Nefrologia_1-08_ingles.pdf

F. Gracia López y cols. Hemodiálisis en ancianos
http://www.senefro.org
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2008 Órgano Oficial de la Sociedad Española de Nefrología Irbesartan in hypertensive non-diabetic advanced
chronic kidney disease. Comparative study with ACEI
F. Coronel, S. Cigarrán*, M. García-Mena, J. A. Herrero, N. Calvo and I. Pérez-Flores
Nephrology Department. Hospital Clínico San Carlos. Madrid. *Nephrology Department. Complex of Vigo. CHUVI. Vigo. Nefrología 2008; 28 (1) 56-60
Angiotensin-converting enzyme inhibitors (ACEI) have proved an Los inhibidores del enzima de conversión de angiotensina
antihypertensive and renoprotective effect with reduction of protei- (IECAs) han demostrado un efecto antihipertensivo, reno-
nuria in diabetic and non diabetic nephropathy, but not exempt of protector y antiproteinurico en pacientes con nefropatía
side effects in advanced chronic kidney disease (ACKD) patients. An- diabética y no diabética, aunque deben administrarse con
giotensin receptor blockers (ARB) have emerged as antiproteinuric, precaución en la enfermedad renal crónica avanzada
renoprotective and cardioprotective therapy. Only a few reports (ERCA). Los antagonistas de los receptores de angiotensina
have been published studying ARB effects on non-diabetic ACKD II (ARA II) muestran un perfil similar a los IECA en la nefro-
patients. Our aim is to study Irbesartan (ARB) on non-diabetic ACKD patía diabética con buena tolerancia clínica, pero existen
patients and compare its effects with ACEI. Patients and methods: pocos estudios sobre su efecto en la ERCA de etiología no
Forty three non-diabetic patients at ACKD stage IV NKF-DOQI (CrCl diabética. Objetivo: Estudiar la acción del Irbesartan (ARA
< 30 ml/min) were enrolled in a prospective study. Group I: 21 recei- II) sobre la TA, proteinuria y evolución de la función renal
ved Irbesartan monodose 150-300 mg/day (63 ± 17 y/o, 12F, 9M, en pacientes con ERCA de etiología no diabética y compa-
ClCr 22.1 ± 8 ml/m.), Group II: 22 received ACEI (65 ± 13 y/o, 8F, rar sus efectos con pacientes de las mismas características
14M, CrCl 22.3 ± 7 ml/m). Parameters studied: blood pressure (BP), tratados con IECAs. Pacientes y métodos: Estudio longitu-
pulse pressure (PP), renal function (CrCl), proteinuria (in patients dinal, prospectivo, no aleatorizado, con 43 pacientes no
with proteinuria ≥ 0.5 g/d), serum K+ and serum uric acid, at month diabéticos en situación de ERCA estadio IV de NKF-DOQI
0, 3, 6, 9 & 12. Results: At 12 months, BP was controlled in 57% of (CLCR < 30 ml/min). Grupo I (G I): 21 pacientes (63 ± 17
Group I vs 39% of Group II. Mean systolic BP was decreased from años; CLCR 22,1 ± 8 ml/min) con Irbesartan en monodosis
154/85 to 138/77 in G I, and from 146/85 to 133/77 in GII, with a de 150-300 mg/día. Grupo II (G II): 22 pacientes (65 ± 13
decrease in 10.7% of mean BP in GI and 8.5% in GII (NS). Irbesartan años; CLCR 22,3 ± 7 ml/min) con IECAs. Se compara la evo-
reduced PP in 7.2% vs 8.3% with ACEI (NS). CrCl reduction with Ir- lución de la TA, función renal, proteinuria (en pacientes
besartan was 0.23 vs 0.21 ml/min/month with ACEI (NS). The anti- con proteinuria > 0,5 g/día), potasio y ácido úrico en 12
proteinuric effect was higher with Irbesartan (from 2.1 to 1.3 g/day) meses. Resultados: En el 57% de los pacientes en el GI y el
vs. ACEI (from 1.35 to 1.33 gr /day), being statistically significant the 39% del G II se obtuvo un buen control de la TA a los 12
reduction percentage between the two groups (p = 0.041). Serum meses. La TA sistólica se redujo de 154/85 a 138/77 en el GI
K+ level do not change in Irbesartan group and increased 10% in y de 146/85 a 133/77 en el G II, con un descenso de la ten-
ACEI group (p < 0.001). Uric acid was decreased by Irbesartan in sión arterial media del 10,7% en G I y 8,5% en el G II (NS).
