Nephroprotection by antihypertensive therapy
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Basic Res Cardiol 93: Suppl. 2, 109119 (1998) Steinkopff Verlag 1998
J. JacobiR. E. Schmieder
Nephroprotection by antihypertensivetherapy
control on renal function, and it isincreasingly recognized that antihyper-tensive therapy aimed at reducingblood pressure well below the targetvalue of 140/90 mmHg furtherimproves the overall renal survivalrate. Different classes of antihyperten-sive agents show disparate specificnephroprotective properties that areunrelated to their blood pressure lower-ing properties. ACE inhibitors andcalcium channel blockers have beenreported to ameliorate renal function by favorably modifying renal and intra-glomerular hemodynamics. In addition,both drugs exert beneficial effects onnon-hemodynamic parameters of renalfunction. In contrast, b-blockers anddiuretics, although still being solely
recommended as first line drugs in themanagement of arterial hypertension,can have adverse effects on renal func-tion. Recently, long-term randomizedcontrolled trials have consistentlydemonstrated the superior nephropro-tective value of ACE inhibitors on renalfunction outcome. Whether AT1 recep-tor antagonists have similar effects on long-term renal survival is stillunder investigation. The outcome offorthcoming clinical trials is likely toinfluence clinical guidelines and opti-mize the medical regimen of humanessential hypertension in patients withchronic renal insufficiency.
Key words Hypertension kidney antihypertensives nephroprotection
R. E. Schmieder (Y) J. JacobiMedizinische Klinik IV/4University of Erlangen-NrnbergBreslauer Str. 201D-90471 Nrnberg, Germany
Abstract Morbidity and mortality dueto end-stage renal failure has become amajor health concern in recent yearsand there is clear evidence that arterialhypertension constitutes a powerfulrisk factor for the progression of renaldisease. Several studies have docu-mented the benefit of blood pressure
Chronic renal failure may be either the cause or consequenceof an elevated arterial blood pressure underlining the crucialrole of kidney function in arterial hypertension. Reports fromthe US Renal Data System (85, 86) point to an alarmingincrease in the prevalence and incidence of progressive renalfailure (Fig. 1) and arterial hypertension has emerged as thesecond most common underlying cause that accounts forapproximately 26 % of the incidence rate. This figure onlyreflects a rough estimate since the relationship between bloodpressure and renal function is dependent on other comorbidfactors, such as age and race (50, 52). The increased incidencehas in part been explained by ageing of the population,improved access to dialysis and transplantation units and
reduced risk of dying from cardiovascular events at a youngerage. Indeed, age adjusted death rates from stroke have declinedby nearly 60 % and from coronary heart disease by 53 %throughout the last decade (82) and this finding may affect thedivergent trend of an increased morbidity and mortality due tochronic renal failure.
Underestimation and unawareness of arterial hypertensionrepresents a major risk factor for end-stage renal disease (86).Recent results from the Multiple Risk Factor Intervention Trial(MRFIT), a prospective epidemiologic study, confirm a strongand graded relationship between blood pressure and renalfunction (45) and data from the Hypertension Detection andFollow-up Program (HDFP) support the assumption that anti-hypertensive intervention can retard the progression of renalfailure (79).
110 Basic Research in Cardiology, Vol. 93, Suppl. 2 (1998) Steinkopff Verlag 1998
The deleterious impact of essential hypertension on kidneyfunction results, at least according to most studies, from theincrease in intraglomerular pressure that is dependent on bothsystemic arterial pressure and the ratio of efferent to afferentarteriole resistance. Pressure-related pathomechanismsinclude loss of renal autoregulation with subsequent greatertransmission of systemic arterial pressure into the glomerularcapillary network, hyperfiltration of single nephrons, increaseof glomerular-capillary permeability to proteins paving theway for the development of glomerulosclerosis, and activationof neurohumoral pressure systems such as the renin-angio-tensin system, to name but a few. All these mechanism that areknown to compromise renal function and accelerate the time-course towards end-stage renal failure can be reversed to somedegree by early onset of antihypertensive therapy.
There is still debate over how aggressively blood pressureshould be lowered and which antihypertensive agent should befavored. With the introduction of new antihypertensivecompounds, such as the AT1 receptor antagonists, the optimaltherapeutic approach in the management of essential hyper-tension in patients with renal insufficiency is under review. Itis widely agreed that first choice drugs should protect targetorgans in addition to resetting blood pressure to normal values.Desired effects include improvement of renal and intrarenalhemodynamics, regression of proteinuria, inhibition of cellu-lar growth-promoting stimuli, down-regulation of activatedneurohumoral pressure systems, improvement of renal endo-thelial function, and other actions. In this context analysis ofpresent data indicate that ACE inhibitors (and maybe calciumchannel blockers) are superior to equipotent doses of conven-tional therapy with (-blockers, diuretics or vasodilators (57),and it has been suggested that coadministration of an ACEinhibitor and a calcium channel blocker exert complementary
nephroprotective properties (20). Encouraging results fromanimal and human studies suggest that AT1 receptor antago-nists display a similar if not superior nephroprotective profilecompared to ACE inhibitors, yet data about their long-termefficacy in human essential hypertension is still lacking.
How to measure renal function in patients
There are a variety of options to determine kidney function inpatients with renal disease and the quality of clinical studiesdepends on the method applied. An absolutely reliable crite-rion for end-stage renal disease is renal death, i.e., the need forrenal replacement therapy or transplantation. In severalclinical trials doubling of serum creatinine or end-stage renalfailure have been defined as combined endpoints for thedeterioration of renal function (28, 49, 55). However, there areseveral other possible ways of assessing the progression ofrenal injury in essential hypertension and kidney disease.
Microscopic evaluation of renal morphology from puncturebiopsies of subjects can be regarded as gold standard sincehistological changes are a good surrogate of actual renal func-tion. In particular, the extent of interstitial fibrosis correlateswith glomerular filtration rate (8). Similarly, the more severethe histological scarring, the lower the renal blood flow (13,14). However, due to its invasive nature, this procedure isinappropriate for serial follow-up analyses and should bereserved for special indications.
Fig. 1 Incidence rates permillion population of reportedend-stage renal disease therapy,1982 to 1995, adjusted for age,race, and sex. Asterisk indicatesprovisional data. Source: USRenal Data System (86).
