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.

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.

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.

Prevalence and clinical significance of antiphospholipid antibodies in renal transplant recipients.

BACKGROUND: The prevalence and clinical significance of antiphospholipid antibodies (APAs) have not been extensively studied in non-systemic lupus erythematosus (non-SLE) renal transplant recipients. METHODS: To further define the prevalence and clinical significance of APAs in non-SLE renal transplant recipients and the appearance of dialysis-related APAs after renal transplantation, we conducted a retrospective study on 178 renal transplant recipients. Documentation of anticardiolipin antibodies (ACAs) and lupus anticoagulant in non-SLE renal transplant recipients, retrospective documentation of ACAs on pretransplant frozen plasma and standardized collection of demographic characteristics and posttransplant history of thrombosis were assessed. RESULTS: Fifty of 178 patients (28.1%) had APAs. Transplant duration was shorter and hemodialysis duration was longer in patients with APAs. A posttransplant history of both venous and arterial thrombosis was more frequent in patients with posttransplant APAs (respectively, 18% vs. 6.2% [P<0.001] and 8% vs. 2.3% [P<0.001]). Pretransplant sera were available from 55 patients. Most of patients with posttransplant ACAs had ACAs in the pretransplant period (85%). Pretransplant ACAs were associated with a posttransplant history of venous thrombosis (P<0.001). CONCLUSIONS: Our study demonstrates a high prevalence of APAs in non-SLE renal transplant recipients. Most of them have been acquired in the pretransplant period. Both pretransplant ACAs and posttransplant APAs are associated with posttransplant episodes of thrombosis. Further studies are required to determine the interest of prophylactic measures.

Mycophenolate mofetil-induced villous atrophy.

Mycophenolate mofetil (MMF) is a new immunosuppressant developed for the prevention and treatment of acute renal rejection after transplantation. Diarrhea is the most frequent side effect observed during treatment with MMF. Its pathogenic mechanisms remain unknown. We describe a case of severe diarrhea due to villous atrophy in a renal transplant recipient during treatment with MMF. The patient was free of symptoms before MMF. Villous atrophy disappeared a few months after MMF withdrawal.

CD4 lymphocytopenia as a risk factor for skin cancers in renal transplant recipients.

BACKGROUND: Renal transplant recipients are at increased risk of developing skin cancer. It remains difficult to establish the actual influence of overimmunosuppression in the development of skin cancers. We investigated whether lymphocyte subset count may predict the risk of developing skin cancer in long-term renal transplant recipients. METHODS: One hundred fifty long-term renal transplant recipients were followed for a mean period of 26 months. Each patient was examined at least annually by a dermatologist. Lymphocyte subsets were measured annually. RESULTS: Fifteen patients exhibited skin cancers. Patients with and without skin cancer did not differ in age, gender, transplant duration, hemodialysis duration before transplantation, immunosuppressive regimen, and serum creatinine concentration. CD4 cell counts were significantly lower in patients with skin cancers (330+/-179/mm3 vs. 503+/-338/mm3; P<0.01), whereas total lymphocyte and CD8 and CD19 cell counts were similar between the two groups. CONCLUSIONS: CD4 cell depletion is associated with skin cancer in long-term renal transplant recipients.

Recurrence of hemolytic-uremic syndrome in renal transplant recipients: a meta-analysis.

BACKGROUND: Recurrence of hemolytic-uremic syndrome (HUS) in the allograft is associated with a very poor renal prognosis. Meta-analysis of previous trials may allow us to better estimate its real frequency, to identify risk factors for recurrence, and to predict the outcome of patients with definite recurrence. METHODS: An exhaustive search was conducted of HUS recurrence in renal transplantation from January 1977 to June 1997 using MEDLINE. RESULTS: Ten studies comprising 159 grafts in 127 patients were identified. The rate of recurrence was 27.8%. One-year graft survival was 76.6% in patients without recurrence and 33.3% in patients with recurrence (P<0.001). Older age at onset of HUS (16.96+/-7.6 years vs. 9.95+/-6.55 years; P<0.02), shorter mean interval between HUS and transplantation (2.51+/-2.7 years vs. 6.03+/-6.4 years; P<0.01), shorter mean interval between HUS and end-stage renal disease (0.79+/-0.39 years vs. 2.78+/-2.47 years; P<0.01), living-related donors, and the use of calcineurin inhibitors were associated with recurrence. CONCLUSION: Risk factors for HUS recurrence in renal transplantation could be identified through this meta-analysis.

Mycophenolate mofetil in renal transplant recipients with cyclosporine-associated nephrotoxicity: a preliminary report.

BACKGROUND: There is a great concern over cyclosporine (CsA) nephrotoxicity in renal transplant recipients, and the effects of conversion from CsA to azathioprine (AZA) remain controversial. Large studies have demonstrated that mycophenolate mofetil (MMF), the morpholinoethyl ester of mycophenolic acid, is superior to AZA as a posttransplant immunosuppressant. METHODS: Six patients with isolated biopsy-proven CsA nephrotoxicity were converted from CsA-AZA to MMF. RESULTS: Mean follow-up was 12+/-2 months. No patient experienced acute rejection. The mean serum creatinine concentration decreased from 225+/-58 to 159+/-66 micromol/L (P<0.0005). Hyperlipidemia and blood pressure improved after CsA withdrawal. CONCLUSION: In a selected transplant population with biopsy-proven CsA nephrotoxicity, CsA withdrawal with a concomitant switch from AZA to MMF seems to be safe and allows a significant improvement of renal function.

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.

Miller-Fisher syndrome and pontine abnormalities on MRI: a case report.

