- Email: [email protected]
L-arginine reverses pentraxin family members in rat pregnancy induced hypertension
100A
POSTERS: Kidney and Hypertension
mmHg). Seven patients (3.4%) showed untoward effects. No one case of oedema was detected and the prevalence of adverse effects related to vasodilatation was extremely low (3 patients, 1.48%) . Plasmatic creatinin did not change (1.9⫾0.5 baseline vs 1.9⫾0.6 mg/dl) but creatinine clearance increased at the end visit (41.8⫾16.0 baseline vs 45.8⫾18.0 ml/min, p ⫽ 0.019). Plasmatic cholesterol also decreased from 221⫾46 to 211⫾35 mg/dl (p ⫽ 0.001). Lercanidipine showed a high antihypertensive effect in CRF patients. It has a good tolerability profile and showed an interesting effect on plasmatic lipids. An improvement in renal function, measured through creatine clearance, was detected. Key Words: Lercanidipine, chronic renal failure
P-169 POSITIVE SIMULTANEOUS EFFECT OF CANDESARTAN DOSE UP-TITRATION ON PROTEINURIA AND BLOOD PRESSURE Julian Segura, Carlos Campo, Javier Nieto, Alberto Torres, Fernando de Alvaro, Ana Vigil, Jose Luno, Luis M Ruilope. Hypertension Unit. Nephrology Department, Hospital 12 Octubre, Madrid, Spain; Nephrology Department, Complejo Hospitalario, Ciudad Real, Spain; Nephrology Department, Hospital La Paz, Madrid, Spain; Nephrology Department, Hospital Severo Ochoa, Leganes, Madrid, Spain; Nephrology Department, Hospital Gregorio Maranon, Madrid, Spain. We have analysed the effect of up-titration (8, 16, 32 mg) of candesartan on 24h proteinuria. Variations of casual BP and creatinine clearance (CC) have been simultaneously analysed. A group of 46 patients (mean age 46 yr, 31 male diagnosed of primary glomerulonephritis, proteinuria ⬎2g/d and CC ⬎30 ml/min) entered, after a 4wk placebo period (baseline), in a prospective, randomised, double blind cross-over design. Patients were randomised to three sequences receiving 8 mg, 8 mg and 16 mg of candesartan respectively for 4wk. Doses were then up-titrated to 32, 16 and 32 mg respectively for a further 4wk period. Determinations were made at baseline, and after 4 and 8 wk. Reductions in 24h proteinuria from baseline were 21.7%(6-30.6%) for 8 mg, 37.7%(25.2-48.2 %) for 16 mg and 44.8% (33.7-54%) for 32 mg. A linear trend was seen for reduction in proteinuria in relation to dose from baseline to week 8 (p⬍0.0007). These changes took place in the absence of significant variations in CC. Meanwhile, mean final systolic BP was 122.4 mm Hg for those receiving 32 mg of candesartan. These figures are to be compared with a mean final systolic BP of 129.2 mm Hg for the group on 16 mg and 129.4 mm Hg for the group on 8 mg. Even in this case a significant linear trend can be detected (p⬍0.001), although there were no significant differences in mean systolic BP between patients treated with 16 mg to those treated with 8 mg. Mean diastolic BP was reduced from baseline, without differences among the final doses. We conclude that up-titration of an AT-1 receptor antagonist obtains a simultaneous salutary effect on both proteinuria and blood pressure. Key Words: Angiotensin receptor antagonists, proteinuria, blood pressure
P-170 EPLERENONE AND SERUM POTASSIUM CHANGE -RELATIONSHIP TO RENAL FUNCTION Domenic A Sica. Department of Medicine and Pharmacology, Virginia Commonwealth University, Richmond, VA. Background: Eplerenone (EPL) is the first selective aldosterone blocker recently approved for antihypertensive therapy. Aldosterone blockade is associated with physiologic increases in serum potassium (sK), and understanding the changes in sK with EPL therapy is of clinical interest. Titration-to-effect (TTE) study designs more accurately reflect recom-
AJH–May 2003–VOL. 16, NO. 5, PART 2
mended clinical practice than forced-titration or fixed-dose designs. We have pooled data from 6 TTE studies with EPL to evaluate the changes in sK associated with titrated doses of EPL and renal impairment. Methods: Patients treated with EPL alone in 6 TTE studies were included for analysis (N⫽1286). Each subjects’ dose experience was divided into up to 4 distinct units of analysis (pre-treatment; 50; 100; 200-mg). We modeled the relationship between the maximum sK (maxsK) for each subject in each dose interval as a function of dose and renal function, adjusting standard error estimates for repeated measures by using a mixed effects model. Patients were initially categorized into 4 levels of renal impairment based on their estimated creatinine clearance at baseline (severe: ⬍40, n⫽3; moderate: 40 to ⬍60, n⫽53; mild: 60 to ⬍80, n⫽146; normal: 80⫹, n⫽1125). Mean Estimates and 95% CI’s* for Maximum Serum Potassium (mmol/ L) in Each Dose Interval by Renal Function Eplerenone Dose Renal Impairment normal mild moderate & severe
