CNIs, which are used almost universally after heart transplant, have nephrotoxic properties and represent one of the leading factors for decline of renal function after transplant. Initiation of CNI therapy results in vasoconstriction of the afferent glomerular arteriole and decrease in GFR. While this acute ‘hemodynamic’ effect is often reversible, continued use of CNIs also results in chronic nephrotoxicity, which is not easily reversible. Some of these chronic effects have been attributed to CNI mediated activation of the renin-angiotensin-aldosterone axis and increase in endothelin levels [38, 39]. Histologically, CNI nephrotoxicity presents as interstitial fibrosis, tubular atrophy, arteriolar hyalinosis and glomerulosclerosis [40].

The acute effects of CNIs appear to be more pronounced with intravenous administration of cyclosporine and tacrolimus, and are related to the serum concentration of these drugs. Therefore, if intravenous administration of CNIs is necessary, it is recommended that these are administered as an infusion, either over 6 h in a twice daily dose, or as continuous infusion, until parenteral administration is possible. As bioavailability of parenteral CNI formulations is only 20–35 %, it is important to adjust the intravenous dose accordingly to avoid excessive serum CNI levels and the resulting nephrotoxicity. Long-term nephrotoxic effects of CNIs have also been correlated with CNI serum levels [41].

Different approaches to reduction of the nephrotoxic effects of CNIs have been proposed. A number of clinical studies tested the utility of calcium channel blockers, angiotensin converting enzyme inhibitors and angiotensin receptor blockers in mitigating CNI nephrotoxicity [30, 42–44]. While the results have not been consistent, it appears prudent to preferentially use these classes of drugs in heart transplant recipients who also have hypertension [45].

Reduction of target CNI levels (or CNI minimization) is another approach to reduce nephrotoxicity and consists of reducing the target serum levels of CNI in patients considered to be at particularly high risk of renal dysfunction. The introduction of mycophenolate mofetil, which antirejection effect is more potent compared to the previously used cell cycle inhibitor azathioprine, has been especially important in enabling reduction of CNI levels without substantially increasing the risk of rejection [46, 47]. While CNI minimization has been shown to preserve renal function when implemented early, it is less clear how effective this approach is if implemented later after transplant in patients with established renal dysfunction [48, 49]. Finally, CNI-free regimens have been tested to determine the efficacy of this approach in preventing or reversing renal injury after heart transplant. Substitution of cyclosporine or tacrolimus by a target of rapamycin (mTOR) inhibitor, sirolimus or everolimus, in patients who developed renal dysfunction after transplant, has been tested. A number of mostly single center studies have shown that discontinuation of CNI and use of an mTOR inhibitor in combination with a cell cycle inhibitor in patients typically several years after heart transplant resulted in improvement of renal function, and this strategy appeared to be safe [50–53]. A recent multicenter study randomized 116 patients at a mean time of 3.9 years after transplant to continuation of CNI based regimen vs conversion of CNI to sirolimus. One year after randomization, the patients assigned to sirolimus had significantly higher creatinine clearance (delta of +4.4 mL/min/1.73 m²), however they also had a numerically higher incidence of acute rejection, and a full one third of the patients had to discontinue sirolimus due to significant side effects [54]. The use of a CNI-free regimen in de novo heart transplantation has been tested in the multicenter randomized STN-Heart trial. This approach has resulted in an unacceptably high rate of acute rejection in the sirolimus/mycophenolate mofetil arm and this trial was stopped prematurely. In summary, most heart transplant recipients remain on CNIs in the current era. In addition to the approaches described above, best outcome as far as renal function will be achieved through careful long-term monitoring of CNI serum levels, avoidance of excessive CNI serum concentrations during times of unstable drug metabolism, and attention to additional nephrotoxic factors.

