Published online August 21, 2006
PEDIATRICS Vol. 118 No. 3 September 2006, pp. e833-e838 (doi:10.1542/peds.2005-2053)
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ARTICLE

Renal and Cardiovascular Effects of Angiotensin-Converting Enzyme Inhibitor Plus Angiotensin II Receptor Antagonist Therapy in Children With Proteinuria

Riccardo Lubrano, MDa, Francesca Soscia, MDa, Marco Elli, MDb, Flavia Ventriglia, MDa, Claudia Raggi, MDa, Elisabetta Travasso, MDa, Simona Scateni, MDa, Valeria Di Maio, MDa, Paolo Versacci, MDa, Raffaele Masciangelo, MDc and Stefano Romero, MDa

a Departments of Pediatrics
c Experimental Medicine and Pathology, University of Rome "La Sapienza," Rome, Italy
b Department of Clinical Sciences "Ospedale Luigi Sacco," University of Milan, Milan, Italy


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
OBJECTIVE. We investigated whether the combination of an angiotensin-converting enzyme inhibitor and an angiotensin II type 1 receptor antagonist offers better control of proteinuria and cardiovascular parameters without causing adverse side effects.

METHODS. We enrolled 10 children (mean age: 12.3 ± 4.06 years) with proteinuria resulting from chronic renal diseases of various causes. The study consisted of 2 phases, 3 months each, for an overall 6-month observation time. During phase 1 (3 months), each child was assigned randomly to treatment with either an angiotensin-converting enzyme inhibitor or an angiotensin II type 1 receptor antagonist alone. During phase 2, each child was advanced to combination therapy with the addition of an angiotensin II type 1 receptor antagonist or an angiotensin-converting enzyme inhibitor, respectively. Renal function tests, echocardiography, and 24-hour ambulatory blood pressure monitoring were performed at the beginning of the study (time 0), at 3 months (time 1), and at 6 months (time 2).

RESULTS. At time 2, proteinuria (change: –80.21 ± 10.75%), interventricular septum index (change: –13.63 ± 18.64%), posterior wall of the left ventricle index (change: –30.71 ± 20.32%), and left ventricular mass index (change: –28.33 ± 24.44%) were reduced significantly, compared with time 0 and time 1. No untoward side effects were detected during the study.

CONCLUSIONS. In the short term, the combination of angiotensin-converting enzyme inhibitors and angiotensin II type 1 receptor antagonists for children with proteinuria of renal origin reduced proteinuria significantly, compared with baseline or either drug alone. Furthermore, echocardiographic studies gave evidence of reduction of left ventricular hypertrophy. Additional studies are needed to evaluate long-term results.

Key Words: chronic kidney disease • proteinuria • left ventricular hypertrophy • angiotensin-converting enzyme inhibitors • angiotensin II receptor antagonist

Abbreviations: ACE—angiotensin-converting enzyme • AT1—angiotensin II type 1 • IVS—interventricular septum • LVM—left ventricular mass • PW—posterior wall of the left ventricle • GFR—glomerular filtration rate

Both proteinuria1–4 and hypertension5 are considered among the most significant nonimmunologic causes of progression of renal damage.6,7 Therefore, their treatment is considered the most effective strategy to preserve renal function.8,9

Angiotensin II is recognized presently as one of the most important mediators of progressive renal failure. It is responsible for several hemodynamic effects such as vasoconstriction, proteinuria (secondary to glomerular hyperfiltration attributable to increased intraglomerular pressure), and structural changes to the glomeruli caused by proinflammatory mediators, fibroblast proliferation, and production of superoxide free radicals.10 The effects of angiotensin II on the kidney are inhibited by drugs such as angiotensin-converting enzyme (ACE) inhibitors and angiotensin II type 1 (AT1) receptor antagonists.9 The administration of ACE inhibitors reduces the progression of renal damage from varying causes,11 by blocking the renin-angiotensin system and therefore lowering proteinuria and/or arterial blood pressure. A similar effect is obtained with AT1 receptor antagonists.12,13 Furthermore, several studies point to increased efficacy of combination therapy with ACE inhibitors and AT1 receptor antagonists.8,14–16

