Kidney transplant donors are not currently implicated in predicting BK polyomavirus (BKPyV) infection in kidney transplant recipients. It has been postulated, however, that BKPyV infection originates ...from the kidney allograft. Because BKPyV seroreactivity correlates with BKPyV replication and thus might mirror the infectious load, we investigated whether BKPyV seroreactivity of the donor predicts viremia and BKPyV‐associated nephropathy (BKPyVAN) in the recipient. In a retrospective cohort of 407 living kidney donor–recipient pairs, pretransplantation donor and recipient sera were tested for BKPyV IgG levels and correlated with the occurrence of recipient BKPyV viremia and BKPyVAN within 1 year after transplantation. Donor BKPyV IgG level was strongly associated with BKPyV viremia and BKPyVAN (p < 0.001), whereas recipient BKPyV seroreactivity showed a nonsignificant inverse trend. Pairing of high–BKPyV‐seroreactive donors with low‐seroreactive recipients resulted in a 10‐fold increased risk of BKPyV viremia (hazard ratio 10.1, 95% CI 3.5–29.0, p < 0.001). In multivariate analysis, donor BKPyV seroreactivity was the strongest pretransplantation factor associated with viremia (p < 0.001) and BKPyVAN (p = 0.007). The proportional relationship between donor BKPyV seroreactivity and recipient infection suggests that donor BKPyV seroreactivity reflects the infectious load of the kidney allograft and calls for the use of pretransplantation BKPyV serological testing of (potential) donors and recipients.
In this retrospective cohort study, the authors find pretransplantation donor–recipient pair BK polyomavirus seroreactivity predicts viremia and nephropathy after kidney transplantation.
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BFBNIB, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Infection with SARS-CoV-2 in high-risk groups such as kidney transplant and dialysis patients is shown to be associated with a more serious course of the disease. Four years after the start of the ...COVID-19 pandemic, crucial knowledge on the immune responses in these patient groups is still lacking. Therefore, this study aimed at investigating the humoral immune response after a SARS-CoV-2 infection compared to vaccination as well as the evolution of immunoglobulins over time. Kidney transplant recipients, patients on haemodialysis or on peritoneal dialysis and healthy controls were included in this longitudinal multicenter study. SARS-CoV-2 anti-RBD, anti-NP and anti-S1S2 immunoglobulin G (IgG) and A (IgA) as well as the neutralizing antibody capacity were measured. Kidney transplant recipients had a significantly better humoral response to SARS-CoV-2 after infection (86.4%) than after a two-dose mRNA vaccination (55.8%) while seroconversion was comparable in patients on haemodialysis after infection (95.8%) versus vaccination (89.4%). In individuals without prior COVID-19, the IgG levels after vaccination were significantly lower in kidney transplant recipients when compared to all other groups. However, the IgA titres remained the highest in this patient group at each time point, both after infection and vaccination. A history COVID-19 was associated with higher antibody levels after double-dose vaccination in all patient categories and, while decreasing, titres remained high six months after double-dose vaccination. Kidney transplant recipients had a more robust humoral response to SARS-CoV-2 following infection compared to a two-dose mRNA vaccination, while patients on haemodialysis exhibited comparable seroconversion rates. Notably, individuals with prior COVID-19 exhibited higher IgG levels in response to vaccination. Hybrid immunity is thus the best possible defence against severe COVID-19 disease and seems also to hold up for these populations. Next, it is not clear whether the higher IgA levels in the kidney transplant recipients is beneficial for neutralizing SARS-CoV-2 or if it is a sign of disease severity.