Summary
Solid organ transplant (SOT) recipients may be at risk for severe COVID‐19. Data on the clinical course of COVID‐19 in immunosuppressed patients are limited, and the effective treatment ...strategy for these patients is unknown. We describe our institutional experience with COVID‐19 in SOT. Demographic, clinical, and treatment data were extracted from the electronic patient files. A total of 23 SOT transplant recipients suffering from COVID‐19 were identified (n = 3 heart; n = 15 kidney; n = 1 kidney‐after‐heart; n = 3 lung, and n = 1 liver transplant recipient). The presenting symptoms were similar to nonimmunocompromised patients. Eighty‐three percent (19/23) of the patients required hospitalization, but only two of these were transferred to the intensive care unit. Five patients died from COVID‐19; all had high Clinical Frailty Scores. In four of these patients, mechanical ventilation was deemed futile. In 57% of patients, the immunosuppressive therapy was not changed and only three patients were treated with chloroquine. Most patients recovered without experimental antiviral therapy. Modification of the immunosuppressive regimen alone could be a therapeutic option for SOT recipients suffering from moderate to severe COVID‐19. Pre‐existent frailty is associated with death from COVID‐19.
Although numbers of pregnancy after kidney transplantation (KT) are rising, high risks of adverse pregnancy outcomes (APO) remain. Though important for pre-conception counselling and pregnancy ...monitoring, analyses of pregnancy outcomes after KT per pre-pregnancy estimated glomerular filtration rate-chronic kidney disease (eGFR-CKD)-categories have not been performed on a large scale before. To do this, we conducted a Dutch nationwide cohort study of consecutive singleton pregnancies over 20 weeks of gestation after KT. Outcomes were analyzed per pre-pregnancy eGFR-CKD category and a composite APO (cAPO) was established including birth weight under 2500 gram, preterm birth under 37 weeks, third trimester severe hypertension (systolic blood pressure over 160 and/or diastolic blood pressure over 110 mm Hg) and/or over 15% increase in serum creatinine during pregnancy. Risk factors for cAPO were analyzed in a multilevel model after multiple imputation of missing predictor values. In total, 288 pregnancies in 192 women were included. Total live birth was 93%, mean gestational age 35.6 weeks and mean birth weight 2383 gram. Independent risk factors for cAPO were pre-pregnancy eGFR, midterm percentage serum creatinine dip and midterm mean arterial pressure dip; odds ratio 0.98 (95% confidence interval 0.96–0.99), 0.95 (0.93-0.98) and 0.94 (0.90-0.98), respectively. The cAPO was a risk indicator for graft loss (hazard ratio 2.55, 1.09-5.96) but no significant risk factor on its own when considering pre-pregnancy eGFR (2.18, 0.92-5.13). This was the largest and most comprehensive study of pregnancy outcomes after KT, including pregnancies in women with poor kidney function, to facilitate individualized pre-pregnancy counselling based on pre-pregnancy graft function. Overall obstetric outcomes are good. The risk of adverse outcomes is mainly dependent on pre-pregnancy graft function and hemodynamic adaptation to pregnancy.
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Bodyweight‐based tacrolimus dosing followed by therapeutic drug monitoring is standard clinical care after renal transplantation. However, after transplantation, a meager 38% of patients are on ...target at first steady‐state and it can take up to 3 weeks to reach the target tacrolimus predose concentration (C0). Tacrolimus underexposure and overexposure is associated with an increased risk of rejection and drug‐related toxicity, respectively. To minimize subtherapeutic and supratherapeutic tacrolimus exposure in the immediate post‐transplant phase, a previously developed dosing algorithm to predict an individual’s tacrolimus starting dose was tested prospectively. In this single‐arm, prospective, therapeutic intervention trial, 60 de novo kidney transplant recipients received a tacrolimus starting dose based on a dosing algorithm instead of a standard, bodyweight‐based dose. The algorithm included cytochrome P450 (CYP)3A4 and CYP3A5 genotype, body surface area, and age as covariates. The target tacrolimus C0, measured for the first time at day 3, was 7.5–12.5 ng/mL. Between February 23, 2019, and July 7, 2020, 60 patients were included. One patient was excluded because of a protocol violation. On day 3 post‐transplantation, 34 of 59 patients (58%, 90% CI 47–68%) had a tacrolimus C0 within the therapeutic range. Markedly subtherapeutic (< 5.0 ng/mL) and supratherapeutic (> 20 ng/mL) tacrolimus concentrations were observed in 7% and 3% of the patients, respectively. Biopsy‐proven acute rejection occurred in three patients (5%). In conclusion, algorithm‐based tacrolimus dosing leads to the achievement of the tacrolimus target C0 in as many as 58% of the patients on day 3 after kidney transplantation.
