Animal models for preclinical research on multifactorial human conditions: The case of cardiovascular-kidney-metabolic syndrome

Cardiovascular-kidney-metabolic (CKM) syndrome is a combined disease condition in which diabetes impacts the cardiovascular and renal systems via a range of multiple pathways. However, no robust rodent phenotype that resembles CKM is currently available for preclinical research. The aim of the study is to determine the extent to which particular rodent models can replicate the multiple comorbidities of human CKM, including diabetes, obesity, dyslipidemia, hypertension, kidney and cardiovascular disease. Two databases were searched for experimental studies published between 1993 and 2024, and these were reviewed using sensitivity analysis (leave-one-out method) and publication bias across studies (Egger’s weighted regression and Duval and Tweedie ‘trim and fill’) according to the PRISMA Protocol. In total, data was extracted from 919 papers. The analysis included a wide spectrum of parameters (metabolic, cardiac and renal), and the possible associations between them. Substantial heterogeneity (P < 0.0001) was observed among particular experimental approaches, and the fullest image of the condition, viz. significant body weight gain, and increased systolic blood pressure, blood glucose with HbA1c and triglyceride level, was demonstrated by rodents with mutations for the leptin gene (receptor) (Lep^ob/ob, Lepr^db mice or Ob-ZSF1, ZDF rats). Significant discrepancies were observed between models with regard to renal performance (P < 0.0001), and most pronounced multifactorial effect was demonstrated by Ob-ZSF1 and Zucker diabetic fatty rats. There is an increasing need for development of multi-factorial animal models that are able to resemble the complexity of human conditions.