Noninfectious Complications After Kidney Transplantation




Abstract


Kidney transplantation is the treatment of choice for selected patients with end-stage renal disease (ESRD) because of improvements in patient survival, quality of life, and reduced long-term health costs. Clearly, the success of transplantation is founded upon the use of potent immunotherapies that prevent allograft rejection and permit long-term engraftment. The complex pathophysiological changes that occurred during kidney failure before transplantation are often compounded by complications that are directly induced by suppression of the immune system. As patient and graft survival rates have improved, attention has been directed to strategies that mitigate the relatively high burden of morbidity and mortality. Cardiovascular disease, infection, and malignancy are the dominant causes of mortality after kidney transplantation. This chapter will focus on the noninfectious complications that develop after transplantation and their management strategies. Complications range in severity from to those that are relatively minor events to those that are allograft- or life-threatening.




Keywords

Cardiovascular disease, electrolyte disorders, kidney transplant, malignancy, musculoskeletal disorders, neuropsychiatric disorders, peripheral vascular disease, visual disturbances

 






  • Outline



  • Introduction, 639



  • Cardiovascular Disease, 639




    • Nontraditional Risk Factors, 640



    • Hypertension, 640



    • Smoking, 641



    • Dyslipidemia, 641



    • New-Onset Diabetes After Transplantation, 642



    • Metabolic Syndrome, 642



    • Obesity, 642



    • Peripheral and Cerebrovascular Disease, 643



    • Posttransplantation Anemia, 643



    • Evaluation of Atherosclerotic Cardiovascular Disease Before Transplantation, 644




  • Malignancy After Kidney Transplantation, 644




    • Effect of Immunosuppression, 645



    • Posttransplantation Lymphoproliferative Disease, 646




  • Electrolyte Disorders, 646



  • Musculoskeletal Complications of Transplantation, 647




    • Osteopenia and Osteoporosis Posttransplantation, 647



    • Tendonitis, 648




  • Neuropsychiatric Complications of Transplantation, 648




    • Depression, 649



    • Suicide, 649



    • Nonadherence, 649



    • Psychopharmacology, 649



    • Neurological Complications, 650




  • Visual Disturbances After Transplantation, 650



  • Summary and Conclusion, 650




Introduction


Kidney transplantation is the treatment of choice for selected patients with end-stage renal disease (ESRD) because of improvements in patient survival, quality of life, and reduced long-term health costs. Clearly, the success of transplantation is founded upon the use of potent immunotherapies that prevent allograft rejection and permit long-term engraftment. The complex pathophysiological changes that occurred during kidney failure before transplantation are often compounded by complications that are directly induced by suppression of the immune system. As patient and graft survival rates have improved, attention has been directed to strategies that mitigate the relatively high burden of morbidity and mortality. Cardiovascular disease, infection, and malignancy are the dominant causes of mortality after kidney transplantation. This chapter will focus on the noninfectious complications that develop after transplantation and their management strategies. Complications range in severity from to those that are relatively minor events to those that are allograft- or life-threatening.




Cardiovascular Disease


Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of mortality in dialysis and transplant patients, accounting for at least one-third of all deaths in transplant recipients, and remains the most common cause of graft loss. ASCVD before kidney transplantation is three to four times more prevalent in the ESRD compared with the general population and has been shown to be the single most important predictor of cardiovascular mortality after transplantation. Vanrenterghem and colleagues reexplored this topic to define current trends. In a cohort of more than 2000 primary allograft recipients, the incidence of cardiovascular events increased over time. Within 15 years of transplantation, only 47% of surviving patients had not experienced any cardiovascular events. Risk factors associated with cardiovascular complications were male gender, age, hypertension (HTN) before transplantation, longer duration of pretransplantation dialysis, cardiovascular event before transplantation, older era of transplantation, center-specific effect, posttransplant diabetes mellitus, increased pulse pressure after transplantation, use of corticosteroids and azathioprine, lower serum albumin after transplantation, and higher serum triglyceride levels after transplantation. The risk for death was also increased in patients with low or elevated hematocrit, whereas it was minimal with values of about 38%. Numerous other reports have underscored the prevalence and importance of “traditional” risk factors for ASCVD in transplant recipients.


In spite of those issues, kidney transplantation has repeatedly been shown to reduce cardiovascular and all-cause mortality compared with dialysis. For example, Meier-Kriesche and associates compared the cardiovascular death (CVD) rates of more than 60,000 adult first kidney transplant recipients with those of 67,000 waitlisted patients over the same time period. A progressive decline in CVD rates was seen in the transplant recipients compared with the opposite trend for patients who remained on the waiting list. Even though CVD rates were higher in the early postoperative period, by 3 months posttransplantation, rates were lower than for dialysis patients.


