Acute Renal Transplant Rejection Research Articles

Transition to the adult nephrologist does not induce acute renal transplant rejection

In spite of the overall increased renal graft survival, long-term allograft survival has remained least successful in adolescent recipients. A major change in their care is the transition from the paediatric to the adult nephrology unit. To analyse the effect of transition on the acute rejection frequency and graft survival, we performed a historical cohort study in all patients transplanted at the paediatric unit between 1980 and 2004. Data were obtained by reviewing medical charts in two of the four Dutch pediatric renal transplantation centers from time of transplantation until 3 years after transition. For analysis, we used a Cox proportional hazards model. The cohort consisted of 162 patients: 133 native Dutch and 29 immigrant patients. Transition occurred at a mean age of 18 years (range 14-22). At transition, 72% had a functioning allograft. Acute rejections occurred in 92/162 patients before (median follow-up 4.8 years, range 0.2-12.8) and in 15/116 patients after transition (median follow-up 3.0 years, range 1.6-3.0). Most rejections (62%) occurred within the first year after transplantation. The relative risk of acute rejections after transition in comparison to before transition was 0.10 [95% confidence interval (95% CI) 0.04-0.28] in Dutch patients and 0.69 (95% CI 0.33-1.40) in immigrant patients. In the 3 years before transition, 28/154 patients (18%) experienced graft failure compared to 19/116 patients (16%) in the 3 years after transition. The risk for acute rejection decreases after transition to the adult unit. There is less risk reduction in immigrant patients. Nephrologists should pay special attention to these patients.

BAFF May Modulate the Rate of B-Cell Repopulation After Rituximab Therapy for Acute Renal Transplant Rejection

BAFF May Modulate the Rate of B-Cell Repopulation After Rituximab Therapy for Acute Renal Transplant Rejection

The histological development of acute antibody-mediated rejection in HLA antibody-incompatible renal transplantation

The aim of this study was to examine the development of acute antibody-mediated rejection in HLA antibody-incompatible renal transplantation in relation to the Banff 07 histological classification. Renal biopsies were scored using the Banff 07 diagnostic criteria, and paraffin-embedded sections were stained with the pan-leucocyte marker CD45. Thirty-six patients had 72 renal biopsies. In biopsies performed 30 min after graft reperfusion, the mean number of CD45+ cells per glomerulus was higher than in control grafts (P < 0.04) and was associated with the donor-specific antibody (DSA) level at transplantation measured by microbeads (P < 0.01), and eight out of nine patients with greater than five CD45+ cells per glomerulus had early post-transplant rejection or oliguria, compared to 11 out of 20 with less than five cells per glomerulus (P < 0.01). In the first 10 days post-transplant, although peritubular capillary (PTC) leucocyte margination grade 3 and C4d deposition were specific for rejection, their sensitivities were low. PTC C4d staining was only seen in two out of 11 biopsies taken in the first 5 days after transplant, even in the presence of rejection, but was present in the majority of later biopsies with rejection. In biopsies stained for CD3, CD68 and CD20, it was notable that CD20+ cells were not seen during acute rejection, the infiltrates comprising CD3+ and CD68+ leucocytes. Glomerular margination of leucocytes occurred early after transplantation and was associated with DSA level and early graft dysfunction. The Banff 07 PTC margination scoring system was easy to apply, especially when CD45 staining was used, and PTC margination grade 3 was always associated with clinical rejection.

