Specificities of Meningitis and Meningo-Encephalitis After Kidney Transplantation: A French Retrospective Cohort Study.

Kidney transplant recipients develop atypical infections in their epidemiology, presentation and outcome. Among these, meningitis and meningoencephalitis require urgent and adapted anti-infectious therapy, but published data is scarce in KTRs. The aim of this study was to describe their epidemiology, presentation and outcome, in order to improve their diagnostic and management. We performed a retrospective, multicentric cohort study in 15 French hospitals that included all 199 cases of M/ME in KTRs between 2007 and 2018 (0.9 case per 1,000 KTRs annually). Epidemiology was different from that in the general population: 20% were due to Cryptococcus neoformans, 13.5% to varicella-zoster virus, 5.5% to Mycobacterium tuberculosis, and 4.5% to Enterobacteria (half of which produced extended spectrum beta-lactamases), and 5% were Post Transplant Lymphoproliferative Disorders. Microorganisms causing M/ME in the general population were infrequent (2%, for Streptococcus pneumoniae) or absent (Neisseria meningitidis). M/ME caused by Enterobacteria, Staphylococci or filamentous fungi were associated with high and early mortality (50%-70% at 1 year). Graft survival was not associated with the etiology of M/ME, nor was impacted by immunosuppression reduction. Based on these results, we suggest international studies to adapt guidelines in order to improve the diagnosis and the probabilistic treatment of M/ME in SOTRs.

Renal and overall outcomes of double-positive (ANCA and anti-GBM antibodies) patients compared to ANCA-associated vasculitis patients with severe renal involvement: A multicenter retrospective study with systematic renal pathology analysis.

OBJECTIVE: Double-positive patients (DPPs), combining serum and/or histological findings for glomerular basement membrane (GBM) disease and anti-neutrophil cytoplasmic antibodies (ANCAs), are rare and poorly described. This study aimed to compare characteristics between DPPs and ANCA-associated vasculitis (AAV) patients with severe renal involvement. METHOD: This retrospective multicentre study compared 33 DPPs and 45 AAV patients with severe renal involvement (serum creatinine > 300 µmol/L), all with biopsy-proven nephropathy. RESULTS: All DPPs (including 18% exhibiting negative serum anti-GBM antibodies) presented severe acute kidney failure with histological GBM involvement. Compared to AAV patients, they had higher serum creatinine (719 vs 501 µmol/L; p = 0.006) and a higher proportion of patients requiring initial renal replacement therapy (82% vs 36%; p < 0.001). Berden classification differed significantly (p = 0.003), with more crescentic glomerulonephritis and fewer sclerotic lesions in DPPs. One-year renal survival was significantly lower in DPPs than in AAV patients (27% vs 64%; p < 0.0002). With comparable proportions of ANCA subtypes (two-thirds with anti-myeloperoxidase autoantibodies), numbers of extrarenal manifestations (mostly pulmonary in two-thirds), remission-inducing immunosuppressants, and median follow-ups (3 years) between groups, relapse rates were similar: 9.1% of DPPs and 10% of AAV patients. CONCLUSION: Although DPPs have features of both kinds of vasculitis, the anti-GBM component is the dominant phenotype, with more severe renal presentation and prognosis compared to AAV patients with severe renal failure. Simultaneous testing of both antibodies and systematically performed renal biopsy should be recommended in all rapidly progressing glomerulonephritis patients to recognize this difficult-to-treat, rare disease.

Trajectory of extracellular fluid volume over time and subsequent risks of end-stage kidney disease and mortality in chronic kidney disease: a prospective cohort study.

