Antihypertensive treatment and stroke prevention in patients with and without chronic kidney disease: a review of controlled trials.

BACKGROUND: Stroke is the leading cause of serious long-term disability and the third leading cause of death in the Western world. In patients with chronic kidney disease (CKD), stroke and vascular dementia are significantly more prevalent than in the general population. However, the optimal stroke prevention strategy in these patients is unclear, because controlled studies are scarce. METHODS: In this paper, the results of the major antihypertensive trials and meta-analyses for stroke prevention in the general high cardiovascular (CV) risk population and in the CKD population are reviewed. RESULTS: The risk of stroke is much more blood pressure (BP)-dependent than the risk of other CV events, and, consistently, risk reduction is also strongly dependent on BP reduction. The magnitude of BP lowering is crucial in both populations. In renal patients, diuretics alone or in combination with angiotensin-converting enzyme (ACE) inhibitors, compared with placebo, are powerful BP-lowering and stroke-protective agents. Calcium channel blockers and ACE inhibitors also seem to be superior to placebo, but with more modest BP-decreasing effects and statistically nonsignificant reductions in stroke risk. In active versus active drug studies, independently of the BP-lowering effect, there are no significant advantages of any class over the others, although the results point to a slight superiority of diuretics and calcium channel blockers. Antihypertensive regimens in CKD patients should always include a diuretic, because, in the pathogenesis of CKD-associated hypertension, volume overload plays a crucial role. Diuretics are also inexpensive and well tolerated. CONCLUSIONS: We suggest that further studies of CV outcomes in CKD patients should compare various combinations of diuretics plus other drugs, such as calcium channel blockers, ACE inhibitors and angiotensin II receptor blockers.

[Diuretic-based therapy]. / Thérapeutique diurétique.

Diuretics are pharmacological agents that increase natriuresis through inhibition of tubular re-absorption of sodium. The mechanisms and site of this inhibition differ with each drug class, accounting for their additive effects on natriuresis increase and their hydroelectrolytic side effects. The response to a given diuretic dose depends on the diuretic concentration on the urine at its action site. This concentration may be decreased by pharmacokinetic factors such as encountered in renal insufficiency or in nephrotic syndrome. These resistance mechanisms of diuretics may be corrected by dose increase, previous diuretic fixation on albumin or warfarin administration. Once these mechanisms are opposed, the diuretic concentration for maximal efficacy is reached at is action site and the natriuresis obtained as the normal maximal plateau. This is not the case when an oedematous systemic disease with effective hypovolemia is present, like in heart failure or cirrhosis, or when chronic use of loop diuretics has induced a hypertrophy of the more distant part of the tubule. In theses cases, a pharmacodynamic resistance exists, resulting in a lower maximal natriuresis plateau in spite of adequate concentration of the diuretic at its action site, even in the absence of pharmacokinetic resistance factors. The main indications of diuretics are systemic oedematous disease and hypertension. In the oedematous diseases, diuretics indication is both straightforward and sufficient only if effective hypervolemia is present. The therapeutic approach is discussed according to the various clinical conditions and pathophysiological background. In uncomplicated hypertension, diuretics are the cornerstone of the therapy. The most suitable diuretic treatment for hypertension is an association of low doses thiazide (12.5-50 mg/day) with potassium sparing diuretics. Rare indications of diuretics are also reviewed.

Does a change in angiotensin II formation caused by antihypertensive drugs affect the risk of stroke? A meta-analysis of trials according to treatment with potentially different effects on angiotensin II.

