Association of Kidney Graft Long-term Outcome With Recipient Cystathionine Gamma-lyase Polymorphisms and Hydrogen Sulfide Levels: A Cohort Study

Background. Hydrogen sulfide (H2S) produced endogenously by the CTH gene-encoded cystathionine gamma-lyase protects from renal ischemia–reperfusion injury in preclinical models. Here, we hypothesized that CTH gene polymorphisms (single nucleotide polymorphism [SNP]) and recipient H2S serum levels influence kidney graft outcomes after transplantation. Methods. We included all consecutive recipients of a first kidney transplant in the Swiss Transplant Cohort Study and with available genotyping. In addition, 192 deceased-donor kidney transplant recipients were randomly selected to measure baseline serum H2S levels. The primary endpoint was graft loss during follow-up. Results. CTH SNPs were identified in up to 50% of the patients. During median follow-up (6.4 y, interquartile range: 3.9–9.8), graft loss was observed in 247 (9.8%) of 2518 patients. The incidence of graft loss was associated with the presence or absence of CTH SNPs. Specifically, rs672203 and rs10458561, increased the risk of graft loss (hazard ratio [HR]: 1.36, 95% confidence interval [CI]: 1.04-1.78, P = 0.02; and HR: 1.29, 95% CI: 1.0-1.66, P = 0.05; respectively), whereas rs113285275 was protective (HR: 0.78, 95% CI: 0.6-1.01, P = 0.05). Interestingly, rs672203 was associated with an increased risk of acute rejection (P = 0.05), whereas rs113285275 was associated with a lower risk of acute rejection (P = 0.01). Finally, in patients with delayed graft function, serum H2S levels correlated with lower graft dysfunction (defined as estimated glomerular filtration rate <30 mL/min/1.73 m2) (P = 0.05). Conclusions. Graft outcome after kidney transplantation was associated with CTH genotype and, to some extent, H2S serum levels. Further research is needed to define the underlying protective mechanisms.