17% and increased in 4% by ACEI (p < 0.001). Conclusions: Irbesar- La presión de pulso descendió un 7,2% con Irbesartan y un
tan in non-diabetics patients with advanced chronic renal disease, 8,3% con IECAs (NS). La disminución de la función renal
compared with ACEI showed similar blood pressure control and si- fue igual en los dos grupos (Irbesartan 0,23 vs 0,21
milar effect on chronic kidney disease progression, with higher anti- ml/min/mes con IECAs): El efecto antiproteinúrico fue
proteinuric effect. On the other side, Irbesartan showed a reduction mayor con Irbesartan (2,1 a 1,3 g/día) que con IECAs (1,35 a
of serum uric acid, and did not increase serum K+ levels. 1,33 g/día), siendo significativa la reducción porcentual
entre los dos grupos (p = 0,041). Los niveles de K sérico no
Key words: Angiotensin-converting enzyme inhibitors. Angioten- se modificaron con Irbesartan y aumentaron un 10% con
sin receptor blockers. Irbesartan. Chronic kidney disease. Protei- IECAs (p < 0,001). Se observó un descenso del ácido úrico
del 17% en los pacientes con Irbesartan, mientras que con
IECAs se aprecio un incremento del 4% (p < 0,001). Conclu-
siones: El empleo de Irbesartan en pacientes no diabéticos
con ERCA muestra un control de la TA similar al obtenido
con IECAs, así como una acción semejante sobre la progre-
sión de la función renal. En estos pacientes Irbesartan pro-
duce una mayor reducción de la proteinuria que los IECAs,
sin incremento del potasio sérico y con un efecto favorable
sobre los niveles de ácido úrico.
Palabras clave: Inhibidores del enzima de conversión de angiotensi- Correspondence: Francisco Coronel
na. Antagonistas de receptores de angiotensina. Irbesartan. Enfer- medad renal crónica avanzada. Proteinuria. Hipertensión arterial.
Nefrología (2008) 1, 56-60
F. Coronel et al. Irbesartan vs ACEIs for non-diabetic advanced CRF
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INTRODUCTION
mean age of group II patients was 6513 years, 8 women and 14 Chronic renal disease is accompanied in most of the cases by men, with baseline CrCl of 22.3 (7.0) mL/min. Baseline epi- arterial hypertension (AHT) and is an important morbidity demiological data for both groups are shown in Table I, with and mortality factor in these patients. Several drugs may be no statistical differences between the groups. Patients on used to control it, and some of them have shown their poten- dialysis therapy or with suspicion of renal artery stenosis tial for decreasing or slowing the progression of renal failure were not included in any of the groups. The causes of renal and/or proteinuria. Angiotensin converting enzyme inhibitors disease for both groups are shown in table II.
