Acute Graft Dysfunction Research Articles

SIROLIMUS AND MICOPHENOLATE MOFETIL: A RELIABLE DRUG COMBINATION TO PREVENT ACUTE REJECTION AND TO PROTECT GRAFT FUNCTION AFTER RENAL TRANSPLANTATION. A RETROSPECTIVE ANALYSIS OF 1-YEAR’S FOLLOW UP IN ADULT KIDNEY-RECIPIENTS.

P219 Aims: A group of 82 renal transplants under SRL/MMF immunpsuppression was followed for a minimum of 1 year, and observed regarding acute rejection, renal function, graft loss and chronic graft dysfunction as well as side effects attributable to SRL. Methods: Eighty patients received 82 renal transplants and were divided into two groups: Group I (all 55 LRD, 3 LNRD and 5 CAD) received a loading dose of SRL 5 mg /5 days with later adjustments to maintain trough blood levels between 5-15 ng/ml. MMF and steroids were started in usual doses, with prednisone tapered to reach a permanent dose of 5 mg/day at day 21. Group II (8 LNRD and 10 CAD, 2 re-transplants incl.) received induction with ATG 1 mg/day, for a maximum of 7 days, and Tacrolimus (TRL, 5-12 ng/ml) once serum creatinine reached <2mg/dl. MMf and steroids were started in usual doses, with the same prednisone-tapering policy as in group I. Once ambulatory (avg. 14 days), patients were started on SRL maintenance doses (2 mg/day, and then blood levels of 5-15 ng/ml), and TRL was withdrawn after a 2-week overlap. No loading dose of SRL was given in this group. In both groups, acute rejection (AR), primary non-function (PNF), chronic graft dysfunction (CGD), graft loss and patient mortality was followed for a minimum of 1 year, and graft function was evaluated at exactly one year post-transplant. Side effects attributable to SRL were notated. Results: 82 transplants were included. AR occurred in 10 patients (global 12%, 11% for LRD, 16% for LNRD/CAD). Six graft losses were observed, 3 following resistant acute rejection, 2 after PNF and one with CGD. Graft survival at 1 year was 93%. Average serum creatinine at 1 year was 1.42 mg/ml+/- 0.8. Conclusions: SRL/MMF based protocols provide strong prophylaxis against AR to renal transplant recipients, and reach excellent graft function after 1 year.

ACUTE HUMORAL REJECTION (AHR) AFTER LIVING-DONOR INTESTINAL TRANSPLANTATION (ITX)? - HOW DO WE MANAGE THIS TYPE OF REJECTION?

P614 Background: De novo AHR after kidney Tx has gained much attention during the last few years. The following criteria for AHR are as follows: 1) steroid and anti-lymphocyte therapy resistant acute graft dysfunction; 2) positive cross match; 3) complement deposition in biopsy specimen (Transpl Proc,35,1677,2003). However, involvement of an humoral component in acute rejection after ITx is poorly described and management strategies for this type of rejection are not defined. We report a case of atypical acute rejection after living-donor ITx that is consistent with AHR in kidney Tx. Methods: A 1 year 8 month old patient received a living-donor combined liver/ITx.(liver from father, intestine from aunt) The patient received tacrolimus and steroid-based immunosuppression (IS) plus anti-IL-2 receptor antibody (Ab) induction therapy. When rejection was detected by biopsy, steroid pulse / OKT3 therapy were administered. The serum was examined for flow cytometry cross match (FCXM) using frozen donor lymphocytes. Positive results were confirmed by complement dependent cytotoxicity (CDC). Direct immunofluorescence was performed using anti-IgM, IgG and complement (C4d) Abs to detect immune complexes on the biopsy specimen in situ. Results: Diffuse mucosal denudation was encountered on post-Tx day 12. Since steroid pulse was not effective, OKT3 was started on post-Tx day 14. OKT3 temporarily improved mucosal denudation on post-Tx day 25. However, rejection eventually progressed to complete destruction of the mucosa on post-Tx day 35. During this rejection episode, the number of crypt apoptosis increased but infiltration by blastic lymphocytes (typical feature of acute rejection) was not observed. On post-Tx day 38, the patient suffered from PTLD leading to septicemia and death, despite reduction of IS. FCXM detected the first elevation of serum anti-donor T cell and B cell IgM on post-Tx day 17 (5 days after onset of severe mucosal damage), which was confirmed by CDC. Consistent with FCXM and CDC, direct immunofluorescence first demonstrated endothelial deposition of IgM and C4din the capillaries on the biopsy specimen on post-Tx day16 but not before this timing. Conclusions: 1) Atypical rejection without cell infiltrate was observed in a case of ITx; 2) Serological and pathological evidence for humoral responses were detectable; 3) This form of rejection was steroid and anti-lymphocyte therapy resistant. In the future, suspicion of involvement of humoral component in a rejection episode after ITx should prompt early therapy with plasma exchange and high dose iv globulins.

