Introduction BK polyomavirus-associated nephropathy (BKPyVAN) is a well-known complication of kidney transplantation (KTx).The mainstay of prevention is reduction of immunosuppression upon detection of BK polyomavirus (BKPyV) viremia, which precedes BKPyVAN. However, this reduction may inadvertently increase the risk of alloimmunity particularly in patients with a high BKPyV load, where significant immunosuppression reduction is often necessary. This single-center, retrospective cohort study assesses the risk of de novo donor-specific antibodies (dnDSA) development and biopsy-proven acute rejection (BPAR) following high and low BKPyV viremia. Methods All patients who underwent KTx at Leiden University Medical Center between 2011 and 2020 were included. Patients were grouped according to high (maximum BKPyV serum load >10E4 copies/ml), low (maximum serum BKPyV load <10E4 copies/ml) and absent BKPyV viremia, and analyzed for the development of dnDSA and BPAR, using Cox regression. Results Of 1076 KTx recipients included, 108(10%) developed a BKPyV viremia with a maximum serum load below 10E4 copies/ml, whereas 121(11.2%) developed a BKPyV viremia exceeding 10E4 copies/ml. The risk of dnDSA development was higher in patients with a high BKPyV viremia, compared to patients without viremia (adjusted Hazard Ratio of 1.9(95% CI1.1-3.2, p=0.017). No significant difference in dnDSA risk was observed between patients with low and absent BKPyV viremia. Risk of BPAR did not differ between groups. Conclusion Our study shows that higher BKPyV loads in KTx patients are associated with a higher risk for dnDSA development, highlighting the importance of exploring additional strategies for the prevention and treatment of BKPyV infections in KTx recipients.

The recent introduction of the European Medical Device Regulation poses stricter legislation for manufacturers developing medical devices in the EU. Many devices have been placed into a higher risk category, thus requiring more data before market approval, and a much larger focus has also been placed on safety. For implantable and Class III devices, the highest risk class, clinical evidence is a necessity. However, the requirements of clinical study design and developmental outcomes are only described in general terms due to the diversity of devices. A structured approach to determining the requirements for the clinical development of high-risk medical devices is introduced, utilising the question-based development framework, which is already used for pharmaceutical drug development. An example of a novel implantable device for haemodialysis demonstrates how to set up a relevant target product profile defining the device requirements and criteria. This can then be used to define specific questions to be answered during clinical development, based upon 5 general questions as specified by the question-based framework. The result is a clear and evaluable overview of requirements and methodologies to verify and track these requirements in the clinical development phase. Development organisations will be guided to the optimal route, also to abandon projects destined for failure in an early stage to minimise development risks. Moreover, the framework facilitates communication with funding agencies, regulators and clinicians, while highlighting remaining “known unknowns” that are to be answered in the post-market phase after sufficient benefit has been established relative to the risks.