REVIEW. KEYWORDS 1αOH-vitamin D derivatives, calcimimetics, chronic kidney disease, hyperparathyroidism, oral phosphate binders

Reappraisal of 2003 NKF-K/DOQI guidelines for management of hyperparathyroidism in chronic kidney disease patients Matthieu Monge, Irina Shahapuni, Roxana Oprisiu, Najeh El Esper, Philippe Morinière, Ziad Massy, Gabriel Choukroun and Albert Fournier* SUMMARY 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 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. KEYWORDS derivatives, calcimimetics, chronic kidney disease, hyperparathyroidism, oral phosphate binders REVIEW CRITERIA We reviewed clinical and experimental articles published between January 2001 and February 2006 relating to renal bone disease, dialysate calcium concentration, clinical use of oral phosphate binders, derivatives, calcimimetics, suppression of parathyroid hormone, and vascular calcification. M Monge and I Shahapuni are assistants in hemodialysis, N El Esper is a consultant for home-based dialysis, P Morinière is a consultant for hemodialysis, G Choukroun is Professor of Nephrology, and A Fournier is Professor of Internal Medicine and Chief of the Department of Nephrology Internal Medicine Intensive Care, all in the Department of Nephrology Internal Medicine, R Oprisiu is a nephrology consultant in the Geriatrics Department, and Z Massy is a nephrology consultant and Professor of Pharmacology and Director of INSERM-ERI-12, all at Amiens University Hospital, Jules Verne University of Picardy, Amiens, France. Correspondence *Hôpital Sud, Department of Nephrology, 80054 Amiens, Cedex 1, France fournier.albert@chu-amiens.fr Received 8 September 2005 Accepted 21 February 2006 www.nature.com/clinicalpractice doi:10.1038/ncpneph0189 INTRODUCTION Availability of lanthanum carbonate and the calcimimetic cinacalcet for the treatment of hyperparathyroidism in dialysis patients has prompted us to critically review the 2003 recommenda tions of the National Kidney Foundation s Kidney Disease Outcomes Quality Initiative (NKF-K/DOQI). 1 In this article we express our opinion on three main issues. First, we comment on the use of three costeffective primary measures for suppression of parathyroid hormone (PTH): (i) not using a PTH-stimulating dialysate calcium concentration below 1.5 mmol/l (6.0 mg/dl); (ii) correcting vitamin D insufficiency in dialysis patients as in predialysis patients with chronic kidney disease (CKD); and (iii) not limiting the oral dose of elemental calcium (used as a phosphate binder) to 1.5 g/day when no [1,25(OH) 2 -vitamin D] is used, unless the albumin-corrected serum calcium concentration exceeds 2.37 mmol/l (9.48 mg/dl). Second, we consider the following alternative approaches for when the above measures fail to achieve K/DOQI recommended ranges for mineral and hormonal parameters, with regard to their potential for suppressing PTH and preventing vascular calcification: (i) calcium-based oral phosphate binders (OPBs) plus sevelamer hydrochloride, nicotinamide or lanthanum carbonate; (ii) plus sevelamer, nicotinamide or lanthanum carbonate; (iii) cinacalcet plus higher doses of calcium-based OPBs (and higher dia lysate calcium) or cinacalcet plus. In contrast to derivatives, calcimimetics such as cinacalcet decrease rather than increase serum concentrations of calcium and phosphate, and induce a circadian pattern of oscillating suppression of PTH. As dyslipidemia, which is quite prevalent in patients with CKD, might influence vascular calcification and clinical complications, we suggest attempting correction to the LDL cholesterol : HDL cholesterol ratio using sevelamer, as recommended by K/DOQI, or using statins in 326 NATURE CLINICAL PRACTICE NEPHROLOGY JUNE 2006 VOL 2 NO 6

