[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.

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.