotherapies have been developed. These include biological immune modifiers such as interferon and IL-6, adoptive immunotherapy with virus-specific T cells, and elimination of B cells using rituximab, an anti-CD20 monoclonal antibody (Straathof, 2003). Although long-term data on the effects of rituximab in PTLD are awaited, the drug is being increasingly used because of its favourable therapeutic index. Antiviral agents are of no value

 

Infection

The transplantation procedure and subsequent immunosuppression increase the risk of serious infection. Patterns of infection can roughly be considered under 3 periods: 0 to 1 month, 1 to 12 months, and more than 12 months after transplantation:


 

                                                 Infections Post Transplant (Jha, 2010)

Most infections in the first month after transplantation are similar to those that can be seen in any surgical ward: infections of wounds, lungs, and urinary tract and vascular catheters; they are usually treated accordingly

Weeks of intense immunosuppression now increase the risk of opportunistic infections from microorganisms such as CMV, EBV, Listeria monocytogenes, Pneumocystis jiroveci (carinii) and Nocardia species. Typical preventive measures for infections from 1 to 6 months after transplantation include anti-viral prophylaxis (for 3-6 months after transplantation) and trimethoprim-sulfamethoxazole prophylaxis (for 6-12 months)

With reduction in immunosuppression, the risk of infection usually decreases in the long term (>6 months after transplantation) and becomes quite similar to that of the general population. Thus, a previously stable patient with a plasma creatinine concentration of 120 µmol/L) presenting 3 years after transplantation with community-acquired pneumonia is much more likely to have pneumococcal or mycoplasmal infection than pneumocystosis. Two groups, however, remain at significantly higher risk for opportunistic infection: those with poor graft function and those receiving late additional immunosuppression (typically in cases of rejection). These patients should continue to receive trimethoprim-sulfamethoxazole

CMV Disease

CMV is the commonest infection post-transplantation. Chances of exposure to CMV (as evidenced by anti-CMV IgG) increases with age, and more than two thirds of donors and recipients are latently infected prior to renal transplantation. Cytomegalovirus disease (confirmed by recent laboratory testing and evidence of tissue inflammation and/or dysfunction) can arise because of reactivation of latent recipient virus, reactivation of latent donor-derived virus, or primary infection with donor-derived virus. Not surprisingly, the risk of CMV disease is highest in CMV-positive donor/CMV-negative recipient pairings; lowest in CMV-negative donor/CMV-negative recipient pairings; and intermediate in CMV-positive donor/CMV-positive recipient pairings and CMV-negative donor/CMV-positive recipient pairings

Cytomegalovirus disease usually arises 1 to 6 months after transplantation, although gastrointestinal and retinal involvement often occurs later. In immunosuppressed patients CMV induces a variety of syndromes including:

    • Non-specific
          o Fever, malaise, myalgia
    • Bone marrow (ganciclovir and valgancyclovir can also cause)
          o Leucopenia
          o Thrombocytopaenia
    • Gastrointestinal
          o Hepatitis (abn LFTs, rarely severe)
          o Oesophagitis/gastritis (often late)
          o Colitis (often late)
    • Respiratory
          o Pneumonitis (dry cough, SOB)
    • Ocular
          o Retinitis (blurred vision, flashes, floaters; rare and late)
    • Neurological
          o Transverse myelitis
          o Encephalitis
     • Other
          o Cutaneous vasculitis

CMV pneumonitis is an important manifestation. It presents with dry cough, dyspnoea and hypoxia. CXR may show bilateral interstitial or reticulonodular infiltrates beginning in the periphery of the lower lobes and spreading centrally and superiorly. Initially it can be normal, or near normal. Localized segmental, nodular or alveolar patterns less commonly involved. Diagnosis requires lung biopsy or BAL. Most cases associated with bacterial, fungal or protozoal superinfection so it can be difficult to assess the clinical relevance of CMV isolation from respiratory secretions or positive serology

CMV pneumonitis: CXR shows multiple small, ill-defined nodules throughout the lungs

Fatal CMV infections often associated with persistent viraemia and multiple organ involvement. Progressive pulmonary infiltrates, pancytopaenia, hyperamylasaemia and hypotension are characteristic. Superinfection with bacterial, protozoa and fungi are also common

