Last updated: Lupus Nephritis…
on 26 Aug 2016

Renal Transplant


Adnan Sharif  -  Review Date Feb 2016 (Senior Editor Paul Cockwell)

Kidney transplantation is the treatment of choice for the majority of patients with end-stage kidney disease. Since the first successful kidney transplant in 1954, the scientific advances over the subsequent decades have led to significant improvements in patient/graft survival and quality of life for kidney allograft recipients, making kidney transplantation one of the success stories of modern medicine. However with increasing success comes increasing expectations and major challenges remain in trying to expand, improve and optimise the option of kidney transplantation to all suitable candidates.

Survival data

The latest data from the NHS Blood and Transplant annual activity report 2010/2011 demonstrates the following patient survival data; living donors (1-year 99%, 5-year 96% and 10-year 90%), donation after brain death (1-year 96%, 5-year 89% and 10-year 74%) and donation after cardiac death (1-year 95%, 5-year 88% and 10-year 66%). Respective graft survival data is; living donors (1-year 97%, 5-year 92% and 10-year 79%), donation after brain death (1-year 94%, 5-year 84% and 10-year 69%) and donation after cardiac death (1-year 92%, 5-year 86% and 10-year 70%).

While these numbers represent excellent graft survival, and early graft losses has dramatically improved, concern remains over long term kidney allograft attrition rates which have remained relatively constant (Lodhi 2010). Understanding the mechanisms for long term kidney allograft loss is an important issue. El-Zoghby (2009) and colleagues have attempted to determine specific causes of kidney allograft loss and suggest glomerular pathology is the leading cause, with alloimmunity the most common mechanism leading to failure. However debate continues on the relative contributions between chronic antibody mediated injury  (Matas 2011) and calcineurin inhibitor nephrotoxicity (Chapman 2011) with regards to long-term graft failure.

Disparity in supply and demand for kidneys

Other concerns remain regarding ongoing disparity in the supply and demand for kidneys and the new strategic plan from NHS Blood and Transplant will focus on ways to tackle this over the upcoming few years. Novel strategies to tackle donation rates are being tried to overcome donor shortages. Some countries (e.g. Spain, Austria) have adopted an 'opt out' system which presumes consent unless an individual has specifically chosen to opt out. Within the United Kingdom, recently Wales has given the go ahead for their own opt out system (BBC News 2013) and it will be interesting to see how their experience unfolds. Other countries have adopted even more novel strategies by attempting to tackle donor apathy by introducing a priority scoring system. Lavee 2012 have demonstrated a marked increase since the recent introduction of a priority scoring system, which gives priority to kidney candidates who have previously donated or who have been previous organ donation registrants for 3 years or more. A similar strategy has been proposed for the United Kingdom Sharif 2013, with an emphasis on the potential to boost organ donation from Black, Asian, Minority Ethnic (BAME) groups.

Benefits of kidney transplantation

Patient survival following kidney transplantation is better in comparison to age-matched individuals remaining on the transplant waiting list. In a landmark study, Wolfe 1999 and colleagues performed a longitudinal study of 228,552 patients with end-stage kidney disease receiving haemodialysis and compared survival between three groups; patients receiving a transplant (n=23,275), wait-listed patients (46,164) and remaining patients not deemed fit for transplantation and continuing on dialysis. Mortality was 68% lower for transplant recipients than for those remaining on the transplant waiting list. This resulted in a mean increase in projected survival of 10 years. The increased survival benefit was seen in both sexes, all age group and in patients with diabetes. Larger benefits were seen in dialysis patients who were younger, white and young with diabetes.

While the findings from this study were replicated in a smaller study from Scotland (Oniscu 2005), more recent data from the UK Renal Registry 2012 report suggest kidney allograft recipients aged over 65 may not enjoy a major survival advantage compared to matched patients on the waiting list.

