Long-Term Primary Care Issues in the Transplant Population

Long-Term Primary Care Issues in the Transplant Population

Jared Brandenberger, MD

University of Washington Medical Center, Seattle, Washington

As posttransplant patients live longer with healthy grafts, primary care issues are becoming more important. Along with longstanding transplant issues such as maintaining graft function and managing infections, concerns about cardiovascular health, diabetes, and cancer screening and detection are hot topics among transplant physicians striving to improve the longevity of their patients. Open communication and an individualized approach are crucial as we await the results of important research to help us better treat our patients.

Dr. BrandenbergerThe 2012 American Transplant Congress showcased many innovations in the field of organ transplantation. From the bench to the clinic to the operating room and beyond, the field of transplantation continues to evolve, improving the lives of our patients and the longevity of their grafts. Now more than ever, the entire patient must be considered, not just the transplanted organ. Unfortunately, long-term care of the transplant patient is often overlooked. Transplant surgeons easily can fail to notice the unique problems often encountered by patients in the years after surgery.

This panel session explored some of the most common issues faced by our patients, touching on key issues, treatment, and misconceptions by the medical community at large. Among topics covered were the management of hypertension, diabetes, and infection in transplant patients. In addition, speakers discussed cancer prevention and screening in this population. These experts discussed each issue in terms of the transplant patient and the general population.

TAILORING TREATMENT IN THE MANAGEMENT OF HYPERTENSION
Based on a presentation by Alan G. Jardine, BSc, MBChB, MD, FRCP, MRCP, Professor of Renal Medicine, University of Glasgow School of Medicine, Scotland

As transplant patients are living longer with healthy grafts, management of hypertension is becoming a crucial issue. Cerebrovascular and cardiovascular events are among the most common causes of death among patients having a functioning graft. Aside from increasing the risk of myocardial infarction and sudden cardiac death, hypertension also has implications for the health of the graft.

The most common factors associated with refractory hypertension among the transplant population are vasoconstriction related to use of calcineurin inhibitors (CNIs), sodium retention related to corticosteroid therapy, a decrease in glomerular filtration rate (GFR) resulting from activation of the renin-angiotensin pathway, and the presence of preexisting comorbidities such as pretransplant hypertension.

Controlling Blood Pressure
Opelz and Döhler1 showed that a drop in systolic blood pressure, even in patients having hypertension for years after kidney transplantation, was associated with improved survival of both patients and grafts. Although this trend was more pronounced in graft recipients < 50 years of age, the authors concluded that improving blood pressure control in all age groups would improve outcomes. With continuing insights into managing immunosuppression, graft loss, and infectious issues, the handling of cardiovascular issues will continue to be important to the long-term health of transplant recipients of all ages.

The most current and widely recognized recommendations are the Kidney Disease: Improving Global Outcomes (KIDGO) guidelines,2 which recommend that blood pressure be measured during each office visit (Grade 1C) and maintained at < 130 mm Hg systolic and < 80 mm Hg diastolic (Grade 2C) for patients 18 years of age and older and for those under 18 who fall below the 90th percentile for gender, age, and height.

Physicians are not limited by the guidelines to any class of antihypertensive agent but should monitor their patients for adverse effects and drug interactions. If proteinuria is detected, use of an angiotensin-converting enzyme (ACE) inhibitor or angiotensin-receptor blocker (ARB) is recommended as first-line therapy (not graded). The KDIGO guidelines also recommend that healthcare personnel identify ideal blood pressure targets, measure the effect that minimizing proteinuria has on progression of chronic renal disease, and determine the effects of ACE inhibitors and ARBs on patient and graft survival.

A recent study of 183 renal transplant patients by Agena et alet al3 showed that home blood pressure measurements agreed to a significantly greater degree with ambulatory blood pressure monitoring than with blood pressure measurements taken in the office. Further, hypertension was controlled in significantly more patients who underwent home and ambulatory blood pressure monitoring than in those who had office monitoring.

