ATG-induced accelerated immune senescence: clinical implications in renal transplant recipients.

Persistent ATG-induced CD4(+) T cell lymphopenia is associated with serious clinical complications. We tested the hypothesis that ATG induces accelerated immune senescence in renal transplant recipients (RTR). Immune senescence biomarkers were analyzed at transplant and one-year later in 97 incident RTR -62 patients receiving ATG and 35 receiving anti-CD25 mAb (α-CD25). This consisted in: (i) thymic output; (ii) bone marrow renewal of CD34(+) hematopoietic progenitor cells (CD34(+) HPC) and lymphoid (l-HPC) and myeloid (m-HPC) progenitor ratio; (iii) T cell phenotype; and (iv) measurement of T cell relative telomere length (RTL) and telomerase activity (RTA). Clinical correlates were analyzed with a 3 year follow-up. Thymic output significantly decreased one-year posttransplant in ATG-treated patients. ATG was associated with a significant decrease in l-HPC/m-HPC ratio. Late stage differentiated CD57(+) /CD28(-) T cells increased in ATG-treated patients. One-year posttransplant T cell RTL and RTA were consequently lower in ATG-treated patients. ATG is associated with accelerated immune senescence. Increased frequency of late differentiated CD4(+) T cell frequency at transplantation tended to be predictive of a higher risk of subsequent opportunistic infections and of acute rejection only in ATG-treated patients but this needs confirmation. Considering pretransplant immune profile may help to select those patients who may benefit from ATG to prevent severe infections and acute rejection.

Polycystic kidney size and outcomes on peritoneal dialysis: comparison with haemodialysis.

BACKGROUND: For many nephrologists, patients with polycystic kidney disease (PKD) have an increased risk of complications and technique failure on peritoneal dialysis (PD) due to enlarged kidneys. The literature showed that PD can be as good a therapeutic option as haemodialysis (HD) for patients with PKD. However, no study has focused on the impact of polycystic kidney size on outcomes for patients on PD. METHODS: This is a retrospective monocentric study. Fifty-eight patients with PKD started dialysis between January 2000 and December 2010: 24 on PD and 34 on HD. Kidney size assessed by abdominal computed tomography scans was available for 45 patients (19 on PD and 26 on HD). PD technique survival, specific PKD complications and mechanical and infectious PD complications, as need for pre-transplant nephrectomy and kidney transplantation, were considered. RESULTS: The two cohorts were similar in terms of age and body surface area. The median kidney size was not significantly different between PD and HD patients [19.1 cm (12.5-32.5) versus 16.5 cm (11.8-33.8), respectively, P = 0.13]. However, we identified an increased number of PD patients with larger kidneys [(>25 cm) (27.8% on PD versus 7.7% on HD (P = 0.07)]. Neither cystic (infection or haemorrhage) nor mechanical complications (hernias and leaks) were different in PD or HD. Ten patients experienced PD-related peritonitis, mainly due to non-enteric bacterial pathogens. The main reason for stopping PD and HD was transplantation. Six PD patients underwent nephrectomy in order to access the transplant programme. Among them, five were maintained on PD after surgical procedure with good adequacy dialysis criteria. CONCLUSIONS: We observed no deleterious impact of kidney size on outcomes on PD when compared with HD. A large kidney size in patients with PKD is not a contraindication to PD. Patients for whom a pre-transplant nephrectomy is mandatory can also safely opt for PD as a dialysis method.

Subclinical Epstein-Barr virus viremia among adult renal transplant recipients: incidence and consequences.

