Cytomegalovirus DNAemia Requiring (Val)Ganciclovir Treatment for More Than 8 Weeks Is a Key Factor in the Development of Antiviral Drug Resistance.

Background: Prolonged (val)ganciclovir [(V)GCV] exposure for ≥6 weeks is a known predisposing factor for cytomegalovirus (CMV) drug resistance. However, the selection of this threshold was based on limited data. In this study, we sought to reappraise the risk factors for the development of (V)GCV resistance through a specific focus on kidney transplant recipients (KTRs). Methods: This single-center retrospective study included 313 consecutive KTRs treated for a first CMV episode. Adjusted Cox multivariate regression analysis was used for identifying independent risk factors. Results: Antiviral drug resistance was identified in 20 (6%) KTRs. A cumulative (V)GCV exposure for more than 6 weeks (regardless of the viral load) was not associated with antiviral drug resistance (hazard ratio [HR] = 2.45, 95% confidence interval [CI] = 0.33-18.30, P = .38). In contrast, persistent CMV DNAemia requiring (V)GCV treatment for more than 8 weeks was the main independent risk factor for antiviral drug resistance (HR = 11.68, 95% CI = 2.62-52.01, P = .001). The (V)GCV treatment for more than 8 weeks was given to 9% and 18% of patients who had persistent or recurrent CMV DNAemia, respectively. These scenarios were associated with the occurrence of drug resistance in 39% and 12% of cases, respectively. Conclusions: Cumulative (V)GCV exposure ≥6 weeks regardless of the viral load is not associated with antiviral drug resistance. In contrast, prolonged exposure to (V)GCV during CMV replication (with a cutoff ³8 weeks) seems to be a key factor.

Is recipient's body mass index a determinant of short term complications in early renal transplantation?

OBJECTIVES: Obesity prevalence has increased over the past 20 years in the general population and among kidney transplant recipients. General surgical belief is that obesity increases surgical difficulty. The aim of this study was to assess the impact of Body Mass Index (BMI) on perioperative complications. METHODS: All kidney transplantations performed in adults in our centre from 2006 to 2011 were analysed. Data on patients' characteristics, surgical protocol, intra and postoperative complications and renal function were collected. Patients were divided into 4 groups as follows: underweight (BMI<18.5kg/m2), normal weight (18.5kg/m2≤BMI<25kg/m2), overweight (25kg/m2≤BMI<30kg/m2) and obese (BMI≥30kg/m2). We also studied the impact of BMI on complications using it as a continuous variable to identify potential threshold values. RESULTS: Among 694 patients included, 52% had normal BMI, 7%, 31% and 9% were underweight, overweight and obese, respectively. In multivariate analysis, overweight was significantly associated with longer operative time compared to normal-weight patients (estimated mean difference of 10,4min, 95% confidence interval (CI) [4.0; 16.9]) and obesity was associated with an increased risk of wound dehiscence (odds ratio 3.1, 95%CI [1.3; 7.3] compared with normal-weight patients). Considering BMI as a continuous variable, the risk of parietal dehiscence significantly increased beyond a BMI of 26kg/m2, intraoperative blood loss and the risk of ureteral stenosis beyond 32kg/m2 and the risk of abdominal wall hematoma beyond a BMI of 34kg/m2. CONCLUSIONS: We found BMI thresholds above which intraoperative blood loss and the risk of parietal dehiscence, ureteral stenosis, and parietal hematoma significantly increased. LEVEL OF EVIDENCE: 3.

Prevalence, distribution and amplitude of the complement interference phenomenon in single antigen flow beads assays.