regimens that do not include sevelamer (which decreases LDL cholesterol) or nicotinamide (which increases HDL cholesterol). Third, we propose that the most appealing treatment combinations (a calcium-based OPB plus a non-calcium-based OPB, or a calciumbased OPB plus cinacalcet) be compared with the previously recommended regimen of plus sevelamer in randomized controlled trials. Evaluation of such data should be on the basis of long-term hard clinical outcomes (e.g. parathyroidectomy, fractures and cardiovascular events) to ensure that future guidelines are evidence-based, rather than opinion-based. MONITORING SERUM MINERAL AND HORMONAL PARAMETERS The optimal range of intact PTH recommended by NKF-K/DOQI in 2003 1 was 150 300 pg/ml, assessed using the Nichols Allegro kit (Nichols Institute Diagnostics, San Juan Capistrano, CA), which measures not only 1 84 PTH but also C-terminal fragments such that the upper limit of the reference range is 55 65 pg/ml. Guidelines recommend an albumin-corrected serum calcium concentration of 2.10 2.37 mmol/l (8.40 9.48 mg/dl), and a concentration of 1.13 1.78 mmol/l (3.50 5.51 mg/dl) for serum phosphorus. As we discussed these recommendations in a previous publication, 2 here we present our conclusions only. We agree with the recommended range for serum calcium but propose a lower upper threshold for serum phosphorus (1.60 mmol/l [4.95 mg/dl] instead of 1.78 mmol/l [5.51 mg/dl]), and a higher lower limit of 1.30 mmol/l [4.03 mg/dl]. This proposition is based on the latest United States Renal Data System (USRDS) study, which showed that cardio vascular risk increased at serum phosphorus levels above 1.60 mmol/l (4.95 mg/dl), or less than 1.30 mmol/l (4.03 mg/dl). 3 With regard to the 300 pg/ml upper limit for intact PTH (5 6 times the upper limit of the reference range) recommended by NKF-K/DOQI, we think it important to recall that an NKF metaanalysis of bone histodynamics 2 found that 150 pg/ml was the best criterion on which to base diagnosis of osteitis fibrosa cystica. If this level is measured 24 h after administration of cinacalcet (as performed during the analyzed trials), oversuppression of PTH and low bone turnover might result, because the nadir of cinacalcet-mediated PTH suppression occurs within 4 12 h. We therefore support initiation of cinacalcet therapy at an intact PTH concentration of 300 pg/ml. We do not believe, however, that the lower limit of intact PTH should necessarily be 150 pg/ml, for two reasons. First, the NKF meta-analy sis of bone histodynamic data indicated that a PTH level below 60 pg/ml is the best criterion on which to base diagnosis of adynamic bone disease. Second, the 2004 USRDS study, 3 which more accurately adjusted mortality data to account for co morbidities, found that the rate of mortality did not increase when PTH fell below 150 pg/ml. The optimal lower limit of intact PTH remains to be defined. The issue of measuring whole PTH, bio intact PTH or true 1 84 PTH (excluding C-terminal PTH as 7 84) is covered further in our previous review in Seminars in Dialysis 2 and our letter to the Journal of Clinical Endocrinology and Metabolism. 4 DIALYSATE CALCIUM LEVEL AND CORRECTION OF VITAMIN D INSUFFICIENCY We see no reason to recommend a routine dia lysate calcium concentration of up to 1.25 mmol/l (5.0 mg/dl), as concentrations within this range stimulate PTH and exacerbate radiological osteitis fibrosa cystica. 5,6 Administration of calcimimetics, which decrease serum calcium levels, permits use of a dialysate calcium concentration of 1.75 mmol/l (7.0 mg/dl). Such a concentration causes PTH to drop dramatically, by 60% on average at a 30 mg dose of cinacalcet, even if the baseline intact PTH level exceeds 2,000 pg/ml. 7 This proportional decrease is twice that of the mean decrease observed in trials in which dia lysate calcium concentration was not adjusted. 8 We do not understand why maintenance of vitamin D sufficiency is not recommended for dialysis patients, when it is recommended for patients with grade 3 or grade 4 CKD. The reason given by the authors of the 2003 NKF- K/DOQI guidelines is lack of proof that correction of vitamin insufficiency suppresses PTH in hemodialysis populations. 1 We acknowledge that there has been no randomized, placebo-controlled trial of vitamin D 2, vitamin D 3 or 25OH-vitamin D 3 in dialysis patients. Three observational studies have, however, indicated that vitamin D in sufficiency stimulates PTH secretion in dialysis patients. A cross-sectional study of 103 Algerian dialysis patients showed that levels of PTH and 25OHvitamin D were inversely correlated, independent of concentra tions of serum calcium, phosphorus JUNE 2006 VOL 2 NO 6 MONGE ET AL. NATURE CLINICAL PRACTICE NEPHROLOGY 327

