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Saudi Journal of Kidney Diseases and Transplantation
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Year : 2002  |  Volume : 13  |  Issue : 3  |  Page : 266-272
Antihypertensive Therapy and Progression of Renal Failure

Unidad de Hipertensión, Servicio de Nefrologia, Hospital 12 de Octubre, Madrid, Spain

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How to cite this article:
Segura J, Campo C, Ruilope LM. Antihypertensive Therapy and Progression of Renal Failure. Saudi J Kidney Dis Transpl 2002;13:266-72

How to cite this URL:
Segura J, Campo C, Ruilope LM. Antihypertensive Therapy and Progression of Renal Failure. Saudi J Kidney Dis Transpl [serial online] 2002 [cited 2022 Nov 29];13:266-72. Available from: https://www.sjkdt.org/text.asp?2002/13/3/266/33115

   Introduction Top

The kidney and arterial hypertension are closely related. A defective capacity to cope with the sodium content of the diet appears to account for the initial increase in blood pressure. Moreover, various primary renal abnormalities are associated with hereditary hypertension. [1] However, the most plausible cause of the deficiency in the renal capacity to excrete sodium is renal vasoconstriction [2] that could represent, not an intrinsic renal defect but a renal response to the hyper­tensive process. [3] Renal vasoconstriction is functional in the initial stages of the disease where it can be reversed by calcium channel blockers (CCBs) and angiotensin-converting enzyme inhibitors (ACEi). [4],[5],[6]

On the other hand, primary and secondary forms of renal disease are accompanied by a progressive elevation in blood pressure (BP) values and the great majority of patients attaining end-stage renal disease (ESRD) present with arterial hypertension. [7] The presence of arterial hypertension, being essential or secondary to renal disease, elevates the risk of cardiovascular disease and provokes renal damage that enhances the velocity of progression of chronic renal failure. Hence, in the presence of renal failure, adequate control of blood pressure is mandatory for prevention of both cardio­vascular disease and progression of renal failure.

   Prevalence and relevance of renal damage in essential hypertension Top

In the last decade, nephrosclerosis asso­ciated with arterial hypertension has been recognized as a very frequent cause of ESRD. [8],[9] This finding led to the conclusion that better degrees of renal protection must be attained in patients with arterial hyper­tension. These statements were in apparent disagreement with the data published in the very few series of patients in which renal function was analysed with adequate criteria for blood pressure control. In these studies, less than 2% of patients presented with mild renal insufficiency (MRI) as diagnosed by the presence of elevated serum creatinine values. [10],[11] The cut-off value of serum creatinine to confirm the presence of MRI has been recently established as 132 µmol/l (1.5 mg/dl) for men, and 123 µmol/l (1.4 mg/dl) for women. [12],[13]

Furthermore, the Hypertension Optimal Treatment (HOT) study that included more than 18,000 patients above 50 years of age of whom half were untreated at entrance to the study, MRI was present in only 2.6% of the total. [14] This figure is relatively low but important if we consider the high prevalence of hypertension in the community. However, the real prevalence of MRI in the hyper­tensive population could have been under­estimated in the HOT study according to what has been recently described in the community of the Framingham Heart Study, where elevated serum creatinine values were found in around 8% of men and women. [12] An elevated prevalence of MRI (10.4%) diagnosed as serum creatinine > 123 µmol/l (1.4 mg/dl) has also been described in the population included in the HOPE study. [15] This study included a total of 9,297 patients with elevated cardiovascular risk, of whom 50% were hypertensive and 35% were diabetics. We reviewed the clinical charac­teristics of the hypertensive population followed in our Hypertension Unit in Madrid. [16] As shown in [Figure - 1], the prevalence of MRI was higher as compared to the HOT study data. MRI (according to serum creatinine levels) was diagnosed in 7.6% of the patients; but, when looked at more closely, 20% of all patients had a decreased creatinine clearance (<60 ml/min). As can be seen in [Table - 1], most of our patients presented with high or very high cardio­vascular risk due to the elevated BP and/or the associated risk factors according to recently published guidelines [17],[18] and the prevalence of MRI (according to serum creatinine values) is similar to that seen in the HOPE study.

