| Abstract|| |
Chronic kidney disease (CKD) is a major problem worldwide. It threatens the lives and health of many people and places severe financial burdens on health economies of even the wealthiest countries. It is clear that the approach to prevention is multifaceted including prevention of cardiovascular disease. Inhibitors of the RAS are the drugs of initial choice in preventing progressive CKD, and may be used cautiously in advanced renal insufficiency. In addition blood pressure must be optimally controlled to < 130/80 mm Hg. Treatment of late CKD results only in a risk reduction and not a prevention of end stage renal disease. It is vital that patients at risk for CKD should be identified early before overt renal damage. Screening for microalbuminuria in patients with hypertension, metabolic syndrome and diabetes is particularly important.
|How to cite this article:|
Rayner B. Importance of Modulating the Renin-Angiotensin System in Preventing Renal Complications of Hypertension. Saudi J Kidney Dis Transpl 2006;17:469-80
|How to cite this URL:|
Rayner B. Importance of Modulating the Renin-Angiotensin System in Preventing Renal Complications of Hypertension. Saudi J Kidney Dis Transpl [serial online] 2006 [cited 2022 Jan 18];17:469-80. Available from: https://www.sjkdt.org/text.asp?2006/17/4/469/32483
| Introduction|| |
End stage renal disease (ESRD) is a silent and growing epidemic worldwide that parallels the rising prevalence of type 2 diabetes, metabolic syndrome and hypertension. In theory this epidemic of CKD can be prevented or at least markedly reduced by early recognition of patients at risk for progressive kidney disease, which in the early phases is largely asymptomatic. It is therefore vital that all health professionals are aware of this problem, undertake active screening programs to identify patients at risk, and institute appropriate preventative strategies.
This review will consider the extent of the problem, briefly consider the interrelationship of cardiovascular and CKD, emphasize the importance of recognizing microalbuminuria especially in patients with diabetes and the metabolic syndrome, discuss the prevention of progressive renal disease with special focus on the renin-angiotensin system (RAS), and consider recent controversies in the prevention of CKD.
| Extent of the Problem|| |
Since 1980 the United States Renal Data System has recorded an exponential increase in the prevalence of ESRD, which is almost exclusively driven by growing numbers of patients with type 2 diabetic nephropathy and hypertensive nephrosclerosis.  The prevalence of chronic glomerulonephritis and cystic kidney disease has remained stable. Similar trends are anticipated in Saudi Arabia as 23.7% of the population has overt type 2 diabetes.  It is estimated hat in 2010 the global maintenance dialysis population will have risen to over 2 million and the 10 year medical costs will exceed 1,000 billion U.S. dollars.  Many more patients will die of cardiovascular complications before reaching ESRD because of the increased risk of cardiovascular (CVS) disease in this population.
Analysis of the NHANES III data showed that 10.1% of the US population has microalbuminuria and 1.1% overt albuminuria, which translates to over 20 million people with either overt nephropathy or at risk for CKD. 31.2% of people had an estimated GFR of between 60-90 ml/min and 4.7% a GFR below 60mls/min. 
| Interrelationship of Cardiovascular and Renal Disease|| |
The major risk factors for CVS disease and CKD are identical namely age, smoking, diabetes, hypertension, metabolic syndrome and obesity, and dyslipidemia. Microalbuminuria and estimated GFR < 60mls/min are independent predictors of adverse cardiovascular outcomes, and therefore it is increasingly recognized that strategies to prevent CVS disease also may prevent progressive CKD, and vice versa. It is an attractive hypothesis that microalbuminuria is the link as it predicts both CVS and renal outcomes.  As the glomerulus is essentially a specialized vascular bed, "leakiness" of the lining endothelial cells resulting in albuminuria may reflect generalized endothelial dysfunction. This is an attractive yet unproven hypothesis, but nevertheless a potentially modifiable risk factor to prevent both CVS and renal disease.
| Importance of Recognizing Micro-albuminuria and Metabolic Syndrome|| |
Microalbuminuria is generally defined as a urine albumin/creatinine ratio between 3-30 mg/mmol on a spot urine. Levels below this are normal and above this macroalbuminuria. Microalbuminuria predicts diabetic nephropathy, CVS events in diabetics, CVS events in large studies outcome studies (LIFE and HOPE), all cause and cardiovascular disease mortality in the general population (PREVEND Study and EPIC-Norfolk Study). ,,, NHANES III [Table - 1] showed that microalbuminuria is highly prevalent in people with type 2 diabetes, which increases with age.  However it is also evident that microalbuminuria occurs in people without diabetes, which also increases with age.