GLOSSARY CALCITRIOL 1,25-Dihydroxychole- or ergocalciferol (1,25[OH] 2 - vitamin D); produced from calcidiol by 1α-hydroxylase CALCIDIOL 25-Hydroxychole- or ergocalciferol (25OHvitamin D); produced in the liver by the 25-hydroxylation of vitamin D 2 (ergocalciferol) or vitamin D 3 (cholecalciferol) and CALCITRIOL. 9 Further evidence comes from a longitudinal study of patients being stably treated with calcium carbonate (CaCO 3 ), 25OH-vitamin D and thrice-weekly dialysis with a dialysate calcium concentration of 1.5 mmol/l (6.0 mg/dl; asso ciated with an approximately neutral per dialytic calcium balance). Discontinuation of 25OH-vitamin D therapy caused serum calcidiol levels to decrease and PTH to increase. 10 The recent study by Mucsi et al. 11 reporting a high prevalence of vitamin D deficiency in Hungarian dialysis patients and its correlation with high PTH levels and abnormal bone mineral density further supports the deleterious effect of vitamin D deficiency on PTH secretion and bone. 1αOH-VITAMIN D DERIVATIVES UNNECESSARY FOR PTH SUPPRESSION Our reasons for disagreeing with routine use of intravenous or oral derivatives in dialysis, as well as predialysis CKD, patients are based on experimental and clinical data, and are outlined below. A high calcium diet alone can suppress hyperparathyroidism in vitamin D receptor-knockout mice Experimental data show that hyperparathyroidism can be suppressed without using to activate the vitamin D receptor; a high calcium diet alone can suppress hyperparathyroidism by activating the parathyroid calcium receptor. Routine use of high intermittent oral doses (or even intravenous injection in dialysis patients) of derivatives has been justified by overinterpretation of basic scientific findings over the past 30 years. These findings included discovery of the kidney s crucial role in enhancing the hypercalcemic and hyper phosphatemic potency of calcidiol via 1α-hydroxylation; 12 hence, these metabolites were dubbed active vitamin D derivatives, implying that other vitamin D compounds are inactive. Sole use of these active metabolites could also be justified by elucidation of the mechanisms of uremia-induced resistance to calcitriol. 13 These concepts supported the idea that low levels of serum calcitriol in uremic patients should be corrected, even to supraphysiological levels. More-recent studies of mice in which the gene encoding 25OH-vitamin D-1α-hydroxylase or the vitamin D receptor was deleted 14,15 have shown, however, that the severe hyper parathyroidism and bone abnormalities induced by these deletions can be rescued solely by increasing dietary calcium intake, so that the calcium : phosphate ratio reaches 2. As simple adjustment of the dietary calcium : phosphate ratio can prevent hyperparathyroidism in mice, in the absence of calcitriol or the vitamin D receptor, why should supraphysiological levels of serum calcitriol be necessary to suppress PTH in dialysis patients or uremic rats? In uremic rats, high calcium and low phosphate diets prevent parathyroid hyperplasia as efficiently as does, and via the same molecular pathways. 16 Only the direct mechanism (proven in vitro) by which PTH synthesis is suppressed differs; 17 calcitriol inhibits transcription of the prepro-pth gene, whereas increased levels of serum calcium and decreased levels of serum phosphorus shorten the half-life of prepro-pth messenger RNA (Figure 1). In vivo studies have shown that calcium-based OPBs suppress synthesis and secretion of PTH as efficiently as they do hyperparathyroid gland hyperplasia, by three primary mechanisms: correction of acidosis, increasing serum calcium concentration, and decreasing serum phosphorus levels. The last mechanism induces overexpression of the calcium receptor, 18 suppresses synthesis of fibroblast growth factor 23 (FGF23) by osteoblasts, and therefore perturbs suppression of renal vitamin D-1α-hydroxylase by FGF23, eventually causing serum calcitriol levels to increase. 19 21 The multiple mechanisms of PTH suppression triggered by calcium-based OPBs explain why suppression of PTH is so marked in uremic rats on a high calcium diet. 22,23 By contrast, exogenous calcitriol alone suppresses PTH by only a single net mechanism: the decrease in prepro-pth transcription. Indeed, the hypercalcemia-mediated suppressive effect of this compound on PTH is counter acted by its hyperphosphatemia-mediated PTHstimulating effect (Figure 1). Furthermore, exo genous enhances production by the osteoblast of FGF23, which decreases intestinal and renal tubular reabsorption of phosphate 19,20 but also suppresses the activity of renal 1α-hydroxylase, 20 further decreasing endogenous renal calcitriol production. Figure 1 shows that parathyroid cells, like renal tubular cells, have 25OH-vitamin D- 1α-hydroxy lase, which catalyzes synthesis of calcitriol in situ. Calcidiol, from which calcitriol is produced, enters the cell via the membrane 328 NATURE CLINICAL PRACTICE NEPHROLOGY MONGE ET AL. JUNE 2006 VOL 2 NO 6

