Nephrol Dial Transplant (2003) 18: 2199
© 2003 European Renal Association-European Dialysis and Transplant Association
Letter and Reply
Are plasma S-nitrosothiol levels elevated in chronic renal failure?
Institute of Clinical Pharmacology Hannover Medical School Hannover Germany Email: tsikas.dimitros{at}mh-hannover.de
Sir,
The L-arginine/nitric oxide (NO) pathway actively and potently participates in the regulation of multiple vital biological functions including regulation of vascular tone. The status of the L-arginine/NO pathway can be characterized by determining the concentration in blood and/or urine of suitable members of the L-arginine/NO family, such as nitrite, nitrate and asymmetric dimethylarginine (ADMA). On the basis of such measurements, there is increasing evidence that NO synthesis is decreased in chronic renal failure (CRF) [1]. Reduced NO synthesis in uraemia seems to be causing the highly elevated cardiovascular risk, and could also be responsible for the hypertension in this disease.
The factors influencing NO availability in health and disease are largely unknown. Circulating S-nitrosoproteins, S-nitrosoalbumin being the most abundant, have been reported to be the main transport and storage forms of endogenous NO (discussed in Tsikas and Frölich [2]), and Stamler has reported values of 7 µmol/l for S-nitrosoproteins for healthy humans [2]. Until today, numerous analytical methods have been reported that have yielded highly divergent values, i.e. 10 nmol/l to 10 µmol/l, for endogenous plasma levels of S-nitrosothiols such as S-nitrosoalbumin [2]. This fact suggests that the measurement of circulating S-nitrosothiols is associated with severe methodological difficulties, to which insufficient attention has been paid. Definite problems originate from low concentration, chemical lability, readily artifactual formation and the inability of direct detection of endogenous circulating and excretory S-nitrosothiols in their intact form.
Recently, Massy et al. [3] have reported in Nephrology Dialysis Transplantation on increased plasma S-nitrosothiol levels in chronic haemodialysis patients. Independently of this group, at the same time, Wlodek et al. [4] have reported in Clinica Chimica Acta that plasma S-nitrosothiol levels are also increased in CRF patients. Both groups have used a fluorimetric method originally reported in Nitric Oxide by Marzinzig et al. [5]. This method is based on the conversion of the S-nitroso groups of S-nitrosothiols to nitrite by HgCl2 and subsequent acid-catalysed nitrosation of 2,3-diaminonaphthalene. Beforehand, nitrite, which is originally present in plasma at concentrations in the low µmol/l range, must be completely removed, because otherwise the values are erroneously attributed to S-nitrosothiols. One possibility is the use of ammonium sulfamate, which reduces nitrite to N2 under acidic conditions. Reportedly, Marzinzig et al. [5], Massy et al. [3] as well as Wlodek et al. [4] have used ammonium sulfamate under neutral pH conditions, under which, however, nitrite cannot be eliminated. Consequently, these groups have not measured S-nitrosothiol levels, but most likely nitrite levels in plasma and urine.
Massy et al. [3] have also determined in their study the plasma levels of 3-nitrotyrosine. Unfortunately, the same numbers for the 3-nitrotyrosine levels have been expressed both as µmol/l (in the text) and as µg/l (in table 2) [3]. Assuming that the ELISA standard curve was constructed in ng/ml and that this concentration unit was also used to determine 3-nitrotyrosine levels, the reported values of 
4 µg/l in all groups correspond to 50 pmol/l, which is three orders of magnitude smaller than literature data. If, however, the correct values are in µmol/l, they will be 40 times higher than reported values for plasma 3-nitrotyrosine.
In conclusion, the circulatory and excretory levels and the importance of S-nitrosothiols and 3-nitrotyrosine in renal diseases, sepsis and other NO-related diseases remain to be investigated applying reliable analytical methods.
Conflict of interest statement. None declared.
References
- Schmidt RJ, Baylis C. Total nitric oxide production is low in patients with chronic renal disease. Kidney Int 2000; 58: 1261–1266[CrossRef][Web of Science][Medline]
- Tsikas D, Frölich JC. S-Nitrosoalbumin plasma levels in health and disease: facts or artifacts? Value of analytical chemistry in nitric oxide clinical research. Circ Res 2002; 90: e39
[Free Full Text] - Massy ZA, Borderie D, Nguyen-Khoa T, Drüeke T, Ekindjian OG, Lacour B. Increased plasma S-nitrosothiol levels in chronic haemodialysis patients. Nephrol Dial Transplant 2003; 18: 153–157
[Abstract/Free Full Text] - Wlodek PJ, Kucharczyk J, Sokolovska MM et al. Alteration in plasma levels of nonproteins sylfhydryl compounds and S-nitrosothiols in chronic renal failure. Clin Chim Acta 2003; 327: 87–94[CrossRef][Web of Science][Medline]
- Marzinzig M, Nussler AK, Stadler J et al. Improved methods to measure end products of nitric oxide in biological fluids: nitrite, nitrate, and S-nitrosothiols. Nitric Oxide 1997; 1: 177–189[CrossRef][Web of Science][Medline]
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  D. Giustarini, R. Rossi, Z. Massy, T. Drueke, D. Borderie, and B. Lacour Plasma S-nitrosothiols and chronic renal failure Am J Physiol Renal Physiol, December 1, 2004; 287(6): F1294 - F1295. [Full Text] [PDF]
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