Low Plasma Hydrogen Sulfide Is Associated with Impaired Renal Function and Cardiac Dysfunction

Abstract

Background: Chronic kidney disease (CKD) has been proposed to associate with decreased hydrogen sulfide (H₂S) level. Nevertheless, the role of H₂S in the pathogenesis of CKD has not been fully investigated. Our study aimed to investigate the plasma level of endogenous H₂S in patients with different stages of CKD, and to identify the role of H₂S in the progression of CKD and its relationship with cardiovascular diseases. Methods: A total of 157 non-dialysis CKD patients were recruited in our study, with 37 age- and sex-matched healthy individuals as control. Plasma concentration of H₂S was measured with spectrophotometry. Sulfhemoglobin, the integration of H₂S and hemoglobin, was characterized and measured by dual wavelength spectrophotometry. Serum levels of homocysteine (Hcy), cardiac troponin T (cTnT), and N-terminal pro B type natriuretic peptide were measured using automated analyzers. Conventional transthoracic echocardiography was performed and left ventricular ejection fraction (LVEF) was analyzed as a sensitive parameter of cardiac dysfunction. Results: The plasma H₂S level (μmol/L) in CKD patients was significantly lower than those in healthy controls (7.32 ± 4.02 vs. 14.11 ± 5.24 μmol/L, p < 0.01). Plasma H₂S level was positively associated with estimated glomerular filtration rate (eGFR; ρ = 0.577, p < 0.01) and negatively associated with plasma indoxyl sulfate concentration (ρ = –0.554, p < 0.01). The mRNA levels of cystathionine β-synthase and cystathionine γ-lyase, 2 catalytic enzymes of H₂S formation, were significantly lower in blood mononuclear cells of CKD patients with respect to controls; however, the mRNA level of 3-mercaptopyruvate sulfurtransferase, as another H₂S-producing enzyme, was significantly higher in CKD patients. The serum concentration of Hcy, acting as the substrate of H₂S synthetase, was higher in the CKD group (p < 0.01). Specifically, the content of serum Hcy in CKD stages 3–5 patients was significantly higher than that in CKD stages 1–2, indicating an increasing trend of serum Hcy with the decline of renal function. Examination of ultrasonic cardiogram revealed a negative ­correlation between plasma H₂S level and LVEF (ρ = –0.204, p < 0.05) in CKD patients. The H₂S level also correlated negatively with cTnT concentration (ρ = –0.249, p < 0.01). Conclusions: Plasma H₂S level decreased with the decline of eGFR, which may contribute to the cardiac dysfunction in CKD ­patients.

Roles of Hydrogen Sulfide Donors in Common Kidney Diseases

“…Decreased GFR affects the removal of waste products by the kidneys. In a recent study, the reduced plasma levels of H 2 S in CKD patients could be significantly correlated with the reduction in GFR which confirms the importance of the gas in regulating the activities of the glomerulus (Kuang et al, 2018). It has been revealed that treatment of anesthetized rat models with CBS and CSE inhibitors, aminooxyacetic acid, and DL-propargylglycine (PAG) respectively, can impede the GFR by reducing vasodilation of the preglomerular arterioles; however, treatment with low doses of NaHS (a fast H 2 S-releasing donor) can protect the glomerulus functions by inducing opposite effects (Xia et al, 2009).…”

“…CKD mainly results from mild-to-severe range of prerenal, intrinsic renal, and/or postrenal processed diseases. Reduced level of H 2 S has been reported in both CKD patients and experimental models (Aminzadeh and Vaziri, 2011;Kuang et al, 2018). In 5/6 nephrectomy mice model, NaHS could effectively improve kidney functions by promoting antioxidant, antiapoptotic, and anti-inflammatory responses via the activation and deactivation of nuclear factor erythroid 2-related factor 2 (Nfr2) and mTOR pathways, respectively (Shirazi et al, 2019).…”

Sulfane sulfur – new findings on an old topic

“…After a single session of hemodialysis, the plasma H 2 S level had increased in these patients (Perna et al, 2011). In another study, a lower H 2 S level in plasma of CKD patients was also documented, which was positively correlated with an estimated glomerular filtration rate (eGFR) (Kuang et al, 2018).…”

Hydrogen sulfide attenuates renal fibrosis by inducing TET‐dependent DNA demethylation on Klotho promoter

“…20 However, the production of H 2 S in plasma or kidney is remarkably reduced in CKD patients and related animal models. 20,21 Interestingly, a recent study showed that H 2 S could facilitate Tet1 and Tet2-dependent Foxp3 demethylation to maintain immune homeostasis. 22 Although Klotho hypermethylation and anti-fibrotic property of H 2 S are well-recognized in renal fibrosis, whether H 2 S can directly change TET hydroxylase expression or activity as well as subsequent DNA demethylation remains elusive.…”