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Despite (repeated) boosting, kidney transplant recipients (KTRs) may remain at increased risk of severe COVID‐19 since a substantial number of individuals remain seronegative or with low antibody ...titers. In particular, mycophenolic acid use has been shown to affect antibody formation negatively and may be an important modifiable risk factor. We investigated the exposure–response relationship between mycophenolic acid 12‐hour area under the curve (AUC0–12h) exposure and seroconversion including antibody titers after vaccination using mRNA‐1273 SARS‐CoV‐2 vaccine (Moderna) in 316 KTRs from our center that participated in the national Dutch renal patients COVID‐19 vaccination – long term efficacy and safety of SARS‐CoV‐2 vaccination in kidney disease patients vaccination study. After two vaccination doses, 162 (51%) KTRs seroconverted. KTRs treated with mycophenolic acid showed less seroconversion and lower antibody titers compared with KTRs without mycophenolic acid (44% vs. 77%, and 36 binding antibody units (BAU)/mL vs. 340 BAU/mL; P < 0.001). The mean mycophenolic acid AUC0–12h exposure was significantly lower in KTRs who seroconverted compared with KTRs who did not (39 vs. 29 mg⋅h/L; P < 0.001). High mycophenolic acid exposure (±90 mg⋅h/L) and no exposure to mycophenolic acid resulted in a seroconversion rate ranging from 10% to 80%. Every 10 mg⋅h/L increase in mycophenolic acid AUC0–12h gave an adjusted odds ratio for seroconversion of 0.87 (95% confidence interval (CI), 0.79–0.97; P = 0.010) and 0.89 (95% CI, 0.85–0.93; P < 0.001) for KTRs on dual and triple maintenance immunosuppressive therapy, respectively. Higher mycophenolic acid AUC0–12h correlated with lower antibody titers (R = 0.44, P < 0.001). This study demonstrates the exposure–response relationship between gold standard mycophenolic acid exposure and antibody formation to support interventional studies investigating mycophenolic acid adjustment to improve antibody formation after further boosting.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Objective/Background Limited information is available on expected health status gains following invasive treatment in peripheral arterial disease (PAD). One year health status outcomes following ...invasive treatment for PAD were compared, and whether pre-procedural health status was indicative of 1 year health status gains was evaluated. Methods Pre-procedural and 1 year health status (Short Form-12, Physical Component Score PCS) was prospectively assessed in a cohort of 474 patients, enrolled from 2 Dutch vascular clinics (March 2006–August 2011), with new or exacerbation of PAD symptoms. One year treatment strategy (invasive vs. non-invasive) and clinical information was abstracted. Quartiles of baseline health status scores and mean 1 year health status change scores were compared by invasive treatment for PAD. The numbers needed to treat (NNT) to obtain clinically relevant changes in 1 year health status were calculated. A propensity weight adjusted linear regression analysis was constructed to predict 1 year PCS scores. Results Invasive treatment was performed in 39% of patients. Patients with baseline health status scores in the lowest quartile undergoing invasive treatment had the greatest improvement (mean invasive 11.3 ± 10.3 vs. mean non-invasive 5.3 ± 8.5 p = .001, NNT = 3), whereas those in the highest quartile improved less (.8 ± 6.3 vs. –3.0 ± 8.2 p = .025, NNT = 90). Undergoing invasive treatment ( p < .0001) and lower baseline health status scores ( p < .0001) were independently associated with greater 1 year health status gains. Conclusion Substantial improvements were found in patients presenting with lower pre-procedural health status scores, whereas patients with higher starting health status levels had less to gain by an invasive strategy.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Aims
Tacrolimus and mycophenolic acid dosing after renal transplantation is individualized through therapeutic drug monitoring (TDM). Home‐based dried blood spot (DBS) sampling has the potential to ...replace conventional TDM sampling at the clinic. A liquid chromatography–tandem mass spectrometry (LC–MS/MS) assay was developed to quantify tacrolimus and mycophenolic acid in DBS and clinically validated for abbreviated area under the concentration–time curve (AUC) monitoring using an innovative volumetric DBS sampling device.
Methods
Clinical validation was performed by direct comparison of paired DBS and whole blood (WB) (tacrolimus) and plasma (mycophenolic acid) concentrations and AUCs. Agreement was evaluated using Passing–Bablok regression, Bland–Altman analysis and DBS‐to‐WB predictive performance. TDM dosing recommendations based on both methods were compared to assess clinical impact.