Further analysis of the NHANES III data gives us further clues to identify the patients at risk for CKD, who do not necessarily have diabetes mellitus. 21.8% of the U.S. population have metabolic syndrome as defined by the ATP III criteria [Table - 2],  and 12.8% of these have microalbuminuria. Hypertension had strongest association with microalbuminuria (OR in women 3.34 and men 2.51) . Chen et al showed that the risk of microalbuminuria and CKD was significant doseresponse relationship with increasing number of traits for the metabolic syndrome.  In addition the individual traits were independently associated with microalbuminuria and CKD in logistic regression analysis [Table - 3]. It is well established that hyperglycemia and hypertension cause CKD, but the independent associations of increased triglycerides, low HDL-Cholesterol and increased waist circumference raise important questions regarding the pathogenesis of CKD, and possible additional strategies besides blood pressure and glucose control to prevent CKD. This remains speculative, but clues to the potential importance of triglycerides and HDL-Cholesterol in CKD were demonstrated in the FIELD Study.  In this study fenofibrate was compared to placebo in the treatment of dyslipidemia in patients with type 2 diabetes. Fenofibrate acting through PPAR-α is known to reduce triglycerides and raise HDL-cholesterol. Although the overall results were disappointing in regard to CVS endpoints, it was associated with less albuminuria progression (p<0.002).
Kincaid-Smith writing in the Journal of Hypertension has similarly argued that analysis of the NHANES III data that obesity and insulin resistance play a major role in ESRD attributed to hypertension.  Similar to type-2 diabetes patients with metabolic syndrome and hypertension may undergo a phase of increased glomerular filtration rate (GFR) and raised intraglomerular pressure leading to structural changes and incipient nephropathy as evidence by microalbuminuria, which then progresses to overt albuminuria and declining GFR, and finally ESRD.
| The Critical Role of Angiotensin II in the Pathogenesis of CKD|| |
The RAS is often inappropriately activated in the kidney in patients with systemic hypertension, diabetes and renal disease, and plays a central role in the pathogenesis of CKD. The kidney is particularly vulnerable to the effects of the inappropriate activation of Angiotensin II (ANG II) through a variety of mechanisms. ANG II constricts the efferent arteriole resulting in an increase in glomerular pressure and loss of renal autoregulation. Glomerular hypertension is damaging to the kidney, particularly in the context of diabetes and hypertension, and leads to endothelial damage and progressive glomerulosclerosis. ANG II also increases glomerular permeability to albumin resulting in albuminuria and influx of macromolecules into the mesangium, and activates transforming growth factor (TGF)-(3 resulting in activation of fibroblasts, collagen deposition and scarring.  Activation of the RAS also plays a role in systemic hypertension, which contributes to renal damage in most forms of renal disease, especially in diabetes.  Albumin leaking from the glomerulus may also lead to tubular toxicity and chronic interstitial inflammation, which is often a better predictor of long term renal function.
In experimental models inhibition of the RAS results in renal protection in a variety of experimental forms of renal disease. For example Abrahamsen showed that spontaneously hypertensive stroke prone rats fed a high fat diet developed increasing proteinuria, expression of matrix protein of collagen I and III, stimulation of matrix protein fibronection, expression of TGF-β and PAI-1, proliferation, hyperplasia and necrosis of the arterial wall, and progressive glomerulosclerosis.  The ARB, eprosartan, in doses that produced a marginal reduction in blood pressure (BP), resulted in significant reduction in all these pathological changes.
