Chronic kidney disease (CKD) is becoming a major public health issue as prevalence is increasing worldwide. It also represents a major challenge for the identification of new early biomarkers, understanding of biochemical mechanisms, patient monitoring and prognosis. Each metabolite contained in a biofluid or tissue may play a role as a signal or as a driver in the development or progression of the pathology. Therefore, metabolomics is a highly valuable approach in this clinical context. It aims to provide a representative picture of a biological system, making exhaustive metabolite coverage crucial. Two aspects can be considered: analytical and biological coverage. From an analytical point of view, monitoring all metabolites within one run is currently impossible. Multiple analytical techniques providing orthogonal information should be carried out in parallel for coverage improvement. The biological aspect of metabolome coverage can be enhanced by using multiple biofluids or tissues for in-depth biological investigation, as the analysis of a single sample type is generally insufficient for whole organism extrapolation. Hence, recording of signals from multiple sample types and different analytical platforms generates massive and complex datasets so that chemometric tools, including data fusion approaches and multi-block analysis, are key tools for extracting biological information and for discovery of relevant biomarkers. This review presents the recent developments in the field of metabolomic analysis, from sampling and analytical strategies to chemometric tools, dedicated to the generation and handling of multiple complementary metabolomic datasets enabling extended metabolite coverage to improve our biological knowledge of CKD.