Late Acute Rejection Episodes Research Articles

Study of the effect of early and late acute rejection episodes on renal graft survival

Background It has been demonstrated that acute rejection (AR) episodes are major risk factors of renal allograft loss. Still the impact of early acute rejection (EAR) on long-term graft survival is debated. The aim of this study was to study the impact of early acute rejection (EAR) and late acute rejection (LAR) on renal allograft survival. Patients and methods In this retrospective study we investigated the timing and frequency of AR episodes in 120 kidney transplant recipients for a 3-years period. Patients were divided into three groups; Group I: No acute rejection (No-AR), Group II: Early acute rejection (EAR), and Group III: Late acute rejection (LAR). The graft survivals in the three groups and the associated risk factors were analyzed. Results Of the 120 recipients one patient died (0.08%) and 14 grafts were lost (11.6%). The graft survival durations were 35.2, 23.6 and 27.2 months and the 3-years survival rates were 93%, 63.3% and 66.7% in the three groups respectively. The graft survival durations and rates were significantly higher in group I compared to groups II and III with no significant differences between the last two groups. Conclusion Both EAR and LAR have deleterious effects on graft survival following kidney transplantation.

Risk factors and prognosis of late acute rejection in Chinese kidney transplant recipients.

Accumulating literature indicates that late acute rejection (LAR) after kidney transplantation portends an unfavourable prognosis. There are no data on the incidence of LAR in Asian subjects, or its risk factors and associated clinical outcomes. We conducted a retrospective single-centre case-+control study to investigate the incidence, risk factors and prognosis of LAR in Chinese kidney transplant recipients. Subjects with or without LAR were matched for age, gender, era of transplantation, allograft type, and maintenance immunosuppression regimen. Thirty-two episodes of LAR occurred within an observation period of 12years giving an incidence rate of 0.46 episodes per 1000 patient-years. Acute rejection within the first year after transplantation was associated with an increased risk of LAR (OR 3.59, P=0.041). In patients receiving maintenance immunosuppression regimen with steroid, cyclosporin A (CsA) and mycophenolate or an m-TOR inhibitor, patients with LAR showed lower trough CsA levels prior to and at the time of rejection compared to Controls (86.0±26.1 vs. 105.6±13.3μg/L, P=0.049; and 75.7±35.7 vs. 106.0±20.5μg/L, P=0.032, respectively). Trough CsA level below 80μg/L was associated with the development of LAR (OR 10.82, P=0.032). Patients with LAR showed an inferior allograft survival (P<0.001) while patient survival rates were similar (P=0.122). Late acute rejection is uncommon in Chinese kidney transplant recipients but is associated with reduced allograft survival. Risk factors include acute rejection in the first post-transplant year and trough CsA level below 80μg/L in patients on CsA-based maintenance immunosuppression. Minimization of immunosuppression in apparently stable kidney transplant recipients must be exercised with caution.

Soluble CD30 does not predict late acute rejection or safe tapering of immunosuppression in renal transplantation

BackgroundPrevious reports revealed the potential value of the soluble CD30 level (sCD30) as biomarker for the risk of acute rejection and graft failure after renal transplantation, here we examined its use for the prediction of safe tapering of calcineurin inhibitors as well as late acute rejection. MethodsIn a cohort of renal transplant patients receiving triple immunosuppressive therapy we examined whether sCD30 can be used as a marker for safe (rejection-free) discontinuation of tacrolimus at six months after transplantation (TDS cohort: 24 rejectors and 44 non-rejecting controls). Also, in a second cohort of patients (n=22, rejectors n=11 and non-rejectors n=11), participating in a clinical trial of rituximab as induction therapy after renal transplantation (RITS cohort), we examined whether sCD30 could predict the occurrence of late (>3months post-transplant) acute rejection episodes. sCD30 was measured by ELISA in serum taken before and at several time points after transplantation. ResultsOverall, in the TDS cohort sCD30 decreased after transplantation. No difference in sCD30 was observed between rejectors and non-rejecting controls at any of the time points measured. In addition, in the RITS cohort, sCD30 measured at three months after transplantation were not indicative for the occurrence of late acute rejection. ConclusionIn two prospectively followed cohorts of renal transplant patients we found no association between sCD30 and the occurrence of either late acute rejection or acute rejection after reduction of immunosuppression.

