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José M Morales
Associate Professor of Medicine
Renal Transplant Unit
Hospital 12 de Octubre
Long-term outcome after renal transplantation (RT) is influenced by maintenance immunosuppression, renal dysfunction, the presence of extrarenal complications, and the risk of death.
This article discusses the management of long-term complications.
Managing late causes of renal failure
Chronic rejection/chronic allograft nephropathy
Chronic rejection (CR)/chronic allograft nephropathy (CAN) is the most frequent cause of graft loss after the first year. Pathologically it is characterised by occlusive vascular disease, interstitial fibrosis and glomerular changes. Deterioration of renal function, proteinuria and arterial hypertension (AH) are the most important clinical features. Although the aetiology is unclear, immunological and nonimmunological factors are involved (see Table 1). Differential diagnoses include: recurrent disease, chronic ciclosporin (CyA)/tacrolimus (TAC) nephrotoxicity and renal
artery stenosis. Graft biopsy is mandatory to establish
a diagnosis, the severity of lesions and prognosis.(1–3)
There is no specific treatment for CR. Adding mycophenolate mofetil (MMF) to the basic regimen may be helpful, and decreasing CyA after starting MMF can slow the progression of renal disease.(4) The possible beneficial effects of sirolimus are under investigation. Other therapeutic options are similar to those used in chronic renal failure with native kidneys. Restriction of proteins in the diet, control of blood
pressure (BP), treatment of anaemia and the use of
antiproteinuric agents – such as angiotensin-converting
enzyme inhibitors (ACEIs) or angiotensin receptor
antagonists (ARAs) – may be useful.
Late acute rejection
Acute rejection (AR) may occur at any time after transplantation, and late AR episodes are strongly
associated with CAN. Patient noncompliance with
immunosuppressive therapy is an important cause of
rejection-associated late graft loss and is the most
common cause of graft loss in adolescent patients.
Firstline treatment of an AR episode is with pulsed steroids, or poly- or monoclonal antibodies in the case of steroid resistance. Switching patients from CyA to TAC can be useful. Preventive measures include an adequate immunosuppressive protocol and educational measures to avoid noncompliance, particularly in younger patients.
Chronic calcineurin inhibitor nephrotoxicity
CyA and TAC are the cornerstone of current maintenance
immunosuppressive regimens. However, both drugs cause acute and chronic nephrotoxicity. Prolonged CyA/TAC exposure can induce tubulointerstitial and vascular changes with renal function deterioration. CyA dose reduction or withdrawal, with the addition of MMF or sirolimus, improves renal function.(4) Stopping CyA/TAC in stable patients with
treatment protocols that include MMF or sirolimus improves renal function and BP.(4) Renal function should be monitored monthly for the risk of AR.
Recurrent or de-novo renal disease
Recurrent or de-novo disease can be responsible for at least 2% of graft losses.(2) In the case of recurrent membranous (M) or membranoproliferative (MP) glomerulonephritis (GN), whether or not it is associated with hepatitis C (HCV) or IgA GN, there is no specific therapy. If nephrotic syndrome is evident, highdose steroids can be useful. Control of BP, hyperlipidaemia, thrombotic complications and heavy
proteinuria is recommended.(2,3) Results with ACEIs or
ARAs as antiproteinuric agents are encouraging.(3)
To avoid recurrent diabetes in the graft, strict control of glycaemia and BP using ACEIs or ARAs are recommended.
In patients with Alport’s syndrome who develop de-novo antiglomerular basement membrane disease, plasma exchange and cyclophosphamide may be used to remove antibodies.
Recently, polyoma BK virus has been implicated as a cause of graft loss, mainly in patients using TAC and MMF.(4) Early laboratory and renal biopsy diagnosis can be followed by a decrease in immunosuppressive treatment, to stabilise renal function.
Death with functioning graft
About 30% of patients from UNOS data died with a functioning graft, 50% of which were as a result of cardiovascular disease (CVD).(4) Risk factors for posttransplant CVD (eg, pretransplant CVD, hypertension,
hyperlipidaemia, renal dysfunction, diabetes, smoking and immunosuppressive therapy) should be targeted for intervention. Before transplantation, CVD must be detected and treated, especially in older people and asymptomatic diabetic patients.
Infectious diseases and cancer are the second highest
causes of death and may occur as a consequence of
long-term excessive immunosuppression, so tailored
regimens are recommended, especially in older recipients.
Chronic liver disease (CLD) from HCV or hepatitis B virus is the fourth highest cause of death in some series.(2) Nonaggressive immunosuppression in patients with viral hepatitis may help.