Nontraditional Risk Factors


So what is it about transplantation that lowers cardiovascular risk? Recently, attention has focused on nontraditional cardiovascular risk factors that are prevalent in patients with chronic kidney disease (CKD) and that are not effectively controlled by dialysis. An overview of the effect of traditional and nontraditional risk factors is provided in Fig. 41.1 . Oxidative stress is now known to be an important factor in the pathogenesis of ASCVD in patients with ESRD. Uremic oxidative stress is characterized biologically by an increase in lipid peroxidation products and reactive aldehyde groups as well as by retention of oxidized thiols. The pathophysiology of oxidative stress in uremia is multifactorial, but the retention of oxidized solute by the loss of kidney function is probably a major contributor. Simmons et al. evaluated time-dependent changes in biomarkers of oxidative stress before and after living donor transplantation. Pretransplantation levels of the proinflammatory proteins interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and C-reactive protein (CRP), and the oxidative stress markers plasma protein carbonyls and F 2 -isoprostanes, were significantly elevated in CKD patients compared with healthy control subjects. There was a rapid and sustained decline in all of these biomarkers after transplantation, and by 2 months posttransplantation, levels had reached those of the controls. Cueto-Manzano and colleagues also reported increased levels of inflammatory markers pretransplantation that initially fell posttransplantation and, in the case of CRP, remained low, whereas levels of TNF-α and IL-6 fell, only to rise by the first posttransplantation year. Ducloux and associates recorded coronary events in 8% of 344 consecutive kidney transplant patients who were free of vascular disease at the time of transplantation. In addition to “traditional” Framingham risk factors, CRP and homocystinemia were found to be independent risk factors for ischemic heart disease events. Sezer and colleagues retrospectively analyzed the predictive role of CRP on the development of chronic allograft dysfunction. No difference was found between the pretransplantation levels of CRP between those transplant recipients who were destined to develop allograft dysfunction and those who were not. However, CRP levels were significantly higher in patients with allograft dysfunction by 1 month posttransplantation and at the time of diagnosis of allograft dysfunction.




FIG. 41.1


Pathogenesis of atherosclerosis after kidney transplantation. Numerous processes interplay to induce atherosclerosis after transplantation, including traditional (or Framingham) and nontraditional factors. ASCVD, Atherosclerotic cardiovascular disease; CAC, coronary artery calcification; IS, immunosuppression.


Hypertension


About 70% of transplant recipients are hypertensive. HTN after transplantation is associated with numerous factors that include pretransplantation HTN, cause of primary disease, as well as posttransplantation factors such as delayed graft function, immunosuppression therapy, rejection, transplant renal artery stenosis, acquired glomerular filtration rate (GFR), chronic immune and nonimmune injury, recurrent or de novo allograft glomerulonephritis, and weight gain. HTN is a risk factor for premature allograft failure, ASCVD, and death with a functioning graft.


It is known that calcineurin inhibitors (CIs) and steroids induce or exacerbate HTN after transplantation. The CIs disrupt the normal balance between endogenous vasodilators and vasoconstrictors, leading to afferent arteriolar vasoconstriction and thus HTN. In part, this effect is mediated via activation of the sympathetic nervous system and also increased expression of endothelin. Watschinger and Sayegh described the pathogenic role of endothelin in this setting by administering an endothelin receptor antagonist that blunted the rise in blood pressure induced by cyclosporin A (CsA) in vivo. Vasoconstriction is compounded by depressed nitric oxide–induced vasodilatory activity. A recent report described a novel mechanism by which CsA causes sodium retention in the thick ascending limb of the loop of Henle, leading to HTN.


It should be recognized that not all CIs induce HTN to the same extent. For example, numerous clinical trials have shown that tacrolimus is associated with a significantly reduced requirement for medications to control HTN compared with CsA. Similarly, ISA 247, a novel CI currently undergoing clinical trials, may also be associated with less HTN compared with CsA. HTN has also been shown to resolve on converting patients from CsA to tacrolimus and to increase again when switched back to CsA treatment. In addition, individuals without kidney disease are more likely to develop HTN when given CsA compared with tacrolimus.


Steroids also elevate blood pressure via mineralocorticoid-induced sodium retention. The effects are dose related, and the relatively low doses of steroids currently used after the first 6 to 12 months are thought to have a small effect on blood pressure. Patients with preexisting HTN appear to be more susceptible to this adverse effect of chronic steroid use. Steroids are associated with multiple complications including HTN, obesity, glucose intolerance, osteoporosis, avascular necrosis, glaucoma, cataracts, myopathy, and neuropsychiatric complications after transplantation. In various older studies, steroid withdrawal was shown to improve blood pressure, glycemic control, and lipid profiles. In truth, although steroid avoidance or early steroid withdrawal is now routinely practiced by many centers in the United States, there are no data to indicate that such a practice has any beneficial effect on patient or graft survival. Furthermore, such practices have been shown to increase the early rejection rate and may adversely affect long-term graft function in at least some patient groups.


