Male Microchimerism at High Levels in Peripheral Blood Mononuclear Cells from Women with End Stage Renal Disease before Kidney Transplantation

Patients with end stage renal diseases (ESRD) are generally tested for donor chimerism after kidney transplantation for tolerance mechanism purposes. But, to our knowledge, no data are available on natural and/or iatrogenic microchimerism (Mc), deriving from pregnancy and/or blood transfusion, acquired prior to transplantation. In this context, we tested the prevalence of male Mc using a real time PCR assay for DYS14, a Y-chromosome specific sequence, in peripheral blood mononuclear cells (PBMC) from 55 women with ESRD, prior to their first kidney transplantation, and compared them with results from 82 healthy women. Male Mc was also quantified in 5 native kidney biopsies obtained two to four years prior to blood testing and in PBMC from 8 women collected after female kidney transplantation, several years after the initial blood testing. Women with ESRD showed statistically higher frequencies (62%) and quantities (98 genome equivalent cells per million of host cells, gEq/M) of male Mc in their PBMC than healthy women (16% and 0.3 gEq/M, p<0.00001 and p = 0.0005 respectively). Male Mc was increased in women with ESRD whether they had or not a history of male pregnancy and/or of blood transfusion. Three out of five renal biopsies obtained a few years prior to the blood test also contained Mc, but no correlation could be established between earlier Mc in a kidney and later presence in PBMC. Finally, several years after female kidney transplantation, male Mc was totally cleared from PBMC in all women tested but one. This intriguing and striking initial result of natural and iatrogenic male Mc persistence in peripheral blood from women with ESRD raises several hypotheses for the possible role of these cells in renal diseases. Further studies are needed to elucidate mechanisms of recruitment and persistence of Mc in women with ESRD

Le microchimérisme foetal chez la femme urémique avant et après transplantation rénale

Le microchimérisme (Mc) foetal est retrouvé fréquemment dans le sang périphérique, les organes solides (les reins, le coeur, les poumons) mais également la moelle osseuse et les ganglions de la femme en bonne santé, plusieurs années après la grossesse. Il est le reliquat d un passage physiologique de cellules d origine maternelle vers le foetus et vice-versa. Ce Mc foetal persistant a été incriminé dans la pathogénie de certaines maladies auto-immunes, mais on lui attribue également un rôle réparateur tissulaire. Première partie : devant les différences liées au sexe dans la survenue de la maladie rénale, mais également dans son évolution plus fréquente et plus rapide chez l homme vers la dialyse, nous avons voulu analyser un éventuel rôle protecteur du microchimérisme acquis après grossesse chez les femmes en insuffisance rénale chronique terminale (IRCT) avant transplantation rénale. Nous avons étudié la prévalence de la présence de l ADN mâle dans le sang périphérique, à l aide d une méthode de PCR quantitative, chez 55 patientes en IRCT et dans l attente d une première transplantation rénale et comparé les résultats à ceux d une population de 72 femmes contrôles. Nous avons également quantifié le Mc dans le sang périphérique chez 8 patientes après transplantation rénale et précédemment étudiées pendant l IRCT. Les patientes IRCT sont, de façon significative, plus fréquemment microchimériques (62%) et à plus haut niveau (98 génomes équivalents par million (gEq/M)) que les femmes contrôles (17% et 0,3 gEq/M, p=0,0005). Finalement, quelques années après la transplantation rénale, le Mc a totalement disparu chez toutes les femmes sauf une. Plusieurs scenarii sont possibles, expliquant ces résultats. Il se peut que les cellules fœtales soient recrutées et prolifèrent chez les patientes en IRCT sous l influence de facteurs inflammatoires systémiques et locaux, jouant un rôle dans la réparation tissulaire, expliquant en partie la dégradation plus lente de la fonction rénale chez la femme. Seconde partie : nous nous sommes demandé si le maintien des anticorps anti-HLA et anti-MICA au long cours ne pouvait être expliqué par la persistance de cellules fœtales chez la patiente IRCT en attente de transplantation rénale. En effet, les modes d acquisition de ces 2 phénomènes sont similaires. Pour répondre à cette question, nous avons testé par une technique de PCR nichée SRY puis par PCR quantitative DYS14 2 groupes de patientes IRCT, immunisées ou non dans le système HLA. Par PCR quantitative, nous ne retrouvons pas de lien entre la présence d anticorps et celle d ADN mâle mais le niveau de Mc semble influencer le PRA classe I et II, de même que la production d anticorps anti-MICA.NICE-BU Sciences (060882101) / SudocSudocFranceF

Outcomes with Tacrolimus-Based Immunosuppression After Kidney Transplantation from Standard- and Extended-Criteria Donors – A Post Hoc Analysis of the Prospective OSAKA Study

