Quantitative EBV Viral Loads and Immunosuppression Alterations can Decrease PTLD Incidence in Pediatric Liver Transplant Recipients

Epstein-Barr virus (EBV) is a common viral infection in pediatric liver transplant patients and can lead to development of post-transplant lymphoproliferative disorder (PTLD). Differing studies have used immunosuppression reduction, antiviral medications or i.v. CMV-immunogloublin for EBV prevention and treatment. The purpose of this study was to determine whether implementation of a protocol for frequent EBV monitoring and EBV viral load-driven immunosuppression reduction could decrease the incidence of PTLD in our patient population. All data were prospectively collected between 2001 and 2004 at a single institution. Seventy-three patients were entered into the study. Patients were divided into a historical control group (pre-2001, 30 patients) and a treatment group (post-2001, 43 patients). Approximately 1271 blood samples of 73 patients were collected between 2001 and 2004. Eleven out of 43 patients received immunosuppression tapering due to high EBV viral loads (>4000 copies/microg DNA). One patient developed allograft rejection after immunosuppression modulation. Prior to 2001, the incidence of PTLD at our institution was 16%. After instituting a protocol for EBV monitoring, the incidence of PTLD decreased to 2% (p-value<0.05). These findings illustrate that frequent EBV viral load monitoring and preemptive immunosuppression modulation have an integral role in preventing PTLD in the pediatric liver transplant population.     

Association Between Calcineurin Inhibitor Treatment and Peripheral Nerve Dysfunction in Renal Transplant Recipients

Neurotoxicity is a significant clinical side effect of immunosuppressive treatment used in prophylaxis for rejection in solid organ transplants. This study aimed to provide insights into the mechanisms underlying neurotoxicity in patients receiving immunosuppressive treatment following renal transplantation. Clinical and neurophysiological assessments were undertaken in 38 patients receiving immunosuppression following renal transplantation, 19 receiving calcineurin inhibitor (CNI) therapy and 19 receiving a calcineurin‐free (CNI‐free) regimen. Groups were matched for age, gender, time since transplant and renal function and compared to normal controls (n = 20). The CNI group demonstrated marked differences in nerve excitability parameters, suggestive of nerve membrane depolarization (p < 0.05). Importantly, there were no differences between the two CNIs (cyclosporine A or tacrolimus). In contrast, CNI‐free patients showed no differences to normal controls. The CNI‐treated patients had a higher prevalence of clinical neuropathy and higher neuropathy severity scores. Longitudinal studies were undertaken in a cohort of subjects within 12 months of transplantation (n = 10). These studies demonstrated persistence of abnormalities in patients maintained on CNI‐treatment and improvement noted in those who were switched to a CNI‐free regimen. The results of this study have significant implications for selection, or continuation, of immunosuppressive therapy in renal transplant recipients, especially those with pre‐existing neurological disability.     

A 16‐Year Multi‐Institutional Study of the Role of Age and EBV Status on PTLD Incidence Among Pediatric Heart Transplant Recipients

The objective was to determine the incidence and hazard for posttransplant lymphoproliferative disease (PTLD) in a study of 3170 pediatric primary heart transplants between 1993 and 2009 at 35 institutions in the Pediatric Heart Transplant Study. 147 of 151 reported malignancy events were classified as PTLD. Overall freedom from PTLD was 98.5% at 1 year, 94% at 5 years and 90% at 10 years. Freedom from PTLD was lowest in children (ages 1 to < 10 years) versus infants (<1 year) and adolescents (10 to < 18 years) with children at highest risk for PTLD with a relative risk of 2.4 compared to infants and 1.7 compared to adolescents. Positive donor EBV status was a strong risk factor for PTLD in the seronegative recipient, but risk magnitude was dependent on recipient age at the time of transplantation. Nearly 25% of EBV seronegative recipients of EBV+ donors at ages 4–7 at transplantation developed some form of PTLD. The overall risk for PTLD declined in the most recent transplant era (2001–2009, p = 0.003). These findings indicate that EBV status and the age of the recipient at the time of transplantation are important variables in the development of PTLD in the pediatric heart transplant recipient.     