Smoking


Smoking remains an important remediable cardiovascular risk factor that is associated in kidney transplant recipients with an increased burden of cardiovascular disease and an increased risk for premature graft failure. In a recent cross-sectional single-center study analyzing smoking habits, it was found that kidney transplantation is a strong incentive for patients to quit. Morphologically, the main allograft lesion associated with smoking is fibrous intimal thickening of small arteries. A recent cross-sectional analysis demonstrated that 76% of the waitlisted patients and 87% of allograft recipients were nonsmokers at the time of investigation. Among the nonsmoking waitlisted patients, only 31% had never smoked, whereas 41% of the allograft recipients had never smoked. Of former smoking patients, only 28% had stopped smoking after transplantation. Patients younger than 55 years of age and females were more likely to quit than older or male patients. Smokers were significantly less likely to be transplanted compared with nonsmokers. Detection of smoking habits is typically dependent on patient self-reporting, seemingly a rather unreliable practice. In a cohort of 233 kidney transplant recipients, 45% were reported never to have smoked. In this group, serum cotinine serum levels were unrecordable. Among the 55% with a lifetime history of smoking, cotinine level was diagnostic of current smoking in 32 (25%). However, only 66% of the current smokers admitted to the nephrologist that they had continued smoking, and 34% claimed to be nonsmokers. The authors concluded that identification of current smokers among kidney transplant recipients should start with questioning about lifetime history of smoking; if positive, cotinine serum level should be measured.


Dyslipidemia


After transplantation, the prevalence of hypercholesterolemia is 60% and hypertriglyceridemia is 35%. Most immunosuppressive drugs, with the exception of the antimetabolites and belatacept, adversely affect dyslipidemia. Various reviews have described the differential effects of sirolimus, cyclosporine, and tacrolimus on dyslipidemia, which range in severity from most to least, respectively. Approximately 70% of CsA-treated kidney transplant patients have serum cholesterol levels higher than 200 mg/dL, and 30% have levels higher than 250 mg/dL. In addition, low-density lipoprotein (LDL) oxidation is increased in patients treated with cyclosporine. Oxidized LDL is thought to play a crucial role in the development of arteriosclerotic lesions because it is toxic for endothelial cells and triggers endothelial dysfunction. Kidney transplant recipients, and particularly those treated by CsA, have an increased incidence of endothelial dysfunction, which is revealed by impaired endothelium-dependent vasodilatation.


Because cardiovascular disease is so prevalent in kidney transplant recipients, it is reasonable to consider the kidney transplantation state to be a “coronary heart disease risk equivalent” when applying guidelines. This implies targeting plasma LDL cholesterol to less than 100 mg/dL via a combination of therapeutic lifestyle changes and drug therapy. Changing immunotherapy may also affect dyslipidemia in a beneficial manner. For example, switching to tacrolimus from sirolimus or cyclosporine and withdrawing steroids may permit normalization of lipid levels without any other pharmacological intervention.


Statins are the lipid-lowering drugs of choice in transplant recipients. A recently published trial that investigated the use of fluvastatin in kidney transplant recipients (Assessment of Lescol in Renal Transplantation [ALERT]) demonstrated efficacy in lowering cholesterol levels. More importantly, cardiac deaths and nonfatal myocardial infarcts, although not overall mortality, were also significantly reduced after a mean of 6.7 years of follow-up. Of note, earlier reports of this study that failed to demonstrate use in reducing cardiovascular events should remind the reader that most statin trials reveal divergent outcomes only after 5 or more years of follow-up.


The reader is reminded that statin metabolism is at least partly inhibited by CI therapy that can lead to elevated blood and tissue concentrations and risk for adverse effects such as rhabdomyolysis. It is currently recommended that statins be used at reduced doses in CI-treated transplant recipients. This interaction is further enhanced if additional inhibitors of cytochrome P-450, such as diltiazem, are administered. Other measures that are often considered to minimize the risk for toxicity include the use of pravastatin or fluvastatin (which appear to have the least interaction with CIs), avoidance of other inhibitors of the cytochrome P-450 system, and avoidance of fibrates; periodic checking of plasma creatine kinase and liver function tests is also advisable. Early reports indicating that pravastatin may reduce the risk for rejection in kidney and heart transplant recipients are probably of less relevance in the current era of “modern” immunosuppression. Rarely, nonstatin drugs are used to lower plasma lipids in transplant patients. Bile acid sequestrants, if used, should be taken separately from CI because they impair absorption of these drugs. Fibrates should be prescribed with extreme caution to patients on statins and CI.


