Late Post-transplant Period Research Articles

Alloantigen-Specific Response Is Preserved and Autoimmunity Is Maintained in an HIV-Positive Patient With Immunoglobulin A Nephropathy Undergoing Renal Transplantation: A Warning About Long-Term Reduction in Immunosuppression—A Case Report

We report the case of a 43-year-old patient with HIV infection treated with antiretroviral therapy, which was complicated by immunoglobulin A (IgA) nephropathy and renal failure, who subsequently was transplanted using a deceased donor kidney transplant. During the late posttransplant period we detected specific anti-donor HLA antibodies showing a preserved alloantigen response. A renal biopsy showed no acute cellular or humoral rejection, an absence of pericapillary C4d deposits or SV40 infected cells, but demonstrated IgA mesangial deposits and mild interstitial fibrosis probably related to calcineurin inhibitor toxicity. This case shows that allo- and autoimmune responses are preserved despite immunosuppressive treatment and original HIV disease. It warns of the importance of maintaining optimal monitoring and immunosuppressive strategies among HIV-positive recipients who become solid organ transplant recipients.

Effect of donor/recipient body weight ratio, donor weight, recipient weight and donor age on kidney graft function in children

We hypothesized that supplementing a higher mass of renal parenchyma from adult donors, and their younger age, would improve graft function in paediatric recipients. We calculated estimated glomerular filtration rate (eGFR; Schwartz formula) and absolute glomerular filtration rate (absGFR) in 57 renal-grafted children (1995-2007) aged 3.1-17.9 years, weighing 12.9-85.0 kg, on discharge from the hospital after transplantation (TPL), 1 year after TPL and at the last follow-up (1.5-11.7 years after TPL). We correlated their eGFR with the individual ratio between the donor and the recipient body weight at the time of TPL (donor/recipient body weight ratio; D/R BWR), and we evaluated the effect of the donor and the actual recipient body weight on the eGFR and absGFR. The D/R BWR varied from 0.65 to 5.23. We found a significant positive correlation between D/R BWR and eGFR at discharge from the hospital (P < 0.001), 1-year post-TPL (P < 0.001) and at the last follow-up (P < 0.05). Using multiple linear regression analyses, we found that both eGFR and absGFR values were much more determined by the actual recipient weight than by the donor weight (27/6% and 43/4% at discharge, by 24/4% and 57/0% 1 year after TPL, and 0/0% and 20/0% at the end of the follow-up). A tendency for lower eGFR with increasing age of donors was apparent at discharge and 1 year after TPL, but it reached statistical significance only at the last follow-up (r = 0.4254, P < 0.01). In paediatric renal transplants, the value of D/R BWR directly correlated with eGFR in the early and late posttransplant periods. However, this correlation was mainly influenced by the recipient weight, while the donor weight played only a minor or negligible role.

Outbreak of pneumocystis pneumonia occurring in late post-transplantation period

Outbreak of pneumocystis pneumonia occurring in late post-transplantation period

Beneficial effects of donor‐specific transfusion on renal allograft outcome

Donor-specific transfusion (DST) is claimed to improve graft survival in living kidney transplantation. The aim of this study was to determine the influence of DST on the incidence of acute rejection (AR), graft function and survival in the early and late post-transplantation period in transfusion-naïve patients. Three patient groups were compared: group 1 received DST (n = 18), group 2 patients received no transfusion prior to surgery (n = 13) and group 3 consisted of 132 randomly transfused patients. The DST protocol consisted of infusion of fresh whole donor blood (3 × 150 mL) at two-wk intervals accompanied by three d of azathioprine. All patients were grafted within one month after the third DST. Triple drug immunosuppression based on cyclosporine A was given to all patients. DST and polytransfused patients experienced significantly less AR compared with group 2 patients. Two-yr graft function was significantly better in patients in groups 1 and 3 compared with group 2. Although similar eight-yr patient and graft survival was found in all the groups, delayed graft function patients had the longest graft half-life. DST imposes a significant beneficial effect on the incidence of AR, DGF and graft function during the first post-transplantation year in transfusion-naïve patients receiving standard immunosuppression therapy.