Results
Paired tacrolimus (n = 200) and mycophenolic acid (n = 192) DBS and WB samples were collected from 65 kidney(–pancreas) transplant recipients. Differences for tacrolimus and mycophenolic acid were within ±20% for 84.5% and 76.6% of concentrations and 90.5% and 90.7% of AUCs, respectively. Tacrolimus and mycophenolic acid dosing recommendation differences occurred on 44.4% and 4.7% of occasions. Tacrolimus DBS dosing recommendations were 0.35 ± 0.14 mg higher than for WB and 8 ± 3% of the initial dose. Mycophenolic acid DBS dosing recommendations were 23.3 ± 31.9 mg lower than for plasma and 2 ± 3.5% of the initial dose.
Conclusions
Tacrolimus and mycophenolic acid TDM for outpatient renal transplant recipients, based on abbreviated AUC collected with a DBS sampling device, is comparable to conventional TDM based on WB sampling. Patient training and guidance on good blood‐spotting practices is essential to ensure method feasibility.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
The present review is part of the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) Study Group for Infections in Compromised Hosts (ESGICH) Consensus Document on the safety ...of targeted and biologic therapies.
To review, from an infectious diseases perspective, the safety profile of therapies targeting different intracellular signaling pathways and to suggest preventive recommendations.
Computer-based Medline searches with MeSH terms pertaining to each agent or therapeutic family.
Although BCR-ABL tyrosine kinase inhibitors modestly increase the overall risk of infection, dasatinib has been associated with cytomegalovirus and hepatitis B virus reactivation. BRAF/MEK kinase inhibitors do not significantly affect infection susceptibility. The effect of Bruton tyrosine kinase inhibitors (ibrutinib) among patients with B-cell malignancies is difficult to distinguish from that of previous immunosuppression. However, cases of Pneumocystis jirovecii pneumonia (PCP), invasive fungal infection and progressive multifocal leukoencephalopathy have been occasionally reported. Because phosphatidylinositol-3-kinase inhibitors (idelalisib) may predispose to opportunistic infections, anti-Pneumocystis prophylaxis and prevention strategies for cytomegalovirus are recommended. No increased rates of infection have been observed with venetoclax (antiapoptotic protein Bcl-2 inhibitor). Therapy with Janus kinase inhibitors markedly increases the incidence of infection. Pretreatment screening for chronic hepatitis B virus and latent tuberculosis infection must be performed, and anti-Pneumocystis prophylaxis should be considered for patients with additional risk factors. Cancer patients receiving mTOR inhibitors face an increased incidence of overall infection, especially those with additional risk factors (prior therapies or delayed wound healing).
Specific preventive approaches are warranted in view of the increased risk of infection associated with some of the reviewed agents.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Summary
Background Skin diseases are frequently observed in organ‐transplant recipients (OTRs).
Objectives To count the registered skin diseases in all 2136 OTRs who had been transplanted in a ...single centre between 1966 and 2006 and to calculate their relative contribution in relation to the number of years after transplantation.
Methods All registered skin diseases which were entered into a computerized system between 1994 and 2006 at the Leiden University Medical Centre were counted and their relative contributions were calculated.
Results Between 1994 and 2006, 2408 skin diseases were registered in 801 of 1768 OTRs who were at risk during this specific time period. The most commonly recorded diagnoses were skin infections (24·0%) followed by benign skin tumours (23·3%) and malignant skin lesions (18·2%). The relative contributions of infectious and inflammatory disorders decreased with time after transplantation, whereas the contribution of squamous cell carcinomas strongly increased with time.
Conclusions This study gives a systematic overview of the high burden of skin diseases in OTRs. The relative distributions of skin diseases importantly changed with time after transplantation, with squamous cell carcinoma contributing most to the increasing burden of skin diseases with increasing time after transplantation.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
The presence of donor‐specific anti‐HLA antibodies (DSAs) is associated with increased risk of graft failure after kidney transplant. We hypothesized that DSAs against HLA class I, class II, or both ...classes indicate a different risk for graft loss between deceased and living donor transplant. In this study, we investigated the impact of pretransplant DSAs, by using single antigen bead assays, on long‐term graft survival in 3237 deceased and 1487 living donor kidney transplants with a negative complement‐dependent crossmatch. In living donor transplants, we found a limited effect on graft survival of DSAs against class I or II antigens after transplant. Class I and II DSAs combined resulted in decreased 10‐year graft survival (84% to 75%). In contrast, after deceased donor transplant, patients with class I or class II DSAs had a 10‐year graft survival of 59% and 60%, respectively, both significantly lower than the survival for patients without DSAs (76%). The combination of class I and II DSAs resulted in a 10‐year survival of 54% in deceased donor transplants. In conclusion, class I and II DSAs are a clear risk factor for graft loss in deceased donor transplants, while in living donor transplants, class I and II DSAs seem to be associated with an increased risk for graft failure, but this could not be assessed due to their low prevalence.
