Low S-adenosylmethionine/S-adenosylhomocysteine Ratio in Urine Is Associated With Chronic Kidney Disease

Maria Petrovna Kruglova, MD; Sergej Vital'evich Grachev, ScD; Polina Olegovna Bulgakova, MS; Alexander Vladimirovich Ivanov, PhD; Edward Danielevich Virus, PhD; Ksenya Alexandrovna Nikiforova, MS; Anatolij Nikolaevich Fedoseev, ScD; Galina Dmitrievna Savina, PhD; Aslan Amirkhanovich Kubatiev, ScD


Lab Med. 2020;51(1):80-85. 

In This Article

Abstract and Introduction


Objective: To evaluate the association of S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH) in urine with chronic kidney disease (CKD).

Methods: Case-control study including 50 patients with CKD and 20 healthy volunteers.

Results: SAM level and SAM/SAH ratio in urine were significantly lower in patients than in control individuals (P <.001 and P = .01, respectively). The estimated glomerular filtration rate was associated with the SAM level (P = .04) and the SAM/SAH ratio in urine (P = .01).

Conclusion: CKD is associated not only with the decline in the SAM level but also with the decrease in the SAM/SAH ratio in urine. Thus, use of the urinary SAM/SAH ratio as a noninvasive diagnostic indicator of renal function seems promising.


Kidneys play an important role in the metabolism of aminothiols. Systemic and local disruption of methionine-dependent pathways is observed in patients with chronic kidney disease (CKD). Hence, an increase in homocysteine (Hcy), cysteine (Cys), S-adenosylmethionine (SAM) levels, and S-adenosylhomocysteine (SAH) levels, and a decrease in the SAM/SAH ratio in blood plasma occur in such patients.[1,2] However, the possibility of using those analytes as CKD markers has not been studied in clinical practice, to our knowledge.

Hcy is a nonproteinogenic thiol-containing amino acid formed from methionine by transferring its methyl group to different substrates by transmethylation (TM). SAM (an activated methionine form) and SAH (a direct precursor of Hcy) are intermediate products. By means of remethylation (RM) and trans-sulfuration (TS) reactions, Hcy can transform back to methionine and Cys, respectively.[3] Hyperhomocysteinemia (HHCy) is observed in more than in 80% of patients with CKD at stages II through V during which the level of Hcy in plasma is greater than 15 μM.[4,5]

It has been shown[6] that significant systemic disruption of TM and RM processes, but not TS, occurs during CKD. However, the molecular mechanisms of Hcy accumulation during CKD have not been fully established. It is assumed that HHCy might be associated with a decrease in the glomerular filtration rate (GFR) or renal perfusion and with systemic dysregulation of the methionine cycle.[2,6] HHCy might predict the progression of renal function decline and incidence of CKD.[7] This analyte is associated with the deterioration of kidney function and with the risk of development of cardiovascular complications,[8] the latter of which is a key factor in the cause of death of patients with CKD.[5] However, it can be assumed that Hcy is only a marker and not the cause of vascular pathologies.

Because Hcy toxicity in endotheliocytes can arise mainly from its inhibition of TM,[9] precursors of Hcy (SAM and SAH) have been considered as promising markers of renal function. The results of a number of clinical studies[10–12] have shown that an elevated level of SAH in blood plasma is more closely associated with the risk of vascular complications than the increased level of Hcy in patients with CKD. Also, an association was shown[13] between the level of SAH in plasma and the GFR.

The average levels of SAM and SAH in blood plasma in healthy subject individuals are approximately 100 nM and 20 nM, respectively.[14,15] In patients with CKD, these levels may increase to 1 μM and higher but usually constitute less than 1 μM.[12] Methods based on high-performance liquid chromatography (HPLC), in combination with mass spectrometry[15,16] or fluorescent[17] detection, are necessary for the determination of these metabolites. However, such methods tend to be unaffordable for clinics. The limit of detection of SAH in commercially available kits based on the use of the enzyme immunoassay method is 15 nM at best,[18] which is insufficient for reliable determination in plasma. Therefore, blood-plasma analysis for the determination of these metabolites is not widely used in clinics.

Because the excretion rates of SAM and SAH are 93% and 39%, respectively,[19] their levels are significantly higher in urine than in plasma and can be determined using common HPLC-ultraviolet (UV) systems.[20] However, when using HPLC, it is difficult to completely separate these analytes from interfering compounds. The use of capillary electrophoresis (CE) with UV detection makes it possible to determine Hcy[21] and SAM with SAH in urine[22] while avoiding the difficulties associated with the use of HPLC. However, to our knowledge, published data on urine analysis in patients with CKD for these compounds are not yet available, although these indicators of one-carbon metabolism might also be of interest as markers of renal dysfunction. In this investigation, we analyzed Hcy, SAM, and SAH levels in urine specimens from patients with CKD to investigate the possibility of the use of those levels as indicators of renal dysfunction.