Avoiding and Managing Hypertension
For years, physicians have believed that lifestyle modifications may improve hypertension; this theory extended to the transplant population. In a study of 660 renal transplant patients, van den Berg et al4 found that a reduction in sodium intake to the recommended maximum of 70 mmol/d could lower systolic blood pressure by 4–5 mm Hg. They concluded that restricting sodium intake could prevent graft failure and mortality resulting from hypertension in this population.

When it comes to medical treatment of hypertension, there is no consensus and somewhat scarce data about optimal therapy. For years, amlodipine has been the backbone of treating the posttransplant patient because the drug mitigates CNI-related vasoconstriction and lowers blood pressure effectively. Emerging evidence suggests that other drug classes may have promise in the transplant population

Heinze et al5 found an increase in both patient and graft survival with the use of ACE inhibitors. Likewise, Weir6 reported a decrease in proteinuria with the use of ACE inhibitors and ARBs. However, in a 2009 Cochrane Database review, Cross et al7 showed that treatment with calcium channel blockers diminished graft loss and improved GFRs; use of ACE inhibitors was associated with a decrease in proteinuria, but it also was linked to an increase in hyperkalemia and a decrease in GFR. Currently, dihydropyridine calcium channel blockers remain a mainstay of antihypertensive treatment for transplant recipients with hypertension.

Maintaining Immunosuppression
Another factor in managing hypertension in the organ transplant population is the type of immunosuppressant used. Minimization or withdrawal of corticosteroids post transplant leads to lower blood pressure at the cost of an increased risk of acute rejection, yet overall graft and patient survival do not suffer.8,9

Maintenance therapy with a low dose of corticosteroids may avoid some immunologic risk while improving hypertension.10 CNI withdrawal with conversion to rapamycin may lead to decreased blood pressure in the stable posttransplant patient over the long term; in addition, conversion from cyclosporine to tacrolimus may benefit some renal transplant patients.11,12 Results from the BENEFIT and BENEFIT-EXT trials also showed a decrease in hypertension with use of CNI-sparing regimens in patients who underwent kidney transplantation.13

Summary
When following renal transplant patients, ambulatory and home blood-pressure monitoring may best reflect the patient’s real hypertensive status. Blood pressure goals of 125–130 mm Hg systolic and 75–80 mm Hg diastolic are reasonable and may reduce left ventricular hypertrophy, a significant risk factor for sudden cardiac death. Calcium channel blockers (eg, amlodipine) and, in certain cases, ACE inhibitors and ARBs are the most effective antihypertensive choices; however, use of thiazide diuretics also may be acceptable. Decreasing immunosuppression to improve hypertension and modifying lifestyle choices may improve outcomes, as well.

In short, “we are doing all right,” but there is much room for continued study of the risk factors and treatment of hypertension in organ-transplant recipients.

DIABETES MANAGEMENT IN TRANSPLANTATION: HOW TIGHT FOR HOW LONG?
Based on a presentation by Steven J. Chadban, PhD, FRACP, Clinical Professor of Medicine, The University of Sydney Medical School, Sydney, Australia

Treatment of the diabetic patient before and after organ transplant is challenging. Diabetes mellitus greatly contributes to end-stage organ dysfunction in the transplant population, and many patients waiting for an organ have undiagnosed diabetes. The prevalence of type 2 diabetes among the general population of Australia jumps after age 45; it is estimated that there is one case of undiagnosed diabetes for each one known.14 Among Australian patients waiting for a kidney, there is one diabetic patient for every five, representing a significant portion of the pretransplant population, according to Dr. Chadban.

Overall, diabetes is extremely common among the renal transplant population—30%–60% of patients with end-stage renal disease and 15%–40% of patients on transplant waiting lists are diabetic. Further, 10%–40% of patients will develop new-onset diabetes after transplant (NODAT), a phenomenon seen more commonly in recent years and especially in the renal transplant population. Many unique factors of the posttransplant patient affect both insulin production and insulin resistance (Table 1). The prevalence of NODAT, along with a greater tendency for labile blood sugar levels after transplant, is responsible for the common need for antidiabetic treatment among patients who have undergone renal transplant.

The clinical importance of diabetes among renal transplant patients from an endocrine standpoint is obvious. Wiesbauer et al15 linked glucose control with survival post transplant. Likewise, Valderhaug et al16 noted the relationship between NODAT and death with a functioning graft. In addition, immunologic consequences may be involved. Thomas and others17 reported a possible link between hyperglycemia and a predisposition to acute allograft rejection.