The natural history and clinical significance of posttransplant Epstein-Barr virus (EBV) infection remain largely unknown. The aims of this study are to describe the incidence, risk factors and consequences of EBV infection after kidney transplantation. A total of 383 consecutive patients having received a kidney transplant between January 2002 and December 2010 were included. EBV polymerase chain reaction (PCR) was performed every 2 weeks for 3 months, and every 4 weeks for the next 9 months. A total of 155 of the 383 patients (40%) had at least one positive viremia during the first year posttransplant. The median time to viremia was day 31 posttransplant (14-329). A total of 73 (47%) had EBV viremia > 10(3) log and 23 (15%) had positive viremia for more than 6 months. EBV D+/R- patients (12/18 (67%) versus 143/365 (39%), p = 0.02) and those having received antithymocyte globulins (ATG) (54% vs. 35%; p<0.001) were more likely to develop EBV infection. EBV infection (hazard ratio [HR], 3.03; 95% confidence interval [CI], 1.72-8.29; p = 0.01) was associated with the occurrence of opportunistic infections. A positive EBV PCR during the first 6 months posttransplant was associated with graft loss (HR, 3.04; 95% CI, 1.36-6.79; p = 0.014). EBV reactivation is frequent after transplantation and reflects overimmunosuppression. Prospective studies should examine the association between EBV and graft loss.

Influence of cyclooxygenase-2 (COX-2) gene promoter polymorphism -765 on graft loss after renal transplantation.

A G-->C polymorphism has been identified in the human cyclooxygenase-2 (COX-2) gene promoter at position -765 with C allele leading to a decreased promoter activity with low prostaglandin E2 (PGE2) production. PGE2 has strong immunomodulatory properties that could influence graft survival. We studied the association between this polymorphism and allograft failure in two independent cohorts of renal transplant recipients (RTRs) including a total of 603 patients. The functional effect of COX-2 gene promoter polymorphism was analyzed by measuring serum levels of PGE2. Median follow-up was 8.7 and 7.9 years for the first and second cohort, respectively. Analysis of 603 patients identified 20 CC (3.3%), 179 GC (29.7%) and 404 GG (67%) carriers. Patients with the GG genotype had significantly higher serum PGE2 concentrations than patients with the C allele. Carriers with a C allele have an independent increased risk of graft loss (hazard ratio (HR) 2.43 [95% CI 1.19-4.97], p = 0.015 for cohort 1; HR 1.72 [95% CI 0.99-3.77], p = 0.051 for cohort 2) compared to GG patients. COX-2 gene promoter polymorphism at position -765 (G-->C) is associated with a higher rate of graft loss in RTRs. Such findings may be used to influence immunosuppressive strategies and optimize patient management.

Hospital costs of renal transplant management.

Renal transplantation is considered to be a cost-effective therapy, but hospital medical costs are not accurately known. The aim of this work was to evaluate the costs of hospital stay for renal transplantation. This retrospective study included all patients who underwent renal transplantation between January 1, 2004, and December 31, 2005, in our University hospital. The incurred costs were determined using our center's analytical accounting (AA). The mean local cost was then compared with the median national cost of hospitalization for renal transplantation, based on a sample of participating centers contributing to the National Cost Scale (NCS) per homogenous diagnosis-related group (DRG). These mean costs were weighed against the financing obtained by national rates of the case-mix based payment system (termed T2A). Data were collected from 77 patients. Their mean length of stay was 19.4 days. AA determined the cost of management to be euro14,100 per patient. National economic approaches were significantly higher: euro16,389 for NCS and euro17,369 for national rates. Thus, the specific DRG rate (case mix index) of renal transplantation covers the expenses incurred by our center. These results are rather interesting; however, it is unlike those obtained for the management of other diseases such as acute myeloid leukemia, where T2A underestimates the actual cost by 2-4 times. Last, the hospital budget and T2A must be considered as a whole. The fact that DRGs with favorable and unfavorable pricing balance out should be taken into account.

Impact of malnutrition-inflammation on the association between homocysteine and mortality.

