Summary
Cardiovascular disease is the leading cause of death following renal transplantation, and renal transplant patients have a greatly increased cardiac risk compared with the general population. ...Death with a functioning graft caused by cardiovascular disease also represents a substantial cause of graft loss. Decreased renal function in transplant recipients is a major contributor to increased cardiac risk, both as an independent risk factor and because of its negative effects on hypertension, anemia, left ventricular hypertrophy, and dyslipidemia. Graft loss and diabetes mellitus are also significant risk factors for cardiac death. Although critical for maintaining the transplanted organs, standard immunosuppressants have toxicities that exacerbate cardiac risk. Preservation of renal function, prevention of graft loss, and reductions in cardiovascular risk factors via improvements in both patient management and immunosuppressive therapies constitute critical strategies for optimizing patient and graft survival over the long term.
Although the incidence of early acute rejection could have been diminished in the past, the long-term renal allograft survival could not benefit from the introduction of more effective ...immunosuppressive regimens mainly aiming at cellular rejection mechanisms. The cause of chronic rejection is still discussed controversially. Here, we demonstrate to what extent human leukocyte antigen (HLA) antibodies (HLAab) posttransplant contribute to late graft outcome.
A total of 1014 deceased kidney transplant recipients transplanted at the Charité hospital were monitored in a cross-sectional manner for the development of HLAab using Luminex Single Antigen beads. Patients with stable kidney function at a median of 5-years posttransplant were tested once for HLAab and monitored for 5.5 years after testing.
Thirty percent of recipients showed HLAab. Donor-specific antibodies (DSA) were found in 31% of antibody positive patients. The presence of DSA was associated with a significantly lower graft survival of 49% vs. 83% in the HLAab negative group (P< or =0.0001). Non-DSAs also had an adverse effect on graft survival (70% vs. 83%; P=0.0001). In a prospective analysis of 195 patients with repeatedly no detectable HLAab, the survival probability was 94% as opposed to 79% survival among patients who developed HLAab de novo after the first testing (P=0.05).
We confirmed that HLAab produced even late after transplantation are detrimental to graft outcome. DSA were proven to have a strong adverse impact on graft survival. The results indicate that a posttransplant HLAab monitoring routine could be appropriate to improve long-term results.
Chronic kidney disease (CKD) is a major health-care burden. Increasing evidence suggests that a considerable proportion of patients are affected by a monogenic kidney disorder.
In this study, the ...kidney transplantation waiting list at the Charité was screened for patients with undetermined cause of CKD. By next-generation sequencing (NGS) we targeted all 600 genes described and associated with kidney disease or allied disorders.
In total, 635 patients were investigated. Of these, 245 individuals had a known cause of CKD (38.5%) of which 119 had a proven genetic disease (e.g., ADPKD, Alport). The other 340 patients (53.5%) were classified as undetermined diagnosis, of whom 87 had kidney failure (KF) onset <40 years. To this latter group genetic testing was offered as well as to those patients (n = 29) with focal segmental glomerulosclerosis (FSGS) and all individuals (n = 21) suspicious for thrombotic microangiopathy (TMA) in kidney biopsy. We detected diagnostic variants in 26 of 126 patients (20.6%) of which 14 of 126 (11.1%) were pathogenic or likely pathogenic. In another 12 of 126 (9.5%) patients, variants of unknown significance (VUS) were detected.
Our study demonstrates the diagnostic value of comprehensive genetic testing among patients with undetermined CKD.
Secondary hyperparathyroidism (sHPT) as a result of chronic kidney disease (CKD) is a common health problem and has been reported to manifest at the sacroiliac joints (SIJ). The aim of this ...investigation was to systematically assess sacroiliac joint changes in asymptomatic sHPT as detected by high-resolution CT. Included in this IRB-approved retrospective case-control study were 56 patients with asymptomatic sHPT as well as 259 matched controls without SIJ disease. Demographic data were retrieved from electronic patient records. High-resolution computed tomography datasets of all patients were subjected to a structured scoring, including erosions, sclerosis, osteophytes, joint space alterations and intraarticular calcifications. Chi
tests were used to compare frequencies of lesions. Erosions were significantly more prevalent in patients with sHPT, and were found mainly in the ventral (28.6% vs. 13.9%; p = 0.016) and middle (17.9% vs. 7.7%; p = 0.040) iliac portions of the SIJ. Partial ankylosis was rare in both cohorts (3.6% vs. 5.0%; p > 0.999); complete ankylosis was not observed. Neither extent not prevalence of sclerosis or calcifications differed significantly between groups. Joint lesions reminiscent of sacroiliitis can be found in a substantial portion of asymptomatic patients with secondary hyperparathyroidism. Further investigations into the clinical significance of these findings are warranted.
Mortality from COVID-19 among kidney transplant recipients (KTR) is high, and their response to three vaccinations against SARS-CoV-2 is strongly impaired. We retrospectively analyzed the serological ...response of up to five doses of the SARS-CoV-2 vaccine in KTR from 27 December 2020 until 31 December 2021. Particularly, the influence of the different dose adjustment regimens for mycophenolic acid (MPA) on serological response to fourth vaccination was analyzed. In total, 4277 vaccinations against SARS-CoV-2 in 1478 patients were analyzed. Serological response was 19.5% after 1203 basic immunizations, and increased to 29.4%, 55.6%, and 57.5% in response to 603 third, 250 fourth, and 40 fifth vaccinations, resulting in a cumulative response rate of 88.7%. In patients with calcineurin inhibitor and MPA maintenance immunosuppression, pausing MPA and adding 5 mg prednisolone equivalent before the fourth vaccination increased the serological response rate to 75% in comparison to the no dose adjustment (52%) or dose reduction (46%). Belatacept-treated patients had a response rate of 8.7% (4/46) after three vaccinations and 12.5% (3/25) after four vaccinations. Except for belatacept-treated patients, repeated SARS-CoV-2 vaccination of up to five times effectively induces serological response in kidney transplant recipients. It can be enhanced by pausing MPA at the time of vaccination.