Elevation of CXCR3-Binding Chemokines in Urine Indicates Acute Renal-Allograft Dysfunction

A noninvasive urinary test that diagnoses acute renal allograft dysfunction would benefit renal transplant patients. We aimed to develop a rapid urinary diagnostic test by detecting chemokines. Seventy-three patients with renal allograft dysfunction prompting biopsy and 26 patients with stable graft function were recruited. Urinary levels of CXCR3-binding chemokines, monokine induced by IFN-γ (Mig/CXCL9), IFN-γ-induced protein of 10 kDa (IP-10/CXCL10), and IFN-inducible T-cell chemoattractant (I-TAC/CXCL11), were determined by a particle-based triplex assay. IP-10, Mig and I-TAC were significantly elevated in renal graft recipients with acute rejection, acute tubular injury and BK virus nephritis. Using 100 pg/mL as the threshold level, both IP-10 and Mig had diagnostic value (sensitivity 86.4%; specificity 91.3%) in differentiating acute graft dysfunction from other clinical conditions. In terms of monitoring the response to antirejection therapy, this urinary test is more sensitive and predictive than serum creatinine. These results indicate that this rapid test is clinically useful.

Surveillance biopsies are superior to functional studies for the diagnosis of acute and chronic renal allograft pathology in children.

In this report of our 3-yr protocol biopsy program, we describe the evolution of acute rejection (AR) and chronic renal allograft nephropathy (CAN) in a cohort of 21 children treated with antibody induction, tacrolimus, mycophenolate mofetil, and prednisone. The aims of this study were to compare the pathogenicity of clinical acute rejection (CAR) and subclinical acute rejection (SAR), and to determine whether functional studies accurately represent acute and chronic renal allograft pathology in pediatric recipients with disproportionately large grafts. Using concurrent biopsies, we evaluated: (i) the utility of changes in the baseline sCr (DeltasCr) to predict both the onset of AR and the response to immunosuppressive therapy; and (ii) the relationship of the calculated creatinine clearance and the presence of pathologic proteinuria to the severity of CAN. We performed 112 biopsies: 11 donor, 73 protocol, 16 acute graft dysfunction and 12 1-month follow-up AR therapy. CAR and SAR were similar in incidence, timing and histologic severity. Progression of CAN was associated with the first episode of CAR (p < 0.02) and the cumulative number of episodes of CAR (p < 0.01), SAR (p < 0.05), CAR plus SAR (p < 0.002) and borderline SAR (B-SAR) (p < 0.006). One-month post-treatment DeltasCrs could not distinguish 1-month follow-up biopsies with histologically confirmed worsened or unchanged AR from those with improved histology (35.2 +/- 74.8% vs. 23.8 +/- 24.9%, p = NS). These findings led to the addition of anti-lymphocyte antibody therapy in five of 10 (50%) cases. Despite 100% 3-yr actuarial graft survival and excellent function (GFR = 111 +/- 36 mL/min/1.73 m(2)), 18 of 21 (86%) patients had grade I CAN or greater chronic histology at a mean +/- sd follow-up period of 18.2 +/- 13.1 months. Thirteen of 21 (62%) patients progressed to grade I CAN at 5.2 +/- 3.6 months and five (38%) of these patients progressed to grade II CAN at 17.8 +/- 11.3 months. Schwartz GFR did not differ between patients with or without CAN (108 +/- 38 mL/min/1.73 m(2) vs. 127 +/- 8 mL/min/1.73 m(2), p = NS). In biopsies with CAN and no associated AR, neither the Banff chronic tubulointerstitial (Banff ci) score nor the Banff chronic grade correlated with the GFR. Proteinuria was not associated with CAN. Clinical AR and SAR are similar histologic lesions with a capacity for CAN progression. In pediatric renal transplant recipients, longitudinal protocol biopsies are superior to functional studies for the diagnosis and post-therapeutic monitoring of AR and for the surveillance of CAN.