J. Jacobi and R. E. Schmieder 111Nephroprotection by antihypertensive therapy
The most accurate clearance methods use endogenous orexogenous tracer substances to measure renal plasma flow(RPF) and glomerular filtration rate (GFR). Both hemo-dynamic parameters correlate with the degree of severity ofhistologic changes (8, 54). Since para-amino-hippurate andinulin clearance require constant infusion techniques andcatheterization of the bladder, they are mainly practicable forlaboratory use. A modified method of this technique withouturinary sampling was introduced by Cole and coworkers (16)and has been successfully applied in various clinical investi-gations (75). In terms of clinical routine serum creatinineclearance, though less accurate, can be considered adequateprovided the patient is compliant and follows the instructionsto collect urine over a period of 24 hours. One concern overthe accuracy of this method lies in the fact that creatinine is notsolely filtered but also secreted into the tubular system lead-ing to an overestimation of the actual renal clearance capacity,in particular in patients with advanced renal failure.
Serum creatinine can be easily measured and allows roughestimation of creatinine clearance by using the Cockcroftformula (15). Another method has been introduced by Mitchet al. who suggested using the reciprocal value for serumcreatinine as an indicator of renal function (58). Since serumcreatinine is not elevated until glomerular filtration rate isreduced below 60 ml/min, this parameter is obviously a poormarker for the detection of early renal impairment. Thesituation is different in patients with markedly impaired renalfunction where serum creatinine serves as a reliable clinicalparameter.
Proteinuria constitutes a strong and independent risk factor forthe progression of nephropathy (43). Further results from theModification of Diet in Renal Disease (MDRD) Study under-line the benefit of protein restriction in reducing the decline inrenal function (46). As in hypertension, microalbuminuria isthe earliest marker for hypertensive renal damage with aprevalence of 1030 % (6, 67). Several studies demonstrateda close correlation between the rate of urinary albumin excre-tion and the level of blood pressure making microalbuminuriaa highly prognostic indicator in human essential hypertension(51, 63).
Only recently attention has been focused on the important roleof vascular endothelium in the pathogenesis of hypertensivetarget organ damage. The rationale for investigating endothe-lial function comes from the observation that pathologicalconditions, such as hypertension or diabetes impair the releaseof endothelium-derived autacoids, particularly nitric oxide(NO), which accounts for the biologic activity of endothelium-derived relaxing factor (EDRF) (64). NO plays an importantrole in the regulation of renal blood flow and decreased for-mation is suggested to aggravate the deleterious impact of anelevated arterial blood pressure on renal hemodynamics (4, 48,72). The integrity of renal endothelial function has beenclinically assessed by either stimulating NO formation viasystemic infusion of the substrate for endothelial NO synthe-sis, the amino acid L-arginine (3638), or by blocking basalnitric oxide release with competitive inhibitors, such as NG-monomethyl-L-arginine (L-NMMA) (5, 93). However, sincesystemic NO inhibtion can increase blood pressure and hasonly been tested in healthy human subjects, the first approachis the method of choice. Higashi et al. found an attenuation ofthe L-arginine induced increase in RPF and plasma cGMP inhypertensive subjects (37). Another interesting parametermight be asymmetrical dimethylarginine (ADMA), anendogenous inhibitor of nitric oxide synthase, which wasfound to be elevated in patients with renal impairment (87).
How far should blood pressure be lowered
There is an ongoing debate as to how far blood pressure shouldbe lowered to reduce the risk of cardiovascular events inpatients with hypertension. Most guidelines recommend athreshold blood pressure for intervention of 140/90 mmHg(33). However, based on evidence that further reductionsimprove survival rates in patients with hypertensive targetorgan damage, more aggressive intervention strategies havebeen proposed (82). Thus, recent results from the Modificationof Diet in Renal Disease (MDRD) trial recommend that hyper-tensive patients with proteinuria exceeding 1 g/day should betreated well into the normotensive range to values around125/75 mmHg to gain most benefit (66).
Control of intervention therapy should also include 24-hour ambulatory blood pressure readings to confirm effectiveantihypertensive treatment throughout the whole day (88).This is an important feature since a high proportion of patientswith renal disease display an abnormal pattern in diurnal bloodpressure variability with attenuation of nocturnal declines inperfusion pressure (non-dippers) and this loss of circadianrhythm may not be detected with self blood pressure
112 Basic Research in Cardiology, Vol. 93, Suppl. 2 (1998) Steinkopff Verlag 1998
measurements during daytime. Furthermore, ambulatory 24-hour blood pressure profiles correlate more closely withhypertensive related organ damage than casual blood pressurereadings (84, 89).
Precise control of blood pressure is also mandatory in postrenal transplantation care. Our recent prospective analysisconfirmed that 24-hour ambulatory blood pressure correlatesmore closely with renal function in patients after transplanta-tion than casual blood pressure (78). Ambulatory blood pres-sure averages of less than 91 mmHg (equals ~125/75 mmHg)were related to a better renal transplant survival (p < 0.05)compared to ambulatory blood pressure averages of greaterthan 97 mmHg (equals ~130/90 mmHg). Thus, 24-hour ambu-latory blood pressure is superior to other methods of bloodpressure recording for evaluation of hypertension-related renalgraft dysfunction (Fig. 2).
Differential use of antihypertensive agents for nephroprotection
The use of diuretics is a cornerstone in the treatment of chronicrenal failure since these drugs favorably modify the distur-bances caused by retention of electrolytes and water (81).Their prompt onset of action is very effective in compensatingthe signs of acute volume or pressure overload (77). Underthese conditions sequential therapy with loop diuretics andthiazides provides added efficacy by combining drug effectson sodium retention at the proximal and distal tubular system.
Caution has been advised concerning the long-term use ofdiuretics in patients with chronic renal impairment sinceintravascular volume depletion adversely affects renal hemo-dynamics and may impair kidney function. Thiazide diureticsreduce renal plasma flow and glomerular filtration rate byapproximately 10 % (65, 71). In addition, diverse metabolicside effects, such as alterations in glucose and lipid profile,may limit the use of diuretics as the drug of choice in chronicrenal failure. If indicated, loop diuretics have been favoredbecause they remain effective until end-stage renal failure isreached. Reconsidering the beneficial effects, diuretics seemto be most valuable when used as adjunct therapy and are irre-placeable tools for the management of acute volume overload.