New-Onset Diabetes After Transplantation


The development of new-onset diabetes after transplantation (NODAT) is a serious complication of transplantation that is associated with dyslipidemia, chronic allograft dysfunction, cardiovascular morbidity, and death. The incidence of NODAT is definition dependent and ranges from 2% to 53%. Risk factors include obesity, weight gain, hepatitis C, steroids, tacrolimus, and restoration of insulin metabolism by the kidney allograft. For reasons that are unclear, autosomal dominant polycystic kidney disease (ADPKD) is also a risk factor for NODAT. The causative pathophysiological mechanisms include a decrease in the number and binding affinity of insulin receptors, malabsorption of glucose in peripheral organs, and activation of the glucose/fatty acid pathway. Such mechanisms appear particularly important in those with significant posttransplantation weight gain.


The introduction of CI therapy, particularly tacrolimus, increases the risk for NODAT. Early studies indicated that up to 20% of tacrolimus-treated patients developed diabetes and required insulin, although the generally accepted number currently is about 7%. Both in vitro and biopsy studies indicate that CI impair pancreatic β-cell function, causing islet cell injury ; this leads to diminished insulin synthesis or secretion, or both. Tacrolimus previously has been shown to impair first-phase (or early) insulin secretion, whereas CsA has been shown to impair second-phase (or later, sustained) insulin secretion. The clinical significance of the latter observation is unclear.


Steroids induce hyperglycemia primarily by causing insulin resistance by increasing hepatic gluconeogenesis, inhibiting peripheral glucose uptake, and also by impairing insulin secretion. Reducing or withdrawing steroids has been shown to ameliorate hyperglycemia.


The prognosis of NODAT is variable, although some studies indicate that up to one-third of patients ultimately regain euglycemia off treatment. This figure may be higher if such patients undergo steroid minimization or withdrawal along with a reduction or change in CI therapy. However, most patients require a long-term approach to management that includes therapeutic lifestyle change, oral hypoglycemics or insulin, or both. Tight control of blood sugars has been shown to slow the progression of end organ damage in diabetes; similar benefits are likely in kidney transplantation patients. It should be remembered that in spite of beneficial effects of tacrolimus on parameters such as HTN, GFR, and lipids, registry data indicate that there is no difference in patient or graft survival between those patients who receive cyclosporine and tacrolimus. This observation is probably explained by the deleterious effect of tacrolimus-induced NODAT on long-term patient survival.


Metabolic Syndrome


The metabolic syndrome (MS) is known to be a risk for cardiovascular disease in the general population. In a study of more than 300 transplant recipients, 32% met criteria for MS at 1 year. Predictive factors for MS included older age, male gender, pretransplantation high body mass index (BMI), and an increase in BMI after transplantation. In addition, the cumulative incidence of adverse events was more than three times greater in patients with MS compared with others without MS. In another study, MS was present in 54% of transplant recipients. In this cohort, there was a significant correlation between the various components of the MS and the severity of coronary artery calcification (CAC). Median CAC scores were 0, 33, 98, and 262 for patients with one, two, three, and four or more positive components of the MS, respectively. It has also been suggested that MS is related to inflammation as measured by CRP levels in transplant recipients. The effect of a 12-month dietary regimen on the nutritional status and metabolic outcome of kidney transplant recipients in the first posttransplantation year was reported by Rike and colleagues. Forty-six deceased-donor kidney transplant recipients were enrolled during the first posttransplant year and followed prospectively for a further 12 months. Compliance with dietary recommendations was related to gender (male better than female) and was associated with weight loss primarily due to a decrease in fat mass, with decrease in total cholesterol and glucose plasma levels and with a concomitant rise in serum albumin concentrations.


Obesity


The epidemic of obesity in the United States has not spared kidney transplant candidates. Obesity trends in transplant recipients tend to mimic those in the general population, 65% of which is now defined as overweight (BMI greater than 25 kg/m 2 ). Several factors contribute to weight gain, including steroid use, removal of dietary restrictions after transplantation, and physical inactivity. Obesity is an established risk factor for atherosclerotic heart disease and increases the risk for diabetes, dyslipidemia, and HTN. Obesity is also known to be associated with depression after transplantation. Bosma and colleagues described an association between obesity and iothalamate-determined glomerular hyperfiltration in 838 kidney transplants. With higher BMI, estimated GFR (eGFR) and filtration fraction (FF) increased significantly. Multivariate analysis supported the effect of BMI on eGFR and determined that this association was not explained by diabetes mellitus. On Cox regression analysis, lower eGFR and higher FF were independent determinants of graft loss and patient mortality. It is now known that the likelihood of receiving a transplant decreases with increasing degree of obesity compared with nonobese patients. Similarly, the likelihood of being bypassed when an organ becomes available increases in a graded manner with category of obesity. The defining questions about obesity and transplantation are whether the former affects outcomes and whether weight loss before transplantation is a mitigating factor. In a study of 5700 patients, obesity was associated with poor graft survival. Patient survival was inferior only in univariate and not in multivariate analyses. Perhaps surprisingly, underweight patients had greater late death-censored graft loss, mainly due to chronic allograft nephropathy. However, obesity was associated with greater odds risk (OR) for delayed graft function and 6-month risk for acute rejection. Management of obesity includes lifestyle changes, dietary modifications, and in some cases gastric bypass or banding, for which the published experiences in transplant recipients are limited.