Alkaline calcium salt Plasma phosphate decreased Lanthanum carbonate Parathyroid cell Ferric ammonium citrate Calcimimetic mrna decreased Nicotinamide Nucleus PTH decreased Acidosis prevented Sevelamer HCI Calcitriol Calcidiol 1α-hydroxylase Calcitriol Plasma calcium increased Plasma calcitriol increased Calcidiol Plasma calcidiol increased Vitamin D 3 synthesized in skin in response to sunlight Dietary vitamin D 2 (from plants) and vitamin D 3 (from animals) Vitamin D 3 Vitamin D 2 Liver Calcidiol 25-hydroxylase Calcidiol Kidney 1αhydroxylase Calcitriol Vitamin D receptor receptor (LRP)-2/megalin receptor Figure 1 Factors and therapeutic agents that modulate synthesis and secretion of parathyroid hormone, and parathyroid gland hyperplasia. Unbroken arrows indicate a suppressing effect; broken arrows indicate a stimulating effect. HCl, hydrochloride; mrna, messenger RNA; PTH, parathyroid hormone. endocytic receptor (LRP)-2/megalin, provided circulating levels of 25OH-vitamin D are optimal (about 75 100 nmol/l [30 40 ng/ml]). Once produced, calcitriol can perturb transcription of the prepro-pth gene, thereby decreasing PTH synthesis. 24 This mechanism explains recent data from the Slatopolsky group. 25 This group found that, in bovine parathyroid cell culture, 25OH-vitamin D at a concentration of 100 nmol/l (40 ng/ml) suppressed PTH synthesis as efficiently as did calcitriol at its maximal suppressive dose. These data strongly support the cost-effectiveness of correcting vitamin D insufficiency in patients with stage 2 4 CKD and in dialysis patients. Figure 1 also shows that calcium acts on parathyroid cells by stimulating their sensor receptors, the sensitivity of which to calcium can be pharma cologically enhanced by calcimimetics such as cinacalcet. The predominance of this calcium receptor over the vitamin D receptor in prevention of hyper parathyroidism in nonuremic animals has been demonstrated in mice via gene deletion. When the calcium receptor is ablated in mice, fatal hyper parathyroidism occurs. These mice can be rescued only by further genetic deletions that prevent synthesis of PTH 26 or parathyroid formation. 27 In uremic rats, preliminary results indicate that cinacalcet prevents parathyroid hyperplasia 28 and might JUNE 2006 VOL 2 NO 6 MONGE ET AL. NATURE CLINICAL PRACTICE NEPHROLOGY 329

even promote regression. 29 The potential for regression has never been reported in association with calcitriol. Use of cinacalcet confers a need for a higher dose of calcium-based OPB to prevent hypocalcemia, thereby facilitating a further decrease of serum phosphate level and therefore other bene ficial effects such as increasing calcium receptor expression 18 and renal synthesis of calcitriol. 21 Increasing dietary calcium : phosphate ratio in vitamin-d-repleted patients suppresses hyperparathyroidism In 1985, Massry and Llach 30 showed, in pre dialysis CKD patients, that a simple low phosphate diet could decrease serum PTH levels without decreasing serum phosphate concentration (but decreasing 24-h phosphaturia) while enhancing intestinal absorption of calcium and also calcium + phosphate balance. This bene ficial effect of decreased phosphate intake on PTH was explained 2 years later by Portale et al., 31 who showed that it was related to an increase in serum calcitriol. PTH suppression by a low phosphate diet explains the positive effect on calcium + phosphate balance demonstrated in 1943 by Liu and Chu. 32 The efficiency of a low phosphate diet in association with higher calcium intake and nonhypercalcemic repletion of 25OHvitamin D in suppressing PTH and correcting osteitis fibrosa cystica or osteomalacia histological lesions has been confirmed by our group 33 and the Bordeaux group. 