Pre-Treatment
50mg
100mg
200mg
4.26 (4.24–4.28) 4.28 (4.22–4.34)
4.62 (4.60–4.64) 4.67 (4.61–4.74)
4.59 (4.56–4.61) 4.71 (4.64–4.77)
4.74 (4.71–4.76) 4.76 (4.69–4.83)
4.27 (4.16–4.37)
4.71 (4.61–4.81)
4.68 (4.56–4.79)
4.75 (4.63–4.87)
* Least-square mean estimates and confidence intervals from mixed effects model to adjust variances for analysis of repeated measures
Results: The maxsK across the 3 doses range uniformly between 4.6 and 4.8; and are different from baseline (p⬍0.0001). Adjusting for dose, the mean maxsK for each of the renal function groups are not significantly different from normal renal function (p⫽0.12). Conclusion: The mean maxsK observed across titrated doses of EPL up to 200mg is 4.8 mmol/L, and is not substantially modified by renal function. This level of sK may be a preferred range of sK for hypertensive/cardiac patients. Renal function in and of itself is not the sole determinant of the highest sK value seen with EPL. Rather, the baseline sK along with underlying homeostatic defense mechanisms will define the sK levels observed with aldosterone-receptor blockade. Key Words: Eplerenone, hyperkalemia, chronic renal failure
P-171 L-ARGININE REVERSES PENTRAXIN FAMILY MEMBERS IN RAT PREGNANCY INDUCED HYPERTENSION Gregory I. C. Simpson, Leslie C. Sharkey, John C. Fray. Department of Physiology, Genomic Physiology Group, University of Masshusetts Medical School, Worcester, MA; Department of Biomedical Sciences, Tufts University of Veterinary Medicine, North Grafton, MA. Pregnancy-induced hypertension (PIH) is a leading cause of maternal mortality and fetal morbidity. Abnormally secreted gene products from the placenta are believed to be the cause. PIH has been characterized by spontaneous and sustained hypertension and intrauterine growth restriction, and has been associated with weak physical attachments such as those mediated by RGD motifs, coiled-coil domains, Asn-glycosylation sites and N-myristoylation signatures. The SHHF rat has been used as an animal model of the human disorder, because it has the above features plus abnormal gene expression profile in placenta and kidney. Although the mechanism responsible for PIH is unknown, altered expression of genes coding for the above signatures in their products has been raised as a logical possibility. To gain an understanding of the molecular mechanism in PIH and the distribution of these physiologically significant signatures, placental mRNA expression profiles of 8,979 mRNAs from the rat genome were screened for candidates, which had the above signatures as well as reversal by L-arginine. We collected placenta and kidney at gestation day 20 and conducted microarray determinations on 3 kidneys and 3 placentas each from pregnant SHHF and WKY rats. Of the 8,178 mRNA transcripts expressed in placental tissue, 33% were glycosylated myristoylated gene products and 56 of these had coiled coil motifs. Only 11 of these transcripts were reversed by L-arginine. Pen-
AJH–May 2003–VOL. 16, NO. 5, PART 2
traxin was the only predicted secreted gene products with all the features stipulated above and reversed by L-arginine. Western blot analysis showed higher pentraxin levels in serum of SHHF rats vs. WKY. Additional pentraxin family members such as amyloid precursor-like protein 2, neuronal pentraxin II, and pentraxin receptor were also upregulated in SHHF rats and reversed by L-arginine. All 4 members of the pentraxin signaling system (pentraxin, neuronal pentraxin II, amyloid precursorlike protein 2, and pentraxin receptor) are N-glycosylated myristoyl proteins with coiled-coil regions, a signal sequence but with different cellular localization. We conclude that pentraxin is a bonafide secretory protein from the placenta of SHHF rat associated with PIH and that the mechanism involves nitric oxide since L-arginine reversed both the hypertension and gene overexpression of pentraxin and family members. Key Words: Pentraxin, pregnancy induced hypertension, microarrays