(ACEIs) have been successfully used in patients with AHT In no one of the groups the patients had previously recei- and nephropathy of both diabetic and non-diabetic origin, re- ved antihypertensive medication with ACEIs or ARA II, nor ducing proteinuria and with a favorable effect on renal failure medications with ionic exchange resins or non-steroidal anti- progression.1-5 Some adverse effects have been described inflammatory drugs during the study. Two patients (one in among which persistent cough is one of the most common each group) were on allopurinol before the study beginning, ones, and an added problem in stage IV advanced chronic which was continued throughout the study. Three patients renal disease (ACRD 4)6 is that ACEIs may contribute to (14%) in group I and four (18%) in group II received diuretics renal function worsening expressed by serum creatinine in- and 14% in GI and 13.6% in GII received dihydropiridinic crease by 30-35% and produce hyperkalemia.7,8 Angiotensin- calcium-channel blockers as added antihypertensive medica- II receptor antagonists (ARA II) have also shown their effect on proteinuria and progression of renal function in patientswith diabetic nephropathy,9-12 with less adverse affects thanACEIs, although there are few clinical trials about their effi- cacy on hypertension, proteinuria, renal function progression The study design did not include randomization or calculation in patients with no-diabetic nephropathy13,14 or with establis- of the sample size since a limited number of patients with the characteristics required attend our outpatient clinic, conside- Irbesartan is a drug belonging to the ARA II family that has ring this a limitation of the study, and thus an observer-depen- shown its effectiveness in the management of AHT, even in dent bias, carrying out the daily clinical practice according to patients with ACRD o on dialysis.15,17 It is a rapidly absorbed drug after oral administration, being mainly cleared through One-year follow-up was done with a baseline control inclu- the liver (78%) and in lower amounts through the kidney ding physical examination, BP measurement in the morning in (22%), with a half-life of 11-15 h,18 with no dose adjustment a seated position, pulse pressure measurement, and laboratory required in ACRD.19 Irbesartan has shown anti-proteinuric ef- work-up. During the first month, fortnightly BP controls with fects and slowing progression of diabetic nephropathy.9,11 antihypertensive medication adjustments were done. At months In this work we undertook a study on the effect of Irbesar- 3, 6, 9, and 12 the same schedule as baseline visit was done.
tan therapy in non-diabetic ACRD patients, analyzing its an- The increase of Irbesartan or ACEIs doses to maximal doses tihypertensive efficacy, its action on proteinuria and progres- was based on the achievement of systolic blood pressure ≤ 140 sion of renal disease, and its effects on some biochemical, as mm Hg and diastolic BP < 90 mm Hg. The laboratory work-up compared to ACEIs therapy in the same type of patients and included creatinine, serum uric acid and potassium, and 24- with the same degree of renal impairment. hour urine creatinine and proteinuria (proteinuria follow-upwas undertaken only in those patients with baseline proteinu-ria ≥ 0.5 g/day at baseline visit). The progression rate of renal PATIENTS AND METHODS
Patients
In this longitudinal non-randomized study we prospectively
Table I. Baseline descriptive statistics in both groups
included for one year 43 patients with non-diabetic stage IV Group I (ARA II)
Group II (ACEI)
ACRD of NKF-DOQI (creatinine clearance (CrCl) < 30 mL/min). Twenty-one patients (group I) were treated with Ir-besartan at starting doses of 150 mg/day, increasing up to 300 mg/day (once daily) as needed to improve BP management.
In those patients not achieving appropriate BP control with full doses of Irbesartan (300 mg/day), other non-ARA-II non- ACEIs drugs were added. The mean age was 6317 years, 12 women and 9 men, with mean CrCl at the beginning of the therapy of 22.1 (8.0) mL/min. Group II was comprised by 22 patients treated with ACEIs (enalapril in 9, captopril in 7, pe- rindopril in 6), starting at daily doses of 5 mg, 50 mg, and 2 mg, respectively, and going up to maximal doses of 20 mg, 100 mg, and 4 mg of enalapril, captopril and perindopril, res- pectively. Those patients not achieving BO control at those doses were added other non-ARA-II non-ACEIs drugs. The Nefrología (2008) 1, 56-60
F. Coronel et al. Irbesartan vs ACEIs for non-diabetic advanced CRF
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Table II. Causes of renal disease in both groups
Frequency Percentage
Frequency Percentage
% Mean decr
aPRD: polycystic renal disease; NAS: nephroangiosclerosis; TIN: tubulointerstitial nephropathy; CGN: chronic glomerulonephritis.