Os et transplantation

Transplantation is an established therapy for many hematologic disorders, as well as for end-stage diseases of the kidney, lung, liver, heart among others. Osteoporosis and a high incidence of fragility fractures have emerged as a major complication of organ transplantation. Many factors contribute to the pathogenesis of osteoporosis following organ transplantation. In addition, most patients have some form of bone disease prior to transplantation, which is usually related to adverse effects of end-stage organ failure on the skeleton and previous therapies, notably glucocorticoids. This chapter reviews the mechanisms of bone loss that occurs both in the early and late post-transplant periods, including the contribution of immunosuppressive agents as well as the specific features of bone loss after kidney, lung, cardiac, liver and bone marrow transplantation. Prevention and treatment for osteoporosis in the transplant recipient will also be addressed.

Late Viral Infections After Cord Blood Transplantation: Comparison with Unrelated Bone Marrow Transplantation

AbstractAbstract 1260Although the efficacy of cord blood transplantation (CBT) from unrelated donors as viable alternative for patients in need of hemtopoietic stem cell transplantation (HSCT) is supported by growing evidences, viral infections related to delayed immune reconstitution remains important problems for further improvement of clinical outcomes. To evaluate incidences and outcomes of late viral infections after CBT by comparison with those after unrelated bone marrow transplantation (uBMT), we retrospectively analyzed the records of 281 Japanese adult patients who underwent allogeneic unrelated HSCT for the first time at the Toranomon Hospital between January, 2002 and March, 2010, and who survived more than 100 days after HSCT without the lost-to-follow-up or retransplantation before day 100. Between 50 days and 5 years after HSCT, 116 patients had at least one late infectious episode with a cumulative incidence of 52.2%, at a median of 157 (50-1597) days after HSCT. The 5-year cumulative incidence of any late viral infections was greater in CBT versus uBMT recipients (60.7% vs. 42.2%, respectively; P=0.039, Figure 1). Thirty-three patients (28.4%) had 2 or more episodes caused by different viruses, and a total of 152 late infectious episodes were documented. The median onset of the episodes was similar between the both groups (median onset 226 days vs 222 days, P=0.89). The most common late viral infection is varicella-zoster virus (VZV) reactivation, accounting for 28.8% (disseminated 10, localized 34), followed by hemorrhagic cystitis associated with adeno- and/or BK viruria (28.2%), cytomegalovirus (CMV) diseases (16.4%; gastrointestinal diseases 23, retinitis 1, pneumonia 1), and respiratory tract infections caused by influenza virus, parainfluenza virus or respiratory syncytial virus (15.8%; upper 26, lower 8), and Epstein-barr virus lymphoproliferative diseases (4.6%). The remaining 10 infectious episodes were caused by relatively rare type of viruses including herpes simplex virus, JC virus, measles virus, mumps virus, norovirus and parvovirus, all of which occurred only in CBT recipients. Of all these viral infections, only VZV reactivation developed significantly more frequent in CBT than in uBMT recipients (P=34.0% vs 17.0%, P=0.023). There was no difference of dissemination rate between the both groups, and all the patients responded well to treatment with antiviral agents. The late viral infection was a primary cause of death in 3 episodes, all of which were pneumonia caused by CMV, influenza virus and parainfluenza virus. The 5-year incidence of infection-related mortality did not differ between CBT and uBMT recipients (0.7% vs 3.1%, P=0.46). Non-relapse mortality occurred in 11.8 % and 16.4 % patients in the CBT and uBMT groups (P=0.71). These findings suggested that cord blood might be as an acceptable and useful stem-cell source as bone marrow from unrelated donors in terms of risks of viral infection in the late posttransplant period. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Managing Invasive Fungal Infection in Hematopoietic Stem-Cell Transplantation

Reduced intensity conditioning regimens and a wider range of donor sources, including cord blood, mean that more patients can be offered potentially curative allogeneic hematopoietic stem cell transplantation than ever before. Although these modalities aim to reduce procedure-related morbidity and mortality, their potential benefit may be overshadowed by a changing spectrum of problems related to the immunocompromised status of affected patients. Acute or chronic extensive graft-versus-host disease, which occasionally emerges in the late post-transplant period, and prolonged neutropenia due to delayed engraftment still carry a substantial risk of invasive fungal and other infections. As a result, advances in antifungal prophylaxis and pre-emptive treatment were widely reported at the 36th Annual Meeting of the European Group for Blood and Marrow Transplantation attended this year by approximately 3800 delegates.

