Genome-Wide Association Study of Acute Renal Graft Rejection.

Acute renal rejection is a major risk factor for chronic allograft dysfunction and long-term graft loss. We performed a genome-wide association study to detect loci associated with biopsy-proven acute T cell-mediated rejection occurring in the first year after renal transplantation. In a discovery cohort of 4127 European renal allograft recipients transplanted in eight European centers, we used a DNA pooling approach to compare 275 cases and 503 controls. In an independent replication cohort of 2765 patients transplanted in two European countries, we identified 313 cases and 531 controls, in whom we genotyped individually the most significant single nucleotide polymorphisms (SNPs) from the discovery cohort. In the discovery cohort, we found five candidate loci tagged by a number of contiguous SNPs (more than five) that was never reached in iterative in silico permutations of our experimental data. In the replication cohort, two loci remained significantly associated with acute rejection in both univariate and multivariate analysis. One locus encompasses PTPRO, coding for a receptor-type tyrosine kinase essential for B cell receptor signaling. The other locus involves ciliary gene CCDC67, in line with the emerging concept of a shared building design between the immune synapse and the primary cilium.

Common hepatic artery as inflow in kidney transplantation.

Kidney transplantation originating from the hepatic artery has not previously been reported. Herein, we report a third kidney transplantation with the common hepatic artery as inflow. A 62-year-old male with chronic renal failure due to polycystic kidney disease was proposed to a third kidney transplantation. CT-scan showed diffuse calcification of the aorto-iliac axis and the splenic artery. The common hepatic artery was the only artery suitable for anastomosis and as such was chosen as the inflow for retransplantation. The operation was performed through a right subcostal laparotomy. A saphenous bypass was interposed between the common hepatic artery and the graft, then the renal vein was anastomosed to the suprarenal inferior vena cava. Duration of warm ischemia was 27 min. Postoperative course was complicated with delayed graft function of 17 days and pulmonary infection. Patient was discharged at day 30. With a follow-up of 40 months, serum creatinine level and eGFR are, respectively, 191 µmol/L and 32 mL/min. Hepato-renal bypass technique can be used in kidney retransplantation when patient anatomy is not compatible with other classical options.

KDIGO Guidelines and Kidney Transplantation: Is the Cystatin-C Based Recommendation Relevant?

The KDIGO guidelines propose a new approach to diagnose chronic kidney disease (CKD) based on estimated glomerular filtration rate (GFR). In patients with a GFR value comprised between 45 and 59 mL/min/1.73 m(2) as estimated by the CKD-EPI creatinine equation (eGFRcreat ), it is suggested to confirm the diagnosis with a second estimation using the CKD-EPI cystatin C-based equations (eGFRcys /eGFRcreat-cys) . We sought to determine whether this new diagnostic strategy might extend to kidney transplant recipients (KTR) and help to identify those with decreased GFR. In 670 KTR for whom a measured GFR was available, we simulated the detection of CKD using the two-steps approach recommended by the guidelines in comparison to the conventional approach relying on creatinine equation. One hundred forty-five patients with no albuminuria had eGFRcreat between 45 and 59 mL/min/1.73 m(2) . Among them, 23% had inulin clearance over 60 mL/min/1.73 m(2) and were thus incorrectly classified as CKD patients. When applying the Kidney Disease: Improving Global Outcomes (KDIGO) strategy, 138 patients were confirmed as having a GFR below 60 mL/min with eGFRcreat-cys . However, 21% of them were misclassified in reference to measured GFR. Our data do no not support the use of cystatin C as a confirmatory test of stage 3 A CKD in KTR.

Rate of renal graft function decline after one year is a strong predictor of all-cause mortality.

The slope of GFR associates with an increased risk for death in patients with native CKD but whether a similar association exists in kidney transplantation is not known. We studied an inception cohort of 488 kidney transplant recipients (mean follow-up of 12 ± 4 years) for whom GFR was longitudinally measured by inulin clearance (mGFR) at 1 year and then every 5 years. Association of mGFR at 1 year posttransplant and GFR slope after the first year with all-cause mortality was studied with a Cox regression model and a Fine and Gray competing risk model. While in Crude analysis, the mGFR value at 1 year posttransplant and the rate of mGFR decline were both associated with a higher risk of all-cause mortality, only the slope of mGFR remained a significant and strong predictor of death in multivariate analysis. Factors independently associated with a more rapid mGFR decline were feminine gender, higher HLA mismatch, retransplantation, longer duration of transplantation, CMV infection during the first year and higher rate of proteinuria. Our data suggest that the rate of renal graft function decline after 1 year is a strong predictor of all-cause mortality in kidney transplantation.

Differential effect of cyclosporine and mycophenolic acid on the human regulatory T cells and TH-17 cells balance.