Clinicopathological characteristics and effect of late acute rejection on renal transplant outcomes.

Late acute rejection (LAR) has been associated with inferior kidney allograft outcomes. We retrospectively evaluated 355 episodes of biopsy-confirmed LAR in a cohort of 5758 kidney transplants performed between 1998 and 2008. Estimated glomerular filtration rate was obtained before, at, and after each LAR episode as well as histology and treatment. Associations of LAR with subsequent death or graft loss were estimated with Cox proportional regression analysis. A total of 215 patients had 1 episode, 57 had 2 episodes, and 13 had 3 episodes of LAR. Rates of LAR-free survival were 97.4% at 1 year and 93.7% at 5 years. Estimated glomerular filtration rate decreased after each episode of LAR (56±21 vs. 44±18 vs. 36±11 mL/min/1.73 m, P<0.01). The majority of rejections were Banff IA or less, but the chronicity scores as well as plasma cell infiltrates increased after each LAR. All patients requiring dialysis lost their grafts. In a multivariable analysis, the severity of histological score (risk ratio [RR], 3.5; 95% confidence interval [CI], 1.58-7.87; P<0.001), the need for dialysis at LAR (RR, 3.31; 95% CI, 1.44-7.59; P<0.001), and treatment with methylprednisolone (RR, 2.31; 95% CI, 1.07-4.94; P=0.03) were independently associated with graft loss at 5 years, whereas tacrolimus and mycophenolate use was associated with reduced risk (RR, 0.46; 95% CI, 0.25-0.87; P<0.001). The prevalence and recurrence of LAR are considerable and associated with increased incidence of graft loss. Patients who need dialysis during LAR should be carefully evaluated owing to the high prevalence of graft failure.

IL-17 Producing CD4+ Cells Infiltrate the Graft During Early Rejection Episodes.

IL-17 is regarded as a major effector cytokine with pro-inflammatory actions in autoimmune diseases. IL-17 has pleiotropic and environmental specific functions by promoting adaptive cytotoxic T-lymphocyte responses during inflammation. Therefore, it is tempting to speculate that IL-17 is important in inflammatory responses seen after organ transplantation. We determined IL-17 mRNA expression in the transplanted heart during early and late acute rejection episodes, and during immunological quiescence. Additionally, we analysed whether IL-17 is derived from graft-infiltrating lymphocytes. Endomyocardial biopsies (EMBs: n=41) from heart transplant recipients (n=29) who experienced an early (≤3 months) or late (>3 months) acute rejection episode or during an immunological quiescence period, were analysed for the presence of IL-17 mRNA. IL-17 production determined by flowcytometry was analysed in cultures of graft-infiltrating lymphocytes (GILs) derived from acute rejection (n=5) and non-rejection (n=5) EMBs stimulated with PMA and ionomycine. Twenty-two percent (9/41) of EMBs were positive for IL-17 mRNA. All (9/26) were observed in the early period after transplantation, while none (0/15) of the late biopsies expressed IL-17 mRNA (p=0.02). During early acute rejection, 56% (5/9) of the EMBs did express IL-17 mRNA, while EMBs from late acute rejections (0/5) did not express IL-17 mRNA (p=0.09). Only CD4+ cells from GIL cultures produced IL-17. In 60% of GIL cultures from acute rejection EMBs a significant proportion of CD4+ cells produced IL-17, while only one GIL culture from non-rejection EMBs contained CD4+IL-17+ cells. All CD4+IL-17+ cells expressed CD161, a cell surface expression marker of Th17 cells. CD8+ cells did not produce IL-17 neither expressed CD161. In conclusion, particularly early after heart transplantation IL-17 producing CD4+ T-cells home to the graft contributing to the acute rejection process.