Characterization of immune responses to cardiac self-antigens myosin and vimentin in human cardiac allograft recipients with antibody-mediated rejection and cardiac allograft vasculopathy

Herein we study the role of donor-specific antibodies (DSA) to mismatched human leukocyte antigen (HLA) and antibodies (Abs) to the cardiac self-antigens myosin (MYO) and vimentin (VIM) in the pathogenesis of acute antibody-mediated rejection (AMR) in the early post-transplant period (EP, <12 months) and cardiac allograft vasculopathy (CAV) in the late post-transplant period (LP, >12 months) after heart transplantation (HTx). One hundred forty-eight HTx recipients (65 in EP, 83 in LP) were enrolled in the study. Development of DSA was determined by Luminex. Circulating Abs against MYO and VIM in sera were measured using enzyme-linked immunoassay (ELISA). Frequency of CD4+ T-helper cells (CD4+ Th) secreting interferon (IFN)-γ, interleukin (IL)-17, IL-10 or IL-5 specific to either MYO or VIM were analyzed in vitro using ELISpot assays. AMR patients were more likely DSA positive (AMR-: 15%; AMR+: 70%; p = 0.03) and demonstrated increased Abs to MYO (AMR-: 144 ± 115 μg/ml; AMR+: 285 ± 70 μg/ml; p = 0.033) and VIM (AMR-: 37 ± 19 μg/ml; AMR+: 103 ± 43 μg/ml; p = 0.014). AMR patients demonstrated increased IL-5 CD4+ Th cells specific to MYO (5.2 ± 0.9 fold, p = 0.003) and VIM (7.3 ± 2.9-fold, p = 0.004) and decreased IL-10 CD4+ Th cells specific to MYO (2.2 ± 0.4-fold, p = 0.009) and VIM (1.7 ± 0.2-fold, p = 0.03). CAV patients were more likely DSA positive (CAV-): 25%; CAV+: 79%; p = 0.03) and demonstrated increased Abs to MYO (CAV-: 191 ± 120 μg/ml; CAV+: 550 ± 98 μg/ml; p = 0.025) and VIM (CAV-: 55 ± 25 μg/ml; CAV+: 255 ± 49 μg/ml; p = 0.001). CAV patients demonstrated increased IL-17 CD4+ Th cells specific to MYO (10.5 ± 7.3-fold, p = 0.002) and VIM (7.0 ± 3.9-fold, p = 0.003). The presence of DSA in AMR and CAV is significantly associated with development of Abs to MYO and VIM in post-HTx patients. Induction of high CD4+ Th cells specific to cardiac self-antigens that secrete predominantly IL-5 and IL-17 plays a significant role in the development of Abs to self-antigens leading to AMR and CAV, respectively.

Hypertension in the kidney transplant recipient

Elevated arterial blood pressure is common after kidney transplantation and contributes to shortened patient and allograft survivals and increased fatal and nonfatal cardiovascular events. Unfortunately, current evidence indicates that arterial blood pressure remains poorly controlled in kidney transplant recipients. One concern is how best to evaluate treated levels of arterial pressure in transplant recipients as office and clinic measurements often differ from blood pressure readings obtained using ambulatory blood pressure monitoring. Some antihypertensive drugs interact with immunosuppressive medications and adversely affect electrolyte balance and kidney function, which complicates the management of kidney transplant patients. Target blood pressure readings have been suggested by different guidelines, but patient-specific management plan is still lacking. Understanding the basic mechanisms responsible for the persistent hypertension after kidney transplantation is helpful in drafting patient-directed management plan that includes both pharmacologic and nonpharmacologic interventions to achieve target blood pressure control. In this review, we propose a multilayered treatment plan that addresses hypertension in both the early and late posttransplant periods, bearing in mind complications of antihypertensive medications, interactions with immunosuppressive drugs, patient comorbidities, and patient-specific cardiovascular risk factors in the posttransplant period.