BACKGROUND: Beyond the usual TH1/TH2 polarization, a reciprocal pathway between FoxP3+ regulatory T cells (Tregs) and interleukin (IL)-17-secreting effector T cells (TH-17) has recently been identified. We have investigated the effects of two immunosuppressive drugs, cyclosporine (CsA) and mycophenolic acid (MPA) on the development of Treg/TH-17 cell responses. METHODS: We compared the influence of CsA and MPA on the transcription levels of FOXP3 (Treg marker) and IL17 (TH-17 marker) in activated human peripheral blood mononuclear cells (PBMC). RESULTS: After 48 hours of activation, IL17 transcription was rapidly induced, remaining stable over 96 hours, whereas only a transient increase in FOXP3 was noted, suggesting that the Treg/TH-17 cell balance was tipped toward TH-17 during PBMC activation. The addition of either CsA or MPA did not affect the level of transcription of FOXP3. MPA but not CsA was found to significantly inhibit IL17 expression by activated PBMC. This effect of MPA seemed to result from its capacity to hamper (1) the production of IL1beta by monocytes and (2) the expression of TIM-1 by CD4+ T cells, two key signals involved in human TH-17 differentiation. CONCLUSION: Through a preferential inhibition of IL17, MPA might favorably influence the Treg/TH- 17 balance. Our results suggest that the immunosuppressive drugs used in the clinic may differentially influence lymphocyte polarization, including the newly identified TH-17 pathway.

Significant risk factors for occurrence of cancer after renal transplantation: a single center cohort study of 1265 cases.

Occurrence of cancer after renal transplantation remains a major problem, and the second cause of death. We performed a retrospective analysis of first cancer, first skin cancer, and first organ cancer (including posttransplant lymphoproliferative disease [PTLD]) among 1265 cases from 1979 to 2006. The occurrence of cancer was clearly a time-dependent event justifiying the use of Kaplan-Meier survival and Cox regression methods. The 10-year cumulative incidences of first cancer, first skin cancer, and first organ cancer were 24.6%, 14.5%, and 14.5%, respectively. Recipient age was a major, independent risk factor for the 3 endpoints with a 6% increased relative risk for each year increment (P < .0001). Female gender was also a major, independent risk factor, but only for skin cancer (P = .0002). We could not demonstrate any difference between the immunosuppressive drugs used for induction or maintenance therapy, especially between antithymocyte globulin (ATG) vs anti-CD25, cyclosporine vs tacrolimus, and azathioprine vs mycophenolate mofetil. Large cohorts are needed with strict stratifications for recipient age and gender to detect any difference, if any, among the drugs.

Anti-factor Xa activity of enoxaparin administered at prophylactic dosage to patients over 75 years old.

AIMS: Major bleeding complications with low-molecular-weight heparin (LMWH) treatment have been reported both in clinical studies and during postmarketing surveillance. Monitoring of antifactor Xa (anti-Xa) activities is therefore recommended in special populations often predisposed to renal impairment. The PROPHRE.75 study was conducted to estimate the distribution parameters of anti-Xa activity in the elderly. METHODS: PROPHRE.75 was a prospective study of a cohort of consecutive patients aged >75 years and treated with 4000 IU of enoxaparin once daily for venous thromboembolism prophylaxis. Dosing history and measurements of anti-Xa activity in sparse samples were recorded throughout treatment. The covariates included weight, gender, age, renal function, medical history and concomitant medication. Population parameters and interindividual variability were estimated using NONMEM V software. RESULTS: Anti-Xa activity was studied in 189 patients (mean age 82 +/- 5 years, 22% weighing <50 kg, 50% presenting renal impairment according to the Cockcroft and Gault formula). A first-order input two-compartment model best fitted the data. Clearance was significantly related to body weight and creatinine clearance based on the simplified Modification of Diet in Renal Disease formula, central volume being related to body weight. According to individual Bayesian estimations, 4% of patients presented with a peak anti-Xa activity >1.0 IU ml(-1), but this group did not include the sole patient experiencing a major bleed (0.53%). CONCLUSIONS: Systematic monitoring of anti-Xa activity in elderly patients treated with enoxaparin at prophylactic doses does not seem to be necessary to prevent the occurrence of major bleeding.

TNFA2 and d2 alleles of the tumor necrosis factor alpha gene polymorphism are associated with onset/occurrence of idiopathic membranous nephropathy.