Peripheral and Cerebrovascular Disease


Dialyzed and kidney-transplanted patients have a higher rate of peripheral vascular complications than the general population. Although transplantation is associated with significantly better survival than maintenance dialysis, kidney transplant recipients still remain at high risk for vascular complications. This risk can be enhanced by immunosuppressive drugs. Kasiske and associates reported a 15% prevalence of peripheral vascular disease at 15 years posttransplantation. Sung and associates retrospectively studied 664 adult recipients and found a cumulative 5- and 10-year incidence of 4% and 6%, respectively; the presence of peripheral vascular disease was independently associated with poorer recipient survival. There is also some evidence from registry data that peripheral vascular disease is a risk factor for poor graft outcomes. It therefore seems reasonable to aggressively treat patients with this condition with measures, such as aspirin, statins, smoking cessation, and revascularization where appropriate.


Posttransplantation Anemia


Posttransplantation anemia is present in more than 50% of kidney recipients at some stage after surgery. Immediately posttransplantation, anemia is a consequence of postoperative blood loss, the use of myelosuppressive immunosuppressive medications such as antimetabolites, sirolimus and antithymocyte globulins (ATG), inflammation, and defective erythropoietin production by the transplanted kidney. Furthermore, anemia can persist months after transplantation due to several factors including antiviral therapy, allograft dysfunction, or infection. Table 41.1 summarizes the major causes of anemia in kidney transplant recipients and their mechanisms.



TABLE 41.1

Causes of Anemia in Kidney Transplant Recipients




































Cause Mediated by Ultimate Effect
Allograft dysfunction Hyperparathyroidism-Inflammation Erythropoietin deficiency Decreased bone marrow production of RBCs
Azathioprine MMF/MPA SRL TMP-SMX(val) ganciclovir Antithymocyte globulins Myelosuppression Decreased bone marrow production of RBCs
ACE inhibitors ARB Impaired production of, or resistance to, erythropoietin Decreased bone marrow production of RBCs
Iron deficiency Impaired synthesis of hemoglobin Decreased bone marrow production of RBCs
Minor ABO incompatibility Donor antibodies RBC hemolysis
Posttransplantation hemolytic uremic syndrome Multiple factors, including genetic defects, viral infection, calcineurin inhibitors, antiphospholipid antibodies RBC hemolysis
Gastrointestinal or other bleeding RBC RBC losses exceed production

This table shows only the more common causes of anemia posttransplantation. Frequently, more than one is present in the individual recipient.

ACE, Angiotensin-converting enzyme; ARB, angiotensin receptor blockers; MMF/MPA, mycophenolic mofetil/mycophenolic acid; RBC, red blood cell; SRL, sirolimus; TMP-SMX, trimethoprim-sulfamethoxazole.


Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) exacerbate or induce anemia in the transplant patient, although for reasons that are incompletely understood. In the Transplant European Survey on Anemia Management (TRESAM) study, data from 4263 patients from 72 transplant centers in Europe was collected 6 months to 5 years posttransplantation. The mean hemoglobin levels before transplantation were significantly higher in the more recently transplanted recipients. At enrollment, 39% of patients were found to be anemic. Of the 8.5% of patients who were considered severely anemic, only 18% were treated with recombinant human erythropoietin (rHuEpo). Anemia was associated with impaired kidney function and use of azathioprine, ACE inhibitors, and ARB therapy.


Recombinant human erythropoietin is often administered to patients with CKD and more frequently to patients on maintenance dialysis. The use of rHuEpo after kidney transplantation remains to be defined. Van Biesen and associates reported the results of a trial in which patients were randomized to either receive rHuEpo three times a week immediately after transplantation or not. The time to reach a hemoglobin level greater than 12.5 g/dL was 66 days in the rHuEpo group compared with 57 days in the control group. The authors concluded that although the administration of rHuEpo reduced the duration of anemia, this effect was marginal, and the doses needed were high. There was no difference in harder endpoints such as length of stay or patient or graft survival between the groups.