BACKGROUND: Extracellular fluid volume (ECF) is independently associated with chronic kidney disease (CKD) progression and mortality in patients with CKD, but the prognostic value of the trajectory of ECF over time beyond that of baseline value is unknown. OBJECTIVES: To characterize ECF trajectory and evaluate its association with the risks of end-stage kidney disease (ESKD) and mortality. METHODS: From the prospective tricentric NephroTest cohort, we included 1588 patients with baseline measured glomerular filtration rate (mGFR) ≥15 mL min-1 /1.73 m2 and ECF measurement. ECF and GFR were measured repeatedly using the distribution volume and clearance of 51 Cr-EDTA, respectively. ESKD and mortality were traced through record linkage with the national registries. Adjusted shared random-effect joint models were used to analyse the association between the trajectory of ECF over time and the two competing outcomes. RESULTS: Patients were mean age 58.7 years, 66.7% men, mean mGFR of 43.6 ± 18.6 mL min-1 /1.73 m2 and mean ECF of 16.1 ± 3.6 L. Over a median follow-up of 5.3 [IQR: 3.0;7.4] years, ECF increased by 136 [95%CI 106;167] mL per year on average, whilst diuretic prescription and 24-hour urinary sodium excretion remained stable. ESKD occurred in 324 (20.4%) patients, and 185 (11.6%) patients died before ESKD. A higher current value of ECF was associated with increased hazards of ESKD (adjusted hazard ratio [aHR]: 1.12 [95%CI 1.06;1.18]; P < 0.001 per 1 L increase in ECF), and death before ESKD (aHR: 1.10 [95%CI 1.04;1.17]; P = 0.002). CONCLUSIONS: The current value of ECF was associated with the risks of ESKD and mortality, independent of multiple potential confounders, including kidney function decline. This highlights the need for a close monitoring and adjustment of treatment to avoid fluid overload in CKD patients.

Diagnosis of congenital toxoplasmosis in a renal transplant recipient mother.

We report the case of a first trimester toxoplasmosis infection in a renal transplant recipient. Real-time polymerase chain reaction in amniotic fluid at 18 weeks was negative for Toxoplasma gondii but at 26 weeks major fetal hydrocephalus was discovered leading to medical termination of pregnancy. Pathological examination confirmed lesions consistent with congenital toxoplasmosis. The herein case report, as well as data from the French reference centre for congenital Toxoplamosis (1835 cases in the past eight years), suggests that the strategy of management of pregnancy's first trimester Toxoplasmosis infection in patients treated by immunosuppressive therapy needs to be reconsidered.

Predictive Modeling of Tacrolimus Dose Requirement Based on High-Throughput Genetic Screening.

Any biochemical reaction underlying drug metabolism depends on individual gene-drug interactions and on groups of genes interacting together. Based on a high-throughput genetic approach, we sought to identify a set of covariant single-nucleotide polymorphisms predictive of interindividual tacrolimus (Tac) dose requirement variability. Tac blood concentrations (Tac C0 ) of 229 kidney transplant recipients were repeatedly monitored after transplantation over 3 mo. Given the high dimension of the genomic data in comparison to the low number of observations and the high multicolinearity among the variables (gene variants), we developed an original predictive approach that integrates an ensemble variable-selection strategy to reinforce the stability of the variable-selection process and multivariate modeling. Our predictive models explained up to 70% of total variability in Tac C0 per dose with a maximum of 44 gene variants (p-value <0.001 with a permutation test). These models included molecular networks of drug metabolism with oxidoreductase activities and the multidrug-resistant ABCC8 transporter, which was found in the most stringent model. Finally, we identified an intronic variant of the gene encoding SLC28A3, a drug transporter, as a key gene involved in Tac metabolism, and we confirmed it in an independent validation cohort.

Reduction of Extended-Release Tacrolimus Dose in Low-Immunological-Risk Kidney Transplant Recipients Increases Risk of Rejection and Appearance of Donor-Specific Antibodies: A Randomized Study.