P-172 COST-EFFECTIVENESS OF RENOPROTECTION IN DIABETIC PATIENTS WITH AN ANGIOTENSIN II RECEPTOR ANTAGONIST AND A CALCIUM CHANNEL BLOCKER: ECONOMIC ANALYSIS OF THE MARVAL TRIAL Dean G Smith, Giancarlo Viberti, Anh Nguyen, Feride F Frech, Krista Yokoyama. Health Management & Policy, University of Michigan, Ann Arbor, MI; Department of Diabetes, Endocrinology and Internal Medicine, GKT School of Medicine, London, United Kingdom; Economics and Outcomes Research, Novartis Pharmaceuticals, East Hanover, NJ; Pharmacy Management, Wellpoint, West Hills, CA. Recent randomized trials have shown that blood pressure can be controlled using a variety of agents and that for diabetic patients, renoprotective benefits may be added with angiotensin II receptor antagonists. The objective of the present study was to evaluate the short-term costs and cost-effectiveness of initiating therapy with an angiotensin II receptor antagonist as compared to a calcium channel blocker in type II diabetic patients with microalbuminuria. An economic model was developed based upon a multicenter, randomized, double-blind, 24-week study comparing the angiotensin II receptor antagonist valsartan (n⫽ 168) with the calcium channel blocker amlodipine (n ⫽ 161) in type 2 diabetic patients with microalbuminuria. Between March 1998 and June 2000, patients were treated with starting dose of study medication, which may have been doubled and augmented with bendrofluazide or doxazosin at four-week intervals until a blood pressure target of 135/85 was achieved. The primary outcome measure was urinary albumin excretion rate (UAER) and the secondary outcome measure was return to normoalbuminuric status. Resource use was collected through adverse event, concurrent medication and study administration reports. Costs were applied to resources at Medicare payment rates for services and average wholesale prices for medications. Changes in UAER were (43.75%) with valsartan and (6.6%) with amlodipine (p ⬍ 0.01). Changes in albuminuric status were 29.9% with valsartan and 15.5% with amlodipine (p ⬍ 0.01). Total costs were $973.11 with valsartan and $992.43 with amlodipine (p ⫽ 0.64). Incremental cost-effectiveness ratios were (52) for changes in UAER and (125) for changes in albuminuric status. Use of valsartan as compared to amlodipine in diabetic patients with microalbuminuria was associated with significantly improved UAER and albuminuric status at similar total treatment costs. The combination of significantly higher efficacy and similar costs indicates that valsartan is more cost-effective than amlodipine. Key Words: Kidney, diabetes, costs
POSTERS: Kidney and Hypertension
101A
P-173 GENE-EXPRESSION PROFILING OF RAT MESENTERIC ARTERY CAUSED BY LONG-TERM ERYTHROPOIETIN TREATMENT Sandor Sonkodi. Laboratory of Functional Genomics,, Biological Research Center, Hungarian Academy of Sciences, Szeged, Hungary; 1st Department of Medicine, Scientific University Medical Faculty, Szeged, Hungary. A previous in vitro experiment demonstrated that erythropoietin (rHuEPO) revealed an increased expression of the angiotensin II receptor in vascular smooth muscle cell cultures of mesenteric arteries from the rat (J Hypertension 1998, 16, 1749). Using cDNA microarrays, we have now conducted a systematic characterization of the gene expression in the mesenteric artery of rats chronically treated with rHuEPO. These preliminary gene expression data highlight the molecular background of the effects of EPO,and mainly those responsible for the generation of high blood pressure. Male Wistar rats weighing 200-220 g were divided into two groups. The first group (n⫽6) was treated intraperitoneally with rHuEPO in a dose of 15 U/100 g twice weekly for 16 weeks. The second group (n⫽6) received the same volume of physiological saline in the same way. Systolic blood pressure (BP) was measured weekly by the tail-cuff method (W⫹W recorder). At the end of the experiment the, systolic BP was 157⫾8 mmHg in the treated group, and 119⫾6 mmHg in the control group (p⬍0.01). Under systemic anesthesia, the mesenteric arteries were separated and taken out for cDNA microarray analysis. A rat cDNA microarray was constructed with 3200 PCR-amplified cDNA clones