Monitoring Infection with Epstein–Barr Virus among Seromismatch Adult Renal Transplant Recipients

Patients who undergo Epstein–Barr virus (EBV) seromismatch (D+/R − ) transplants have a higher risk for the development of post‐transplant lymphoproliferative disorder (PTLD). Adult renal transplant recipients at a single institution were prospectively monitored for EBV during the first year post‐transplant. Over a 2‐year period, 34 patients (7.78%) were identified as being EBV D+/R − recipients. Patients who developed symptoms or had persistent viremia were pre‐emptively administered rituximab. Six recipients were discharged without monitoring on the protocol. Of those six, three (50%) developed PTLD and all three lost their grafts. Twenty (60.6%) of the 34 recipients developed viremia during the first year post‐transplant. Of the recipients who became viremic, six (30%) received rituximab. None of the six who received rituximab‐developed PTLD. We found that recipients who were not monitored on the protocol were more likely to have PTLD and graft loss compared to those who were (p = 0.008). Post‐transplant monitoring of adults who undergo EBV D+/R − kidney transplants for viremia and symptoms associated with EBV infection may prompt intervention which reduces the incidence of PTLD within the first year. Use of rituximab in preventing PTLD among patients with primary EBV infection requires further prospective study to determine its overall safety and efficacy.     

Cellular Immunity to Epstein-Barr Virus in Liver Transplant Recipients Treated with Rituximab for Post-Transplant Lymphoproliferative Disease

The evaluation of long-term cellular immunity to EBV in pediatric orthotopic liver transplant (OLT) recipients after treatment with the humanized anti-CD20 monoclonal antibody (Rituximab) has not yet been explored. At our institution, one child with EBV-related mononucleosis-like syndrome and five children with polymorphic-EBV-PTLD occurring 6-88 months after OLT were treated with Rituximab. Treatment was well tolerated. All children achieved complete remission. After Rituximab, B-lymphocytes were undetectable in the peripheral blood and EBV-load, monitored with real-time PCR, decreased to undetectable levels in all children from >4000 copies/microg DNA at diagnosis. Four to eight months after Rituximab, EBV-load increased (>4000 copies/microg DNA) in four children, and PTLD recurred in three. Their frequency of EBV-specific T-cell precursors, measured by Elispot analysis, remained lower than in healthy controls. Rituximab effectively induced regression of PTLD in OLT recipients. However, EBV-specific T-cell immunocompetence, which may be crucial for the long-term control of EBV-mediated proliferation, did not improve.     

Hyperhomocysteinemia in Renal Transplant Recipients

Renal transplantation is a commonly performed curative procedure for end-stage renal disease. With the increase in renal allograft half-lives, attention is now being focused on cardiovascular morbidity and death in the renal transplant recipient (RTR) population. Among the more novel cardiovascular disease (CVD) risk factors for which this group is at risk is hyperhomocysteinemia. Hyperhomocysteinemia has been associated with an increased risk of CVD, although prospective randomized trials designed to prove causality are still ongoing. Since plasma total homocysteine levels are inversely related to renal function, RTRs have a greatly increased prevalence of hyperhomocysteinemia. Other determinants of homocysteine include B-vitamins, albumin, age, and genetic polymorphisms. Although RTRs are resistant to the typical B-vitamin doses used to correct hyperhomocysteinemia in the general population, they do respond to supraphysiologic dose therapy. In terms of prevalence, etiology, and treatment of hyperhomocysteinemia, RTRs are very similar to the much larger chronic renal insufficiency population. For this reason, RTRs have been chosen as an ideal study population in investigating the effect of reducing hyperhomocysteinemia on CVD outcomes.     