Beta blockers exhibit somewhat unwanted actions on renalfunction. They increase reabsorption of sodium via a directtubular effect and thereby aggravate the negative effect ofsodium retention on pressure and volume overload (47). Inaddition, b-blockers have disadvantageous effects on renalhemodynamics. Our own comparison of a- versus b-blockadeon hypertensive target organ damage revealed that 6 monthtreatment with metoprolol significantly decreased renal per-fusion by approximately 10 % whereas bunazosin tended toimprove hemodynamic parameters (76). The detrimentaleffect of b-blockers on renal function is typical for theseagents (92) and may be related to an increase in vascularresistance that has been explained by an impaired balance ofa- versus b-activity in favor of a-mediated vasoconstriction.Two other prospective randomized trials compared b-blockerto treatment with ACE inhibitors (35, 40). The outcome of bothstudies disclosed that the cumulative renal survival rate was
Fig. 2 Twenty four hour ambula-tory blood pressure and renalgraft survival. Patients (n = 46)are divided into tertiles accordingto their mean arterial 24-hourambulatory blood pressure; NTX,renal transplantation; MAP, meanarterial pressure (unpublisheddata from ref. 78).
J. Jacobi and R. E. Schmieder 113Nephroprotection by antihypertensive therapy
significantly better for patients being treated with ACEinhibitors. Different effects of b-blockers on renal functionhave been described in diabetic patients. Nielsen et al. com-pared the long-term effects of lisinopril and atenolol on kid-ney function in 36 hypertensive NIDDM subjects with diabeticnephropathy (62). Mean arterial blood pressure and decline ofrenal function, defined as the decrease of GFR in ml/min/month, were equally effectively reduced by both agents after42 months of treatment, but urinary albumin excretion wasreduced to a greater extent by ACE inhibition (55 vs. 15 %).These results are in contrast to those of Bjrck et al., whostudied the impact of 24 months therapy with either enalaprilor metoprolol on kidney function in 40 patients with IDDM(7). Despite an equal reduction in mean arterial blood pressurethe ACE inhibitor was more effective in reducing the rate ofdecline in renal function than the beta blocker. Only enalaprilconsistently lowered urinary albumin excretion significantly.
Calcium channel blockers
The nephroprotective properties of calcium channel blockershave been extensively reviewed in recent years (21, 69, 96).Of undisputed value is the repeatedly proven nephroprotectivepotential of these drugs in the management of acute renalfailure and renal allograft survival (5961). The main targetsite of calcium channel blockers within the kidney is the pre-glomerular region where they lower afferent arteriolar tone(12, 70) and, thus, increase glomerular filtration rate and renalplasma flow (17, 53). Predominant afferent arteriolar vaso-dilation seems to be a maladaptive process since it enhancesthe rate of pressure transmission into the glomerular capillarynetwork, a mechanism that should cause detericration of renalfunction on a long-term basis. However, several studies inanimals (18, 42, 74) and humans (19, 98) have demonstrateda nephroprotective potential for calcium channel blockers. Thus,Eliahou et al. compared the influence of nisoldipine againstsympatholytics and diuretics in 17 patients suffering from non-diabetic chronic renal disease and described a less pronouncedloss of renal function in patients treated with the calcium chan-nel blocker than in those treated with conventional therapy,although blood pressure was lowered to the same extent inboth groups (19). In a prospective randomized trial Zucchelliet al. compared the effects of captopril and nifedipine on theprogression of renal failure in 121 patients over a period ofthree years (98). Both drugs were equally effective in reduc-ing the incidence rate of end-stage renal failure and themortality curves of the two groups were comparable.However, progression of renal failure was defined by 1/serumcreatinine which has to be evaluated critically (90). The impactof treatment on urinary protein excretion initially showeddisparate effects. Captopril decreased average proteinuria by40 % within the first year of treatment whereas treatment with
nifedipine had no effect at that timepoint. However, after threeyears both agents displayed similiar antiproteinuric properties.In patients with diabetes the impact of calcium channelblockers on proteinuria was evaluated in a metaanalysis of 126studies including 2151 subjects (Fig. 3) (91). The effect ofcalcium channel blockers on urinary albumin excretion waslower than that of ACE inhibitors (mean study duration 8.4 vs9.8 months, respectively) but higher than that of conventionaltherapy (mean study duration 17.3 months) with exception ofnifedipine that enhanced proteinuria by approximately 5 %(mean study duration 5.9 months). However, the averagechanges in urinary albumin excretion under nifedipine variedfrom 18 to +28 % and these differences might support thefinding of Zucchelli et al. that the antiproteinuric effect ofcalcium channel blockers is in part dependent on duration oftherapy. Overall, further clinical studies with reliable primarystudy endpoints are needed to clarify the long-term effects ofcalcium channel blockers on the development of chronic renalfailure.
Fig. 3 Effects of different classes of antihypertensives on urinary proteinexcretion and mean arterial pressure. Data are weighted means and 95 %confidence intervals. Abbreviations are ACEI, angiotensin convertingenzyme inhibitors; CCB, calcium channel blockers except nifedipine;Conventional, beta blockers and/or diuretics; MAP, mean arterialpressure; N, number of studies; n, number of patients (from Remuzzi etal. (68) modified from ref. 91).
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The use of ACE inhibitors has become an indispensable partin the treatment regimen of patients with renal disease. ACEinhibitors exert a variety of specific nephroprotective effectsreflecting the crucial role of systemic and local actions of therenin-angiotensin system in cardiovascular disorders.Intrarenal actions of the effector hormone angiotensin IIinclude preferential vasoconstriction of the efferent arterioleleading to a rise in intraglomerular pressure and direct effectson sodium transport (34, 83). Non-hemodynamic effectsinclude stimulation of growth of renal vascular and glomeru-lar cells and increased synthesis of matrix molecules (39).Inhibition of angiotensin II formation with ACE inhibitorsconversely affects renal function. In hypertenive patients thehemodynamic response consists of an increase in GFR andRPF (41, 73) and a reduction in the filtration fraction combinedwith a reduction in intraglomerular pressure. The inhibition ofgrowth promoting factors counteracts the progression ofglomerulosclerosis (83) and in part explains the powerfulantiproteinuric effect of ACE inhibitors. A recent metaanaly-sis of 41 studies comprising 1124 patients with either non-dia-betic or diabetic renal disease disclosed that despite an equalreduction in blood pressure the mean antiproteinuric effect ofACE inhibitors was significantly greater compared to otherantihypertensive agents (39.9 % vs. 17 %) (25).