Adenovirus nephritis and obstructive uropathy in a renal transplant recipient: case report and literature review.

We report an unusual case of adenoviral nephritis in a 45-year-old woman who presented with fever, gross haematuria, acute kidney injury and obstructive uropathy 17 months following renal transplantation. Adenoviral nephritis was confirmed with immunohistochemistry. We identified 10 other published cases of adenoviral nephritis proven by immunohistochemistry. Obstructive uropathy has been reported only once before in a renal transplant recipient with adenoviral nephritis. Contrary to other reports, this case series shows that renal function may not always recover to baseline following the acute adenoviral disease. Adenoviral nephritis should be considered in the renal transplant patient with fever, haematuria, acute kidney injury and hydronephrosis in both the early and late post-transplant periods.

Post-transplantation osteoporosis

Transplantation is an established therapy for many hematologic disorders as well as for end-stage diseases of the kidney, lung, liver, heart among others. Osteoporosis and a high incidence of fragility fractures have emerged as a complication of organ transplantation. Many factors contribute to the pathogenesis of osteoporosis following organ transplantation. In addition, most patients have some form of bone disease prior to transplantation, which is usually related to adverse effects of end-stage organ failure on the skeleton. This chapter reviews the mechanisms of bone loss that occur both in the early and late post-transplant periods including the contribution of immunosuppressive agents as well as the specific features of bone loss after kidney, lung, liver, cardiac and bone marrow transplantation. Prevention and treatment for osteoporosis in the transplant recipient will also be addressed.

Early and Late Infections in Lung Transplantation Patients

Infections are an important cause of morbidity and mortality among transplanted patients. Their pathophysiology is associated with anatomic factors, immunosuppression, and pretransplant viral exposure. The aim of this investigation was to characterize infections following lung transplantation. We retrospectively analyzed the charts of 51 lung transplant recipients, who were transplanted between 1999 and 2008. Infections were classified according to their origin, etiology, occurrence time, and risk factors. The patient mean age was 55 years (range 13–71), 65% were male, and pulmonary fibrosis was the lung disease etiology in 59% of cases. Seventy-one episodes of infection were reported in the 51 patients, including (75%) during the first year after transplantation and 30 within the first 3 months (42%). Between the 4th and 11th months the number of infections decreased to 23 (32%), and afterwards there were 18 additional cases. The original site of infection was pulmonary in 43 episodes (60%), and the etiology was bacterial in 34 (48%), with Pseudomonas in 12 instances (35% of bacterial infections). Viruses were involved in 25 episodes, especially cytomegalovirus (CMV) in seronegative patients. The nine infections of fungal etiology (13%) were all caused by Aspergillus and always associated with either an acute rejection episode or suture damage. Three cases of tuberculosis were diagnosed, including two in the late post-transplant period. Three patients died of early infections. Conclusions The critical period for infections in lung transplantation patients is the first 3 months, especially for those of bacterial etiology. CMV diseases were more common in seronegative patients and fungal infections in airway injury cases.

Miyelodisplastik Sendrom-Aşırı Blastlı Refrakter Anemi Tanılı Hastada Allogeneik Kök Hücre Nakli Sonrası Görülen Listeria Monocytogenes Menenjiti

Viral, fungal and bacterial infections are commonly seen in patients early after the allogeneic bone marrow transplantation (BMT), because of neutropenia in the early period, later they occur due to cell mediated immune deficiency and at the late post transplant period due to immunoglobulin deficiency. Listeria monocytogenes is a gram positive bacterium that invades and proliferates in macrophages and epithelium. Because it is an intracellular bacterium, besides its virulence, host immune system is also important for defence mechanism against bacterium. Life threatening bacteriemia and meningitis caused by L. monocytogenes are generally seen in newborns, elderly and immunosuppressive patients including organ recipients. Herein we reported a patient who had allogeneic BMT due to myelodysplastic syndrome-refractory anemia with excess blasts (MDS-RAEB), presented with L. monocytogenes meningitis six months after allogeneic transplantation.