Feasibility of, and critical paths for mycophenolate mofetil Bayesian dose adjustment: Pharmacological re-appraisal of a concentration-controlled versus fixed-dose trial in renal transplant recipients

The aim of this study was to analyze retrospectively and critically the different steps of the individual dose adjustment procedure employed in the concentration-controlled (CC) versus fixed-dose trial Apomygre, which showed that mycophenolate mofetil (MMF) dose adjustment using a limited sampling strategy significantly reduced the risk of treatment failures and acute rejection in renal transplants at one year posttransplantation. The number of AUCs performed during the study and circumstances of collection, time of blood sampling, Bayesian mycophenolic acid (MPA) area-under-the-curve (AUC) estimation procedures and physicians’ compliance with MMF dose recommendations were retrospectively analyzed. 92% of AUCs scheduled over the study were actually performed. Sampling times were very well respected. Bayesian estimation of MPA exposure was done by the pharmacologists locally in accordance with the protocol instructions and the AUC estimates obtained were virtually all confirmed a posteriori. On the other hand, a second AUC estimated by multiple linear regression could only be provided for 84% of the profiles and showed a large overestimation with respect to Bayesian estimates for AUC values between 10 and 55 mg h/L. In the CC arm, a very good physicians’ compliance was observed (85%) and application of the dose recommendations led to higher values of AUCs (42.1 ± 14.6 mg h/L versus 36.7 ± 16.3 mg h/L, p = 0.0035) and to more AUCs in the target range (69% versus 56%, p = 0.0343) than when dose recommendations were not applied. By analyzing in detail the feasibility criteria of MMF Bayesian dose adjustment, this study highlighted the requirements for successful extrapolation of the Apomygre trial results to routine practice: (i) respect of the PK sampling time-windows; (ii) use of relevant tools for accurate drug exposure estimation and dose adjustment calculation; and (iii) good compliance of the physicians with regard to the recommended doses.

Cytokine gene polymorphisms as risk factors in acute rejection in renal transplantation

Cytokine gene polymorphisms as risk factors in acute rejection in renal transplantation

Clinical research of domestic tacrolimus in management of rejection following renal transplant

Objective To evaluate the efficacy and safety of domestic taerolimus in the manage-ment of acute rejection in renal transplantation reeipienta. Methods A multieeneter, open and com-parative study for domestic Taerolimua and Prograf was performed. Eighty reeipienta of first allogenie renal transplantation were randomized into 2 groups: ①Experimental group (accepting Fumeixin ad-ministration, n=58) included 23 males and 35 females with the mean age of(39.1±9.6)years. ②Control group(accepting Prograf administration, n=22) included 12 males and 10 females with the mean age of(41.34±8.5)years. There was no significant difference in the volume, warm and cold is-chemia time of donor renal, age and sex of donor. All of the 80 cases accepted tacrolimus (domestic or foreign made, at the dose of 0. 10～0. 15 mg·kg-1·d-1 , q 12 h) treatment that combined with MMF and prednisone posttransplantation. Tacrolimus CO was aimed to 8-12 ng/ml in the first 60 days and 5-10 ng/ml later. The dose of MMF was according to the rule of each transplantation center based on the following recommendation: 1.5-2.0 g/d for the weight above 70 kg, 1.5 g/d for the weight 50-69 kg, and 1.0 g/d for the weight below 49 kg, in two divided doses. Prednisone was ad- ministrated as per ruler of each center. Results Observation termination was 3 months. Morbility of actue rejection was 3.40% (2/58)and 13.6% (3/22) in experimental and control group(P>0.05). Ad-verse events including hypertension, hyperlipemia, hyperglycemia and slight abnormality of liver func-tion occurred in 36. 2%(21/58) and 36. 4% (8/22) cases of experimental and control group(P> 0. 05). The survival rate in the 2 groups was 100%. The dose of tacrolimus in experimental group was significantly lower than that in the control group at 8 and 12 weeks posttransplant, while drug valley concentration in serum was proximal in 2 groups during the whole observation period. Conclusion Domestic tacrolimus capsules can be used effectively and safely in the management of acute rejection in renal transplantation. Key words: Tacrolimus; Kidney transplantation; Rejection

Anti-interleukin-2 receptor antibodies&amp;mdash;basiliximab and daclizumab&amp;mdash;for the prevention of acute rejection in renal transplantation