The benefit of ACE inhibition on renal function has beenclearly demonstrated in three large prospective, placebo con-trolled trials with well defined endpoints (28, 49, 55) (Table 1).After three years of continous treatment the outcome of allstudies showed remarkable risk reductions for the group ofpatients that received ACE inhibitors despite almost similarreductions in blood pressure. It is important to note that no
such results are available for antihypertensive agents otherthan ACE inhibitors and it remains a future task to close thisgap in the field of nephrology.
The superiority of ACE inhibition has also been delineatedin several comparative trials in which ACE inhibitors were com-pared to b-blockers or other conventional therapy (35, 40, 44).
Combination of calcium channel blockers and ACE inhibitors
The rationale of combining calcium channel blockers and ACEinhibitors results from the fact that both agents exert theirnephroprotective properties via different target sites, and it hasbeen suggested that coadministration provides additive effectsthat might be superior to those achieved by monotherapy (3,20, 56). Following this approach, experimental studies in ratsdemonstrated pronounced reductions in the rate of glomeru-losclerosis and proteinuria under combined therapy (80). Sim-ilar findings have been reported in humans. Thus, Bakris et al.showed that the combination of lisinopril and sustained releaseverapamil was more effective in attenuating proteinuria anddecline in glomerular filtration rate in subjects with diabeticnephropathy (2). Combination of calcium channel blockersand ACE inhibitors also seems to have beneficial effects inpatients with post-transplant hypertension and proteinuria asreported by a Greek study group (32). However, further stud-ies are needed to confirm the value of combined interactionsof these two drug classes.
Only a few studies have investigated the effect of a-blockertherapy on renal function. In a previous study we found that
Table 1 Outcome of long-term prospective placebo controlled trials studying the impact of ACE inhibitors on ESRD (primary endpoints = doublingof serum creatinine or need for dialysis or transplantation; * adjusted)
number of underlying baseline baseline treatment BP primarysubjects disease crea. (mg/dl) proteinuria (g/day) (mmHg) endpoints
Lewis et al. (49)captopril 75 mg n = 207 1.3 0.4 2.5 2.5 128 to 134 / 77 to 82 n = 25
insulin-dependent p < 0.02 p = 0.007placebo n = 202 diabetic nephropathy 1.3 0.4 3.0 2.6 129 to 136 / 80 to 84 n = 43
Gisen group (28)ramipril 1.255.0 mg n = 78 2.4 1.0 5.6 2.8 144 2 / 88 1 n = 18
non-diabetic p = 0.04placebo n = 88 nephropathy 2.4 1.0 5.1 2.0 144 2 / 89 1 n = 40
Maschio et al. (55)benazepril 10 mg n = 300 non-diabetic 2.1 0.6 1.8 2.6 ~ 136 / 84 * n = 31
nephropathy p = 0.001placebo n = 283 2.1 0.6 1.8 2.2 ~ 145 / 88 * n = 57
J. Jacobi and R. E. Schmieder 115Nephroprotection by antihypertensive therapy
sixth month treatment with bunazosin did not alter renal hemo-dynamic profile although GFR tended to increase and serumcreatinine significantly decreased (76). Consistent with otherstudies (94, 95) the treatment with bunazosin significantlylowered plasma lipid concentrations, a favorable effect of a-blockers that reduces total cardiovascular risk. In anotherstudy Anderton et al. (1) compared the impact of three monththerapy with bunazosin or prazosin on renal hemodynamics in53 hypertensive patients with normal and impaired renalfunction. Interestingly, only in patients with markedly reducedrenal function did bunazosin significantly improve glomeru-lar filtration rate and effective renal plasma flow, whereas wefound that even patients with normal renal function showed aslight increase of these parameters. In contrast, prazosinadversely affected renal hemodynamics by decreasing renalhemodynamics in both groups which may be related to differ-ent pharmacodynamic properties. In patients with diabeticnephropathy three month treatment with doxazosin (n = 10)significantly increased glomerular filtration rate and decreased24-hour urinary protein excretion (29).
Overall, further large scale prospective trials with well-defined ultimate endpoints are needed to consolidate thedistinct nephroprotective value of a-blockers. In addition, theeffect of a-blockers on intraglomerular hemodynamicsremains unknown to date.
AT1 receptor antagonists
Like ACE inhibitors, AT1 receptor antagonists interfere with therenin-angiotensin pressor system and it has therefore beenanticipated that both agents confer similar actions on bloodpressure and target organ protection. Compared to ACEinhibitors, AT1 receptor antagonists have the advantage ofselectively blocking the action of angiotensin II at the receptorlevel and their pharmacodynamic properties are not counter-acted by non ACE-dependent pathways of angiotensin II for-mation. In addition, AT1 receptor antagonists are well toleratedand have a side-effect profile that is not distinct from placebo.Major differences between both compounds have been referredto diverse effects on kinin metabolism. Thus, the effects of ACEinhibitors can be related to decreased formation of angiotensinII as well as increased bioavailability of bradykinin.
In human hypertension various studies investigated theblood pressure lowering and nephroprotective potential of AT1receptor antagonists; however, it should be noted that resultsof long-term prospective trials will not be available until theyear 2000. The AT1 receptor antagonists have been clinicallytested in several thousand hypertensive patients with normalrenal function and found to effectively lower blood pressure(30, 31). Repeated control of serum creatinine levels, althoughbeing a poor marker of renal function, suggested no deteriora-tion of kidney function under therapy.