The Influence of Calcineurin Inhibitors on Pulse Wave Velocity in Renal Transplant Recipients

Background. Pulse wave velocity (PWV) is a marker of the arterial wall stiffness and independent cardiovascular risk factor in hemodialysis patients. Cyclosporine A (CyA) and tacrolimus (TAC) are known to differ in the influence on cardiovascular risk factors in renal transplant recipients. Recent studies suggest that CyA may decrease arterial compliance. The aim of the study was to assess the influence of CyA and TAC on the PWV and arterial wall stiffness in renal transplant recipients. Methods. The study population consisted of two groups of cadaveric renal transplant recipients, 76 patients each, matched for age, sex, blood pressure, body mass index, and length of the post-transplant follow-up. PWV between carotid and femoral artery was measured using a Complior device. Fasting blood was sampled for serum creatinine, lipid profile, uric acid, glucose, and C-reactive protein. Results. Aortic pulse wave velocity—a marker of increased arterial stiffness—was significantly higher in CyA group compared with TAC group (9.33 ± 2.10 vs. 8.54 ± 1.35, respectively; p < 0.01). Uric acid, total cholesterol, triglycerides, and LDL-cholesterol concentrations were significantly higher in CyA group. Significant correlations were found between PWV and age, systolic and diastolic blood pressure, and fasting glucose in the CyA group, but only between PWV and age in TAC group. Conclusion. CyA-based immunosuppressive therapy is associated with an unfavorable profile of cardiovascular risk factors and increased arterial stiffness in renal transplant recipients.     

Predominant Th1 and Cytotoxic Phenotype in Biopsies from Renal Transplant Recipients with Transplant Glomerulopathy

Transplant glomerulopathy (TGP) appears to be a pathogenic feature of chronic antibody-mediated rejection, but the pathogenesis of this histologic entity is still poorly understood. Previous studies suggest the involvement of lymphocytes but the phenotypes of these cells have never been analyzed. Here, we report the first study of mRNAs for specific markers of CD4+ T cells including Th1 (T-bet and INFγ), Th2 (IL4 and GATA3), Treg (Foxp3) and Th17 (IL-17 and RORγt) subsets, cytotoxic CD8 T cells (Granzyme B) and B-cell markers (CD20) in renal biopsies from renal transplant recipients suffering interstitial fibrosis and tubular atrophy (IF/TA) with or without TGP but with a similar inflammatory score and controls including transplant recipients with normal renal function. Only INFγ, T-bet (both functionally defined markers of Th1 CD4 T cells) and granzyme B (a CD8 cytotoxic marker) were significantly more strongly expressed in patients with TGP than in patients without TGP and normal controls. These results indicate a role of an active T-mediated inflammatory and cytotoxic process in the pathogenesis of TGP.     

Rejection Profile of Recent Pediatric Renal Transplant Recipients Compared with Historical Controls: a Report of the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS)

Historically, higher acute rejection rates, earlier first rejection, and an inability to reverse the rejection characterize pediatric renal transplantation. In recent years, short-term (1-year) graft survival of pediatric renal transplants has steadily improved. To test the hypothesis that these improvements were mediated by changes in acute rejection, we considered the rejection profile of patients who received a renal allograft between 1987 and 1989 (cohort A) and compared it with recipients transplanted between 1997 and 1999 (Cohort B). Cohort A comprised 1469 transplants and cohort B comprised 1189 transplants. Restricting the data to the first year of follow-up, rejection ratios were 1.6 and 0.7, respectively (p < 0.001). Sixty per cent of the later cohort (B) were rejection free at 1 year, compared with 29% for the earlier cohort (A) (p < 0.001). Controlling for donor source, the rejection reversal rate for the later cohort was significantly better than that of the early cohort (p < 0.001). Cumulative distribution of times to first rejection was significantly better for cohort B (p < 0.001). One-year graft survival for cohort B at 94% was significantly better than 80% for cohort A (p < 0.001). We conclude that the improved short-term graft survival is mediated by improvements in the rejection profile in more recently transplanted patients and that this may translate into a better half-life for pediatric renal transplant recipients who received an allograft in the years 1997-99.     

Improved 24-Hour Blood Pressure Control With Sirolimus Versus Calcineurin Inhibitor Based Immunosuppression in Renal Transplant Recipients

Introduction

Calcineurin inhibitors (CNI) have brought dramatic improvements in early renal allograft survival. However, CNI are associated with posttransplant hypertension (PTHTN), a risk factor for mortality from cardiovascular disease and graft failure. Sirolimus (SRL) is emerging as an alternative to CNI. SRL effects on blood pressure (BP) in humans are unclear. We compared the prevalence of PTHTN among patients receiving SRL as maintenance immunosuppression with a group receiving CNI by using 24-hour ambulatory BP (AMBP). AMBP has been shown to predict cardiovascular events and progression of kidney disease better than casual office BP measurements in chronic kidney disease (CKD) patients.