Evidence That Humoral Allograft Rejection in Lung Transplant Patients Is Not Histocompatibility Antigen-Related

We have recently recognized humoral rejection (HR) in lung allograft recipients and its association with acute and chronic graft dysfunction. We have shown that C4d, a stable marker of classic complement activation, is deposited in lung allografts, correlating with clinical rejection and parenchymal injury. The antigenic target may be endothelium in the setting of recurrent acute rejection while varying components of the bronchial wall may be important in chronic graft dysfunction. We sought to establish whether there is a role for antibodies with histocompatibility antigen specificity in the lung humoral allograft phenomenon. Flow cytometric and ELISA assays to assess donor-specific antigens were conducted on sera from 25 lung transplant recipients who had experienced one or more episodes of clinical rejection; in addition, the serum samples were tested for evidence of antiendothelial cell antibody activity. Morphologically, each case had biopsies showing septal capillary injury with significant deposits of immunoreactants with microvascular localization and positive indirect immunofluorescent antiendothelial cell antibody assay. Panel-reactive antibody testing showed absence of MHC Class I/II alloantibodies; ELISA based crossmatch detecting donor-specific MHC Class I/II specific antibodies was negative. HR can occur in the absence of antibodies with HLA specificity; antigenic targets may be of endothelial cell origin.

Safety of inhaled nitric oxide after lung transplantation

Background The present study tests the hypothesis that therapy with inhaled nitric oxide (iNO) at the time of lung transplantation in patients undergoing bilateral single lung transplantation: (i) is safe; and (ii) does not increase either the duration of mechanical ventilation or the incidence of acute graft dysfunction. Methods We conducted a prospective, non-randomized trial of iNO at 20 parts per million. The treatment group was comprised of 14 patients (10 females, 4 males) undergoing lung transplantation to address severe end-stage lung disease and pulmonary hypertension (mean pulmonary artery pressure > 30 mmHg). Clinical and histologic parameters were compared with 22 historical control subjects who were matched with the study population for age, diagnosis and disease severity (17 females, 5 males) and had undergone lung transplantation in the preceding 2-year time period. No significant differences were noted between the 2 study groups at baseline. Results No toxic effect of iNO treatment was evident. Although the incidence of acute graft dysfunction was the same in both groups, the occurrence of acute graft rejection in the initial 4 weeks after transplant was less frequent in the iNO group than in the control group (7% vs 32%, p = 0.05). Fifty percent of the treatment group, as compared with 22% of the control group, were discharged from the hospital within 2 weeks of the procedure ( p = 0.05). Conclusions Early initiation of iNO in lung transplant patients with pulmonary hypertension is safe and may decrease the incidence of acute graft rejection. We speculate that iNO may exert an immunomodulatory effect. J Heart Lung Transplant 2003.