The effect of short-term administration of AT1 receptorantagonists on renal hemodynamics has been investigated bothin healthy subjects (911) and in hypertensive patients withnephrotic range proteinuria (22, 23, 27). In healthy subjectsAT1 receptor blockade with losartan or irbesartan induced nochanges in blood pressure, glomerular filtration rate or renalblood flow. However, both drugs significantly increasedurinary sodium excretion. In subjects treated with losartan thisnatriuretic response was enhanced under conditions of salt-depletion (11). In addition, losartan increased urinary uric acidexcretion, which seems to be a unique property within thisclass of antihypertensives. In hypertensive patients with renaldisease short-term treatment with losartan significantlydecreased mean arterial pressure and microalbuminuria in allstudies, whereas renal hemodynamics remained unchanged orwere slightly altered (22, 23, 27). Gansevoort et al. (26)compared the effect of ACE inhibition and receptor blockadeon renal hemodynamics in eleven hypertensive patients withnon-diabetic proteinuria. The cross-over designed study con-sisted of seven periods (3 x placebo, losartan 50 and 100 mg,enalapril 10 and 20 mg) each of which lasted for four weeks.Both drugs were equally effective in reducing mean arterial
Fig. 4 Impact of 4 week treatment with losartan (50 and 100 mg) orenalapril (10 and 20 mg) on blood pressure (BP), protein excretion, andrenal hemodynamics; RBF, renal blood flow; GFR, glomerular filtrationrate; FF, filtration fraction (modified from ref. 26).
116 Basic Research in Cardiology, Vol. 93, Suppl. 2 (1998) Steinkopff Verlag 1998
blood pressure and proteinuria, and the effects on renalhemodynamics were identical (Fig. 4).
The antiproteinuric effect of AT1 receptor antagonists hasalso been described in patients with type II diabetes mellitus.Three months treatment with the novel receptor blockercandesartan reduced microalbuminuria by 57 % (24). Similarfindings have been reported for the AT1 receptor antagonistsirbesartan, eprosartan, and losartan, and results from animalexperimental studies indicate that reductions in proteinuria areassociated with marked reductions in glomerulosclerosisreflecting effective inhibition of growth stimulating propertiesof angiotensin II (97).
In general, it is expected that AT1 receptor antagonists areat least as effective if not superior to ACE inhibitors in arrest-ing the progression of renal disease. However, ongoing long-term prospective controlled trials will have to prove thisassumption.
The incidence of end-stage renal disease is steadily risingwhereas that for stroke or coronary heart disease is declining.Among identified risk factors diabetes and hypertension
account for more than two-third of the incidence rate ofchronic renal failure. Since treatment of both disorders can bereadily achieved, it remains a great challenge to reduce theincidence of disease related target organ damage. The benefitof antihypertensive therapy in preventing the progression ofrenal failure has been confirmed in several clinical studies andevidence has been raised that blood pressure lowering therapyshould exceed the classic target value of 140/90 mmHg inpatients with chronic renal failure. Independent of their bloodpressure lowering properties, antihypertensive agents vary intheir ability to slow down the progression of hypertensiverenal disease and this variation can be attributed to differentspecific nephroprotective effects. Thus, ACE inhibitors havebeen shown to exert superior, blood pressure unrelated,nephroprotective effects compared to conventional therapywith diuretics or b-blockers.
New antihypertensives, such as the AT1 receptor antago-nists, are expected to become an alternative to current treat-ment options. Promising experimental and clinical results withsurrogate parameters for progression of renal insufficiencysuggest that AT1 receptor antagonists are as effective as ACEinhibitors in slowing down the progression of chronic renalfailure. Whether the long-term use of AT1 receptor antagonistsconfers a similar benefit to that provided by ACE inhibitorsremains to be determined.
1. Anderton JL, Gill M, Nothgi A (1994)Renal hemodynamic effects of bunazosinand prazosin in mild to moderately hyper-tensive patients with normal to moderatelyimpaired renal function. Nephrol DialTransplant 9: 607612
2. Bakris GL, Barnhill BW, Sadler R (1992)Treatment of arterial hypertension in dia-betic humans: Importance of therapeuticselection. Kidney Int 41: 912919
3. Bakris GL, Williams B (1995) Angiotensinconverting enzyme inhibitors and calciumantagonists alone or combined: Does theprogression diabetic renal disease differ? JHypertens 13 (suppl. 2): S95101
4. Baylis C, Qiu C (1996) Importance of nitricoxide in the control of renal hemodyna-mics. Kidney Int 49: 17271731
5. Bech JN, Nielsen B, Pedersen B (1996)Effects of systemic NO synthesis inhibitionon RPF, GFR, UNa, and vasoactive hor-mones in healthy humans. Am J Physiol270: F845F851
6. Bigazzi R, Bianchi S, Campese VM, BaldariG (1992) Prevalence of microalbuminuriain a large population of patients with mildto moderate essential hypertension.Nephron 61 (1): 947
7. Bjrck S, Mulec H, Johnsen SA, Norden G,Aurell M (1992) Renal protective effect ofenalapril in diabetic nephropathy. BMJ304: 33943
8. Bohle A, Mackensen-Haen S, von Gise H(1987) Significance of tubulointerstitialchanges in the renal cortex for the excretoryfunction and concentration ability of thekidney: a morphometric contribution. Am JNephrol 7: 42133
9. Burnier M, Hagman M, Nussberger J,Biollaz J, Armagnac C, Brouard R, WaeberB, Brunner HR (1995) Short-term andsustained renal effects of angiotensin IIreceptor blockade in healthy subjects.Hypertension 25 (1): 602609
