Search

Aims: Pregnancy after kidney transplantation is realistic but immunosuppressants should be continued to prevent rejection. Tacrolimus is safe during pregnancy and is routinely dosed based on whole‐blood predose concentrations. However, maintaining these concentrations is complicated as physiological changes during pregnancy affect tacrolimus pharmacokinetics. The aim of this study was to describe tacrolimus pharmacokinetics throughout pregnancy and explain the changes by investigating covariates in a population pharmacokinetic model. Methods: Data of pregnant women using a twice‐daily tacrolimus formulation following kidney transplantation were retrospectively collected from 6 months before conception, throughout gestation and up to 6 months postpartum. Pharmacokinetic analysis was performed using nonlinear mixed effects modelling. Demographic, clinical and genetic parameters were evaluated as covariates. The final model was evaluated using goodness‐of‐fit plots, visual predictive checks and a bootstrap analysis. Results: A total of 260 whole‐blood tacrolimus predose concentrations from 14 pregnant kidney transplant recipients were included. Clearance increased during pregnancy from 34.5 to 41.7 L/h, by 15, 19 and 21% in the first, second and third trimester, respectively, compared to prior to pregnancy. This indicates a required increase in the tacrolimus dose by the same percentage to maintain the prepregnancy concentration. Haematocrit and gestational age were negatively correlated with tacrolimus clearance (P ≤ 0.01), explaining 18% of interindividual and 85% of interoccasion variability in oral clearance. Conclusions: Tacrolimus clearance increases during pregnancy, resulting in decreased exposure to tacrolimus, which is explained by gestational age and haematocrit. To maintain prepregnancy target whole‐blood tacrolimus predose concentrations during pregnancy, increasing the dose is required. [ABSTRACT FROM AUTHOR]

Objectives: Unspecified donors give a kidney to a stranger with end‐stage kidney failure. There has been little research on the long‐term impact of unspecified donation on mental health outcomes. The aim of this study was to assess the positive and negative aspects of mental health among unspecified donors. Design: We invited all unspecified donors who donated a kidney between 2000 and 2016 at our centre to participate in an interview and to complete validated questionnaires. Methods: We measured positive mental health using the Dutch Mental Health Continuum‐Short Form (MHC‐SF), psychological complaints using the Symptoms Checklist‐90 (SCL‐90) and psychiatric diagnoses using the Mini‐International Neuropsychiatric Interview (M.I.N.I.) Screen for all donors and the M.I.N.I. Plus on indication. Results: Of the 134 eligible donors, 114 participated (54% female; median age 66 years), a median of 6 years post‐donation. Scores on emotional and social well‐being subscales of the MHC‐SF were significantly higher than in the general population. Psychological symptoms were comparable to the general population. Thirty‐two per cent of donors had a current or lifetime psychiatric diagnosis. Psychological symptoms did not significantly change between the pre‐donation screening and the post‐donation study. Conclusions: We concluded that, with the appropriate screening, unspecified donation is a safe procedure from a psychological perspective. [ABSTRACT FROM AUTHOR]

Urinary extracellular vesicles (uEVs) are emerging as non‐invasive biomarkers for various kidney diseases, but it is unknown how differences in nephron mass impact uEV excretion. To address this, uEV excretion was measured before and after human kidney donor nephrectomy and rat nephrectomy. In male and female donors, uEVs were quantified in cell‐free spot and 24‐h urine samples using nanoparticle tracking analysis (NTA), EVQuant, and CD9‐time‐resolved fluorescence immunoassay. Female donors had significantly lower total kidney volume (TKV) and excreted 49% fewer uEVs than male donors. uEV excretion correlated positively with estimated glomerular filtration rate (eGFR), creatinine clearance, and TKV (R's between 0.6 and 0.7). uEV excretion rate could also be predicted from spot urines after multiplying spot uEV/creatinine by 24‐h urine creatinine. Donor nephrectomy reduced eGFR by 36% ± 10%, but the excretion of uEVs by only 16% (CD9+ uEVs ‐37%, CD9‐ uEVs no decrease). Donor nephrectomy increased the podocyte marker WT‐1 and the proximal tubule markers NHE3, NaPi‐IIa, and cubilin in uEVs two‐ to four‐fold when correcting for the nephrectomy. In rats, the changes in GFR and kidney weight correlated with the changes in uEV excretion rate (R = 0.46 and 0.60, P < 0.01). Furthermore, the estimated degree of hypertrophy matched the change in uEV excretion rate (1.4‐ to 1.5‐fold after uninephrectomy and four‐fold after 5/6th nephrectomy). Taken together, our data show that uEV excretion depends on nephron mass, and that nephrectomy reduces uEV excretion less than expected based on nephron loss due to compensatory hypertrophy. The major implication of our findings is that a measure for nephron mass or uEV excretion rate should be included when comparing uEV biomarkers between individuals. [ABSTRACT FROM AUTHOR]