Evaluation of Atherosclerotic Cardiovascular Disease Before Transplantation


Given the high incidence of preexisting ASCVD in the ESRD population, screening for such disease remains an important part of the transplant evaluation before surgery. Such investigations generally include electrocardiography, echocardiography, provocative stress testing, and cardiac catheterization when needed as the standard of care. Nevertheless, the efficacy of such an approach has been debated because patients awaiting transplantation have high mortality rates despite careful preselection. Hage and coworkers examined mortality outcomes in 3700 patients with ESRD referred to a single center for transplantation. The mean age of the cohort was 48 years, and 42% were female. Stress myocardial perfusion imaging (MPI) was performed in 60% and coronary angiography in 7%. Over a period of 30 months, 17% of the cohort died. Interestingly, neither the presence nor severity of coronary disease as defined by angiography predicted survival. Coronary revascularization did not affect survival, either, except in patients with three-vessel disease. The best predictor of death was left ventricular ejection fraction (LVEF), as measured by gated myocardial perfusion imaging, with 2.7% mortality increase for each 1% ejection fraction decrease. Conversely, Bergeron and colleagues studied the outcome of 485 patients with CKD who had undergone dobutamine stress echocardiography (DSE) as part of an evaluation for transplantation and who were followed for more than 2 years. Almost 40% of the patients died during the follow-up period. Patients with more extensive ischemia had inferior outcomes compared with those with lesser degrees of ischemia and also those with a normal stress testing. By multivariate analyses, the percentage of ischemic segments on DSE was an independent predictor of all-cause mortality. Vanrenterghem et al. reported the prognostic power of stress MPI in 150 patients with ESRD being evaluated for kidney transplantation with known coronary anatomy based on angiography. An abnormal MPI result was present in 85% of patients, 30% had LVEF of less than 40%, and 40% had multivessel coronary artery disease using angiography. After 3 years, 35% of patients had died. Low ejection fraction, left ventricular dilatation, and diabetes mellitus were all associated with higher mortality. In a multivariate model, abnormal MPI results (low LVEF or abnormal perfusion) and diabetes alone were independent predictors of death, whereas number of narrowed arteries using coronary angiography was not. Thus MPI was a strong predictor of all-cause mortality in patients with ESRD. In truth, as a consequence of the observation that cardiovascular disease is the major cause of mortality in the peritransplant period, most transplant programs insist on echocardiography and provocative stress testing as a prerequisite for listing.


Hickson et al. reported a different approach to cardiac risk stratification using cardiac troponin T (cTnT) from a cohort of 644 patients, of whom 61% had elevated levels. Higher levels related to diabetes, longer time on dialysis, history of ASCVD, and low serum albumin. High cTnT levels related to specific cardiac anomalies including left ventricular hypertrophy, wall motion abnormalities, and stress-inducible ischemia. Importantly, increasing cTnT levels were associated with reduced patient survival independent of serum albumin. In this study, the results of the stress testing or coronary angiography, or both, did not affect survival. However, high cTnT identified patients with abnormal echocardiogram findings and poor survival. Wait-listed patients with normal cTnT had excellent survival irrespective of other factors.


It has been suggested that normalization of GFR may alter CAC after transplantation. Schankel et al. studied this issue by performing electron beam computed tomography (CT) in 82 subjects at the time of transplantation and at least 1 year later. Curiously, calcification scores actually increased over time. In multivariate analysis, diastolic blood pressure, Caucasian race, GFR, months posttransplant, BMI, and baseline CAC score were independent predictors of annualized rate of CAC change. Consequently, it seems that reasons other than arterial calcification are responsible for the favorable outcome–associated transplantation from a cardiovascular perspective.


Table 41.2 summarizes the adverse effects associated with the various immunosuppressant medications currently in clinical use.



TABLE 41.2

Adverse Effects of Immunotherapy































































































Biological Effect CsA Tac SRL Pred MMF/MPA
Hypertension ++ + ++
Nephrotoxicity +++ ++ + ++
Dyslipidemia ++ + ++++ ++
Hyperglycemia + ++ ++
Hyperkalemia ++ +++
GI side effects + ++ ++
Tremor + ++
Malignancy + + Less ?
Osteoporosis + + + ++
Hirsutism +
Gingival hypertrophy +
Alopecia +

CsA, Cyclosporine; GI, gastrointestinal; MMF/MPA, mycophenolic mofetil/mycophenolic acid; Pred, prednisone; SRL, sirolimus; Tac, tacrolimus.




