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Saudi Journal of Kidney Diseases and Transplantation
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Year : 1999  |  Volume : 10  |  Issue : 3  |  Page : 275-278
Antihypertensive Therapy in Chronic Renal Failure

Division of Nephrology, University Hospital, Verona, Italy

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How to cite this article:
Maschio G. Antihypertensive Therapy in Chronic Renal Failure. Saudi J Kidney Dis Transpl 1999;10:275-8

How to cite this URL:
Maschio G. Antihypertensive Therapy in Chronic Renal Failure. Saudi J Kidney Dis Transpl [serial online] 1999 [cited 2023 Feb 4];10:275-8. Available from: https://www.sjkdt.org/text.asp?1999/10/3/275/37234
It is well known that systemic hyper­tension is an important risk factor for cardiovascular disease, while glomerular hypertension is a more specific risk factor for renal disease.

We know from the old Perera's study [1] that non-pharmacological treatment of systemic hypertension has only a small protective effect on hypertension-related organ damage. Coronary heart disease, cardiac failure, stroke, proteinuria and renal failure were observed in 12 to 50% of 500 patients receiving only symptomatic treatment, with a poor mean survival (1 to 5 years).

Antihypertensive agents may protect renal function through at least four mechanisms: a) reduction of systemic blood pressure; b) prevention of glomerular hypertension and hypertrophy; c) reduction of proteinuria; d) improvement of endothelial function.

In this review we will briefly discuss the role of newer groups of antihypertensive agents.

Calcium Channel Blockers:

The calcium-channel blockers were first used in the 1960s in hypertensive patients with or without renal disease. They are still widely prescribed in hypertensive emergencies, myocardial ischemia, ischemic acute renal failure, diabetic nephropathy and progressive renal diseases.

In experimental studies, the remarkable renoprotective effect of calcium-channel blockers was found to be based on several mechanisms:

a) Control of systemic hypertension, with variable effects on glomerular hypertension.

b) Antagonism of vasoconstrictor agents and cellular calcium overflow.

c) Inhibition of growth-factor-induced proliferative effects.

d) Reduction of proteinuria (a variable effect).

However, the efficacy of calcium-channel blockers on the progression of experimental renal disease seems to be quite variable and this has been attributed to several reasons. Firstly, the heterogeneity of the studies: 33 studies were performed in 14 different models of renal disease, 18 with positive results and 15 with no effect or negative results. Secondly, the heterogeneity of the drugs: most calcium-channel blockers cause dilation of the afferent arteriole and impair autoregulation, which results in no change in glomerular pressure. In addition, dihydropyridine calcium-channel blockers fail to reduce permeability of glomerular basement membrane and to affect the synthesis of key matrix protein. Thirdly, the timing of treatment, which was found to be critical: the earlier it is started, the better are the results. [2],[3],[4]

The protective effect of calcium-channel blockers on residual renal function in progressive renal disease has not been clearly demonstrated as yet. A recent meta­analysis examined 53 studies in 754 diabetic patients and 26 studies in non­diabetic patients, who were all treated with calcium-channel blockers. [4] The calcium­channel blockers included both dihydro­pyridine and non-dihydropyridine agents. Both these compounds were able to reduce proteinuria in patients in whom urine protein excretion was lower than 0.5 g/24 hours, but only non-dihydropyridine calcium­channel blockers were effective in patients with higher levels of proteinuria.

Only one study showed a better protective effect of calcium-channel blockers on renal function when compared to the so-called "conventional" antihypertensive agents. [5]

Angiotensin Converting Enzyme (ACE)­inhibitors:

Almost all studies performed in experi­mental animals have shown a striking protective efficacy of ACE-inhibitors on renal function. These agents protect the kidney through a series of different mechanisms, including:

a) Reduction of both systemic and glomerular hypertension.

b) Inhibition of the hypertrophic hyperplastic processes in glomerular cells.

c) Reduction of permeability of glomerular capillary to proteins.

d) Down regulation of accumulation of extra cellular matrix in glomeruli.

e) Attenuation of both the inflammatory cell response and the fibroblastic activity in the tubulointerstitium.