The use of antibody induction after kidney transplantation has increased from 25% to 63% in the past decade and roughly one half of the induction agent used is anti-interleukin-2 receptor antibody (IL-2RA, ie, basiliximab or daclizumab). When combined with calcineurin inhibitor (CNI)-based immunosuppression, IL-2RAs have been shown to reduce the incidence of acute rejection, one of the predictors of poor graft survival, without increasing risks of infections and malignancies in kidney transplantation. For low-immunological-risk patients, IL-2RAs, as compared with lymphocyte-depleting antibodies, are equally efficacious and have better safety profiles. For high-risk patients, however, IL-2RAs may be inferior to lymphocyte-depleting antibodies for the prophylaxis of acute rejection. In an effort to reduce toxicities of other immunosuppressive medications without increasing the risk of acute rejection and chronic graft loss, IL-2RAs have often been combined with steroid- and CNI-sparing immunosuppression protocols. More data support the benefits of early steroid withdrawal with IL-2RA in low-risk patients, but preferred induction therapy for high-risk patients has yet to be determined. Although CNI-sparing protocols with IL-2RA may preserve renal function and improve long-term survival in selected patients, further studies are needed to identify those who benefit most from this strategy.

Anti-interleukin-2 receptor antibodies&amp;mdash;basiliximab and daclizumab&amp;mdash;for the prevention of acute rejection in renal transplantation

Anti-interleukin-2 receptor antibodies&amp;mdash;basiliximab and daclizumab&amp;mdash;for the prevention of acute rejection in renal transplantation

T10B9 monoclonal antibody: A short-acting nonstimulating monoclonal antibody that spares &amp;gamma;&amp;delta; T-cells and treats and prevents cellular rejection

T10B9.1A-31/MEDI-500 is a nonmitogenic immunoglobulin M kappa murine monoclonal antibody (mAb) directed against the alpha-beta (alphabeta) heterodimer of the T-lymphocyte receptor complex. The hybridoma was first produced by fusing spleen cells from BALB/C mice immunized with human peripheral blood T-lymphocytes with SP2/O-Ag14 mutant myeloma cells. The mAb is produced and purified using multistep ion exchange and molecular sieve chromatography protocols. T10B9 has been used successfully to treat acute cellular rejection in renal transplantation and as an immunosuppression induction agent in heart and simultaneous kidney-pancreas transplantation. Because T10B9 is nonmitogenic and causes minimal cytokine release, both treatment of rejection and induction of immunosuppression were accomplished with significantly fewer and milder untoward effects (cytokine release syndrome) than its comparator OKT3. Since T10B9 is directed against the alphabeta heterodimer of the CD3 epitope, it spares the gamma delta (gammadelta) region. These gamma delta (gammadelta) T cells have a unique role in the immune response controlling many serious human diseases and perhaps facilitating the development of immunologic tolerance. T10B9 has a relatively short duration of action, depleting T cells for only 10 to 14 days, unlike the protracted depletion seen with thymoglobulin and Campath-1H. There is no B-lymphocyte depletion with T10B9 as there is with both of the aforementioned reagents. The lack of prolonged lymphocyte depletion may account for less infection observed with T10B9 treatment.

Urinary Peptidomic Analysis Identifies Potential Biomarkers for Acute Rejection of Renal Transplantation

Abstract Introduction Human urine is a complex matrix of proteins, endogenous peptides, lipids, and metabolites. The level of any or all of these components can reflect the pathophysiological status of an individual especially of the kidney at the time of urine collection. The naturally occurring endogenous urinary peptides which are thought to be the product of several proteolytic and degradation processes may provide clinically useful biomarkers for different renal and systemic diseases. Materials and Methods To examine if specific differences in the urinary peptidome (&lt;10 kDa) occur at the time of acute renal transplant rejection (AR), we undertook a study of urine samples collected from biopsy-proven AR (n = 10), stable graft function (n = 10), and healthy normal control (n = 10). The peptides (&lt;10 kDa) were extracted and fractionated with high-performance liquid chromatography followed by matrix-assisted laser desorption/ionization (MALDI) time-of-flight mass spectrometric (MS) analysis. Results We identified 54 endogenous peptides, including multiple peptides for Tamm–Horsfall protein (UMOD). A panel of peptides are identified which discriminate renal transplant patients with AR from stable graft. We have shown that liquid chromatography followed by MALDI is a useful tool to identify potential biomarkers, which after verification with larger patient cohort can be used as a non-invasive monitoring tool for renal transplant rejection.