Urgent investigation and immediate empiric treatment is needed in severe cases. The virus can be detected in blood or tissue fluids by rapid shell-vial culture, antigen assays, or polymerase chain reaction (serology studies are of little benefit in the acute setting); the optimal test depends on local expertise. CMV in blood is more clinically significant than in oropharyngeal secretions/urine as excretion from the latter sites may continue for months to years following illness

The virus can also be identified in involved tissue by immunohistochemistry techniques. Importantly, low or negative CMV concentrations in peripheral blood do not exclude organ involvement (especially of the gastrointestinal tract); therefore, bronchoscopy, endoscopy, or any other appropriate investigation should be aggressively pursued according to symtoms and signs. A tissue diagnosis is also required to exclude coinfection with other microbes, eg P jiroveci

Cytomegalovirus disease is treated with reduction in immunosuppression and specific antiviral agents, usually ganciclovir or valganciclovir. The latter has much better oral bioavailability and is increasingly used instead of intravenous ganciclovir. Foscarnet is nephrotoxic and should only be used for the rare cases resistant to ganciclovir. Although supportive data for the treatment are unavailable, it is reasonable to add CMV hyperimmune globulin in severe cases

The prevention of CMV disease is of great clinical importance. One strategy is to provide prophylaxis to all patients at risk, ie, when the donor and/or recipient has positive serology findings for CMV. Another strategy is to provide prophylaxis only to those at greatest risk or those who show laboratory evidence of new virus replication. Both have advantages and disadvantages. Valganciclovir is a commonly used as preventive agent, typically for 3 to 4 months after transplantation

BK Nephropathy

Polyoma BK virus (BKV) is a ubiquitous DNA virus from the papova virus family. Although the two human polyomaviruses, BK virus (BKV) and JC virus (JCV), were reported in 1971 (BK by Gardner, 1971), their influence and importance were limited. It has subsequently been discovered that approximately 60-80% of the adult population worldwide is seropositive for BKV. BKV causes latent infection of the kidney, with reactivation during immunosuppression

Key Point: Post-transplantation reactivation is common (20-45%). Only 1–10% of patients progress from reactivated infection to histologically proven polyoma BKV nephropathy (BKVN). BKVN may present as a rising creatinine. Most polyomavirus infections are asymptomatic and occur within the first 3 months after transplantation; with the virus establishing latency within the genitourinary tract. The daignosis requires a transplant biopsy demonstrating viral inclusion bodies in renal tubular cells, and positive for the SV40 antigen. Polymerase chain reaction (PCR) of serum for BKV DNA and viral load is useful fro diagnosis and monitoring the disease

Like CMV, it is the consequence of modern potent immunosuppression aimed at reducing acute rejection and improving allograft survival. In early studies of BK, up to 80% of the patients with BKVN were reported to lose their graft, but early reduction of immunosuppression has been associated with improved prognosis (15-50%)

Decreased immunosuppression is the principle treatment but predisposes to acute and chronic rejection. Screening protocols for early detection and prevention of symptomatic BKV nephropathy have improved outcomes. Although no approved antiviral drug is available, leflunomide, cidofovir, quinolones, and intravenous Ig have been used. Retransplantation after BKV nephropathy has been successful. The subject has been reviewed by Bohl in 2007

Pneumocystosis

In the absence of prophylaxis, pneumocystosis occurs most commonly in the first year after transplantation (although not in the first month) but can occur later, especially if immunosuppression is increased. Typical symptoms of pneumonia due to P jiroveci are fever, shortness of breath, and non-productive cough. Chest radiography characteristically shows bilateral interstitial-alveolar infiltrates, especially in the lower zones. Like CMV, it can be normal or near-normal initially. Diagnosis requires detection of the organism in a clinical specimen by colorimetric or immunofluorescent stains

CXR: Pneumocystis jiroveci pneumonia shows slight reticular abnormality (arrows) in the lower part of both lungs

Because the organism burden is usually lower than in HIV-infected patients, the sensitivity of induced sputum or bronchoalveolar lavage specimens is lower in renal transplant recipients; tissue biopsy should be quickly obtained if these tests are negative and the clinical suspicion remains high. The treatment of choice remains trimethoprim-sulfamethoxazole. High-dose trimethoprim-sulfamethoxazole may increase plasma creatinine concentration without affecting glomerular filtration rate, ie 'real' kidney function. Unlike in HIV-positive patients, there is no firm evidence to support the use of higher-dose steroids during the early treatment phase of pneumocystosis in renal transplant patients