Tissue injury and repair in allografts: novel perspectives

Recent research achievements might considerably alter scientific concepts of pathways involved in tissue injury and repair. Accumulating evidence for an important role of alloantibodies in acute and chronic allograft rejection led to a renewed interest in humoral kidney transplant rejection. Studies reassessing the mechanisms of antibody- and complement-mediated injury now shed new light on the pathogenic mechanisms underlying acute or chronic graft dysfunction and injury. A closer look at humoral effector mechanisms revealed that endothelial cell activation and injury may play a key role in humoral rejection, and further uncovered an important interplay between humoral and cellular alloimmunity. Regeneration of cells after injury has been thought to rely on activation of local progenitor cells. Recent investigation indicates that regeneration of grafted solid organs is not exclusively based on self-renewal of tissues but obviously also involves repopulation of the graft by recipient cells, creating chimerism in the vasculature and other compartments. Besides reparative compensation of cell loss, chimerism of endothelial cells might also alter immunologic properties of the graft, thus favoring adaptation and graft survival. On the other hand, however, myofibroblasts mediating deleterious arterial intimal proliferation may also be of recipient origin. A possible source of graft-repopulating recipient cells are bone marrow-derived adult stem cells with the amazing capacity of differentiating into cell types of all three germ cell layers. Reliable diagnosis of humoral mechanisms in allograft rejection and identification of involved effector mechanisms should provide the basis for development and targeted application of specific anti-humoral treatment. Recently emerged new concepts of mechanisms underlying tissue regeneration might pave the way for entirely new therapeutic approaches in human disease.

Cariporide (HOE-642) improves cardiac allograft preservation in a porcine model of orthotopic heart transplantation.

Acute graft dysfunction caused by ischemia-reperfusion injury is recognized as a major source of morbidity and mortality following adult heart transplantation. The aim of this study was to determine whether treating the donor and recipient with cariporide, an inhibitor of the sodium-hydrogen exchanger, could reduce ischemia-reperfusion injury. A porcine model of donor brain death, hypothermic ischemic preservation, and orthotopic cardiac transplantation was used. Allografts in both the control group (CON, n=6) and treatment group (CAR, n=6) were arrested and stored for 4 hours in the extracellular crystalloid cardioplegia currently used in the clinical transplantation program at our institution. In addition, both the donor and recipient animals in the CAR group received a single intravenous dose of cariporide (2 mg/kg) 15 minutes before harvesting and reperfusion, respectively. The initial rate of troponin I release was significantly lower in recipients of CAR hearts than in recipients of CON hearts (P =0.020). All hearts were weaned successfully from bypass. More CAR hearts were weaned successfully at the first attempt, at 1 hour post-reperfusion, than CON hearts (6 of 6 vs 3 of 6), but this did not achieve statistical significance. Left ventricular contractility (preload recruitable stroke-work relationship) and left ventricular compliance (end-diastolic pressure-volume relationship) were significantly better preserved in CAR hearts than CON hearts (both P <0.0001). Myocardial injury was reduced, and contractile function was better preserved in allografts that received cariporide, compared with allografts that received conventional preservation alone.

Indirect fluorescent antibody testing of nasopharyngeal swabs for influenza diagnosis in lung transplant recipients

Background: Rapid and reliable diagnosis of respiratory viral infections (RVI) in lung transplant recipients is essential to direct therapy of acute graft dysfunction and identify epidemic trends. Traditional techniques of serology and viral culture are limited by the lack of antibody response and delay in diagnosis. Methods: We examined the clinical utility of indirect fluorescent antibody (IFA) testing in adult lung transplant patients with suspected RVI, compared with serology and culture. Nasopharyngeal and throat swabs (NT) were obtained to sample epithelial cells, followed by application of monoclonal antibody to respiratory syncytial virus, adenovirus, parainfluenza 1–3 and influenza A and B. The Bartels Respiratory Viral Detection kit was used with IFA results available within 24 hours. Results: Nine of 18 patients tested positive for RVI with influenza A ( n = 8) and influenza B ( n = 1) detected. The sensitivity of IFA (67%) was higher than that of cell culture (45%). With intensive supportive therapy, infection was self-limiting in bronchiolitis obliterans syndrome (BOS) Grade 0–2 patients. However, patients with BOS Grade 3 manifested an acute exacerbation of airflow obstruction, which proved to be irreversible. Conclusions: Lung transplant patients with “flu-like” symptoms should proceed to IFA testing of NT swab specimens for early diagnosis. Samples collected within 7 days of symptom onset have high sensitivity as compared with serology and viral culture techniques.