Photopheresis therapy for problematic renal allograft rejection

Photopheresis is an immunomodulatory therapy for the treatment of T cell-mediated disorders. It has been used for rejection prophylaxis in cardiac transplantation, adjuvant treatment of bronchiolitis obliterans in lung transplantation, treatment of graft verse host disease, and in a small number of cases, for treatment of acute rejection in renal transplantation. Little is known of long-term outcomes following the use of photopheresis in solid organ transplantation. We report prospective follow-up of our consecutive experience of the use of photopheresis as adjuvant/salvage therapy for problematic rejection in patients undergoing renal transplantation. Transplant graft survival, infective and malignant outcomes were reported. A cohort of 10 renal transplants recipients received photopheresis therapy for therapy-resistant rejection. Conventional therapy included an average of 6.2 g pulse methyl-prednisolone and 17.1 days antilymphocyte therapy. The cohort received additional photopheresis therapy when the unresponsive nature of their rejections raised concerns of graft loss. Median follow-up censored for patient loss was 66.7 months following photopheresis commencement. Rejection resolved in association with photopheresis use in all 10 patients. Six patients continued to have stable graft function (median serum creatinine: 191.5 micromol/L) at a median follow-up of 71.0 months. There has been one patient death from sepsis and two from malignancy with functioning grafts while one graft has been lost to disease recurrence. Photopheresis may have a role as an adjuvant or salvage antirejection therapy in solid organ transplantation. Furthermore, evaluation in randomized controlled clinical trials is required to evaluate its potential.

Lymphocytic HLA-A mRNA Is a Reliable Indicator of Acute Rejection in Renal Transplantation

Background Rejection in renal transplantation is the most frequent event causing transplant failure. It is important to identify parameters to predict rejection, which are helpful in a timely fashion. Methods Fifty-nine renal transplant recipients were divided into two groups: group 1 (stable renal function) and group 2 (acute rejection episodes). The levels of HLA-A mRNA in peripheral blood lymphocytes (both pre- and posttransplantation) were measured by reverse transcriptase-polymerase chain reaction (RT-PCR) with glucose-6-phosphate dehydrogenase (G6PDH) as an internal reference. The TEST software was used to analyze the relative expressions of HLA-A mRNA. Results There was no statistical significance between features of the two groups pretransplant versus normal controls. Posttransplant, the HLA-A mRNA levels decreased significantly compared to those of pretransplant and normal control individuals. The levels of HLA-A mRNA among the 10 patients with acute rejection episodes were significantly increased. There was no significant change in the lymphocyte populations in the early stage of an acute rejection episode compared with the prerejection value. Conclusion HLA-A mRNA expression was strongly correlated with immune status. The HLA-A mRNA levels may provide an effective and reliable indicator to predict acute rejection episodes in renal transplantation.

Mast Cells Tryptase in Patients After Renal Transplantation

Mast cells (MC) are involved in the pathogenesis of interstitial fibrosis, acute renal transplant rejection, and chronic allograft nephropathy. The aim of this study was to evaluate MC tryptase concentrations in the sera of 58 renal transplant recipients at various times after surgery in relation to graft function. We observed that kidney transplantation patients showed much higher serum tryptase concentrations than healthly controls. We demonstrated a positive correlation between serum tryptase concentration and hemoglobin, hematocrit, red blood cell count, and hepatic cell damage. We were not able to show any direct correlation between serum tryptase concentration and graft function. The clinical relevance of these findings demand further investigation.