HLA antibody detection with single antigen flow beads (SAFB) assays is impaired by complement interference whose frequency, predictability and distribution among HLA antigens have not been analyzed in large cohorts. We compared in two patients' cohorts the routine follow-up SAFB profiles obtained in class I (n = 129) and class II (n = 85) with and without ethylenediaminetetraacetic acid (EDTA)-treatment. The presence of complement interference was defined according to the reproducibility of the SAFB assays evaluated with our class I and II routine positive control sera. Interference occurred in 29.5% and 45.9% of patients in class I and II, respectively. In the untreated condition, at serum level, neither the number of positive beads, the highest bead mean fluorescence intensity (MFI) nor MFI at bead level, satisfactorily predicted interference. HLA-C were the least affected among class I beads. HLA-DQ beads were the most affected in class II. At least one antibody specificity was falsely negative without EDTA for about 3% of sera in class I and 9% in class II. EDTA-treatment did not significantly modify the low-MFI strengths (500-3000 range). This study emphasizes the high frequency of complement interference and the importance and advantages of systematically pretreating sera with EDTA before performing SAFB assays.

Intravenous Immunoglobulins in the Prevention of Rejection of a Second or Third Kidney Graft.

BACKGROUND: Intravenous immunoglobulin (IVIg) reduces acute rejection episodes in kidney transplantation, but adverse events (AEs) are common. The aim of this study was to assess whether human IVIg enhances immunosuppressive effects without increasing AEs in the prevention of acute kidney graft rejection. METHODS: Patients receiving a second or third kidney graft were treated with standard immunosuppressant therapy with (n = 18) or without (n = 10) IVIg. The primary efficacy endpoint was biopsy-proven acute rejection (BPAR) rate at 3 months, and secondary endpoints included acute rejection rate at 12 months, intensity of rejection, and patient survival. RESULTS: Patients in the experimental arm received 3 infusions of IVIg. The BPAR rate decreased with IVIg versus standard immunosuppression alone over 12 months of follow-up. Experimental versus control rates of survival without BPAR were 94% versus 63% and 82% versus 63% at 3 and 12 months. The intensity of the acute rejection episodes (BANFF 97 grade) was similar between groups. One patient from each group died during the 12-month follow-up period. Treatment-emergent AEs were reported in 100% and 94.4% of the control and experimental arms. Most AEs were considered unrelated or unlikely to be related to treatment. CONCLUSIONS: This study supports the efficacy and safety of IVIg in highly sensitized transplant patients for improving transplant rates and reducing graft rejection episodes.

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.

Easier Control of Late-Onset Cytomegalovirus Disease Following Universal Prophylaxis Through an Early Antiviral Immune Response in Donor-Positive, Recipient-Negative Kidney Transplants.

Universal prophylaxis for cytomegalovirus (CMV) prevention is viable but, compared with a preemptive strategy, leads to higher incidence of late-onset disease (LOD) associated with poor patient and graft survival. The purpose of this study was to compare LOD with early onset disease (EOD), with a focus on the highest risk kidney transplant recipients (KTRs): CMV seronegative recipients transplanted from seropositive donors (D+R-). Since CMV control depends on both antiviral treatment and specific immune response, we also compared Vδ2-negative (Vδ2(neg) ) γδ T cell expansion involved in CMV infection resolution. EOD was defined as occurring <3 mo and LOD as occurring >3 mo after transplantation. Depending on the period, universal prophylaxis or preemptive treatment was used. Overall, 168 D+R- KTRs were included between 2003 and 2011. LOD was associated with a lower peak DNAemia (p = 0.04), fewer recurrences (odds ratio 0.16; 95% confidence interval 0.05-0.55; p = 0.01) and shorter anti-CMV curative treatment (40 vs. 60 days, p < 0.0001). As a corollary, we found that Vδ2(neg) γδ T cell expansion was faster in LOD than in EOD (31 vs. 168 days after the beginning of CMV disease, p < 0.0001). In D+R- KTRs, universal prophylaxis is associated with more LOD, which had better infection management and a faster immune response. These results support the use of universal prophylaxis over a preemptive strategy and reappraise outcomes of LOD.

Two-year post-transplantation cytomegalovirus DNAemia in asymptomatic kidney transplant recipients: incidence, risk factors, and outcome.