The impact of kidney transplantation on heart failure risk varies with candidate body mass index

The relationship of body mass index (BMI) with heart failure (HF) risk before and after kidney transplant is not well described. We examined United States Renal Data System records for 67,591 kidney transplant candidates (1995-2004) with Medicare insurance and BMI data at listing. Heart failure diagnoses were ascertained from Medicare billing claims. Body mass index was categorized per World Health Organization criteria. We modeled time-dependent associations (adjusted hazard ratio, aHR) of transplant with HF risk after listing compared with waiting in each BMI group by multivariable, stratified Cox regression. The time-dependent exposure variables partitioned relative risk of HF after transplant versus waiting into early (<or=90 days) and late (>90 days) posttransplant periods. The BMI distribution of listed candidates was as follows: 3.7% under, 40.4% normal, 32.0% over, 16.2% obese, and 7.7% morbidly obese weight. The prevalence of HF among patients awaiting transplant reached 57.4% by 3 years. Deceased-donor transplant was associated with increased early HF risk compared with continued waiting-aHRs ranged from 2.23 for normal-BMI to 2.82 for morbidly obese patients. However, transplant reduced the risk of HF in the late posttransplant period from 54% (aHR 0.46) in normal-BMI to 32% (aHR 0.68) for morbidly obese patients. Relative benefits were largest for normal-weight candidates who received live-donor transplants (aHR 0.31). Heart failure risk improves in obese patients in the long term after kidney transplant, but not as much as for nonobese patients. There is need for close monitoring and for new strategies to reduce HF risk in obese patients before and after transplant.

Invasive Aspergillosis in Solid Organ Transplant Recipients

This chapter discusses the current status and evolving trends in the epidemiology, risk factors, diagnostic laboratory assays, and the approach to antifungal prophylaxis and treatment of invasive aspergillosis in Solid Organ Transplant (SOT) recipients. Most invasive fungal infections in these high-risk patients occur within the first month posttransplant; the median time to onset of invasive aspergillosis after renal replacement therapy and retransplantation was 13 and 28 days, respectively, in one study. Other factors associated with invasive aspergillosis in liver transplant recipients include transplantation for fulminate hepatic failure, cytomegalovirus (CMV) infection, and prolonged intensive care unit stay. A retrospective survey documented invasive pulmonary aspergillosis in 7.5% (19/251) of lung transplant recipients, of whom 47% (9/19) had disseminated aspergillosis. In a survey of antifungal prophylactic strategies in lung transplant units in the United States, aerosolized amphotericin B was the most frequently employed antifungal prophylactic agent. In order of preference, the prophylactic agents used in lung transplant centers in this study were inhaled amphotericin B (61%), itraconazole (46%), parenteral amphotericin formulations (25%), and fluconazole (21%); many centers used more than one agent. Preemptive therapy, where antifungal prophylaxis is directed towards lung transplant recipients colonized with Aspergillus spp. immediately before or within 6 to 9 months after transplantation, is another approach to the prevention of invasive aspergillosis in lung transplant recipients.

Report of the first international liver transplantation society expert panel consensus conference on renal insufficiency in liver transplantation