Early Steroid Withdrawal Compared With Steroid Avoidance Correlates With Graft Failure Among Kidney Transplant Recipients With an History of Diabetes

BackgroundSteroid minimization strategies attempt to reduce morbidity in kidney transplantation. Concern still exists regarding long-term outcomes using either steroid withdrawal or steroid avoidance regimens. MethodsDuring a 10-year period, 572 primary kidney transplant recipients were treated with basiliximab, calcineurin inhibitors, and mycophenolate mofetil: 417 (72.9%) underwent a steroid-taper regimen over 2–3 months (steroid withdrawal) and 155 (27.1%), complete steroid avoidance (steroid avoidance). ResultsDespite no significant difference during the first 3 months (hazard ratio [HR], 1.23; P = .5349), steroid withdrawal recipients showed an increased risk of late acute rejection episodes (HR, 4.06; P = .0585), independent of recipient age >55 years (HR, 1.84; P = .0272). The risk of any adverse event was not different among steroid regimen groups (HR, 0.98; P = .8458), independent of recipient age >55 years (HR, 1.69; P = .0002), delayed graft function (DGF) (HR, 1.54; P = .0001), and positive donor Epstein-Barr virus serology (HR, 0.68; P = .0471). Intention-to-treat analyses revealed a significantly greater risk of graft failure only in diabetic recipients in the steroid withdrawal group (HR, 8.18; P = .0065), independent of confounding risk factors such as recipient age >55 years (HR, 1.99; P = .0244), >4 human leukocyte antigen-A, -B, and -DR incompatibilities (HR, 1.64; P = .0475), and DGF occurrence (HR, 2.63; P < .0001). ConclusionAlthough both steroid minimization strategies were comparable regarding long-term safety and efficacy, an increased rate of graft failure was observed among diabetics who underwent steroid withdrawal compared with steroid avoidance.

Delayed graft function, allograft and patient srvival in kidney transplantation.

Delayed Graft Function (DGF) is a common complication of renal transplants and the long-term relation between DGF and survival of patients and grafts is not well established. This is a historical cohort study of transplanted patients in Taleghani Hospital of Shahid Beheshti University in Iran between 1994 and 2010. Patients who required dialysis during the first week after transplantation were considered to have DGF. The patients' conditions were updated to determine existing graft function, graft loss or patients' death at one year and five years post transplantation in relation to the presence or absence of DGF. DGF complicated 67/385 transplants (17.4%). Causes included acute tubular necrosis (58.2%), accelerated rejection (29.9%), transplant renal artery thrombosis (9%) and renal vein thrombosis (3%). More kidneys in the DGF group were procured from cadaveric donors (6% versus 0.9%, P = 0.02). At hospital discharge, patients with DGF had significantly higher mean creatinine level (4.4 ± 2.8 versus 2.0 ± 1.7; P = 0.001) compared to other patients. They also had more early acute rejection episodes and more late acute rejection episodes (34.3% versus 2% and 16.4% versus 3%, respectively; P = 0.0001) compared to other patients. The proportion of functioning grafts was significantly lower in the DGF group at 1-year (53.7% versus 95.3%, P = 0.0001) and 5-years (22.4% versus 61.6%, P = 0.001) compared to patients without DGF. The DGF group had a significantly higher acute rejection rate and an increased risk of graft loss at one and five years.