BACKGROUND: The incidence and the impact of asymptomatic cytomegalovirus (CMV) DNAemia occurring after the first year post transplantation is unknown. METHODS: In this retrospective cross-sectional study, we analyzed the incidence, risk factors, and impact of 2-year post-transplantation asymptomatic CMV DNAemia (2YCD) on graft function. We included 892 consecutive asymptomatic kidney transplant recipients transplanted for at least 2 years and all were monitored using whole blood CMV quantitative nucleic acid amplification testing (CMV-QNAT). RESULTS: Twenty-eight patients displayed 2YCD (3.1%). Using multivariate analysis in 578 patients, we found that female gender (odds ratio [OR] = 2.57, P = 0.02), a past history of CMV drug-resistance mutation (OR = 8.73, P = 0.005), and corticosteroid use (OR = 2.37, P = 0.03) were independently associated with an increased risk of 2YCD. 2YCD was associated with an increased incidence of subsequent CMV disease over the year following its diagnosis (7% vs. 0.6%, P = 0.02). Patients with 2YCD also exhibited a declining estimated glomerular filtration rate more frequently (77%) than patients with a negative CMV-QNAT (56%, P = 0.02). CONCLUSION: 2YCD appears to be a rare entity, which appears to be associated with chronic graft dysfunction.

Embolization of renal arteries before transplantation in patients with polycystic kidney disease: a single institution long-term experience.

PURPOSE: We aimed to retrospectively assess the long-term safety and efficacy of embolization of renal arteries (ERA) in patients with polycystic kidney disease (PKD) before renal transplantation. MATERIAL AND METHODS: Between January 2008 and November 2013, 82 ERA procedures were performed on 76 kidneys in 73 patients (mean age 53 years, range: 34-72). All patients had terminal-stage PKD and were under dialysis and on the renal transplant waiting list with a temporary contraindication due to excessive renal volume. RESULTS: ERA was considered successful in 89.5% (68/76) of embolized kidneys, meaning that the temporary contraindication for transplantation could be withdrawn for 65 patients (on average 5.6 months, range: 2.8-24.3, after ERA). Mean volume reduction was 40 (range: 2-69) at 3 months and 59% (35-86) thereafter (both p < 0.001). Post-embolization syndrome occurred after 15 of 82 procedures (18.3%). The severe complication rate was 4.9%. Forty-three (67.7%) transplantations were successfully conducted after ERA, with a mean follow-up of 26.2 months (range: 1.8-59.5), and the estimated 5-year graft survival rate was 95.3% [95% CI: 82.7-98.8]. CONCLUSIONS: ERA is a safe and effective alternative to nephrectomy before renal transplantation in patients with PKD. KEY POINTS: • Embolization of non-functioning polycystic kidneys allowed transplantation in 89.5% of cases. • Technical failure rate was 7.9% after embolization, irrespective of the technique used. • Post-embolization syndrome occurred after 18.3% of the procedures. • A low rate of severe complications (4.9%) was observed after renal embolization.

Fibrosis progression according to epithelial-mesenchymal transition profile: a randomized trial of everolimus versus CsA.

Markers of epithelial-mesenchymal transition (EMT) may identify patients at high risk of graft fibrogenesis who could benefit from early calcineurin inhibitor (CNI) withdrawal. In a randomized, open-label, 12-month trial, de novo kidney transplant patients received cyclosporine, enteric-coated mycophenolate sodium (EC-MPS) and steroids to month 3. Patients were stratified as EMT+ or EMT- based on month 3 biopsy, then randomized to start everolimus with half-dose EC-MPS (720 mg/day) and cyclosporine withdrawal (CNI-free) or continue cyclosporine with standard EC-MPS (CNI). The primary endpoint was progression of graft fibrosis (interstitial fibrosis/tubular atrophy [IF/TA] grade increase ≥1 between months 3-12) in EMT+ patients. 194 patients were randomized (96 CNI-free, 98 CNI); 153 (69 CNI-free, 84 CNI) were included in histological analyses. Fibrosis progression occurred in 46.2% (12/26) CNI-free EMT+ patients versus 51.6% (16/31) CNI EMT+ patients (p = 0.68). Biopsy-proven acute rejection (BPAR, including subclinical events) occurred in 25.0% and 5.1% of CNI-free and CNI patients, respectively (p < 0.001). In conclusion, early CNI withdrawal with everolimus initiation does not prevent interstitial fibrosis. Using this CNI-free protocol, in which everolimus exposure was relatively low and administered with half-dose EC-MPS, CNI-free patients were overwhelmingly under-immunosuppressed and experienced an increased risk of BPAR.

