High-dimensional mass cytometry identified circulating natural killer T-cell subsets associated with protection from cytomegalovirus infection in kidney transplant recipients.

Cytomegalovirus (CMV) infection is associated with poor kidney transplant outcomes. While innate and adaptive immune cells have been implicated in its prevention, an in-depth characterization of the in vivo kinetics of multiple cell subsets and their role in protecting against CMV infection has not been achieved. Here, we performed high-dimensional immune phenotyping by mass cytometry, and functional assays, on 112 serially collected samples from CMV seropositive kidney transplant recipients. Advanced unsupervised deep learning analysis was used to assess immune cell populations that significantly correlated with prevention against CMV infection and anti-viral immune function. Prior to infection, kidney transplant recipients who developed CMV infection showed significantly lower CMV-specific cell-mediated immune (CMI) frequencies than those that did not. A broad diversity of circulating cell subsets within innate and adaptive immune compartments were associated with CMV infection or protective CMV-specific CMI. While percentages of CMV (tetramer-stained)-specific T cells associated with high CMI responses and clinical protection, circulating CD3+CD8midCD56+ NK-T cells overall strongly associated with low CMI and subsequent infection. However, three NK-T cell subsets sharing the CD11b surface marker associated with CMV protection and correlated with strong anti-viral CMI frequencies in vitro. These data were validated in two external independent cohorts of kidney transplant recipients. Thus, we newly describe the kinetics of a novel NK-T cell subset that may have a protective role in post-transplantation CMV infection. Our findings pave the way to more mechanistic studies aimed at understanding the function of these cells in protection against CMV infection.

Expression of Rejection-Associated Transcripts in Early Protocol Renal Transplant Biopsies Is Associated with Tacrolimus Exposure and Graft Outcome.

Subclinical inflammation in protocol biopsies relates to tacrolimus exposure and human leukocyte antigen (HLA) matching. We aimed to characterize transcripts associated with rejection and tacrolimus exposure and the latter's association with transplant outcomes. We tested whether gene expression is associated with rejection using strictly normal protocol biopsies (n = 17) and biopsies with T cell-mediated rejection (TCMR) or antibody-mediated rejection (ABMR) according to Banff criteria (n = 12). Subsequently, we analyzed these transcripts in a set of 4-month protocol biopsies (n = 137) to assess their association with donor and recipient characteristics, the intensity of immunosuppression, and the graft outcome. Differential expression (false discovery rate (FDR) < 0.01, fold (change (FC) > 3) between normal and rejection biopsies yielded a set of 111 genes. In the protocol biopsy cohort (n = 137), 19 out of these 111 genes correlated with tacrolimus trough levels at the time of biopsy (TAC-C0), and unsupervised analysis split this cohort into two clusters. The two clusters differed in donor age and tacrolimus trough levels. Subclinical rejection, including borderline lesions, tended to occur in the same cluster. Logistic regression analysis indicated that TAC-C0 at the time of biopsy (OR: 0.83, 95%CI:0.72-0.06, p = 0.0117) was associated with cluster 2. In a follow-up averaging 70 ± 30 months, this patient group displayed a significant decline in renal function (p = 0.0135). The expression of rejection-associated transcripts in early protocol biopsies is associated with tacrolimus exposure and a faster decline in renal function.

mTOR inhibitors a potential predisposing factor for chronic hepatitis E: Results from the prospective collaborative CHES study (Chronic Hepatitis EScreening in patients with immune impairment and increased transaminases levels).