At least one of these mechanisms i.e., the improvement in the permselectivity of the basement membrane has been confirmed in clinical studies.[6],[7],[8]

At present, ACE-inhibitors are among the drugs of choice in many clinical settings like essential hypertension, refractory and renovascular hypertension, scleroderma renal crisis, congestive heart failure, myocardial remodeling after infarction, diabetic nephropathy, proteinuric and progressive non-diabetic renal disease.

The effects of ACE-inhibitors on the progression of chronic, non-diabetic renal disease have been compared with those of either calcium-channel blockers or conventional agents.

A comparison with calcium-channel blockers has been made in several controlled trials, with inconclusive results due to a number of methodological problems. The most important of these studies failed to show statistically significant differences in renal function outcomes between ACE­inhibitor-treated and calcium-channel blocker­treated patients, although a trend toward a better renal survival was observed in the ACE-inhibitor-treated group. [9]

Many additional studies have compared ACE inhibitors and conventional agents. Important lessons could be learned from some of these trials.

The AIPRI trial has shown that in patients with non-diabetic renal disease, in the range of creatinine clearance between 60 and 30 ml/min, the risk of progressive renal failure can be halved with ACE-inhibitors. [10] It was also shown that ACE-inhibitors may have a selective effect, being more effective in proteinuric than in non-proteinuric nephro-pathies. The survival of renal function was clearly influenced by the magnitude of proteinuria at the start of treatment. Also, the effective control of blood pressure achieved with ACE­inhibitors was critical for slowing the rate of progression. Finally, the earlier the treatment was started, the greater was the benefit. [10]

The REIN trial has confirmed that ACE­inhibitors protect the residual renal function mainly by reducing proteinuria and, in addition, has suggested that these drugs may have a direct effect on the kidney. [11]

The results of a meta-analysis of the most important randomized trials including 1,688 patients followed for a mean period of 22.8 months suggest that ACE inhibitors protect the residual renal function better than other antihypertensive agents in non-diabetic nephropathies, even after accounting for their observed greater effect on blood pressure.[12],[13]

Clinical experience with angiotensin­receptor antagonists is not expanded enough to allow a definite answer to the question whether they are superior to ACE­inhibitors. In experimental studies, no difference between these agents has been observed in a variety of models of both hypertensive and normotensive renal disease. [14] The results of clinical studies are largely inconclusive as yet. An effective reduction of blood pressure has been observed in the majority of treated patients. In addition, the antiproteinuric effect has been reported to be similar to that obtained with ACE-inhibitors.[15],[16]

Endothelin Receptor Antagonists

The endothelin receptor antagonists are very promising new agents to control blood pressure and to slow the progression of renal disease.

Experimental studies have shown favo­rable effects on the evolution of renal damage in several models (remnant kidney, lupus nephritis, diabetes, and immune­complex nephritis) by a mechanism that might be independent of reduction of systemic blood pressure. [17] The first clinical experiences with these agents in patients with essential hypertension are quite promising. [18]

Combination Therapy:

A combination therapy with two or more agents is now the treatment of choice for most patients with hypertensive renal disease. The advantages of such combination are: greater blood pressure response rate than to monotherapy; a complementary action on different targets in the kidney; and fewer side effects with small doses of each drug.

In conclusion, over the last 30 years, the evolution of antihypertensive therapy in Nephrology has moved from the target of an effective blood pressure control as the sole objective, to more specific renoprotective targets: the reduction of proteinuria and the slowing of progression of renal failure.

Much remains to be done to reach the goal of a complete arrest of the progression of chronic renal disease.