A Randomized, Prospective Trial of Rituximab for Acute Rejection in Pediatric Renal Transplantation

We report 1-year outcomes of a randomized study of Rituximab versus standard-of-care immunosuppression (Thymoglobulin and/or pulse steroids) for treatment of biopsy confirmed, acute transplant rejection with B-cell infiltrates, in 20 consecutive recipients (2-23 years). Graft biopsies, with Banff and CADI scores, CD20 and C4d stains, were performed at rejection and 1 and 6 months later. Peripheral blood CMV, EBV and BK viral loads, graft function, DSA, immunoglobulins, serum humanized antichimeric antibody (HACA) and Rituximab, and lymphocyte counts were monitored until 1 year posttreatment. Rituximab infusions were given with a high index of safety without HACA development and increased infections complications. Rituximab therapy resulted in complete tissue B-cell depletion and rapid peripheral B-cell depletion. Peripheral CD19 cells recovered at a mean time of approximately 12 months. There were some benefits for the recovery of graft function (p = 0.026) and improvement of biopsy rejection scores at both the 1- (p = 0.0003) and 6-month (p < 0.0001) follow-up biopsies. Reappearance of C4d deposition was not seen on follow-up biopsies after Rituximab therapy, but was seen in 30% of control patients. There was no change in DSA in either group, independent of rejection resolution. This study reports safety and suggests further investigation of Rituximab as an adjunctive treatment for B-cell-mediated graft rejection.

Haplotypic Structure of ABCB1/MDR1 Gene Modifies the Risk of the Acute Allograft Rejection in Renal Transplant Recipients

Bioavailability of tacrolimus (Tac) and cyclosporine is determined by cytochrome P450IIIA and by P-glycoprotein encoded by the CYP3A4/CYP3A5 and ABCB1 genes. Polymorphisms in these genes have been suggested to influence acute rejection and pharmacokinetics in renal transplantation. We aimed to validate these findings in a haplotype analysis. A total of 832 renal transplant recipients were genotyped for the CYP3A4 -288A>G, CYP3A5 +6986G>A, ABCB1 +1236C>T, +2677G>T>A, and +3435C>T polymorphisms. Their association with acute rejection and with pharmacokinetic parameters was analyzed in haplotype models. Apart from human leukocyte antigen-DR mismatches, delayed graft function and age at renal transplantation, acute rejection was also predicted by the [ABCB1 +1236C; +2677G; +3435T] haplotype. Allograft survival was determined by donor age, age at renal transplantation, delayed graft function, cold ischemia, and history of more than two acute rejections. Homozygotes for the [CYP3A4 -288A; CYP3A5 +6986G] haplotype achieved earlier therapeutic concentrations of Tac and a higher concentration to dose ratio at week 1. ABCB1 haplotypes did not influence pharmacokinetic parameters. ABCB1 haplotypes modify the risk of acute rejection, suggesting that ABCB1 allelic arrangement is a stronger regulator of P-glycoprotein activity than single polymorphisms. The risk of acute rejection determined by ABCB1 is independent of pharmacokinetic parameters. CYP3A haplotypes control the bioavailability of Tac, but do not modify the risk of acute rejection.

Influence of cytokine and intercellular adhesion molecule‐1 gene polymorphisms on acute rejection in pediatric renal transplantation

Immune response regulation by cytokines is a key to understanding AGR. The influence of the functional polymorphisms in genes coding for TNF-alpha (-308G > A), IL-10 (-819C > T, and -1082A > G), IFN-gamma [(CA)n], TGF-beta1 (+869T > C), and iCAM-1 (R241G and E469K), in addition to HLA and gender matching on the presentation of AGR in 51 pediatric renal recipients during a 36-month post-transplantation follow-up were analyzed. Also, donors and a control group were genotyped. All groups were within Hardy-Weinberg equilibrium for all polymorphisms except IL-10-819C > T and TNF-alpha (p < 0.005 and p < 0.01, respectively) in recipients. Transplants with gender mismatch showed a higher risk for AGR than those between individuals with gender match (OR, 4.227; p = 0.010). Recipients with a high-production compared with low-production TNF-alpha allele experienced earlier AGR (p = 0.030), and those with high-production alleles of both TNF-alpha and IFN-gamma showed a further increased risk (OR = 11.129, p = 0.024). These findings support the notion that a single genotype cannot by itself explain an event as complex as AGR. The sum or combination of different specific alleles of these genes could better account for the immune response to an allograft.

