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Home , Lipid metabolism, Mevalonate pathway

Kidney International, Vol. 51 (1997), pp. 908—912

Plasma mevalonate concentrations in uremic patients

ALESSANDRO SCOPPOLA, PAOLO DE PAOLIs, GuIDo MENZINGER, ALBERTO LALA, and SALVATORE DiGluLlo

Cattedra di Endocrinologia Università di Roma "Tor Vergata" and Servizio di Nefrologia e Dialisi, Ospedale G.B. Grassi di Ostia, Rome, Italy

Plasma mevalonate concentrations in uremic patients. different disorders [12—161. The plasma MVA concentrations (mevalonate or MVA), is an obligate precursor in the biosyntheticin humans are determined by the balance between MVA produc- pathway of . It is partially metabolized by the kidneys and its plasma concentrations are an index of endogenous cholesterol synthesis. tion (intracellular synthesis in response to HMG CoA reductase The aim of the present study was to evaluate plasma MVA concentrations activity) and MVA [17—19]. The appears to be in uremic patients with different degrees of chronic renal failure (CRF; the main source of MVA production, while the kidneys are the group A), and the effects of a single hemodialysis treatment on plasma major site for metabolism via both the sterol and the shunt MVA in a group of patients with end-stage renal disease (ESRD; group pathways [19—21]. A fivefold rise in plasma mevalonate levels has B). CRF patients exhibited a higher mean basal mevalonate concentration (13.3 6.5 ng/ml) than control subjects (4.68 1.32 nglml; P < 0.001). A been reported by Kopito et a! [22], following bilateral nephrec- statistically significant direct correlation was evident in CRF patients tomy in rats. In addition, mice with CRF exhibited a significant between mevalonate and creatinine plasma levels (r =0.86;P < 0.001). A increase in plasma mevalonate levels with a concomitant decrease single hemodialysis treatment was associated with a significant reduction in the urinary excretion of mevalonate [23]. of plasma mevalonate concentrations four hours after the hemodialysis session (—57%; P < 0.001) and an increase up to the basal values 24 hours The aim of the present study was to evaluate: (a) the relation- after the end of the treatment. In conclusion, our results demonstrated: (i) ship between plasma MVA concentrations and the degree of higher plasma MVA concentrations in patients with decreased renal chronic renal failure; and (b) the effects of a single hemodyalisis function; (ii) a direct relationship between plasma MVA levels and the treatment on plasma MVA concentrations in uremic patients with degree of kidney failure as expressed by ereatinine plasma concentrations; end-stage renal disease. and (iii) a clear cut reduction of elevated plasma MVA levels after a single hemodialysis treatment. Methods