in duplicate, isolated from rat brain, liver, kidney and vessels. To eliminate most of the unspecific signals, replicate and “color-flip”, experiments were performed on pooled samples. Genes determined to have significantly altered expression levels in rat kidneys relative to the controls following the long-term administration of rHuEPO were sequenced, and their function was verified by using a homology search in the sequence database. The noteworthy changes in gene expression observed suggest an increased activity of those genes which are responsible for hypertension. We also found several candidate genes with a repressed expression whose products could have a role in causing hypotension. The combined modes of action of the repressed and induced genes could explain the hypertension observed in humans chronically treated with rHuEPO. Key Words: rHuEPO, cDNA microarray
P-174 LONG-TERM VARIATION OF QT INTERVAL IN UREMIC PATIENTS ON CHRONIC HEMODIALYSIS Simonetta Genovesi, Paolo Fabbrini, Chiara Dossi, Luca Mircoli, Rodolfo Rivera, Alberto U Ferrari, Andrea Stella, Marco Stramba-Badiale. DIMEP, University of Milano-Bicocca, Monza, MI, Italy; Department of CardiologyIRCCS,, IRCCS Ospedale Maggiore, Milan, Italy; Department of Nephrology, Ospedale Civile di Vimercate, Vimercate, MI, Italy; Department of Cardiology, IRCCS Istituto Auxologico Italiano, Milan, Italy. Patients requiring maintenance hemodialysis (HD) show high mortality rate and sudden cardiac death. Previous studies have shown that at the end of the HD session the QT interval on standard ECG prolongs and its dispersion increases, but little is known on the long-term variation of QT interval and on its relationship with heart rate changes. The dynamic behaviour of ventricular repolarization assssed in 29 consecutive patients (age 66 ⫾ 11; 15 females) on chronic HD from 24 hour Holter recordings. A dedicated algorithm (ELA medical) automatically measured QT and RR interval from 2880 30-sec segments. QT corrected for heart rate (QTc) and the slope of the QT/RR regression line were analysed during a 20-hour period before HD, the HD session, the hour before HD and during each HD hour. In all patients K, Mg and Ca plasma concentrations
POSTERS: Kidney and Hypertension
mmHg). Seven patients (3.4%) showed untoward effects. No one case of oedema was detected and the prevalence of adverse effects related to vasodilatation was extremely low (3 patients, 1.48%) . Plasmatic creatinin did not change (1.9⫾0.5 baseline vs 1.9⫾0.6 mg/dl) but creatinine clearance increased at the end visit (41.8⫾16.0 baseline vs 45.8⫾18.0 ml/min, p ⫽ 0.019). Plasmatic cholesterol also decreased from 221⫾46 to 211⫾35 mg/dl (p ⫽ 0.001). Lercanidipine showed a high antihypertensive effect in CRF patients. It has a good tolerability profile and showed an interesting effect on plasmatic lipids. An improvement in renal function, measured through creatine clearance, was detected. Key Words: Lercanidipine, chronic renal failure
P-169 POSITIVE SIMULTANEOUS EFFECT OF CANDESARTAN DOSE UP-TITRATION ON PROTEINURIA AND BLOOD PRESSURE Julian Segura, Carlos Campo, Javier Nieto, Alberto Torres, Fernando de Alvaro, Ana Vigil, Jose Luno, Luis M Ruilope. Hypertension Unit. Nephrology Department, Hospital 12 Octubre, Madrid, Spain; Nephrology Department, Complejo Hospitalario, Ciudad Real, Spain; Nephrology Department, Hospital La Paz, Madrid, Spain; Nephrology Department, Hospital Severo Ochoa, Leganes, Madrid, Spain; Nephrology Department, Hospital Gregorio Maranon, Madrid, Spain. We have analysed the effect of up-titration (8, 16, 32 mg) of candesartan on 24h proteinuria. Variations of casual BP and creatinine clearance (CC) have been simultaneously analysed. A group of 46 patients (mean age 46 yr, 31 male diagnosed of primary glomerulonephritis, proteinuria ⬎2g/d and CC ⬎30 ml/min) entered, after a 4wk placebo period (baseline), in a prospective, randomised, double blind cross-over design. Patients were randomised to three sequences receiving 8 mg, 8 mg and 16 mg of candesartan respectively for 4wk. Doses were then up-titrated to 32, 16 and 32 mg respectively for a further 4wk period. Determinations were made at baseline, and after 4 and 8 wk. Reductions in 24h proteinuria from baseline were 21.7%(6-30.6%) for 8 mg, 37.7%(25.2-48.2 %) for 16 mg and 