Malignancy After Kidney Transplantation


Improvements in patient and graft survival rates in renal transplantation remain overshadowed by the long-term risk for malignancy. With the exception of skin cancer, recipients of kidney transplants are about three to four times more likely to develop neoplastic disorders than the general population. In general, three types of malignancy have features specific to the transplanted population:




  • Posttransplant lymphoproliferative disease (PTLD)



  • Nonmelanoma skin cancer



  • Kidney cell carcinoma arising from (atrophic) native kidneys



The relationship between the nature and intensity of immunotherapy and subsequent malignancy is well defined and has been described in prior reviews. It remains clear that the incidence of all types of cancer is higher for allograft recipients than for the general population. In a recent study of more than 2000 kidney transplant recipients with 20 or more years of graft function, more than 40% had developed skin cancer and more than 10% had developed cancer at other sites. Importantly, cancer was the second most common cause of death after cardiovascular disease. In another study, the cumulative incidence of cancer after 25 years was 49% for all tumors. The most frequent tumors observed were nonmelanoma skin cancer (21%), kidney cancer (12%), and cancers of the pharynx, larynx, or oral cavity (8%). The increase in cancer risk was 4.3-fold. Webster and associates reported standardized ratios of cancer in transplant recipients compared with the general population using the Australia and New Zealand Dialysis and Transplant Registry data. Over a 20-year period, 11% of 15,000 recipients developed cancer. The risk for cancer was found to be inversely related to age, and women aged 25 to 29 years had rates equivalent to those in women aged 55 to 59 years from the general population. Within the transplanted population, the cancer risk was affected by age differently for each sex and was elevated by prior malignancy but reduced by diabetes. The authors concluded that cancer rates in kidney recipients are similar to those in people in the general population that are 20 to 30 years older, but the absolute risk differs across patient groups.


The increase in cancer risk after transplantation is thought to result from the complex interplay of numerous factors that include cumulative exposure to immunosuppression that leads to disruption of both antitumor and antiviral immune surveillance. In addition, some drugs may promote carcinogenesis by mechanisms independent of their immunosuppressive effects. Viral infections (particularly herpes, hepatitis, and papilloma viruses) are clearly linked to some malignancies, and chronic antigen stimulation from the transplanted organ, repeated infections, and transfusions of blood products have also been implicated.


Effect of Immunosuppression


It has been suggested that the use of antilymphocyte antibody therapy and tacrolimus increases the risk for PTLD. Hardinger and associates recently reported the 10-year follow-up of a randomized trial of Thymoglobulin (Genzyme, Cambridge, MA) or ATGAM (Pharmacia-Upjohn, NY) induction. Event-free survival was significantly higher with Thymoglobulin compared with ATGAM (48% vs. 29%). At 10 years, patient and graft survival rates were similar, whereas acute rejection remained lower (11% vs. 42%) in the Thymoglobulin group. The incidence of all types of cancer was numerically although not significantly lower with Thymoglobulin compared with ATGAM (8% vs. 21%). There were no posttransplant lymphoproliferative disorder cases in the Thymoglobulin group, and there were two cases in the ATGAM group. Kidney function and measures of quality of life were found to be higher in the Thymoglobulin compared with ATGAM group. Wimmer and colleagues reported that the use of IL-2 receptor antagonists as induction therapy significantly reduced the cancer risk for transplant recipients. With the exception of mammalian target of rapamycin (mTOR) inhibitors (sirolimus and everolimus), tumor risk between immunosuppressive drugs typically used for maintenance immunosuppression was not significantly different. However, mTOR inhibitor–based immunosuppressive protocols showed a clear tendency for lower malignancy rates. Acknowledging the potential anticancer actions of the mTOR inhibitors demonstrated in clinical studies, de Fijter analyzed the effect of conversion from CIs in 53 renal transplant recipients developing nonmelanoma skin cancer after transplantation. Remission was observed in 37 patients, and therapy was generally well tolerated with minimal adverse events reported. Fifteen patients developed new lesions after conversion. Drug levels did not seem to affect the outcomes of conversion. Interestingly, the use of sirolimus has recently been shown to reduce levels of prostate-specific antigen by 50% in patients without prostate cancer. Why this occurs is unknown.


Reports continue to accumulate indicating that Kaposi sarcoma (KS) after transplantation is exquisitely sensitive to conversion from CI to mTOR inhibitor therapy. As an example, Campistol and Schena reported that conversion to either everolimus or sirolimus led to regression of KS lesions in 11 out of 12 patients. Conversion was generally well tolerated, stable kidney function was maintained in most patients, and there was no rejection. Similarly, Di Paolo and colleagues studied mTOR-signaling pathways in 10 renal transplant patients with KS who successfully responded to mTOR inhibitor conversion therapy. Patients with KS showed markedly increased basal P70 (S6K) activation and depressed phosphorylation of AKT. Long-term treatment with sirolimus was associated with marked inhibition of phosphorylation of both AKT and P70 (S6K), in parallel with regression of the dermal neoplasm.