Monitoring Blood Glucose Levels
Important differences to keep in mind when monitoring and treating patients who have undergone organ transplant are the inaccuracy of fasting blood glucose levels as compared with postprandial measurements, the inaccuracy in hemoglobin A1c (HbA1c) values, and the importance of the oral glucose tolerance test in screening efforts.

Monitoring blood glucose levels is somewhat different for the transplant population than for the general population. In posttransplant patients, preprandial insulin levels may be more sensitive than fasting levels, possibly because blood glucose levels rise continuously and additively throughout the day after each meal. This effect improves somewhat at 3 and 6 months after surgery, but preprandial measurements are a much better gauge of glucose control than postprandial levels. This is an area where continuous blood glucose monitoring may be of help in the future.

Because the immediate posttransplant period is so volatile with regard to blood glucose levels, HbA1c values also are not accurate in this population; further, they have not been studied long term in renal transplant recipients. The standard diagnostic for NODAT remains the oral glucose tolerance test. In all, the accurate measurement of blood glucose levels in the posttransplant population remains challenging.

Managing Diabetes
Effective treatment of diabetes mellitus in the posttransplant population continues to evolve. Few data regarding the optimal antidiabetic regimen in renal transplant recipients are available, and insulin remains the mainstay of treatment. Use of sulfonylureas or thiazolidinediones is safe in renal transplant patients, but these drug classes may not be as widely used as insulin due to the prevalence of refractory diabetes in this population. For the most part, biguanides are contraindicated for use in patients who have received a kidney transplant.2

Modification of immunosuppression to improve control of blood glucose levels also has been explored. Results from the Symphony study showed both an increase in diabetes that was related to immunosuppression and an association between tacrolimus therapy and NODAT.18 Unfortunately, corticosteroid-free immunosuppression does not impact NODAT greatly; further, it is associated with an increase in acute rejection. Thus, many transplant programs are now choosing to pursue minimization of corticosteroids in immunosuppressive regimens to improve glucose tolerance.

Zelle et al19 reported an increase in survival among renal transplant patients who took part in exercise. This intuitive finding is difficult to attribute to the effect of physical exercise on blood glucose levels and requires further study.
The optimal treatment for patients with NODAT remains a moving target. The KDIGO guidelines suggest that physicians consider modifying immunosuppression when NODAT is diagnosed while weighing the risks of graft rejection and subsequent treatment.2 In addition, physicians should help patients to achieve a target HbA1c level < 7.5%.

Summary
Development of NODAT is related to early concerns about a possible association with and an increased risk of acute rejection; late concerns include end-organ damage, vascular disease, and the risk of death, most commonly from cardiovascular causes. To treat patients with NODAT, physicians may consider modification of immunosuppressive regimens in selected individuals, improvement in diet and exercise, and judicious control of blood glucose levels, taking care to avoid hypoglycemia. No pharmacologic treatment is firmly recommended, but insulin-based therapeutic regimens remain the mainstay of antidiabetic management in this population.

AVOIDING INFECTION: VACCINES AND LIFESTYLE AFTER TRANSPLANTATION
Based on a presentation by Robin K. Avery, MD, Professor of Medicine, Cleveland Clinic Foundation, Cleveland, Ohio

The prevention of infection in transplant patients is extremely important. It is also a source of considerable confusion among providers. In many cases, use of vaccinations in transplant patients, especially when there are infants and young children in the household, is a major quandary, and physicians must help dispel some of the myths surrounding immunization as they pertain to our patients.

One common fear is that immunizations are related to acute rejection. However, there is no compelling evidence in the literature showing an increased risk of rejection with immunization. Likewise, any concerns about using immunizations in the early posttransplant period are related to the vaccines’ lack of efficacy, not patient safety.

Recommendations for Immunization
Current recommendations for immunization can be divided into pre- and posttransplant guidelines.