Adherence to immunosuppression: a critical aspect for the success of organ transplantation*

Organ transplantation has made great strides in reaching its goal as a long-term replacement treatment for irreversible failed organs. However, a significant portion of grafts are lost as a consequence of nonadherence (NA) to immunosuppressants and agents treating co-morbidities. In this issue of Transplant International, Leentje De Bleser and coworkers from Leuven, Belgium, address this important topic in heart, lung and liver transplant recipients. Comparing different methodological approaches and applying combined readouts, they provide a sensitive and alarming picture: 23.9–70% of transplant patients do not take their immunosuppressants as prescribed. Interestingly, lung transplant patients were less compliant than heart or liver transplant recipients in this study explained by the authors with a prolonged recovery after transplantation, younger recipient age and larger amounts of immunosuppressants and co-medications. Although the clinical relevance of NA to medication and clinical appointments has been recognized for many years, imprecise definitions in addition to a lack of standardized methods make existing studies in this field difficult to compare. However, an estimated 20% of late acute rejection episodes and 16% of graft loss have been linked to noncompliance. Poor adherence by 1 year after transplantation has been identified as a significant risk factor for graft loss and patient death [1,2]. The death of one in ten liver transplant recipients has been linked to NA in a study of the Scottish database [3]. Besides, NA represents a significant economic burden for local transplant centers and national healthcare systems. In renal transplantation, NA increased medical costs by more than 12 000$ over a 3-year period, whereas the overall difference in medical costs between a poor compliant and a persistently highly compliant patient exceeded 33 000$ [2]. With its multifactorial and complex etiology, NA has been difficult to analyze and to target. Known risk factors for NA include younger age, psychiatric disorders, and patient’s belief that medication is harmful and has considerable side effects. In a broader sense, cultural, social, and religious belief systems seem to play a role. Economic aspects are of critical importance, particularly in countries without life-long support for Correspondence Stefan G. Tullius MD, PhD, FACS, Division of Transplant Surgery, Brigham & Women’s Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA. Tel.: +1 617 732 6446; fax: 617-582-6167; e-mail: stullius@partners.org

Factors Associated with Self-Rated Health after Kidney Transplantation: A Prospective Study

Background: This prospective study explores and compares the relationship between patients’ self-rated health (SRH) after kidney transplantation (KT) at different follow-up periods and its medical and nonmedical predictors over time. Methods: Patients (n = 128) who completed a questionnaire (the SRH question of the SF-36 and the End-Stage Renal Disease Symptom Checklist – Transplantation Module) were enrolled. Clinical data were retrieved from medical files. The sample was stratified into early (n = 89) and late (n = 39) cohorts according to time since KT at baseline. Linear regression was used to identify predictors of SRH at follow-up. Results: In both cohorts, a change in glomerular filtration rate (GFR) over time remained a predictor of SRH; in the early cohort, age was an additional predictor; in the late cohort, a change in transplantation-associated psychological distress over time and the number of late acute rejection episodes during the observation period were additional predictors. Conclusions: Improvement in GFR over time predicted better SRH at each period after KT. Decreased transplantation-associated psychological distress and fewer late acute rejection episodes seemed to predict better SRH at a later follow-up period. Despite these observations, higher SRH was associated with better clinical outcomes.

ATG‐Fresenius Treatment and Low‐Dose Tacrolimus: Results of a Randomized Controlled Trial in Liver Transplantation

We report the results of a prospective randomized controlled trial in liver transplantation assessing the efficacy and safety of antithymocyte globulin (ATG-Fresenius) plus tacrolimus monotherapy at gradually decreasing doses. Patients were randomized to either: (a) standard-dose tacrolimus plus steroids;or (b) peritransplant ATG-Fresenius plus reduced-dose tacrolimus monotherapy followed by weaning of tacrolimus starting 3 months after transplantation. The primary end-point was the achievement of very low-dose tacrolimus (every-other-day or once daily dose with <5 ng/mL trough levels) at 12 months after transplantation. Acute rejection occurring during the first 3 months after transplantation was more frequent in the ATG group (52.4% vs. 25%). Moreover, late acute rejection episodes occurred in all recipients in whom weaning was attempted and no recipients reached the primary end-point. This motivated the premature termination of the trial. Tacrolimus trough levels were lower in the ATG-Fresenius group but no benefits in terms of improved renal function, lower metabolic complications or increased prevalence of tolerance-related biomarkers were observed. In conclusion, the use of ATG-Fresenius and tacrolimus at gradually decreasing doses was associated with a high rate of rejection, did not allow for the administration of very low doses of tacrolimus and failed to provide detectable clinical benefits. ClinicalTrials.gov identifier: NCT00436722.

