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Renin and Blood Pressure Regulation: Protecting the Kidney and the Heart

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

39th Annual Meeting and Scientific Exhibition of the American Society of Nephrology

San Diego, California / November 14-19, 2006

Blood pressure (BP) and diabetic kidney disease are closely related, as Dr. Hans-Henrik Parving, Steno Diabetes Center, Gentofte, Denmark, observed, as BP is an important risk factor for the development of diabetic kidney disease and end-stage renal disease (ESRD). “Lowering the BP is important if you want to protect the kidney,” he confirmed. As Dr. Parving went on to debate, how BP is lowered matters in terms of how well the kidney is protected, although it is still important to aggressively treat BP to preserve kidney function, he conceded.

In Dr. Parving’s opinion, microalbuminuria is a powerful predictor of kidney disease and is not, as others have argued, solely a marker of cardiovascular (CV) disease. Affirming the use of antihypertensive agents that block the renin-angiotensin system (RAS), Dr. Parving cited a study in which Ruggenenti et al. (N Engl J Med 2004;351:1941-51) compared the cumulative incidence of microalbuminuria in hypertensive patients with normal levels of albumin at baseline.

After 48 months of treatment with placebo, trandolapril or verapamil, the cumulative risk of developing microalbuminuria was approximately 50% lower in patients treated with the ACE inhibitor compared with the other two treatment groups. Moreover, verapamil did not reduce the cumulative incidence of microalbuminuria compared with placebo over the same 48-month study, even though BP was lower in patients receiving verapamil.

In a meta-analysis by Chaturvedi et al. involving type 1 diabetic patients with microalbuminuria who received treatment with an ACE inhibitor (Ann Intern Med 2001;134:370-9), results showed that RAS blockade with an ACE inhibitor reduced progression to nephropathy by 62% and urinary albumin excretion by 50% at two years, more frequently induced remission to normoalbuminuria, and helped preserve the glomerular filtration rate (GFR).

“More importantly, based on a study lasting more than eight years, we can continue to preserve the GFR [in type 1 diabetic patients] with these compounds,” Dr. Parving added. Findings from the IRMA (Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria) trial showed that blocking the RAS with high doses of an angiotensin II receptor blocker (ARB) reduced the risk of progressing from microalbuminuria to overt diabetic nephropathy by almost 70% over 24 months compared with a conventional BP-lowering regimen. Across the entire course of the study, BP control was notably identical in both treatment arms. Any additional benefit from RAS inhibition was not due to early or late differences in BP control between the two groups, as Dr. Parving emphasized. In contrast, lower doses of the same ARB were associated with only a 40% relative risk reduction in the primary end point, suggesting that dosing is key to providing optimal renoprotective benefits.

The same positive benefit of blocking the RAS with different ARBs was again demonstrated in patients with overt diabetic nephropathy in both IDNT (Irbesartan Diabetic Nephropathy Trial) and in RENAAL (Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan Study), where the primary composite end point, including doubling of serum creatinine, ESRD or death, was at least 20% lower in patients receiving an ARB compared with those treated with non-RAS-blocking agents. Historically, if patients with type 2 diabetes and proteinuria receive no treatment, their rate of renal disease progression is around 10 mL/min/year. Results from IDNT and RENAAL both showed that good BP control with any antihypertensive agent reduced the rate of decline to approximately 6.5 mL/min/year. Inclusion of an ARB in the treatment regimen further reduced the rate of decline to between 4.4 and 5.5 mL/min/year, depending on the agent used.

In another study by Schmieder et al. (J Am Soc Nephrol 2005;16:3038-45), patients with normal or mildly impaired renal function and a protein excretion rate of 1 to 10 g/day received candesartan, titrated up to either 32 or 64 mg/day for 12 weeks, followed by another four weeks of lower-dose candesartan 16 mg/day. After 12 weeks of double-blind treatment, proteinuria was reduced from 2.54 to 1.42 g/day in the 64-mg group, but no significant change in proteinuria was observed in the 32-mg group. Once candesartan had been downtitrated to 16 mg, proteinuria increased again to 2.38 g/day in the 64-mg group and remained unchanged in the 32-mg group. These data suggest that there are additional antiproteinuric effects of ultra-high-dose candesartan compared with the standard dose.

“Blocking RAS with an ARB gives you added benefit for protection of the kidney,” Dr. Parving concluded, adding that while BP undoubtedly needs to be treated aggressively to postpone renal failure and prolong life, “you have to use an ACE inhibitor or an ARB to get the full benefit.”