34 By contrast, placebo-controlled studies in vitamin-d-deficient and calciumdeficient pre dialysis CKD patients showed that hyper calcemic and hyperphosphoremic doses of alfa calcidol 35 or nonhypercalcemic doses of calcitriol 36 could not suppress elevated baseline PTH levels. These treatments could only prevent further increases of PTH concentrations. In dialysis patients, we 37 have shown that, for suppression of PTH, CaCO 3 (3.6 g elemental calcium) is as effective as the combina tion of plus aluminum hydroxide (Al[OH] 3 ) and 1.2 g of CaCO 3. The former treatment has the added advantage of preventing aluminum overload. 37 More recently, Indridason and Quarles 38 performed a randomized controlled trial comparing CaCO 3 (dose increasing from 2 g to 6 g per day) with oral or intravenous calcitriol plus Al(OH) 3. These investigators found that the degree of PTH suppression was comparable between regimens, whereas the increases of serum concentrations of calcium and phosphorus were less when oral calcium load was higher. derivatives increase the risk of vascular calcification, accelerate renal failure and increase mortality In Fgf23, as well as klotho, null mice, the premature-aging phenotype is associated with vascular calcification, premature death and high serum calcitriol levels. Lowering calcitriol levels in klotho mutants by dietary means, or by ablation of vitamin D-1α-hydroxylase in Fgf23 / mice, markedly improved phenotypic abnormalities and prolonged survival. 39 In uremic rats, even nonhypercalcemic doses of calcitriol decreased survival in association with progression of renal failure and extensive aortic calcifications. 40 By contrast, maintaining uremic rats on a high calcium diet enhances survival and is associated with less severe hypertension, less proteinuria, slower progression of renal failure and absence of vascular calcification. The type 1 angiotensin II receptor is concomitantly underexpressed in the kidney. 22,23 The same observations have been made in uremic ApoE / mice prone to premature atherosclerosis; that is, a high oral calcium load minimized aortic calcification in association with decreased serum phosphorus levels. 41 These beneficial effects of a high calcium diet have also been reported by the Slatopolsky group in uremic rats overloaded by a high phosphate diet. 42 Figure 2 shows that enhances active absorption of calcium and phosphate, pre disposing patients to hyper phosphatemia and hypercalcemia, which are phosphocalcic risk factors for vascular calcifica tion and clinical complications. 2 These increases in serum calcium and phosphorus were documented in dialysis patients during the first Teng et al. cohort study, 43 even following treatment with pari calcitol (Zemplar ; Abbott Laboratories, Abbott Park, IL), the so-called non hypercalcemic, non hyperphosphatemic vitamin D derivative. First-year increases in serum calcium were 6.5% and 8.0% with Zemplar and Calcijex (calcitriol; Abbott Laboratories), respectively. Corresponding increases in serum phosphorus were 12% and 14%. Interestingly, mortality after 3 years was reduced by Zemplar compared with Calcijex (18% vs 22%), indicating that the less pronounced hypercalcemic and hyperphosphatemic effects of the former might be causally related to survival. 330 NATURE CLINICAL PRACTICE NEPHROLOGY MONGE ET AL. JUNE 2006 VOL 2 NO 6

The hypercalcemic and hyperphosphatemic effects of calcitriol and alfacalcidol have probably contributed to the acceleration of renal failure progression in the early trials. 44,45 High calcitriol levels have also been shown to increase the risk of vascular calcifications independently of serum calcium and phosphate in dialysis patients. 