Proceedings of the Fourth Genoa Meeting on Hypertension, Diabetes, and Renal Diseases
Importance of Blood Pressure Control in Chronic Kidney Disease
Maura Ravera,
Michela Re,
Luca Deferrari,
Simone Vettoretti and
Giacomo Deferrari
Division of Nephrology, Dialysis and Transplantation, Department of Internal Medicine, University of Genoa Department of Cardio-Nephrology Azienda Ospedaliera Universitaria San Martino, Genoa, Italy
Address correspondence to: Dr. Giacomo Deferrari, Division of Nephrology, Dialysis and Transplantation, Department of Internal Medicine, University of Genoa, Viale Benedetto XV 6, 16123 Genoa, Italy. Phone: +39-010-353-8959; Fax: +39-010-353-8959; E-mail: deferrar{at}unige.it
Arterial hypertension together with proteinuria is one of themost important factors associated with the progression of bothdiabetic and nondiabetic chronic kidney disease. In this review,the role of hypertension and proteinuria in renal disease progression,the BP target that should be achieved to slow the progressionof renal damage, and the influence of baseline and current proteinuriaon the renoprotective effects of antihypertensive therapy arediscussed thoroughly. The interaction between the renoprotectiveeffects of specific antihypertensive agents—mostly angiotensin-convertingenzyme inhibitors and angiotensin receptor blockers—andthe level of achieved BP also are evaluated. The body of evidenceprovided by several studies emphasizes the importance of bothlowering BP and inhibiting the renin-angiotensin system as specificgoals for renal and cardiovascular protection in chronic kidneydisease.
Chronic kidney disease (CKD) is a worldwide public health problem.In the United States, there is an increasing incidence and prevalenceof renal failure with poor outcome and high costs and an evenhigher prevalence of earlier stages of CKD (approximately 80times greater than ESRD prevalence). Moreover, CKD is associatedwith elevated cardiovascular morbidity and mortality (1). Therefore,strategies that are aimed at identifying, preventing, and treatingCKD and its related risk factors are needed.
In the following sections, we focus on the role of hypertensionand proteinuria as both independent and interdependent riskfactors for renal disease progression. We also discuss BP targetsthat should be achieved to slow the progression of renal damage,the influence of baseline and current proteinuria on the renoprotectiveeffects of antihypertensive therapy, and the interaction betweenthe renoprotective action of specific antihypertensive agents—mostlyangiotensin-converting enzyme inhibitors (ACE-I) and angiotensinreceptor blockers (ARB)—and the level of achieved BP.
Role of Hypertension and Proteinuria on the Progression of Renal Disease
High BP can be either a cause or a consequence of CKD. HighBP may develop early in the course of CKD and can be associatedwith adverse outcomes such as worsening renal function and developmentof cardiovascular disease. Hypertension is a major promoterof the decline in GFR in both diabetic and nondiabetic kidneydisease (2,3). Furthermore, large, observational, prospectivetrials in the general population showed that hypertension isa strong independent risk factor for ESRD. A strong relationshipwas observed between both systolic (SBP) and diastolic BP (DBP)and ESRD, regardless of other known risk factors, in men whowere recruited in the Multiple Risk Factor Intervention Trial.The relative risk (RR) for ESRD was >20-fold higher for patientswith stage 4 hypertension (SBP > 210 mmHg or DBP > 120mmHg) than for patients with optimal BP levels (SBP < 120mmHg and DBP < 80 mmHg) (4). The recent study by the OkinawaGeneral Health Maintenance Association confirmed these resultsin women as well (5).
Hypertension-related mechanisms that are involved in the progressionof renal damage include the systemic BP load, the degree towhich it is transmitted to the renal microvasculature (i.e.,renal autoregulation), and local susceptibility factors to barotrauma,which is the degree of damage for any degree of BP load. Amongthese last factors, proteinuria, glomerular hypertrophy, fibrogenicmediators, genetic factors, and age are the most important.Figure 1 shows the theoretical relationship between mean arterialpressure (MAP) and the changes in renal blood flow (RBF) and,hence, in the glomerular capillary pressure both in normal kidneysand in pathologic conditions (6). Under normal conditions, RBFvaries very little within a broad range of systemic MAP (80to 160 mmHg). Increases in BP within this range lead to vasoconstrictionof the glomerular afferent arteriole, thereby maintaining RBFand glomerular capillary pressure constant. As a protectiveadaptation, chronic hypertension tends to shift the curve tothe right. When MAP is >160 mmHg or when the autoregulatorymechanism is blunted as a result of renal disease, diabetes,high protein intake, dihydropyridine calcium channel blockers(CCB), we can expect an almost linear relationship between BPand capillary pressure. The increase in pressure load to thekidney vasculature results in a mechanical stretch of the glomerularcapillaries and mesangial cells, which induces a repair responsethat is mediated by fibrogenic cytokines and angiotensin II.Repetitive injuries and repairs can result in glomerulosclerosis,which is worsened further by local factors such as proteinuria(7).