The effects of hypertension after heart transplant are described in detail earlier in this chapter. Hypertension before heart transplant is a risk factor for renal dysfunction after transplant. Heart transplant recipients without history of hypertension are likely to develop hypertension after transplant. CNIs, mTOR inhibitors, mycophenolate mofetil and corticosteroids can all cause or contribute to the development of hypertension. At 1 year after transplant, 72 % of adult heart transplant recipients are treated for hypertension, and this number increases to >90 % at 5 years after transplant [1]. Strict blood pressure control should be pursued in heart transplant recipients who also have hypertension and renal dysfunction [55]. ACE-I and ARBs should be considered as first line therapy. Calcium channel blockers may also have specific advantages in this patient population [45].

Abnormal renal function before transplant represents a risk factor for developing severe renal dysfunction after transplant (Fig. 24.1 ). Twenty-four hour urine collection for determination of creatinine clearance should be obtained in patients being evaluated for heart transplantation. In patients with abnormal renal function, etiology of the renal dysfunction should be determined. While patients with cardiorenal syndrome have a good chance for improvement and stabilization of renal function after transplant, renal dysfunction of other causes is likely to further progress after transplant and represent a challenge in clinical management of the heart transplant recipient. Therefore, irreversible renal dysfunction with estimated GFR <40 ml/min should be considered a relative contraindication for heart transplantation [56]. Combined heart and kidney transplantation can be considered in carefully selected candidates who have advanced heart and kidney disease in the absence of additional comorbidities likely to compromise post-transplant survival.

Recipients with history of diabetes mellitus are more likely to develop renal dysfunction after heart transplant. Strict control of normoglycemia and ACE-I or ARB therapy in patients with diabetes mellitus and proteinuria may decrease the risk of progressive renal dysfunction in this patient cohort.

Older patients are more likely to develop renal dysfunction after transplant, independently of their baseline renal function at the time of transplant or additional relevant comorbidities [1].

Polyoma BK virus infection in heart transplant recipients is relatively rare [57]. This diagnosis should however be ruled out in patients with unexplained worsening of renal function. Reduction of immunosuppression is likely to result in clearance of the BK virus and improvement in renal function.

Additional predictors of renal dysfunction after heart transplant are listed in Table 24.2.

Renal dysfunction is a potent risk factor for short and long-term mortality after heart transplant [1]. Control of progression of renal disease should be addressed by aggressively pursuing all modifiable risk factors. When etiology of renal disease, or of an unexpected progression of renal dysfunction, is not certain, renal biopsy should be considered [58]. The incidence of severe renal failure after transplant has been gradually decreasing. This has been attributed to reduction of the target serum CNI levels (partly enabled by the introduction of mycophenolate mofetil), as well as to implementation of renal protective strategies described above. Despite that, some heart transplant recipients will develop end-stage kidney disease. These patients will be candidates for renal replacement therapy. This should include kidney transplantation in eligible heart transplant recipients.

In a healthy individual, T lymphocytes, natural killer cells and various cytokines are believed to participate in cancer immune surveillance—protection of the host from newly forming tumors [74]. Immunosuppressive medications impair the ability of the host immune system to eliminate tumor cells. More recent investigations have shown, however, that direct effects of immunosuppressive medications (e.g. CNIs and azathioprine) at the site of tumor development may also play a role, raising mutagenesis in cells and speeding up tumor growth [75]. This explains why certain malignancies, e.g. skin cancers, or cancers associated with viral infections, are frequent in transplant recipients. Interestingly, the effect of mTOR inhibitors on cancer risk may be favorable. The effects of rapamycin on TGF-β and angiogenesis are opposite to CNIs— rapamycin suppresses TGF- β and decreases angiogenesis [76]. As an extension of these experimental findings, several clinical investigations have suggested that use of mTOR inhibitors may be associated with lower incidence of skin malignancy after organ transplant [77, 78].