10. Burnier M, Roch-Ramel F, Brunner HR(1996) Renal effects of angiotensin IIreceptor blockade in normotensive sub-jects. Kidney Int 49 (6): 178790
11. Burnier M, Rutschmann B, Nussberger J,Versaggi J, Shahinfar S, Waeber B, BrunnerHR (1993) Salt-dependent renal effects ofan angiotensin II antagonist in healthy sub-jects. Hypertension 22: 339347
12. Carmines PK, Navar G (1989) Disparateeffect of Ca2+-channel blockade on afferentand efferent arteriolar responses to ANG II.Am J Physiol 256: F10151020
13. Castleman B, Smithwick RH (1943) Rela-tion of vascular disease to hypertensivestate based on study of renal biopsies from100 hypertensive patients. JAMA 121:12561261
14. Castleman B, Smithwick RH (1948) Rela-tion of vascular disease to hypertensivestate: Adequacy of renal biopsy as deter-mined from study of 500 patients. N Engl JMed 239: 729732
15. Cockcroft DW, Gault MH (1976) Pre-diction of creatinine clearance from serumcreatinine. Nephron 16: 3141
J. Jacobi and R. E. Schmieder 117Nephroprotection by antihypertensive therapy
16. Cole RB, Giangiacomo J, Ingelfinger JR,Robsa AU (1972) Measurement of renalfunction without urine collection. A criticalevaluation of the constant-infusion-technique for determination of inulin andpara-aminohippurate. N Engl J Med 287:11091114
17. Dworkin LC (1991) Effects of calciumantagonists on glomerular hemodynamicsand structure in experimental hypertension.Am J Kidney Dis 17 (suppl. 1): 8993
18. Dworkin LD, Benstein JA, Parker M,Tolbert E, Feiner HD (1993) Calciumantagonists and converting enzymeinhibitors reduce renal injury by differentmechanisms. Kidney Int 43: 808814
19. Eliahou HE, Cohen D, Hellberg B (1988)Effect of the calcium channel blocker nisol-dipine on the progression of chronic renalfailure in man. Am J Nephrol 8: 285
20. Epstein M (1996) The benefits of ACEinhibitors and calcium antagonists in slow-ing progressive renal failure: Focus onfixed-dose combination antihypertensivetherapy. Ren Fail 18 (6): 81332
21. Epstein M (1991) Calcium antagonists andthe kidney. Implications for renal protec-tion. Am J Hypertens 4 (suppl. 7): 482486
22. Erley CM, Bader B, Scheu M, Wolf S,Braun N, Risler T (1995) Renal hemody-namics in essential hypertensives treatedwith losartan. Clin Nephrol 43 (suppl 1):S811
23. Fauvel JP, Velon S, Berra N, Pozet N,Madonna O, Zech P, Laville M (1996)Effects of losartan on renal function inpatients with essential hypertension. JCardiovasc Pharmacol 28 (2): 25963
24. Forsblom C, Trenkwalder P, Dahl K,Mulder H for the MC Study Group (1997)Candesartan cilexetil, a novel angiotensinII antagonist reduces microalbuminuria inpatients with type II diabetes mellitus andmild hypertension. Am J Hypertens 10 (4):86A
25. Gansevoort RT, Sluiter WJ, HemmelderMH, de Zeeuw D, de Jong PE (1995)Antiproteinuric effect of blood-pressure-lowering agents: A meta analysis of com-parative trials. Nephrol Dial Transplant 10(11): 196374
26. Gansevoort RT, de Zeuuw D, de Jong PE(1994) Is the antiproteinuric effect of ACEinhibition mediated by interference in therenin-angiotensin system? Kidney Int 45(3): 861867
27. Gansevoort RT, de Zeeuw D, Shahinfar S,Redfield A, de Jong PE (1994) Effects ofthe angiotensin II antagonist losartan inhypertensive patients with renal disease. JHypertens 12 (suppl. 2): S3742
28. The GISEN Group (1997) Randomizedplacebo-controlled trial of effect of ramiprilon decline in glomerular filtration rate andrisk of terminal renal failure in proteinuric,non-diabetic nephropathy. Lancet, 349:1855763
29. Giordano M, Sanders LR, Castellino P,Canessa ML, de Fronzo RA (1996) Effectof alpha-adrenergic blockers, ACE inhi-bitors and calcium channel antagonists onrenal function in hypertensive non-insulin-dependent diabetic patients. Nephron 72(3): 44753
30. Goldberg AI, Dunlay MC, Sweet CS (1992)Safety and tolerability of losartan, anangiotensin II receptor antagonist, com-pared with hydrochlorothiazide, atenolol,felodipine ER, and angiotensin convertingenzyme inhibitors for the treatment ofsystemic hypertension. Am J Cardiol 75:793795
31. Gradman AH, Arcuri KE, Goldberg AI,Ikeda LS, Nelson NS, Snavely DB, SweetCS (1995) A randomized, placebo-con-trolled, double-blind parallel study of vari-ous doses of losartan potassium comparedwith enalapril maleate in patients withessential hypertension. Hypertension 25:13451350
32. Grekas D, Dioudis C, Kalevrosoglou I,Papoulidou F, Goutsaridis N, Alivanis P,Tourkantonis A (1995) Management ofmoderate to severe hypertension and pro-teinuria by nifedipine retard and perindoprilafter renal transplantation. Clin Nephrol 44(5): 299302
33. Guidelines Sub-Committee (1993) Guide-lines for the management of mild hyperten-sion: Memorandum from a World HealthOrganization/International Society ofHypertension meeting. J Hypertens 11:90518
34. Hall JE (1989) Intrarenal actions of con-verting enzyme inhibitors. Am J Hypertens2: 875884
35. Hannedouche T, Landais P, Goldfarb B, elEsper N, Fournier A, Godin M, Durand D,Chanard J, Mignon F, Suo JM (1994) Ran-domized controlled trial of enalapril andbeta-blockers in non-diabetic chronic renalfailure. BMJ 309: 8337
36. Higashi Y, Oshima T, Ozono R, MatsuuraH, Kajiyama G (1997) Aging and severityof hypertension attenuate endothelium-dependent renal vascular relaxation inhumans. Hypertension 30 (1): 252258
37. Higashi Y, Oshima T, Ozono R, WatanabeM, Matsuura H, Kajiyama G (1995) Effectsof L-arginine infusion on renal hemody-namics in patients with mild essentialhypertension. Hypertension 25 (2): 898902