AT1 receptor antagonists have been shown to reduce heart hypertrophy secondary to hypertension in rats.17 They are thought to act by blocking angiotensin II profibrotic activity on fibroblasts, which are responsible for increased production of extracellular matrix and the resulting cardiac fibrosis.18 In our study, we investigated whether combined therapy with ACE inhibitors and AT1 receptor antagonists for children with renal diseases and proteinuria could reduce proteinuria and improve hemodynamic features without significant side effects.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patients
We studied 10 children (8 male patients and 2 female patients; mean age: 12.3 ± 4.06 years; range: 6–17 years). The primary renal disease was renal dysplasia for 3 patients, focal glomerulosclerosis for 2, reflux nephropathy for 2, polycystic renal disease for 1, Alport syndrome for 1, and interstitial nephropathy for 1. For at least 3 months before entering the study, all patients had mean systolic and diastolic arterial blood pressures that were constantly below the 90th percentile for height and gender19 (either with or without drug therapy), as measured with 24-hour ambulatory blood pressure monitoring, and overt proteinuria20 of >150 mg per day.

Study Design
The study was organized over 6 months, divided into 2 subsequent phases of 3 months each. Clinical evaluations, consisting of renal function tests, 24-hour recordings of blood pressure, and echocardiography, were performed at the beginning of the study (time 0), at the end of the first 3-month phase (time 1), and at the end of the second phase (time 2). During the time 0 to time 1 interval, the children were assigned randomly to treatment with an ACE inhibitor or an AT1 receptor antagonist. During the time 1 to time 2 interval, all children received combination therapy with both an ACE inhibitor and an AT1 receptor antagonist.

Drugs and Dosages
We used the ACE inhibitor enalapril at 0.1 mg/kg per day (maximum: 10 mg/day) and the AT1 receptor antagonist losartan at 1 mg/kg per day (maximum: 50 mg/day). During phase 2, the 2 drugs were administered in combination, at the same dosages as reported above.

Biochemical and Instrumental Analyses
A 24-hour urine collection and a 5-mL blood sample, drawn at the end of the urine collection itself, were obtained at time 0, time 1, and time 2. Urinary and blood concentrations of creatinine, sodium, potassium, and proteins were used to calculate the glomerular filtration rate (GFR) through creatinine clearance, fractional excretion of sodium, fractional excretion of potassium, and proteinuria. All analyses were performed with a Beckman Synchron CX5 Delta Clinical System automatic analyzer (Beckman Coulter Inc, Fullerton, CA).

Echocardiography was performed with an Acuson Siemens Aspen system (Siemens Medical Solutions Inc, Malvern, PA) with a 2.5- to 5-MHz probe; we measured the thickness of the interventricular septum (IVS) expressed as the IVS index, the thickness of the posterior wall of the left ventricle (PW) expressed as the PW index, and the left ventricular mass (LVM) expressed as the LVM index. Twenty-four-hour recording of blood pressure was performed with a model N 90207–30 monitor (Spacelabs Medical, Richmond, WA).

Statistical Analyses
The differences among 3 related samples in the parameters under evaluation were first analyzed with the Friedman test. After they proved significant with the Friedman test, the differences among parameters obtained at time 0, time 1, and time 2 were analyzed with the nonparametric Wilcoxon signed-rank test. Correlations were studied with the R2 test. P values of <.05 were considered significant.

Ethics
Informed consent was obtained from both parents of each child. The study protocol conformed to the ethical guidelines of the 1975 Declaration of Helsinki, as revised in 2000.21


   RESULTS
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 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Six of 10 patients in the study were assigned initially to receive treatment with an ACE inhibitor during phase 1; the remaining 4 children received an AT1 receptor antagonist. During phase 2, all 10 patients received the 2 drugs in combination.

