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This paper extends dynamic prediction by landmarking to recurrent event data. The motivating data comprised post-kidney transplantation records of repeated infections and repeated measurements of multiple markers. At each landmark time point t s , a Cox proportional hazards model with a frailty term was fitted using data of individuals who were at risk at landmark s. This model included the time-updated marker values at t s as time-fixed covariates. Based on a stacked data set that merged all landmark data sets, we considered supermodels that allow parameters to depend on the landmarks in a smooth fashion. We described and evaluated four ways to parameterize the supermodels for recurrent event data. With both the study data and simulated data sets, we compared supermodels that were fitted on stacked data sets that consisted of either overlapping or non-overlapping landmark periods. We observed that for recurrent event data, the supermodels may yield biased estimates when overlapping landmark periods are used for stacking. Using the best supermodel amongst the ones considered, we dynamically estimated the probability to remain infection free between t s and a prediction horizon t hor , conditional on the information available at t s .

Background: The use of potent immunosuppressive drugs and increased travel by renal transplant recipients (RTR) has augmented the risk for infectious complications. Immunizations and changes in lifestyle are protective. The Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work Group has developed guidelines on vaccination following solid organ transplantation. The degree of adherence to these guidelines is unknown, as is which barriers must be overcome to improve adherence., Methods: We performed a cross-sectional national survey among Dutch nephrologists to assess vaccination policy and adherence to the KDIGO guidelines. In addition, to investigate awareness and attitude of RTR regarding their risk of infection, we performed a cross-sectional survey of RTR in our outpatient clinic., Results: A total of 132 (63%) nephrologists completed the survey. Reported immunization rates were 90.8% for influenza and 27.3% for hepatitis B. However, pneumococcal, tetanus toxoid, and meningococcal immunization rates were low. Twenty-seven percent of respondents were familiar with the guideline contents. The most frequent perceived barrier to guideline adherence was expectation of low effectiveness. A total of 403 RTR (62%) completed the survey. Sixty-eight percent perceived more risk for complicated infection. A significant correlation was found between education level and variables concerning awareness and attitude toward risk of infection., Conclusions: Our results show that nephrologists' knowledge of and adherence to the recommendations regarding immunization after renal transplantation is suboptimal. Most Dutch RTR are aware of their increased risk and the possible seriousness of infectious complications. However, their behavior does not match their awareness. This disparity points to an important role for nephrologists in providing adequate counseling., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The use of inhibitors of the mammalian target of rapamycin (mTORi) in renal transplantation is associated with many side effects, the potentially most severe being interstitial pneumonitis. Several papers have reported on sirolimus-induced pneumonitis, but less is published on everolimus-induced pneumonitis (EIP). Data on risk factors for contracting EIP are even more scarce. In the present case-cohort study in renal transplant recipients (RTR), we aimed to assess the incidence and risk factors of EIP after renal transplantation. This study is a retrospective substudy of a multicenter randomized controlled trial. All patients included in the original trial and treated with prednisolone/everolimus were included in this substudy. RTR who developed EIP were identified as cases. RTR without pulmonary symptoms served as controls. Thirteen of 102 patients (12.7%) developed EIP. We did not find any predisposing factors, especially no correlation with everolimus concentration. On pulmonary CT scan, EIP presented with an organizing pneumonia-like pattern, a nonspecific interstitial pneumonitis-like pattern, or both. Median time (range) to the development of EIP after start of everolimus was 162 (38-407) days. In conclusion, EIP is common in RTR, presenting with an organizing pneumonia, a nonspecific interstitial pneumonitis-like pattern, or both. No predisposing factors could be identified (Trial registration number: NTR567 (www.trialregister.nl), ISRCTN69188731)., (© 2014 Steunstichting ESOT.)

Background: Pneumocystis jiroveci pneumonia (PCP) is an important cause of morbidity and mortality in renal transplant recipients (RTRs). Chemoprophylaxis with trimethoprim/sulphamethoxazole is recommended during the early post-transplantation period, but the optimal duration has not been determined and a main drawback of chemoprophylaxis is the development of resistance of the commensal faecal flora. A cluster outbreak of PCP occurred in our outpatient Renal Transplant Unit. We aimed to investigate risk factors for PCP in RTRs to determine who should receive long-term chemoprophylaxis., Methods: In a case-control study, we investigated common demographic variables and immunological parameters. Nine PCP cases diagnosed between August 2006 and April 2007 were matched with 18 control patients, who did not develop PCP, received their transplant in the same time-period and had a similar follow-up period with a comparable immunosuppressive drug regimen., Results: The median time from transplantation to PCP was 19 months. We observed no significant differences in gender, age, donor type or number of rejections. In PCP cases, the median lymphocyte count just before PCP diagnosis was 0.49 (0.26-0.68), which was significantly reduced compared to the control patients after a similar follow-up period (median 1.36, 0.59-3.04, P = 0.002). This lymphocytopaenia was chronic and existed in most patients already for many months. CD4(+) T-cell counts were also significantly reduced in the PCP cases. We found no difference in the Th1, Th2 and Th17 subsets between PCP cases and control patients., Conclusion: Long-term prophylactic therapy for PCP may be indicated for RTR with persistent severe lymphocytopaenia.

While the guidelines for vaccination in renal transplant recipients recommend the use of pneumococcal polysaccharide (PPS) and tetanus toxoid (TT), their efficacy in immunocompromised renal transplant recipients is not known. Here we tested the effect of everolimus on immune responses after vaccination by measuring the capacity of 36 stable renal transplant recipients to mount cellular and humoral responses after vaccination. Twelve patients in each treatment arm received immunosuppressive therapy consisting of prednisolone (P) plus cyclosporine (CsA), mycophenolate sodium (MPA), or everolimus. Patients were vaccinated with the T-cell-dependent antigens immunocyanin and TT, and the T-cell-independent PPS. Treatment with CsA partially inhibited and MPA completely abolished the capacity to mount a primary humoral response, whereas everolimus left this largely intact. Recall responses were inhibited by MPA only. All drug combinations inhibited cellular responses against TT. In patients treated with MPA, B-cell numbers were severely reduced. Thus, combined with P, treatment with MPA completely disturbed primary and secondary humoral responses. Everolimus or CsA allowed the boosting of T-cell-dependent and -independent secondary humoral responses. Treatment with everolimus allowed a primary response.