The aim of this study (ClinicalTrials.gov, NCT01744470) was to determine the efficacy and safety of two different doses of extended-release tacrolimus (TacER) in kidney transplant recipients (KTRs) between 4 and 12 mo after transplantation. Stable steroid-free KTRs were randomized (1:1) after 4 mo: Group A had a 50% reduction in TacER dose with a targeted TacER trough level (C0 ) >3 µg/L; group B had no change in TacER dose (TacER C0 7-12 µg/L). The primary outcome was estimated GFR at 1 year. Of 300 patients, the intent-to-treat analysis included 186 patients (group A, n = 87; group B, n = 99). TacER C0 was lower in group A than in group B at 6 mo (4.1 ± 2.7 vs. 6.7 ± 3.9 µg/L, p < 0.0001) and 12 mo (5.6 ± 2.0 vs. 7.4 ± 2.1 µg/L, p < 0.0001). Estimated GFR was similar in both groups at 12 mo (group A, 56.0 ± 17.5 mL/min per 1.73 m²; group B, 56.0 ± 22.1 mL/min per 1.73 m²). More rejection episodes occurred in group A than group B (11 vs. 3; p = 0.016). At 1 year, subclinical inflammation occurred more frequently in group A than group B (inflammation score [i] >0: 21.4% vs. 8.8%, p = 0.047; tubulitis score [t] >0: 19.6% vs. 8.7%, p = 0.076; i + t: 1.14 ± 1.21 vs. 0.72 ± 1.01, p = 0.038). Anti-HLA donor-specific antibodies appeared only in group A (6 vs. 0 patients, p = 0.008). TacER C0 should be maintained >7 µg/L during the first year after transplantation in low-immunological-risk, steroid-free KTRs receiving a moderate dose of mycophenolic acid.

Long-Term Clinical Impact of Adaptation of Initial Tacrolimus Dosing to CYP3A5 Genotype.

Pretransplantation adaptation of the daily dose of tacrolimus to CYP3A5 genotype is associated with improved achievement of target trough concentration (C0 ), but whether this improvement affects clinical outcomes is unknown. In the present study, we have evaluated the long-term clinical impact of the adaptation of initial tacrolimus dosing according to CYP3A5 genotype: The transplantation outcomes of the 236 kidney transplant recipients included in the Tactique study were retrospectively investigated over a period of more than 5 years. In the Tactique study, patients were randomly assigned to receive tacrolimus at either a fixed dosage or a dosage determined by their genotype, and the primary efficacy end point was the proportion of patients for whom tacrolimus C0 was within target range (10-15 ng/mL) at day 10. Our results indicate that the incidence of biopsy-proven acute rejection and graft survival were similar between the control and the adapted tacrolimus dose groups, as well as between the patients who achieve the tacrolimus C0 target ranges earlier. Patients' death, cancer, cardiovascular events, and infections were also similar, and renal function did not change. We conclude that optimization of initial tacrolimus dose using pharmacogenetic testing does not improve clinical outcomes.

[Spot urinary protein to creatinine ratio: Which role in preeclampsia diagnosis?]. / Rapport protéinurie/créatininurie : quelle place dans le diagnostic de la pré-éclampsie ?

Preeclampsia remains a serious and feared complication of pregnancy. Its diagnosis is confirmed upon detection of hypertension and significant proteinuria starting from 20 weeks of gestation. The 24-hour urine collection is considered to be the gold standard test for quantitative diagnosis of proteinuria despite its downsides. Recent studies have brought into question its accuracy during pregnancy as complete samples are hard to get, but above all, as this time consuming procedure often delays treatment and may preclude optimal management. Several publications looked at the spot urinary protein to creatinine ratio (PCR) as a replacement to the 24-hour urine collection. Largely used outside pregnancy, this fast and less invasive test seems a compelling alternative. In this paper, data from previous meta-analysis and guidelines have been reviewed in an attempt to clarify the role of the PCR in clinical practice and elaborate an algorithm in case of suspicion of preeclampsia. Thus, this test seems a valid "rule-out test" when using the optimal threshold of 30mg/mmol. Higher values require a 24-hour urine collection for confirmation.

