Predictors of postoperative cardiovascular complications up to 3 months after kidney transplantation.

BACKGROUND: Renal transplant patients have a high peri-operative risk for cardiovascular events. Pre-operative screening for cardiac ischaemia might lower this risk, but there are no specific guidelines. METHODS: We conducted a chart review for all renal transplants performed between January 2010 and December 2013. We collected data about patient characteristics, pre-operative cardiac evaluation before referral, diagnostic tests and interventions. Logistic regression analyses were then applied to relate these factors to the composite endpoint of cardiac death, myocardial infarction, coronary revascularisation or admission for heart failure within 3 months after transplantation. RESULTS: A total of 770 kidney transplants were performed in 751 patients. In 750 cases (97%) a referral to the cardiologist was made. Non-invasive ischaemia detection by myocardial perfusion scintigraphy, exercise stress test or dobutamine stress echocardiography was carried out in 631 cases (82%). Coronary angiography was performed in 85 cases, which revealed significant coronary artery disease in 19 cases. Prophylactic revascularisation was done in 7 cases. The incidence of the study endpoint was 8.6%. In multivariable regression analysis, age at transplantation, pre-transplant myocardial infarction or heart failure, post-operative decrease in haemoglobin and positive non-invasive ischaemia testing were significantly associated with the study endpoint. However, when analysed separately, none of the different non-invasive ischaemia detection modalities were related to the study endpoint. CONCLUSION: Especially those renal transplant candidates with a cardiac history carry a high risk for a cardiovascular event post-transplantation. Uniformity in cardiac screening of renal transplant candidates and better pre-operative preparation might lower this post-operative risk. Besides, post-transplant anaemia should be prevented.

Disrupted regulation of serpinB9 in circulating T cells is associated with an increased risk for post-transplant skin cancer.

Cutaneous squamous cell carcinoma (cSCC) is a serious complication after organ transplantation and patients benefit from an early risk assessment. We hypothesized that functional differences in circulating T cells may represent risk factors for post-transplant cSCC development. Here, we analysed genome-wide DNA methylation of circulating T cells of kidney transplant recipients before the clinical onset of cSCC, to identify differences associated with post-transplant cSCC development. This analysis identified higher DNA methylation of SERPINB9, which is an intracellular inhibitor of granzyme B, a protein that induces apoptosis in target cells. High DNA methylation of SERPINB9 in circulating T cells was confirmed in a second patient cohort during recurrent cSCC, indicating that high SERPINB9 methylation represents a persistent risk factor for cSCC development. At the functional level, the inverse correlation between DNA methylation and messenger RNA expression present in non-cSCC patients was absent in the cSCC patients. Also, a significant difference in serpinB9 protein expression between cSCC patients and non-cSCC patients was observed. It was concluded that disturbed regulation of serpinB9 in circulating T cells represents a novel risk factor for post-transplant cSCC in kidney transplant recipients.

A Randomized Controlled Trial Comparing the Efficacy of Cyp3a5 Genotype-Based With Body-Weight-Based Tacrolimus Dosing After Living Donor Kidney Transplantation.

Patients expressing the cytochrome P450 (CYP) 3A5 gene require a higher tacrolimus dose to achieve therapeutic exposure compared with nonexpressers. This randomized-controlled study investigated whether adaptation of the tacrolimus starting dose according to CYP3A5 genotype increases the proportion of kidney transplant recipients being within the target tacrolimus predose concentration range (10-15 ng/mL) at first steady-state. Two hundred forty living-donor, renal transplant recipients were assigned to either receive a standard, body-weight-based or a CYP3A5 genotype-based tacrolimus starting dose. At day 3, no difference in the proportion of patients having a tacrolimus exposure within the target range was observed between the standard-dose and genotype-based groups: 37.4% versus 35.6%, respectively; p = 0.79. The proportion of patients with a subtherapeutic (i.e. <10 ng/mL) or a supratherapeutic (i.e. >15 ng/mL) Tac predose concentration in the two groups was also not significantly different. The incidence of acute rejection was comparable between both groups (p = 0.82). Pharmacogenetic adaptation of the tacrolimus starting dose does not increase the number of patients having therapeutic tacrolimus exposure early after transplantation and does not lead to improved clinical outcome in a low immunological risk population.