Whether high total serum homocysteine levels (tHcy) contribute to increase mortality or offer a survival advantage in chronic hemodialysis patients remains controversial. We conducted a prospective study to determine the impact of tHcy on survival in this population with special respect to chronic inflammation-malnutrition state (CIMS). In this prospective study, 459 hemodialysis patients from 10 dialysis centers located in two regions of France were included. A number of baseline parameters were measured including tHcy and markers of CIMS. Over a mean follow-up period of 54 months, 219 deaths (47.7%) occurred, of which 114 (52%) were of cardiovascular (CV) origin. tHcy of equal to or greater than 30 micromol/l was associated with a higher risk of all-cause mortality in patients without CIMS (hazard ratio (HR): 1.55 (confidence interval (CI): 1.12-4.72)), but not in overall dialysis population or those with CIMS. When only CV mortality was considered, tHcy of equal to or greater than 30 micromol/l was associated with a higher risk in patients without (CIMS HR: 1.91 (CI: 1.23-3.23)), but not in those with CIMS. Hyperhomocysteinemia is a strong risk factor for all-cause and CV mortality in hemodialysis patients who do not present CIMS. This association might be masked in patients with CIMS.

Intravenous apoptotic spleen cell infusion induces a TGF-beta-dependent regulatory T-cell expansion.

Apoptotic leukocytes are endowed with immunomodulatory properties that can be used to enhance hematopoietic engraftment and prevent graft-versus-host disease (GvHD). This apoptotic cell-induced tolerogenic effect is mediated by host macrophages and not recipient dendritic cells or donor phagocytes present in the bone marrow graft as evidenced by selective cell depletion and trafficking experiments. Furthermore, apoptotic cell infusion is associated with TGF-beta-dependent donor CD4+CD25+ T-cell expansion. Such cells have a regulatory phenotype (CD62L(high) and intracellular CTLA-4+), express high levels of forkhead-box transcription factor p3 (Foxp3) mRNA and exert ex vivo suppressive activity through a cell-to-cell contact mechanism. In vivo CD25 depletion after apoptotic cell infusion prevents the apoptotic cell-induced beneficial effects on engraftment and GvHD occurrence. This highlights the role of regulatory T cells in the tolerogenic effect of apoptotic cell infusion. This novel association between apoptosis and regulatory T-cell expansion may also contribute to preventing deleterious autoimmune responses during normal turnover.

One-year post-transplant weight gain is a risk factor for graft loss.

Metabolic syndrome (MS) and obesity participate in the pathogenesis of kidney disease. We explored the impact of MS and post-transplant weight gain on graft survival. Two hundred ninety-two renal transplant recipients (RTRs) were included in the study. Various parameters (e.g. anthropometric, biological) were measured at the time of transplantation as well as 1 year post-transplant. The proportion of patients with overweight or obesity significantly increased during the first year post-transplant (p = 0.04). Mean weight gain was 2.7 +/- 5.8 kg. Thirty patients (10.3%) lost their graft during follow-up. In multivariate analysis, patients with an increase in body mass index (BMI) of more than 5% at 1 year post-transplant had an increased risk of graft loss with (HR: 2.82 [95% CI: 1.11-7.44], p = 0.015) or without death censoring (HR: 2.31 [95% CI: 1.06-5.04], p = 0.035). Low creatinine clearance (HR: 4.72 [95% CI: 1.63-13.69], p = 0.004), high urinary protein excretion (HR: 3.21 [95% CI: 1.27-8.18], p = 0.014) and delayed graft function (DGF) (HR: 2.621 [95% CI: 1.07-6.39], p = 0.036) were also independent risk factors for graft loss. MS did not independently predict graft loss, partly due to significant interactions with low-grade inflammation. We conclude that post-transplant weight gain significantly reduces graft survival.

Cytomegalovirus-associated bleeding diathesis in renal transplant recipients.

Cytomegalovirus (CMV) infection is reported to be capable of modifying endothelial surface with subsequent increased risk of thromboembolic complications. Nevertheless, there are only sparse reports on its role in the development of bleeding diathesis. Here we report two renal transplant recipients who manifested severe coagulation disorders associated with acute CMV infection. Antiviral therapy was followed by consistent correction of coagulation abnormalities.

T-cell flow-cytometry crossmatch and long-term renal graft survival.