Transplant recipients exhibit an impaired protective immunity after SARS-CoV-2 vaccination, potentially caused by mycophenolate (MPA) immunosuppression. Recent data from patients with autoimmune ...disorders suggest that temporary MPA hold might greatly improve booster vaccination outcomes. We applied a fourth dose of SARS-CoV-2 vaccine to 29 kidney transplant recipients during a temporary (5 weeks) MPA/azathioprine hold, who had not mounted a humoral immune response to previous vaccinations. Seroconversion until day 32 after vaccination was observed in 76% of patients, associated with acquisition of virus-neutralizing capacity. Interestingly, 21/25 (84%) calcineurin inhibitor-treated patients responded, but only 1/4 belatacept-treated patients responded. In line with humoral responses, counts and relative frequencies of spike receptor binding domain-specific (RBD-specific) B cells were markedly increased on day 7 after vaccination, with an increase in RBD-specific CD27++CD38+ plasmablasts. Whereas overall proportions of spike-reactive CD4+ T cells remained unaltered after the fourth dose, frequencies were positively correlated with specific IgG levels. Importantly, antigen-specific proliferating Ki67+ and in vivo-activated programmed cell death 1-positive T cells significantly increased after revaccination during MPA hold, whereas cytokine production and memory differentiation remained unaffected. In summary, antimetabolite hold augmented all arms of immunity during booster vaccination. These data suggest further studies of antimetabolite hold in kidney transplant recipients.
Sleep deprivation and disruption of the circadian rhythms could impair individual surgical performance and decision making. For this purpose, this study identified potential confounding factors on ...surgical renal transplant patient outcomes during day and night. Our retrospective cohort study of 215 adult renal cadaver transplant recipients, of which 132 recipients were allocated in the "day-time" group and 83 recipients in the "night-time" group, primarily stratified the patients into two cohorts, depending on the start time. Within a 24 h operational system, "day-time" was considered as being from 8 a.m. to 8 p.m. and "night-time" from 8 p.m. to 8 a.m.. Primary outcomes examined patient and graft survival after three months and one year. Secondary outcomes included the presence of acute rejection (AR) and delayed graft function (DGF), as well as the rate of postoperative complications. In log-rank testing, "day-time" surgery was associated with a significantly higher risk of patient death (
= 0.003), whereas long-term graft survival was unaffected by the operative time of day. The mean cold ischemia time (CIT), which was 12.4 ± 5.3 h in the "night-time" group, was significantly longer compared to 10.7 ± 3.6 for those during the day (
= 0.01). We observed that "night-time" kidney recipients experienced more wound complications. From our single-centre data, we conclude that night-time kidney transplantation does not increase the risk of adverse events or predispose the patient to a worse outcome. Nevertheless, further research is required to explore the effect of fatigue on nocturnal surgical performance.
Summary
Currently, no international standard for the pre‐transplant evaluation of living donor renal function exists. Following a standardized questionnaire on current practice in all Eurotransplant ...(ET) centers, we compared a new CT‐based technique to measure renal cortex volume with our standard of DTPA‐clearance combined with MAG3‐scintigraphy (DTPA × MAG3) and with creatinine‐based methods in 167 consecutive living kidney donors. Most ET centers use creatinine‐clearance (64%) to measure total renal function and radioistopic methods (82%) to assess split renal function. Before transplantation, CT‐measured total cortex volume (r = 0.67; P < 0.001) and estimated GFR using the Cockcroft‐Gault formula eGFR(CG) (r = 0.55; P < 0.001) showed the strongest correlation with DTPA‐clearance. In contrast, the correlation between DTPA‐clearance and creatinine clearance was weak (r = 0.21; P = 0.02). A strong correlation was observed between CT‐measured split cortex volume and MAG3‐measured split renal function (r = 0.93; P < 0.001). A strong correlation was also found between pre‐transplant split renal function assessed by eGFR(CG) together with cortex volume measurement and post‐transplant eGFR(CG) of both, the donor (r = 0.83; P < 0.001) and the recipient (r = 0.75; P < 0.001). In conclusion CT‐based assessment of renal cortex volume bears the potential to substitute existing methods to assess pre‐transplant living donor split renal function.
Transplant candidates are facing incremental mortality risks on the waiting list. Here, we report a novel strategy to expand the donor pool by including hepatitis C seropositive (HCV+) donors. We ...investigated a pre-exposure prophylactic (PrEP) treatment with direct-acting antivirals (DAA) to allow transplantation for HCV seronegative (HCV-) kidney transplant recipients (KTR) with the aim to prevent HCV infection post transplantation. In this prospective trial, a pan-genotypic PrEP with daclatasvir and sofosbuvir once daily for 12 week was administered at transplantation. The primary endpoint sustained virological negativity (SVN) 12 weeks after the end of PrEP. Seven patients received a transplantation from four HCV+ donors. Accumulated waiting time was 70 ± 31.3 months already. Of note, study subjects underwent transplantation 24.7 ± 16.1 days after given consent. All KTR developed excellent graft function without any rejection episodes. One patient died with a functioning graft due to sepsis 13 months after transplantation. PrEP demonstrated efficacy with no signs of HCV transmission with excellent tolerability. Two out of four HCV+ donors were viremic at the time of explantation. Interestingly, KTR developed HCV antibodies also from non viramic donors. The acceptance of HCV+ donor was safe and reduced waiting time under the protection of PrEP DAA in kidney transplantation.
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