BACKGROUND: Stroke prevention by antihypertensive therapy is believed to be related to the fall in blood pressure (BP). Experimental data have documented that activation of non-AT1 receptors of angiotensin II may exert anti-ischaemic mechanisms in the brain. The present meta-analysis of various randomized clinical trials attempts to relate stroke risk to angiotensin II formation during antihypertensive therapy. METHODS: Primary and secondary stroke prevention was examined in 26 prospective, randomized clinical trials including 206,632 patients without heart failure, in whom a total of 7,108 strokes occurred. The trials were selected because a difference in angiotensin II generation was expected between the two treatment arms on the basis of the drugs' pharmacodynamic effects, and allowed 36 evaluations of the relative risk of stroke. FINDINGS: In placebo-controlled trials, stroke risk was significantly higher with angiotensin II-decreasing than increasing drugs, but systolic BP decreased less in the former. Compared with an active therapy having a neutral effect on angiotensin II formation, stroke risk was also higher with angiotensin-decreasing drugs than with angiotensin-increasing drugs, whereas BP decrease was comparable with both drug classes. When angiotensin II-decreasing drugs were directly compared with angiotensin II-increasing drugs in the same trials, stroke risk was significantly increased. On-treatment systolic BP was minimally and significantly higher with angiotensin II-decreasing drugs, but not large enough to explain the excess in stroke risk. CONCLUSION: Within the limitations of the methodology, our meta-analysis supports the hypothesis that angiotensin II-decreasing drugs are less stroke protective than angiotensin II-increasing drugs, although this difference is not entirely explained by their smaller BP-lowering effect.

[Which optimal antihypertensive bitherapy for kidney patients?]. / Quelle bithérapie antihypertensive optimale pour les patients néphrologiques?

In this editorial review on the optimal antihypertensive treatment for chronic kidney disease (CKD) patients, we start with the controversy triggered by Casas et al., for proposing a bitherapy optimal not only for nephroprotection, but also for global cardiovascular protection. The incidence of cardiovascular complications are indeed much greater than the occurrence of end stage renal disease (ESRD) in these patients, so that their prevention has at least the same priority. We explain the huge amount of discordant papers, on the basis of methodology deficiencies in the studies aiming at evidencing the truth of 2 antinomic concepts underlying this controversy: 1) "The correction by antihypertensive drugs of the cardiovascular risk excess in hypertensive patients is exclusively related to their blood pressure lowering effect, the optimal blood pressure (BP) level being defined by epidemiologists at 115/75 mmHg"; 2) "Independently of BP lowering effect, antihypertensive drugs may have intrinsic, protective or deleterious, renal and cardiovascular effects which may be variable according to the target organ". We think that truth is conciliating and that both mechanisms should not be exclusive. However more rigorous studies are still needed to evidence it. Meanwhile we propose the optimal therapy by hypokaliemic diuretics (thiazides+/-loop diuretics according to glomerular filtration decline)+inhibitors of the angiotensin AT1-receptor (ACE inhibitors or AT1RB), in preference to the association of dihydropyridines with diuretics. This recommendation is strong however, only for CKD patients with macroproteinuria. The priority that we give to diuretic therapy is based on the evidence that this class confers good prevention against both heart failure and strokes, which is not the case for all AT1-inhibitors and dihydropyridines. Furthermore the diuretics are the drugs with the longest antihypertensive effect (many weeks) and their efficiency in CKD patients is proportional to the sodium depletion they initially induce and therefore to the dose (specially of the loop diuretics). Indeed volemia control is an incontrovertible factor for optimal BP control in renal insufficiency. As regards the use of betablockers, they should no more be considered as first drug for hypertension because they have the strongest diabetogenic effect. They should be used selectively for their specific cardiologic indications such as angina, heart failure, arythmia and as substitute for ACEI or AT1RB when general anesthesia is considered. Regarding the choice between ACEI and AT(1)RB, on the basis of indirect comparisons, we think that the latter may grant a comparable cardiac protection while giving a better cerebral protection. We shall have to wait the results of ONTARGET study to have or not the evidence for this preference. Finally, we want to stress the necessity to individualize the treatment by taking into account coexistence of cardiovascular complications and of other diseases, as well as the tolerance of the treatment (which may be influenced by seasons, in particular the canicula one), and the cost of the drugs.

Drug Insight: renal indications of calcimimetics.

Calcimimetics suppress the secretion of parathyroid hormone by sensitizing the parathyroid calcium receptor to serum calcium. Cinacalcet (Sensipar/Mimpara), Amgen Inc., Thousand Oaks, CA), the first-in-class calcimimetic agent approved for treatment of secondary hyperparathyroidism in dialysis patients, is, in association with higher dose of a calcium-based oral phosphate binder, a well-tolerated and effective alternative to standard treatments such as vitamin D derivatives in association with a non-calcium-based oral phosphate binder. Here, we present an overview of evidence in support of this assertion. We extend our discussion to encompass other indications for calcimimetics -- secondary hyperparathyroidism in predialysis chronic kidney disease patients, hypercalcemic hyperparathyroidism in renal transplant recipients, primary hyperparathyroidism, and hypercalcemia associated with parathyroid carcinoma -- as well as providing guidance on optimal usage of this drug.