Acute Graft Dysfunction Due to Pyelonephritis: Value and Safety of Graft Biopsy

Acute Graft Dysfunction Due to Pyelonephritis: Value and Safety of Graft Biopsy

Elective withdrawal of cyclosporin following renal transplantation: A single centre experience

SUMMARY: Withdrawal of cyclosporin in the early post‐transplant period may provoke acute graft dysfunction, although the reported incidence is variable. We have reviewed our experience of 212 renal transplant recipients to determine the incidence of early post‐withdrawal acute graft dysfunction and examine which factors predict it. Gender, age at initiation of withdrawal, timing and duration of withdrawal, pre‐withdrawal immunosuppression, doses of prednisolone and azathioprine at initiation of withdrawal and, during the first 6 months post witfidrawal, episodes of prior acute transplant rejection, human leucocyte antigen match and previous renal transplantation were considered. In classifying acute graft dysfunction, a 50% increase in serum creatinine from baseline was taken as a minimum criterion, and additional evidence (biopsy, fine needle aspirate, response to immunotherapy) was sought for evidence of a link with cyclosporin withdrawal. Acute graft dysfunction was documented in 28 (13.2%) patients, 26 episodes occurring within 4 months of completion of cyclosporin withdrawal. the mean time interval from transplantation to initiation of withdrawal was significantly shorter in this group (239 vs 299 days, P &lt; 0.02). the median withdrawal period was of similar duration in the groups with and without acute dysfunction, but for the subgroup of patients previously on triple therapy (cyclosporin, prednisolone and azathioprine, n= 78), withdrawal had occurred more rapidly in those with dysfunction (25 vs 67 days, P &lt; 0.05). None of the remaining variables that were considered had a significant effect on outcome, although subgroups tended to be small. Cyclosporin withdrawal may be safer if delayed until after the first post‐transplant year with gradual dose reduction over a period of months.

The molecular adsorbents recycling system as a liver support system based on albumin dialysis: a summary of preclinical investigations, prospective, randomized, controlled clinical trial, and clinical experience from 19 centers.

Artificial liver support aims to prolong survival time of patients with liver failure by detoxification. Albumin as a molecular adsorbent in dialysis solution is capable of attracting even tightly albumin-bound toxins from blood into the dialysate if a specific dialysis membrane is used and if the albumin's binding sites are on-line-purified by a sorbent/dialysis-based recycling system (i.e., molecular adsorbents recycling system, or MARS). The MARS technology has been shown to remove water-soluble and albumin-bound toxins and to provide renal support in case of renal failure. Fourteen centers have reported that MARS treatment improved mental status of patients with liver failure and hepatic encephalopathy. In treating liver failure and cholestasis, MARS was associated with hemodynamic stabilization, improvement of hepatic and kidney function, and disappearance of pruritus. In hepatic failure and hepatorenal syndrome, a prospective, randomized, controlled trial of MARS treatment was able to prolong survival time significantly. MARS has been used in 26 patients with acute liver failure or primary graft dysfunction. Nineteen centers reporting on 103 patients have shown that MARS treatment is safe, easy to handle, feasible, and effective.

Association of Factor V Leiden Mutation with Delayed Graft Function, Acute Rejection Episodes and Long-term Graft Dysfunction in Kidney Transplant Recipients

We analysed whether the factor V Leiden mutation--the most common hereditary predisposing factor for venous thrombosis--is associated with early and long-term graft dysfunction after kidney transplantation in 394 Caucasian kidney transplant recipients. The presence of factor V Leiden mutation was identified by allele specific PCR. The prevalence of the factor V Leiden mutation was compared to 32216 unselected neonates. The prevalence of the factor V Leiden mutation (GA genotype) was similar in 394 kidney transplant recipients and 32216 neonates. The frequency of known factors predicting long-term graft function were similar in patients with the GA genotype and with the normal factor V gene (GG genotype). The GA genotype was associated with the occurrence of no primary graft function (risk: 2.87: 95% confidence interval: 1.01-8.26; p < 0.05), the number of dialysis after transplantation in patients with no primary graft function until graft function (7.5 +/- 2.06 dialysis in GA patients; 4.2 +/- 0.36 dialyses in GG patients; p < 0.05), and the risk for at least one acute rejection episode (risk: 3.83; 95% confidence interval: 1.38-10.59; p < 0.02). The slope of l/creatinine per year was significantly lower in patients with the GA genotype (GA patients: -0.0204 +/- 0.008 dl/mg per year; GG patients: 0.0104 +/- 0.004 dl/mg per year; p < 0.02). The annual enhancement of the daily protein excretion rate was elevated in patients with the GA genotype (GA patients: 38.5 +/- 16.6 mg/24 h per year; GG patients: 4.9 +/- 4.4 mg/24 h per year; p < 0.02). Our study showed that the factor V Leiden mutation is associated with the occurrence of delayed graft function, acute rejection episodes and chronic graft dysfunction after kidney transplantation.