On the other hand, it is well known that the serum creatinine is a poor indicator of the renal filtration capacity and measurement of glomerular filtration rate (GFR) is a much more reliable index. [19] Unfortunately, an accurate methodology to adequately estimate GFR is rarely available in clinical practice. This has led to the utilization of different formulas used to estimate creatinine clearance, to further evaluate the presence of MRI in essential hypertension. [12],[20] We have used the Cockcroft and Gault formula [21]

and a cut-off point of 60 ml/min as in the HOT study and found a prevalence of 12.3% MRI by these criteria. [14] By using a similar methodology, data from the NHANES III, a cross-sectional survey conducted between 1988 and 1994, demonstrated that the presence of low estimated creatinine clearance values is also significantly higher than expected in the general population. [20]

Elevated serum creatinine above 150 µmol/l (1.7 mg/dl) at baseline was found to be a very potent predictor for 5 and 8 year all cause-mortality in the Hypertension Detection and Follow-up Program trial. [22] The asso­ciation of elevated serum creatinine with mortality has been reported in several other studies [23],[24],[25],[26] to be as potent a predictor as the presence of heart failure. Data from the HOT study [14] have confirmed the relevance of serum creatinine as a predictor by demon­strating that values above 132 µmol/l (1.5 mg/dl) predict an elevated cardiovascular risk, in particular for total and cardio­vascular death. Similar data have been found in the analysis of the data from the HOPE study. [15] A positive predictive value for cardiovascular events and death was also observed for estimated creatinine clearance values below 60 ml/min in the HOT study. [14] Such a higher prevalence of events and death accompanying the presence of MRI, occurred in the presence of an "excellent" BP control at least for cardio­vascular protection in the HOT study. Furthermore, serum creatinine was shown to be the most potent predictor well above any of the other accompanying risk factors. [27] Both in the general population [12] and in the patients with essential hypertension, [28] the elevated cardiovascular risk has been inter­preted as secondary to the association of MRI with other cardiovascular risk factors.

The relevance of proteinuria to cardio­vascular prognosis in the community was described in the Framingham Heart Study. [29] Prevalence of proteinuria in essential hypertension ranges between 4% and 16% in different series, and is associated with a much higher prevalence of cardiovascular morbidity and mortality. [30] The recently published INSIGHT study [31] compared the capacity of a long-acting dihydropyridine and a diuretic to diminish cardiovascular events and death in essential hypertensives with at least one associated risk factor. In this study proteinuria was considered for the first time as an associated risk factor. The analysis of the predictive power of the different associated risk factors showed that proteinuria was the most powerful among them. The presence of microalbuminuria, that constitutes the renal expression of generalized endothelial dysfunction, has also been shown to correlate with an elevated cardiovascular risk. [32]

All these data indicate that the prevalence of MRI in the general population as well as in essential hypertension is higher than previously thought. The data also show that renal involvement in cardiovascular disease is a very powerful predictor for a worse cardiovascular prognosis and reinforce the need to maintain renal function as near to normal as possible.

   Renal consequences of control of blood pressure Top

In the absence of antihypertensive treatment, renal involvement was very frequent in primary hypertension. Perera [33] followed a series of 500 untreated essential hypertensive patients till death. This author described the presence of proteinuria in 42% of patients and chronic renal failure in 18%, with only 7% developing malignant hypertension. Interestingly, the life expectancy of patients with renal damage was of only 5 to 7 years, indicating the relevance of renal involvement to the cardiovascular disease and mortality.