However there are other advantage of kidney transplantation that are equally important such as quality of life (Fiebiger 2004) that should always be factored into the decision to proceed with transplantation for each individual candidate. In addition successful kidney transplantation is more cost effective than expensive dialysis (Sharif 2011). The benefits and risks of kidney transplantation should be discussed on an individual basis with potential candidates. However for the majority of patients with end-stage kidney disease, kidney transplantation will be a more suitable modality of renal replacement therapy than dialysis.

Types of kidney transplants

Living versus deceased kidneys

The proportion of kidney transplants from living donors has increased significantly in the last decade and as shown in the latest Transplant activity report in the UK. Living donation requires careful medical and psychological assessment of the potential donor to assess the suitability and safety of donation.

There are five important principles in assessing potential living kidney donors (British Transplant Society guidelines);

1. Is the candidate medically, surgically and anaesthetically fit for surgery?

2. Does the candidate have any kidney problem that would preclude kidney donation?

3. Does the candidate have an risk factors for developing kidney disease?

4. Is there any risk of disease transmission from donor to recipient?

5. Is the candidate fully counselled and informed?

In the contemporary era living donor nephrectomy is usually performed laparoscopically, an approach that is associated with less wound pain, a shorter hospital stay and faster recovery. Nevertheless, donation is not without risk, with a mortality rate of 1:3000, and a major and minor complication rate of approximately 2% and 20% respectively. The advantages for recipients of living kidneys are significant; better patient survival, better graft survival and more likelyto receive pre-emptive or timely kidney transplants.

Donation after brain versus cardiac death

Most deceased kidney donation occurs following certification of death using brainstem criteria, so-called donation after brain death (DBD, formerly called heart-beating donation). Such donors receive cardiorespiratory support until donation occurs in the operating theatre, at which point the kidneys are cooled by flushing with ice- cold preservation solution. One-third of kidneys are donated following circulatory-determined death (DCD, formerly non-heart- beating donation), when the donor is transferred to the operating theatre after death has been certified by the absence of a circulation. The additional period of warm ischaemia results in a higher incidence of acute tubular necrosis (leading to delayed graft function) in DCD kidneys (50-60%) compared to DBD kidneys (20-30%); by contrast, most live donor kidneys function immediately with no requirement for post-operative dialysis (Sharif 2013).

Although previous DCD kidneys were considered inferior to DBD kidneys, recent work (Summers 2010) has demonstrated equivalent results for many kidney allograft recipients who receive a DCD kidneys (especially if receiving first kidney). Certainly in the UK, the use of DCD kidneys is on the increase.

Standard versus expanded criteria deceased kidneys

Increasing donor age, a history of hypertension and a history of cardiac disease all predict poorer long-term graft survival. Expanded criteria kidneys are defined as any deceased kidney over the age of 60 or over 50 with additional risk factors (hypertension, renal dysfunction and death from cerebrovascular accident). Although outcomes are inferior to standard criteria kidneys, they may still be preferable with regards to comparisons to dialysis (Metzger 2003).

Organ preservation techniques

Emerging technology is seeking to improve deceased donor quality by minimising the insults from ischaemic-reperfusion injury (clinically manifesting as delayed graft function) (Sharif 2013). They inlcude cold storgae (with preservation solutions), hypothermic machine perfusion and normothermic perfusion. The latter is the most encouraging and experimental, with the recent proof of concept study extended to human kidneys (Nicholson 2013). Further work is required in this area to determine the optimum preservation (and optimisation) of deceased kidneys for transplantation.

Antibody-incompatible kidney transplantation

For approximately a third of living donor transplant pairs there will be an incompatibility (blood group or anti-HLA)  that prohibits transplantation conventionally. For such pair there are novel frameworks to facilitate transplantation (Sharif 2012) involving either desensitisation or kidneys paired donation. Desensitisation, which involves removing or attenuating antibodies prior to transplantation, has been successfully performed in many centres for over a decade with good results. Kidney paired donation is an alternative, which provides a framework for swapping kidneys to facilitate transplantation (Wallis 2011). For the most immunologically difficult patients, a combination of the two strategies may be necessary to allow transplantation to proceed (Montgomery 2010).


