Serum uric acid, renal status, cardiovascular-kidney-metabolic syndrome and drug therapy, a wide-angled Mendelian randomization analysis

Abstract

Background: Serum uric acid (SUA) and renal status are associated with the Cardiovascular-Kidney-Metabolic (CKM) syndrome. However, the causal association among them along with drug therapy need to be explored.

Methods: We employed univariable, multivariate, mediation and drug-target mendelian randomization. Inverse variance weighting was the primary result, with extensive sensitivity analyses conducted to ensure robustness and reliability.

Results: Regarding SUA, genetically predicted SUA demonstrated a potential risk effect on stage 4 of CKM syndrome (ischemic heart disease (IHD), OR = 1.090, 95 %CI: 1.003-1.184; peripheral artery disease, OR = 1.174, 95 %CI: 1.058-1.303). SUA remained a significant risk factor after excluding the confounding of eGFR and proteinuria (IHD: OR = 1.137, 95 %CI: 1.043-1.238; peripheral artery disease: OR = 1.224, 95 %CI: 1.107-1.354). SUA mediated the following causal effect: sleep apnea (2.37 %), income (1.92 %) and education (1.79 %) on IHD; C-reactive protein (11.65 %) and education (4.29 %) on peripheral artery disease. Regarding renal status, renal dysfunction led to a wider phenotype of CKM syndrome including hypertension, cerebrovascular disease, chronic kidney disease and renal failure. Similarly, renal status mediated the causal effect of education on hypertension (1.84 %), depression on cerebrovascular (0.46 %) and family history of diabetes on chronic kidney disease (3.49 %) and renal failure (2.81 %). Lesinurad targeting SLC22A11 and SLC22A12 was validated for treating IHD.

Conclusion: Our study clarified the complex relationship among SUA, renal status and CKM syndrome. Simultaneously providing innovative drug and social interventions for CKM syndrome.

Keywords: Cardiovascular-kidney-metabolic syndrome; Mendelian randomization; Renal status; Serum uric acid.

Graphical abstract

Fig. 1

The overall research design. CKM: Cardiovascular-kidney-metabolic, MR: Mendelian randomization, MVMR: Multivariable mendelian randomization, SUA: Serum uric acid, UA: Uric acid.

Fig. 2

Causal effect of SUA and renal status on 4 stages of CKM syndrome. CKMS: Cardiovascular-kidney-metabolic syndrome, IVW: Inverse variance weighted, NT-proBNP: N-terminal B-type natriuretic peptide, SUA: Serum uric acid, OR: odd ratio.

Fig. 3

The results of MVMR and drug-target MR. (3A): The Causal effect of SUA on 4 stages of CKM syndrome after adjusting renal status. (3B): MR for UA-lowering drug targets on IHD and PAD. BMI: Body mass index, CI: Confidence interval, CKMS: Cardiovascular-kidney-metabolic syndrome, IVW: Inverse variance weighted, MVMR: Multivariable mendelian randomization, OR: odd ratio, SNP: Single nucleotide polymorphism.

Fig. 4

Bidirectional causal effect between CKM syndrome risk-enhancing factors, SUA and renal status. (4A): The circular heatmap depicting the causal effect of SUA and renal status on CKM syndrome risk-enhancing factors. (4B): The circular heatmap depicting the causal effect of CKM syndrome risk-enhancing factors on SUA and renal status. (4C): The forest plot describing the causal effect of SUA and renal status on CKM syndrome risk-enhancing factors. (4D): The forest plot describing the causal effect of CKM syndrome risk-enhancing factors on SUA and renal status. AIDS: Acquired Immune Deficiency Syndrome, CRP: C-reactive protein, CI: Confidence interval, IVW: Inverse variance weighted, OR: odd ratio, RA: Rheumatoid arthritis, SLE: Systemic lupus erythematosus, SNP: Single nucleotide polymorphism, SUA: Serum uric acid.

Fig. 5

The mediation effect of SUA and renal status in CKM syndrome and its risk factors. AIDS: Acquired Immune Deficiency Syndrome, NT-proBNP: N-terminal B-type natriuretic peptide, SUA: Serum uric acid.