In spite of the benefits described earlier, mTOR inhibitors have failed to gain traction because of the high incidence of symptomatic adverse effects, including increased risk for infection, wound problems, edema, mouth ulcers, and proteinuria, which are seen in up to 25% of patients and lead to conversion to alternate immunotherapy. Nevertheless, for those recipients suffering from cancer after transplantation, such agents may be useful. The reader’s attention is directed to a report prepared by an international group pertaining to the use of “proliferation signal inhibitors” (referred to earlier as mTOR inhibitors), everolimus and sirolimus, and their antioncogenic effects.


Posttransplantation Lymphoproliferative Disease


Transplant recipients are at the greatest risk for developing PTLD within the first year after transplantation. Most cases of PTLD are induced by Epstein-Barr virus (EBV) infection causing uncontrolled proliferation of B cells. The incidence is higher in EBV-seronegative children who receive seropositive grafts from adult donors. Heart-lung transplants showed the highest relative risk among various types of organ transplants. The use of tacrolimus and induction or rescue therapy with OKT3 or ATG is known to increase the risk for PTLD.


Although EBV infection is known to be associated with the development of PTLD, the prognosis of such transplant recipients has been less clear. Smith and colleagues described the outcomes of pediatric kidney transplant recipients with PCR-defined EBV infection after ganciclovir prophylaxis. Primary infection developed in 46 patients, of whom 50% were asymptomatic, 26% were symptomatic, and 24% developed PTLD. Adolescents were more likely to develop PTLD than younger transplant recipients. Among the 11 cases of PTLD, there were 2 deaths and 2 graft failures, all in adolescent recipients. Suzuki and colleagues performed a prospective study of 32 tacrolimus-treated kidney transplant recipients that included EBV serology and PCR testing. Seroconversion occurred in five of six patients approximately 22 weeks after transplantation. The viral load was significantly higher in seronegative compared with seropositive patients.


The diagnosis of PTLD is generally suggested by clinical symptoms (organ involvement or fever, or both) and imaging study results. The clinical symptoms that patients complain of are extremely variable and depend on the site and stage of PTLD. Traditionally, CT scanning with oral and intravenous contrast has been the test of choice for defining the presence and extent of PTLD. It has been suggested that fluorodeoxyglucose-positron emission tomography (FDG-PET) in-line with CT scanning may be a superior methodology. In a report of four transplant recipients with histologically confirmed PTLD, scans at diagnosis showed increased FDG uptake in all examined PTLD lesions, and the disease was upstaged on the basis of FDG-PET/CT scan results over conventional CT scanning in one patient. Furthermore, PET/CT scans no longer demonstrated FDG uptake in the original PTLD lesions in all patients at the end of treatment.


Treatment of Posttransplant Lymphoproliferative Disease


The current approach to the treatment of PTLD involves a number of therapeutic options that include:




  • Reduction of basal immunosuppression



  • Antiviral treatment in the case of EBV-positive B-cell lymphoma



  • Rituximab in the case of CD20-positive lymphomas



  • Cyclophosphamide, hydroxydaunomycin/doxorubicin, Oncovin, prednisone (CHOP) chemotherapy alone or in combination with rituximab for diffuse lymphoma or incomplete response to previous treatment



Swinnen and associates reported the results of a prospective, multicenter study that examined the efficacy of a PTLD treatment algorithm that started with a defined course of reduced immunotherapy and escalated to interferon-α2b, and finally to chemotherapy. Intravenous acyclovir was given to all patients. The CI was reduced by 50% for 2 weeks and then by another 50% unless the patient was in complete remission. Sixteen patients with biopsy-proven PTLD were eligible to participate in the study; 13 had received heart transplants, and 3 had received kidney transplants. Reduced immunotherapy resulted in only 1 of 16 partial responses and no complete remissions. Progressive disease developed in half, and 40% experienced rejection. Only 1 of 13 patients achieved durable remission with interferon. Five of seven patients who received chemotherapy achieved remission. The applicability of such a study to kidney transplantation remains uncertain, because most patients in that study were heart transplant recipients. The authors concluded, “A strong case can be made for adding rituximab to RI [reduction in immunosuppressives] as initial therapy.” Trappe and colleagues performed a retrospective analysis to determine the efficacy and safety of salvage therapy in recipients of solid organ transplants with progression of PTLD after rituximab first-line therapy. Eleven patients who had received reduced immunotherapy and single-agent rituximab were analyzed. Of these, 10 had received CHOP. This cohort seems to have been quite different from the usual PTLD cohort in that most of these patients had late disease (median onset of disease 145 months posttransplant) and had monomorphic histology, and only 36% were associated with EBV. CHOP therapy achieved complete remission in 50% of patients at 44 months posttreatment and partial remission of 20% of patients. The median overall survival was 46.5 months.

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Feb 24, 2019 | Posted by in NEPHROLOGY | Comments Off on Noninfectious Complications After Kidney Transplantation
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