The transplantation of non-human kidneys into humans has been speculated for many decades. Although it remains in the translational stage, there is continued expectation that perhaps this generation of genetically-modified non-human organs (e.g. from pig) may be able to be transplanted into humans to overcome organ shortages (Ekser 2012).

Implantable artificial kidney

Scientists are working on the creation of artificial kidneys that may ameliorate the need for alternative renal replacement therapy. UCSF scientists are postulating that human trials may be possible by 2017 and their centre is on an accelerated FDA program to drive developments.


Immunosuppression post kidney transplantation can be divided into induction and maintenance therapy. Over the last few decades the armamentarium of immunosuppressants has expanded to allow tailored therapy to be administered to kidney allograft recipients based upon available evidence from clinical trials.

Induction Therapy

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 depletion of peripheral lymphocytes.

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. Administration results in depletion of peripheral lymphocytes. This drug is rarely used now due to its intense activity and profound side effects.

Alemtuzumab (Campath)

This is a monoclonal antibody that binds to CD52 (present on surface of mature lymphocytes) and is used in some UK and USA centres as induction therapy.

Humanised anti-CD25 Monoclonal Antibodies

Basiliximab and daclizumab are humanised (genetically engineered to resemble human immunoglobulins) 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 (without causing any depletion).


Maintenance Therapy

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

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)

Many centres now use steroid avoidance or early withdrawal regimens (Pascual 2011). While the evidence for early withdrawal is good, the potential benefits of late corticosteroid withdrawal is not so robust.

Anti-proliferative Drugs: Azathioprine and Mycophenolate

Azathioprine was first introduced into clinical practice by Sir Roy Calne in 1962 (Calne, 1962). 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. Mycophenolic acid 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).

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

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 intracellular 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

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 ciclosporin 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 and Everolimus

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 substituted 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.

Everolimus is the newest mTOR inhibitor on the market but is not currently licenced for use in kidney transplantation.


New immunosuppressants


Belatacept  is a fusion protein composed of the Fc fragment of a human IgG1 immunoglobulin linked to the extracellular domain of CTLA-4, which is a molecule crucial for T-cell costimulation and selectively blocks the process of T-cell activation. The BENEFIT study (Vincenti 2010) demonstrated equivalent patient/graft survival versus ciclosporin (also better renal function despite higher incidence of acute rejection). BENEFIT-EXT (Durrbach 2010) demonstrated equivalent patient/graft survival, similar rejection, more PTLD but better cardio-metabolic risk profile of belatacept versus ciclosporin in extended criteria kidneys.


Assessment and treatment of rejection

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

Graft Dysfunction

In the early period post-transplant the differential diagnosis for acute transplant dysfunction 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.

Possible Causes for Early Graft Dysfunction

There are some common causes, with quite different treatments

  • Acute rejection
  • Calcineurin inhibitor toxicity
  • Acute tubular injury in context of delayed graft function
  • Obstruction
  • BK virus nephropathy (unlikely if immediately after transplantation)
  • Recurrence of original disease (FSGS especially 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); including urine output and daily weight
  • Blood tests - FBC, U&E’s, levels of calcineurin inhibitors, inflammatory markers
  • Doppler ultrasound
  • Renal Biopsy

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


The complications of transplantation can be divided into 5 categories:

  • Cardiovascular (and Atherosclerotic) Disease
  • Cancer
  • Infection
  • Bone Disorders
  • Renal (Chronic Allograft Loss, Recurrent or De Novo 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

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


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


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


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


Post-transplant anemia is a common problem

Key Point: The prevalence of anaemia is 40% 

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



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:
               ï‚§ 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



The transplantation procedure and subsequent immunosuppression increase the risk of serious infection. In the first year after transplantation infection is the biggest cause of death (responsible for 21.6% of all 1-year mortality events) (Farrugia 2013). 

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. 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


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


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


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


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


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 longâ€�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. Preâ€�existing ageâ€�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%)


Top Tips: Living renal transplantation is the treatment of choice for many patients with ESRD

  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)