Adherence to the immunosuppressive regimen in pediatric kidney transplant recipients: A systematic review

As most prior reviews on NA focus on adult transplant patients, there is a need for a comprehensive overview on adherence to the immunosuppressive regimen in pediatric kidney transplant patients. This systematic review searched for English-language papers (1990-2008) addressing the prevalence of NA to the immunosuppressive regimen, its consequences, determinants, and interventions in pediatric kidney transplant patients (< age 21 yr). We found 36 papers, showing a prevalence of NA (weighted mean) of 31.8% with adolescents being more at risk compared to younger patients. About 44% of all graft losses and 23% of late acute rejection episodes are associated with NA. Most studies investigated socio-economic, condition-related or treatment-related determinants. Only one educational intervention has been tested but yielded inconclusive results. NA to the immunosuppressive regimen is prevalent with serious clinical consequences in pediatric kidney transplant patients, but the economic consequences have not yet been explored. More studies on determinants of NA are needed. The literature currently lacks fully powered RCTs testing adherence-enhancing interventions. The results of this systematic review identify the gaps in the present evidence-based information regarding NA and can be used as a tool to pursue future adherence research in pediatric populations.

Patient and graft survival of kidney allograft recipients with minimal hepatitis C virus infection: a case-control study.

The impact of pretransplant hepatitis C virus (HCV) infection on the outcome of kidney transplantation is controversial. This study was designed to determine the impact of pretransplant minimal HCV infection on the patient and graft survival at a single center in southwest of Iran. We designed a historical cohort study on 337 kidney transplant recipients and selected 35 patients with HCV infection and a histological activity index score less than 4 (minimal HCV infection). A group of kidney recipients with negative anti-HCV antibody were compared with the anti-HCV-positive patients in terms of acute allograft rejection, graft loss, mortality, causes of death, and patient and graft survival. The controls were matched for age, sex, donor source, pretransplant dialysis duration, and panel reactive antibodies test. All of the participants had a follow-up period of at least 5 years. There were no significant differences in terms of early and late acute allograft rejection episodes between the groups. Although patient and graft survival rates were lower in HCV-positive patients at 2 and 5 years, the differences between the two groups were not significant. The main causes of death among patients with and without HCV infection were sepsis and cardiovascular events, respectively. Our findings suggest that pretransplant minimal HCV infection had no detrimental effect on the short-term patient and graft survival. However, we suggest that kidney transplant recipients with minimal HCV infection be monitored for severe systemic bacterial infections.

Sirolimus-based, calcineurin-inhibitor sparing immunotherapy, long-term (6-year) results

At the Albany Medical Center, we have a long-term experience, mean follow-up of 75 months, in 50 renal transplant recipients treated with maintenance sirolimus, prednisone and a calcineurin-inhibitor sparing immunosuppressive regimen. One-year patient and graft survival was 98% and six-year patient and graft survival was 82% and 72% respectively. The rate of early acute rejection (< 3 months) was only 10%. Furthermore, no late (> 3 months) acute rejection episodes developed despite calcineurin-inhibitor dose minimization. In addition, recipient mean serum creatinine remained stable at 1.6 mg/dl throughout the 6-year follow-up period. Sirolimus is an effective maintenance immunosuppressive agent that safely allows for a reduction in calcineurin-inhibitor dosing.