Skin cancer is the most frequent type of malignancy after heart transplant. Analysis of a multicenter U.S. registry has demonstrated that at 10 years after transplant, 11 % of patients have developed squamous cell skin cancer, 8 % have developed basal cell carcinoma and 1 % of patients have developed melanoma [79]. The risk factors for skin cancer development included lighter skin, older age, pre-transplant history of skin cancer and residence in latitude with higher UV-light exposure. Patients receiving higher doses of cyclosporine, azathioprine and mycophenolate were also shown to have higher incidence of skin cancer. Compared to age- and gender-matched general population, the incidence of the different types of skin cancer was elevated up to 30-fold, and the diagnosis of skin cancer was associated with higher mortality [79].

The incidence of non-skin malignancies after heart transplantation is also increased compared to a general population. An analysis of the Canadian Organ Replacement Register, Canadian Mortality Database and Canadian Cancer Registry has shown that the 15-year cumulative incidence of all cancers excluding squamous basal cell skin carcinoma among 1,703 heart transplant recipients was 17 %. A total of 160 cancers developed in these patients, compared to an expected 59. Among specific cancers, the incidence was statistically higher for lymphoma, lung cancer, oral cancer and multiple myeloma, and numerically higher for a number of additional malignancies, including cancer of kidney, prostate, pancreas and others [80]. A study that included large number of transplant recipients in Australia demonstrated higher risk of 12 types of cancer in heart transplant recipients compared to the matched general population [81]. Increased incidence of non-skin cancer in solid organ recipients has also been confirmed by a number of other reports (Fig. 24.2) [1, 82–84].

Apart from skin cancer, hematological malignancies after solid organ transplant show the highest increase in incidence compared to the general population. Post-transplant lymphoproliferative disorder (PTLD) represents the bulk of the hematological malignancies. Its incidence in children is approximately 1.5 % and 6 %, and in adults 0.3 % and 0.7 %, 1- and 5-years after heart transplant, respectively [85]. Epstein Barr Virus (EBV) plays a key role in PTLD pathogenesis. EBV is a herpesvirus with a seroprevalence of approximately 50 % in children by the age of 5 years and of over 90 % in adults [86]. The lack of an effective T-cell response in immunosuppressed recipients compromises the ability of the organism to control EBV replication and leads to uncontrolled polyclonal or monoclonal replication of EBV-infected lymphocytes—PTLD. The risk of PTLD development is especially high after a primary EBV infection. Therefore, pediatric heart transplant recipients are at a higher risk of developing PTLD than adults, and most cancers diagnosed after heart transplant in children are PTLD [87]. In the pediatric heart transplant population, children between 1 and 10 years are at the highest risk, with 25 % of patients in this age group who were seronegative at the time of transplant developing PTLD [88]. In addition to young age and EBV seronegativity, use of certain immunosuppressive agents has been associated with increased risk of PTLD – OKT3, antilymphocyte globulin, and most recently belatacept [89, 90].

EBV positive forms of PTLD often occur early after transplant. EBV-negative forms of PTLD do not appear to be linked to EBV infection, can occur in both pediatric and adult heart transplant recipients, and typically presents later (years) after transplant [91].

The PTLD presentation may be somewhat non-specific. This diagnosis should be considered in patients with high EBV viral load in blood and pharyngitis, enlarged tonsils, lymphadenopathy, hepatomegaly or splenomegaly. Gastrointestinal symptoms including indigestion, diarrhea and abdominal pain may be present as lymphocyte proliferation often takes place in the abundant gut lymphoid tissue. Neurological symptoms can be seen when central nervous system is involved, which is considered a marker of worse outcome. Focal presentation in the form of EBV-associated lymphoma can also be seen, and the lymphoma may infiltrate any organ. The full diagnostic workup of a suspected PTLD is outlined in Table 24.4 [92].