Pregnancy can have risks after kidney transplantation (KT). This mixed‐methods study aimed to identify the percentage of women getting pregnant after KT and explore motives for and against pregnancy together with psychosocial and medical factors involved in decision making. Furthermore, experiences of pregnancy and child‐raising were explored. Women who got pregnant after KT were matched with women who had not been pregnant after KT. Semi‐structured interviews were conducted, transcribed verbatim and analyzed using directed content analysis. After KT, only 12% of women got pregnant. Eight women with pregnancies after KT were included (P‐group) and matched with 12 women who had not been pregnant after KT (NP‐group). Women after KT experienced a high threshold to discuss their pregnancy wish with their nephrologist. The nephrologists' advice played an important role in decision‐making, but differed between the groups. In the P‐group, a desire for autonomy and positive role models were decisive factors in proceeding with their pregnancy wish. In the NP‐group, disease burden and risk perception were decisive factors in not proceeding with their pregnancy. Nephrologists need to be proactive in broaching this subject and aware of factors influencing the decision and outcomes. Standardized preconception guidelines on pregnancy counseling are recommended. [ABSTRACT FROM AUTHOR]

van de Wetering J, Koumoutsakos P, Peeters A, van der Mast BJ, de Kuiper P, IJzermans JNM, Weimar W, Baan CC. Discontinuation of calcineurin inhibitors treatment allows the development of FOXP3+ regulatory T-cells in patients after kidney transplantation. Clin Transplant 2011: 25: 40-46. © 2010 John Wiley & Sons A/S. This study investigated specific gene expression profiles in patients with donor-specific cytotoxic-hyporesponsiveness, reflected by cytotoxic T-lymphocyte precursor frequency (CTLpf). The effect of calcineurin inhibitor (CNI) withdrawal was studied on markers for cytotoxicity (perforin, granzyme B), apoptosis (Fas,FasL), Th1 and Th2 cytokines (IL-2, IL-10), Th1 and Th2 transcription factors (T-bet, GATA 3), Th17 transcription factor and cytokine (RORγt, IL-17), and for immune regulation/activation (CD25, FOXP3). Peripheral blood samples from renal allograft recipients (n = 18) more than two yr after transplantation with stable renal function were analyzed before and four months after CNI withdrawal. Additionally, systolic and diastolic blood pressure, cholesterol, serum creatinine and proteinuria were evaluated, and no significant differences were measured before and after CNI withdrawal. However, CNIs' discontinuation influenced peripheral gene expression profiles. After CNI withdrawal, the mRNA expression of Granzyme B, Perforin, Fas, FasL, T-bet, GATA3 and CD25 were significantly lower than during CNI treatment. After CNI discontinuation, donor-specific CTLpf decreased, while FOXP3 expression discriminated between detectable and non-detectable donor-specific cytolysis reactivity; FOXP3 transcript values were highest in absence of donor-specific cytotoxicity (p < 0.01). Our study shows CNI withdrawal in stable kidney transplant recipients two yr after transplantation is safe. Moreover, discontinuation of CNIs' treatment allows FOXP3+ regulatory T-cells development, resulting in a significant decrease of anti-donor immune reactivity. [ABSTRACT FROM AUTHOR]

Background: It has been reported that donor-reactive T-cell responses may decrease during the first year after HLA-mismatched organ transplantation. We wondered whether donor-reactive T-cell responses directed to minor histocompatibility antigens (mHAgs) or other non-HLA antigens also decrease after HLA-identical living-related (LR) kidney transplantation. Methods: We studied donor-reactive T-cell responses by IFN-γ and granzyme B (GrB) Elispot assays in 15 HLA-identical LR kidney transplant recipients before, six months and one yr after transplantation. Third-party reactivity was used as control. Patient and donor peripheral blood mononuclear cells were typed for 11 known mHAgs. Results: During the study period, 60% and 36% of the patients demonstrated donor-reactive IFN-γ and GrB producing cells (pc), respectively. The number of donor-reactive IFN-γ and GrB pc was significantly lower than the number of third-party reactive IFN-γ and GrB pc. After transplantation, donor-reactivity and third-party reactivity were comparable to pre-transplant values. No relation was found in mHAg mismatches between donor and recipient and donor-reactive T-cell response. Conclusions: Donor-reactivity could be detected before and after HLA-identical LR kidney transplantation, but was not related with the number of mHAg mismatches, and did not decrease after transplantation. [ABSTRACT FROM AUTHOR]

Background: Recently, we described a significant decrease in donor-specific cytotoxic T-lymphocyte precursor frequency (CTLpf) after discontinuation of calcineurin inhibitors (CNI), while the proliferative capacity in mixed lymphocyte culture (MLC), and the number of interferon-γ (IFN-γ) producing cells (pc) in Elispot remained unchanged. Methods: We tested T-cell reactivity in CNI free patients with stable renal graft function, on mycophenolate mofetil (MMF) or azathioprine (AZA) plus prednisone, who were tapered to 50% of their MMF or AZA dose. Results: Furthermore, tapering of the MMF or AZA dose resulted in a decrease of donor-reactive CTLpf in all patients with detectable CTLpf. Detectable numbers decreased from a median of 32 to 8 CTLp/106 peripheral blood mononuclear cell (PBMC). No effect on third-party reactive CTLpf was found, while the T-cell reactivity to donor and third-party cells as tested in MLC and in IFN-γ Elispot was not affected either by tapering of immunosuppression. Third-party reactivity was significantly higher than donor-specific reactivity in all tests. A control group showed no changes in any of the in vitro assays. Conclusion: Both withdrawal of CNI and tapering of MMF or AZA dose decreases the donor-specific CTLpf. Our data suggest that reduction of immunosuppression results in a specific decrease of donor-directed cytotoxic capacity of immunocompetent cells, while their proliferation and cytokine production capacity remained unchanged. Immunosuppression hinders development of cytotoxic non-responsiveness. [ABSTRACT FROM AUTHOR]