Genetic Polymorphisms Impact the Risk of Acute Rejection in Pediatric Heart Transplantation: A Multi-Institutional Study

The objective of this study was to determine the association between the genetic polymorphisms of proinflammatory and regulatory cytokines and long-term rates of repeat and late acute rejection episodes in pediatric heart transplant (PHTx) recipients. Three hundred twenty-three PHTx recipients: 205 White non-Hispanic, 43 Black non-Hispanic, and 75 Hispanic were analyzed for time to first repeat and late acute rejection episodes by race, age at transplantation, and gene polymorphism (interleukin [IL]-6, -174 G/C, IL-10, -1082 G/A, -819 C/T, 592 C/A; vascular endothelial growth factor (VEGF) -2578 C/A, -460 C/T, +405 C/G; tumor necrosis factor alpha (TNF-alpha)-308 G/A). Recipient black race and older age at transplant were risk factors for both repeat and late rejections, though black race was more significantly related to late rejection (P=0.006). Individually, TNF-alpha high, IL-6 high, VEGF high, and IL-10 low phenotypes did not impact the risk of repeat or late rejection. However, the combination VEGF high/IL-6 high and IL-10 low was associated with increased estimated risk of late rejection (P=0.0004) and only marginally with repeat rejection (P=0.051). In a multivariate analysis, adjusting for age and race, VEGF high/IL-6 high and IL-10 low still remained an independent risk factor for late acute rejection (RR=1.91, P<0.001). This is the largest multicenter study to document the impact of genetic polymorphism combinations on PHTx recipients' outcome. The high proinflammatory (VEGF high/IL-6 high) and lower regulatory (IL-10 low) cytokine gene polymorphism profile exhibited increased risk for late rejection, irrespective of age and race/ethnicity.

Circulating Alloreactive T Cells Correlate with Graft Function in Longstanding Renal Transplant Recipients

Monitoring for alloreactive memory T cells after organ transplantation may allow individualization of immunosuppression. Two pathways of T cell allorecognition have been implicated in chronic graft dysfunction: Direct (recipient T cells respond to donor peptides presented by donor antigen-presenting cells) and indirect (donor peptides are processed and presented by recipient antigen-presenting cells). Previous studies have assessed these alloresponses only during the first 2 yr after kidney transplantation,so this study correlated the presence of circulating donor-reactive memory/effector T cells, primed by both pathways, in 34 longstanding living-donor renal transplant recipients using the highly sensitive IFN-gamma Elispot assay. Remarkably, 59% of patients had directly primed donor-reactive T cells, and their presence correlated directly with serum creatinine (P = 0.001) and inversely with estimated GFR (P = 0.042). Multivariate analysis revealed that hyporesponsiveness of direct, donor-specific T cells was the only variable that significantly correlated with graft function and that antidonor indirect alloreactivity was the only variable that significantly correlated with proteinuria. Interestingly, when both allorecognition pathways were considered together, patients with undetectable direct alloreactivity had better longterm graft function, independent of allosensitization by the indirect pathway. In conclusion, circulating donor-specific alloreactive T cells primed by both pathways are detectable long after transplantation and are associated with graft injury. Assessment of alloreactive memory/effector T cells might be helpful to tailor individual immunosuppression regimens for transplant recipients in the future.

Association of MCP‐1 and CCR2 polymorphisms with the risk of late acute rejection after renal transplantation in Korean patients

