12.3
Immunosuppressants (Solid Organ Transplantation)
Section I: Clinical Scenario and Dental Considerations
Clinical Scenario
A 47‐year‐old male has been referred by his nephrologist for management of ‘loose teeth’. The patient reports he pulled out a lower incisor and upper right molar himself using his fingers. The patient believes it may be best to have all his teeth removed.
Medical History
- History of renal failure secondary to bilateral polycystic kidney disease
- Right kidney transplant 9 years ago
- Hypertension
- Osteopenia
- Absolute polycythaemia diagnosed three years ago
- Obstructive sleep apnoea (moderate severity)
Medications
- Mycophenolate mofetil
- Tacrolimus
- Prednisolone (5 mg daily)
- Trimethoprim/sulfamethoxazole
- Irbesartan
- Calcium and vitamin D
- Pantoprazole
- Intermittent venesections (phlebotomy)
Dental History
- Last dental visit 9 years ago for pretransplant work‐up
- Did not return as had no dental pain
- Good compliance: all previous dental treatment under local anaesthetic in the dental chair
- Reports brushing twice per day; does not use interdental brushes
Social History
- Caucasian origin
- Married, lives with wife and two daughters
- Ceased tobacco smoking when he had the renal transplant; previously smoked seven cigarettes per day for 23 years
- Alcohol: Two to three bottles of beer per month
Oral Examination
- Halitosis
- Poor oral health
- Carious retained roots #17, #35, #45 and #46
- Caries in #26 distal and #36 mesial
- Generalised severe gingivitis with generalised extensive supra‐ and subgingival calculus (Figure 12.3.1)
- Multiple teeth with 4–7 mm periodontal pockets
- Multiple mobile teeth, notably grade III mobility of #26 and #48
Radiological Examination
- Orthopantomogram undertaken showing advanced bone loss, subgingival calculus and retained roots #17, #35, #45 and #46
- Right bitewing radiograph: horizontal bone loss; calculus; retained roots #17, #45 and #46 (Figure 12.3.2)
- Left bitewing radiograph: horizontal bone loss; calculus; retained root #35
Structured Learning
- Why is this patient taking mycophenolate mofetil, tacrolimus and prednisolone?
- All three drugs are immunosuppressive agents that act to prevent transplant T‐cell alloimmune rejection
- Mycophenolate mofetil
Figure 12.3.1 Anterior view of the dentition showing generalised hard and soft deposits and gingival recession.
Figure 12.3.2 (a,b) Bite‐wing radiographs showing horizontal bone loss, subgingival calculus and retained roots #17, #45, #46 and 35.
- Antiproliferative agent that inhibits purine biosynthesis (selective for lymphocytes)
- Common adverse effects include gastrointestinal disturbances and myelosuppression
- Antiproliferative agent that inhibits purine biosynthesis (selective for lymphocytes)
- Tacrolimus
- Calcineurin inhibitor that inhibits IL‐2 production
- Highly potent immunosuppressant that has nephrotoxic, hepatotoxic, neurotoxic, diabetic and hypertensive side‐effects
- Prednisolone
- Corticosteroid used for its immunosuppressive effects, as well as to treat other inflammatory and endocrine disorders
- What oral changes may be associated with mycophenolate mofetil and tacrolimus?
- Mycophenolate mofetil: stomatitis, petechiae/gingival bleeding, dental erosion
- Tacrolimus: oral ulceration, circumoral paraesthesia
- Both: opportunistic infections (candidiasis, herpes simplex virus, varicella zoster virus, cytomegalovirus, oral hairy leucoplakia caused by Epstein–Barr virus), impaired wound healing, increased malignancy risk
- The patient feels that his periodontal disease and related tooth mobility have worsened after his renal transplantation. Could he be correct?
- Recipients of the new organ (except when the donor and the recipient are identical twins) undergo immunosuppressive therapy throughout life to prevent the rejection process
- As this patient is immunosuppressed, his periodontal disease activity may have accelerated
- Other factors will also have had an impact, namely his irregular dental visits and poor oral health
- Conversely, could this patient’s periodontal disease affect the survival of the renal transplant?
- There is evidence of an association between periodontal status and worsening of graft function and systemic health among kidney transplant recipients
- In view of this, it is especially important to manage the patient’s periodontal disease and remove this risk
- What factors are considered important in assessing the risk of managing this patient?
- Social
- History of smoking
- Lack of motivation for oral health maintenance
- Possible fatigue
- Medical
- Bleeding (renal impairment, myelosuppression, absolute polycythaemia)
- Thrombotic tendency (thromboembolism and myocardial infarction risk)
- Hypertension in relation to polycythaemia
- Blood glucose level monitoring (e.g. corticosteroids, calcineurin inhibitors)
- Risk of an adrenal crisis due to corticosteroid medication
- Drug interactions and metabolism
- Increased risk of secondary malignancy (e.g. squamous cell carcinoma, Kaposi sarcoma, lymphoma)
- Dental
- Dental erosion risk (due to emesis)
- Impaired wound healing
- History of irregular attendance
- Mouth breathing (obstructive sleep apnoea)
- Oral side‐effects of immunosuppressants (e.g. oral ulceration and stomatitis)
- Social
- Given the poor status of the patient’s remaining teeth, he consents for dental extraction of multiple teeth, namely the retained roots #17, #35, #45, #46, teeth with very poor periodontal prognoses #26, #48 and non‐functional periodontally involved teeth #16, #36, #38. Would you consider antibiotic prophylaxis when undertaking these dental extractions?