44.8% (33.7-54%) for 32 mg. A linear trend was seen for reduction in proteinuria in relation to dose from baseline to week 8 (p⬍0.0007). These changes took place in the absence of significant variations in CC. Meanwhile, mean final systolic BP was 122.4 mm Hg for those receiving 32 mg of candesartan. These figures are to be compared with a mean final systolic BP of 129.2 mm Hg for the group on 16 mg and 129.4 mm Hg for the group on 8 mg. Even in this case a significant linear trend can be detected (p⬍0.001), although there were no significant differences in mean systolic BP between patients treated with 16 mg to those treated with 8 mg. Mean diastolic BP was reduced from baseline, without differences among the final doses. We conclude that up-titration of an AT-1 receptor antagonist obtains a simultaneous salutary effect on both proteinuria and blood pressure. Key Words: Angiotensin receptor antagonists, proteinuria, blood pressure
P-170 EPLERENONE AND SERUM POTASSIUM CHANGE -RELATIONSHIP TO RENAL FUNCTION Domenic A Sica. Department of Medicine and Pharmacology, Virginia Commonwealth University, Richmond, VA. Background: Eplerenone (EPL) is the first selective aldosterone blocker recently approved for antihypertensive therapy. Aldosterone blockade is associated with physiologic increases in serum potassium (sK), and understanding the changes in sK with EPL therapy is of clinical interest. Titration-to-effect (TTE) study designs more accurately reflect recom-
AJH–May 2003–VOL. 16, NO. 5, PART 2
mended clinical practice than forced-titration or fixed-dose designs. We have pooled data from 6 TTE studies with EPL to evaluate the changes in sK associated with titrated doses of EPL and renal impairment. Methods: Patients treated with EPL alone in 6 TTE studies were included for analysis (N⫽1286). Each subjects’ dose experience was divided into up to 4 distinct units of analysis (pre-treatment; 50; 100; 200-mg). We modeled the relationship between the maximum sK (maxsK) for each subject in each dose interval as a function of dose and renal function, adjusting standard error estimates for repeated measures by using a mixed effects model. Patients were initially categorized into 4 levels of renal impairment based on their estimated creatinine clearance at baseline (severe: ⬍40, n⫽3; moderate: 40 to ⬍60, n⫽53; mild: 60 to ⬍80, n⫽146; normal: 80⫹, n⫽1125). Mean Estimates and 95% CI’s* for Maximum Serum Potassium (mmol/ L) in Each Dose Interval by Renal Function Eplerenone Dose Renal Impairment normal mild moderate & severe
Pre-Treatment
50mg
100mg
200mg
4.26 (4.24–4.28) 4.28 (4.22–4.34)
4.62 (4.60–4.64) 4.67 (4.61–4.74)
4.59 (4.56–4.61) 4.71 (4.64–4.77)
4.74 (4.71–4.76) 4.76 (4.69–4.83)
4.27 (4.16–4.37)
4.71 (4.61–4.81)
4.68 (4.56–4.79)
4.75 (4.63–4.87)
* Least-square mean estimates and confidence intervals from mixed effects model to adjust variances for analysis of repeated measures
Results: The maxsK across the 3 doses range uniformly between 4.6 and 4.8; and are different from baseline (p⬍0.0001). Adjusting for dose, the mean maxsK for each of the renal function groups are not significantly different from normal renal function (p⫽0.12). Conclusion: The mean maxsK observed across titrated doses of EPL up to 200mg is 4.8 mmol/L, and is not substantially modified by renal function. This level of sK may be a preferred range of sK for hypertensive/cardiac patients. Renal function in and of itself is not the sole determinant of the highest sK value seen with EPL. Rather, the baseline sK along with underlying homeostatic defense mechanisms will define the sK levels observed with aldosterone-receptor blockade. Key Words: Eplerenone, hyperkalemia, chronic renal failure