Among the factors modulating transplant rejection, chemokines and their respective receptors deserve special attention. Increased expression of monocyte chemoattractant protein-1 (MCP-1) and its corresponding receptor (chemokine receptor-2, CCR2) has been implicated in renal transplant rejection. To determine the impact of the MCP-1-2518G and CCR2-64I genotypes on renal allograft function, 167 Korean patients who underwent transplantation over a 25-year period were evaluated. Genomic DNA was genotyped using polymerase chain reaction followed by restriction fragment length polymorphism analysis. Fifty-five (32.9%) patients were homozygous for the MCP-1-2518G polymorphism. Nine (5.4%) patients were homozygous for the CCR2-64I polymorphism. None of the investigated polymorphism showed a significant shift in long-term allograft survival. However, a significant increase was noted for the risk of late acute rejection in recipients who were homozygous for the MCP-1-2518G polymorphism (OR, 2.600; 95% CI, 1.125–6.012; P = 0.022). There was also an association between the MCP-1-2518G/G genotype and the number of late acute rejection episodes (P = 0.024). Although there was no difference in the incidence of rejection among recipients stratified by the CCR2-V64I genotype, recipients with the CCR2-V64I GG genotype in combination with the MCP-1-2518G/G genotype had a significantly higher risk of acute or late acute rejection among the receptor-ligand combinations (P = 0.006, P = 0.008, respectively). The MCP-1 variant may be a marker for risk of late acute rejection in Korean patients.

Mycophenolate Mofetil Use Is Associated with Decreased Risk of Late Acute Rejection in Adult Liver Transplant Recipients

Mycophenolate mofetil (MMF) used in a triple-drug regimen has been shown to decrease acute rejection rates, compared to a double-drug regimen. The impact of MMF on late acute rejection (LAR) episodes has not been well described. To investigate the risk of LAR (rejection > or = 6 months post-transplantation) data from the Scientific Registry of Transplant Recipients (SRTR) were used. We studied adult primary liver transplant recipients transplanted between June 1, 1995, and April 30, 2004, with hepatitis C virus (HCV) (n = 3356), hepatitis B virus (HBV) (n = 550) or a nonviral (n = 5740) primary cause of liver disease who were recorded as receiving continuous 3-(MMF + Tacro + steroids) versus 2-drug (Tacro + steroids) therapy for at least 6 months immediately post transplantation. Kaplan-Meier analysis showed significantly lower LAR rates 4 years post-transplant in 3- versus 2-drug HCV, HBV and nonviral disease patients. Multivariate regression confirmed 3- versus 2-drug therapy to be associated with a decreased risk of LAR. Late graft survival was significantly lower at 4 years post-transplant for patients with LAR 6-12 months post-transplantation versus patients with early rejection (78.0% vs. 87.0%, p < 0.001) and no rejection (88.1%, p < 0.001). Three-drug versus 2-drug therapy for a minimum of 6 months may offer a better treatment strategy to avoid the consequences and expense of LAR episodes.

Adolescent non‐adherence: Prevalence and consequences in liver transplant recipients

Few studies have examined the prevalence, demographic variables and adverse consequences associated with non-adherence to immunosuppressive therapy in the adolescent liver transplant population. Our hypothesis is that a significant proportion of adolescent liver transplant recipients exhibit non-adherence to medical regimens and that certain demographic and medical condition-related characteristics can be identified as potential predictors of non-adherent behavior. Furthermore, non-adherence leads to a greater incidence of morbidity and mortality in this population as compared with the adherent subset of adolescent patients. We reviewed the charts of 97 patients from 1987 to 2002 who by December of 2002 had survived at least 1 yr post-transplant and were followed by the Pediatric Liver Transplant Service at any point during their adolescent period (ages of 12-21). Non-adherence was defined as documentation of a report of non-adherence by a patient, parent or healthcare provider that was recorded in the patient's legal medical record. Descriptive statistics were used to determine the prevalence, demographic variables and adverse outcomes associated with non-adherence to immunosuppressive therapy. Categorical variables were analyzed using the chi-square test or the Fisher exact probability test. The unpaired Student's t-test was used to analyze the continuous variable of age at transplant. Using the inclusion criteria, a total of 97 patients represented the study sample of whom 37 subjects (38.1%) were defined as non-adherent and 60 (61.8%) were adherent. Non-adherent subjects were more likely to be female, older (>18 yr) and from a single-parent household. There was no significant difference in immunosuppressive regimen between non-adherent and adherent patients. Non-adherence was significantly (p<0.025) associated with lower socioeconomic status (SES), older age at transplant (p<0.005, 95% CI: -5.5 to -.99, Student's t-test) and episodes of late acute rejection (p<.001). Non-adherence was also significantly associated with re-transplantation and death secondary to chronic rejection by the Fisher exact test (p<0.006 and p<0.05, respectively). Non-adherence to immunosuppressive therapy is a prevalent problem that is correlated with certain demographic and medical condition-related risk factors and more frequent adverse consequences in the adolescent liver transplant population. The greater incidence of late acute rejection, death and re-transplantation owing to chronic rejection in non-adherent patients suggests that non-adherence is significantly associated with an increased risk of morbidity and mortality. Further investigation to identify patients at greatest risk for non-adherence is necessary to design the most effective intervention to increase patient survival and well being.