Daclizumab Versus Rabbit Antithymocyte Globulin in High-Risk Renal Transplants: Five-Year Follow-up of a Randomized Study.

We previously reported a randomized controlled trial in which 227 de novo deceased-donor kidney transplant recipients were randomized to rabbit antithymocyte (rATG, Thymoglobulin) or daclizumab if they were considered to be at high immunological risk, defined as high panel reactive antibodies (PRA), loss of a first kidney graft through rejection within 2 years of transplantation, or third or fourth transplantation. Patients treated with rATG had lower incidences of biopsy-proven acute rejection (BPAR) and steroid-resistant rejection at 1 year. Patients were followed to 5 years posttransplant in an observational study; findings are described here. Treatment with rATG was associated with a lower rate of BPAR at 5 years (14.2% vs. 26.0% with daclizumab; p = 0.035). Only one rATG-treated patient (0.9%) and one daclizumab-treated patient (1.0%) developed BPAR after 1 year. Five-year graft and patient survival rates, and renal function, were similar between the two groups. Overall graft survival at 5 years was significantly higher in patients without BPAR (81.0% vs. 54.8%; p < 0.001). In conclusion, rATG is superior to daclizumab for the prevention of BPAR among high-immunological-risk renal transplant recipients. Overall graft survival at 5 years was approximately 70% with either induction therapy, which compares favorably to low-risk cohorts.

Three-year outcomes in kidney transplant patients randomized to steroid-free immunosuppression or steroid withdrawal, with enteric-coated mycophenolate sodium and cyclosporine: the infinity study.

In a six-month, multicenter, open-label trial, de novo kidney transplant recipients at low immunological risk were randomized to steroid avoidance or steroid withdrawal with IL-2 receptor antibody (IL-2RA) induction, enteric-coated mycophenolate sodium (EC-MPS: 2160 mg/day to week 6, 1440 mg/day thereafter), and cyclosporine. Results from a 30-month observational follow-up study are presented. Of 166 patients who completed the core study on treatment, 131 entered the follow-up study (70 steroid avoidance, 61 steroid withdrawal). The primary efficacy endpoint of treatment failure (clinical biopsy-proven acute rejection (BPAR) graft loss, death, or loss to follow-up) occurred in 21.4% (95% CI 11.8-31.0%) of steroid avoidance patients and 16.4% (95% CI 7.1-25.7%) of steroid withdrawal patients by month 36 (P = 0.46). BPAR had occurred in 20.0% and 11.5%, respectively (P = 0.19). The incidence of adverse events with a suspected relation to steroids during months 6-36 was 22.9% versus 37.1% (P = 0.062). By month 36, 32.4% and 51.7% of patients in the steroid avoidance and steroid withdrawal groups, respectively, were receiving oral steroids. In conclusion, IL-2RA induction with early intensified EC-MPS dosing and CNI therapy in de novo kidney transplant patients at low immunological risk may achieve similar three-year efficacy regardless of whether oral steroids are withheld for at least three months.

Kidney intragraft donor-specific antibodies as determinant of antibody-mediated lesions and poor graft outcome.

Allograft pathology, antibody-tissue interaction as demonstrated by C4d deposition and serological evidence of donor-specific antibodies (DSA) are the cardinal diagnostic features of antibody-mediated lesions (AML) in kidney transplantation. However, discrepancy between histological and serological findings is common, and more reliable diagnostic tools are called for. Here, we asked whether the in situ detection of DSA could serve as marker for AML. To that end, we applied the anti-HLA single antigen flow bead assay to eluates from 51 needle core graft biopsies performed for cause. Intragraft antibody profiles were correlated to serum DSA (sDSA), histological data and transplant outcome. The prevalence and the mean number of intragraft DSA (gDSA) were lower than that of sDSA (15/51 gDSA+ vs. 37/51 sDSA+ patients; 1.64 gDSA vs. 2.24 sDSA per patient). DSA were detected in all anti-HLA antibody-positive biopsies (15/15). The presence of gDSA was significantly associated with (1) microcirculation lesions taken individually (g, cg) and analyzed in functional clusters (ptc + g + cg > 0, cg + mm > 0), (2) C4d positivity and (3) a worse short-term transplant outcome (p = 0.05). These associations were not found for patients presenting only sDSA. Taken together, these results indicate that gDSA is a severity marker of antibody-mediated pathogenic process.

