Cardiovascular-kidney-metabolic (CKM) syndrome represents a distinct entity describing a highly comorbid group of patients and is disproportionately found in patients with kidney disease. This syndrome manifests as early presentations of cardiovascular disease even with mildly decreased kidney function and markedly increased rates of mortality as a result. However, there is currently a dearth of suitable preclinical tools to investigate and understand the progression and development of CKM.1 In this issue of Kidney360, Lotfollahzadeh et al.2 report data from a new murine model designed to recapitulate the complexities of CKM, in renal, metabolic, and cardiovascular pathophysiology, with peripheral arterial disease (PAD) as a functional manifestation. This model combines three interventions: high-fat diet obesity-related metabolic dysfunction, adenine-induced kidney disease, and finally overlaying a hind-limb ischemia model to represent PAD. Integrating Interventions The new model effectively combines key domains of CKM. First, renal injury with features such as tubular atrophy and glomerulomegaly, which are consistent with obesity-related hyperfiltration superimposed onto CKD damage.3 Second, metabolic disruption including hypercholesterolemia, impaired glucose tolerance, and hepatic steatosis (which was absent in adenine only mice). Third, cardiovascular involvement with myocardial fibrosis and reduced postischemic hind limb reperfusion to reflect impaired angiogenesis and microvascular rarefaction.4 Finally, skeletal muscle pathology with loss of type-2 fibers and reduced cross-sectional area.5 An essential strength is the inclusion of both sexes. Female mice showed synergistic deficits in endurance, grip strength, and fatigue resistance without a corresponding difference in perfusion, to suggest some intrinsic dysfunction. This aligns well with corresponding human data showing female patients with PAD experience greater functional impairment despite similar disease burden.6 The Importance of PAD in CKM PAD is often underemphasized in CKM despite its high prevalence and prognostic merit. PAD acts as a signal for wider vascular disease, but is also responsible for impaired quality of life by limiting exercise and increasing amputation risk.7 By including PAD in their model, the authors effectively include clinically relevant end points—endurance capacity, strength, and postexercise perfusion which mimic patient outcomes such as walking distance and claudication severity.7 Translational Potential The current model represents more than the sum of its individual parts. Previous studies have focused on renal progression alone,8 without the cardiovascular components so essential to insights into the holistic picture of CKM in clinical practice. These results may allow studies investigating therapies such as: Pleiotropic therapies like sodium-glucose cotransporter 2 inhibitors,9 glucagon-like peptide 1 inhibitors,10 or anti-fibrotic agents that may have efficacy across all arms of CKM, cardiovascular, renal, and metabolic. Investigate shared mechanisms like inflammation through TNF-α, and IL-6, oxidative stress and subsequent endothelial dysfunction, TGF-β mediated fibrosis and uremic toxin effects like aryl hydrocarbon signaling.1 Further understand sex differences to form and drive tailored therapeutic strategies. Lotfollahzadeh et al. acknowledge that adenine induced CKD is a very rapid aggressive induction of kidney disease akin to stage 3 or 4 in humans. This may potentially obscure additive progressive inductions of cardiovascular changes by metabolic stressors at milder levels of kidney damage. There is an opportunity to combine the other interventions with a milder form of CKD like nephrectomy and extend the experimental window to further understand synergistic nuanced changes. Relatedly, the model captures many features of CKM, but not all the readouts were synergistic between CKD and metabolic injuries. Seemingly, a disadvantage, but human data show ten distinct and highly-diverse CKM trajectories driven by wide variability in how risk factors combine.1 From this perspective, a partially additive set of interventions may actually be a strength. Additional interpretation of the murine response to diet and surgical interventions must be cautious, but nonetheless the model's design lends itself to hypothesis-driven testing of pathophysiology, therapeutics, and new candidate drug targets. A New CKM Research Landscape This study is timely because CKM and multiorgan interactions are rapidly moving from conceptual frameworks into well-distinguished clinical manifestations with defined staging systems and new diagnostic criteria.1 There remains a significant unmet clinical need and knowledge gap in the disproportionate cardiovascular disease risk in CKD patients with metabolic dysfunction, which this model potently pushes forward. This reproducible integrated multidomain platform expands the toolkit for researchers seeking to understand CKM and develop tools to ease the disease burden. Conclusion CKM represents a complex deeply heterogenous syndrome with a paucity of effective clinical interventions. The new murine adenine+high fat diet with peripheral artery disease imposition is a new way to unpick this complexity in vivo. The model may be further refined, but it presents fertile ground for further mechanistic exploration and therapeutic innovation. While the recognition of the import of CKM continues to increase, models like the one described here by Lotfollahzadeh et al. will be essential to alter the trajectory of disease for patients.
Kane et al. (Sun,) studied this question.