38. Higashi Y, Oshima T, Sasaki N, Ishioka N,Nakano Y, Ozono R, Yoshimura M,Ishibashi K, Matsuura H, Kajiyama G(1997) Relationship between insulin resis-tance and endothelium-dependent vascularrelaxation in patients with essential hyper-tension. Hypertension 29 (2): 280285
39. Hilgers KF, Mann JF (1996) Role of angio-tensin II in glomerular injury: Lessons fromexperimental and clinical studies. KidneyBlood Press Res 19 (5): 25462
40. Himmelmann A, Hansson L, Hansson BG,Hedstrand H, Skogstrm K, hrvik J,Furngen A (1996) Long-term renal pre-servation in essential hypertension. Am JHypertens 9 (9): 850853
41. Hollenberg NK, Swartz SL, Passan DR,Williams GH (1979) Increased glomerularfiltration rate after converting enzyme inhi-bition in essential hypertension. N Engl JMed 301: 915
42. Ishimitsu T, Ono H, Ogawa Y, Tsukada H,Oka K, Yagi S (1994) Renoprotective effectof nisoldipine in rats with severe hyperten-sion. J Hypertens 12: 751759
43. Janssen WM, de Jong PE, de Zeuuw D(1996) Hypertension and renal disease;Role of microalbuminuria. J Hypertens 14(suppl. 5): 1737
44. Kamper AL, Strandgaard S, Leyssac PP(1992) Effect of enalapril on the progres-sion of chronic renal failure: A randomizedcontrolled trial. Am J Hypertens 5: 42330
45. Klag MJ, Whelton PK, Randall BL, NeatonJD, Brancati FL, Ford CE, Shulman NB,Stamler J (1996) Blood pressure and end-stage renal disease in men. N Engl J Med334: 138
46. Klahr S, Levey AS, Beck GJ, Caggiula AW,Hunsicker L, Kusek JW, Striker G (1994)The effects of dietary protein restriction andblood pressure control on the progressionof chronic renal disease. N Engl J Med 330:877884
47. Krusell JR, Jespersen LT, Christensen CK,Thomsen K, Pedersen OL (1997) Proximaltubular function in essential hypertensiveson beta-blocker therapy with atenolol.Blood Press 6 (3): 16670
48. Lahera V, Navarro-Cid J, Cachofeiro V,Garcia-Estan J, Ruilope LM (1997) Nitricoxide, the kidney, and hypertension. Am JHypertens 10: 129140
118 Basic Research in Cardiology, Vol. 93, Suppl. 2 (1998) Steinkopff Verlag 1998
49. Lewis EJ, Hunsicker LG, Bain RP, RohdeRD (1993) The effect of angiotensin-converting-enzyme inhibition on diabeticnephropathy. N Engl J Med 329: 145662
50. Lindeman RD, Tobin JD, Shock NW(1984) Association between blood pressureand rate of decline in renal function withage. Kidney Int 26: 8618
51. Ljungman S (1990) Microalbuminuria inessential hypertension. Am J Hypertens 3:956960
52. Lopes AA, Hornbuckle K, James SA, PortFK (1994) The joint effects of race and ageon the risk of end-stage renal diseaseattributed to hypertension. Am J KidneyDis 24 (4): 55460
53. Loutzenhiser R, Epstein M (1989) Therenal hemodynamic effects of calciumantagonists. In: Epstein M, Loutzenhiser R(eds) Calcium Antagonists and the Kidney.Philadelphia: Hanley & Belfus, pp 3373
54. Mackensen-Haen S, Haen M, Namhoffer J,Frotscher U, Klehr U, Bohle A (1988) Kor-relationen zwischen der glomerulren Fil-trationsrate sowie der Nierendurchblutung.Nieren Hochdruckkrankheiten 17: 4751
55. Maschio G, Alberti D, Janin G, Locatelli F,Mann JF, Motolese M, Ponticelli C, Ritz E,Zucchelli P (1996) Effect of the angio-tensin-converting-enzyme inhibitor bena-zepril on the progression of chronic renalinsufficiency. N Engl J Med 344: 93945
56. Messerli FH (1997) Complementaryactions and risk reduction: The rationale forcombination of an angiotensin convertingenzyme inhibitor with a non-dihydropyri-dine calcium antagonist. J Hypertens 15(suppl. 2): S35S38
57. Mimran A, Ribstein J (1994) Angiotensin-converting enzyme inhibitors versuscalcium antagonists in the progression ofrenal disease. Am J Hypertens 7 (9 part 2):S73S81
58. Mitch M, Buffington G, Lemann J, WalserM (1976) Progression of chronic renal fail-ure: A simple method of estimation. Lancetii: 13261331
59. Morales JM, Rodriguez-Paternina E,Araque A, Andres A, Hernandez E, RuilopeLM, Rodicio JL (1994) Long-term protec-tive effect of a calcium antagonist on renalfunction in hypertensive renal transplantpatients on cyclosporine therapy: A 5-yearprospective randomized study. TransplantProc 26 (5): 25989
60. Neumayer HH, Junge W, Kfner A, Wen-ning A (1989) Prevention of radiocontrast-media-induced nephrotoxicity by thecalcium channel blocker nitrendipine: Aprospective randomized clinical trial.Nephrol Dial Transplant 4: 10306
61. Neumayer HH, Kunzendorf U, SchreiberM (1992) Protective effects of calciumantagonists in human renal transplantation.Kidney Int 36 (suppl): S8793
62. Nielsen FS, Rossing P, Gall MA, Skott P,Schmidt UM, Parving HH (1997) Long-term effects of lisinopril and atenolol onkidney function in hypertensive NIDDMsubjects with diabetic nephropathy. Dia-betes 46 (7): 11828
63. Palatini P, Graniero GR, Mormino P,Mattarei M, Sanzuol F, Cignacco GB, Gre-gori S, Garavelli G, Pegoraro F, MaraglinoG, Bortolazzi A, Accurso V, Dorigatti F,Graniero F, Gelisio R, Businaro R, Vriz O,Dal Follo M, Camarotto A, Pessina AC(1996) Prevalence and clinical correlates ofmicroalbuminuria in stage I hypertension.Results from the Hypertension and Ambu-latory Recording Venetia Study (HAR-VEST Study). Am J Hypertens 9 (4 Pt 1):33441
64. Palmer RM, Ferrige AG, Moncada S (1987)Nitric oxide release accounts for thebiologic activity of endothelium-derivedrelaxing factor. Nature 327: 5246
65. Pedersen EB, Danielsen H, Spencer ES(1984) Effect of indapamide on renalplasma flow, glomerular filtration rate andarginine vasopressin in plasma in essentialhypertension. Eur J Clin Invest 26 (5):5437
66. Peterson JC, Adler SA, Burkart JM, GreeneT, Hebert LA, Hunsicker LG, King AJ,Klahr S, Massry SG, Seifter JL (1995)Blood pressure control, proteinuria, and theprogression of renal disease. The Modifica-tion of Diet in Renal Disease Study. AnnIntern Med 123: 754762