Fortunately, antimicrobial prophylaxis is very effective in preventing pneumonia due to P jiroveci. The preventive agent of choice is trimethoprim-sulfamethoxazole; it is inexpensive and generally well tolerated, and also prevents urinary tract infections and opportunistic infections such as nocardiosis, toxoplasmosis, and listeriosis. Alternatives drugs include dapsone with or without pyrimethamine, atovaquone, and aerosolized pentamadine

Immunisation in Renal Transplant Recipients

This topic has been reviewed by Duchini (2003). Generally accepted guidelines are as follows: (1) immunisations should be completed at least 4 weeks before transplantation; (2) immunisation should be avoided in the first 6 months after transplantation because of ongoing administration of high-dose immunosuppressive agents and a risk of provoking graft dysfunction; and (3) live vaccines should be avoided altogether after transplantation. Household members of transplant recipients should receive yearly immunisation against influenza

Summary

Minimising infection risk after transplantation requires a meticulous surgical technique; monitoring or prophylaxis for viral infection in the first 3 to 6 months; trimethoprim-sulfamethoxazole prophylaxis for the first 6 to 12 months; and, of course, avoidance of excessive immunosuppression. The last point is particularly relevant for elderly recipients. When infection is suspected, early aggressive diagnosis (eg by bronchoscopy in patients with suspected pneumonitis) and therapy are essential. If life-threatening infection occurs, immunosuppression must be stopped or greatly reduced (stress-dose steroids may still be required)
 

Bone Disorders

Bone disease in the dialysis patient is multifactorial and involves varying degrees of hyperparathyroidism, vitamin D deficiency, adynamic bone disease, aluminum intoxication, and amyloidosis. Successful renal transplantation offers the potential to reverse or at least prevent further progression of these conditions. Unfortunately, bone disease can be a major problem after renal transplantation because of the persistence of the above conditions, suboptimal kidney function, and the superimposed effects of steroids on bone

Osteoporosis

Reduction in bone mineral density is now recognised as a very common complication of solid organ transplantation, affecting up to 60% in the first 18 months after renal transplantation. It is important to note that the pathophysiology and treatment of osteoporosis may differ from that seen in the general population. The principal cause is steroid use—through direct inhibition of osteoblastogenesis, induction of apoptosis in bone cells, inhibition of sex hormone production (in both men and women), decreased gut calcium absorption, and increased urinary calcium excretion

Other factors that may play a role include persistent hyperparathyroidism after transplantation, postmenopausal state, vitamin D deficiency and/or resistance, and phosphate depletion. Low bone mineral density is likely to be a risk factor for fractures in renal transplant recipients, although this has not yet been proven. In fact, limited evidence suggests that low bone mineral density, as identified by dual-energy x-ray absorptiometry (DEXA), is not a risk factor for future fracture (Torres, 2002). There is no doubt, however, that pathological fractures are common after renal transplantation. The estimated total fracture rate after renal transplantation, which is 2% per year in non-diabetic patients, 5% per year in type 1 diabetic patients, and up to 12% per year in pancreas-kidney recipients

Interventions to minimise posttransplantation bone loss include weight-bearing exercise, calcium, vitamin D and bisphiosphonates if indicated. Implementation of these measures immediately after transplantation is essential, as most of the bone loss occurs in the first 6 months when the doses of steroids are highest. There is evidence that bisphosphonates effectively prevent post-transplantation bone loss, but trials reported to date have been underpowered to detect reductions in post-transplantation fracture rates. There is still some concern that these agents, by suppressing bone remodeling, could worsen the mechanical integrity of bone in conditions such as osteomalacia or adynamic bone. Furthermore, albeit at very high doses, bisphosphonates can be nephrotoxic

A reasonable approach is to obtain DEXA of 3 bone sites (lumbar spine, forearm, and hip) at the time of transplantation in patients with conventional risk factors for osteoporosis. In those considered to be at high risk for osteoporosis-related fracture based on clinical features and DEXA results, post-transplantation administration of bisphosphonates and the use of minimal-dose steroids or of nonsteroid protocols should be considered. In all patients, DEXA scan is recommended every two years, and bisphosphonates prescribed if indicated. Close collaboration with a bone endocrinologist in these situations is also advised. All patients should receive calcium and synthetic forms of vitamin D after kidney transplantation, if indicated by calcium and PTH levels, unless there are contraindications