40,46 Furthermore, exacerbates hyperoxalemia by enhancing passive oxalate absorption by the colon. Less calcium is available to complex oxalate as rates of calcium absorption by the duodenojejunum are increased 47 (Figure 2). The risk of hypercalcemia and vascular calcifica tion is logically enhanced when calciumbased OPBs, rather than non-calcium-based OPBs, are administered together with 1αOHvitamin D. Even though the short-term CARE study 48 detected more rapid and substantial decreases in serum phosphorus and serum calcium phosphate product with calcium acetate than with sevelamer, the assumption regarding increased risk of hypercalcemia and vascular calcification with calcium-based OPBs was supported by the Treat to Goal Study, 49 in which sevelamer was compared with a calciumbased OPB. Factors other than lower incidence of hypercalcemia (linked to decreased calcium load), however, could account for the greater protective effect of sevelamer against vascular calcification. Serum levels of bicarbonate, LDL cholesterol and C-reactive protein were lower, while PTH (and therefore bone turnover) was 100 pg/ml higher, with sevelamer. Concomitant use of and a calcium-based OPB in patients previously overloaded with aluminum further increases the risk of vascular calcification; long-term aluminum-induced adynamic bone disease prevents calcium and phosphate deposition in bone. This effect at least partially explains the independent association between vascular calcification and dose of calcium-based OPB observed by the London group. 50 Interestingly, although this group detected an independent association between vascular calcification on one hand, and mortality and oral calcium load on the other hand, it was unable to show a direct relationship between mortality and oral calcium dose. By contrast, in the Amiens dialysis center, where aluminum intoxication has been prevented (via dialysate since 1978 and via phosphate binder since 1980), we have repeated ly 51 53 been unable to detect any independent link between the CaCO 3 dose and extension of vascular Calcitriol Oxalate Sevelamer HCI H + Oxalate + + + + calcification. This association was not detected despite the mean daily dose of elemental calcium administered as a phosphate binder being about 3.2 g, while serum concentration of 25OHvitamin D was 50 62 nmol/l (20 25 ng/ml) and the prevalence of use of was 17%. Interestingly, in our patients, in contrast to those of Erlangen, 54 we could not detect an inverse correlation between extension of aortic calcifica tion and bone mineral density, indicating that our treatment better prevented calcium mobiliza tion from bone to aorta. Regarding predialysis CKD patients, it should be stressed that 1.2 2.4 g of elemental calcium as carbonate plus correction of vitamin in sufficiency with 25OH-vitamin D was associated with a decreased slope of the reciprocal of serum creatinine. This finding indicates slower deterioration of renal function 33 than that observed with calcitriol or alfacalcidol. 44,45 Benefits of calcitriol or paricalcitol only detected in vitamin-d-insufficient dialysis or predialysis patients In the second study by Teng et al., 55 a survival advantage was observed following treatment with either Calcijex or Zemplar. Calcidiol levels were not measured in study patients, but were probably low (as shown by LaClair et al. 56 in patients with grade 4 CKD). As such, it is possible that the higher rate of mortality among patients who Ca-OPB H + Oxalate Figure 2 Effect of calcitriol (), sevelamer hydrochloride and a calcium-based oral phosphate binder on active (upper section of illustrated intestinal segments) and passive (lower section of illustrated intestinal segments) intestinal absorption of calcium, phosphate and oxalate, and on net transfer of hydrogen ions. Plus signs indicate increased absorption; minus signs indicate decreased absorption. Ca-OPB, calcium-based oral phosphate binder; HCl, hydrochloride. JUNE 2006 VOL 2 NO 6 MONGE ET AL. NATURE CLINICAL PRACTICE NEPHROLOGY 331

did not receive injections was simply a reflection of their poor vitamin D status. Sunshine vitamin repletion is associated not only with a lower risk of bone disease, but also with a lower risk of developing diabetes, cardiovascular disease, cancer, and immunological and infectious diseases. 57 The beneficial effects of vitamin D might be mediated directly even in uremic patients by calcidiol, or by in situ transformation of calcidiol into calcitriol at the level of immunocompetent cells or vascular smooth muscle cells, which contain 25OH-vitamin D- 1α-hydroxylase. 58 So, the second study by Teng and colleagues supports the hypothesis that the beneficial non-mineral effects of vitamin D deriva tives override their deleterious hypercalcemic and hyper phosphatemic effects (which mainly occurred when administered together with a calcium-based OPB). In predialysis CKD patients, an antiproteinuric effect of oral paricalcitol has been reported. 