| Clinical Strategy for the Prevention and Treatment of Renal Disease in Hypertensive Patients - Focus on the RAS|| |
This is clearly a multi-faceted that includes early identification of patients at risk for progressive kidney disease, treatment of the patients overall cardiovascular risk, control of systemic BP and inhibition of the RAS as summarized in [Table 4]. Full discussion of all theses issues is beyond the scope of this review, which will focus on the inhibition of the RAS. Most major guidelines recommend that BP in patients with CKD should be lowered to below 130/80, , and certain guidelines to below 125/75 if more than 1 gram of proteinuria present . 19 Either an ARB or ACE inhibitor is the preferred first choice. ,
1. Treatment of patients with type 2 diabetes and hypertension
Several studies show that inhibitors of the RAS (especially the ARBs) are effective in the prevention of progression of CKD in patients with type 2 diabetes. In patients with established diabetic nephropathy losartan compared to placebo (RENAAL) and irbesartan compared to either placebo or amlodipine (IDNT) was associated with significant a risk reduction in the composite end point of death, ESRD, and doubling of serum creatinine. ,
In patients with microalbuminuria and hypertension (or incipient nephropathy) the ARB, irbesartan, was associated with a significant risk reduction of progression to established overt albuminuria.  Of importance is that patients receiving 300mg irbesartan rather than 150mg had greater benefit.
The Benedict Trial studied patients with diabetes and hypertension without evidence of microalbuminuria.  The primary endpoint of the study was the progression to microalbuminuria. This was a 3 arm study comparing the ACE inhibitor, trandolopril, or trandolopril plus the calcium channel locker (CCB) varapamil or placebo. The BP goal was < 120/80. The progression to microalbuminuria was significantly delayed by trandolopril, but not by verapamil or placebo for comparable BP control.
Although all these studies show positive benefits for both ACE inhibitors and ARBs, there was only a risk reduction. In RENAAL and IDNT the majority of patients still progressed to ESRD, , and in IRMA2 only 34% of patients had normalization of microalbuminuria.  In the Benedict study approximately 7% of patients progressed to microalbuminuria despite trandolopril.  This suggest that earlier intervention is warranted particularly in patient with metabolic syndrome before overt diabetes develops, and that a more comprehensive strategy especially including optimal diabetic control should be implemented.
2. Patients with hypertension and CKD
There is surprisingly little data on the progression of kidney disease in patients with hypertensive nephrosclerosis. The African American Study of Kidney Disease (AASK) examined this issue because of the high incidence of CKD due to hypertension in African Americans. Carefully selected patients with hypertensive nephrosclerosis were randomized to either the ACE inhibitor (ramipril) or the CCB (amlodipine) or the beta blocker (metoprolol) plus intensive or routine BP control.  The study demonstrated that ramipril compared to amlodipine had a greater reduction in renal endpoints. There was a 44% reduction in ESRD (p=0.01) and a 31% non-significant reduction in death in favor of ramipril. Ramipril had most effective in patients with a urinary protein/creatinine ratio > 0.22. Intensive BP control was not associated with further benefit.
3. Patients with hypertension
No major hypertension study has examined progression of renal disease as a primary endpoint. In the ALLHAT study involving over 42,000 high risk hypertensive patients chlorthalidone was compared to doxazosin, amlodipine or lisinopril.  The primary endpoint was cardiovascular, but renal outcomes (reciprocal serum creatinine, ESRD, estimated GFR) were part of the secondary outcomes. No difference in renal outcomes was demonstrated between the treatment arms although the difference in control of BP between the diuretic and ACE inhibitor arm made interpretation of the study difficult.
In the ASCOT-Blood Lowering Arm high risk hypertensive patients were assigned to either amlodipine (5-10mg) adding perindopril (4-8mg) as required (amlodipine-based regimen, n = 9639) or atenolol 50-100mg adding bendroflumethiazide 1.25-2.5mg and potassium as required (atenolol-based regimen, n=9618).  Development of renal impairment was examined as a tertiary endpoint, and there was a 15% reduction (p=0.018) in favor of the amlodipinebased regimen. The reasons for the difference in renal outcomes were not established, but could have been partly due to small BP differences in favor of the amlodipine arm, the favorable effects of the ACE inhibitor on renal function, or even the deleterious effects of the beta blocker/ diuretic combination.