Flow cytometry crossmatch (FCXM) is a more sensitive technique than classical complement-dependent cytotoxicity (CDC) for the detection of donor-directed antibody before renal transplantation. Nevertheless, the role of FCXM in predicting long-term survival of kidney grafts is still unclear. The purpose of our study was to evaluate the impact of a positive T-cell FCXM (T-FCXM) on long-term kidney allografts outcome. Of the 184 consecutive kidney transplantations performed in our center between 1 January1991 and 15 November 1996 a FCXM, performed concurrently to the pre-transplant CDCXM, was available for 170 patients. The CDCXM was negative in all recipients. Among these recipients, 12 (7.1%) had a positive T-FCXM. These patients were not different from patients with a negative T-FCXM for donor and recipient age, sex, frequency of second transplantation, number of human leukocyte antigen matches or mismatches. Frequency of immunized patients was higher in kidney recipients with a positive FCXM (58.3% vs. 24.7%; p=0.02, chi-square test). Survival analysis revealed that kidney graft outcome was better in negative T-FCXM recipients (p=0.03), while patient survival was not statistically different. Our results suggest that a positive pre-transplant T-FCXM despite a negative CDCXM is associated with an impaired long-term graft survival in renal allotransplantation.

Cutaneous Alternaria infection in renal transplant recipients: a report of two cases with an unusual mode of transmission.

We report two cases of cutaneous alternariosis in renal transplant recipients. The diagnosis was made by mycologic and histologic examination. The patients were treated with itraconazole. In one patient who had undergone surgical resection of the cutaneous lesion along with antifungal treatment, the follow-up period was uneventful with no signs of recurrence. In the other patient, surgical excision of the lesion was not performed prior to antifungal therapy. The lesion disappeared following treatment but local recurrence was observed 1.5 years later with an unfavorable evolution despite administration of the second course of therapy. Resection of the lesion and prolongation of the treatment resulted in a satisfactory course with no signs of local recurrence over a follow-up period of 4.5 years. Interestingly, both of the patients had a previous history of a mild traumatic event with a stretcher in our outpatient clinic where the follow-up visits were made. A vast mycologic survey was then made in our department, which disclosed that some of the stretchers were contaminated by the fungi and could have potentially served as the reservoirs and vectors for the transmission of the fungus.

Hypertension in renal transplantation: donor and recipient risk factors.

AIMS: To determine the respective roles of donor and recipient factors in the subsequent development of hypertension after renal transplantation. PATIENTS AND METHODS: All the patients transplanted between January 1990 and December 1999 who still had a functioning graft 1 year post-transplant (n = 321) were retrospectively studied. Blood pressure was assessed at 1 year post-transplant. Hypertension was defined as a systolic BP > or equal 140 mmHg or diastolic BP > or equal 90 mmHg, or use of antihypertensive medication. Relevant donor and recipient characteristics were recorded. RESULTS: Two-hundred-and-sixty-three patients (82%) were hypertensive. In multivariate analysis, pretransplant hypertension (RR, 1.74, 95% CI, 1.07 to 2.87), anticalcineurin use (RR, 2.59, 95% CI, 1.13 to 5.92), urinary protein excretion (RR, 1.84, 95% CI, 1.06 to 3.18), BMI (RR, 1.08, 95% CI, 1.01 to 1.16), donor age (RR, 1.28,95% CI, 1.05 to 1.59, for each 10-year increase in donor age) and donor aortorenal atheroma (OR, 2.34; 95% CI, 1.24 to 4.46) were associated with hypertension. Among patients under calcineurin inhibitors, those receiving cyclosporine were more prone to have hypertension than those receiving tacrolimus (88.7% vs 78%; p = 0.04). CONCLUSION: Both recipient and donor factors contribute to hypertension in RTR.

Determinants of mean arterial pressure and pulse pressure in chronic haemodialysis patients.