Figure 1. Relationships between renal blood flow and systemic BP (6). AHT, arterial hypertension; DM, diabetes mellitus; RBF, renal blood flow; MAP, mean arterial pressure.
Proteinuria is a strong, independent promoter of the progressionof renal disease, as clearly demonstrated in nondiabetic renaldisease by the Modification of Diet in Renal Disease study (8).Data from a secondary analysis of the Irbesartan Diabetic NephropathyTrial (IDNT) confirmed that baseline proteinuria also is animportant risk factor for renal failure in patients with type2 diabetes and overt nephropathy. The cumulative incidence ofrenal failure at 3 yr was only 7.7% for patients with <1g of proteinuria, 11.4% for those with 1 to 2 g, 22.9% for thosewith 2 to 4 g, 34.3% for those with 4 to 8 g, and 64.9% forthose with >8 g. Doubling of proteinuria was associated withdoubling of the risk for renal end point (9).
The major pathogenetic determinants of proteinuria-induced progressionof renal damage are mesangial injury; the accumulation of filteredproteins in the lysosomes of proximal tubules, causing celldisruption and injury; the overexpression of proinflammatorycytokines and chemokines, growth factors, TGF-, and endothelinby injured tubular cells and interstitium, with consequent interstitialinfiltration of inflammatory cells and tubulointerstitial fibrosis;and the direct tubular toxicity of some proteins (e.g., complement,oxidized LDL, IGF-I, iron species) (10). In summary, hypertensionpromotes the progression of renal disease by worsening glomerularinjury and proteinuria, which in turn promote further glomerularand tubulointerstitial injury. As a consequence, a fall in GFRmay ensue.
Impact of Changes in BP and Proteinuria on Renal Outcome
Optimal BP control is the most important target that must beachieved to prevent adverse renal outcomes in patients withCKD. A recent meta-analysis (11) of 11 randomized, controlledtrials that included ACE-I arms evaluated the impact of currentSBP on renal outcome in 1860 patients with nondiabetic renaldisease. The lower risk for kidney disease progression was demonstratedfor current SBP that ranged from 110 to 129 mmHg. Higher levelsof SBP were associated with a steep increase in the RR, regardlessof the drug that was used. Compared with the reference range,achieved SBP <110 mmHg was associated with increased risk,and this is consistent with the negative renal effects of reducedkidney perfusion or the presence of pre-existing cardiovasculardisease (11). A study showed that in type 1 diabetes, regressionor remission of the clinical evidence of diabetic nephropathycould be achieved with the combination of intensive BP controland ACE-I treatment (12). Moreover, with regard to type 1 diabetes,a meta-analysis of nine longitudinal studies that involved variousantihypertensive drugs clearly showed that the achieved valuesof BP play an overwhelming role in determining the decline ofGFR. A four-fold reduction in the decline of GFR was observedfor mean BP levels <99 mmHg, regardless of the type of treatment(13). Last, in type 2 diabetes, as demonstrated by secondaryanalysis of the IDNT study, the risk for reaching a renal endpoint is reduced progressively and continuously at lower levelsof the achieved SBP. An optimal renoprotective effect was demonstratedfor SBP between 120 and 130 mmHg, with no further benefits below120 mmHg (Figure 2) (14). In summary, the reduction in BP ismarkedly renoprotective regardless of the type of drug thatis administered, in both diabetic and nondiabetic renal disease.SBP between 120 and 125 mmHg or MAP that ranged from 90 to 96mmHg seemed to be the optimal BP target for patients with CKD.
Figure 2. Impact of achieved systolic BP (SBP) on renal end point (doubling of serum creatinine or ESRD) in 1715 proteinuric patients with type 2 diabetes (14). ln, natural log.
The antiproteinuric effect of lowering BP is one of the mostimportant mechanisms involved in the renoprotection that isinduced by BP control. The Modification of Diet in Renal Diseasestudy showed that achieving low BP, even by using non-renin-angiotensinsystem (RAS) acting agents, markedly reduced proteinuria duringthe 3 yr of follow-up (8). Although ACE-I and ARB have beenshown to reduce proteinuria by 40 to 45% for similar BP reduction,proteinuria was 15 to 20% lower even in patients who were treatedwith different classes of drugs, including CCB, provided thata reduction in BP levels was achieved (9,15).