failure was calculated in mL/min/month of CrCl in bothgroups. Treatment tolerability was checked by means of occu- SBP: Systolic blood pressure; DBP: Diastolic blood pressure; MBP: Mean blood rrence of adverse events or laboratory changes, at each visit. The statistical analysis was done with SPSS 11.5 (Chicago, Figure 1. Mean decrease of blood pressure in both treatment groups: Ir-
Ill.). Baseline results were compared with those obtained at bersartan (ARA II) and ACEIs. NS: Not significant.
12 months of follow-up by using Student’s t test, Chi-squaredtest, and Mann-Whitney test, as required. The null hypothesiswas rejected when p < 0.05.
RESULTS
All patients completed 12 months of treatment, with no one of
them being included in dialysis during the study period. At 12months of follow-up, BP was controlled in 57% of the pa- tients in group I only using Irbesartan versus 39% of the pa-tients in group II only treated with ACEIs; however, the goal of BP control established at the study beginning was obtained in both groups with no significant differences for SBP, DBP,and mean blood pressure (MBP), as shown in Fig. 1. At 12 % Mean variation
months with Irbesartan, mean SBP was reduced from 154 to 138 mm Hg and DBP from 138 to 77 mm Hg. With ACEIs a decrease in SBP from 146 to 133 mm Hg and in DBP from 85to 77 mm Hg was observed. MBP was reduced by 10.7 %with Irbesartan and by 8.5 % with ACEIs. Similarly, the pulse pressure decreased in the Irbesartan group and in the group treated with ACEIs, with no differences between them (7.2% vs 8.3%). Figure 2 shows the behavior of serum K levels,which are not changed from baseline values in group I, and Figure 2. Percentage variation of serum K+ and uric acid at 12 months of
with a 10% increase in group II (p < 0.001). Uric acid increa- treatment, comparing Irbesartan (ARA II) with ACEIs.
sed by 4% from baseline in the group treated with ACEIs,whereas it was reduced by 17% in the patients treated with Ir-besartan (p < 0.001) (fig. 2). We did not observe differencesin renal function decrease, which progressed similarly in both changes, or reaching CrCl values requiring inclusion into groups. The CrCl decrease throughout the study was 0.23 dialysis. Moderate increases in serum K levels at some analy- mL/min/month in group I and 0.21 mL/min/month in group II tical checkpoint did not oblige to patient withdrawal in any case. One patient from group II who months before had been Mean 24-h protein excretion decreased at 12 months in pa- treated with captopril, which was discontinued because of tients treated with Irbesartan from 2.1 g/day to 1.3 g/day, the persistent cough, and who remained coughing in spite of me- difference being significant as compared with the ACEIs dication discontinuation, was assigned to the enalapril group group, in which proteinuria is slightly reduced from 1.35 at the study beginning; the cough persisted without being able to ascertain the cough with ACEIs therapy. Two other patients Treatment with Irbesartan and with ACEIs has been well from group II had mild cough and decided to keep on taking tolerated by the patients, with no patient being withdrawn the medication. SBP < 100 mm Hg was observed at some me- from the study for adverse reactions, important biochemical asurement in 2 patients from group I and in 1 from group II, Nefrología (2008) 1, 56-60
F. Coronel et al. Irbesartan vs ACEIs for non-diabetic advanced CRF
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with no clinical repercussion obliging study medication dis- at three months, De Rosa et al.15 describe proteinuria decrease with Irbesartan as compared with baseline values. The known effect of the increase in serum potassium levels in some patients with renal failure treated with ACEIs has DISCUSSION