The authors report a patient with Miller-Fisher syndrome in whom MRI of the brain stem showed increased signal density on T2 sequence anterior to the fourth ventricle, on the right and the left. The authors discuss the relation between these MRI abnormalities and some clinical features of the syndrome. The authors believe that the cardinal features of Miller-Fisher syndrome are due to peripheral nervous system dysfunction, but that this does not preclude a possible central nervous system involvement.

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.

Chronic congestive heart failure associated with bilateral renal artery stenosis.

The sudden onset of pulmonary edema in patients with renal artery stenosis is an increasingly recognized entity. Some data also support an association between renal artery stenosis and chronic cardiac failure. We report a 60-year-old man with chronic renal failure who had most normal arterial blood pressure despite highly severe chronic congestive heart failure. Renovascular disease was suspected and an arteriography revealed very tight bilateral artery stenosis. Removal of stenosis led to both renal and cardiac functions improvement.

Hyperhomocyst(e)inemia in renal transplant recipients with and without cyclosporine.

Studies have demonstrated that hyperhomocyst(e)inemia is present in renal transplant recipients and is correlated with cardiovascular disease. It is still unclear whether hyperhomocyst(e)inemia observed in renal transplant recipients solely depends on the moderate reduction of renal function in these patients or if additional mechanisms are operative in this patient category. A recent study suggested that cyclosporine (CsA) increased plasma homocyst(e)ine concentration in interfering with folate-assisted remethylation of homocysteine. To confirm this hypothesis, we studied plasma homocyst(e)ine folic acid and cobalamin concentrations in 122 renal transplant recipients (104 on CsA and 18 not receiving CsA). After adjusting for age, gender, transplant duration and serum creatinine concentration, patients with and without CsA had similar plasma homocyst(e)ine concentrations (17.9 +/- 6.1 mumol/l in CsA(+)patients vs 17.1 +/- 5.6 mumol/l in CsA(-)patients; p = 0.3). Moreover, we found a significant inverse relationship between plasma homocyst(e)ine and folic acid concentrations in both CsA(+) (r = 0.218; p < 0.01) and CsA(-) (r = -0.678; p < 0.05) patients. Patients with a past history of cardiovascular incidents had higher plasma homocyst(e)ine concentrations than those without cardiovascular antecedent (20.5 +/- 7.8 mumol/l vs. 18.01 +/- 9.9 mumol/l; p < 0.05. To conclude: 1, We did not find any influence of CsA on plasma homocyst(e)ine concentrations. 2. We demonstrated that as in other patient category, plasma folic acid and homocyst(e)ine concentrations are significantly correlated in CsA(+) patients. 3. Homocyst(e)ine-lowering therapy would be prescribed in CsA(+) patients to allow correction of hyperhomocyst(e)inemia.

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.

[Systemic scleroderma and cancers: 21 cases and review of the literature]. / Sclérodermie systémique et cancers: 21 observations et revue de la littérature.

Twenty one cases of the association systemic scleroderma and cancer are reported. Neoplasic localisations were the following: pulmonary five cases; breast two cases; esophageal cancer one case; stomach one case; colon one case; uterus four cases; ovarian cancer one case; prostatic cancer one case; renal cancer one case; malignant hemopathies six cases. In the literature, more than three hundred cases of such an association have been reported since 1886, essentially lung cancers (more than 100). Recent epidemiological studies allow to conclude to a higher frequency of lung and breast cancers. We suggest that systemic scleroderma patients should be examined attentively and carefully for these risks.

[Treatment of refractory congestive cardiac insufficiency by continuous peritoneal dialysis. Long-term course]. / Traitement de l'insuffisance cardiaque congestive au stade terminal par dialyse péritonéale continue. Evolution à long terme.

Continuous and progressive fluid removal was performed by continuous peritoneal dialysis in 19 patients (14 men, 5 women, mean age 60.7 years) suffering from refractory congestive heart failure. All patients were in NYHA class IV and had a life-threatening fluid overload. Twelve had normal renal function or functional renal failure, and 7 had organic renal failure. The continuous peritoneal dialysis technique with a high K+ concentration in the dialysate did not raise any particular problem. Mean survival of the whole group was 7.1 months. This figure rose to 16 months (rang 2-51 months) in the patients who survived at the end of the first month. Sixteen out of 19 patients eventually died, most of them suddenly and probably of ventricular arrhythmia. Nine patients were discharged on continuous ambulatory peritoneal dialysis and remained on it for 2 to 48 months. Drug therapy could be reduced in all cases. Dialysis was discontinued in 5 patients without organic renal failure who thereafter survived for a mean period of 5 months. Functional improvement and duration of survival were uncorrelated with heart disease, fluid overload, initial renal function or initial left ventricular ejection fraction. A cardiothoracic ratio greater than 0.70 and the need for mechanical ventilation seemed to be of poor prognosis. Such results justify the pursuit of this study before defining selection criteria.

[Intra-alveolar hemorrhages in systemic diseases]. / Hémorragies intra-alvéolaires au cours des maladies systémiques.

Alveolar haemorrhage is usually, but often belatedly, diagnosed in patients presenting with haemoptysis and radiological alveolar syndrome. Its occurrence frequently marks a turn for the worst in the course of a systemic disease, since its prognosis is sombre. Recognizing its early signs might enable treatment to be instituted and prognosis to be improved. In the presence of typical alveolar haemorrhage, if high-dose corticosteroid therapy and immunosuppressants do not improve the symptoms within 48 hours plasmapheresis must be started. Alveolar haemorrhage must be considered a vital emergency justifying this therapeutic approach without waiting for the hypothetical diagnosis of the underlying systemic disease.

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.