The Friedman test applied to the groups studied at time 0, time 1, and time 2 for all parameters in the study indicated significant differences among dependent groups (in particular, proteinuria, P < .0005; LVM, P < .0006). No statistically significant difference was detected in renal function test, echocardiographic, and blood pressure results at time 0 and time 1 between children receiving the ACE inhibitor and children receiving the AT1 receptor antagonist.

Renal function test results at time 0, time 1, and time 2 are reported in Table 1. GFR, fractional excretion of sodium, fractional excretion of potassium, and serum potassium levels remained constant throughout the entire study. Proteinuria remained constant between time 0 and time 1, whereas it was significantly lower at time 2, compared with both time 0 (P < .005) and time 1 (P < .005). Furthermore, a reduction of proteinuria was present, with a decrease equal to –80.21 ± 10.75%.


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  		TABLE 1 Renal Function Tests at the Beginning of the Study (Time 0), at the End of Phase 1 (Single-Drug Therapy) (Time 1), and at the End of Phase 2 (Combination Therapy) (Time 2)

 
Mean arterial blood pressures at time 0, time 1, and time 2, as recorded with a Holter device for 24-hour ambulatory blood pressure measurements, are plotted in Fig 1. No statistically significant differences were found at any study time.


Figure 1
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  		FIGURE 1 Systolic arterial blood pressure (SBP) (A) and diastolic arterial blood pressure (DBP) (B) (mean ± SD) at time 0 (T0), time 1 (T1), and time 2 (T2), recorded with a noninvasive 24-hour recording device. Error bars indicate 1 SD.

 
IVS index, PW index, and LVM index are reported in Fig 2. It is of interest that all echocardiographic parameters were reduced significantly at time 2 (end of phase 2, double-drug treatment), compared with time 0 and time 1. In contrast, no statistically significant differences were found between time 0 and time 1. Between time 0 and time 2, the mean reduction of the IVS index was –13.63 ± 18.64%, that of the PW index was –30.71 ± 20.32%, and that of the LVM index was –28.33 ± 24.44%. It is interesting to observe that, between time 0 and time 2, the change in proteinuria was correlated directly with the change in IVS thickness (P > .02) but not with the LVM index and PW index (Fig 3).


Figure 2
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  		FIGURE 2 LVM index (A), PW index (B), and IVS index (C) (mean ± SD) at time 0 (T0), time 1 (T1), and time 2 (T2). Error bars indicate 1 SD; mq, square meters. LVM index and PW index: time 0 versus time 1, P = not significant; time 0 versus time 2, P < .005; time 1 versus time 2, P < .005; IVS index: time 0 versus time 1, P = not significant; time 0 versus time 2, P < .035; time 1 versus time 2, P < .02.

 

Figure 3
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  		FIGURE 3 Correlation between reduction of proteinuria (prot) and reduction of IVS index between time 0 and time 2 (y = –92.407 + 1.322x; R2 = 0.582; P < .02).

 

   DISCUSSION
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 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
In this study, single-drug therapy with either ACE inhibitors or AT1 receptor antagonists proved insufficient to reduce proteinuria and LVM significantly. Other authors1,13 observed significant reductions with a single-drug regimen, possibly because of the higher dosages they used. This interpretation is supported by the findings of Liern et al,14 who observed reduced proteinuria only when high dosages of ACE inhibitors were used. Other authors reported that the antiproteinuric effect of ACE inhibitors was strictly dose dependent.8 Because the antiproteinuric effect of these drugs goes into effect after an average 4 weeks of treatment22 and our study lasted 12 weeks, we can rule out a time factor to explain why the single-drug therapy had no influence on proteinuria.