BACKGROUND: Chronic hepatitis E virus (HEV) in persons with immune impairment has a progressive course leading to a rapid progression to liver cirrhosis. However, prospective data on chronic HEV is scarce. The aim of this study was to determine the prevalence and risk factors for chronic HEV infection in subjects with immune dysfunction and elevated liver enzymes. PATIENTS AND METHODS: CHES is a multicenter prospective study that included adults with elevated transaminases values for at least 6 months and any of these conditions: transplant recipients, HIV infection, haemodialysis, liver cirrhosis, and immunosuppressant therapy. Anti-HEV IgG/IgM (Wantai ELISA) and HEV-RNA by an automated highly sensitive assay (Roche diagnostics) were performed in all subjects. In addition, all participants answered an epidemiological survey. RESULTS: Three hundred and eighty-one patients were included: 131 transplant recipients, 115 cirrhosis, 51 HIV-infected subjects, 87 on immunosuppressants, 4 hemodialysis. Overall, 210 subjects were on immunosuppressants. Anti-HEV IgG was found in 94 (25.6%) subjects with similar rates regardless of the cause for immune impairment. HEV-RNA was positive in 6 (1.6%), all of them transplant recipients, yielding a rate of chronic HEV of 5.8% among solid-organ recipients. In the transplant population, only therapy with mTOR inhibitors was independently associated with risk of chronic HEV, whereas also ALT values impacted in the general model. CONCLUSIONS: Despite previous abnormal transaminases values, chronic HEV was only observed among solid-organ recipients. In this population, the rate of chronic HEV was 5.8% and only therapy with mTOR inhibitors was independently associated with chronic hepatitis E.

Parathyroid hormone and phosphate homeostasis in patients with Bartter and Gitelman syndrome: an international cross-sectional study.

BACKGROUND: Small cohort studies have reported high parathyroid hormone (PTH) levels in patients with Bartter syndrome and lower serum phosphate levels have anecdotally been reported in patients with Gitelman syndrome. In this cross-sectional study, we assessed PTH and phosphate homeostasis in a large cohort of patients with salt-losing tubulopathies. METHODS: Clinical and laboratory data of 589 patients with Bartter and Gitelman syndrome were provided by members of the European Rare Kidney Diseases Reference Network (ERKNet) and the European Society for Paediatric Nephrology (ESPN). RESULTS: A total of 285 patients with Bartter syndrome and 304 patients with Gitelman syndrome were included for analysis. Patients with Bartter syndrome type I and II had the highest median PTH level (7.5 pmol/L) and 56% had hyperparathyroidism (PTH >7.0 pmol/L). Serum calcium was slightly lower in Bartter syndrome type I and II patients with hyperparathyroidism (2.42 versus 2.49 mmol/L; P = .038) compared to those with normal PTH levels and correlated inversely with PTH (rs -0.253; P = .009). Serum phosphate and urinary phosphate excretion did not correlate with PTH. Overall, 22% of patients had low serum phosphate levels (phosphate-standard deviation score < -2), with the highest prevalence in patients with Bartter syndrome type III (32%). Serum phosphate correlated with tubular maximum reabsorption of phosphate/glomerular filtration rate (TmP/GFR) (rs 0.699; P < .001), suggesting renal phosphate wasting. CONCLUSIONS: Hyperparathyroidism is frequent in patients with Bartter syndrome type I and II. Low serum phosphate is observed in a significant number of patients with Bartter and Gitelman syndrome and appears associated with renal phosphate wasting.

Bioavailability of once-daily tacrolimus formulations used in clinical practice in the management of De Novo kidney transplant recipients: the better study.

Multicenter, prospective, observational study to compare the relative bioavailability of once-daily tacrolimus formulations in de novo kidney transplant recipients. De novo kidney transplant recipients who started a tacrolimus-based regimen were included 14 days post-transplant and followed up for 6 months. Data from 218 participants were evaluated: 129 in the LCPT group (Envarsus) and 89 in the PR-Tac (Advagraf) group. Patients in the LCPT group exhibited higher relative bioavailability (Cmin /total daily dose [TDD]) vs. PR-Tac (61% increase; P < .001) with similar Cmin and 30% lower TDD levels (P < .0001). The incidence of treatment failure was 3.9% in the LCPT group and 9.0% in the PR-Tac group (P = .117). Study discontinuation rates were 6.2% in the LCPT group and 12.4% in the PR-Tac group (P = .113). Adverse events, renal function and other complications were comparable between groups. The median accumulated dose of tacrolimus in the LCPT group from day 14 to month 6 was 889 mg. Compared to PR-Tac, LCPT showed higher relative bioavailability, similar effectiveness at preventing allograft rejection, comparable effect on renal function, safety, adherence, treatment failure and premature discontinuation rates.