Hypertension is highly prevalent in the dialysis population, and has been implicated in the pathogenesis of the observed excess of cardiovascular morbidity and mortality in these patients. Nevertheless, there are no reports on the clinical and biochemical determinants of both pulse pressure (PP) and mean arterial pressure (MAP) in dialysis populations. A total of 541 haemodialysed patients from 11 dialysis centres were included in the study. The demographic, clinical, and biological characteristics were recorded. Both pre- and post- dialytic blood pressures (systolic and diastolic) were measured. PP and MAP were calculated. Mean predialytic PP was 67 +/- 17 mm Hg and significantly decreased after dialysis (60 +/- 18 mm Hg; P < 0.0001). In multivariate analysis, a 10 mm Hg increase in PP was positively associated with age (RR, 2.01; 95% CI, 1.35-5.01, for a 10-year increase in age), diabetes mellitus (RR, 1.08; 95% CI, 1.04-1.14), interdialytic weight gain (IWG) (RR, 1.84; 95% CI, 1.07-3.18, for 1% increase in IWG), and current smoking (RR, 2.59; 95% CI, 1.13-5.92) and negatively with Hb concentration (RR, 0.92; 95% CI, 0.84-0.99, for a 1 g/100 ml in Hb). Mean predialytic MAP was 98 +/- 15 mm Hg and significantly decreased after dialysis (91 +/- 16 mm Hg; P < 0.0001). In multivariate analysis, a 10 mm Hg increase in MAP was positively associated with parathyroid hormone (PTH) (RR, 1.32; 95% CI, 1.15-1.6, for 50 ng/ml in PTH), erythropoietin (EPO) treatment (RR, 1.09; 95% CI, 1.03-1.16), and current smoking (RR, 1.87; 95% CI, 1.39-2.41). PP and MAP are associated with different clinical parameters. Most of these factors are potentially reversible. Smoking cessation, correction of anaemia and limitation of IWG should be important challenges for physicians in care of dialysis patients.

Flow-PRA evaluation for antibody screening in patients awaiting kidney transplantation.

Flow-PRA is a flow cytometric method for both anti-HLA class I and class II antibody (Ab) detection. We evaluated this technique for Ab screening in patients awaiting kidney transplantation. After having established a rigorous threshold for positivity, a three-dilution difference in sensitivity between Flow-PRA and complement-dependent cytotoxicity (CDC) persisted. The sensitivity of the method was satisfactory since all CDC-positive sera were also found to be positive with the Flow-PRA method. Discrimination between anti-HLA class I and class II Abs was excellent. Furthermore, all sera responsible for a positive flow cytometry crossmatch (FCXM) and a negative CDC-crossmatch (CDCXM) at the time of a putative transplant were found to be positive with Flow-PRA beads. The specificity was excellent for anti-class I Ab detection since no false positive serum was found. On the other hand, the specificity was lower for anti-class II detection, since 8.3% (2/24) false positive results were detected among all the negative sera tested. Overall, our results suggested that Flow-PRA should be of value for anti-HLA Ab screening prior to kidney transplantation.

Cyclosporine withdrawal in stable renal transplant recipients after azathioprine-mycophenolate mofetil conversion.

BACKGROUND: Cyclosporine A (CsA) nephrotoxicity is a nonimmunologic factor of chronic allograft dysfunction (CAD) in kidney transplant recipients. Mycophenolate mofetil (MMF) may allow CsA dosage reduction or even complete withdrawal in selected populations with CsA nephrotoxicity or CAD. The aim of the present study was to evaluate the efficacy and safety of CsA withdrawal after azathioprine (AZA)-MMF conversion in a population of stable renal transplant recipients. METHODS: Twenty-eight first cadaver kidney recipients were included. AZA was then discontinued, MMF was introduced and after 4 months CsA was completely withdrawn. All patients underwent inuline clearance measurement and renal biopsy at inclusion and at the end of the follow-up (40 wk). RESULTS: CsA was completely discontinued in 20 patients. No patient lost his graft during the study period, but 1 patient experienced a reversible acute rejection episode. Inuline clearance improved significantly in the whole series. At the end of follow-up, histological worsening was observed in 50% of patients without any specific risk factor. In these patients, inuline clearance did not improve. Systolic blood pressure, the need for anti-hypertensive drugs and HDL cholesterol improved. CONCLUSION: In stable kidney transplant recipients, CsA withdrawal after AZA replacement by MMF switch was safe with regard to acute rejection. It improved blood pressure and the lipid profile, but, in 50% of patients was associated with histologic deterioration.