In contrast, our results showed that, by combining an ACE inhibitor with an AT1 receptor antagonist, significant results could be obtained in both the kidney and heart in a 3-month period. We found a significant reduction of proteinuria (Table 1), consistent with the observations of other authors who described an antiproteinuric effect of the combination of the 2 drugs for adults8 and children.14,15 Liern et al14 reported reduction of proteinuria, although with high doses of ACE inhibitors. Tanaka et al15 reported reduction of proteinuria and histologic patterns for 4 children with IgA-related nephropathy, with ACE inhibitor and losartan doses comparable to ours but after a 12-month treatment. It is noteworthy that, with our protocol for therapy, the reduction of proteinuria between time 0 and time 2 was greater than that observed for children by White et al13 with the 2 drug families in single-drug therapy. To our knowledge, the efficacy of 2-drug therapy at low doses had not been proved for children; however, it was studied in adults.16,23 Those authors reported more-pronounced reduction of proteinuria and a lack of unwanted side effects on tubules and on GFR, compared with the use of a single drug at higher dosages. This better clinical outcome is particularly desirable for nephropathic patients and is in full agreement with our present observations for children with low doses of an ACE inhibitor and an AT1 receptor antagonist in association.

We also observed reductions in the LVM index, PW index, and IVS index (Fig 2). He et al24 reported a significant reduction of the LVM in hypertensive rats after 8- to 16-week treatment with losartan or fosinopril as a single drug. Similar findings were reported by Asai et al,17 who described LVM reduction after treatment of hypertensive rats with losartan for 6 weeks. For adult hypertensive human patients, Devereux et al25 reported reduction of the LVM after 12 and 24 months of treatment with losartan. Suzuki et al26 reported that, for diabetic adults with end-stage renal disease undergoing hemodialysis, combined therapy with ACE inhibitors and AT1 receptor antagonists was more effective in reducing the LVM after 6 and 12 months of treatment than was single therapy with ACE inhibitors or AT1 receptor antagonists alone. It is noteworthy that the experimental studies with rats suggested that the heart mass reduction could become evident much earlier than commonly described, which supports our observation.16,17

GFR, fractional excretion of sodium, fractional excretion of potassium, and serum potassium levels remained constant throughout the entire study, showing that the chosen drugs at the dosages used, both alone and in combination, did not produce adverse effects on renal function and potassium levels. During the study, we did not observe any significant reduction in blood pressure at time 1 and time 2, compared with the starting values at time 0. Similarly, we observed no difference in blood pressure readings between time 1 and time 2 (Fig 1). There is no general agreement on the action of these families of drugs on blood pressure. Some studies reported that ACE inhibitors and AT1 receptor antagonists, used in single-drug therapy for control of proteinuria, had no effect on blood pressure,4,27 whereas some studies observed that ACE inhibitors caused a reduction of diastolic blood pressure only28 and others reported a reduction of arterial blood pressure with administration of AT1 receptor antagonists for ≥1 year.23 Finally, Liern et al,14 using a combination of an ACE inhibitor and a AT1 receptor antagonist, but with higher doses of the ACE inhibitor, reported a reduction of arterial blood pressure; the latter finding was correlated significantly with the reduction of proteinuria. In our study, proteinuria decreased significantly (Table 1) without a concomitant reduction in blood pressure readings at time 0, a likely demonstration that the 2 effects are unrelated, as suggested also by Viberti and Wheeldon.27

Furthermore, our findings showed a correlation between the reduction of proteinuria and the reduction of IVS thickness. This points to direct actions of the 2 drugs on the kidney and heart, not mediated by systemic blood pressure decreases (Fig 3).

In our opinion, more than the reduction of proteinuria, the most important finding in the study was the reduction of the cardiac mass, which should decrease cardiovascular risk and improve heart function. Like proteinuria, the IVS hypertrophy found in chronic renal diseases is likely to result from high blood levels of angiotensin II.18

Definitive assessment of the beneficial effects of the 2-drug combination therapy on preservation of renal and cardiac function requires collaborative studies with much longer follow-up periods. It could also be important to compare the effects (including possible adverse effects) of the combined therapy with those of a single-drug treatment at a double dose. Similarly, larger studies with longer follow-up periods are needed to assess possible side effects such as hyperkalemia and excessive decreases in blood pressure, which are linked frequently to the use of these drugs.


