Cysteinesulfinic Acid in Chronic Dialysis Patients
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Kidney International, Vol. 50 (1996), pp. 1713—1 717 Evidence of taurine depletion and accumulation of cysteinesulfinic acid in chronic dialysis patients MOHAMED E. SULIMAN, BJORN ANDERSTAM, and JONAS BERGSTROM Divisions of Renal Medicine and Baxter Novum, Department of Clinical Science, Huddinge University Hospital, Karolinska Institute, Stockholm, Sweden Evidence of taurine depletion and accumulation of cysteinesulfinic acid coenzyme for cysteinesulfinic acid decarboxylase (CSAD) [17], in chronic dialysis patients. Methionine, taurine and cysteinesulfinic acid which is a rate-limiting enzyme in the conversion of GSA to (CSA) were determined by reversed-phase high-performance liquid chro- matography (RP-HPLC) in plasma from ten patients treated with hemo- taurine. dialysis (HD) and eight patients treated with continuous ambulatory In several studies where plasma taurine concentrations have peritoneal dialysis (CAPD). The patients' data were compared with data been examined in patients with CRF, who either were not obtained from ten healthy controls. Significant reductions in plasma dialyzed or had undergone maintenance dialysis, the taurine level taurine levels were observed in the RD patients (34 13jtmol/liter, was found to be low [4, 6, 18, 19]. However, normal or elevated mean SD) andthe CAPD patients (47 12j.mol/liter) compared to the controls (66 5itmol/liter), while the CSA levels were markedly higher levels have been reported [10, 11, 20]. in the I-ID patients (9.1 2.8mol/liter) and the CAPD patients (9.1 The present study was designed to evaluate further the concen- 2.4j.mol/liter) than in the controls (0.79 0.15jmol/liter). A single HD trations of plasma taurine and some of its precursors in ten treatment significantly reduced the plasma taurine and CSA concentra- patients on HD treatment and in eight patients on continuous tions (P <0.01 and P <0.001), respectively. The plasma methionine levels were normal in both patient groups. The finding of a low plasma taurine ambulatory peritoneal dialysis (CAPD). In HD patients, the level and a large accumulation of CSA suggests that the metabolicamino acid concentrations were evaluated before and after dial- conversion of CSA to taurinc is impaired in uremic patients and thisysis. Free amino acids in plasma were determined with reversed- metabolic abnormality may cause taurine depletion. phase high-performance liquid chromatography (RP-HPLG). The results showed low plasma taurine concentrations, despite an accumulation of GSA in these uremic patients. Patients with chronic renal failure (GRE) exhibit various ab- Methods normalities in extracellular and intracellular amino acid profiles. Some of the changes are ascribed to uremia per se or impaired Study population renal degradation or deficient excretory and metabolic functions Ten patients with CRF, six males with a mean age of 67 (range in the diseased kidney, but other abnormalities may reflect60 to 81) years and four females with a mean age of 73 (64 to 79) inadequate nutritional intake or malnutrition [1—5]. In dialysisyears, underwent HD for 9 to 168 (mean 42) months. The etiology patients, the loss of protein and amino acids due to the dialysisof CRF and the numbers of patients in each category were as procedure may also contribute to such abnormalities [6]. follows: chronic glomerulonephritis 4, chronic pyelonephritis 1, Abnormal values of sulfur amino acids in CRF have been diabetic nephropathy 1, nephrosclerosis 1, polycystic kidney I and reported in many studies. In most of them the plasma concentra-two cases of renal disease of undetermined etiology. tion of methionine has been normal in untreated uremic patients Eight patients, five males with a mean age of 53 (range 30 to 70) [7—9]anddialyzed uremic patients [4, 6, 10, 11]. Furthermore,years and three females with a mean age of 54 (range 47 to 75) accumulations of eysteine and homocy.steine in the plasma haveyears, were studied after 5 to 47 (mean 23) months of treatment been noted in untreated uremic patients and in those on hemo-with CAPD. One of the patients had been on HD treatment for 15 dialysis (HD) [11—141. months and was then treated with a low protein diet for 60 months Taurine (2-aminoethanesulfonic acid) is an end product of thebefore he started GAPD treatment. The causes of CRF were metabolism of sulfur amino acids [151andit is one of the mostchronic glomcrulonephritis in five patients, hypertensive nephrop- abundant free amino acids in the human body [16]. The majorathy, nephrosclerosis and renal failure of unknown etiology in one pathway for the biosynthesis of taurine (Fig. 1) is that viapatient each. cysteinesulfinic acid (GSA), and this pathway depends on vitamin All patients were receiving various medications, mainly antihy- B6, in the form of pyridoxal—5'-phosphate, which is required as apertensive agents, diuretics, sodium bicarbonate, calcium carbon- ate and