Methods

Renal transplant recipients with office hypertension (defined as BP > 130/80 or on antihypertensive medications), receiving stable immunosuppression and displaying consistent serum creatinine values for ≥6 months were eligible. We enrolled the first 40 patients to consent. Office BP was measured twice using a BP-Tru machine. AMBP was then analyzed for systolic BP (SBP), diastolic BP (DBP), and nocturnal blood pressure fall (NF; “dipping”). Patients were placed in the SRL group (n = 18) and the CNI group (n = 20) based on their maintenance immunosuppressive protocol. Two patients were excluded because of incomplete data. All patients received mycophenolate mofetil, and 14/38, maintenance steroids. We collected, demographics as well as type and date of renal allograft, medications, comorbidities, CKD stage, proteinuria, and plasma creatinine at the time of study enrollment.

Results

Patients in the SRL group displayed lower 24-hour SBP than the CNI group (128.0 ± 10.8 vs 137.7 ± 14; P = .029). Nightime MAP, nightime SBP, and nighttime DBP were all lower in the SRL group. NF did not reach significance between the SRL and CNI groups (44% vs 15%; P = .074). Patient demographics and number of antihypertensive medications did not differ.

Conclusion

The lower 24-hour SBP seen in the SRL group by AMBP may lead to improved cardiovascular and renal outcomes over time. Long-term patient follow-up will be needed to clarify the effect of the lower 24-hour SBP.     

Coronary Artery Calcification in Renal Transplant Recipients

Cardiovascular disease is the leading cause of mortality in renal transplant recipients. Although renal transplant recipients frequently undergo cardiac functional tests prior to surgery, coronary atherosclerosis can remain undetected. Coronary artery calcification (CAC), an early marker of atherosclerosis can be quantified using EBCT. The purpose of this study was to determine the extent and characteristics of CAC at the time of renal transplantation. We evaluated 79 consecutive incident asymptomatic renal transplant recipients. Patients were mostly White (62%), male (54%) and had a deceased donor renal transplant (61%). The mean age was 47 (12.1) years. Sixty-five percentage of subjects had CAC. The mean CAC score was 331.5 (562.4) with a median of 43.3. Older age, presence of diabetes, not having a preemptive transplant, deceased donor transplantation and hypercholesterolemia were significantly associated with presence of CAC univariately. Median CAC scores were significantly increased in subjects with diabetes (127.8 vs. 28.9, p=0.05), exposed to dialysis (102.9 vs. 3.7, p<0.001) and deceased donor recipients (169.7 vs. 7.5, p=0.02). Using multiple logistic regression, age and time on dialysis were significantly associated with the presence of CAC at the time of transplant. In summary, CAC is prevalent in patients undergoing kidney transplant. CAC may be a method to identify renal transplant recipients at increased risk for future cardiovascular events.     

Sirolimus May Reduce Fertility in Male Renal Transplant Recipients

Assessment of sex hormones in organ transplant recipients suggests that sirolimus may impair testicular function. The aim of this study was to evaluate the frequency and severity of sirolimus-associated alterations in sperm parameters and their impact on fathered pregnancy rate. An observational study was carried out in male patients aged 20–40 years who received a kidney transplant during 1995–2005. Patients were sent a questionnaire by post, and sperm analysis was proposed. The fathered pregnancy rates according to the immunosuppressive regimen were estimated and compared using the Poisson model. Complete information was obtained from 95 out of 116 recipients. Patients treated with sirolimus throughout the post-transplant period had a significantly reduced total sperm count compared to patients who did not receive sirolimus (28.6 ± 31.2 × 10⁶ and 292.2 ± 271.2 × 10⁶, respectively; p = 0.006), and a decreased proportion of motile spermatozoa (22.2 ± 12.3% and 41.0 ± 14.5%, p = 0.01). Moreover, the fathered pregnancy rate (pregnancies/1000 patient years) was 5.9 (95% CI, 0.8–42.1) and 92.9 (95% CI, 66.4–130.0) in patients receiving sirolimus-based and sirolimus-free regimens, respectively (p = 0.007). Of six patients in whom sirolimus treatment was interrupted, only three showed a significant improvement in sperm parameters. Sirolimus is associated with impaired spermatogenesis and, as a corollary, may reduce male fertility.     