Hepatitis E virus infection as a new probable cause of de novo membranous nephropathy after kidney transplantation.

Hepatitis E virus (HEV) has been identified as a cause of chronic viral hepatitis in immunocompromised patients. Some glomerular diseases were found to be associated with this infection. We report the first case, to our knowledge, of a kidney transplant recipient who developed an HEV infection and de novo membranous nephropathy (MN) concomitantly. The patient displayed a hepatic cytolysis first and a nephrotic syndrome occurred 3 months later. HEV infection was diagnosed upon positive polymerase chain reaction on plasma and stool samples, and renal allograft biopsy revealed de novo MN. Typical causes of MN were definitively excluded. A 3-month course of ribavirin monotherapy allowed the patient to mount a sustained viral response that was rapidly followed by complete remission of the nephrotic syndrome. The chronology of the onset and remission of both diseases is highly suggestive of a causal relationship between hepatitis E and MN.

Preemptive therapy versus valgancyclovir prophylaxis in cytomegalovirus-positive kidney transplant recipients receiving antithymocyte globulin induction.

International consensus guidelines on the management of cytomegalovirus (CMV) infections in kidney transplantation recommend the use of universal prophylaxis over preemptive therapy for the highest risk kidney transplant recipients (KTR), namely donor+/recipient - CMV serostatus. However, no universal recommendations have been made for R+ KTR undergoing antithymocyte globulin (ATG) induction. In this retrospective study, we compared 1-year outcomes among 24 R+ KTR who received 3 months of valgancyclovir prophylaxis with 72 R+ KTR who were subjected to a preemptive strategy. All subjects received ATG induction. The incidence of CMV infection was significantly higher among the preemptive subjects versus the prophylaxis group (78% versus 38%, respectively; P = .0003), whereas the incidence of CMV disease was low and did not differ significantly between the cohorts (8% versus 7% respectively, P = .8). Late-onset CMV infections were only observed in the prophylaxis group (25% versus 0%, P = .0001). Finally, the rate of opportunistic infections, acute rejection episodes, and graft/patient survivals at 1 year were also similar between the two groups. In light of this study, preemptive therapy and universal prophylaxis were almost equally effective to prevent CMV infection among R+ KTR receiving ATG induction.

High incidence of anticytomegalovirus drug resistance among D+R- kidney transplant recipients receiving preemptive therapy.

Anti-cytomegalovirus (CMV) prophylaxis is recommended in D+R- kidney transplant recipients (KTR), but is associated with a theoretical increased risk of developing anti-CMV drug resistance. This hypothesis was retested in this study by comparing 32 D+R- KTR who received 3 months prophylaxis (valganciclovir) with 80 D+R- KTR who received preemptive treatment. The incidence of CMV infections was higher in the preemptive group than in the prophylactic group (60% vs. 34%, respectively; p = 0.02). Treatment failure (i.e. a positive DNAemia 8 weeks after the initiation of anti-CMV treatment) was more frequent in the preemptive group (31% vs. 3% in the prophylactic group; p = 0.001). Similarly, anti-CMV drug resistance (UL97 or UL54 mutations) was also more frequent in the preemptive group (16% vs. 3% in the prophylactic group; p = 0.05). Antiviral treatment failures were associated with anti-CMV drug resistance (p = 0.0001). Patients with a CMV load over 5.25 log(10) copies/mL displayed the highest risk of developing anti-CMV drug resistance (OR = 16.91, p = 0.0008). Finally, the 1-year estimated glomerular filtration rate was reduced in patients with anti-CMV drug resistance (p = 0.02). In summary, preemptive therapy in D+R- KTR with high CMV loads and antiviral treatment failure was associated with a high incidence of anti-CMV drug resistance.