Idiopathic membranous nephropathy (IMN) has a strong association with the major histocompatibility complex HLA B8DR3(17)DQ2 haplotype. The tumor necrosis factor (TNF)A gene is located within the major histocompatibility complex region on chromosome 6. We have studied the influence of two functional polymorphisms; the -308 (promoter region) and the TNFd microsatellites on initiation and/or progression of IMN. This was a case-control study comparing data from 100 Caucasians patients (67 male subjects; 67%) with IMN to 232 Caucasians local controls (171 male subjects; 74%). We have analyzed genotypes and alleles distributions and the role of these polymorphisms in disease progression towards end-stage renal failure or patient death. For -308 TNFA polymorphism, distribution of genotypes was significantly different between IMN and controls (chi(2)=16.25; P=0.0003): the A2 allele frequency was 28.0% in IMN vs 15.3% in controls (chi(2)=14.57; P=0.0001). For TNFd polymorphism, alleles distribution (from d1 to d7) was also significantly different between IMN and controls (chi(2)=56.74; P<0.0001) with both diminished d3 allele frequency (chi(2)=27.30; P<0.0001; Pc=0.001) and increased d2 allele frequency (chi(2)=29.95; P<0.0001; Pc=0.001) in IMN. We could not isolate any significant and independent influence of these different genotypes on IMN disease progression. The TNFA2 and TNFd2 alleles were strongly associated with occurrence/initiation of IMN and should be considered as susceptibility genes for this disease.

Sentinel lymph node detection in primary melanoma with preoperative dynamic lymphoscintigraphy and intraoperative gamma probe guidance.

BACKGROUND: This study assessed the value of the radioisotopic method used alone, and factors influencing relapse rates, for sentinel lymph node (SLN) mapping in primary melanoma. METHODS: One hundred and thirty-three patients with a diagnosis of melanoma (thickness greater than 0.75 mm) underwent gamma probe-directed lymphatic mapping in a prospective single-centre study. RESULTS: Mean Breslow thickness was 3 mm. At least one SLN was identified in 132 patients (mean 1.8 nodes per patient); the success rate was 99.2 per cent. Twenty-two patients (16.7 per cent) had a metastasis within the SLN. The mean tumour thickness in patients with a metastatic SLN was 4.4 mm compared with 2.7 mm for patients with a negative SLN (P < 0.001). The median time to recurrence was 20.4 months in SLN-negative patients compared with 8.5 months in those with SLN metastasis (P < 0.001). Ten (9.1 per cent) of the 110 SLN-negative patients developed recurrence. Three patients relapsed in the previously mapped lymphatic basin after a median follow-up of 27.1 months. CONCLUSION: This study confirmed the reliability and accuracy of SLN mapping using a radioisotope technique, and also the importance of the SLN as a predictive factor for survival. There was a low risk of locoregional recurrence when the SLN was not involved.

Induction versus noninduction in renal transplant recipients with tacrolimus-based immunosuppression.

BACKGROUND: The aim of this study was to compare the efficacy and safety of induction treatment with antithymocyte globulins (ATG) followed by tacrolimus therapy with immediate tacrolimus therapy in renal transplant recipients. METHODS: This 12-month, open, prospective study was conducted in 15 centers in France and 1 center in Belgium; 309 patients were randomized to receive either induction therapy with ATG (n=151) followed by initiation of tacrolimus on day 9 or immediate tacrolimus-based triple therapy (n=158). In both study arms, the initial daily tacrolimus dose was 0.2 mg/kg. Steroid boluses were given in the first 2 days and tapered thereafter from 20 mg/day to 5 mg/day. Azathioprine was administered at 1-2 mg/kg per day. RESULTS: At month 12, biopsy-confirmed acute rejections were reported for 15.2% (induction) and 30.4% (noninduction) of patients (P=0.001). The incidence of steroid-sensitive acute rejections was 7.9% (induction) and 22.2% (noninduction)(P=0.001). Steroid-resistant acute rejections were reported for 8.6% (induction) and 8.9% (noninduction) of patients. A total of nine patients died. Patient survival and graft survival at month 12 was similar in both treatment groups (97.4% vs. 96.8% and 92.1% vs. 91.1%, respectively). Statistically significant differences in the incidence of adverse events were found for cytomegalovirus (CMV) infection (induction, 32.5% vs. noninduction, 19.0%, P=0.009), leukopenia (37.3% vs. 9.5%, P<0.001), fever (25.2% vs. 10.1%, P=0.001), herpes simplex (17.9% vs. 5.7%, P=0.001), and thrombocytopenia (11.3% vs. 3.2%, P=0.007). In the induction group, serum sickness was observed in 10.6% of patients. The incidence of new onset diabetes mellitus was 3.4% (induction) and 4.5% (noninduction). CONCLUSION: Low incidences of acute rejection were found in both treatment arms. Induction treatment with ATG has the advantage of a lower incidence of acute rejection, but it significantly increases adverse events, particularly CMV infection.

Excessive body weight as a new independent risk factor for clinical and pathological progression in primary IgA nephritis.