Ischemia–reperfusion treatment: opportunities point to modulation of the inflammatory response

Ischemia-reperfusion injury is the leading cause of acute renal failure and determinant of renal-transplant outcome. Although many experimental studies show decreased injury and preserved renal function after dampening of the inflammatory response, surprisingly little progress has been made in the development of novel therapies.

Gene expression profiling on acute rejected transplant kidneys with microarray

To investigate the gene expression profiles in acute allograft rejection of renal transplantation, and identify the markers for the early diagnosis of acute rejection, heterotopic kidney transplantation was performed by using F344 or Lewis donors and Lewis recipients. No immunosuppressant was used. Renal grafts were harvested on days 3, 7, and 14. A commercial microarray was used to measure gene expression levels in day-7 grafts. The expression levels of 48 genes were up-regulated in the allograft in comparison with the isograft control, and interferon-gamma-induced GTPase gene was most significantly up-regulated in allografts. It is concluded that a variety of pathways are involved in organ transplant rejection which is dynamic and non-balanced. IFN-inducible genes, such as IGTP, may play an important role in the rejection. A lot of important factors involved in acute rejection are unnecessary but sufficient conditions for the rejection. We are led to conclude that it is virtually impossible to make an early diagnosis based on a single gene marker, but it could be achieved on the basis of a set of markers.

The value of serum neopterin, interferon-gamma levels and interleukin-12B polymorphisms in predicting acute renal allograft rejection

Acute rejection remains a poor predictor of graft outcome. In this study, we measured serum levels of interferon (IFN)-gamma and neopterin by enzyme-linked immunosorbent assay and a single nucleotide polymorphism (SNP) within the 3' untranslated region of the interleukin (IL)-12 B gene (1188 A/C) to determine whether either of these factors could predict acute rejection in renal transplantation. Significantly higher early post-transplant neopterin levels (days 5-7; 35.7 versus 19.9 nmol/l) were observed in recipients who subsequently rejected their grafts. Post-transplant neopterin levels showed a strong positive correlation with 1-month creatinine levels (Spearman's correlation 0.62, P < 0.001), suggesting macrophage activation early after transplantation. Pretransplant neopterin and IFN-gamma levels and the IL-12B gene SNP did not predict acute rejection in this small retrospective study. The ability to predict acute rejection non-invasively early after transplantation could lead to individual tailoring of immunosuppressive regimens and perhaps lead eventually to longer graft survival.

Protective role of NHE-3 inhibition in rat renal transplantation undergoing acute rejection

Acute rejection in renal transplantation disturbs solute and volume maintenance in humans accompanied by delayed graft function and poor prognosis. We recently reported that decreased expression and function of Na+/H+ exchanger type 3 (NHE-3) in proximal tubules and epithelial Na+ channels and aquaporin 2 in collecting ducts are major mechanisms involved in Na+ and water imbalances shortly after transplantation in rat undergoing acute rejection. We performed kidney transplantations in rats with bilaterally nephrectomized recipients with acute rejection and, in addition, systemically administered a specific inhibitor of NHE-3 (NHE-I). NHE inhibition in acute renal failure was shown to improve tubular function and recovery. The aim of this therapy was to reduce energy consumption of the graft and preserve NHE-3 function. Imbalances in electrolyte excretion declined in NHE-I-treated animals and NHE-3 activity was preserved. Observed NHE-I-dependent changes in electrolyte excretion, polyuria, and reduced protein reabsorption in the acute postoperative phase are predictors of favorable graft outcome in humans.