Proteinuria changes per se are an important risk factor forthe progression of renal disease. In type 2 diabetes, data fromthe Reduction of Endpoints in NIDDM with the Angiotensin IIAntagonist Losartan (RENAAL) trial showed that changes in albuminuriain the first 6 mo of therapy were roughly linearly related tothe degree of long-term renal protection: every 50% reductionin albuminuria in the first 6 mo was associated with a 45% reductionin the risk for ESRD during later follow-up (16). Furthermore,a secondary analysis of the IDNT study demonstrated that therisk for renal failure was reduced by more than half (hazardratio 0.44; P < 0.001) for each halving of proteinuria inthe first year of the study. The cumulative incidence of adverserenal outcome (doubling of serum creatinine or ESRD) at 3 yrfor patients with a >50% reduction in proteinuria was only9.6%, whereas for those with a reduction that ranged between0 and 50%, it was 26.2%. This compared with 34.5% for patientswith up to a 50% increase in proteinuria and 38% for those witha >50% increase (9).
Moreover, the renoprotective effect of lowering BP by antihypertensivetreatment is affected by baseline proteinuria and its changes(i.e., current proteinuria). In nondiabetic renal disease, greatervalues of baseline proteinuria were associated with greaterbenefit of achieving lower BP (8). In patients with baselineproteinuria >3 g/d, a steeper decline in GFR becomes apparentat 92 mmHg of mean BP, whereas for proteinuria between 0.25and 3 g/d, the decline increases at 98 mmHg. In nonproteinuricpatients, lowering mean BP to <107 mmHg does not seem toconfer any additional benefits in reducing the progression ofrenal disease (8). In the ACE Inhibition in Progressive RenalDisease meta-analysis, the relationship between current SBPand the risk for progression of renal disease markedly differedbetween patients with current proteinuria of 1 g/d or greaterand those whose proteinuria was <1 g. In patients with higherproteinuria, the optimal SBP ranged from 110 to 119 mmHg. Theadjusted risk for ESRD for these patients increased steeply,even for BP values above 120 mmHg, and was eight-fold higherfor SBP values of 160 mmHg or higher. By contrast, the adjustedrisk for renal failure in patients with lower levels of proteinuriaincreased two-fold only when SBP was 160 mmHg or greater. Last,the risk for ESRD increased when SBP was <110 mmHg, especiallyin proteinuric patients, therefore suggesting a J-curve behaviorof the relationship between BP and the progression of renaldisease (Figure 3) (11). In summary, the renoprotective effectof lower BP is actually evident in patients with higher proteinuria,thus providing additional support for recommending lower BPtargets for these patients.
On the basis of available studies, there is evidence showingthat ACE-I or ARB are more effective in slowing the progressionof renal disease than other classes of antihypertensive drugs.The ACE Inhibition in Progressive Renal Disease meta-analysis(17) of 11 randomized, controlled trials that compared the efficacyof antihypertensive regimens both with and without ACE-I innondiabetic renal disease showed that the use of this classof drugs was associated with lower risk for both ESRD and doublingserum creatinine. In the large cohort of hypertensive, microalbuminuricpatients with type 2 diabetes of the Microalbuminuria, Cardiovascular,and Renal Outcomes-Heart Outcomes Prevention Evaluation trial(18) and in two other, smaller studies (19,20), greater efficacywas demonstrated for ACE-I compared with other treatments inreducing the incidence of overt nephropathy. Furthermore, theIrbesartan in Patients with Type 2 Diabetes and Microalbuminuriastudy showed that treatment with the ARB irbesartan was muchmore effective than conventional therapy at both preventingthe development of clinical proteinuria and favoring regressionto normoalbuminuria in microalbuminuric patients with type 2diabetes, despite similar BP control (21). Adding ACE-I to theconventional therapy that was administered to patients withtype 1 diabetes and overt nephropathy significantly reducedboth the need for replacement therapy and the mortality rate(22). As far as patients with type 2 diabetes and overt nephropathyare concerned, two studies (IDNT and RENAAL) demonstrated thatARB (irbesartan or losartan) were more effective than conventionaltherapy or CCB in slowing the progression of nephropathy, regardlessof BP control (23,24). Moreover, secondary analysis of thesetwo large trials demonstrated that there was some interactionbetween the effect of the ARB and the levels of BP that wereachieved. With regard to the IDNT trial, a 33% reduction ofthe RR for reaching a renal end point was demonstrated for theirbesartan arm as compared with the combined amlodipine plusconventional therapy arms, regardless of the reduction of SBP.The RR for adverse renal outcomes in patients with SBP <134mmHg was actually significantly lower in patients who were treatedwith irbesartan than in the other two combined groups (RR 55%,P = 0.034). Lower SBP and irbesartan were independent (P = 0.61for interaction) and therefore additive (Figure 4) (14). Inthe RENAAL study, losartan induced a 28% RR reduction of reachinga renal end point as compared with usual care, beyond what wasachieved by lowering the BP. In patients with BP <140/90mmHg, the RR further decreased to 59% (25). In summary, optimallevels of BP tended to magnify the renoprotective effects ofARB in both trials.