Corrigendum: Enteric Budesonide in Transplant and Native IgA Nephropathy: Real-World Clinical Practice.

[This corrects the article DOI: 10.3389/ti.2022.10693.].

Treatment of early borderline lesions in low immunological risk kidney transplant patients: a Spanish multicenter, randomized, controlled parallel-group study protocol: the TRAINING study.

BACKGROUND: Subclinical inflammation, including borderline lesions (BL), is very common (30-40%) after kidney transplantation (KT), even in low immunological risk patients, and can lead to interstitial fibrosis/tubular atrophy (IFTA) and worsening of renal function with graft loss. Few controlled studies have analyzed the therapeutic benefit of treating these BL on renal function and graft histology. Furthermore, these studies have only used bolus steroids, which may be insufficient to slow the progression of these lesions. Klotho, a transmembrane protein produced mainly in the kidney with antifibrotic properties, plays a crucial role in the senescence-inflammation binomial of kidney tissue. Systemic and local inflammation decrease renal tissue expression and soluble levels of α-klotho. It is therefore important to determine whether treatment of BL prevents a decrease in α-klotho levels, progression of IFTA, and loss of kidney function. METHODS: The TRAINING study will randomize 80 patients with low immunological risk who will receive their first KT. The aim of the study is to determine whether the treatment of early BL (3rd month post-KT) with polyclonal rabbit antithymocyte globulin (Grafalon®) (6 mg/kg/day) prevents or decreases the progression of IFTA and the worsening of graft function compared to conventional therapy after two years post-KT, as well as to analyze whether treatment of BL with Grafalon® can modify the expression and levels of klotho, as well as the pro-inflammatory cytokines that regulate its expression. DISCUSSION: This phase IV investigator-driven, randomized, placebo-controlled clinical trial will examine the efficacy and safety of Grafalon® treatment in low-immunological-risk KT patients with early BL. TRIAL REGISTRATION: clinicaltrials.gov : NCT04936282. Registered June 23, 2021, https://clinicaltrials.gov/ct2/show/NCT04936282?term=NCT04936282&draw=2&rank=1 . Protocol Version 2 of 21 January 2022. SPONSOR: Canary Isles Institute for Health Research Foundation, Canary Isles (FIISC). mgomez@fciisc.org .

A case series of confusional states and other neurotoxic effects caused by ertapenem.

Ten cases of ertapenem neurotoxicity, mainly confusional states, are described, some of them with fatal outcomes. The majority of patients (90%) had a creatinine clearance (CrCl) < 50 mL/min/1.73m2 at some point during treatment and hypoalbuminaemia was always present when ertapenem treatment was started. The pharmacokinetic and pharmacodynamic properties of this carbapenem could favour a different profile, and approved doses can be excessive in some patients with moderate renal failure (CrCl 31-59 mL/min/1.73 m2 ). It may be necessary to re-evaluate renal function during treatment and adjust doses or reconsider the adequacy of treatment based on clinical judgement, especially if relevant changes in the CrCl occur (i.e. a reduction to ≤30 mL/min/1.73 m2 ) or unexplained behavioural disorders are detected. The onset of the symptoms of ertapenem neurotoxicity can be insidious and go unnoticed, and so a knowledge and early suspicion of confusional states are important to improve the patient prognosis.

Secondary antibody deficiency is associated with development of infection in kidney transplantation: Results of a multicenter study.