Sirolimus Versus Cyclosporine in Kidney Recipients Receiving Thymoglobulin®, Mycophenolate Mofetil and a 6-Month Course of Steroids

To evaluate the efficacy and tolerance of a calcineurin inhibitor (CNI)-free regimen, 145 renal recipients were prospectively randomized to receive either sirolimus (n = 71) or cyclosporine (CsA; n = 74). All patients received polyclonal antilymphocyte antibodies, mycophenolate mofetil (MMF) and steroids (6 months). The primary endpoint, estimated glomerular filtration rate (eGFR) was not significantly different at 12 months comparing sirolimus- and CsA-treated patients (60 +/- 27 vs. 57 +/- 21 mL/min). At 12 months, patient and graft survival, incidence of biopsy-proven rejection and rates of steroid withdrawal were not statistically different (97% vs. 97%; 90% vs. 93%; 14.3% vs. 8.6% and 82.8% vs. 84.1%, respectively). Delayed and slow graft function (SGF) was not significantly different (18.6% vs. 12.3% and 11.4% vs. 13.7%, respectively). In patients who remained on treatment according to protocol at 12 months, eGFR was significantly higher with sirolimus (69 +/- 19 vs. 60 +/- 14 mL/min, p = 0.01). Overall study drug discontinuation rates were 28.2% with sirolimus and 14.9% with CsA. Adverse events (wound complications, mouth ulcers, diarrhea, hypokalemia, bronchopneumonia) and proteinuria >0.5 g/24h (38.8% vs. 5.6%, p < 0.001) were significantly more frequent in sirolimus-treated patients. Cytomegalovirus (CMV) infections were significantly less frequent with sirolimus (6% vs. 23%, p < 0.01). A CNI-free regimen using sirolimus-MMF can achieve excellent renal function, but patients on sirolimus experienced a high rate of adverse events and study drug discontinuation.     

Posttransplant Lymphoproliferative Disorder Presenting as Multiple Cystic Lesions in a Renal Transplant Recipient

We report a case of a 67‐year‐old man who experienced allograft dysfunction following a renal transplantation from a donation after cardiac death. The postoperative course was initially complicated by episodes of E. coli urinary sepsis causing pyrexia and a raised creatinine level. Ultrasound scanning 5 weeks posttransplant revealed mild hydronephrosis with several parenchymal cystic areas measuring up to 2 cm with appearances suggestive of fungal balls. Aspirated fluid again grew Escherichia coli, and this was treated with the appropriate antimicrobial therapy. The patient continued to have episodes of culture‐negative sepsis; therefore, a computed tomography scan was performed 6 months posttransplant, which revealed multiple lesions in the renal cortex as well as liver and spleen. Subsequent biopsy revealed an Epstein–Barr virus‐driven lymphoproliferation consistent with a polymorphic posttransplantation lymphoproliferative disorder (PTLD). This rare case of PTLD presenting as multiple renal, hepatic and splenic lesions emphasizes the need for a high index of clinical suspicion for this condition. Abnormal para‐renal allograft masses should be biopsied to allow swift and effective management of a disease that can disseminate and become significantly more challenging to manage.     

Sirolimus Does Not Exhibit Nephrotoxicity Compared to Cyclosporine in Renal Transplant Recipients

Sirolimus and cyclosporine (CsA) prevent acute rejection in man when used as primary therapies in triple drug regimens. Sirolimus does not act via the calcineurin pathway and therefore is not expected to produce the same renal side-effects. This paper presents the pooled 2-year data analysis of renal function parameters from two open-label, randomized, multicenter studies. Patients (18-68 years) receiving a primary renal allograft were randomized to receive concentration-controlled sirolimus (n = 81) or CsA (n = 80), in combination with azathioprine and steroids (n = 83), or mycophenolate mofetil (MMF) and steroids (n = 78). From week 10 through year 2, calculated glomerular filtration rate (GFR) was significantly higher in sirolimus--than in CsA-treated patients (69.3 vs. 56.8 mL/min, at 2 years, p = 0.004). Serum uric acid was significantly higher in the CsA-treated patients and magnesium was significantly lower; these parameters were more likely to be within normal limits in the sirolimus group. Mean serum potassium and phosphorus were lower in sirolimus-treated patients. In conclusion, sirolimus, when administered as primary therapy in combination with azathioprine or MMF, has a favorable safety profile compared to CsA with regards to renal function.     