Hyperparathyroidism

Incomplete resolution of hyperparathyroidism is very common after renal transplantation. This reflects multiple factors: inherent slow involution of parathyroid cells, suboptimal renal function, suboptimal production of 1,25-dihydroxyvitamin D3, and steroid-induced reduction in intestinal calcium absorption.125 Post-transplantation hyperparathyroidism can cause hypercalcemia and exacerbate bone loss. If hypercalcemia is severe and associated with complications such as graft dysfunction, early parathyroidectomy is indicated. Less severe cases can be given a trial of medical therapy. Better control of hyperparathyroidism before transplantation remains the key to preventing significant post-transplantation parathyroid disease

Osteonecrosis (Avascular Necrosis)

Osteonecrosis or avascular necrosis (AVN) of bone has been reported to occur in 3% to 16% of renal transplant recipients (Heaf, 2003). Femoral head (90%), knee, ankle, shoulder, or elbow joints can be involved. It can occur early, even in the first 3 months. The principal cause is steroid use. Fortunately, the incidence has greatly declined because renal transplant recipients now receive lower cumulative doses of steroids (maintenance doses are lower, and fewer 'pulses' are required because acute rejection is less common). The presenting symptom is joint pain. Magnetic resonance imaging, radionuclide bone scan, and plain films (in order of decreasing sensitivity) are used to confirm the diagnosis. Core compression of hip replacement (60%) is required for AVN of the femoral head
 

Renal

Chronic Allograft Nephropathy 

After censoring for death, chronic allograft nephropathy is the most important cause of long-term graft loss. The majority of kidney allografts deteriorate in the long‐term and are eventually lost. Chronic allograft nephropathy is preferable to the older designation of 'chronic rejection' because it encompasses the role of immunological and non-immunological factors. Nephrotoxicity, ischaemia, hypertension, scarring as a consequence of previous acute rejections, and hyperfiltration due to low nephron mass are among those discussed. Pre‐existing age‐related damage of the donated kidney is another relevant factor

This subject has been reviewed by Li in 2009

Typical clinical features of chronic allograft nephropathy are hypertension, low-grade proteinuria, and slowly rising plasma creatinine level more than 6 months after transplantation. Inflammatory or proliferative processes in the arterial walls attract much interest, and are sometimes described as key events. Interstitial fibrosis and tubular atrophy are other prominent features. Nonspecific arterial wall thickening is partly dependent on baseline conditions and lacks prognostic impact in this late stage. CAN was classified as 'Class 5 Rejection' in the Banff '07 Classification. There is often a history of acute rejection

                                    Transplant Biopsy (Chronic Allograft Nephropathy)

Specific treatment options are limited and progression to ESRF is usually slow and usuallly inevitable. Recipients with failing allografts should be managed similarly to those with native CKD with regard to treatment of anaemia, hyperparathyroidism, hypertension, and other complications of renal failure. Chronic allograft nephropathy itself is not a contraindication to future transplantation; indeed, allograft loss is a common diagnosis in those joining the organ waiting list

Recurrent Renal Disease

The most common causes of post-transplant proteinuria is chronic allograft nephropathy (60%), followed by recurrent (15%) and de novo (10%) glomerulonephritis. The most common cause of recurrence is FSGS (25-30% with first transplant). The risk rises to 50% if a previous kidney has been lost through recurrence. Other causes include:

  • HUS/TTP (classic 1%, atypical 20%, familial 80%). De novo HUS/TTP has been attributed to OKT3, vascular rejection and CNIs
  • Mesangioproliferative glomerulonephritis (Type 1, 25%; Type 2 80%)
  • Membranous glomerulonephritis (30%)
  • IgA Nephropathy (25%) and Henoch Schonlein Purpura Nephritis
  • ANCA-related vasculitis (20%); a positive ANCA is not a contraindication to transplantation
  • Anti-GBM disease (10-25%); most units wait 12 months from when antibodies are negative before offering transplantation
  • Primary oxalosis (should have a liver transplant)
  • Secondary amyloidosis (if cause is still present)
  • Diabetic nephropathy (recurs in 100%, but causes kidney loss in <2%)

Summary

Top Tips: Living renal transplantation is the treatment of choice for many patients with ESRF. Think about it in patients with CKD3B or above