In the LIFE study atenolol-based therapy was compared to losartan based therapy in hypertensive patients with left ventricular hypertrophy based on ECG criteria.  The effects of microalbuminuria were examined in the study. Firstly increasing deciles of albumin/creatinine ratio at baseline predicted CVS events, and this occurred at levels of albumin/creatinine ratios well below the traditional values for microalbuminuria (3-30 mg/mmol). A decile of albumin/creatinine ratio between 1.28-1.88 mg/mmol was associated with an almost doubling events compared with the first decile below <0.26 mg/mmol. Secondarily losartan compared to atenolol was associated with a more significant reduction in albumin/creatinine ratio, and it was predicted that about 20% of the favorable effects in the study may have been accounted by these changes.
The MARPLE study was a prospective controlled multi-centre study of 3529 of essential hypertension without diabetes using ramipril based treatment.  The objective was to evaluate the impact of microalbuminuria and tubular proteinuria on CVS morbidity and mortality, and to assess if normalization with ramipril improves outcomes. Tubular proteinuria, microalbuminuria, tubular proteinuria and microalbuminuria, and macroalbuminuria was associated with a 20.4, 27.4, 64, and 74.4% increase in CVS events respectively when compared to normal values. Ramipril therapy was associated with about a 30% normalization of microalbuminuria and tubular proteinuria, and a 10% normalization of macroalbuminuria. However 25.1% had progression from normal to pathological levels. In treatment reduction in microalbuminuria or tubular proteinuria suggested a trend for reduction in cerebrovascular events.
4. ACE inhibitor versus ARB
From a theoretical perspective ARBs should offer greater renal protection than an ACE inhibitor because of better blockade of the RAS. Firstly the production of ANG II is never be fully inhibited by ACE inhibitors because inhibition of the ACE is competitive. Negative feedback results in increased production of Angiotensin I, and ANG II levels increase towards baseline over time despite continued BP control.  Secondly ACE inhibitors can not inhibit non-ACE generation of ANG II, which may be as high as 50%. On the other hand ARBs block the angiotensin type 1 receptor fully, and this blockade can not be generally overcome by negative feedback. Additionally ARBs block ANG II produced from non-ACE pathways.
Several elegant clinical studies have demonstrated this phenomomen. Fifteen healthy men aged 24 - 48 years admitted to metabolic ward and given an ultra low dose sodium diet (10 mmol/day) to stimulate the RAS.  In response to ARB the renal blood flow increased by 140 ml/min, whereas with an ACE inhibitor renal blood flow increased by 80 ml/min. This difference represents nonACE generation of ANG II and incomplete inhibition of the RAS by ACE inhibitors. Similarly in a study in patients the renal blood flow response after L-NMMA in patients treated for 9 weeks with either telmisartan or ramipril was examined in patients with diabetic nephropathy.  The percentage change from baseline in the ramipril group was 43% and 60% in the telmisartan group.
Very few data is available comparing the effects of ACE inhibition vs. ARBs in patients with nephropathy. In the DETAIL study telmisartan was compared to enalapril in patients with early diabetic nephropathy with both micro and microalbuminuria.  GFR decline was no different between the 2 groups, but definitive conclusions on the relative efficacy of each agent were marred by 30% drop out rate in both groups.
5. Combination therapy with both ACE inhibitors and ARBs
The idea that both ACE inhibitors and ARBs should be combined in patients with renal disease makes some degree of sense by providing more complete inhibition of the RAS.
There are a few trials that support this concept. In the CALM study patients with type 2 diabetes mellitus and microalbuminuria were randomized to candesartan 16 mg or lisinopril 20 mg daily or the combination of both agents.  Both candesartan and lisinopril lowered BP and reduced microalbuminuria, but the combination resulted in a further significant reduction in BP and microalbuminuria. In the COOPERATE study patients with CKD without diabetes were randomized to either losartan or trandolopril or their combination.  The primary end point of the study was doubling of serum creatinine or ESRD. The progression to the primary end point was similar between trandolopril and losartan, but the combination resulted in a significant risk reduction of progression of CKD (p=0.18).