Treatment of PTLD includes aggressive reduction of immunosuppression, aimed at restoring of the recipient’s ability to generate cytotoxic lymphocytes and control the proliferation of the EBV infected lymphocytes. Reduction of immunosuppression alone can lead to PTLD remission in up to 40 % of patients with EBV positive PTLD [93]. Additional pharmacotherapy includes the use of antivirals acyclovir and ganciclovir, anti-CD-20 antibody rituximab, or cyclophosamide and prednisone chemotherapy. The efficacy of intravenous immunoglobulin and interferon is less well established. The utility of a proteasome inhibitor bortezomib is also being tested. Surgical debulking may be needed in selected cases, and radiation has been used, especially when CNS involvement is present [92].

Chronic chemoprophylaxis with acyclovir in recipients who are EBV seronegative at the time of transplant, especially if the donor is EBV seropositive, has been practiced by some heart transplant programs. The intent is to reduce the likelihood of PTLD development in this high risk cohort of patients, but data evaluating the efficacy of this approach are limited. Surveillance monitoring of EBV load and preemptive reduction in immunosuppressive therapy is an alternate approach used especially in pediatric programs. This strategy has been shown to decrease PTLD incidence in pediatric kidney and liver transplant [55, 94].

One-year survival after PTLD diagnosis has been reported at 55–75 %, with 5-year survival 40–60 % [7, 12–14]. Survival in children is in general better compared to adults and survival in EBV positive PTLD is better compared to EBV negative forms of the disease. Outcomes after PTLD have been improving recently, likely a result of earlier diagnosis allowed by EBV surveillance, use of preemptive reduction in immunosuppressive therapy and introduction of therapy with rituximab [92].

Prevention of malignancy after transplant starts with heart transplant candidate evaluation. All candidates should undergo age appropriate cancer screening, including colonoscopy, mammogram and PAP cervical smear. Skin exam should also be done and a Dermatology consultation obtained should any suspicious skin lesions be identified. If precancerous lesions are identified during cancer screening, treatment should be initiated without delay. After transplant, cancer screening should be continued. Patients should be instructed to protect their skin from UV radiation by appropriate clothing, head cover and skin sun-block. Dermatology skin cancer screening should be done every 6–12 months. Annual physical examination for adenopathy or abnormal masses should be done, and age appropriate colon, breast and cervical cancer screening should be continued. Chest radiography is in general performed annually, as is serum prostate-specific antigen (PSA) level, although data regarding its utility is limited. Surveillance monitoring of EBV load or chemoprophylaxis with antivirals should be done in patients who are at high risk for PTLD. All patients should be encouraged to report any unusual findings or symptoms. Minimization of immunosuppression is recommended when safe and feasible in heart transplant candidates at risk of, or with history of, malignancy [45].

While donor derived malignancy is relatively rare, the consequences of such an event can be devastating [95, 96]. A detailed personal medical history obtained from donor family at the time of organ procurement should specifically inquire about any history of tumor diagnosis or treatment. A careful physical exam of the donor should focus on ruling out malignancy that could be detected by physical exam, such as skin cancer. Results of imaging studies obtained during donor evaluation should also be reviewed to rule out possible diagnosis of cancer. This should especially apply to older donors, and donors whose cause of death is an intracranial bleed or whose cause of death may not be fully explained.

In donors with history of a tumor, the risk of donor related malignancy transmission needs to be assessed and balanced with a benefit of using the particular organ for transplantation. In 2011, the Disease Transmission Advisory Committee (DTAC) of the Organ Procurement and Transplantation Network/United Network for Organ Sharing (OPTN/UNOS) published a report that assigned various tumors with specific levels of risk for transmission to the recipient (Table 24.5) [97]. Benign tumors in which malignancy is excluded represents no significant risk to the recipient and their presence should not alter organ allocation decisions. A minimal risk category designates tumors with a risk of transmission of <0.1 %. Donors with tumors in this category should be strongly considered for heart transplantation. Use of organs from donors with tumors with low risk of transmission (0.1–1 %) should be evaluated on a case by case basis, and the risk of transmission weighed against the benefit of transplantation in the particular recipient. Transplantation of heart allografts from donors with more than low risk (>1 %) of malignancy transmission should only be considered in exceptional circumstances.