Multi-GeV wakefield acceleration in a plasma-modulated plasma accelerator.

We investigate the accelerator stage of a plasma-modulated plasma accelerator (P-MoPA) [Jakobsson et al., Phys. Rev. Lett. 127, 184801 (2021)0031-900710.1103/PhysRevLett.127.184801] using both the paraxial wave equation and particle-in-cell (PIC) simulations. We show that adjusting the laser and plasma parameters of the modulator stage of a P-MoPA allows the temporal profile of pulses within the pulse train to be controlled, which in turn allows the wake amplitude in the accelerator stage to be as much as 72% larger than that generated by a plasma beat-wave accelerator with the same total drive laser energy. Our analysis shows that Rosenbluth-Liu detuning is unimportant in a P-MoPA if the number of pulses in the train is less than ∼30, and that this detuning is also partially counteracted by increased red-shifting, and hence increased pulse spacing, towards the back of the train. An analysis of transverse mode oscillations of the driving pulse train is found to be in good agreement with 2D (Cartesian) PIC simulations. PIC simulations demonstrating energy gains of ∼1.5GeV (∼2.5GeV) for drive pulse energies of 2.4J (5.0J) are presented. Our results suggest that P-MoPAs driven by few-joule, picosecond pulses, such as those provided by high-repetition-rate thin-disk lasers, could accelerate electron bunches to multi-GeV energies at pulse repetition rates in the kilohertz range.

Stability of the modulator in a plasma-modulated plasma accelerator.

We explore the regime of operation of the modulator stage of a recently proposed laser-plasma accelerator scheme [Phys. Rev. Lett. 127, 184801 (2021)0031-900710.1103/PhysRevLett.127.184801], dubbed the plasma-modulated plasma accelerator (P-MoPA). The P-MoPA scheme offers a potential route to high-repetition-rate, GeV-scale plasma accelerators driven by picosecond-duration laser pulses from, for example, kilohertz thin-disk lasers. The first stage of the P-MoPA scheme is a plasma modulator in which a long, high-energy "drive" pulse is spectrally modulated by copropagating in a plasma channel with the low-amplitude plasma wave driven by a short, low-energy "seed" pulse. The spectrally modulated drive pulse is converted to a train of short pulses, by introducing dispersion, which can resonantly drive a large wakefield in a subsequent accelerator stage with the same on-axis plasma density as the modulator. In this paper we derive the 3D analytic theory for the evolution of the drive pulse in the plasma modulator and show that the spectral modulation is independent of transverse coordinate, which is ideal for compression into a pulse train. We then identify a transverse mode instability (TMI), similar to the TMI observed in optical fiber lasers, which sets limits on the energy of the drive pulse for a given set of laser-plasma parameters. We compare this analytic theory with particle-in-cell (PIC) simulations and find that even higher energy drive pulses can be modulated than those demonstrated in the original proposal.

Fasting before living-kidney donation: effect on donor well-being and postoperative recovery: study protocol of a multicenter randomized controlled trial.

BACKGROUND: One of the main effectors on the quality of life of living-kidney donors is postoperative fatigue. Caloric restriction (CR) and short-term fasting (STF) are associated with improved fitness and increased resistance to acute stress. CR/STF increases the expression of cytoprotective genes, increases immunomodulation via increased anti-inflammatory cytokine production, and decreases the expression of pro-inflammatory markers. As such, nutritional preconditioning by CR or STF represents a non-invasive and cost-effective method that could mitigate the effects of acute surgery-induced stress and postoperative fatigue. To investigate whether preoperative STF contributes to a reduction in fatigue after living-kidney donation, a randomized clinical trial is indicated. METHODS: We aim to determine whether 2.5 days of fasting reduces postoperative fatigue score in subjects undergoing living-kidney donation. In this randomized study, the intervention group will follow a preoperative fasting regime for 2.5 days with a low-dose laxative, while the control group will receive standard care. The main study endpoint is postoperative fatigue, 4 weeks after living-kidney donation. Secondary endpoints include the effect of preoperative fasting on postoperative hospital admission time, the feasibility of STF, and the postoperative recovery of donor and recipient kidney function. This study will provide us with knowledge of the feasibility of STF and confirm its effect on postoperative recovery. DISCUSSION: Our study will provide clinically relevant information on the merits of caloric restriction for living-kidney donors and recipients. We expect to reduce the postoperative fatigue in living-kidney donors and improve the postoperative recovery of living-kidney recipients. It will provide evidence on the clinical merits and potential caveats of preoperative dietary interventions. TRIAL REGISTRATION: Netherlands Trial Register NL9262 . EudraCT 2020-005445-16 . MEC Erasmus MC MEC-2020-0778. CCMO NL74623.078.21.