BACKGROUND: We performed a multicenter study to assess the association between secondary antibody deficiency (immunoglobulin G [IgG] hypogammaglobulinemia combined with low levels of specific antibodies) and development of infection in kidney transplantation. METHODS: We prospectively analyzed 250 adult kidney recipients at four centers. The assessment points were before transplantation and 7 and 30 days after transplantation. The immune parameters were as follows: IgG, IgA, and IgM and complement factors C3 and C4 tested by nephelometry; specific IgG antibodies to cytomegalovirus (CMV) and IgG and IgG2 antibodies to pneumococcal polysaccharide (anti-PPS) determined using enzyme-linked immunosorbent assay. The clinical follow-up period lasted 6 months. The clinical outcomes were CMV disease and recurrent bacterial infections requiring antimicrobial therapy. STATISTICS: Multivariate logistic regression. RESULTS: At day 7, IgG hypogammaglobulinemia (IgG levels < 700 mg/dL) combined with low IgG anti-CMV antibody titers (defined as levels < 10 000 units) was present in 12% of kidney recipients. IgG hypogammaglobulinemia combined with low IgG anti-PPS antibody titers (defined as levels < 10 mg/dL) at 1 month after kidney transplantation were recorded in 16% of patients. At day 7 the combination of IgG hypogammaglobulinemia and low anti-CMV titers was independently associated with the development of CMV disease (odds ratio [OR], 6.95; 95% confidence interval [CI], 1.17-41.31; P = .033). At day 30 after transplantation, the combination of IgG < 700 mg/dL and IgG anti-PPS < 10 mg/dL, was independently associated with recurrent bacterial infection (OR, 5.942; 95% CI, 1.943-18.172; P = .002). CONCLUSION: In a prospective multicenter study, early immunologic monitoring of secondary antibody deficiency proved useful for the identification of kidney recipients who developed severe infection.

Clinical characteristics and risk factors for severe COVID-19 in hospitalized kidney transplant recipients: A multicentric cohort study.

Kidney transplant recipients might be at higher risk for severe coronavirus disease 2019 (COVID-19). However, risk factors for relevant outcomes remain uncertain in this population. This is a multicentric kidney transplant cohort including 104 hospitalized patients between March 4 and April 17, 2020. Risk factors for death and acute respiratory distress syndrome (ARDS) were investigated, and clinical and laboratory data were analyzed. The mean age was 60 years. Forty-seven patients (54.8%) developed ARDS. Obesity was associated to ARDS development (OR 2.63; P = .04). Significant age differences were not found among patients developing and not developing ARDS (61.3 vs 57.8 years, P = .16). Seventy-six (73%) patients were discharged, and 28 (27%) died. Death was more common among the elderly (55 and 70.8 years, P < .001) and those with preexisting pulmonary disease (OR 2.89, P = .009). At admission, higher baseline lactate dehydrogenase (257 vs 358 IU/mL, P = .001) or ARDS conferred higher risk of death (HR 2.09, P = .044). In our cohort, ARDS was equally present among young and old kidney recipients. However, the elderly might be at higher risk of death, along with those showing higher baseline LDH at admission.

Effectiveness and safety of the conversion to MeltDose® extended-release tacrolimus from other formulations of tacrolimus in stable kidney transplant patients: A retrospective study.

Tacrolimus is the cornerstone of immunosuppressive therapy after kidney transplantation. Its narrow therapeutic window mandates serum level strict monitoring and dose adjustments to ensure the optimal risk-benefit balance. This observational retrospective study analyzed the effectiveness and safety of conversion from twice-daily immediate-release tacrolimus (IR-Tac) or once-daily prolonged-release tacrolimus (PR-Tac) to the recent formulation once-daily MeltDose® extended-release tacrolimus (LCP-Tac) in 365 stable kidney transplant recipients. We compared kidney function three months before and three months after the conversion. Three months after conversion, the total daily dose was reduced ~35% (P < .0001), and improved bioavailability and stable serum LCP-Tac concentrations were observed. There was no increase in the number of patients requiring tacrolimus dose adjustments after conversion. Renal function was unaltered, and no cases of BPAR were reported. Reports of tremors, as collected in the clinical histories for each patient, decreased from pre-conversion (20.8%) to post-conversion (11.8%, P < .0001). LCP-Tac generated a cost reduction of 63% compared with PR-Tac. In conclusion, the conversion strategy to LCP-Tac from other tacrolimus formulations in stable kidney transplant patients showed safety and effectiveness in a real-world setting, confirming the data from RCTs. The specific pharmacokinetic properties of LCP-Tac could be potentially advantageous in patients with tacrolimus-related adverse events.