Kidney transplant recipients carrying the CYP3A4*22 allelic variant have reduced tacrolimus clearance and often reach supratherapeutic tacrolimus concentrations.

CYP3A4*22 is an allelic variant of the cytochrome P450 3A4 associated with a decreased activity. Carriers of this polymorphism may require reduced tacrolimus (Tac) doses to reach the target residual concentrations (Co). We tested this hypothesis in a population of kidney transplant recipients extracted from a multicenter, prospective and randomized study. Among the 186 kidney transplant recipients included, 9.3% (18 patients) were heterozygous for the CYP3A4*22 genotype and none were homozygous (allele frequency of 4.8%). Ten days after transplantation (3 days after starting treatment with Tac), 11% of the CYP3A4*22 carriers were within the target range of Tac Co (10-15 ng/mL), whereas among the CYP3A4*1/*1 carriers, 40% were within the target range (p = 0.02, OR = 0.19 [0.03; 0.69]). The mean Tac Co at day 10 in the CYP3A4*1/*22 group was 23.5 ng/mL (16.6-30.9) compared with 15.1 ng/mL (14-16.3) in the CYP3A4*1/*1 group, p < 0.001. The Tac Co/dose significantly depended on the CYP3A4 genotype during the follow-up (random effects model, p < 0.001) with the corresponding equivalent dose for patients heterozygous for CYP3A4*22 being 0.67 [0.54; 0.84] times the dose for CYP3A4*1/*1 carriers. In conclusion, the CYP3A4*22 allelic variant is associated with a significantly altered Tac metabolism and carriers of this polymorphism often reach supratherapeutic concentrations.

Angiogenic response following renal ischemia reperfusion injury: new players.

Ischemia-reperfusion (IR) injury can negatively influence the short- and long-term outcomes of kidney transplantation because it promotes acute tubular necrosis and tissue scarring and activates innate alloimmunity. The adaptive responses to IR are centrally involved in reducing tissue damage but can also be deleterious when they activate programmed cell death and inflammation. The HIF-1α-mediated angiogenic responses following IR at early and late stages are complex and poorly understood. The early stages of IR seem to be associated with an antiangiogenic response, whereas the hypoxia that follows IR at later stages may activate angiogenic factors such as vascular endothelial growth factor (VEGF) and may be beneficial by stabilizing the microvasculature and favoring local blood supply. In addition to HIF-1α, new players in angiogenesis, including mTOR and the unfolded protein response, may lead to innovative therapeutic strategies for treating patients with ischemia- and reperfusion-associated tissue inflammation and organ dysfunction.

Treating diabetes with islet transplantation: lessons from the past decade in Lille.

Type 1 diabetes (T1D) is due to the loss of both beta-cell insulin secretion and glucose sensing, leading to glucose variability and a lack of predictability, a daily issue for patients. Guidelines for the treatment of T1D have become stricter as results from the Diabetes Control and Complications Trial (DCCT) demonstrated the close relationship between microangiopathy and HbA1c levels. In this regard, glucometers, ambulatory continuous glucose monitoring, and subcutaneous and intraperitoneal pumps have been major developments in the management of glucose imbalance. Besides this technological approach, islet transplantation (IT) has emerged as an acceptable safe procedure with results that continue to improve. Research in the last decade of the 20th century focused on the feasibility of islet isolation and transplantation and, since 2000, the success and reproducibility of the Edmonton protocol have been proven, and the mid-term (5-year) benefit-risk ratio evaluated. Currently, a 5-year 50% rate of insulin independence can be expected, with stabilization of microangiopathy and macroangiopathy, but the possible side-effects of immunosuppressants, limited availability of islets and still limited duration of insulin independence restrict the procedure to cases of brittle diabetes in patients who are not overweight or have no associated insulin resistance. However, various prognostic factors have been identified that may extend islet graft survival and reduce the number of islet injections required; these include graft quality, autoimmunity, immunosuppressant regimen and non-specific inflammatory reactions. Finally, alternative injection sites and unlimited sources of islets are likely to make IT a routine procedure in the future.