been extended to ARA II due to inhibition of the renin-angio- Most of the studies done with ARA II among hypertensive pa- tensin system that occurs with both drug families.8 Our results tients with renal impairment have been carried out in diabetic show the different behavior of serum potassium by using nephropathy.9-12 The outcomes on AHT control as well as on ACEIs or Irbesartan in ACRD patients, observing a 10% in- proteinuria and renal disease progression have been success- crease with the former as compared with sustained potassium ful, as those reported with ACEIs in diabetic and non-diabetic levels with the ARA II agent. Bakris et al.22 have described si- patients.1-5 In our work, the antihypertensive efficacy of an in- milar results when comparing Lysinopril (ACEIs) with Val- termediate half-life ARA II, such as Irbesartan, has been sartan (ARA II) in patients with glomerular filtration rate < 60 shown in non-diabetic with mild to moderate hypertension mL/min, relating the significant lysinopril-induced increase and advanced chronic renal disease, followed at a specific in serum potassium with a relatively lower reduction in plas- outpatient clinic, with similar results to those obtained in pa- ma aldosterone produced by the ARA II agent. We do not tients on ACEIs and with similar characteristics; better effect know whether this hypothesis would be applicable to our pa- on serum uric acid and potassium levels, and on proteinuria tients with higher renal function impairment. The ACEIs and has been shown in the former as compared with the latter. In ARA II doses used in our patients are the usual ones, not too one of the few published studies including a subgroup of pa- high due to their degree of renal disease, although there alre- tients with ACRD of non-diabetic origin and followed-up for ady exist studies using high doses of candersartan (5 times 3 months, outcomes similar to ours are obtained for BP con- higher than the maximal usual ones) in chronic renal disease, trol and decrease of proteinuria, even when used as monothe- without observing changes in baseline serum potassium le- vels.23 Another finding in our study was the reduction with Our study was carried out at a single center, with patients time in serum uric acid levels with Irbesartan that is not obtai- coming from the advanced chronic disease clinic, which im- ned in the group treated with ACEIs. There are several works plies the difficulty on recruiting ACRD patients near to be in- describing the decrease in uric acid using Losartan.24-26 This cluded into dialysis techniques and that may be followed for a action of Losartan seems to be transient and related with its long time in order to assess the efficacy of an antihypertensi- uricosuric effect. In a study comparing Losartan with enala- ve therapy; so are the study limitations. In spite of these limi- pril in healthy subjects, ACEIs showed no effects on fractio- tations, the 12-month follow-up period has allowed us analy- nal clearance of uric acid, by contrast with the ARA II agent.24 zing the progression of renal failure and verifying that this is The comparison of the uricosuric effect of Losartan as com- not different when using ACEIs or Irbesartan (-0.21 and -0.23 pared with other ARA II drugs yields controversial results, so mL/min/month, respectively), and similar to what has been that in the work by Wurzner et al.25 with hyperuricemic pa- published. Renal disease progression rates of -0.46 tients comparing Losartan with Irbesartan, a decrease in uric mL/min/month of CrCl have been described in patients with acid is obtained only with the former. In another study26 in pa- non-diabetic chronic renal disease treated with standard an- tients with mild to moderate AHT, Losartan, as compared tihypertensive medication.20 This progression rate is reduced with Eprosartan, increased uric acid urinary excretion but down to -0.23/mL/min/month when in a random way patients none of them produced changes in serum levels of uric acid.