Reappraisal of 2003 NKF-K/DOQI guidelines for management of hyperparathyroidism in chronic kidney disease patients.

The 2003 guidelines for the management of hyperparathyroidism in chronic kidney disease compiled by the Kidney Disease Outcomes Quality Initiative of the National Kidney Foundation (NKF-K/DOQI) were formulated on the basis of work published up until 2001. Since then, new drugs (e.g. calcimimetics and lanthanum carbonate) have become available, and others (e.g. sevelamer, nicotinamide and paricalcitol) have been more stringently clinically evaluated. Because of these advancements, a reappraisal of the 2003 guidelines is justified. In this article we critically review the following recommendations of the NKF-K/DOQI: (i) routine use of 1.25 mmol/l (5.0 mg/dl) dialysate calcium and 1 alphaOH-vitamin D derivatives; (ii) limitation of the maximal daily dose of calcium-based oral phosphate binders to 1.5 g of elemental calcium; and (iii) not correcting vitamin D insufficiency in dialysis patients.

How do calcimimetics fit into the management of parathyroid hormone, calcium, and phosphate disturbances in dialysis patients?

As suggested by its American brand name (Sensipar), the calcimimetic cinacalcet sensitizes the parathyroid cells to the extracellular calcium signal, suppressing parathyroid hormone (PTH) release and synthesis and preventing parathyroid cell proliferation. This primary PTH suppression decreases the release of calcium and phosphate from bone without increasing intestinal absorption of calcium and phosphate. Therefore cinacalcet decreases the risk of hypercalcemia and hyperphosphatemia in contrast to 1alpha-OH vitamin D derivatives. Compared with calcium-containing oral phosphate binder (OPB), it increases the risk of hypocalcemia and may decrease the PTH-mediated phosphaturia in predialysis patients. This justifies its combined use with calcium-containing OPB in order to prevent hypocalcemia and enhance the hypophosphatemic effect of the latter, while improving PTH suppression. The National Kidney Foundation (NKF) Kidney Disease Outcomes Quality Initiative (K/DOQI) has recommended restriction of supplemental elemental calcium to 1.5 g/day, a recommendation that we believe should be revised. No pathophysiologic or randomized trial data have yet evidenced the absolute necessity for systematically using 1alpha-OH vitamin D derivatives and noncalcium-containing OPB rather than higher doses of calcium-containing OPB alone in uremic patients without vitamin D insufficiency. In patients with hyperparathyroidism as severe as in the "Treat to Goal Study," the Durham study showed that a calcium carbonate dose more than three times the K/DOQI limit could decrease PTH into the recommended range, with the advantage of a lower calcium-phosphate product compared with the combination of calcitriol and noncalcium OPB. Besides the efficient PTH suppression associated with lower calcium-phosphate product and a good gastrointestinal tolerance, long-term data suggest that cinacalcet may decrease the risk of parathyroidectomy and fracture, while high bone turnover lesions are improved. However, no long-term data on bone mineral density and cardiovascular calcification and complications are yet available. Such studies, along with those comparing cinacalcet and 1alpha-OH vitamin D-based approaches to hyperparathyroidism, are needed.

Is the angiotensin II Type 2 receptor cerebroprotective?

Most of the deleterious effects of angiotensin II (Ang II) on blood pressure (BP), cardiovascular remodeling, and atherosclerosis are mediated by Ang II type 1 (AT1)-receptor activation. This explains why Ang-II-decreasing or blocking drugs have been successful in decreasing global cardiovascular morbimortality in patients with cardiac complications. However, in primary or secondary stroke prevention trials in patients with low cardiac risk, b-blockers and angiotensin-converting enzyme inhibitors (ACEIs), which decrease Ang II formation, seem to be less protective than thiazides and dihydropyridines, which increase Ang II. When compared with a beta-blocker, an Ang II-increasing AT1-receptor blocker better protects against stroke but not against cardiac events, whereas an ACEI gives the same protection against both cardiac and cerebral events. This dissociation between blood-pressure-independent cardiac and cerebral protection between b-blockers or ACEIs versus AT1-blockers in patients with low cardiac risk can be best explained if, besides the beneficial vascular effect of AT1-receptor blunting, there is evidence of a beneficial effect of non-AT1-receptor activation. In this review, we present experimental evidence for AT2- and AT4-receptor-mediated brain-anti-ischemic mechanisms and propose a direct comparison of AT1-blockers with ACEIs to prove the clinical effectiveness of non-AT1-mediated mechanisms in stroke prevention, particularly in patients with a higher risk for stroke than for cardiac complications.