Outcome of kidney transplantations performed with preformed donor-specific antibodies of unknown etiology.

The detection of preformed donor-specific alloantibodies (DSA) with multiplex-bead arrays has led to the common observation that individuals without a history of pregnancy, transfusion or transplantation can have circulating anti-HLA antibodies of unknown etiology. We retrospectively analyzed the risk of antibody-mediated rejection (AMR) and graft outcome in 41 kidney transplant recipients with DSA of unknown etiology (DSA cause-unk) at the time of transplantation. Twenty-one patients received a posttransplantation desensitization protocol, and 20 received standard immunosuppressive therapy. The mean number of DSA was 1.4 ± 0.8, ranging from 1 to 5. Complement-dependent cytotoxicity crossmatches were negative for all the patients. Flow cytometry crossmatches were positive in 47.6% of cases. The incidence of acute AMR was 14.6% at 1 year, regardless of the immunosuppressive regimen. No patients experienced graft loss following AMR. At month 12, across the entire population of patients with DSA cause-unk, the outcomes were favorable: the measured glomerular filtration rate was 63.8 ± 16.4 mL/min/1.73 m(2), the screening biopsies showed low frequencies of microvascular inflammation and no transplant glomerulopathy, and graft and patient survival were 100%. In conclusion, patients with DSA cause-unk are able to mount AMR but have favorable 1-year outcomes.

Acute kidney injury in patients with severe rash on vemurafenib treatment for metastatic melanomas.

Vemurafenib, a selective BRAF (v-raf murine sarcoma viral oncogene homologue B1) kinase inhibitor, is a new targeted biotherapy that improves survival in patients with metastatic melanomas harbouring the BRAF V600E mutation. However, this drug has significant dermatological adverse effects. We report a new severe cutaneous reaction to this drug associated with acute kidney injury (AKI). Four patients presented a generalized grade 3 (Common Terminology Criteria for Adverse Events) erythematous eruption with hyperkeratosis pilaris, 5-14 days after the introduction of vemurafenib. These symptoms were associated with AKI in all cases and transitory hypereosinophilia in two cases. Vemurafenib treatment was stopped in three patients and the dose was reduced in the fourth, leading to a gradual improvement of skin symptoms and renal function. Positron-emission tomography scans showed a complete response in three cases and a major response in one case. Vemurafenib was reintroduced at a lower dose, without a relapse of the rash, but renal function again deteriorated. Thus, we report a cluster of four cases of AKI associated with similar, severe, grade 3 cutaneous drug reactions related to vemurafenib.

PARVG gene polymorphism and operational renal allograft tolerance.

A unique blood transcriptional profile of 49 genes has been previously highlighted that may be used to distinguish drug-free operationally tolerant kidney recipients (TOL) from other kidney recipients with contrasted clinical situations and healthy volunteers. The aim of this study was to investigate whether the pattern of these 49 genes could be influenced by genetic polymorphisms located in the corresponding genomic sequences and whether some of these single nucleotide polymorphisms (SNPs) could be associated with clinical status of kidney transplant recipients. In this study, 1152 candidate tag SNPs spanning these genes were genotyped using a Golden Gate Illlumina assay in a sample of 164 kidney transplant recipients, including 11 operationally tolerant patients, 134 patients with stable graft function, 19 with proven signs of chronic rejection, and 27 healthy volunteers. The gene expression and clinical status were studied according to the different SNPs. Among the genes demonstrating expression difference between TOL compared with CR&STA patients, PARVG, which is a member of a family of actin-binding proteins associated with focal contacts, stands out with 2 SNPs, (rs139144 and rs5764592) explaining about 20% of the gene expression variability. Linkage disequilibrium analysis of these 2 SNPs showed the rs139144GG genotype was associated with decreased PARVG expression and was numerically more frequent in TOL (60%) than in CR&STA (28%) patients (P = .068). These preliminary results, which should be confirmed in a larger population, open new perspective of regulation pathways and hypothesis in operational tolerance mechanism.