Via a retrospective multicenter study, the authors investigate the impact of pretransplant donor‐specific HLA antibodies on long‐term graft survival in deceased and living donor kidney transplantations.
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BFBNIB, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
BK polyomavirus (BKPyV)-associated nephropathy (BKPyVAN) is a major threat for kidney transplant recipients (KTRs). The role of specific BKPyV genotypes/serotypes in development of BKPyVAN is poorly ...understood. Pretransplantation serotyping of kidney donors and recipients and posttransplantation genotyping of viremic recipients, could reveal the clinical relevance of specific BKPyV variants.
A retrospective cohort of 386 living kidney donor-recipient pairs was serotyped before transplantation against BKPyV genotype I-IV viral capsid protein 1 antigen, using a novel BKPyV serotyping assay. Replicating BKPyV isolates in viremic KTRs after transplantation were genotyped using real-time polymerase chain reaction and confirmed by means of sequencing. BKPyV serotype and genotype data were used to determine the source of infection and analyze the risk of viremia and BKPyVAN.
Donor and recipient BKPyV genotype and serotype distribution was dominated by genotype I (>80%), especially Ib, over II, III and IV. Donor serotype was significantly correlated with the replicating genotype in viremic KTRs (
< .001). Individual donor and recipient serotype, serotype (mis)matching and the recipient replicating BKPyV genotype were not associated with development of viremia or BKPyVAN after transplantation.
BKPyV donor and recipient serotyping and genotyping indicates the donor origin of replicating BKPyV in viremic KTRs but provides no evidence for BKPyV genotype-specific virulence.
Background
The mental health of dialysis patients during the COVID-19 pandemic may have been modulated by dialysis modality. Studies comparing mental health of in-center hemodialysis and peritoneal ...dialysis patients during the first 2 years of the pandemic are lacking.
Methods
We conducted repeated cross-sectional and multivariable regression analyses to compare the mental health of in-center hemodialysis and peritoneal dialysis patients from March 2019 until August 2021 using data from the Dutch nOcturnal and hoME dialysis Study To Improve Clinical Outcomes. The study period was divided into one pre-pandemic and six 3-month pandemic periods (period 1–period 6). Mental health was assessed with the Mental Component Summary score of the 12-item Short Form health survey and mental symptoms of the Dialysis Symptom Index.
Results
We included 1274 patients (968 on in-center hemodialysis and 306 on peritoneal dialysis). Mental Component Summary scores did not differ between in-center hemodialysis and peritoneal dialysis patients. In contrast, in-center hemodialysis patients more often reported nervousness during period 3 (27% vs 15%,
P
= 0.04), irritability and anxiety during period 3 (31% vs 18%,
P
= 0.03, 26% vs. 9%,
P
= 0.002, respectively) and period 4 (34% vs 22%,
P
= 0.04, 22% vs 11%,
P
= 0.03, respectively), and sadness in period 4 (38% vs 26%,
P
= 0.04) and period 5 (37% vs 22%,
P
= 0.009). Dialysis modality was independently associated with mental symptoms.
Conclusions
In-center hemodialysis patients more often experienced mental symptoms compared to peritoneal dialysis patients from September 2020 to June 2021, which corresponds to the second lockdown of the COVID-19 pandemic. Mental health-related quality-of-life did not differ between in-center hemodialysis and peritoneal dialysis patients.
Trial registration number
Netherlands Trial Register NL6519, date of registration: 22 August, 2017.
Graphical abstract
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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