BOOP is Common in Cardiac Transplant Recipients Switched from a Calcineurin Inhibitor to Sirolimus

While bronchiolitis obliterans organizing pneumonia (BOOP) has been associated with the use of sirolimus (SIR), the incidence in a consecutive group of patients given SIR to replace a calcineurin-inhibitor (CI) is unknown. Twenty-nine consecutive cardiac transplant recipients were switched from a CI to SIR to ameliorate CI-associated nephropathy or coronary graft atherosclerosis. Seven patients (24%) developed BOOP. The clinical characteristics and biopsy results of these patients are presented. The clinical course and response to withdrawal of SIR in all and steroids in four of seven patients suggested the diagnosis of BOOP. Chest X-rays and CT scans showed typical findings of BOOP in all seven patients. Infection was excluded in all patients. Biopsy results were characteristic of BOOP in six of seven patients. Six patients recovered and one died. BOOP is a common and potentially serious adverse event in cardiac transplant patients switched from a CI to SIR, especially when SIR is started late post-transplantation.     

Last Resort for Renal Transplant Recipients, 'Restored Kidneys' from Living Donors/Patients

Because of the grave shortage of deceased kidney allografts in Japan, we have embarked on a new source of organs, 'Restored kidneys' from living patients. From January 1991 through September 2006, 42 kidneys (eight benign pathology, eight small renal cancers, eight ureteral cancers, six aneurysms, eight severe nephrotic syndrome from four patients and four ureteral stenosis) were obtained from 38 patients/donors after extensive discussion of treatment modalities and risks. All patients/donors agreed to undergo total nephrectomy. The lesions were removed/repaired ex vivo on the back table, then transplanted. All recipients were notified of all possible risks including donor disease recurrence. One, 5 and 10-year patient survival rates of restored transplant patients were 92.9%, 79.3% and 63.8%, respectively. One, 5 and 10-year graft survival rates of restored kidney transplant patients were 78.6%, 51.8% and 42.7%, respectively. There were no recurrences of small renal cell carcinomas. There was one recurrence of ureteral cancer in the transplanted kidney 15 months after operation.
In countries where deceased donors are scarce, such as Japan, the restored kidneys can be a last resort for renal allografts.     

Increased Incidence of Colorectal Malignancies in Renal Transplant Recipients: A Case Control Study

This study was to evaluate the frequency of colorectal neoplasia in renal transplant recipients and to investigate the association with Epstein‐Barr virus (EBV) and cytomegalovirus (CMV) infection. We compared the frequency of colorectal neoplasia among renal transplant recipients with that of the healthy subjects. Specimens of colorectal neoplasia were examined for EBV and CMV using in situ hybridization and immunohistochemistry, respectively. Of 796 renal transplantation cohorts, 315 were enrolled. The frequency of colorectal neoplasia among the patients was 22.9%. Compared with the healthy subjects, the odds ratio (OR) for advanced adenoma was 3.32 (95% CI, 1.81–6.10). The frequency of cancer among the patients was 1.9% (OR, 12.0; 95% CI, 1.45–99.7). A long interval between transplantation and colonoscopy was a significant factor in the development of advanced colorectal neoplasia. EBV positivity was detected in 30.6% of colorectal neoplasia specimens from renal transplant recipients, which was higher than that for the controls (p = 0.002). CMV was not detected in any lesions of patients or controls. In conclusion, renal transplant recipients have a significantly increased risk of advanced colorectal neoplasia. EBV was more frequently found in specimens of advanced colorectal neoplasm obtained from the renal transplant recipients.