Pretransplant guidelines. Patients may receive pneumococcal vaccine within 5 years of transplant surgery and influenza vaccine annually. Patients awaiting transplant also should receive tetanus-diphtheria-pertussis (Tdap) immunization (especially if they are at risk for developing pertussis) and hepatitis A and B vaccine (if they are seronegative). Pretransplant patients also may receive varicella vaccination, but not within 4 weeks of transplant surgery and not if they have started taking immunosuppressants.

Some population-specific recommendations for immunizing pretransplant patients also have been issued. For example, administration of the herpes zoster vaccine may be considered for wait-listed patients over 60 years of age; this product is indicated for patients over 50 years of age and often is not covered by insurance. For young men and women awaiting transplant, administration of the human papillomavirus vaccine may be considered. If patients may undergo splenectomy during the operation, Haemophilus influenzae type B vaccine and meningococcal vaccine may be given; in addition, if possible, pneumococcal vaccine may be given at least 2 weeks before transplant surgery. It is important to immunize pretransplant patients as soon as possible, since vaccination is less effective once the patient has progressed to end-organ disease.

Posttransplant guidelines. Recommendations for immunizing patients who already have undergone renal transplant include pneumococcal vaccination every 5 years, hepatitis A and B immunization (if the patient was not immunized before surgery), and any other indicated vaccination. However, measles-mumps-rubella vaccine, oral polio vaccine, and yellow-fever vaccine are contraindicated for renal transplant patients.

Maintaining Health and Everyday Activities

Employment. Job-related safety is a concern for transplant patients when it comes to infectious issues. Most patients can return to work with little risk. However, individuals employed in agriculture and the construction industry need to avoid contact with soil if they are not wearing gloves. Pet stores are also an area of concern; patients working with animals should discuss their employment with an infectious disease specialist before returning to work.

Likewise, healthcare personnel who receive a transplant also should discuss their return to work with an infectious disease specialist. Those returning to work should practice strict hand hygiene and avoid exposure to patients infected with cytomegalovirus, hepatitis C virus, respiratory viruses, tuberculosis, fungi, or multidrug-resistant organisms. They should be careful to wear gloves when treating patients in wound-care or intensive care units and avoid working in walk-in clinics, urgent care facilities, homeless shelters, or jails.

Home and hobbies. Gardening and activities such as caving pose the same risk and involve similar precautions for soil-borne pathogens as do jobs related to soil exposure. Hunting and cleaning of game also should be accomplished with gloves. These and other high-risk activities, such as scuba diving, should be discussed with an infectious disease specialist before transplant recipients take part in them.

Specific recreational exposures to avoid include marijuana use and contact with untreated water, caves, hot tubs, and chicken coops. At home, in the workplace, or during recreational activities, fastidious hand hygiene is indispensable.20

Travel is of particular concern; a study showed that 17% of patients reviewed felt ill enough to seek medical attention during or immediately after travel. A dedicated travel clinic is a particularly valuable resource for patients who wish to visit other areas. Further, individuals who undergo transplant surgery and plan to travel should receive appropriate immunizations and prophylaxis and consult with their transplant surgeons. Such individuals should refrain from traveling out of the country immediately after surgery or during times of increased immunosuppression.21

Pets also are associated with infections. Toxoplasmosis and cat scratch disease are related to contact with cats; psittacosis, histoplasmosis, and cryptococcosis are linked to contact with birds; mycobacterial infections are related to contact with aquariums; and Salmonella infection is linked to contact with reptiles.22 During the first year after transplant surgery or during periods of increased immunosuppression, patients should follow compulsive hand hygiene and not acquire new pets or clean bird cages or litter boxes.

Summary
Education is crucial to prevent infection following kidney transplant. The availability of a dedicated transplant infectious disease service and a travel clinic is valuable for active individuals. When seeking answers to infection-related questions, physicians must consider the patient’s total burden of immunosuppression, periods of increased immunosuppression (eg, during treatment for rejection, neutropenia), and the presence of appropriate support. Common sense, caution, and above all communication are essential to preventing infection in our patients.