A Rejection Gene Expression Score in Indication and Surveillance Biopsies Is Associated with Graft Outcome.

Rejection-associated gene expression has been characterized in renal allograft biopsies for cause. The aim is to evaluate rejection gene expression in subclinical rejection and in biopsies with borderline changes or interstitial fibrosis and tubular atrophy (IFTA). We included 96 biopsies. Most differentially expressed genes between normal surveillance biopsies (n = 17) and clinical rejection (n = 12) were obtained. A rejection-associated gene (RAG) score was defined as its geometric mean. The following groups were considered: (a) subclinical rejection (REJ-S, n = 6); (b) borderline changes in biopsies for cause (BL-C, n = 13); (c) borderline changes in surveillance biopsies (BL-S, n = 12); (d) IFTA in biopsies for cause (IFTA-C, n = 20); and (e) IFTA in surveillance biopsies (IFTA-S, n = 16). The outcome variable was death-censored graft loss or glomerular filtration rate decline ≥ 30 % at 2 years. A RAG score containing 109 genes derived from normal and clinical rejection (area under the curve, AUC = 1) was employed to classify the study groups. A positive RAG score was observed in 83% REJ-S, 38% BL-C, 17% BL-S, 25% IFTA-C, and 5% IFTA-S. A positive RAG score was an independent predictor of graft outcome from histological diagnosis (hazard ratio: 3.5 and 95% confidence interval: 1.1-10.9; p = 0.031). A positive RAG score predicts graft outcome in surveillance and for cause biopsies with a less severe phenotype than clinical rejection.

Phaeohyphomycosis caused by Medicopsis romeroi in solid organ transplant recipients: Report of two cases and comprehensive review of the literature.

Medicopsis romeroi is a melanized coelomycetous fungus, mainly found in tropical and subtropical regions and an uncommon cause of infection in solid organ transplant (SOT) recipients. We describe two cases of SOT recipients diagnosed with phaeohyphomycosis due to M romeroi and provide a comprehensive literature review. These infections should be considered in patients native to tropical countries with a localized skin and soft tissue infection. Sequencing is needed for accurate identification of uncommon melanized fungi. Surgical treatment is recommended to cure the infection and co-adjunctive oral antifungals should be considered.

Treatment of chronic antibody mediated rejection with intravenous immunoglobulins and rituximab: A multicenter, prospective, randomized, double-blind clinical trial.

There are no approved treatments for chronic antibody mediated rejection (ABMR). We conducted a multicenter, prospective, randomized, placebo-controlled, double-blind clinical trial to evaluate efficacy and safety of intravenous immunoglobulins (IVIG) combined with rituximab (RTX) (EudraCT 2010-023746-67). Patients with transplant glomerulopathy and anti-HLA donor-specific antibodies (DSA) were eligible. Patients with estimated glomerular filtration rate (eGFR) <20 mL/min per 1.73m2 and/or severe interstitial fibrosis/tubular atrophy were excluded. Patients were randomized to receive IVIG (4 doses of 0.5 g/kg) and RTX (375 mg/m2 ) or a wrapped isovolumetric saline infusion. Primary efficacy variable was the decline of eGFR at one year. Secondary efficacy variables included evolution of proteinuria, renal lesions, and DSA at 1 year. The planned sample size was 25 patients per group. During 2012-2015, 25 patients were randomized (13 to the treatment and 12 to the placebo group). The planned patient enrollment was not achieved because of budgetary constraints and slow patient recruitment. There were no differences between the treatment and placebo groups in eGFR decline (-4.2 ± 14.4 vs. -6.6 ± 12.0 mL/min per 1.73 m2 , P-value = .475), increase of proteinuria (+0.9 ± 2.1 vs. +0.9 ± 2.1 g/day, P-value = .378), Banff scores at one year and MFI of the immunodominant DSA. Safety was similar between groups. These data suggest that the combination of IVIG and RTX is not useful in patients displaying transplant glomerulopathy and DSA.