These studies suggest the combination of ARBs and ACE inhibitors may be beneficial. However it is no completely determined if these effects are independent of BP or if the dose of the ARB or ACE inhibitor was sufficiently high to appropriately inhibit the RAS before the combination.
6. Do very high doses of inhibitors of the RAS provide additional protection?
The IRMA2 study demonstrated that irbesartan 300mg daily provided superior protection against protection to overt nephropathy in patients with type 2 diabetes and microalbuminuria.  Parving and colleagues examined if irbesartan titrated to 900mg would provide even greater protection to the kidney.  Patients with type 2 diabetes,, hypertension and microalbuminuria were studied. After a wash out period bendroflumethiazide was added to control BP. Patients were then randomized to irbesartan 300, 600, 900mg daily, and underwent ambulatory BP monitoring and testing for microalbuminuria at baseline and after 8 weeks. BP reduction was almost identical between the 3 groups based on ambulatory BP monitoring. Irbesartan 300 mg reduced albumin excretion by 52%, 600 mg by 47% and 900mg by 59%. The difference between 300m and 900mg was significantly different (p=0.01).
7. What about aldosterone antagonists?
Both ACE inhibitors and ARBs do not fully suppress aldosterone levels, and increasing laboratory and clinical evidence suggests that aldosterone may have effects beyond sodium retention and potassium excretion. In rats, chronic treatment with aldosterone results in severe proteinuria and renal injury, characterized by glomerular changes, tubulointerstitial fibrosis, and collagen accumulation. Treatment with eplerenone has been shown to ameliorate renal injury. 
In patients with hypertension aldosterone antagonists show preliminary renoprotective effects. In a study involving 499 patients with stage 1-2 hypertension were randomized to enalapril or eplerenone for 6 months. BP reduction virtually identical, but there was a 61.5% reduction in albuminuria with eplerenone vs. 25.7% with enalapril (p=0.01).  In another study 269 patients with isolated systolic hypertension were randomized to amlodipine or eplerenone.  BP reduction was -20.5/4.4 mm Hg for eplerenone vs. -20.1/6.9 mm Hg for amlodipine, but the urinary albumin/ creatinine ratio was reduced 52% by eplerenone and 10% by amlodipine (p=0.04).
8. Can inhibitors of the RAS be used in advanced chronic renal insufficiency?
Many practitioners avoid inhibitors of the RAS in advanced chronic renal insufficiency because of concerns about hyperkalemia and deterioration in renal function. The JNC 6 recommended that these antihypertensives be used with caution in patients with serum creatinine > 2.5mg/dl (>220µmol/L).  In a recent study patients with stable non-diabetic CKD not having received an ACE inhibitor or ARB 6 weeks prior to entry were enrolled in a study if they met the following inclusion criteria: serum creatinine 1.5 - 5 mg/dl (132- 440 µmol/L) and persistent proteinuria > 300mg/24 hours for at least 3 months prior to entry.  Patients were divided into 2 groups based on serum creatinine. Group 1 had a serum creatinine between 1.5 - 3 mg/dl (132 -264 µmol/L), and group 2 between 3.1-5 mg/ dl (265 - 490 µmol/L). All group 1 patients received benazepril 10 mg twice daily, and group 2 either placebo or benazepril 10mg twice daily. The primary end point was a composite of doubling of serum creatinine, ESRD or death. After a mean of 3.4 years 41% of patients receiving benazepril reached the primary end point and 60% of the placebo (p=0.0004). In group 1 only 20% of the patients reached the primary end point (p=0.003 vs. Group 2). Hyperkalemia (serum potassium > 6 mmol/L) was seen in 5% of patients (11 patients), of whom 8 could be successfully continued with dietary modification and the other 3 withdrew from the study.