CANCER PREVENTION AND SCREENING: HOW BIG IS THE RISK?
Based on a presentation by Bryce A. Kiberd, MD, FRCPC, Professor of Medicine and Medical Director of the Division of Nephrology, Dalhousie University, Halifax, Nova Scotia, Canada

Transplant recipients have a twofold to fourfold higher cancer rate than does the general population. As organ recipients live longer, mortality from malignancy may be increasing; in particular, young females have a higher relative risk of cancer than do males < 45 years of age. All transplant recipients carry a risk of malignancy that is comparable to that of the members of the general population who are 20–30 years their senior.23 However, whereas young patients have an increased overall cancer risk, transplant recipients > 55 years of age have a lower all-cancer mortality than do people of the same age in the general population.24

Although overall cancer risk increases among young transplant recipients, the incidence of all cancers is not increased; in fact, the incidence of certain malignancies differs widely between transplant recipients and the general population. Common posttransplant malignancies, such as skin cancer, renal cell carcinoma, and lymphoma, are five times more likely to develop in transplant patients. The incidence of other cancers, including melanoma; multiple myeloma; and colon, cervical, lung, stomach, hepatocellular, bladder, and endometrial cancers, is two to four times more common among transplant recipients. However, the posttransplant population does not have an increased risk of developing two very common cancers—prostate cancer and breast cancer.23

Screening
Screening for cancer has had a proven impact in the general population. In the posttransplant population, the considerations are slightly different. Transplant recipients have a somewhat lower life expectancy and develop certain malignancies much more commonly, which changes the risk-benefit ratio for some types of screening. Table 2 outlines proposed screening recommendations and grading for transplant patients as compared with the general population.


For cancers that develop more commonly in the transplant population, there are no firm recommendations for screening. The KDIGO guidelines for renal transplant recipients call for individualized cancer screening on a case-by-case basis.2 They also recommend annual skin cancer screening by healthcare professionals and patient self-screening for skin malignancies, minimization of sun exposure, and use of sunblock.2 Nonmelanomatous skin cancers contribute more to the mortality of transplant recipients than does melanoma. However, melanoma also carries a significant risk in this population.

Transplant recipients have a significant risk of developing lymphoma (incidence, 1.6 cases/100 patient-years; 25% mortality). This is especially relevant in high-risk populations (children, patients infected with Epstein-Barr virus [EBV]). Since EBV is a predisposing factor, some physicians have suggested following EBV titers and potentially lowering patients’ immunosuppression when titers are high. This, of course, must be balanced against the risk of rejection. More study is needed in this area.

Renal cell cancer is another common posttransplant malignancy, and screening is a topic of debate. Some centers screen for this malignancy routinely. Advantages include the availability of noninvasive tests and increased effectiveness if the cancer is detected early. Disadvantages of routine screening include the relatively high incidence of incidental lesions found and the minimal proven benefit of most analyses. Screening may be worthwhile in high-risk populations or transplant recipients with previous disease, but, again, more study is needed.

Overall, transplant recipients should be screened for cancer using an individualized approach. Physicians should pay special attention to younger patients and to older patients having good function and fewer comorbidities. In older patients or individuals having multiple comorbidities, physicians should focus more on active issues and less on screening for low-yield malignancies. In all, medical personnel should emphasize the prevention of cancer deaths, not the prevention of cancer itself.

REFERENCES

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  2. Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work Group. KDIGO clinical practice guideline for the care of kidney transplant recipients. Am J Transplant. 2009;9(suppl 3):S1–S155.
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  14. Diabetes Australia: Awareness, prevention, detection, management, and a cure. Diabetes Australia Web site. March 15, 2012. http://www.diabetesaustralia.com.au/Understanding-Diabetes/Diabetes-in-Australia/. Accessed June 28, 2012.
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  17. Thomas MC, Moran J, Mathew TH, Russ GR, Rao MM. Early peri-operative hyperglycaemia and renal allograft rejection in patients without diabetes. BMC Nephrol. 2000;1:1–1.
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  19. Zelle D, Corpeleijin E, Stolk R, et al. Low physical activity and risk of cardiovascular and all-cause mortality in renal transplant recipients. Clin J Am Soc Nephrol. 2011;6:898–905.
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Dr. Brandenberger is Acting Instructor and Senior Fellow in Transplant Surgery, University of Washington Medical Center, Seattle, Washington.

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