Cardiovascular diseases are the major causes of morbility and Patients mortality in patients with end-stage renal disease. Abnormalities of are involved in the atherogenic process in Group A. Twenty-two patients from our outpatient population, (16 males, 6 females), aged 62 14 years, body mass index (BMI) these patients. Among the atherogenic risk factors, high serum24 1.9 kg/rn2, with different levels of CRF, plasma ereatinine total cholesterol has been reported in 31% of patients withrange from 1.41 to 8.57 mg/dl (mean SD =4.8 2.4), and a chronic renal failure (CRF) on peritoneal dialysis and in 10% of24-hour excretion less than 2.5 g/day, were admitted to the subjects on hemodialysis treatment [1]. The majority of studiesstudy. Ten out of the 22 patients were hypercholesterolemic (total reported a normal or reduced total cholesterol levels in CRFcholesterol > 240 mg/dl). Clinical characteristics, plasma creati- patients under different dialysis treatment schedules [2—41 often nine levels, 24-hour urinary protein excretion, lipid and lipopro- associated with a low levels of high-density cholesteroltein levels are reported in Table 1. [5]. The mechanisms underlying cholesterol metabolism in CRF Group B. Eleven male patients with end-stage renal disease patients are still a matter of discussion. (ESRD), aged 62 10 years, with BMI 222.3 kg/rn2, on regular Mevalonic acid (MVA) is the direct product of the rate-limiting hemodialysis treatment (since 55 34 months of dialysis) were step in cholesterol synthesis catalyzed by 3-hydroxy-3-methylglu-included. Clinical characteristics, plasma creatinine values, taryl- (1-1MG CoA) reductase. The MVA pathway has plasma and are reported in Table 2. been suggested to play a role in progressive renal disease [6] in Group C. Ten healthy males, aged 59.98 years, with a BMI diabetic ncphropathy [7], in essential hypertension [8, 91andtheof 23 1.2 kg/rn2, formed the conlrol group. Creatinine plasma lipid abnormalities in nephrotic syndrome [10, ii]. Plasma andlevels and lipid profiles are shown in Table 3. urinary MVA concentrations in humans correlate with cholesterol Normal subjects, patients in group A having creatinine levels production rates in normal subjects as well as in patients withless than 5 mg/dl and all patients in group B were maintained under a diet of 35 Kcal/kg/body wt (55% , 25% , total cholesterol < 400 mg/day and P/S < 1, 20% protein). Received fur publication April 5, 1996 Patients in group A with creatinine levels higher than 5 mg/dl, and in revised form September 3, 1996 were maintained under a diet containing 68% carbohydrate, 25% Accepted for publication September 3, 1996 fat (total cholesterol < 400 mg/day and P/S < 1) and 7% protein. © 1997 by the International Society of Nephrology Hepatic and thyroid tests were in the normal range in all

908 Scoppola et a!: MVA in uremia 909

Table 1.Clinical characteristics, plasma creatinine, lipid and lipoprotein levels and 24/h urinary protein excretion in all patients with chronic renal failure (CRF):

Age Creatinine Tot. Chol. HDL-Chol. LDL-Chol. Tg. ApoA ApoB Albuminuria Name (years) Sex Etiology of CRF (mg/dl) (mg/dl) (mg/dl) (mg/dl) (mg/dl) (mg/dl) (mg/dl) (mgI24h) T.L. 77 m nephrosclerosis 1.41 222 43 156 117 171 123 <30 CA. 70 m nephrosclerosis 1.5 220 38 160 112 120 144 70 B.M. 71 m nephrosclerosis 1.64 253 33 189 153 153 181 0 P.C. 68 f nephrosclerosis 2.13 225 41 128 281 105 142 90 M.A. 69 m nephrosclerosis 2.3 297 44 218 167 120 131 80 P.S. 88 m lithiasis 2.84 175 36 127 63 98 113 60 D.E. 55 m nephrosclerosis 2.85 220 48 116 280 121 135 60 B.G. 62 m APKD 3.1 224 41 151 152 130 142 300 A.E. 55 f lithiasis 3.16 242 36 158 238 146 137 200 CI. 77 f nephrosclerosis 4.38 331 46 329 269 211 166 500 C.E. 63 m nephrosclerosis 4.46 221 29 151 208 82 140 0 D.L. 61 m ncphrosclerosis 4.98 199 43 133 119 128 127 80 V.M. 64 f nephrosclerosis 5.41 280 30 214 183 147 169 50 S.M. 65 f nephrosclerosis 5.9 260 22 185 266 123 156 70 P.P. 80 m nephrosclerosis 6.33 194 29 146 94 168 143 300 GA. 30 m Chronic GN 6.38 104 32 57 79 133 64 900 F.C. 50 m membranous GN 6.85 269 44 201 119 156 174 1600 M.L. 66 f interstit. nephr. 7.46 345 70 240 174 247 203 700 CO. 60 m nephrosclerosis 7.67 172 50 83 195 281 94 500 D.M. 54 m membranous GN 7.96 249 38 185 141 178 155 700 M.B. 46 m APKD 8.21 284 56 200 139 203 164 150 S.M. 33 m APKD 8.57 160 58 651 100 84 0 mean 62 4.8 233 41 161 177 150 140 14 2.4 56 11 63 75 49 32 *TheLDL-cholesterol value was not calculated because of high levels