The prognosis of renal function has improved significantly with the utilization of pharmacologic therapy. However, the Hypertension Detection and Follow-up

Program in which the evolution of renal function was examined showed a progressive rise in serum creatinine values. [22] A more strict BP control to less than 140/90 mm Hg, as was studied by the group of Alderman in New York, concluded that less than 2% of patients exhibited a rise in serum creatinine. [11] The HOT study confirmed these results, as less than 1% of their patients had progressive renal failure defined by a rise in serum creatinine to values above 176 µmol/l (2 mg/dl) at the end of the study. [14] However, an increase in the serum creatinine by more than 30% as compared to the baseline value, was seen in 7.8% of the patients in the same study. [14] Studies are needed in which the evolution of renal function is performed through an adequate estimation of GFR because evolution of serum creatinine will greatly underestimate the real evolution of renal function. A progressive and undetected fall in GFR could occur even in the presence of an adequate BP control. In this sense, data from the INSIGHT study have shown a greater decrease in the estimated creatinine clearance in patients treated with the diuretic than in those who received dihydropyridine. [31]

   Goal of blood pressure control according to the current guidelines. Is it attainable? and at what cost? Top

Both the Joint National Committee (JNC)-VI and the World Health Organization (WHO)­ ISH guidelines 17],[18] agree that in the presence of renal failure BP must be lowered to values below 130/85 mm Hg. This goal is even lower(less than 125/75 mm Hg) if renal insufficiency is accompanied by proteinuria in excess of one gram/day.

It is well known that in the presence of advanced chronic renal failure BP control is very difficult and requires combined therapy in the great majority of patients. [7] As demonstrated in the HOT study, the presence of MRI did not impede the attainment of a diastolic BP of less than 90 mmHg in essential hypertension, although more drugs were required. [34] No data are available related to the possibility of lowering BP to the newly set goals in the presence of renal failure.

In a recently performed study [35] we tested the hypothesis of attaining the new goal of BP control in the presence of renal insuf­ficiency by an early start of pharmacologic therapy at a lower threshold of BP. In this study, we compared in a double blind fashion, the capacity of three different mono therapies (Beta-blocker, CCB, ACEi) and the combination of two of them (CCB+ ACEi) to lower BP in patients with primary renal disease and proteinuria above one gram/day. Patients with baseline BP around 140/90 mm Hg after four weeks placebo­washout period were included. Blood pressure fell to mean values around the expected goal for patients with renal insufficiency and proteinuria above one g/day. Interestingly, the good effect on BP was attained in the great majority of patients by means of an adequate titration of monotherapy; a diuretic was required in only 15% of patients. These data indicate that if therapy is initiated early, the attainment of the expected goal BP is feasible.

   Is the strict control of blood pressure comparable with angiotensin blockade for control of proteinuria? Top

Another interesting aspect is the relation­ship between the control of systemic BP and the decrease of proteinuria. It is well known that BP control with any therapy can be accompanied by a significant drop in proteinuria. [7] Furthermore, when the mean blood pressure (equivalent to renal perfusion pressure) falls by a mean value of 20 mm Hg ACEi do not seem to exhibit any particular advantage in reducing proteinuria over the other therapies. [36] In other words, an elevated systemic BP can, in the presence of a defective renal autoregulation, affect the glomeruli and results in the passage of proteins through the glomerular barrier. [37] Accordingly, the fall in systemic BP is paralleled by a drop in proteinuria, indepen­dently of the type of antihypertensive drug(s) used.

On the other hand, ACEi have been shown to lower proteinuria in the absence of changes in systemic BP 36 and to reduce the appearance of renal events in patients with hypertensive nephrosclerosis. [38] The question remains, on whether a strict BP control, e.g. actual goal BP in the presence of renal failure and proteinuria, obtained by any means would suffice to attain a drop in proteinuria comparable to that achieved with an ACEi or an angiotensin receptor blocker. Data from our previously quoted work [35] seem to indicate that, at similar levels of BP control obtained, atenolol (beta blocker) and verapamil (CCB) were significantly less effective than trandolapril (ACFi), alone or in combinations, in the capacity to lower proteinuria. Although these data need further confirmation, it seems reasonable to recommend ACEi as the first step therapy if our aim is to simultaneously control BP and proteinuria.

   Summary Top

Chronic renal failure and arterial hyper­tension run in parallel. New goal blood pressure levels have been established as 130/85 mm Hg and 125/75 mm Hg depending on the level of proteinuria being below or above one g/day, respectively.

New and lower threshold BP (>130/85 mm Hg) to initiate pharmacologic therapy is required in the presence of renal failure in order to facilitate the strict BP control.