Invited commentary

Invited commentary

Intensive care and immediate follow-up of children after renal transplantation

The renal allograft provides a distinctive human experiment where a healthy kidney is denervated, subjected to preservation ischemia, and later engrafted into new milieu with abnormal electrolytes and hormones. Optimal postoperative management depends on a thorough understanding of peritransplant physiology. The kidney has extensive adrenergic innervation supplied by preganglionic sympathetic nerves originating from T6-L2 and postganglionic adrenergic vasomotor fibers. Denervation of the renal artery in normal kidneys results in ipsilateral natriuresis, diuresis, and impaired ability to increase renin production in response to low-sodium diet. Denervation is not permanent as reinnervation starts within 1 to 3 months and is complete by 6 months following engraftment. Preservation injury, when moderate in severity, can result in a spectrum of tubular transport defects. Cold ischemia injury afflicts the proximal tubule and results in isolated glucosuria, aminoaciduria, hyperphosphaturia, acidosis, or more generalized transport defect (Fanconi’s syndrome). Preservation injury can also cause several distal tubular transport defects resulting in acidosis and decreased urinary concentration. Severe ischemia could result in acute tubular necrosis (ATN) and early graft dysfunction. Tubular injury, residual osmolar load from pretransplant renal failure, intraoperative mannitol, and atrial natriuretic factor result in copious urine flow. Hypokalemia and hypomagnesemia may follow the diuresis. Residual hyperparathyroidism from renal failure prior to transplant may lead to increased serum calcium and decreased serum phosphorus usually resolving within 18 months.

Endocrine Alteration in the Adrenal Gland in Kidney Transplant Patients

Introduction: Endocrine alterations associated with chronic renal failure have been reviewed recently. Some of these alterations are of clinical relevance. The aim of this study was to investigate the effect of renal transplantation on the endocrine system of the adrenal gland of the transplant recipients. Methods: The serum angiotensin-converting enzyme (SACE), plasma renin (PR) and plasma aldosterone (PA) were examined in 30 patients before and after renal allotransplantation. Additionally measured parameters were blood pressure, serum creatinine, potassium, sodium, the duration of dialysis and immunosuppressive medication. Results: Six weeks after renal transplantation, serum creatinine decreased from 820.07 ± 172.01 to 138.12 ± 67.54 µmol/l. In the same periode, serum potassium decreased from 5.42 ± 0.89 to 4.17 ± 0.42 mmol/l. PA and PR decreased from 1,150.84 ± 976.06 to 233.52 ± 217.07 µmol/l, and from 121.07 ± 100.12 to 26.16 ± 10.86 µU/ml, respectively. SACE decreased from 0.21 ± 0.21 to 0.13 ± 0.11 µmol/l. No significant correlation was seen with blood pressure, serum sodium, the duration of dialysis and immunosuppressive drugs. Additionally, 2 patients with acute renal graft dysfunction showed significant increases in PR and PA. After successful treatment both levels declined very quickly to prerejection levels. Patients after binephrectomy show no elevation in PR (5–47 µU/ml) or PA (21–416 µmol/l) neither before nor after renal transplantation. Conclusions: We conclude that renal transplantation has profound effects on the recipient’s renin-angiotensin-aldosterone system. Because of the rapid depression after renal transplantation, it does not appear to be involved in the pathogenesis of post transplantation hypertension but may reflect a role for repair processes after renal allotransplantation.

Cytomegalovirus infection and graft rejection in renal transplantation.