The detrimental effect of donor-specific antibodies is irrespective of its level in highly-immunized living donor kidney transplant recipients: A case-control series.

Background: The impact of donor-specific antibodies (DSA) in (highly-) immunized living donor kidney transplant recipients is reported differentially in various patient cohorts. Methods: We have performed a retrospective analysis of all consecutive HLA-incompatible living donor kidney transplant recipients in our center between 2010-2019. Recipients who underwent plasmafiltration for a positive CDC-crossmatch were excluded. For each DSA+ recipient (DSA+), one immunized recipient without DSA (pPRA+) and two non-immunized recipients (pPRA-) were included. Patient and graft survival were analyzed and a subgroup analysis of DSA+ recipients was performed. Results: For 63 DSA+ recipients, 63 PRA+ and 126 PRA- recipients were included. 26 (41%) had class I, 24 (38%) class II and 13 (21%) combined HLA class I and II DSA. Death-censored graft survival was inferior in DSA+ recipients compared to pPRA+ (HR 2.38 [95% CI 1.00-5.70]) as well as to pPRA- (HR 3.91 [1.86-8.22]). In multivariate analysis, DSA remained of negative influence on death-censored graft survival. Flowcytometric crossmatch, MFI value, HLA class and origin of DSA were not of significant impact. Conclusion: In our cohort of (highly-) immunized recipients, pretransplant DSA led to inferior death-censored graft survival. There were no "safe" DSA characteristics since only DSA per se impacted death-censored graft survival.

Pharmacokinetics, efficacy and safety of alitretinoin in moderate or severe chronic hand eczema.

BACKGROUND: Recent studies have found that alitretinoin can induce clinically significant responses in subjects with severe chronic hand eczema (CHE) unresponsive to topical corticosteroids. AIMS: To assess the pharmacokinetics (PK), efficacy and safety of alitretinoin 10 or 30 mg once daily. METHODS: This was a randomized, double-blind study, which enrolled 32 subjects aged 18-75 years with CHE unresponsive to potent topical corticosteroids. Subjects received alitretinoin 10 mg (n = 16) or 30 mg (n = 16) once daily for 12 or 24 weeks. Standard PK variables [area under the curve (AUC) of plasma concentration vs. time, maximum plasma concentration (C(max)), time to maximum plasma concentration (t(max)), elimination half-life (t(1/2)), total systemic clearance (CL/F) and volume of distribution (Vd/F)] were determined for alitretinoin and metabolites. Efficacy was assessed using the Physician's Global Assessment (PGA) scale. RESULTS: Chronic administration of alitretinoin for up to 24 weeks did not result in accumulation or time-dependent changes in the disposition of alitretinoin. Exposure was found to be proportional to dose. Systemic exposure (AUC) to alitretinoin was proportional to dose for 10 and 30 mg alitretinoin; 62.8% of subjects achieved clear/almost clear hands in the 30 mg group and 12.5% in the 10 mg group. Alitretinoin was well tolerated. CONCLUSIONS: Chronic administration of alitretinoin for 12-24 weeks did not lead to accumulation or time-dependent changes in drug exposure. Alitretinoin was effective and well tolerated in the treatment of subjects with moderate or severe CHE unresponsive to potent topical corticosteroids.

Altruistic donor triggered domino-paired kidney donation for unsuccessful couples from the kidney-exchange program.

