Abstract Background and Aims Informal caregivers are essential to patients with chronic kidney disease (CKD) in all stages of the disease. They provide, most often unpaid, practical and emotional support to someone with whom they have a personal relationship, mostly spouses, family members and friends. Support from caregivers helps CKD patients adjust to their disease and increase treatment adherence. However, CKD puts a large burden on both patients themselves and their caregivers. Overburdening is especially seen in spousal caregivers, as they are more often older, co-residents, perform longer hours of care, and suffer more from relational stress compared to other types of informal caregivers. Although previous studies show high levels of caregiver burden, a comprehensive understanding of caregiver role, caregiver burden, and factors that may relieve this burden is lacking. Therefore, our aim was to explore both the contributing and alleviating determinants of well-being of spousal caregivers of patients with CKD in a qualitative way. Method A qualitative interview study was performed among spousal caregivers of patients with CKD. Informal caregivers were recruited by the Dutch Kidney Patients Association to assist in the development of an informal caregiver module with interviews for the Kidney Guide (Nierwijzer.nl). Fifteen face-to-face interviews were held between December 2021 and April 2022 at participants’ homes. Interviews lasted approximately 1 to 1.5 hours. All participants were adults and able to speak and understand Dutch. A directed qualitative content analysis was performed, using the stress-appraisal model as a framework. The model proposes that the care demand (primary stressors) leads to the actual provision of care by the informal caregiver (primary appraisal). Consequently, the provision of care leads to consequences for the caregiver's own life (secondary stressors), leading to burden (secondary appraisal). Finally, the experienced burden leads to the outcome, namely caregivers’ well-being. Moderators change the effect of stressors (e.g., social support may alleviate burden by sharing care tasks). Results Of the fifteen participating spousal caregivers, nine were female. Caregivers’ age ranged from 34 to 82 years. Duration of informal caregiving ranged from approximately 4 to 37 years. Most patients were on a type of kidney replacement therapy (KRT). In this study, we extended the stress-appraisal model to the context of CKD, providing a disease-specific model for practice (Fig. 1). Through this model, we describe the impact of care provision on all aspects of spousal caregivers’ lives and the burden associated with it, and identify possible modifiable factors to prevent overburdening of spousal caregivers. CKD-specific determinants included, amongst others, the impact of kidney disease and KRT on patients themselves as well as the associated caregiver tasks, for example adjusting to dietary restrictions and attending dialysis appointments. KRT options and flexibility (e.g., the choice for home or in-center dialysis) were CKD-specific moderators that alleviated burden. The care for someone on dialysis led to additional tasks (e.g., transportation to the dialysis center or assisting with home dialysis), negative impact on caregivers’ personal and social lives, and additional burden, emphasizing a distinction with caring for a CKD patient not on dialysis. Conclusion To our knowledge, this is the first study that gives a comprehensive overview of the contributing and alleviating determinants of the well-being of spousal caregivers of CKD patients. A disease-specific version of the stress-appraisal model for use in practice was provided, with evidence for all paths in the model. Moreover, we underline the need for acknowledgement of spousal caregivers in four areas: (1) personal and relational, (2) social environment, (3) healthcare, and (4) work and legislation (Fig. 2). This acknowledgement is of great importance to support and facilitate informal care within nephrology.