are treated with drugs such as captopril or nifedipine.20 Our Our study does not include data on uric acid renal excretion results seem to indicate that the reduction in the progression that may clear the mechanism of uric acid serum levels reduc- of renal disease achieved with ACEIs or an ARA II such as Ir- tion when using Irbesartan, although the follow-up of our pa- besartan also occurs when renal disease is at advanced stages, tients has been longer than in the above-mentioned studies as is the case in the patients included in this study in which and than in patients with important renal function impair- dialysis therapy was not required in any one during the 12- month follow-up period. It is likely that the lack of a differen- To conclude, our results (considering the mentioned limita- ce in renal disease progression in between the groups is rela- tions) show that while keeping similar antihypertensive effi- ted with the low number of sample patients. cacy and behavior in the progression of renal function, Irbe- Irbesartan has shown to have an anti-proteinuric effect in sartan reduces proteinuria at a higher degree than ACEIs, whit diabetic nephropathy in large studies such as IRMA9 or no increase in serum potassium and with a significant decrea- IDNT,11 similarly to other ARA II such as Losartan (RENAAL se in uric acid levels in patients with advanced chronic renal study)10 o valsartan (MARVAL study).12 In non-diabetic neph- ropathy, smaller studies have shown this same effect on pro-teinuria with Losartan.14,21 All of these studies included pa-tients with mild degrees of renal failure and in most of them REFERENCES
the benefit on renal function was independent of blood pres- 1. Lewis EJ, Hunsicker LG, Bain RP, Rohde Rd. The effect of angioten- sure control.10,12,14,21 The higher effect on proteinuria with Irbe- sin-converting enzyme inhibition on diabetic nephropathy: the Co-llaborative Study Group. N Eng J Med 329: 1456-62, 1993. sartan as compared with ACEIs observed in our patients has 2. Lebovitz HE, Wiegmann TB, Cnaan A, Shainfar S, Sica DA, Broadstone the peculiarity to occur in non-diabetic patients with ACRD.
V et al. Renal protective effect of enalapril in hypertensive NIDDM: role In a group of patients with the same characteristics, assessed of baseline albuminuria. Kidney Int 45 (Supl.): S150-55, 1994. Nefrología (2008) 1, 56-60
F. Coronel et al. Irbesartan vs ACEIs for non-diabetic advanced CRF
o r i g i n a l s
3. Ihle BU, Whitworth JA, Shainfar S, Cnaan A, Kinkaid-Smith PS, Bec- renal impairment and hipertension: a drug withdrawal study. J Car- ker GJ. Angiotensin-converting enzyme inhibition in nondiabetic diovasc Pharmacol 38: 482-89, 2001. progressive renal inssufiency: a controlled double-blind trial. Am J 16. Sharma AM, Hollander A, Köster J: Efficacy and Safety in Pa- tients with Renal Impairment treated with telmisartan (ESPRIT) 4. The GISEN group (Gruppo Italiano di Studi Epidemiologici in nefrolo- Study Group. Telmisartan in patients with mild/moderate hyper- gia): Randomised placebo-controlled trial of effect of ramipril on decli- tension and chronic kidney disease. Clin Nephrol 63: 250-57, ne in glomerular filtration rate and risk of terminal renal failure in pro- teinuric, non-diabetic nephropathy. Lancet 349: 1857-63, 1997. 17. Coronel F, Ruiz E, Herrero JA, Martín P, Mateos P, Touchard A et al.
5. Jafar TH, Schmid CH, Ianda M, Giatras I, Toto R, Remuzzi G, for the Effect of an angiotensin receptor antagonist (irbesartan) on perito- ACE Inhibition in Progressive Renal Disease Study Group: angioten- neal dialysis patients. Perit Dial Int 20 (Supl. 1): S62, 2000. sin-coverting enzyme inhibitors and progression of nondiabetic 18. Burnier M, Brunner HR. Angiotensin II receptor antagonist in hyper- renal disease. A meta-analysis of patient-level data. Ann Intern Med tension. Kidney Int 54 (Supl. 68): S107-S111, 1998. 19. Gillis JC, Markam A. Irbesartan. A review of its pharmacodynamic 6. The Seventh Report of the Joint National Committee on Prevention, properties and therapeutic use in the management of hypertension.
Detection, Evaluation, and Treatment of High Blood Pressure. JAMA 20. Zucchelli P, Zuccalà A, Borghi M, Fusaroli M, Sasdelli M, Stallone 7. Parving HH, Lehnert H, Brochner-Mortensen J, Gomis R, Andersen C et al. Long-term comparison between captopril and nifedipine S, Arner P. The effect of irbesartan on the development of diabetic in the progression of renal insufficiency. Kidney Int 42: 452-58, nephropathy in patients with type 2 diabetes. N Eng J Med 345: 21. Iino Y, Hayashi M, Kawamura T, Shiigai T, Tomino Y, Yamada K et al.