  1. In the UK, deceased donor graft survival rates are 93% and 85% at one and five years after transplantation, respectively; while comparable rates for grafts from living donors are 96% and 90%
  2. For deceased donor transplants, patient survival is 96% and 87% at one and five years. For living donor transplants, its is 99% and 96%
  3. Hypertension should be aggressively managed in all transplant recipients; including a target blood pressure of less than 130/80 mm Hg
  4. Prevalence of hypercholesterolaemia and hypertriglyceridemia after transplantation has been estimated as 60% and 35%
  5. Anaemia occurs in 40% patients
  6. Cumulative incidence of post-transplant lymphoproliferative disease (PTLD) is 1-5%; most occur in the first 24 months of transplantation
  7. For transplant patients, there is >3-fold risk for many cancers, with an average time to cancer after transplantation of approximately 10 years
  8. CMV is the most frequent infection post-transplantation
  9. Post-transplantation reactivation of BK virus is common (20-45%). Only 1–10% of patients progress from reactivated infection to histologically proven polyoma BKV nephropathy (BKVN) 

References

Articles

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A good review article 

Bae J, Jarcho JA, Denton MD, Magee CC. Statin specific toxicity in organ transplant recipients: case report and review of the literature. J Nephrol 2002; 15: 317-319

Baid S, Tolkoff-Rubin N, Farrell ML, et al. Tacrolimus-associated posttransplant diabetes mellitus in renal transplant recipients: role of hepatitis C infection. Transplant Proc 2002; 34: 1771-1773

Billingham RE, Medawar PB. The Technique of Free Skin Grafting in Mammals. J Exp Biol 1951; 28: 385-402
A classic paper, important in the field of transplant immunology

Billingham RE, Brent L, Medawar PB. Actively Acquired Tolerance of Foreign Cells, Nature 1953; 172: 603–606

Bohl DL, Brennan DC. BK Virus Nephropathy and Kidney Transplantation. CJASN 2007; 2 (Supplement 1): S36-S46

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Caillard S et al. Post-transplant lymphoproliferative disorders occurring after renal transplantation in adults: report of 230 cases from the French Registry. Am J Transplant 2006; 6(11): 2735-42

Calne RY, Alexandre GP, Murray JE. A study of the effects of drugs in prolonging survival of homologous renal transplants in dogs. Ann N Y Acad Sci 1962; 99: 743-61

Calne RY, White DJG, Thiru S, Evans DB, McMaster P, Dunn DC et al. Cyclosporin A in patients receiving renal allografts from cadaver donors. The Lancet 1978; 2: 1323-1327

Cameron JI, Whiteside C, Katz J, Devins GM. Differences in quality of life across renal replacement therapies: a meta-analytic comparison. Am J Kidney Dis 2000; 35: 629-637

Carrel A: The operative technique for vascular anastomoses and transplantation of viscera. Lyon Medical 1902; 98: 859

Carrel A. The transplantation of organs: a preliminary communication. JAMA 1905;45: 1654

Desai SP et al. A Semi-Centennial Report on the Participants Depicted in Joel Babb’s Portrait, ‘The First Successful Kidney Transplantation’. American Journal of Transplantation 2007; 7: 1683-1688
A fascinating article that follows up the team that assisted Joseph Murray in his pioneering transplant in 1954

Druml W. The beginning of organ transplantation: Emerich Ullmann (1861-1937). Wien Klin Wochenschr 2002; 114: 128

Dubost C, Oeconomos N, Nenna A, Milliez P: Resultats d'une tentative de greffe renale. Bull Soc Med Hop Paris 1951; 67: 1372-1382

Duchini A et al. Vaccinations for Adult Solid-Organ Transplant Recipients: Current Recommendations and Protocols. Clin Microbiol Rev 2003; 16(3): 357-364

Ducloux D, Motte G, Challier B, Gibey R, Chalopin JM. Serum total homocysteine and cardiovascular disease occurrence in chronic, stable renal transplant recipients: a prospective study. J Am Soc Nephrol 2000; 11: 134-137

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Gardner SD, Field AM, Coleman DV, Hulme B. New human papovavirus (B.K.) isolated from urine after renal transplantation. Lancet 1971; 1: 1253-1257

Goodwin WE, Kaufman JJ, Mims MM, et al. Human and renal transplantation. I. Clinical experiences with six cases of renal transplantation. J Urol 1963; 89: 13

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Groth CG: Landmarks in clinical renal transplantation. Surg Gynecol Obstet 1972; 134: 323-328