Figure 4. Renal outcomes (doubling of serum creatinine or ESRD) as a function of both achieved SBP and treatments in proteinuric patients with type 2 diabetes (14). Ave, average.
An overwhelming body of evidence shows that arterial hypertensionin patients with CKD is associated with overactivity of thesympathetic nervous system (26–28). This activation isdue to afferent stimuli that arise from the diseased kidneysand lead to increased efferent sympathetic nerve activity. Moreover,sympathetic activity is associated with poor cardiovascularoutcomes, thus suggesting that reducing it might be beneficialto the patients. ACE-I and ARB are able to reduce but not tonormalize sympathetic hyperactivity in patients with CKD (29).Moxonidine is a selective imidazoline-I1 receptor agonist thatlowers BP by decreasing sympathetic nerve activity and therebyreducing peripheral resistance. Adding moxonidine to ARB inpatients with CKD has proved to be effective at significantlyreducing both MAP and sympathetic hyperactivity as comparedwith ARB administration alone (30). Moreover, moxonidine hasa renoprotective effect that goes beyond its effect on BP. Nonhypotensivedoses of moxonidine have been shown to reduce significantlyglomerulosclerosis and albuminuria in subtotally nephrectomizedrats (31). A total of 177 hypertensive patients that had advancedrenal failure and were being treated with RAS inhibitors plusloop diuretics were given moxonidine for 6 mo as add-on therapy.This seemed to be associated with a lower decline in GFR ascompared with adding nitrendipine. The renoprotective effectof moxonidine likely was independent of BP lowering, which waseven more pronounced in the nitrendipine group (32). Furthermore,nonhypotensive doses of moxonidine had an anti-albuminuric effecton 15 normotensive patients who had type 1 diabetes with microalbuminuriaand adequate glycemic control (33). Moreover, moxonidine mayelicit beneficial adaptations in the glucose and lipid metabolism(34), thereby possibly contributing to a reduction in the globalcardiovascular risk in patients with CKD.
Consistent with these results and according to the internationalguidelines, BP target values <130/80 mmHg for patients withCKD and <120/75 mmHg in patients with proteinuria 1 g/d noware being recommended, regardless of the type of antihypertensivedrug (1,35–37). Moreover, RAS-blocking agents are thestandard therapy for renoprotection in patients with diabeticand nondiabetic CKD (1,35–37). Last, with regard to sympathetichyperactivity, the use of the sympatholytic agent moxonidinein multidrug therapy seems to be a promising strategy in anattempt to achieve optimal BP levels in patients with CKD.
Furthermore, both lowering BP and inhibiting the RAS are specificgoals for cardiovascular protection in CKD. A recent meta-analysisshowed that lowering BP was the main target to reduce the incidenceof major cardiovascular events in hypertensive patients (38).With regard to patients with type 2 diabetic nephropathy, theIDNT trial showed a linear relationship between mortality andachieved SBP that ranged between 120 and 180 mmHg or more. However,patients whose SBP was <120 mmHg had higher mortality rates,which was possibly related to pre-existing cardiovascular disease(14,39). Moreover, consistent with the data from the HOPE study,treatment with ACE-I has been shown to reduce the high cardiovascularrisk in patients with mild renal insufficiency (40). However,BP control, especially SBP control, is very difficult to achievein renal patients (14,41,42). For instance, only 30% of thepatients in the IDNT trial achieved their target systolic goals,despite their using four antihypertensive agents, further confirminghow difficult it is to treat these high-risk patients (14).The percentage of patients with controlled BP is much lowerin the clinical practice setting (42–44).
In summary, BP levels markedly influence the renal outcomesof patients both with diabetic and with nondiabetic CKD, inparticular of the proteinuric ones. Accordingly, a "goal BP-oriented management" is mandatory for reno- and cardiovascularprotection. In addition, the use of RAS-blocking agents is stronglyrecommended owing to their renoprotective effect, which is magnifiedfurther by optimal BP control.
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Abstract
Introduction
, and endothelin by injured tubular cells and interstitium, with consequent interstitial infiltration of inflammatory cells and tubulointerstitial fibrosis; and the direct tubular toxicity of some proteins (e.g., complement, oxidized LDL, IGF-I, iron species) (10). In summary, hypertension promotes the progression of renal disease by worsening glomerular injury and proteinuria, which in turn promote further glomerular and tubulointerstitial injury. As a consequence, a fall in GFR may ensue. 
1 g/d now are being recommended, regardless of the type of antihypertensive drug (1,35–37). Moreover, RAS-blocking agents are the standard therapy for renoprotection in patients with diabetic and nondiabetic CKD (1,35–37). Last, with regard to sympathetic hyperactivity, the use of the sympatholytic agent moxonidine in multidrug therapy seems to be a promising strategy in an attempt to achieve optimal BP levels in patients with CKD. 