Between January 2000 and July 2009, 132 individuals inquired about altruistic kidney donation to strangers. These donors were willing to donate to genetically and emotionally unrelated patients. Some altruistic donors wished to donate to a specific person, but most wished to donate anonymously. In domino-paired donation, the altruistic donor donates to the recipient of an incompatible couple; the donor of that couple (domino-donor) donates to another couple or to the waiting list. In contrast to kidney-exchange donation where bilateral matching of couples is required, recipient and donor matching are unlinked in domino-paired donation. This facilitates matching for unsuccessful couples from the kidney-exchange program where blood type O prevails in recipients and is under-represented in donors. Fifty-one altruistic donors (39%) donated their kidney and 35 domino-donors were involved. There were 29 domino procedures, 24 with 1 altruistic donor and 1 domino-donor, 5 with more domino-donors. Eighty-six transplantations were performed. Donor and recipient blood type distribution in the couples limited allocation to blood type non-O waiting list patients. The success rate of domino-paired donation is dependent on the composition of the pool of incompatible pairs, but it offers opportunities for difficult to match pairs that were unsuccessful in the kidney-exchange program.

Successful expansion of the living donor pool by alternative living donation programs.

Between January 2000 and December 2007, 786 potential recipients and 1059 potential donors attended our pretransplant unit with the request for a living-donor renal transplant procedure. The recipients brought one potential donor in 77.2% and two or more donors in 22.8% of cases. In the regular living donor program, a compatible donor was found for 467 recipients. Without considering alternative donation, 579 donors would have been refused. Alternative living donation programs led to 114 compatible combinations: kidney-exchange program (35), ABO-incompatible donation (25), anonymous donation (37) and domino-paired anonymous donation (17). Together, the 114 alternative program donations and the 467 regular living donations led to 581 living donor transplantations (24.4% increase). Eventually for 54.9% (581/1059) of our donors, a compatible combination was found. Donor-recipient incompatibility comprised 19.4% (89/458) in the final refused population, which is 8.8% of the potential donor-recipient couples. Without considering alternative donation, 30.1% (174/579) of the refused donors would have been refused on incompatibility and 6.4% (37/579) because they were anonymous. This is 20% of the potential donor population (211/1059). The implementation of alternative living donation programs led to a significant increase in the number of transplantations, while transplantations via the direct donation program steadily increased.

Conversion from tacrolimus to everolimus with complete and early glucocorticoid withdrawal after kidney transplantation: a randomised trial.

BACKGROUND: While conversion from cyclosporine to everolimus is well documented, conversion from tacrolimus has been poorly studied. In this randomised, controlled trial the safety and tolerability of switching from tacrolimus to everolimus with glucocorticoid withdrawal after living-donor kidney transplantation was studied. METHODS: A total of 194 patients were planned to be randomised 1:1 to either continue tacrolimus or to convert to everolimus at month 3 after transplantation. At randomisation, all patients received tacrolimus, mycophenolate mofetil and prednisolone. Everolimus was started in a dose of 1.5 mg twice daily, aiming for predose concentrations of 4-7 ng/ml. Prednisolone was gradually withdrawn in both groups. RESULTS: The trial was stopped prematurely after the inclusion of 60 patients. The interim analysis showed an unacceptably high rejection rate in the everolimus group as compared with the control group: 30.0% vs. 6.7% (95% CI: 0.047-0.420; p = 0.045). An additional 8 patients stopped everolimus because of toxicity. At the end of follow-up (month 12) only 12 (40%) patients assigned to everolimus were still on the study drug. CONCLUSIONS: Conversion from tacrolimus to everolimusbased immunosuppression with withdrawal of prednisolone three months after kidney transplantation results in an unacceptably high risk of acute rejection and causes considerable toxicity. Based on our findings, such a switch strategy cannot be recommended.

Successful Use of Ectopic Pelvic Kidney for Living Related Donation Technical Aspects and Literature Review.

Ectopic pelvic kidneys can provide an additional source of organs for transplantation. They are often excluded from donation in living donation programs mainly due to aberrant vascular and urinary anatomies. We present a donor with an ectopic left kidney, who successfully donated his kidney. The use of ectopic pelvic kidney for living kidney transplantation is a highly demanding surgical procedure but after extensive preoperative investigation in high volume centers with surgical expertise in vascular reconstruction and access surgery, ectopic pelvic kidneys should not be a contraindication for donation and should be considered as a viable option.

Determination of the bioavailability of [14C]-hexaminolevulinate using accelerator mass spectrometry after intravesical administration to human volunteers.