Michael R. Charlton, William J. Wall, Akinlolu O. Ojo, Pere Gines, Stephen Textor, Fuad S. Shihab, Paul Marotta, Marcelo Cantarovich, James D. Eason, Russell H. Wiesner, Michael A. Ramsay, Juan C. Garcia-Valdecasas, James M. Neuberger, Sandy Feng, Connie L. Davis, Thomas A. Gonwa, and the International Liver Transplantation Society Expert Panel Mayo Clinic, Rochester MN; Department of General Surgery, London Health Science Center, London, Ontario, Canada; Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI; Liver Unit, Hospital Clinic, University of Barcelona School of Medicine, Barcelona, Spain; Department of Nephrology, University of Utah School of Medicine, Salt Lake City, UT; Medical School, University of Western Ontario, London, Ontario, Canada; Department of Medicine, McGill University Health Center, Montreal, Quebec, Canada; Transplant Institute, University of Tennessee, Memphis, TN; Baylor University Medical Center, Dallas, TX; Hospital Clinic I Provincial, Barcelona, Spain; Queen Elizabeth Hospital, Birmingham, England; Department of Transplant Surgery, University of California San Francisco Medical Center, San Francisco, CA; Department of Medicine, University of Washington Medical Center, Seattle, WA; and Mayo Clinic, Jacksonville, FL

Voriconazole is safe and effective as prophylaxis for early and late fungal infections following allogeneic hematopoietic stem cell transplantation

Seventy-two patients undergoing allogeneic transplantation were treated with voriconazole (VOR) as antifungal prophylaxis starting from day -2 of transplantation and continuing until withdrawal of immunosuppression. Patients were assessed for safety and the incidence of definite, probable, or possible fungal infection throughout transplantation was evaluated. VOR was well tolerated. Only 14% of patients required interruption of VOR therapy because of toxicity: liver toxicity (8%), cardiac Q-T interval prolongation (1%), or other side effects (5%). In the early post-transplant period (<120 days), only 2 patients developed invasive fungal infection: 1 mucormycosis infection and 1 disseminated Aspergillus infection. In the late post-transplant period (>120 days), no patients developed probable or definite fungal infection while receiving VOR. No Candida infections were seen in either period. These data suggest that fungal prophylaxis with VOR following allogeneic transplantation is safe and effective.

Post-transplant increased levels of serum sCD30 is a marker for prediction of kidney allograft loss in a 5-year prospective study

Background Levels of sCD30 represent a biomarker for early outcome in kidney transplantation. The purpose of this study was to determine the role of sCD30 levels for prediction of graft loss in the late post-transplant period. Methods Sera were collected immediately pre-transplant and yearly thereafter for up to 5-year post-transplant in 37 primary renal transplant recipients. Levels of serum sCD30 were tested using a fluorescent microsphere assay. Results Levels of sCD30 significantly decreased after transplantation and remained normal in 34 patients without graft loss up to 5-year post-transplant. Elevated levels of serum sCD30 preceded the increase of serum creatinine in patients with subsequent graft loss. Conclusions Elevated levels of serum sCD30 post-transplant might be a marker for predicting subsequent graft loss in the post-transplant period.

Circadian Rhythms in the Urinary Excretion of Phosphate and Cyclic 3′ ,5′-Adenosine Monophosphate in Kidney Graft Recipients

Circadian rhythms of urinary phosphate excretion in 13 supine and 8 ambulatory kidney graft recipients in the late post-transplant period were studied. A comparison of serum phosphate level and urinary phosphate excretion revealed two groups of patients: a) with normal serum phosphate level and a high urinary phosphate excretion, and b) patients with subnormal serum phosphate and a moderate phosphate excretion. Compared to control group of 9 healthy volunteers much greater variations in phosphate and cyclic 3',5'-AMP excretion in grafted patients were recorded. An inversed phosphate excretion rhythm was observed in 5 out 13 supine patients.

Considerations in sirolimus use in the early and late post-transplant periods

Sirolimus is an antiproliferative immunosuppressive agent that inhibits the mammalian target of rapamycin. It is highly effective in preventing acute renal allograft rejection and can be used with either calcineurin inhibitors, antimetabolites or corticosteroids. Early studies in renal transplantation have provided insight into optimal dosing strategies of sirolimus and of concomitant immunosuppressive agents. Familiarity with the adverse effect profile of sirolimus and pharmacokinetic and dynamic interactions with other immunosuppressive agents allows for earlier recognition and better management of sirolimus-related complications. The role of sirolimus in preserving long-term renal function, post-transplant malignancies and in prevention of atherosclerosis is currently being considered.