- Due to increased risk of infection in the immunosuppressed transplant patient, many transplant centres recommend antibiotic prophylaxis for dental procedures that may produce a transient bacteraemia
- However, no data exist to indicate whether this is effective practice, and protocols vary between different countries
- Selection of the best antibiotic is difficult since the oral flora is altered by both immunosuppression and repeated/background antibiotic prophylaxis
- Furthermore, drug interactions between immunosuppressants and multiple antibiotics exist
- Given the lack of scientific evidence regarding any benefit from antibiotic prophylaxis, usage should be determined on an individual patient basis in consultation with the transplant team
General Dental Considerations
Oral Findings
- Fungal infection (candidiasis most common)
- Viral infection (herpes simplex virus, varicella zoster virus, cytomegalovirus)
- Oral hairy leucoplakia (Epstein–Barr virus)
- Petechiae, gingival bleeding
- Reduced salivary flow
- Oral ulceration and stomatitis (Figure 12.3.3)
- Mucosal pallor, angular cheilitis, glossitis, fissured/burning tongue, ulcers (anaemia)
- Impaired healing
- Dental erosion
- Progressive gingivitis and periodontitis (indication of immunosuppression)
- Gingival hyperplasia (cyclosporine) (Figure 12.3.4)
- Dysgeusia (mTOR inhibitors)
- Circumoral paraesthesia (tacrolimus, cyclosporine)
Figure 12.3.3 Sirolimus‐induced oral ulceration.
Figure 12.3.4 Cyclosporine‐induced gingival hyperplasia.
- Medication‐related osteonecrosis of the jaws (mTOR inhibitors, bone‐altering medications prescribed secondary to corticosteroid osteoporosis, possibly methotrexate)
- Graft‐versus‐host disease‐related side‐effects
- Malignancy
- Virally driven: carcinoma of skin/lip (human papillomavirus), Kaposi sarcoma (human herpes virus‐8), lymphoma (Epstein–Barr virus)
- Cutaneous: squamous cell carcinoma, melanoma, basal cell carcinoma
- Post‐transplant lymphoproliferative disorder (ranging from benign B‐cell hyperplasia to immunoblastic malignant lymphoma); incidence ~2%; most cases develop within the first year post‐transplant; association with Epstein–Barr virus; rapidly progressive and often fatal
Dental Management
- Patients who receive organ transplantation are immunosuppressed to prevent organ rejection; in view of this they are at increased risk of local and systemic infections
- Since these infections can be life‐threatening, maintenance of good oral care and aggressive treatment of odontogenic infections are crucially important, with dental management considerations summarised in Table 12.3.1
- In addition, there are specific risks which need to be considered in relation to the specific type of organ transplant and immunosuppressive agents used post‐transplant (Tables 12.3.2 and 12.3.3)
Section II: Background Information and Guidelines
Definition
A solid organ transplant is a highly effective treatment for advanced organ failure via transplantation of a healthy organ. Transplanted solid organs may come from a living or deceased donor, with clinical and ethical guidelines for organ transplantation developed in many countries. Organs from deceased donors are retrieved after either brain death or circulatory death (cadaveric).
The first documented successful kidney transplantation was performed between living identical twins in Boston, USA, by Joseph Murray and John Merrill in 1954. However, it was not until the 1980s that transplantation survival rates showed significant improvement. This was linked to the development of antimicrobial agents, prophylaxis strategies, enhancement in monitoring methods and advancement of immunosuppressive induction and maintenance agents.
Transplant activity data reported in 2017 to the World Transplant Registry (in partnership with the World Health Organization) showed that ~135 860 solid organ transplants were performed worldwide: 89 823 kidney transplants (40% from living donors), 30 352 liver transplants (19% from living donors), 7626 heart transplants, 5497 lung transplants, 2342 pancreas transplants and 220 small bowel transplants. Solid organ transplantation can save lives affected by terminal organ failure and also improve quality of life.
Classification
- The most common organs, tissues and cells transplanted include kidneys, hearts, lungs, pancreas, liver and small bowel; bone marrow, cornea, bone and skin; and cells of muscle, bone and pancreas
- Types of transplants include autografts, allografts and isografts (Table 12.3.4)
- Most solid organ transplants are allografts, whereas autografts are more commonly used in haemopoietic stem cell transplantation or bone marrow transplantation
- Due to the shortage of organs for transplantation, the focus has been on stem cell research to enable healthy organs to be grown outside the human body
- One such method, called blastocyst complementation, has already produced promising results. These have been injected with stem cells from a normal donor, not necessarily of the same species. The stem cells then differentiate to form the entire missing organ in the resulting animal. The new organ retains the characteristics of the original stem cell donor, and can thus potentially be used in transplantation therapy
Indications
- Limited life expectancy
- Untreatable end‐stage disease
- Substantial limitation of daily activities
- Ambulatory patient with rehabilitation potential
- Acceptable nutritional status
- Satisfactory psychosocial profile and emotional support system
- Absence of other severe concomitant underlying diseases
Immunosuppression
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