Managing extrarenal complications
Cardiovascular risk factors (Table 2)
The incidence of arterial hypertension (AH) varies between 50 and 80%.(3) CR and immunosuppressive drugs (steroids, CyA and to a lesser extent TAC) are the most important causes. AH is associated with an increased incidence of CVD and decreased graft survival, so strict control of BP is mandatory: <130/85mmHg in patients without proteinuria, and <125/75mmHg in those with proteinuria, is recommended.(3) General measures and antihypertensive medications (calcium antagonists and ACEIs are most frequently used) are necessary. In proteinuric patients, antihypertensive and antiproteinuric agents such as ACEIs or ARAs are recommended.
Renal artery stenosis should be suspected in patients with uncontrolled AH and/or renal function deterioration. Selective angiography and spiral computer angiography are the best methods for diagnosis. Percutaneous transluminal angioplasty, stents or surgery are useful treatments.
Post-transplant hyperlipidaemia is common and may be associated with older age, male gender, obesity, proteinuria, diabetes, antihypertensive drugs and immunosuppression, especially steroids, CyA and sirolimus. Hypercholesterolaemia and hypertriglyceridaemia are associated with CVD.
Management of hyperlipidaemia includes general measures, such as exercise, diet with low calorie intake and avoidance of alcohol. Reduction or withdrawal of steroids, CyA or sirolimus may be useful. Statins should be used in low doses as they interact with CyA and TAC. With this approach,
cholesterol levels and LDL-cholesterol should be reduced to <130mg/dl. Fibrates may be used with caution in combination with statins in patients with severe hypercholesterolaemia and hypertriglyceridaemia.
Pre- and post-transplant diabetes (PTDM) are independent
risk factors for CVD after renal transplantation. The incidence of PTDM is related to the use of immunosuppressants: steroids, CyA and particularly TAC. In patients taking MMF, the incidence of PTDM is no different between CyA and TAC users.(5)
Management of PTDM includes general lifestyle and treatment measures, stricter control of hyperglycaemia
and dose modification of steroids and TAC.
Chronic liver disease
HCV and hepatitis B virus (HBV) are the most frequent causes of post-transplant CLD. HCV-positive patients may present with worsening liver function, glomerulonephritis, increased infections and decreased long-term patient and graft survival. After transplantation, HCV-positive patients should be carefully monitored for alanine aminotransferase (ALT) levels, viral replication (HCV-RNA) and renal disease. Tailored immunosuppression is recommended. Interferon is
contraindicated after renal transplantation, except in severe cases of fulminant hepatitis.
HBV-positive patients can present with similar complications following renal transplantation. Monitoring of ALT and HBV-DNA is recommended.(2) Tailored immunosuppression and antiviral therapy with lamivudine is a good option for these patients.
Bone and mineral metabolism
Hypophosphataemia, hypercalcaemia, hypomagnesaemia,
hyperparathyroidism, osteopenia and osteonecrosis are the most frequent abnormalities after transplantation.
Recommendations to prevent bone disease include using low doses of corticosteroids, vitamin D and calcium supplementation, sex hormone substitution, and appropriate use of thiazide diuretics.(3) Results with bisphosphonate in established osteopenia are encouraging, and therefore they should be considered.(3) Surgery for persistent hyperparathyroidism is indicated if spontaneous involution is not observed.
In patients with glomerular filtration rate (GFR) <50ml/min after transplantation, measures to prevent uraemic osteodystrophy should be recommended.
Anaemia is caused by renal dysfunction and by the use of MMF, ACEIs and ARAs. Improvements in renal function and dose adjustment of these drugs can improve anaemia. EPO treatment is indicated in accordance with European guidelines.
Dose-dependent leucopenia is often a consequence of treatment with azathioprine or MMF. The combination of allopurinol and azathioprine should be avoided. Leucopenia is often associated with cytomegalovirus infection. ACEIs and ARAs are useful in patients with polyglobulia.(3)
In the first year post-transplant there is a great risk of lymphoproliferative diseases, frequently induced by Epstein–Barr virus (EBV). The incidence is 1–2%.(3) Treatment includes reduction/withdrawal immunosuppression and antiviral therapy.
Nonmelanoma skin cancers are the most frequent, and primary prevention should include avoidance of sun exposure and protection of unclothed skin. In recurrent cancers, reduction of immunosuppression should be indicated.
Cancers of the thyroid, native kidney, colon, bladder and female genitals occur more frequently in transplant patients. Guidelines for screening and prevention of solid organ cancers should be strictly applied to transplant recipients.
Pneumocystis carinii pneumonia (PCP) can be prevented by prophylaxis with trimethoprim–sulfamethoxazole for at least four months.(3) In the case of PCP, firstline therapy is high-dose trimethoprim–sulfamethoxazole. Alternatively, steroids and pentamidine may be used.
Tuberculosis is not uncommon after transplantation.
Treatment of active TB should be the same as for the general population. Rifabutin is an alternative to rifampicin in patients taking CyA or TAC.
Side-effects of immunosuppressive drugs
Immunosuppressive therapy induces considerable morbidity due to side-effects. The most important long-term complications of currently used drugs are listed in Table 3.