Background: This post hoc analysis of data from the prospective OSAKA study evaluated the efficacy and safety of prolonged- and immediate-release tacrolimus in patients who received kidneys from extended-criteria (ECD) and standard-criteria (SCD) donors. Material/Methods: Within the ECD and SCD groups, patients were randomized to one of 4 tacrolimus-based regimens (initial dose): Arm 1, immediate-release tacrolimus (0.2 mg/kg/day); Arm 2, prolonged-release tacrolimus (0.2 mg/kg/day); Arm 3, prolonged-release tacrolimus (0.3 mg/kg/day); Arm 4, prolonged-release tacrolimus (0.2 mg/kg/day) plus basiliximab. All patients received mycophenolate mofetil and bolus corticosteroids; Arms 1-3 also received tapered corticosteroids. ECDs met the definition: living/deceased donors aged >= 60 years, or 50-60 years with >= 1 other risk factor, and donation after circulatory death. Primary composite endpoint: graft loss, biopsy-confirmed acute rejection or renal dysfunction by Day 168. Outcomes were compared across treatment arms with the chi-squared or Fisher's exact test. Results: A total of 1198 patients were included in the analysis (ECD: n=620 [51.8%], SCD: n=578 [48.2%]). Patients with kidneys from ECDs were older versus SCDs (mean age, 55.7 vs. 44.5 years, p<0.0001). A higher proportion of patients with kidneys from ECDs versus SCDs met the primary composite endpoint (56.8% vs. 32.4%, p<0.0001). However, no statistically significant differences in clinical outcomes or the incidence of treatment-emergent adverse events were seen between treatment arms within each donor group. Conclusions: Worse outcomes were experienced in patients who received kidneys from ECDs versus SCDs. Prolonged-release tacrolimus provided similar graft survival to the immediate-release formulation, with a manageable tolerability profile

Investigation of measurement invariance in longitudinal health-related quality of life in preemptive or previously dialyzed kidney transplant recipients

International audiencePurpose: Kidney transplantation (KT) can impact patients' evaluation of health-related quality of life (HRQoL) as they adapt to their new life with a graft and its changes. Patients may adapt to KT in a different way, depending on whether they were on dialysis prior to transplantation or not (i.e. preemptive group). This may result in lack of measurement invariance between these patients' groups and/or over time (i.e. response shift, RS) which may invalidate the between-group comparison of HRQoL change scores. The aim of this study was to investigate and compare RS before and after KT between these two patients' groups. Measurement invariance was investigated between groups and over time with three measurement occasions.Methods: Adult patients completed the SF-36 at the last visit before KT, and 3, 6 months after. A structural equation model-based procedure was used to (i) detect and take into account measurement non-invariance between groups and RS, if appropriate, (ii) identify the period of occurrence of RS, (iii) study the heterogeneity of RS between the two groups.Results: Before KT (i.e. baseline), measurement invariance was not rejected between dialyzed (n = 196) and preemptive (n = 178) patients' groups. Between baseline and 3 months after KT, similar uniform recalibration was detected on the general health domain in both groups. Uniform recalibration was found between 3- and 6 months after KT on the vitality domain for preemptive patients only.Conclusion: HRQoL, adjusted for RS, increased overall for preemptive and dialyzed kidney transplant patients after transplantation. RS may reflect differing adaptation processes following KT

Evaluation of Protocol Biopsy Utility 12 Months after Renal Transplantation: A Multicenter Observational Analysis

The clinical merit of surveillance kidney graft biopsies remains controversial. A retrospective, multicenter analysis evaluated 12-month surveillance biopsies (SB, 154 patients) versus no SB (NSB, 138 patients (11 with diagnostic biopsy)) in patients >18 months posttransplant with estimated GFR (eGFR) ≥30 mL/min. The primary objective was to describe renal function at 18 months post-transplant in patients with or without SB at month 12. Globally, most recipients in both cohorts were at low immunological risk (<10% of patients with PRA ≥30%). The immunosuppressive regimen remained unchanged following more than half of SB that exhibited chronic lesions (18/33, 54.5%). Mean (SD) eGFR at month 18 (primary endpoint) was 56 (19) mL/min/1.73 m² with SB and 54 (15) mL/min/1.73 m² with NSB (=0.48). In the SB group, slight nonspecific changes were observed in 51 cases, rejection (acute or chronic) in 6 cases, CNI-related toxicity in 15 cases, recurrence of initial disease in two cases, and interstitial fibrosis/tubular atrophy (IF/TA) in 83 cases (71.6%), of which 35 cases (30.2%) were grade II/III lesions. eGFR <50 mL/min/1.73 m² at month 6 predicted IF/TA grade II or III (OR 3.85, 95% CI 1.64, 9.05, <0.002). SB at 12 months posttransplant did not prompt significant modification of immunosuppression, and no renal benefit was observed

Male Mc in women with ESRD and healthy women according to pregnancy and transfusion history.

<p>TSF+: women who had received at least one blood transfusion; TSF−: women who had never received a blood transfusion; S+: women who had given birth to at least one son; S−: women who had never given birth to a son (S−);</p>*<p>no stats: statistical analyses were not done due to small numbers.</p

Characteristics from healthy women and women with ESRD.

a<p>pregnancy and transfusion information was incomplete for one healthy woman. ns: not significant.</p

Quantification of Mc in kidney biopsies prior to transplantation from five women with ESRD.

*<p>ANCA: antineutrophil cytoplasmic antibodies, SLE: systemic lupus erythematosus; HUS: hemolytic-uremic syndrome, FSGS: Focal segmental glomerulosclerosis.</p

Quantification of male Mc in PBMC from 8 women with ESRD after female kidney transplantation.

*<p>GFR: glomerular filtration rate.</p><p>All patients from this table are different from patients presented <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0032248#pone-0032248-t003" target="_blank">table 3</a>, except Patient 4 who is Patient 1 in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0032248#pone-0032248-t003" target="_blank">Table 3</a>.</p