Dr. George Bakris, Professor of Medicine, University of Chicago, Illinois, argued that renal protection is more a matter of achieving early and sustained BP control and less about RAS blockade, at least in patients with earlier-stage chronic kidney disease (CKD). He cited the Appropriate Blood Pressure Control in Diabetes trial, which failed to demonstrate an advantage of RAS blockade on either renal or CV outcomes in patients whose average GFR was generally above 80 mL/min.

In the meta-analysis by Cases et al. (Lancet 2005; 366:2026-33) cited by Dr. Bakris, investigators again failed to show a benefit of RAS blockade in patients where the mean GFR was 74 mL/min. Nevertheless, for patients with proteinuric CKD—regardless of the level of GFR—RAS blockade is unquestionably associated with a reduced risk of progressing to ESRD, Dr. Bakris conceded.

“Patients with proteinuria or albuminuria do better on an ACE inhibitor or an ARB, so for these patients, there is no question, you need an ACE inhibitor or an ARB as part of your cocktail,” he told listeners. He added, however, that it is “irrelevant” which antihypertensive drugs are used in patients with stage I to III CKD (GFR 50 to 60 mL/min) with either normal levels of albumin or microalbuminuria.

Maximal-dose ARB

Japanese investigators sought to establish whether maximal-dose candesartan can precipitate additional reductions in proteinuria in patients with renal disease and extend renoprotection in patients with CKD stage IV (mean creatinine 2.5 mg/dL). In this analysis, seven patients (group 1) who had been started on losartan 50 mg or valsartan 80 mg, and after one to two months of therapy, changed their medication to candesartan 12 mg/day. In nine patients (group 2), the previous dose of candesartan was increased to 12 mg/day at the same time point (in Japanese patients, the maximal dose of candesartan is 12 mg/day).

As reported by Dr. Hiroyuki Matsushima, Kobe West City Hospital, Japan, and colleagues, at the end of 1.5 years, all patients had become normotensive (BP 130/70 mm Hg). Urinary protein excretion was also reduced by 35% at the same study end point, and patients in group 2 in particular had evidence of preserved renal function (creatinine 2 mg/dL, blood urea nitrogen [BUN] 30 mg/dL). Investigators concluded that increasing the ARB dose to the maximal recommended dose of 12 mg/day in Japan could confer “substantial” renal benefits in patients with advanced chronic renal insufficiency.

At least part of the renoprotective benefits seen in association with ARB therapy in general and high-dose candesartan in particular may be explained by its effect on inflammation and injury. As discussed by Dr. Chen Yu, Brown University School of Medicine, Providence, Rhode Island, the greater renoprotective effects from higher than usual doses of ARBs may result from more complete inhibition of the AT1 receptors.

The purpose of her study was to examine the anti-inflammatory effects of high-dose candesartan on the progression of experimental CKD in vivo and on pro-inflammatory responses in human kidney proximal tubule epithelial cells in vitro.

Spontaneously hypertensive rats underwent unilateral nephrectomy. They were assigned to one of four groups: the control arm; the standard-dose arm (candesartan 5 mg/kg/day); the high-dose group (25 mg/kg/day); or the ultra-high-dose cohort (75 mg/kg/day).

Fourteen months after surgery, investigators observed “very pronounced effects” with both high and ultra-high doses of candesartan on suppression of renal inflammation and amelioration of renal fibrosis.

Cardioprotective Benefits in Hemodialysis

Up to half of all ESRD deaths are caused by CV disease, most commonly arising from left ventricular (LV) hypertrophy (LVH) and associated arrhythmias and sudden cardiac death. Reducing LVH therefore has the potential to be life-saving in this vulnerable patient group. According to Dr. Hannelore Hampl, KFH Kidney Center, Charlottenburg, Berlin, Germany, hemodialysis patients, especially those with diabetes, are in great need of optimal cardioprotection. She and co-investigators sought to assess the effect of both optimal medical therapy (metoprolol 190 mg, ramipril 10 mg and candesartan 32 mg) together with correction of anemia (hemoglobin target of 13.5 to 14.5 g/dL) on LVH regression in 268 non-diabetic hemodialysis patients and in 80 with diabetes.

Results showed that treatment led to a significant regression in the LV mass index in approximately 75% of non-diabetic hemodialysis patients at a mean follow-up of 5.4 years and in approximately 60% of those with diabetes, at a mean follow-up of 28 months. “Our data show that therapy with beta blockers and ACE inhibitors, given in combination with an ARB, to target dosages and anemia correction to normal values is successful and safe and leads to a significant improvement in cardiac function in hemodialysis patients,” investigators concluded.