67. Pontremoli R, Cheli V, Sofia A, Tirotta A,Ravera M, Nicolella C, Ruello N, TomolilloC, Antonucci GC, Bessarione D (1995)Prevalence of micro- and macroalbumin-uria and their relationship with other car-diovascular risk factors in essential hyper-tension. Nephrol Dial Transplant 10 Suppl6: 69
68. Remuzzi G, Ruggenenti P, Benigni A(1997) Understanding the nature of renaldisease progression. Kidney Int 51 (1):215
69. Rodicio JL, Morales JM, Alcazar JM,Ruilope LM (1993) Calcium antagonistsand renal protection. J Hypertens 11 (suppl.1): S49S53
70. Romero C, Raij L, Granger JP (1987)Multiple effects of calcium entry blockerson renal function in hypertension. Hyper-tension 10: 140151
71. Rudd P, Blaschke TF (1985) Antihyperten-sive agents and the drug therapy of hyper-tension. In: Gilman AG, Goodman LS, RallTW, Murad F (eds) The PharmacologicalBasis of Therapeutics. 7th ed. New York:Mac Millan Publishing, pp 784804
72. Ruilope LM, Lahera V, Rodicio JL,Romero JC (1994) Participation of nitricoxide in the regulation of renal function:Possible role in the genesis of arterialhypertension. J Hypertens 12: 625631
73. Ruilope LM, Miranda B, Morales JM,Rodicio JL, Romero JC, Raij L (1989) Con-verting enzyme inhibition in chronic renalfailure. Am J Kidney Dis 13: 1206
74. Saruta T, Kanno Y, Hayashi K, Konishi K(1996) Antihypertensive agents and renalprotection: calcium channel blockers.Kidney Int 49 (suppl. 55): S52S56
75. Schmieder RE, Gatzka C, Schobel H,Schchinger H, Weihprecht H (1994) Renalhemodynamic response to stress is influ-enced by ACE-inhibitors. Clin Nephrol 42(6): 381388
76. Schmieder RE, Langenfeld MRW, GatzkaCD, Weidinger G, Schobel HP (1997)Impact of a- versus b-blockers on hyper-tensive target organ damage; results of adouble-blind, randomized, controlled clin-ical trial. Am J Hypertens 10: 985991
77. Schmieder RE, Messerli FH, de CarvalhoJG, Husserl FE (1987) Immediate hemody-namic response to furosemide in patientsundergoing chronic hemodialysis. Am JKidney Dis 9: 5559
78. Schmieder RE, Rockstroh J, Schreiber M,John S, Schlaich MP, Neumayer HH (1997)Prospective analysis of the value of 24 hourambulatory blood pressure on renal func-tion after kidney transplantation. J Am SocNephrol 8 (abstract): A3269
79. Shulman NB, Ford CE, Hall WD, BlaufoxMD, Simon D, Langford HG, SchneiderKA (1989) Prognostic value of serum crea-tinine and effect of treatment of hyperten-sion on renal function. Results from the theHypertension Detection and Follow-upProgram. Hypertension 13 (suppl I): 8093
80. Stefanski A, Amann K, Ritz E (1995) Toprevent progression: ACE inhibitors,calcium antagonists or both? Nephrol DialTransplant 10: 151153
81. Suki WN (1997) Use of diuretics in chronicrenal failure. Kidney Int 59 (suppl.): S3335
82. The sixth report of the Joint National Com-mittee on prevention, detection, evaluation,and treatment of high blood pressure (1997)Arch Intern Med 157: 24132446
83. Tolins JP, Raij L (1990) Comparison ofconverting enzyme inhibitor and calciumchannel blocker in hypertensive glomerularinjury. Hypertension 16: 452461
84. Townsend R, Ford V (1996) Ambulatoryblood pressure monitoring: Coming of agein nephrology. J Am Soc Nephrol 7:22792287
J. Jacobi and R. E. Schmieder 119Nephroprotection by antihypertensive therapy
85. U.S. Renal Data System, excerpts from theUSRDS 1997 annual data report (1997) AmJ Kidney Dis 2 (suppl. 1)
86. U.S. Renal Data System, USRDS 1997Annual Report. Bethesda, MD: US Dept. OfHealth and Human Services, National Insti-tute of Diabetes and Digestive and KidneyDisease; 1997
87. Vallance P, Leone A, Calver A, Collier J,Moncada S (1992) Accumulation of anendogenous inhibitor of nitric oxide synthe-sis in chronic renal failure. Lancet 339:5725
88. Verdecchia P, Porcellati C, Schillaci G, Bor-gioni C, Ciucci A, Battistelli M, GuerrieriM, Gatteschi C, Zampi I, Santucci A, San-tucci C, Reboldi G (1994) Ambulatoryblood pressure; an independent predictor ofprognosis in essential hypertension. Hyper-tension 24: 793801
89. Verdecchia P, Schillaci G, Guerrieri M,Gatteschi C, Benemio G, Boldrini F, Por-cellati C (1990) Circadian blood pressurechanges and left ventricular hypertrophy inessential hypertension. Circulation 81:528536
90. Walser M, Drew HH, La France ND (1989)Reciprocal creatinine slopes often giveerroneous estimates of progression ofchronic renal failure. Kidney Int 36(suppl.): S815
91. Weidmann P, Schneider M, Bhlen L(1995) Therapeutic efficacy of differentantihypertensive drugs in human diabeticnephropathy: An updated meta-analysis.Nephrol Dial Transplant 10 (suppl. 9):3945
92. Wilkinson R (1982) Beta-blockers andrenal function. Drugs 23: 195206
93. Wolzt M, Schmetterer L, Ferber W, ArtnerE, Mensik C, Eichler HG, Krejcy K (1997)Effect of nitric oxide synthase inhibition onrenal hemodynamics in humans: Reversalby L-arginine. Am J Physiol 272: F178F182
94. Yashiro A, Sugano M, Nakashima Y (1987)Effects of a new a1-blocker, bunazosinhydrochloride, on plasma lipid componentsin hypertensive patients with hypercholes-terinaemia. Clin Ther 10: 98106
95. Yoshino G, Kazumi T, Okada K (1989) Theeffect of bunazosin, a new a1-blocker, onplasma lipids in diabetic subjects withessential hypertension. Curr Ther Res 45:677683
96. Zanchi A, Brunner HR, Waeber B, BurnierM (1995) Renal hemodynamic and protec-tive effects of calcium antagonists in hyper-tension. J Hypertens 13: 13631375
97. Ziai F, Ots M, Provoost AP, Troy JL,Rennke HG, Brenner BM, Mackenzie HS(1996) The angiotensin receptor antagonistirbesartan reduces renal injury in experi-mental chronic renal failure. Kidney Int 57(suppl): 1326
98. Zucchelli P, Zuccala A, Gaggi R (1995)Comparison of the effects of ACEinhibitors and calcium channel blockers onthe progression of renal failure. NephrolDial Transplant 10 (suppl.9): 4651