Table 2.Clinical characteristics, plasma creatinine values, plasma lipids and apolipoproteins in 11 normocholesterolemic patients with end-stage renal disease (ESRD):

Age Months of Tot. Chol. HDL-Chol. LDL-Chol. ApoA ApoB Name (years) Sex dialysis (mg/dl) (mg/dl) (mg/dl) (mgldl) (mg/dl) A.G. 64 m 53 168 33 110 122 78 G.S. 64 m 20 194 27 109 107 104 B.A. 72 m 32 137 40 67 133 96 B.G. 56 m 96 153 38 87 156 100 C.M. 48 m 63 183 28 116 150 116 FR. 70 m 110 202 40 138 177 143 M.G. 74 m 25 115 37 60 152 65 P.C. 40 m 6 125 46 65 148 89 SE. 65 m 78 174 56 98 175 82 A.A. 71 m 86 201 40 124 156 127 P.E. 64 m 38 122 27 71 142 81 mean 62 55 161 37 95 147 98 10 34 32 9 26 20 23

participants. Fourteen patients (group A) received ACE inliihi- Hem odialysis sets tors for hypertension. None of the patients were given medica- The hemodialysis patients were treated for four hours with tions known to affect cholesterol metabolism. All of the subjects buffer bicarbonate in the dialyzate, with flow rate 300 25 had previously signed an informed consent for this investigation. mi/mm, UF/hr .1 0.80.2 liter/hr. with a cuprophane membrane Experimental design hemodialyzer. At the start the first heparine bolus (1500 500 UI) was followed during the dialysis session by continuous infu- Basal samples for creatinine, lipids and mevalonate determina- sion of 3500 500 UI. Before the hemodialysis session at 9:30 tions were withdrawn at 9 am. after a 12 hour fast. Blood samples a.m. the patients received a low fat (< 5%) cholesterol-free meal. for the mevalonate assay were heparinized and the plasma was separated by centrifugation and then stored at —70°C. In group B, plasma mevalonate concentrations were measured before (T-0), Assays at the end of the session (T-4) and 24 hours after (T-24). The Serumcreatinine, cholesterol 1241 and [25] were hemodialysis treatment started at 9 a.m. determined in whole plasma by enzymatic colorimetric methods 910 Scoppolaet al: MVAinuremia

Table 3. Clinical Characteristics, plasma lipids and creatinine values in 10 control subjects

Age Creatinine Tot. Chol. HDL-Chol. LDL-Chol. Tg Apo Al Apo B100 Name (years) Sex (mgldl) (mgldl) (mgldl) (mgldl) (mgldl) (mg!dl) (mgldl) V.F. 59 m 0.97 210 48 135 1117 132 92 M.A. 62 m 1.02 209 52 130 136 109 75 F.A. 50 in 0.8 192 46 116 152 144 102 TI. 72 m 0.72 183 47 111 126 155 99 N.G. 49 m 0.92 187 44 124 108 147 84 D.G. 57 m 1.1 196 46 134 79 133 69 Q.I. 66 m 1.06 201 49 121 155 129 77 I.M. 68 m 0.88 191 53 114 119 178 81 U.G. 51 m 0.92 185 46 115 121 154 109 E.T. 65 m 1.03 205 42 137 132 98 125 mean 59.9 0.94 195 47 123 124 138 91 8 0.11 9 4 10 21 23 17 using commercially available kits (Boehringer-Mannheim, Mann- 20 heim, Germany). Plasma HDL cholesterol concentration was determined after precipitation of Apo B containing lipoproteins * with sodium phosphotungstate/magnesium chloride, as described previously [26]. LDL-cholesterol was determined by Friedewald's * formula. Apolipoproteins A-I and B-100 were determined by 15 immunoturbidimetric assays (Boehringer-Mannheim). The 24- hour albumin excretion rate was determined by radioimmunoas- say (Amersham, UK). The plasma MVA concentrations were quantified using an extension of our previously described method 10 [271. Briefly, plasma was incubated with Dowex 50 (H) to convert free MVA to its lactone. The nonpolar lipids were extracted in hexane, after the mevalonlactone from the acqueous solution was extrated into CH2CI2-PrOH (9:1 vol/vol) which was 5 loaded into a Lc-Si silica cartridge for the purification. The lactone was finally reconverted to free mevalonic acid and then converted to its 3,5-bis(trifluoromethyl)benzyl ester. The trimeth- ylsilyl ether derivate was then prepared and reconstitued in 0 n-octane for gas chromatography-mass spectrometry (CG-MS). The CG column was routed into the ion source of a VGFig. 1. Mean plasma mevalonate concentrations (MVA) at 9:00 am, in (U) Biotech-Quattro mass spectrometer. The amount of the derivedhypercholesterolemic and ()normocholesterolemicCRF patients (group A), MVA was measured by Cl/MS using CH4 as reactant gas,and in (LI) control subjects (group C); *< 0.001versus group C. operating the spectrometer in the single-ion mode to enhance the sensitivity and the accurancy of the analysis. All MVA concentra- tions were assayed in duplicate.