Tacrolimus and mycophenolate regimen and subclinical tubulo-interstitial inflammation in low immunological risk renal transplants.

The aim was to evaluate the relationship between maintenance immunosuppression, subclinical tubulo-interstitial inflammation and interstitial fibrosis/tubular atrophy (IF/TA) in surveillance biopsies performed in low immunological risk renal transplants at two transplant centers. The Barcelona cohort consisted of 109 early and 66 late biopsies in patients receiving high tacrolimus (TAC-C0 target at 1-year 6-10 ng/ml) and reduced MMF dose (500 mg bid at 1-year). The Oslo cohort consisted of 262 early and 237 late biopsies performed in patients treated with low TAC-C0 (target 3-7 ng/ml) and standard MMF dose (750 mg bid). Subclinical inflammation, adjusted for confounders, was associated with low TAC-C0 in the early (OR: 0.75, 95% CI: 0.61-0.92; P = 0.006) and late biopsies (OR: 0.69, 95% CI: 0.50-0.95; P = 0.023) from Barcelona. In the Oslo cohort, it was associated with low MMF in early biopsies (OR: 0.90, 95% CI: 0.83-0.98; P = 0.0101) and with low TAC-C0 in late biopsies (OR: 0.77, 95% CI: 0.61-0.97; P = 0.0286). MMF dose was significantly reduced in Oslo between early and late biopsies. IF/TA was not associated with TAC-C0 or MMF dose in the multivariate analysis. Our data suggest that in TAC- and MMF-based regimens, TAC-C0 levels are associated with subclinical inflammation in patients receiving reduced MMF dose.

The reproducibility and predictive value on outcome of renal biopsies from expanded criteria donors.

Reproducibility and predictive value on outcome are the main criteria to evaluate the utility of histological scores. Here we analyze the reproducibility of donor biopsy assessment by different on-call pathologists and the retrospective evaluation by a single renal pathologist blinded to clinical outcomes. We also evaluate the predictive value on graft outcome of both evaluations. A biopsy was performed in donors with any of the following: age≥55 years, hypertension, diabetes, creatinine>1.5 mg/dl, or stroke. Glomerulosclerosis, interstitial fibrosis, tubular atrophy, intimal thickening, and arteriolar hyalinosis evaluated according to the Banff criteria were added to obtain a chronic score. Biopsies were classified as mild (≥3), intermediate (4-5), or advanced (6-7) damage, and unacceptable (≥8) for transplantation of 127 kidneys biopsied. Weighted κ value between both readings was 0.41 (95% CI: 0.28-0.54). Evaluation of biopsies by the renal pathologist was significantly and independently associated with estimated 12-month glomerular filtration rate and a significant composite outcome variable, including death-censored graft survival and time to reach an estimated glomerular filtration rate<30 ml/min per 1.73 m2. Thus, there was no association between readings of on-call pathologists and outcome. The lack of association between histological scores obtained by the on-call pathologists and graft outcome suggests that a specific training on renal pathology is recommended to optimize the use of kidneys retrieved from expanded criteria donors.

Comparing transplant glomerulopathy in the absence of C4d deposition and donor-specific antibodies to chronic antibody-mediated rejection.