P-171 L-ARGININE REVERSES PENTRAXIN FAMILY MEMBERS IN RAT PREGNANCY INDUCED HYPERTENSION Gregory I. C. Simpson, Leslie C. Sharkey, John C. Fray. Department of Physiology, Genomic Physiology Group, University of Masshusetts Medical School, Worcester, MA; Department of Biomedical Sciences, Tufts University of Veterinary Medicine, North Grafton, MA. Pregnancy-induced hypertension (PIH) is a leading cause of maternal mortality and fetal morbidity. Abnormally secreted gene products from the placenta are believed to be the cause. PIH has been characterized by spontaneous and sustained hypertension and intrauterine growth restriction, and has been associated with weak physical attachments such as those mediated by RGD motifs, coiled-coil domains, Asn-glycosylation sites and N-myristoylation signatures. The SHHF rat has been used as an animal model of the human disorder, because it has the above features plus abnormal gene expression profile in placenta and kidney. Although the mechanism responsible for PIH is unknown, altered expression of genes coding for the above signatures in their products has been raised as a logical possibility. To gain an understanding of the molecular mechanism in PIH and the distribution of these physiologically significant signatures, placental mRNA expression profiles of 8,979 mRNAs from the rat genome were screened for candidates, which had the above signatures as well as reversal by L-arginine. We collected placenta and kidney at gestation day 20 and conducted microarray determinations on 3 kidneys and 3 placentas each from pregnant SHHF and WKY rats. Of the 8,178 mRNA transcripts expressed in placental tissue, 33% were glycosylated myristoylated gene products and 56 of these had coiled coil motifs. Only 11 of these transcripts were reversed by L-arginine. Pen-
AJH–May 2003–VOL. 16, NO. 5, PART 2
traxin was the only predicted secreted gene products with all the features stipulated above and reversed by L-arginine. Western blot analysis showed higher pentraxin levels in serum of SHHF rats vs. WKY. Additional pentraxin family members such as amyloid precursor-like protein 2, neuronal pentraxin II, and pentraxin receptor were also upregulated in SHHF rats and reversed by L-arginine. All 4 members of the pentraxin signaling system (pentraxin, neuronal pentraxin II, amyloid precursorlike protein 2, and pentraxin receptor) are N-glycosylated myristoyl proteins with coiled-coil regions, a signal sequence but with different cellular localization. We conclude that pentraxin is a bonafide secretory protein from the placenta of SHHF rat associated with PIH and that the mechanism involves nitric oxide since L-arginine reversed both the hypertension and gene overexpression of pentraxin and family members. Key Words: Pentraxin, pregnancy induced hypertension, microarrays
P-172 COST-EFFECTIVENESS OF RENOPROTECTION IN DIABETIC PATIENTS WITH AN ANGIOTENSIN II RECEPTOR ANTAGONIST AND A CALCIUM CHANNEL BLOCKER: ECONOMIC ANALYSIS OF THE MARVAL TRIAL Dean G Smith, Giancarlo Viberti, Anh Nguyen, Feride F Frech, Krista Yokoyama. Health Management & Policy, University of Michigan, Ann Arbor, MI; Department of Diabetes, Endocrinology and Internal Medicine, GKT School of Medicine, London, United Kingdom; Economics and Outcomes Research, Novartis Pharmaceuticals, East Hanover, NJ; Pharmacy Management, Wellpoint, West Hills, CA. Recent randomized trials have shown that blood pressure can be controlled using a variety of agents and that for diabetic patients, renoprotective benefits may be added with angiotensin II receptor antagonists. The objective of the present study was to evaluate the short-term costs and cost-effectiveness of initiating therapy with an angiotensin II receptor antagonist as compared to a calcium channel blocker in type II diabetic patients with microalbuminuria. An economic model was developed based upon a multicenter, randomized, double-blind, 24-week study comparing the angiotensin II receptor antagonist valsartan (n⫽ 168) with the calcium channel blocker amlodipine (n ⫽ 161) in type 2 diabetic patients with microalbuminuria. Between March 1998 and June 2000, patients were treated with starting dose of study medication, which may have been doubled and augmented with bendrofluazide or doxazosin at four-week intervals until a blood pressure target of 135/85 was achieved. The primary outcome measure was urinary albumin excretion rate (UAER) and the secondary outcome measure was return to normoalbuminuric status. Resource use was collected through adverse event, concurrent medication and study administration reports. Costs were applied to resources at Medicare payment rates for services and average wholesale prices for medications. Changes in UAER were (43.75%) with valsartan and (6.6%) with amlodipine (p ⬍ 0.01). Changes in albuminuric status were 29.9% with valsartan and 15.5% with amlodipine (p ⬍ 0.01). Total costs were $973.11 with valsartan and $992.43 with amlodipine (p ⫽ 0.64). Incremental cost-effectiveness ratios were (52) for changes in UAER and (125) for changes in albuminuric status. Use of valsartan as compared to amlodipine in diabetic patients with microalbuminuria was associated with significantly improved UAER and albuminuric status at similar total treatment costs. The combination of significantly higher efficacy and similar costs indicates that valsartan is more cost-effective than amlodipine. Key Words: Kidney, diabetes, costs