   FOOTNOTES
 
Accepted Mar 29, 2006.

Address correspondence to Riccardo Lubrano, MD, Dipartimento di Clinica Pediatrica, Policlinico "Umberto I," Università degli Studi di Roma "La Sapienza," Viale Regina Elena 324, 00161, Rome, Italy. E-mail: riccardo.lubrano{at}uniroma1.it

The authors have indicated they have no financial relationships relevant to this article to disclose.


   REFERENCES
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Ellis D, Vats A, Morits ML, et al. Long-term antiproteinuric and renoprotective efficacy and safety of losartan in children with proteinuria. J Pediatr. 2003;143 :89 –97[CrossRef][Web of Science][Medline]
  2. Burton MB, Harris KGP. The role of proteinuria in the progression of chronic renal disease. Am J Kidney Dis. 1996;27 :765 –775[Web of Science][Medline]
  3. Remuzzi G, Bertani T. Pathophysiology of progressive nephropathies. N Engl J Med. 1998;339 :1448 –1456[Free Full Text]
  4. GISEN Group. Randomised placebo-controlled trial of effect of ramipril on decline in glomerular filtration rate and risk of terminal renal failure in proteinuric, non-diabetic nephropathy. Lancet. 1997;349 :1857 –1863[CrossRef][Web of Science][Medline]
  5. Soergel M, Schaefer F. Effect of hypertension on the progression of chronic renal failure in children. Am J Hypertens. 2002;15 (suppl 1):53–56
  6. Klahr S, Schreiner G, Ichikawa I. The progression of renal disease. N Engl J Med. 1998;318 :1657 –1666
  7. Campbell RC, Ruggenti P, Remuzzi G. Halting the progression of chronic nephropathy. J Am Soc Nephrol. 2002;13(suppl 3) :S190 –S195
  8. Laverman GD, Navis G, Henning RH, et al. Dual renin-angiotensin system blockade at optimal doses for proteinuria. Kidney Int. 2002;62 :1020 –1025[CrossRef][Web of Science][Medline]
  9. Wolf G, Ritz E. Combination therapy with ACE inhibitors and angiotensin II receptor blockers to halt progression of chronic renal disease: pathophysiology and indications. Kidney Int. 2005;67 :799 –812[CrossRef][Web of Science][Medline]
  10. Wolf G, Butzmann U, Wenzel UO. The renin-angiotensin system and progression of renal disease: from hemodynamics to cell biology. Nephron Physiol. 2003;93 :P3 –P13[CrossRef][Medline]
  11. Ruggenti P, Perna A, Benini R, et al. In chronic nephropathies prolonged ACE inhibition can induce remission: dynamics of time-dependent changes in GFR: investigators of the GISEN Group. J Am Soc Nephrol. 1999;10 :997 –1006[Abstract/Free Full Text]
  12. Tikkanen I, Omvik O, Jensen HE. Comparison of the angiotensin II antagonist losartan with the angiotensin-converting enzyme inhibitor enalapril in patients with essential hypertension. J Hypertens. 1995;13 :1343 –1351[Web of Science][Medline]
  13. White CT, Macpherson CF, Hurley RM, Matsell DG. Antiproteinuric effects of enalapril and losartan: a pilot study. Pediatr Nephrol. 2003;18 :1038 –1043[CrossRef][Web of Science][Medline]
  14. Liern M, Dieguez SM, De Reyes V, et al. The additive antiproteinuric effect of enalapril and losartan to normotensive patients with pathology proteinuria [in Spanish]. Nefrologia. 2004;24 :553 –558[Web of Science][Medline]
  15. Tanaka H, Suzuki K, Nakahata T, et al. Combined therapy of enalapril and losartan attenuates histologic progression in immunoglobulin A nephropathy. Pediatr Int. 2004;46 :576 –579[CrossRef][Web of Science][Medline]