INTRODUCTION: Transplant glomerulopathy (TG) is the characteristic lesion of chronic antibody-mediated rejection (AMR). However, in some patients presents with no circulating HLA antibodies or C4d positivity. AIM: Patients with TG accomplishing criteria for chronic AMR were compared to patients with isolated TG. PATIENTS AND METHODS: We reviewed late (>6 months) graft biopsies performed between 2007 and 2010 (n = 75). Biopsies with C4d-negative TG and no circulating donor-specific antibody were called isolated TG (n = 12), and chronic AMR was defined according to Banff consensus (n = 17). HLA antibodies were evaluated by Luminex technology. Immunohistochemistry was performed to quantify graft infiltrating cells. RESULTS: Patients with isolated TG were older (52 ± 14 vs. 35 ± 14; p = 0.0048), received grafts from older donors (54 ± 16 vs. 41 ± 18; p = 0.0554), and displayed a lower inflammation in the glomerular (g-score: 0.5 ± 0.5 vs. 1.0 ± 0.9; p = 0.0865; CD3 positive cells/glomeruli: 1.5 ± 2.9 vs. 4.4 ± 4.1; p = 0.0147), interstitial (i-score: 1.2 ± 0.9 vs. 1.9 ± 1.0; p = 0.0685; CD45 positive cells/hpf: 18 ± 11 vs. 57 ± 68; p = 0.0132), and peritubular capillary (ptc-score 0.2 ± 0.6 vs. 1.1 ± 0.9; p = 0.0089; CD45 positive cells/hpf: 3.7 ± 3.1 vs. 10.1 ± 7.4; p = 0.0290) compartments. Fifteen grafts were lost and graft survival was significantly lower in patients with chronic AMR (p = 0.0122). CONCLUSION: Isolated TG is associated with less severe allograft inflammation and with a better outcome than chronic AMR.

Long-term outcome of antineutrophil cytoplasmic antibody-associated small vessel vasculitis after renal transplantation.

The survival after renal transplantation of patients with antineutrophil cytoplasmic antibody (ANCA)-associated to systemic vasculitis is as good as in other diseases, although most of the reports are based on small numbers of patients. Furthermore, it is not known whether comorbidities (cardiovascular [CV] disease and cancer) are more frequent than in general population. We report our experience and the analysis of the published data on this topic. The outcome after transplantation in 49 patients with ANCA-associated small vessel vasculitis was compared with a control group. The relapse rate of vasculitis was 0.01 per patient per year. Comparison with the control patients revealed no difference in long-term outcome, CV mortality or incidence of malignancies. In the published literature, patients with ANCA at transplantation and with Wegener's granulomatosis are at greater risk of relapse. Taking our own results together with the review of the literature, we conclude that patient and graft survival rates compare favorably with those in control group that the recurrence rate is very low and that there is no increase in the incidence of cancer or in CV mortality. Patients with ANCA at transplantation and with Wegener's granulomatosis have a higher relapse rate.

Tocilizumab in the treatment of active chronic humoral rejection resistant to standard therapy.

INTRODUCTION: There is no consensus on the most appropriate treatment for chronic active antibody-mediated rejection (cAMR). Recent studies suggest that treatment with tocilizumab (TCZ) may stabilize graft function, decrease the intensity of donor-specific HLA antibodies (DSAs) and reduce inflammation of microcirculation. PATIENTS AND METHODS: Observational study with renal allograft recipients diagnosed with cAMR (n = 5) who had not submitted a response to traditional treatment based on the combination of plasma replacements, immunoglobulins, and rituximab. Patients were told to be treated with TCZ as compassionate use in six doses per month (8 mg/kg/month). Renal function, proteinuria, and the intensity of DSAs were monitored during follow-up. RESULTS: Five patients, average age 60 ± 13 years, three male and two retrasplants (cPRA average 55%) with preformed DSAs. Treatment with TCZ was initiated within 47 ± 52 days of biopsy. In two cases treatment was discontinued after the first dose, by severe bicitopenia with cytomegalovirus viremia and by graft failure, respectively. In the three patients who completed treatment, no stability of renal function (serum creatinine from 1.73 ± 0.70 to 2.04 ± 0.52 mg/dL, e-FGR 4 6 ± 15 to 36 ± 16 mL/min), showed increased proteinuria (3.2 ± 4.0 to 6.9 ± 11.0 g/g) and the intensity of DSAs maintain stable. No changes were observed in the degree of inflammation of microcirculation (g+pt 4.2 ± 0.8 vs. 4.3 ± 1.0) or in the degree of transplant glomerulopathy (cg 1.2 ± 0.4 vs. 1.8 ± 1.0). CONCLUSIONS: TCZ therapy does not appear to be effective in modifying the natural history of chronic active antibody-mediated rejection, does not improve the degree of inflammation of microcirculation and does not reduces the intensity of DSAs.