   References Top

1.Perera GA. Hypertensive vascular disease,description and natural history. J Chron Dis 1995;l:33-42.  Back to cited text no. 1    
2.Ritz E, Orth SR, Strzelczyk P. Angio­tensin converting enzyme inhibitors, calcium channel blockers, and their combination in the treatment of glomerular disease. J Hypertens Suppl 1997; 15(2):S21-6.  Back to cited text no. 2    
3.Tarif N, Bakris GL. Preservation of renal function: the spectrum of effects by calcium-channel blockers. Nephro! Dial Transplant 1997;12:2244-50.  Back to cited text no. 3    
4.Kloke HJ, Branten AJ, Huysmans FT, Wetzels JF. Antihypertensive treatment of patients with proteinuric renal diseases: risks or benefits of calcium channel blockers? Kidney Int 1998;53:1559-73.  Back to cited text no. 4  [PUBMED]  [FULLTEXT]
5.EHahou HE, Cohen D, Hellberg B, etal.Effect of the calcium channel blocker nisoldipine on the progression of chronic renal failure in man. Am J Nephrol 1988;8:285-90.  Back to cited text no. 5    
6.Morelli E, Loon N, Meyer T, Peters W,Myers BD. Effects of converting­enzyme inhibition on barrier function in diabetic glomerulopathy. Diabetes 1990;39:76-82.  Back to cited text no. 6  [PUBMED]  
7.Remuzzi A, Perticucci E, Ruggenenti P,Mosconi L, Limonta M, Remuzzi G. Angiotensin converting enzyme inhibition improves glomerular size­selectivity in IgA nephropathy. Kidney Int 1991;39: 1267-73.  Back to cited text no. 7  [PUBMED]  
8.Remuzzi A, Ruggenenti P, Mosconi L, etal.Effect of low-dose enalapril on glomerular size-selectivity in human diabetic nephropathy. J Nephrol 1993;6:36-43.  Back to cited text no. 8    
9.Zucchelli P, Zuccala A, Borghi M, et al.Long-term comparison between captopril and nifedipine in the progression of renal insufficiency. Kidney Int 1992;42:452-8.  Back to cited text no. 9    
10.Maschio G, Alberti D, Janin G, et al.Effect of the angiotensin-conver­tingenzyme inhibitor Benazepril on the progression of chronic renal insufficiency. The angiotensin-converting-enzyme inhibit­tion in pro-gressive renal insufficiency study groups. New Engl J Med 1996;334:939-45.  Back to cited text no. 10    
11.Randomized Placebo-controlled trial ofeffect of ramipril on decline in glomerular filtration rate and risk of terminal renal failure in proteinuric, non-diabetic nephropathy. The GISEN Group (Gruppo Italiano di Studi Epidemiologici in Nefrologia). 1997;349:1857-63.  Back to cited text no. 11    
12.Giatras I, Lau J, Levey AS. Effect of angiotensin-converting enzyme inhibitors on the progression of non­diabetic renal disease: a meta-analysis of randomized trials. Angiotensin­converting-enzyme inhibition and progressive renal disease study group. Ann Intern Med 1997; 127:337-45.  Back to cited text no. 12    
13.Jafar TH, Landa M, Schmid C for theAIPRD study group, Boston, MA. The effect of angiotensin converting enzyme inhibitors (ACEI) on the progression of non-diabetic renal disease: interim results from a pooled analysis of randomized control trial. JASN 1998;9:A37-8.  Back to cited text no. 13    
14.Ots M, Mackenzie HS, Troy JL, Rennke HG,Brenner BM. Effects of combination therapy with enalapril and losartan on the rate of progression of renal injury in rats with 5/6 renal mass ablation. J am Soc Nephrol 1998;9:224-30.  Back to cited text no. 14  [PUBMED]  
15.Gansevoort RT, de Zeeuw D, Shahinfar S,Redfield A, de Jong PE. Effects of the angiotensin II antagonist losartan in hypertensive patients with renal disease. J Hypertension 1994;12:S37-42.  Back to cited text no. 15    
16.Nielsen S, Dollerup J, Nielsen B, Jensen HA,Mogensen CE. Losartan reduces albumi-nuria in patients with essential hypertension. An enalapril controlled 3 months study. Nephrol Dial Transplant 1997; 12 Suppl 2:19-23.  Back to cited text no. 16    
17.Benigni A, Remuzzi G. Endothelin receptorantagonists: which are the therapeutic perspectives in renal diseases? Nephrol Dial Transplant 1998; 13:5-7.  Back to cited text no. 17  [PUBMED]  [FULLTEXT]
18.Krum H, Viskoper RJ, Lacourciere Y,Budde M, Charlon V. The effect of an endothelin-receptor antagonist, bosentan, on blood pressure in patients with essential hypertension. Bosentan Hypertension Investigators. New Engl J Med 1998;338:784-90.  Back to cited text no. 18    

Correspondence Address:
Giuseppe Maschio
Division of Nephrology, Ospedale Civile Maggiore 37126, Verona
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Source of Support: None, Conflict of Interest: None

PMID: 18212436

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