Halloran PF. Sirolimus and cyclosporin for renal transplantation. Lancet 2000; 356: 179-180

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Hamilton DN, Reid WA. Yu Yu Voronoy and the first human kidney allograft. Surg Gynecol Obstet 1984; 159: 289

Hariharan S, Pirsch JD, Lu CY, et al. Pancreas after kidney transplantation. J Am Soc Nephrol 2002; 13: 1109-1118

Heaf JG. Bone disease after renal transplantation. Transplantation 2003; 75: 315-325

Holdaas H, Fellstrom B, Jardine A, et al. Effect of fluvastatin on cardiac outcomes in renal transplant recipients: a multicentre, randomised, placebo-controlled trial. Lancet 2003; 361: 2024-2031

Hojo M, Morimoto T, Maluccio M, et al. Cyclosporine induces cancer progression by a cell-autonomous mechanism. Nature 1999; 397: 530-534

Hricik D. Steroid-free immunosuppression in kidney transplantation: an editorial review. Am J Transplant. 2002; 2: 19-24

Hubner GI, Eismann R, Sziegoleit W. Drug interaction between mycophenolate mofetil and tacrolimus detectable within therapeutic mycophenolic acid monitoring in renal transplant patients. Ther Drug Monit 1999; 21: 536-539

Hume OM, Merrill JP, Miller BF, Thorn GW: Experiences with renal homotransplantation in the human: report of nine cases. J Clin Invest 1955; 34: 327-382

Internation Neoral Renal Transplantation Study Group. Randomized, international study of cyclosporine microemulsion absorption profiling in renal transplantation with basiliximab immunoprophylaxis. Am J Transplant 2002; 2: 157-166

Jaboulay M. Greffe de reins au pli du coude par soudure arte. Bull Lyon Med 1906; 107: 575

Jha V. Post-transplant infections: An ounce of prevention. Indian J Neph; 2010; 20(4): 171-178

Joekes AM, Porter KA, Dempster WJ. Immediate post-operative anuria in a human renal homotransplant. Br J Surg 1957; 44(188): 607-15

Kahwaji J, Bunnapradist S, Hsu JW, Idroos ML, Dudek R. Cause of death with graft function among renal transplant recipients in an integrated healthcare system. Transplantation 2011; 91(2): 225-30

Kasiske BL, Vazquez MA, Harmon WE, et al, for the American Society of Transplantation. Recommendations for the outpatient surveillance of renal transplant recipients. J Am Soc Nephrol 2000; 11(Suppl 15): S1-S86

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Laskow DA, Vincenti F, Neylan JF, Mendez R, Matas AJ. An open-label, concentration-ranging trial of FK506 in primary kidney transplantation: a report of the United States Multicenter FK506 Kidney Transplant Group. Transplantation 1996; 62(7): 900-5

Laupacis A, Keown P, Pus N, et al. A study of the quality of life and cost-utility of renal transplantation. Kidney Int 1996; 50: 235-242

Lawler RH. West JW, McNulty PH. et al: Homotransplantation of the kidney in the human. JAMA 1950; 144: 844-845

Li C, Yang CW. The pathogenesis and treatment of chronic allograft nephropathy. Nature Reviews Nephrology 2009; 5: 513-519 

Magee CC, Pascual M. Update in Renal Transplantation. Arch Intern Med 2004; 164: 1373-1388
Another good review article

McAlister VC. Clinical kidney transplantation: a 50th anniversary review of the first reported series. Am J Surg 2005; 190(3): 485-8
Description of Gordon Murrays series of transplants (1950-2)

Merrill JP, Murray JE, Harrison JH, Guild WR. Successful homotransplantation of the human kidney between identical twins. JAMA 1956; 160: 277-282

Michon L. Hamburger J, Oeconomos N, et al: Une tentative de transplantation renale chez l'homme: aspects medicaux et biologiques. Presse Med 1953; 61: 1419-1423

Morath C et al. Sirolimus in renal transplantation. Nephrol Dial Transplant 2007; 22 (Suppl 8): viii61-viii65
A good review article on sirolimus

Murgia MG, Jordan S, Kahan BD. The side effect profile of sirolimus: a phase I study in quiescent cyclosporine-prednisone-treated renal transplant patients. Kidney Int 1996; 49: 209-216

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87: 508–15

Murray JE. Merrill Jr, Harrison JH. Renal homotransplantation in identical twins. Surg Forum 1955; VI: 432-436