Renal insufficiency is associated from its initial stages by a marked increase in risk of cardiovascular disease. Serum creatinine, creatinine clearance and the presence of proteinuria are very powerful predictors of poor outcome. Hence, there is need to consider both renal and cardiovascular protection with strict BP control by blockade of angiotensin II effects, especially when proteinuria above one g/day is present.

   References Top

1.Woolfson RG, de Wardener HE. Primary renal abnormalities in hereditary hyper­tension. Kidney Int 1996;50:717-31.  Back to cited text no. 1  [PUBMED]  
2.Ruilope LM, Lahera V, Rodicio JL, et al. Are renal hemodynamics a key factor in the development and maintenance of arterial hyper­tension in humans? Hypertension 1994;23:3-9.  Back to cited text no. 2  [PUBMED]  
3.Folkow B. Kidneys in primary hyper­tension initiators, stabilizers, or/and victim aggravators? Blood Press 1994;3:212-5.  Back to cited text no. 3  [PUBMED]  
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6.Ramirez AJ, Gimenez MI, Gallo G, Marco EJ, Sanchez RA. Renal sodium handling abnor­malities in hypertensive and normotensive patients with a family history of hypertension. J Hypertens 1989;7(Suppl 6): S178-9.  Back to cited text no. 6    
7.Locatelli F, Marcelli D, Comelli M, et al. Proteinuria and blood pressure as causal components of progression to end-stage renal failure. Nephrol Dial Transplant 1996;11:461-7.  Back to cited text no. 7  [PUBMED]  [FULLTEXT]
8.National Institute of Diabetes and Digestive and Kidney diseases. US Renal Data System: annual data report. Bethesda, MD: National Institutes of Health, 1989.  Back to cited text no. 8    
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12.Culleton BF, Larson MG, Wilson PW, et al. Cardiovascular disease and mortality in a community-based cohort with mild renal insufficiency. Kidney Int 1999;56:2214-19.  Back to cited text no. 12  [PUBMED]  [FULLTEXT]
13.Levey AS, Bosch JP, Lewis JB, et al. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med 1999;130:461-70  Back to cited text no. 13    
14.Ruilope LM, Salvetti A, Jamerson K, et al. Renal function and intensive lowering of blood pressure in the hypertensive participants of the Hypertension Optimal Treatment (HOT) Study. J Am Soc Nephrol 2000;12:218-25.  Back to cited text no. 14    
15.Mann JF, Gerstein HC, Pogue J, et al. Renal insufficiency as predictor of cardiovascular outcomes and impact of ramipril: The HOPE randomized trial. Ann Intern Med 2001;134:629-36.  Back to cited text no. 15  [PUBMED]  [FULLTEXT]
16.Segura J, Campo C, Rodicio JL, Ruilope LM. How relevant and frequent is the presence of mild renal insufficiency in essential hypert­ension? J Clin Hypertens 2002, in press.  Back to cited text no. 16    
17.The Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Arch Intern Med 1997;157:2413-46.  Back to cited text no. 17    
18.Guidelines Subcommittee. 1999 World Health Organization-International Society of Hypertension Guidelines for the Management of Hypertension. J Hypertens 1999;11:905-18.  Back to cited text no. 18    
19.Zanchetti A, Stella A. Cardiovascular disease and the kidney: an epidemiologic overview. J Cardiovasc Pharmacol 1999; 33(Suppl 1):S1-6.  Back to cited text no. 19  [PUBMED]  [FULLTEXT]
20.Clase CM, Kiberd BA. Prevalence of renal insufficiency in non-diabetic adults: Third National Health and Nutrition Examination Survey (NHANES III). J Am Soc Nephrol 2000;11:58A (abstract).  Back to cited text no. 20    
21.Cockroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 1976;16:31-41.  Back to cited text no. 21    