Experimental evidence suggests a role for obesity in the formation and progression of some glomerular lesions, but data for human glomerulonephritis are lacking. In a cohort of 162 incident patients with biopsy-proven immunoglobulin A (IgA) nephropathy, we assessed whether the presence of an elevated body mass index (BMI >/= 25 kg/m(2)) at the time of the first renal biopsy (RB1) correlated with clinical data at RB1 (24-hour proteinuria, arterial hypertension, and renal function), pathological data (global optical score [GOS] with detailed pathological indices), and clinical progression to both arterial hypertension and chronic renal failure (CRF). In both univariate and multivariate analyses, the presence of an elevated BMI at RB1 was significantly associated with the severity of pathological renal lesions (GOS and vascular, tubular, and interstitial indices). Hypertension-free survival was significantly less in overweight patients (P: < 0.0001) compared with those with normal weight. In a Cox regression analysis for hypertension-free survival including 24-hour proteinuria greater than 1 g, GOS, and metabolic parameters, only elevated BMI and GOS were independent factors for the development of arterial hypertension. CRF-free survival was also significantly less in patients with an excessive BMI. In a multivariate Cox regression analysis for CRF-free survival, hypertension, GOS, and BMI at RB1 were independent risk factors for CRF. In IgA nephropathy, excessive body weight and/or BMI are underestimated predictive factors for the development of arterial hypertension and, ultimately, CRF.

A randomized prospective study comparing low-dose OKT3 to low-dose ATG for the treatment of acute steroid-resistant rejection episodes in kidney transplant recipients.

Acute steroid-resistant rejection episodes in kidney allograft recipients require treatment with antilymphocyte antibodies. Monoclonal anti-CD3 and polyclonal antilymphocyte antibodies have been widely used but seldom compared. Recent data have suggested that these antibodies could be used at reduced doses without jeopardizing their efficacy. In this study, we randomized renal transplant recipients who encountered a first acute steroid-resistant rejection episode to low-dose ATG or low-dose OKT3 treatment. Sixty patients were enrolled in the study. They received prophylactic immunosuppression with cyclosporin, azathioprine, and prednisolone. Treatment of biopsy-proven rejection consisted of a 10-day course of either ATG (n = 31) or OKT3 (n = 29). The total ATG dose was 484 +/- 110 mg, i.e., 0.75 mg/kg per day. The total OKT3 dose was 32 +/- 4 mg, i.e., 0.05 mg/kg per day. We compared reversion of rejection, side effects, immunodepression, and graft function. Reversion of rejection was similar in the two groups, although we noted a trend in favor of ATG. Results were 3% vs 10% early graft failures, 13% vs 23% overall graft failures, 28% vs 38% 3-month actuarial incidence of rebound rejection, and 89% vs 81% 1-year graft survival rate in the ATG and OKT3 groups, respectively. Tolerance was worse in the OKT3 group due to the first-dose syndrome. Infections and cancers occurred with the same frequency. ATG resulted in a deeper and longer decrease in peripheral lymphocyte subsets. Graft function was similar in the two groups. We conclude that low-dose ATG and low-dose OKT3 are equally effective in reversing steroid-resistant acute rejection. Tolerance was better with ATG, which also gave a more potent and longlasting immunodepression. The use of reduced doses of ATG and OKT3 did not appear to lessen their efficacy.

Advantage of antithymocyte globulin induction in sensitized kidney recipients: a randomized prospective study comparing induction with and without antithymocyte globulin.

BACKGROUND: Sensitized kidney allograft recipients require special management to improve their outcome. One strategy is heavy immunosuppression with antilymphocyte antibodies. Controversy continues about the actual advantage of induction protocols whilst infections and cancers are a constant risk. In addition, little is known about how to handle sensitized patients with low levels of sensitization. METHODS: In this study, we randomized sensitized renal transplant recipients, who received prophylactic treatment with or without antithymocyte globulin (ATG), in addition to a standard triple regimen consisting of cyclosporin, steroids and azathioprine at ATG discontinuation. The induction treatment consisted of a low-dose ATG course over 10 days. Randomization was stratified on the maximum PRA, according to the five following classes: 5% < PRA < or = 20%, 20% < PRA < or = 40%, 40% < PRA < or = 60%, 60% < PRA < or = 80% and 80% < PRA < or = 100%. RESULTS: Eighty nine patients were enrolled: 47 patients received ATG and 42 did not. ATG induction lowered the incidence of biopsy-proven acute rejection episodes from 64 to 38%, increased 1 year graft survival from 76 to 89% and was associated with a higher 1 year inulin clearance (37+/-15 vs 49+/-18 ml/min). ATG-associated side effects were restricted to leucopenia and thrombocytopenia, whereas bacterial and viral infections, gammopathies and cancers did not occur more frequently. ATG induction benefited all sensitized patients, and not only the hypersensitized patients. CONCLUSIONS: We conclude that ATG induction is beneficial for all sensitized patients, regardless of their level of sensitization, with regard to acute rejection episodes, graft survival and graft function. Low-dose ATG is sufficient and prevents additional complications.