8. Bakris GL, Weir MR : Angiotensin-converting enzyme inhibitor –as- Japanese Losartan Therapy Intended for the Global Renal Protection sociated elevations in serum creatinine: Is the cause for concern? in Hypertensive Patients (JLIGHT) Study Investigators. Interim evi- Ann Intern Med 160: 685-693, 2000. dence of the renoprotective effect of the angiotensina II receptor 9. Ruggenenti P, Schieppati A, Remuzzi G: Progression, remission, re- antagonist losartan versus the calcium channel blocker amlodipine gression of chronic renal diseases. Lancet 357: 1601-1608, 2001. in patients with chronic kidney disease and hypertension: a report 10. Brenner BM, Cooper ME, de Zeeuw D, Keane WF, Mitch WE, Par- of the Japanese Losartan Therapy Intended for Renal Global Protec- ving HH y cols. Effects of losartan on renal and cardiovascular out- tion in Hypertensive Patients (JLIGHT) Study. Clin Exp Nephrol 7: comes in patients in patients with type 2 diabetes and nephropathy.
22. Bakris GL, Siomos M, Richardson D, Jannsen I, Bolton WK, Hebert L 11. Lewis EJ, Hunsicker LG, Clarke WR, Berl T, Pohl MA, Lewis JB et al.
et al. ACE inhibition or angiotensin receptor blockade: impact on Renoprotective effect of the angiotensin-receptor antagonist irbe- potassium in renal failure. VAL-K Study Group. Kidney Int 58: 2084- sartan in patients with nephropathy due to type 2 diabetes. N Eng J 23. Weinberg AJ, Zappe DH, Ashton M, Weinberg MS. Safety and tole- 12. Viberti G, Wheeldon NM, for the MicroAlbuminuria Reduction with rability of high-dose angiotensin receptor blocker therapy in pa- Valsartan (MARVAL) Study Investigators: Microalbuminuria reduc- tients with chronic kidney disease. A pilot study. Am J Nephrol 24: tion with valsartan in patients with type 2 diabetes mellitus. A blood pressure-independent effect. Circulation 106: 672-78, 2002. 24. Hamada T, Hisatome I, Kinugasa Y, Matsubara K, Shimizu H, Tanaka 13. Plum J, Bunten B, Nemeth R, Grabensee B. Effect of the angiotensin H et al. Effect of the angiotensin II receptor antagonist losartan on II antagonist valsartan on blood pressure, proteinuria and renal he- uric acid and oxypurine metabolism in healthy subjects. Intern Med modynamics in patients with chronic renal failure and hypertension.
J Am Soc Nephrol 9: 2223-34, 1998. 25. Wurzner G, Gerster JC, Chiolero A, Maillard M, Fallab-Stubi CL, 14. Praga M, Fernández-Andrade C, Luño J, Arias M, Poveda R, Mora J et Brunner HR, Burnier M. Comparative effects of losartan and irbesar- al. Antiproteinuric efficacy of losartan in comparison with amlodipine tan on serum uric acid in hypertensive patients with hyperuricaemia in nondiabetic proteinuric renal disease: a double-blind, randomized and gout. J Hypertens 19: 1855-60, 2002. clinical trial. Nephrol Dial Transplant 18: 1806-13, 2003. 26. Puig JG, Torres R, Ruilope LM. AT1 blockers and uric acid metabo- 15. De Rosa ML, De Cristofaro A, Rossi M, Baiano A, Cardace P, Albane- lism: are there relevant differences? J Hypertens Supl. 20: S29-31, se L, Vigorito C. Irbesartan effect on renal function in patients with Nefrología (2008) 1, 56-60

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