22.Shulman NB, Ford CE, Hall WD, et al. Prognostic value of serum creatinine and effect of treatment of hypertension on renal function. Results from the Hypertension Detection and Follow-up Program Coope­rative Group. Hypertension 1989;13(Suppl 5):180-93.  Back to cited text no. 22    
23.Wannamethee SG, Shaper AG, Perry IJ. Serum creatinine concentration and risk of cardiovascular disease: a possible marker for increased risk of stroke. Stroke 1997; 28:557-63.  Back to cited text no. 23  [PUBMED]  [FULLTEXT]
24.Matts JP, Karnegis JN, Campos CT, et al. Serum creatinine as an independent predictor of coronary heart disease mortality in normo­tensive survivors of myocardial infarction. J Fam Pract 1993;36:497-503.  Back to cited text no. 24  [PUBMED]  
25.Friedman PJ. Serum creatinine: an inde­pendent predictor of survival after stroke. J Intern Med 1991;229:175-9.  Back to cited text no. 25  [PUBMED]  
26.Fried LP, Kronmal RA, Newman AB, et al. Risk factors for 5-year mortality in older adults: the Cardiovascular Health Study. JAMA 1998;279:585-92.  Back to cited text no. 26  [PUBMED]  [FULLTEXT]
27.Zanchetti A, Hansson L, on behalf of the HOT investigators. The incidence of cardiovascular events in the hypertensive patients of the Hypertension Optimal Treatment (HOT) study: effects of additional risk factors. J Hypertens 1999;17(Suppl 3):S86 (abstract).  Back to cited text no. 27    
28.Ruilope LM. The kidney as part of the cardiovascular system. J Cardiovasc Phar­macol 1999;33(Suppl 1):S7-10.   Back to cited text no. 28    
29.Kannel WB, Stampfer MJ, Castelli WP, Verter J. The prognostic significance of proteinuria. Am Heart J 1984;108:1347-52.  Back to cited text no. 29  [PUBMED]  
30.Samuelsson O. Hypertension in middle­aged men: management, morbidity and prognostic factors during long-term hyper­tensive care. Acta Med Scand 1985;702 (Suppl):1-79.  Back to cited text no. 30    
31.Brown MJ, Palmer CR, Castaigne A, et al. Morbidity and mortality in patients randomised to double-blind treatment with a long-acting calcium-channel blocker or diuretic in the International Nifedipine GITS study: intervention as a Goal in Hypertension Treatment. Lancet 2000;356: 366-72.  Back to cited text no. 31  [PUBMED]  [FULLTEXT]
32.Agrawal B, Berger A, Wolf K, Luft FC. Microalbuminuria screening by reagent strip predicts cardiovascular risk in hyper­tension. J Hypertens 1996;14:223-8.  Back to cited text no. 32  [PUBMED]  
33.Perera GA. Hypertensive vascular disease: description and natural history. J Chronic Dis 1955;1:33-42.  Back to cited text no. 33  [PUBMED]  
34.Ruilope LM, Hansson L, Zanchetti A. Renal aspects of the HOT study. J Nephrol 1996;9:147-51.  Back to cited text no. 34    
35.PROCOPA Study Group. Dissociation between strict blood pressure control and fall in proteinuria in primary renal disease: a randomized double-blind trial. J Hypertens 2002;20:729-37.  Back to cited text no. 35  [PUBMED]  [FULLTEXT]
36.Weidmann P, Schneider M, Bohlen L. Therapeutic efficacy of different antihyper­tensive drugs in human diabetic nephro­pathy: an updated meta-analysis. Nephrol Dial Transplant 1995;10(Suppl 9):39-45.  Back to cited text no. 36    
37.Ruilope LM, Campo C, Rodicio JL. Blood pressure control, proteinuria and renal outcome in chronic renal failure. Curr Opin Nephrol Hypertens 1998;7:145-8.  Back to cited text no. 37  [PUBMED]  [FULLTEXT]
38.Segura J, Campo C, Rodicio JL, Ruilope LM. ACE inhibitors and appearance of renal events in hypertensive nephro­sclerosis. Hypertension 2001;38:645-9.  Back to cited text no. 38  [PUBMED]  [FULLTEXT]

Correspondence Address:
Julian Segura
Unidad de Hipertensión, Hospital 12 de Octubre, 28041 Madrid
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Source of Support: None, Conflict of Interest: None

PMID: 18209423

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