Hexaminolevulinate (HAL) is a diagnostic agent that allows the visualization of tumor tissue in the bladder by fluorescence cystoscopy. It is administered intravesically via a catheter for 1 hour, followed by blue light bladder inspection to induce selective red tumor fluorescence. Hexaminolevulinate should ideally be confined to the bladder only, but it is likely that some absorption occurs during administration, and therefore the systemic bioavailability is of interest. The bioavailability of HAL was determined by intravesical and intravenous administration of [14C]-HAL hydrochloride to 8 human volunteers. To reduce the radiation dose as low as possible, the ultrasensitive analytical technique of accelerator mass spectrometry was used to measure [14C]-HAL. The bioavailability of [14C]-HAL after intravesical and intravenous administration was determined from the respective area under the curve based on total radioactivity and was determined to be 7% (range, 5%-10%; 90% confidence interval). The systemic absorption of [14C]-HAL after intravesical administration is low and supports previous clinical experience with HAL showing no systemic side effects.

Donor-reactive cytokine production after HLA-identical living related kidney transplantation: a protein-array analysis.

In the present pilot study, we investigated which proteins are produced after donor stimulation of peripheral blood mononuclear cells from recipients of HLA-identical living related kidney transplant. We used a protein-array analysis to determine cytokines, chemokines, and growth factors in supernatant from donor-stimulated mixed lymphocyte reaction cultures. Autologous cultures were considered to be negative controls. In 38 out of 42 proteins (90%), the donor response was higher compared with the autologous response. Therefore, we concluded that even after HLA-identical living related kidney transplantation we could measure a donor-reactive response, which we assumed was directed toward minor histocompatibility or non-HLA antigens.

Granzyme B ELISPOT assay determines the cytotoxic T lymphocyte precursor frequency after HLA-identical living-related kidney transplantation.

A major goal in organ transplantation is to define the optimal immunosuppressive dose. Recently, we demonstrated that the frequency of cytotoxic T lymphocytes (CTLpf) identifies patients in whom the immunosuppressive load can be safely reduced. However, in peripheral blood mononuclear cells (PBMC) from HLA-identical living-related kidney transplant patients, no donor-specific CTLpf can be measured. The determination of the functional activity of cytotoxic T lymphocytes (CTLs) could be an alternative method for the CTLpf. Granzyme B (GrB) is present in the granules of CTLs and is involved in the direct lethal hit of donor target cells. Therefore, we wondered whether the GrB ELISPOT assay is an alternative method to determine the activity of CTLs after HLA-identical living-related kidney transplantation. We measured the number of GrB producing cells (pc) against donor PBMC and third-party PBMC in PBMC from HLA-identical patients who were reduced in their immunosuppression from 100% to 50% azathioprine with 5 to 10 mg/day prednisone. We found low numbers of GrB pc before reduction of immunosuppression, as only 20% of the patients' PBMC responded to donor cells, whereas 57% of the patients' PBMC responded to donor cells after reduction of immunosuppression. After third-party stimulation, the number of GrB pc increased after tapering the immunosuppressive load (P = .03). Our results demonstrate that the GrB ELISPOT assay might be used as an alternative for the CTLpf after HLA-identical living-related kidney transplantation.

Reduction of immunosuppressive load in renal transplant recipients with a low donor-specific cytotoxic T-lymphocyte precursor frequency is safe.

BACKGROUND: Tapering of immunosuppressive medication is indicated to prevent long-term side effects. Recently, we have shown that renal transplant recipients can safely be converted from calcineurin inhibitors to MMF or AZA when their donor-specific cytotoxic T-lymphocyte precursor frequencies (CTLpf) are below 10/10(6) PBMC. We wondered whether a low CTLpf also had predictive value when immunosuppressive medication was reduced in patients only on MMF or AZA and steroid medication. METHODS: Renal transplant recipients with stable renal function at least 2 years after transplantation and with low (<10/10(6) PBMC) CTLpf were included. Their MMF or AZA dose was reduced to 75% and to 50% of the original dose at 4 months and 8 months after inclusion. Endpoint of the study was 12 months after inclusion or developing acute rejection. RESULTS: Forty-five patients have reached the 1-year follow up endpoint. Their median time after transplantation was 4.2 years (range 2.0-15.5 years). Acute rejection was seen in one patient only (who had discontinued all his medication). CONCLUSION: In patients with low CTLpf long after kidney transplantation, a 50% reduction of immunosuppression is safe and further decreasing their immunosuppressive load is the obvious next step.