Statistics shown in Figure 2, a significant direct correlation was noted One-way analysis of variance (ANOVA) and paired or un-between plasma MVA and serum creatinine in group A (r =0.86; paired t-tests were applied to the results. The relationship be-P < 0.001). tween the MVA and creatinine plasma levels were explored by univariate regression analysis. A P value of < 0.05 was considered Group B to he statistically significant. Data are presented as means SD.

Results In the group of uremic patients on intermittent hemodialysis treatment, mean basal (T-0) plasma MVA concentration was Group A 17,2 5.63 ng/ml, three- to fourfold increased than in control The mean plasma total cholesterol levels were 281 34 mg/dlsubjects (P < 0.001). Plasma MVA concentrations decreased to in the hypercholesterolemic, 194 36 mg/dl in normocholcstcr-7.4 1.61 ng/ml after the dialysis session (T-4; T-0 vs. T-4, P < olemic CRF patients (P < 0.01) and 195 9 mg/dl in the control0.001) and then increased up to 17.7 3.3 ng/ml 24 hours after subjects, (hypercholesterolemic CRF vs. control subjects, P

30 20 27.5 0 25 0 0 22.5 15 20 0 0 17.5 0 15 0 E 12.5 10 SI 7.5 5 5 2.5 1 2 3 4 5 6 7 8 9

Plasma creatiriine, mg/dl 0 Fig. 2. Relationship between plasma mevalonate (MVA) and serum creati- T-0 T-4 T-24 nine in patients of group A. r =0.86;P <0.01. Time from die ysis session, hours Fig.3. Mean plasma mevalonate conc ntrations (MV4) in uremic patients Discussion before (T-0), four hours after (T-4) an 24 hours after (T-24) the hemodi- The kidneys are the major site for the metabolism of circulatingalysis treatment; *P <0.00]versus T-C and T-24. MVA via both the sterol and shunt pathways, and all mammals, including humans, participate to the clearance of the compound, with no significant differences between males and females [281.reduced renal function. Alternatively, one might hypothesise an Moreover, the MVA, which is the obligate precursor in theincreased MVA synthesis or a reduced utilization of MVA along biosynthetic pathway of cholesterol, is also a precursor of otherthe sterol and non-sterol pathways. several substances (such as isoprenoids) and has been proposed to The importance of MVA pathway in renal diseases has been play an important role in progressive renal disease and essentialindirectly demonstrated by the beneficial effects of HMG CoA hypertension [291. The recent introduction of a highly sensitivereductase inhibition in animal models of progressive glomerular CG[C1]MS assay for MVA determination has provided ainjury [6, 31, 321. These effects are probably due to a combination method to investigate MVA metabolism in patients with renalof multiple factors as the reduction of circulating lipoproteins, a disease [27]. decrease in glomerular lipoprotein deposition, an influence on the In this study, MVA was found to be markedly affected by renalsynthesis of isoprenoids and on the mesangial cell proliferation disease. Patients with CRF exhibited significantly increased[33]. Farnesyl GTP-binding may be critical for mitogenic plasma MVA levels that paralleled the degree of renal failure, assignalling stimulated by growth factors [17]. esterified reflected by serum creatinine values. These results are in keepingwith phosphates is essential for the synthesis of with previous studies in experimental animals, demonstrating aincluding transporters such as the Na7H antiport [7]. The fivefold rise in plasma MVA levels following