Researchers at the Yokohama City University School of Medicine, Japan, assessed whether an ARB might be cardioprotective in patients on continuous ambulatory peritoneal dialysis (CAPD). Thirteen patients, average duration of CAPD of 3.4 years, with a baseline BP of 159.5/91.1 mm Hg, were treated with either valsartan 40 mg/day or candesartan 4 mg/day, plus or minus other antihypertensive agents, for six months. At the end of the six-month treatment interval, BP had dropped to 145/79 mm Hg. Subsequent analyses revealed that the ARBs did not affect heart rate, body weight, CAPD output, residual urine volume, hematocrit, erythropoietin doses, BUN, serum albumin, creatinine or potassium. The BP-lowering effect seen with different ARB regimens was accompanied by concomitant improvements in plasma ANP (220 to 127 pg/mL) and plasma BNP (492 to 324 pg/mL), changes in both markers being significant. Based on these findings, researchers felt that the ARBs are safe and effective in the control of BP in ESRD patients on CAPD and that they may improve LV dysfunction which is often present in these patients.

Another important study reported by Dr. Yoshihiko Kanno, Saitama Medical School, Iruma, Japan, was designed to evaluate whether treatment with an ARB could prevent or reduce the risk of CV disease events in patients on hemodialysis. (As has been well established, renal function is closely associated with CV disease risk and even minor renal abnormalities increase the risk of CV disease, target-organ damage and death.) A total of 360 patients who had received hemodialysis for more than three years but for less than five years were enrolled in the study. Half were randomized to treatment with an ARB—valsartan, candesartan or losartan—at starting doses 50% lower than those used in the West. The other 180 patients did not receive treatment with an ARB. Weekly dialysis times ranged from 12 to 16 hours in the group overall and hemoglobin levels were maintained at approximately 10 g/dL. At the end of three years of treatment, patients treated with an ARB were significantly less likely to experience a CV disease end point, including myocardial infarction, stroke or congestive heart failure, compared with the non-ARB controls, especially patients with diabetes. Specifically, at study end, 18% of patients receiving an ARB had experienced either a fatal or non-fatal CV disease event, compared with 28% of those who had not received an ARB.

Research presented by Dr. Yudai Kitamura, Minami-Tama Hospital, Tokyo, Japan, also suggests that the vasoprotective properties seen with the ARBs may arise from their effect on pulse-wave velocity and stromelysin-1 levels, a matrix metalloprotease-3 (MMP-3). After one year of treatment with candesartan, serum markers of synthesis and degradation of extracellular matrix were significantly altered.

Pulse-wave velocity values were significantly reduced compared with baseline values, whereas levels of the MMP-3 were significantly lower than baseline. Patients with the greatest change in pulse-wave velocity also had the greatest changes in stromelysin-1.

“Some consider this MMP-3 to be a kind of master switch for activation of the MMP cascade,” Dr. Kitamura observed, “and the changes in extracellular matrix synthesis and degradation we saw after one year of treatment with an ARB could be involved in amelioration of vascular stiffness and play a possible role in the vasoprotective actions of the ARBs.”

Summary

Experts continue to debate whether RAS inhibition offers additional vasoprotective benefits in patients at risk for kidney disease and its progression. In reality, that debate becomes irrelevant in light of the fact that most high-risk patients, and certainly those with either diabetes or diabetic kidney disease, typically require three or four antihypertensive agents to achieve the new more aggressive BP targets. As effective and well-tolerated antihypertensive agents, ACE inhibitors and ARBs are logical choices for inclusion in the antihypertensive strategy for any patient requiring aggressive BP control but especially when kidney disease is more advanced. Whether ultra-high doses of ARBs extend the vasoprotective benefits of currently used doses requires further exploration but early results are promising, such as those with candesartan.

Questions and Answers

The following question-and-answer session is based on discussions with Dr. Hans-Henrik Parving, Steno Diabetes Center, Gentofte, Denmark, during the ASN scientific sessions.

Q: Do patients with type 1 diabetes and diabetic kidney disease in Europe have the same prognosis as they do in the US?

A: No. In America, half of type 1 patients with diabetic kidney disease have died five years after its onset, so we are speaking about malignant disease here. But in our part of the world, survival of patients with type 1 diabetes and diabetic kidney disease is 21 years. We have expanded survival threefold during the last three decades due to good BP control with RAS inhibition.

Q: Are ACE inhibitors or ARBs controlling congestive heart failure well enough, or should we be giving patients aldosterone blockade, at which point they will have more proteinuria and less GFR?

A: We are lucky in that we have data from the Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity (CHARM-Added) study which was in congestive heart failure patients who were treated with dual blockade using an ACE inhibitor and an ARB. The good news from CHARM was that survival was improved and hospitalization for heart failure was minimized, so there was improvement by adding the ARB.

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