Cytomegalovirus (CMV) infection and CMV disease have been associated with acute and chronic graft rejection. The introduction of the sensitive CMV antigenemia pp65 assay for detection of CMV infection allowed us to study the time course of CMV infection and acute rejection and the long-term outcome in renal transplant recipients with and without a CMV risk constellation. Prospective single center study including 48 renal transplant recipients at risk for CMV infection (donor and/or recipient CMV seropositive) and a control group of 36 CMV seronegative recipients of CMV seronegative kidney donors. Evidence of CMV infection was monitored by the CMV antigenemia pp65 assay every 1 to 2 weeks and compared with the occurrence of acute rejection in the posttransplant period and graft function at 5 years. CMV infection developed in 83% (40/48) of patients of the CMV risk group within 4 months posttransplant. A total of 18 of patients experienced an acute rejection episode (control group 16/36; P=0.65). In 12/18 CMV infection followed rejection and in three patients antigenemia preceded the diagnosis of rejection. In three patients CMV antigenemia remained negative. Five-year follow up: Patient survival (44/48 vs. 31/36; P=0.48), graft survival (38/48 vs. 27/36; P=0.79), number of patients with at least one acute rejection episode: CMV risk group: 42.1%, control group 51% (P=0.46), serum creatinine: CMV risk group:130 +/- 66 micromol/iter, control group: 126 +/- 37 micromol/ liter (P=0.56), proteinuria: CMV risk group: 0.02 +/- 0.02 g/mmol creatinine, control group: 0.02 +/- 0.02 g/mmol creatinine (P=1.0). CMV infection within 4 months posttransplant, as defined by a positive antigenemia assay was not found to be a risk factor for acute graft rejection or chronic graft dysfunction at 5 years.

Adult man with primary allograft nonfunction

Immediate renal allograft dysfunction is a catastrophic event. Common causes include hyperacute rejection and mechanical problems. We report an uncommon cause of acute graft dysfunction, which may become more prevalent as organs from donors of increasing age are used.

Quantification of cytotoxic T-cell gene transcripts in human lung transplantation.

Differentiating between acute rejection and cytomegalovirus (CMV) infection is one of the major challenges of lung transplantation. The aims of this study were to: (1) quantify the transcription of the cytotoxic T lymphocyte (CTL) effector molecules in the bronchoalveolar lavage (BAL) of lung transplant recipients and (2) evaluate the clinical usefulness of this technique. Sixty-six single-lung, double-lung, or heart-lung transplant patients were prospectively enrolled in the study. BAL was performed either for routine surveillance or for acute graft dysfunction. RNA was extracted from BAL cell pellets and underwent competitive reverse transcription-assisted polymerase chain reaction (RT-PCR) for perforin, granzyme B, granulysin, and Fas ligand. Gene transcript analysis was compared to clinical diagnosis established by conventional methods [BAL microbiological and transbronchial biopsy (TBB) analyses]. After exclusion of several BAL according to the study criteria, 62 BAL were submitted for data analysis. Significantly higher expression of all the analyzed transcripts was found during CMV infection, compared with each of the other defined diagnostic categories, namely nonsignificant pathology, acute rejection, and nonviral pulmonary infection. Quantification by competitive RT-PCR of the CTL effector molecule transcripts (perforin, granzyme B, granulysin, and Fas ligand) could represent a valuable tool for the differential diagnosis of graft dysfunction in lung transplantation.

Does subclinical rejection contribute to chronic rejection in renal transplant patients?

Renal allograft biopsies have traditionally been performed in the setting of acute graft dysfunction. However, several groups have performed graft biopsies at times of stable graft function, and more recently, after treatment of rejection episodes. Surprisingly, unequivocal histologic criteria for acute rejection have been demonstrated in a high proportion of these protocol biopsies. The Winnipeg Transplant Group has documented the high prevalence of clinically silent inflammatory infiltrates in early protocol biopsies, and demonstrated their inflammatory and cytotoxic potential by immunohistochemical and molecular biological techniques. Furthermore, in a randomized trial, our group has demonstrated that subclinical rejection, if untreated, is associated with the development of early chronic pathology and late graft dysfunction. In this overview, we will summarize the early data on subclinical allograft inflammation, present the experience of the Winnipeg Transplant Group, and discuss the possible implications of subclinical rejection on the development of chronic rejection.