bilateral nephrec-activity of Na/H antiport can be reduced by the HMG CoA tomy in rats [22] and an increased plasma MVA with a decreasedreductase inhibitors in diabetic patients with nephropathy [7]. A urinary excretion in CRF mice [231. previous study demonstrated that lovastatin is able to reduce The conversion of MVA to and sterol in the kidney isglomerular injury in the Dahl S rat [31. In this animal, hyperlip- confined to the proximal and distal convoluted tubules in theidemia and progressive renal disease occur and may be responsi- cortex [201. Little activity is present in the glomerulus. Besides,ble, at least in part, for the initiation of glomerular injury. circulating MVA metabolism is different among species. In the ratInterestingly, the lovastatin treatment markedly reduced albumin- 85% of this metabolism occurs in the renal tissues [201, while inuria and the blood pressure [34]. On the other hand, a recent the monkey renal metabolism represents 42% and in the humanhuman study in vitro [9] suggested that metabolites of the meva- 39 to 46% [21]. Data in experimental animal models haveInnate pathway other than cholesterol could potentially control demonstrated that uremia induces alterations in the metabolismvascular functions and cardiovascular hemodynamics. The in vitro of MVA that are characterized by a reduction in the shuntexposure of human conductance vessels to lovastatin increased pathway activity with an inverse relationship with either plasmathe response to vasoconstrictors and decreased - BUN or creatinine [30], and an enhancement of the steroldependent and independent relaxations, The authors suggested pathway, even in the presence of intact renal mass. This in turnthat metabolic disorders of the mevalonatc pathway might con- produces a large increase in the hepatic cholesterol and non-tribute to the pathogenesis of cardiovascular diseases, including saponificable products synthesized from circulating MVA levelsessential hypertension [8, 9]. Therefore, the possibility exists that [301. Finally, in the liver of the same animal models, this enhance-alterations of MVA concentrations in CRF patients may exert ment of sterologenesis directly correlates with plasma BUN andsome effects on hypertension associated to chronic renal failure. creatinine values [20, 21, 30]. The clear cut increase of MVA Given the above considerations, we sought to determine the concentrations in our CRF patients is likely to result from theeffects of hemodialysis treatment on plasma MVA concentrations. 912 Scoppolaet al: MVA in uremia

A single treatment reduces plasma MVA levels by 57%. At the Simultaneous determination of mevalonate and 7ahydroxycholesterol end of the dialytic session, MVA concentrations are in the upper in human plasma by gas chromatography-mass spectrometry as indices of cholesterol and biosynthesis. J Cromatogr 613:185—193, normal range reaching a plateau 24-hours after with levels three- 1993 to fourfold higher than normal. The reduction after hemodialysis 15. PAPPU AS, ILLINGWORTH DR, BACON 5: Reduction in plasma low- of plasma MVA is likely to be due to the clearance of hemodia- density lipoprotein cholesterol and urinary mevalonic acid by lova- lyzer, since MVA has a molecular weight of 148 and a serum in patients with heterozygous familial . protein binding of approximately 30%. Accordingly, the MVA Metabolism 38:542—549, 1989 16. 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