Collapsing glomerulopathy associated lupus in a black female with homozygous APOL1 mutation.

Collapsing glomerulopathy (CG), characterized by collapse of the glomerular capillary loops onto the mesangial stalks is rarely associated to systemic lupus erythematosus (SLE). Recently a genetic predisposition to HIV associated nephropathy (HIVAN) has been shown in Afro-Americans: MYH9 polymorhism in 2008 and then APOL1 variants (G1 and G2 alleles) in 2010 were shown to be strongly associated with HIVAN. We describe here for the first time the association of CG in a young Afro-American female with SLE having a homozygous mutation of APOL1. The clinical history, laboratory findings and immunofluorescence all confirmed a diagnosis of SLE. However, studies for factors associated with collapsing glomerulopathy in other situations were consistently negative. As this Afro-American patient developed a CG, we performed genotyping of APOL1. It was found that she is homozygotic for the G2 allele of APOL1. Despite.

Comparison of C4d detection on erythrocytes and PTC-C4d to histological signs of antibody-mediated rejection in kidney transplantation.

C4d on erythrocytes (EC4d), C4d peritubular capillary deposition (PTC-C4d) staining and histology were compared in a cross-sectional cohort of 146 renal allograft biopsies (132 patients). EC4d levels paralleled PTC-C4d staining, but were more predictive of peritubular capillaritis (PTC). Donor-specific antibodies (DSA), PTC-C4d, EC4d and PTC were analyzed in an independent longitudinal follow-up cohort (96 biopsies, 76 patients). Seventy-six samples were PTC and EC4d concordant, 11 positive and 65 negative, 7 PTC-EC4d+ and 13 PTC+EC4d-. EC4d levels were related to DSA occurrence. With ABMR defined by PTC and DSA, all apparently discordant patients, EC4d negative, were correctly reassigned comparing EC4d level curves with rejection kinetics, with positive EC4d samples predating biopsy or late biopsies compared with ABMR flare-ups. All EC4d-positive patients without PTC or DSA had permanent high EC4d levels unrelated to rejection. EC4d was more abundant in PTC-positive (mean = 108.5%± 3.4; n = 50) than PTC-negative samples (mean = 88.1%± 1.3; n= 96; p < 0.0001). Sensitivity, specificity, positive predictive value and negative predictive value of PTC-C4d and EC4d for PTC were, respectively, 75%, 79%; 64%, 76% (p < 0.05); 28%, 46% (p < 0.05) and 93%, 94%. Values were similar for DSA. A noninvasive blood test, EC4d, and particularly longitudinally monitoring EC4d levels, may increase surrogate ABMR testing options.

Increased body mass index after kidney transplantation in activating transcription factor 6 single polymorphism gene carriers.