Cardiac and metabolic effects in patients who present with a multinodular goitre.

Twenty-six consecutive patients who presented with clinically euthyroid multinodular goitre were studied for an overnight fasting serum lipid profile and 24 h Holter monitoring. Mean serum TSH was 0.6 +/- 0.4 vs 2.4 +/- 1.3 mU/l (p < 0.0001) and mean TT3 2.4 +/- 0.4 vs 2.0 +/- 0.5 nmol/l (p = 0.009) in patients vs controls (n = 15) while mean FT4 was not different from controls. Total serum HDL, LDL cholesterol and triglycerides were lower in patients but creatinine, ferritin and SHBG levels did not differ between patients and controls. The 24-hour ambulatory continuous ECG recordings did not demonstrate significant differences in mean, minimal and maximal heart rate between the study and the control group. Nocturnal heart rate, measured between 23.00 and 06.00 hours, also showed no differences between the two groups. Atrial fibrillation was absent in both the study and the control group. Premature atrial and ventricular complexes occurred equally frequently in both groups. Comparison of patients with a serum TSH below 0.4 mU/l (n = 11) and patients with a TSH above 0.4 mU/l revealed no differences. In conclusion, in consecutive patients who present with multinodular goitre, effects were found on the lipid profile, but not on the heart. It is argued that in this type of patients, cardiac effects depend on the degree of subclinical hyperthyroidism.

Acute epiglottitis as a cause of airway obstruction in an adult patient.

Epiglottitis in adults is a dangerous infectious disease with a rising incidence and potential fatal complications as illustrated in this case report. Like in children, skilled and aggressive airway protection with appropriate antibiotic therapy have been effective in reducing mortality.

Oral alitretinoin: a review of the clinical pharmacokinetics and pharmacodynamics.

Alitretinoin is an endogenous retinoid related to vitamin A. Studies have shown that oral alitretinoin is effective and well tolerated in the treatment of severe chronic hand eczema. This review summarizes the clinical pharmacokinetic and pharmacodynamic data from a number of studies involving alitretinoin. These include the effect of food on the pharmacokinetics of alitretinoin, interactions between alitretinoin and ketoconazole, simvastatin or cyclosporin A, the effect of alitretinoin on the pharmacokinetics of a combined oral contraceptive, alitretinoin in seminal fluid after repeated dosing, and the pharmacokinetics of alitretinoin and its metabolites in a clinical setting.

Randomised clinical trial: anti-viral activity of ANA773, an oral inducer of endogenous interferons acting via TLR7, in chronic HCV.

BACKGROUND: The ANA773 is an oral prodrug of a small-molecule toll-like receptor (TLR)7 agonist. Preclinical and healthy volunteer clinical studies with ANA773 have demonstrated induction of endogenous interferon-α (IFN-α) of multiple subtypes, which supports the potential utility in the treatment of chronic hepatitis C virus (HCV) infection. AIM: To examine safety, tolerability, pharmacodynamics, pharmacokinetics and anti-viral activity of ANA773. METHODS: The ANA773 was investigated in a double-blind, placebo-controlled study in 34 patients chronically infected with HCV of any genotype. Patients were treatment-naïve or had relapsed following previous interferon-based treatment. This dose escalation study was composed of four dose groups (800, 1200, 1600 and 2000mg). In each group, six to eight patients received ANA773 and two received placebo. Patients were dosed with ANA773 every-other-day for either 28 days (800, 1200 or 1600mg) or 10days (2000mg). RESULTS: Mild to moderate adverse events were reported, with an increase in frequency and intensity with increasing dose. No serious AEs were reported and there were no early discontinuations. There were dose-related increases in various markers of IFN-α response. The mean maximum change in serum HCV RNA level from baseline was -0.34, -0.29, -0.40, -0.97 and -1.26log(10) in the placebo, 800, 1200, 1600 and 2000mg cohorts, respectively. At the 2000mg dose, ANA773 significantly (P=0.037) reduced serum HCV RNA levels (range: 0.14 to -3.10log(10) ). CONCLUSION: The ANA773 was generally well tolerated and resulted in a dose-related IFN-dependent response leading to a significant decrease in serum HCV RNA levels in the 2000mg dose group.