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.
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.
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.
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.
Background
Live donor nephrectomy is a safe procedure. However, long-term donor prognosis is debated, necessitating high-quality studies.
Methods
A follow-up study of 761 living kidney donors was ...conducted, who visited the outpatient clinic and were propensity score matched and compared to 1522 non-donors from population-based cohort studies. Primary outcome was kidney function. Secondary outcomes were BMI (kg/m
2
), incidences of hypertension, diabetes, cardiovascular events, cardiovascular and overall mortality, and quality of life.
Results
Median follow-up after donation was 8.0 years. Donors had an increase in serum creatinine of 26 μmol/l (95% CI 24–28), a decrease in eGFR of 27 ml/min/1.73 m
2
(95% CI − 29 to − 26), and an eGFR decline of 32% (95% CI 30–33) as compared to non-donors. There was no difference in outcomes between the groups for ESRD, microalbuminuria, BMI, incidence of diabetes or cardiovascular events, and mortality. A lower risk of new-onset hypertension (OR 0.45, 95% CI 0.33–0.62) was found among donors. The EQ-5D health-related scores were higher among donors, whereas the SF-12 physical and mental component scores were lower.
Conclusion
Loss of kidney mass after live donation does not translate into negative long-term outcomes in terms of morbidity and mortality compared to non-donors.
Trial registration
Dutch Trial Register NTR3795.
Background.
In The Netherlands, 60% of deceased-donor kidney offers are after donation after circulatory death. Cold and warm ischemia times are known risk factors for delayed graft function (DGF) ...and inferior allograft survival. Extraction time is a relatively new ischemia time. During procurement, cooling of the kidneys is suboptimal with ongoing ischemia. However, evidence is lacking on whether extraction time has an impact on DGF if all ischemic periods are included.
Methods.
Between 2012 and 2018, 1524 donation after circulatory death kidneys were procured and transplanted in The Netherlands. Donation and transplantation-related data were obtained from the database of the Dutch Transplant Foundation. The primary outcome parameter was the incidence of DGF.
Results.
In our cohort, extraction time ranged from 14 to 237 min, with a mean of 62 min (SD 32). In multivariate logistic regression analysis, extraction time was an independent risk factor for incidence of DGF (odds ratio per minute increase 1.008; 95% confidence interval, 1.003-1.013;
P
= 0.001). The agonal phase, hypoperfusion time, and anastomosis time were not independent risk factors for incidence of DGF.
Conclusions.
Considering all known ischemic periods during the donation after the circulatory death process, prolonged kidney extraction time increased the risk of DGF after kidney transplantation.
Summary
Perioperative antithrombotic therapy could play a role in preventing thromboembolic complications (TEC) after kidney transplantation (KTx), but little is known on postoperative bleeding ...risks. This retrospective analysis comprises 2000 single‐organ KTx recipients transplanted between 2011 and 2016 in the two largest transplant centers of the Netherlands. TEC and bleeding events were scored ≤7 days post‐KTx. Primary analyses were for associations of antithrombotic therapy with incidence of TEC and bleeding. Secondary analyses were for associations of other potential risk factors. Mean age was 55 ± 14 years, 59% was male and 60% received a living donor kidney. Twenty‐one patients (1.1%) had a TEC. Multiple donor arteries OR 2.79 (1.15–6.79) and obesity OR 2.85 (1.19–6.82) were identified as potential risk factors for TEC. Bleeding occurred in 88 patients (4.4%) and incidence varied significantly between different antithrombotic therapies (P = 0.006). Cardiovascular disease OR 2.01 (1.18–3.42), pre‐emptive KTx OR 2.23 (1.28–3.89), postoperative heparin infusion OR 1.69 (1.00–2.85), and vitamin K antagonists OR 6.60 (2.95–14.77) were associated with an increased bleeding risk. Intraoperative heparin and antiplatelet therapy were not associated with increased bleeding risk. These regimens appear to be safe for the possible prevention of TEC without increasing the risk for bleeding after KTx.
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