It was concluded that benazepril is safe and beneficial to patients with advanced renal insufficiency due to non-diabetic CKD provided serum potassium and renal function is carefully monitored. However caution must be exercised in applying this data to patients with type 2 diabetic nephropathy because of the higher propensity to hyperkalemia related to hyporeninemic hypoaldosterism. However in the authors experience hyperkalemia can usually be controlled with diet, increased use of diuretics and ion exchange resins with continued use of ACE inhibitors or ARBs.
| Recent Controversies Regarding Inhibitors of the RAS|| |
Recently Strippoli et al published a metaanalysis of diabetic nephropathy studies showing that while both ACE inhibitors and ARBs reduce renal end points, ARBs did not reduce mortality.  These results must be treated with considerable circumspection for the following reasons. There was an inherent flaw in the meta-analysis that has been missed by most commentators. The reason that a composite endpoint of death, doubling serum creatinine and ESRD are used in clinical trials is because the individual endpoints may be influenced by differing criteria and timing of institution of dialysis that may differ between centers, or even the unavailability or restrictive dialysis policies in certain countries. Thus patients left for longer periods with more advanced renal failure waiting for dialysis may have increased chance of death, whilst patients started early on dialysis have greater chance of reaching the renal endpoint rather than death. Furthermore the major divers of the results were the Micro-Hope study,  the Lewis Study,  RENAAL  and IDNT. 
The inclusion of the Micro-Hope data that strongly favors ACE inhibitors for mortality outcomes is extremely interesting as the majority of patients did not have diabetic nephropathy, and is therefore highly likely to have more mortality events rather than ESRD. Furthermore the patients in the Lewis study were all type I diabetes, whereas the Micro-Hope, RENAAL and IDNT were almost exclusively type 2 diabetes, making mortality comparisons between the studies difficult.
Casas et al undertook a meta-analysis that purported to show that both ACE inhibitors and ARBs did not conclusively show renoprotective effects beyond BP control.  Their analysis suggested that control of BP was more important than use of RAS inhibitors. Careful analysis of their data showed that indeed there was significant 13% reduction of ESRD by inhibitors of the RAS, but Casas et al argued that this benefit was seen more in smaller studies but not larger studies suggesting a bias in reporting. Secondly the analysis suggested that most benefits from inhibitors of the RAS, was seen in studies where BP differences were greatest. Again there were several important problems in their analysis. Firstly the separation of ESRD from the composite endpoint as discussed above is problematical. Secondly the inclusion of ALLHAT study, which was a major driver of their results because of its sheer size, creates difficulties, because most of the participants would have had normal or slightly impaired renal function.  The length of time to reach renal endpoints would have been beyond the short duration of this study. Thirdly Casas does not explain the problem that when BP favored conventional therapy there was no evidence of a reduction of the relative risk of ESRD.
| Conclusions|| |
CKD is a major problem worldwide. It threatens the lives and health of many people and places severe financial burdens on health economies of even the wealthiest countries. It is clear that the approach to prevention is multifaceted including prevention of CVS disease. Inhibitors of the RAS (despite recent controversies) are the drugs of choice in preventing progressive CKD in addition to achieving optimal BP control (< 130/80 mm Hg). Treatment of late CKD results only in a risk reduction and not a prevention of ESRD. It is vital that patients at risk for CKD should be identified early before overt renal damage. Screening for microalbuminuria in patients with hypertension and metabolic syndrome is particularly important.
ARBs and ACE inhibitors show evidence for renal protection in clinical studies, but given that ANG II is a major driver of progression of CKD and that ARBs provide more complete inhibition of the RAS, they should be the preferred initial therapy for patients at risk or with established kidney disease. Both BP and albuminuria must be targeted. If albuminuria does not normalize, the addition of either an ACE inhibitor or aldosterone or both with careful attention to the serum potassium should be considered although definitive data is lacking in large outcome studies. It is not recommended at present that ARBs should be titrated to ultra high doses. If BP targets are still not reached additional antihypertensives like sympatholytics (e.g. moxonidine), CCBs and diuretics should be considered.
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E13 Groote Schuur Hospital, Observatory 7925, Cape Town
[Figure - 1]
[Table - 1], [Table - 2], [Table - 3]