Bone mineral density directly correlates with elevated serum leptin in haemodialysis patients.

BACKGROUND: Experimentally, leptin has a positive effect on bone mass when infused intravenously, but a negative one after intracerebroventricular administration. Renal failure increases its serum level above the concentration beyond which its transport to the brain may be saturated. Thus, we tested, in a chronic haemodialysis population, the hypothesis of a positive relationship between serum leptin and bone mineral density (BMD) when serum levels are above this threshold. METHODS: Serum leptin (using a two-site RIA), and BMD at the femoral neck, midshaft, and ultradistal radius, as measured by DEXA, were assessed in 17 female and 16 male chronic dialysis patients, with comparable calcium and phosphate metabolism, age and dialysis duration. RESULTS: Polynomial regression analysis showed a U-shaped correlation between BMD Z-score, with an inflexion point, which may correspond to the concentration threshold at which leptin blood-brain carrier is saturated. Linear regression analysis showed no correlation between BMD and serum leptin levels below these points but a significant positive correlation between BMD at the two radius sites and leptin levels above these points. The correlation remained significant after adjustment for BMI, serum PTH and duration of dialysis. Leptin levels were twice as high in female patients and associated with higher BMD Z-scores close to zero. CONCLUSIONS: This study suggests a bone-sparing effect of serum leptin in haemodialysis patients only when the serum levels of leptin were higher than the presumed threshold of blood-brain transport saturation. Higher leptin levels in post-menopausal female haemodialysis patients than in male patients may account for their slower bone loss with ageing.

Sevelamer hydrochloride with or without alphacalcidol or higher dialysate calcium vs calcium carbonate in dialysis patients: an open-label, randomized study.

BACKGROUND: Sevelamer hydrochloride was recently proposed as a phosphate binder to prevent hypercalcaemia in place of calcium alkaline salts in dialysis patients. So far, it has been evaluated only in patients receiving calcitriol, without comparison with CaCO(3) alone, although the latter was found to be as effective as the combination of calcitriol and Al(OH)(3) in suppressing parathyroid hormone (PTH) without inducing hypercalcaemia and to have a better lowering effect on serum phosphate. Moreover, this bile salt binder may decrease serum 25-OH vitamin D. Therefore, we compared for 5 months two strategies for controlling moderate hyperparathyroidism: CaCO(3) alone vs sevelamer in conjunction with measures to increase calcium balance. METHODS: Forty-two patients were randomized: 21 continued their treatment with 4.8 g/day CaCO(3) and 21 were switched to sevelamer (initial dose: 2.4 g/day, increased to 4.4 g/day). Each month, when serum-corrected calcium decreased below 2.30 mmol/l, dialysate calcium was increased or alphacalcidol was given at each dialysis session, according to serum PO(4) levels. The following parameters were monitored: serum Ca, PO(4), bicarbonate and protein, weekly; and serum PTH, 25-OH vitamin D and total, LDL and HDL cholesterol monthly. RESULTS: Except for higher serum phosphate at month 1, lower serum bicarbonate at month 2 and lower LDL cholesterol at month 5 in the sevelamer group, no difference was found between the two groups. Compared with baseline levels, PTH increased and 25-OH vitamin D decreased significantly in both groups, these two parameters being inversely correlated. CONCLUSIONS: Given comparable control of plasma calcium, phosphate and 25-OH vitamin D, PTH control is comparable in both strategies. Sevelamer does not induce greater vitamin D depletion than CaCO(3). The transient decrease of serum bicarbonate after discontinuation of CaCO(3) in the sevelamer group suggests a less optimal prevention of acidosis. The sevelamer-induced decrease in LDL cholesterol gives this drug a potential advantage in cardiovascular prevention.