all were prescribed a daily supplement of water-soluble vitamins, including pyridoxine 10 mg/day. None of the patients was treated with corticosteroids or cytotoxic drugs. All had normal Received for publication December 28, 1995 transaminase levels in plasma and no signs of liver disease. and in revised form May 29, 1996 Ten healthy volunteers, four males with a mean age of 39 Accepted for publication June 3, 1996 (range 31 to 44) years and six females with a mean age of 38 (27 © 1996 by the International Society of Nephrology to 53) years, were selected for comparative analysis in the present 1713 1714 Sulimanet al: Taurine and cysteinesulfinic acid in uremia diet—---p Methionine I Transsulfuration I diet —---b Cysteine O2inedioxygenase cysteinesulfinate (CSA) carboxylase Uremia? NH2 CO2 3-sulfinylpyruvate Hypotaurine Pyruvate SO3 °2 aurinedehydrogenase Taurine f—--— diet Fig. 1. Metabolic pathways related to Sulfate (SO4) cysteinesulfinate and taurine. Table 1. Clinical characteristics and biochemistries of uremic patients drawn in the morning, after the patients and healthy subjects had and healthy subjects (mean SD) fasted overnight. The post-dialysis samples were drawn four hours HD later from HD patients who had continued fasting until the end of N = Controls 10 CAPD the dialysis session. N =10 Pre-HD Post-HD N =8 Blood was collected in evacuated tubes containing heparin and was centrifuged immediately at 2300 x g for 15 minutes at 4°C Sex male/female 4/6 6/4 5/3 and the upper part of the supernatant was removed with a pipette, Age years 38 8 69 7 55 15 Weight kg 67 13 67 13 67 13 leaving a 5 mm layer next to the blood cells in order to avoid Heightcm 169±7 172±8 170±9 contamination of amino acids released from blood cells and Body mass index 24 4 23 5 23 3 thereby minimize artefactual elevation of the plasma taurine level — 1.34 0.30 1.09 0.20 nPNAg/kg body wt/day [23]. Plasma was quickly deproteinized by mixing 1 ml of plasma Serum albumin g/liter 35—46° 32 3 — 35 5 Serum creatinine 90 13 754 140 322 75 764 140 with 100 il 5-sulfosalicylic acid (30%), including L-norvaline (2 pinol/liter mM) as an internal amino acid standard. The samples were kept at Serum urea mmol/liter 5 1 28 7 9 3 23 11 4°C for one hour, then centrifuged at 2300 X g for 20 minutes at Creatinine clearance 112 14 — — 4°C and the supernatant was pipetted and filtered through a 0.45 mI/mm Urea clearance mI/mm 59 17 — — m membrane filter (Millipore, Nilhon Millipore, Kogyo K.K., Japan). All samples were stored at —70°C until the amino acids Abbreviation is: nPNA, normalized protein equivalent of total nitrogen were analyzed. appearance. Normal range of serum albumin in the clinical laboratory of the For the analysis of sulfur amino acids in the urine of healthy hospital subjects, four-hour urine samples, collected in the morning of the day when the blood samples were obtained, were frozen at —70°C until the day of analysis, when they were processed similarly to the study and for determinations of urinary excretion and clearance ofdeproteinized plasma samples, after addition of the internal CSA and taurine. standard. The clinical characteristics and routine biochemistries of the The protocol of the study was approved by the Ethics Commit- patients and controls are presented in Table 1. The serumtee at Karolinska Institute, Huddinge University Hospital, Stock- albumin level tended to be low in the uremic patients. The proteinholm, and informed consent was obtained from each patient and equivalent of total nitrogen appearance (nPNA) was calculatedcontrol subject. from the urea appearance rate [21, 22].Themean values were above 1 g/kg body wt/day in both the HD and the CAPD patients. Analytical methods Blood samples were obtained from a peripheral vein in CAPD The determinations of amino acids in plasma and urine were patients and normal subjects and from a vascular access fistula incarried out using RP-HPLC and fluorometric detection. The HD patients at the onset and termination of dialysis. Blood wasmethod was based on automated pre-column derivitization of Suliman et al: Taurine and cysteinesulfinic acid in uremia 1715 Table 2.Plasma sulfur free amino acid concentrations (jtmol/liter Table 3.Urinary excretion and renal clearance of taurine and mean SD) in uremic patients and control subjects cystcinesulfinic acid in 10 healthy controls (mean SD) HD CSA Taurine N =10 Controls ._________ CAPD Excretion pjnol/hr 2.02 1.02 30.7 16.1 N =10 Pre-HD Post-HD N = 8 Renal clearance mI/mm 43.4 19.3 10.3 6.5 Methionine 31 5 30 5 28 6 29 4 Cysteinesulfinic acid0.790.159.1 2.8°2.40.6°" 9.1 2.4" Results Taurine 66 5 34 13' 20 +5ad 47 12L Taurine/CSA ratio 85 16 4.22.8"8.62.1"'5.4 1.8" The plasma concentrations of sulfur amino acids in control and Statistical significance: aP< 0.001 when compared to controls, hp<patient groups and the effect of a single HD treatment as well as 0.01 when compared to controls, "P < 0.001 when compared to Pre-HD, the ratio of taurine to CSA are shown in Table 2.