  16. Tylicki L, Rutkowski P, Renke M, et al. Renoprotective effect of small doses of losartan and enalapril in patients with primary glomerulonephritis: short term observation. Am J Nephrol. 2002;22 :356 –362[CrossRef][Web of Science][Medline]
  17. Asai T, Kushiro T, Fujita H, Kammatsuse K. Different effects on cardiac hypertrophy in spontaneously hypertensive rats by monotherapy and combination therapy of adrenergic receptor antagonists and/or the angiotensin II type 1 receptor blocker under comparable blood pressure reduction. Hypetens Res. 2005;28 :79 –87[CrossRef]
  18. Stawowy P, Margeta C, Blaschke F, et al. Protein kinase C {epsilon} mediates angiotensin II-induced activation of ß1-integrins in cardiac fibroblasts. Cardiovasc Res. 2005;67 :50 –59[Abstract/Free Full Text]
  19. National High Blood Pressure Education Program Working Group on High Blood Pressure in Children and Adolescents. The fourth report on the diagnosis, evaluation and treatment of high blood pressure in children and adolescents. Pediatrics. 2004;114 :555 –576[Free Full Text]
  20. Bergstein JM. A practical approach to proteinuria. Pediatr Nephrol. 1999;13 :697 –700[CrossRef][Web of Science][Medline]
  21. World Medical Association. Declaration of Helsinki: ethical principles for medical research involving human subjects. JAMA. 2000;284 :3043 –3045[Free Full Text]
  22. Ganservoort RT, De Zeeuw D, De Jong PE. Is the antiproteinuric effect of ACE inhibition mediated by interference in the renin-angiotensin system? Kidney Int. 1989;36 :272 –279[Web of Science][Medline]
  23. Renke M, Tylicki L, Rutkowski P, et al. Low-dose blockade of renin-angiotensin system improves tubular status in non-diabetic proteinuric patients. Scand J Urol Nephrol. 2005;6 :511 –517
  24. He BX, Yu GL, Liang XQ. Effects of losartan, fosinopril on myocardial fibrosis, angiotensin II and cardiac remolding in hypertensive rats [in Chinese]. Hunan Yi Ke Da Xue Xue Bao. 2001;26 :118 –120[Medline]
  25. Devereux RB, Palmieri V, Liu JE, et al. Progressive hypertrophy regression with sustained pressure reduction in hypertension: the Losartan Intervention For Endpoint Reduction Study. J Hypertens. 2002;20 :1445 –1450[CrossRef][Web of Science][Medline]
  26. Suzuki H, Kanno Y, Kaneko K, et al. Comparison of the effects of angiotensin receptor antagonist, angiotensin-converting enzyme inhibitor, and their combination on regression of left ventricular hypertrophy of diabetes type 2 patients on recent onset hemodialysis therapy. Ther Apher Dial. 2004;8 :320 –327[CrossRef][Web of Science][Medline]
  27. Viberti G, Wheeldon NM. Microalbuminuria reduction with valsartan in patients with type 2 diabetes mellitus: a blood pressure independent effect. Circulation. 2002;106 :672 –678[Abstract/Free Full Text]
  28. Maschio G, Alberti D, Janin G, et al. Effect of the angiotensin-converting-enzyme inhibitor benazepril on the progression of chronic renal insufficiency: the Angiotensin-Converting-Enzyme Inhibition in Progressive Renal Insufficiency Study Group. N Engl J Med. 1996;334 :939 –945[Abstract/Free Full Text]
PEDIATRICS (ISSN 1098-4275). ©2006 by the American Academy of Pediatrics

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