Early post-transplant urinary IP-10 expression after kidney transplantation is predictive of short- and long-term graft function

The early identification of renal transplant recipients at enhanced risk of developing acute and subclinical rejection would allow individualized adjustment of immunosuppression before functional graft injury occurs and would exclude these patients from drug-weaning studies. Protein and reverse transcriptase-polymerase chain reaction-based analyses of candidate markers in urine open the opportunity to closely monitor kidney-transplanted patients non-invasively. The chemokine interferon-inducible protein 10 (IP-10; CXCL10) might be an interesting candidate to uncover ongoing immune processes within the graft. Urine samples from kidney-transplanted recipients were retrospectively analyzed for IP-10 mRNA and protein expression. IP-10 levels were correlated with the incidence of acute rejection episodes proven by histology and long-term graft function assessed by the glomerular filtration rate 6 months post transplantation. IP-10 expression in urine identified patients with ongoing acute rejection episodes several days before a biopsy was indicated by rising serum creatinine levels. Most importantly, elevated levels of urinary IP-10 protein within the first four postoperative weeks were predictive of graft function at 6 months even in the absence of acute rejection. These data reveal a correlation between elevated IP-10 expression in urine at early time points post-transplantation and intragraft immune activation that leads to acute rejection and compromised long-term graft function.

Health-Related Quality of Life in Two Hundred-Eighty Lung Transplant Recipients

Health-related quality of life (HRQoL) has increasingly been accepted as a supplementary outcome measure for patients after lung transplantation (LTx). Using a retrospective cross-sectional study design, 280 LTx recipients (3 months to 14 years after LTx) were asked to assess their HRQoL using a generic (Quality of Life Profile for Chronic Diseases) questionnaire, which was previously validated for this specific population. In addition, the questionnaire was also performed by 155 healthy participants. All sub-scale findings ranged from 2.40 to 3.08 (0 to 4) for all patients after LTx. A significantly reduced HRQoL was reported by the sub-cohort of patients living 5 to 6 years with the allograft for all sub-scales (p < 0.006), except for Social Functioning, and was associated with the incidence of bronchiolitis obliterans syndrome (BOS; p < 0.05). Cystic fibrosis patients (p < 0.05), single-lung transplant recipients (p < 0.05) and patients of older age (p < 0.05) showed significantly decreased physical ability ratings. Patients who remained free of infection and late acute rejection episodes scored themselves significantly higher with regard to their Relaxation Capabilities (p < 0.05 for rejection; p < 0.05 for infection) and Social Functioning (p < 0.01 for rejection; p < 0.05 for infection) vs patients who experienced infection or rejection episodes. Comparisons with a normative cohort showed similar HRQoL scales for LTx patients and the healthy population, except with regard to Social Functioning (p < 0.01). Self-ratings for HRQoL were high for all dimensions for the entire sample, and remained relatively similar even for medium- and long-term survivors. HRQoL was dependent on incidence of infections, rejections and the onset of BOS. Despite differences in life expectancy of LTx patients compared with the healthy population, HRQoL self-ratings were within similar ranges.