OBJECTIVES: Endoplasmic reticulum stress has been implicated in the pathogenesis of new-onset diabetes after transplantation (NODAT) and of metabolic disorders. Activated Transcription Factor 6 (ATF6), which is activated during endoplasmic reticulum stress, is involved in lipogenesis and gluconeogenesis. Tacrolimus may induce endoplasmic reticulum stress in pancreatic beta cells. Since studies have demonstrated that single nucleotide polymorphisms (SNPs) of ATF6 are associated with type 2 diabetes, we sought to determine whether their mutations were associated with NODAT among renal transplant recipients treated with tacrolimus. METHODS: We genotyped 269 renal transplant recipients using TaqMan assays for allelic discrimination for 6 ATF6 gene polymorphisms: rs10918215, rs7514053, rs1058405, rs4479731, rs2340721, and rs13401. All patients received an immunosuppressive regimen including tacrolimus. We analyzed all previously known risk factors for NODAT. RESULTS: We could not confirm are association between ATF6 SNP and NODAT. We observed a significant association between ATF6 SNP rs2340721 and increased body weight and body mass index (BMI) both upon univariate and multivariate analyses. The average BMI was higher among patients with 2 mutant SNP2 (rs2340721) alleles (CC) than those with 2 wild-type alleles (AA): 23.8 ± 3.7 versus 25.5 ± 4.4 kg/m2 (P = .02). The odds ratio (95% confidence interval [CI]) for BMI associated with the CC genotype was 2.43 (1.16-5.09; P = .02). CONCLUSION: ATF6 polymorphisms were not associated with NODAT among our population of renal transplant recipients treated with tacrolimus. However, these data underscore the role of ATF6 and endoplasmic reticulum stress in the regulation of metabolic flux among patients treated with tacrolimus, suggesting that inherited disturbances of endoplasmic reticulum stress signaling could predispose people to obesity.

Immunosuppressant regimen based on sirolimus decreases aortic stiffness in renal transplant recipients in comparison to cyclosporine.

Whether or not a cyclosporine A (CsA)-free immunosuppressant regimen based on sirolimus (SRL) prevents aortic stiffening and improves central hemodynamics in renal recipients remains unknown. Forty-four patients (48 ± 2 years) enrolled in the CONCEPT trial were randomized at week 12 (W12) to continue CsA or switch to SRL, both associated with mycophenolate mofetil. Carotid systolic blood pressure (cSBP), pulse pressure (cPP), central pressure wave reflection (augmentation index, AIx) and carotid-to-femoral pulse-wave velocity (PWV: aortic stiffness) were blindly assessed at W12, W26 and W52 together with plasma endothelin-1 (ET-1), thiobarbituric acid-reactive substances (TBARS) and superoxide dismutase (SOD) and catalase erythrocyte activities. At W12, there was no difference between groups. At follow-up, PWV, cSBP, cPP and AIx were lower in the SRL group. The difference in PWV remained significant after adjustment for blood pressure and eGFR. In parallel, ET-1 decreased in the SRL group, while TBARS, SOD and catalase erythrocyte activities increased in both groups but to a lesser extent in the SRL group. Our results demonstrate that a CsA-free regimen based on SRL reduces aortic stiffness, plasma endothelin-1 and oxidative stress in renal recipients suggesting a protective effect on the arterial wall that may be translated into cardiovascular risk reduction.

Long-term impact of subclinical inflammation diagnosed by protocol biopsy one year after renal transplantation.

The long-term impact of subclinical acute rejection (SCAR) on renal graft function remains poorly understood. Furthermore, the interpretation of borderline lesions is difficult and their incidence is variable. The aim of this study was to analyze the characteristics of subclinical inflammation (SCI) in protocol biopsies performed 1-year after renal transplantation. SCI was defined as the presence of borderline lesions or SCAR according to the Banff 2005 classification. The patients included were a subpopulation of the CONCEPT study in which patients were randomized 3 months after transplantation to receive either sirolimus (SRL) or cyclosporine A (CsA) in combination with mycophenolate mofetil. At 1 year, we observed SCI in 37 of the 121 patients observed with an evaluable biopsy. The incidence was more frequent in the SRL group (SRL 45.2% vs. CsA 15.3%). At 30 months , SCI was associated with a significantly lower level of estimated glomerular filtration rate (mean MDRD 50.8 [±13.3] vs. 57.7 [±16.3] mL/min/1.73 m(2) , p = 0.035). In conclusion, SCI at 1-year posttransplantation is associated with worsening renal function and is more frequent in SRL-treated patients. Therefore, evaluation of SCI may be a valuable tool to allow the optimization of immunosuppressive regimens.