Murray JE, Merrill JP, Harrison JH, et al. Prolonged survival of human-kidney homografts by immunosuppressive drug therapy. N Engl J Med 1963; 268: 1315

Murray JE. Human kidney transplant conference. Transplantation 2: 147, 1964

Murray JE. Nobel Lecture. 2nd December, 1990

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Moore FO. Transplant The Give and Take of Tissue Transplantation. New York. Simon & Schuster, 1972: 1-364

NHS Blood and Transplant. UK Activity Report (2009-10)

Oh YW et al. Pulmonary Infections in Immunocompromised Hosts: The Importance of Correlating the Conventional Radiologic Appearance with the Clinical Setting. Radiology 2000; 217: 647-656
A good review of the pulmonary infections that may affect transplant patients

Ojo AO, Meier-Kriesche HU, Hanson JA, et al. Mycophenolate mofetil reduces late renal allograft loss independent of acute rejection. Transplantation 2000; 69: 2405-2409

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Pichard L et al. Cyclosporin A drug interactions. Screening for inducers and inhibitors of cytochrome P-450 (cyclosporin A oxidase) in primary cultures of human hepatocytes and in liver microsomes. Drug Metab Dispos 1990; 18(5): 595-606

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Rigatto C, Parfrey P, Foley R, Negrijn C, Tribula C, Jeffery J. Congestive heart failure in renal transplant recipients: risk factors, outcomes, and relationship with ischemic heart disease. J Am Soc Nephrol. 2002; 13: 1084-1090

Rigatto C, Foley R, Jeffery J, Negrijn C, Tribula C, Parfrey P. Electrocardiographic left ventricular hypertrophy in renal transplant recipients: prognostic value and impact of blood pressure and anemia. J Am Soc Nephrol 2003; 14: 462-468

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A good review of mechanisms of action of immunosuppression

Servelle M, Soulie P, Rougeulle J: Greffe d'une rein de supplicie a une malade avec rein unique congenital, atteinte de nephrite chronique hypertensive azatemique. Bull Soc Med Hop Paris 1951; 67: 99-104

Solez K et al.  Banff 07 classification of renal allograft pathology: updates and future directions. Am J Transplant 2008; 8(4): 753-60

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A fascinating account of the important French contribution to the history of transplantation in 1950s and early 60s

Starzl TE. History of Clinical Transplantation. World J Surg 2000; 24(7): 759–782
An excellent history of renal transplantation

Starzyl TE. The Birth of Clinical Organ Transplantation. J Am Coll Surg. 2001; 192(4): 431–446
A very good history of the early years of transplantation

Stewart JH et al.  The pattern of excess cancer in dialysis and transplantation. Nephrol Dial Transplant 2009; 24(10): 3225-31

Straathof KC, Savoldo B, Heslop HE, Rooney CM. Immunotherapy for post-transplant lymphoproliferative disease. Br J Haematol 2002; 118: 728-740

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Another good history of transplantation

Torres A, Lorenzo V, Salido E. Calcium metabolism and skeletal problems after transplantation. J Am Soc Nephrol 2002; 13: 551-558

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Vajdic CM et al. Cancer Incidence Before and After Kidney Transplantation. JAMA 2006; 296(23): 2823-2831

Vincenti F, Jensik SC, Filo RS, Miller J, Pirsch J. A long-term comparison of tacrolimus (FK506) and cyclosporine in kidney transplantation: evidence for improved allograft survival at five years. Transplantation 2002; 73: 775-782

Voronoy U. Sobre bloqueo del aparato reticuloendotelial del hombre en algunas formas de intoxicacion por el sublimado y sobre la transplantacion del rinon cadaverico como metoda de tratamiento de la anuria consecutiva a aquella intoxicacion. Siglo Medico 1937; 97: 296-297

Wolfe RA, Ashby VB, Milford EL, et al. Comparison of mortality in all patients on dialysis, patients on dialysis awaiting transplantation, and recipients of a first cadaveric transplant. N Engl J Med 1999; 341: 1725-1730

Woodle ES, Thistlethwaite JR, Gordon JH. Tacrolimus therapy for refractory acute renal allograft rejection: a prospective multicenter trial. Tacrolimus Kidney Transplantation Rescue Study Group. Transplant Proc 1996; 28(6): 3163-4

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Guidelines

US/KDIGO. Management of Kidney Transplant Recipients. Sept 2009