POSTERS: Kidney and Hypertension
101A
P-173 GENE-EXPRESSION PROFILING OF RAT MESENTERIC ARTERY CAUSED BY LONG-TERM ERYTHROPOIETIN TREATMENT Sandor Sonkodi. Laboratory of Functional Genomics,, Biological Research Center, Hungarian Academy of Sciences, Szeged, Hungary; 1st Department of Medicine, Scientific University Medical Faculty, Szeged, Hungary. A previous in vitro experiment demonstrated that erythropoietin (rHuEPO) revealed an increased expression of the angiotensin II receptor in vascular smooth muscle cell cultures of mesenteric arteries from the rat (J Hypertension 1998, 16, 1749). Using cDNA microarrays, we have now conducted a systematic characterization of the gene expression in the mesenteric artery of rats chronically treated with rHuEPO. These preliminary gene expression data highlight the molecular background of the effects of EPO,and mainly those responsible for the generation of high blood pressure. Male Wistar rats weighing 200-220 g were divided into two groups. The first group (n⫽6) was treated intraperitoneally with rHuEPO in a dose of 15 U/100 g twice weekly for 16 weeks. The second group (n⫽6) received the same volume of physiological saline in the same way. Systolic blood pressure (BP) was measured weekly by the tail-cuff method (W⫹W recorder). At the end of the experiment the, systolic BP was 157⫾8 mmHg in the treated group, and 119⫾6 mmHg in the control group (p⬍0.01). Under systemic anesthesia, the mesenteric arteries were separated and taken out for cDNA microarray analysis. A rat cDNA microarray was constructed with 3200 PCR-amplified cDNA clones in duplicate, isolated from rat brain, liver, kidney and vessels. To eliminate most of the unspecific signals, replicate and “color-flip”, experiments were performed on pooled samples. Genes determined to have significantly altered expression levels in rat kidneys relative to the controls following the long-term administration of rHuEPO were sequenced, and their function was verified by using a homology search in the sequence database. The noteworthy changes in gene expression observed suggest an increased activity of those genes which are responsible for hypertension. We also found several candidate genes with a repressed expression whose products could have a role in causing hypotension. The combined modes of action of the repressed and induced genes could explain the hypertension observed in humans chronically treated with rHuEPO. Key Words: rHuEPO, cDNA microarray
P-174 LONG-TERM VARIATION OF QT INTERVAL IN UREMIC PATIENTS ON CHRONIC HEMODIALYSIS Simonetta Genovesi, Paolo Fabbrini, Chiara Dossi, Luca Mircoli, Rodolfo Rivera, Alberto U Ferrari, Andrea Stella, Marco Stramba-Badiale. DIMEP, University of Milano-Bicocca, Monza, MI, Italy; Department of CardiologyIRCCS,, IRCCS Ospedale Maggiore, Milan, Italy; Department of Nephrology, Ospedale Civile di Vimercate, Vimercate, MI, Italy; Department of Cardiology, IRCCS Istituto Auxologico Italiano, Milan, Italy. Patients requiring maintenance hemodialysis (HD) show high mortality rate and sudden cardiac death. Previous studies have shown that at the end of the HD session the QT interval on standard ECG prolongs and its dispersion increases, but little is known on the long-term variation of QT interval and on its relationship with heart rate changes. The dynamic behaviour of ventricular repolarization assssed in 29 consecutive patients (age 66 ⫾ 11; 15 females) on chronic HD from 24 hour Holter recordings. A dedicated algorithm (ELA medical) automatically measured QT and RR interval from 2880 30-sec segments. QT corrected for heart rate (QTc) and the slope of the QT/RR regression line were analysed during a 20-hour period before HD, the HD session, the hour before HD and during each HD hour. In all patients K, Mg and Ca plasma concentrations