Nephroprotection by antihypertensive therapy

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<ul><li><p>Basic Res Cardiol 93: Suppl. 2, 109119 (1998) Steinkopff Verlag 1998</p><p>J. JacobiR. E. Schmieder</p><p>Nephroprotection by antihypertensivetherapy</p><p>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</p><p>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. </p><p>Key words Hypertension kidney antihypertensives nephroprotection</p><p>R. E. Schmieder (Y) J. JacobiMedizinische Klinik IV/4University of Erlangen-NrnbergBreslauer Str. 201D-90471 Nrnberg, Germany</p><p>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</p><p>Introduction</p><p>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</p><p>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.</p><p>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).</p></li><li><p>110 Basic Research in Cardiology, Vol. 93, Suppl. 2 (1998) Steinkopff Verlag 1998</p><p>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. </p><p>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</p><p>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. </p><p>How to measure renal function in patients</p><p>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.</p><p>Renal histology</p><p>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.</p><p>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).</p></li><li><p>J. Jacobi and R. E. Schmieder 111Nephroprotection by antihypertensive therapy</p><p>Clearance methods</p><p>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.</p><p>Serum creatinine</p><p>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. </p><p>Proteinuria</p><p>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).</p><p>Prospective parameters</p><p>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).</p><p>How far should blood pressure be lowered</p><p>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).</p><p>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</p></li><li><p>112 Basic Research in Cardiology, Vol. 93, Suppl. 2 (1998) Steinkopff Verlag 1998</p><p>measurements during daytime. Furthermore, ambulatory 24-hour blood pressure profiles correlate more closely withhypertensive related organ damage than casual blood pressurereadings (84, 89).</p><p>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 &lt; 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).</p><p>Differential use of antihypertensive agents for nephroprotection</p><p>Diuretics</p><p>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.</p><p>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. </p><p>b-blockers</p><p>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-blo...</p></li></ul>