59 These patients were, however, probably vitamin D deficient, as the study was performed in the US where the prevalence of vitamin D in sufficiency was 83% in 2005 (2 years after K/DOQI guidelines recommended correction of deficiency). 56 To prove that paricalcitol has specific survival or renal benefits, a placebo-controlled study should be performed in predialysis or dialysis patients with an optimal serum calcidiol level of 75 nmol/l (30 ng/ml), as recommended for grade 3 4 CKD by K/DOQI. So, in agreement with our 1982 proposal 60 and with a 2002 editorial by Cannata-Andia and Gomez Alonso, 61 the most logical, cost-effective and safest option for suppressing PTH and preventing vascular calcification or progression of renal failure seems to be prevention of vitamin D insufficiency plus administration of a calcium-based OPB, rather than treatment with plus a non-calcium-based OPB. LIMITING DAILY DOSES OF CALCIUM- BASED ORAL PHOSPHATE BINDERS In the US, calcium acetate is the only FDAapproved calcium-based OPB on the market, and is routinely injected at each dia lysis session. NKF-K/DOQI guidelines recommend limiting elemental calcium supplementa tion via calcium-based OPBs to 1.5 g/day, which we think is common sense. When CaCO 3 is used, however, we recommend a double dose (as elemental calcium) because the risk of hypercalcemia is probably twofold lower. Two crossover studies 62,63 have shown that half the dose of calcium acetate (as elemental calcium) controls hyperphosphatemia with similar efficacy to CaCO 3, and with an equivalent risk of hypercalcemia (which occurs mainly in patients taking ). The reason underlying this apparent paradox is the solubility of calcium acetate, which in the duodenum exceeds that of CaCO 3 because of the alkaline ph. We believe that the only justification for limiting the dose of calcium-based OPBs is elevation of serum calcium above 2.37 mmol/l (9.48 mg/dl), the threshold above which cardiovascular risk increases. 2 The safety of this threshold has not yet been validated in a controlled trial. Observational studies 51 53 have detected no independent link between CaCO 3 dose on the one hand and serum calcium or vascular calcification on the other, in spite of a mean oral CaCO 3 dose of 3.2 g (as elemental calcium). These results support the safety of such doses, at least in patients without vitamin D insufficiency, and therefore sparing use of. In patients routinely receiving, we think that if serum calcium exceeds 2.37 mmol/l (9.48 mg/dl) the dose of calcium-based OPB should be decreased to below 1.5 g elemental calcium. SUPPRESSING PTH AND PREVENTING VASCULAR CALCIFICATION Provided that the 2003 NKF-K/DOQI guidelines for treatment of hyperparathyroidism in CKD patients are modified with regard to correction of vitamin D insufficiency and maximal dose of calcium-based OPBs, a cost-effective, safe basic regimen for suppression of hyperparathyroidism would comprise systematic correction of vitamin D insufficiency and calcium-based OPBs without dose limitation other than that required when serum calcium exceeds 2.37 mmol/l (9.48 mg/dl). In addition, for dialysis patients, a dialysate calcium level of 1.5 mmol/l (6.0 mg/dl) should be advised routine use, instead of 1.25 mmol/l (5.0 mg/dl). Table 1 presents alternative strategies for instances in which additional treatment is required, and the asso ciated independent mechanisms involved in PTH suppression or prevention of vascular calcification. For simplicity, we have not taken into account the intrinsic potency of each mechanism. It might be presumed that, for PTH suppression, activation of the calcium receptor is more potent than activation of the vitamin D receptor, and that the effect of a decrease in the level of serum phosphate might be amplified by 332 NATURE CLINICAL PRACTICE NEPHROLOGY MONGE ET AL. JUNE 2006 VOL 2 NO 6

Table 1 Effect of various treatments on secretion of parathyroid hormone and vascular calcification risk, expressed as changes in serum parameters and parathyroid calcium receptor sensitization, in chronic kidney disease patients corrected for vitamin D insufficiency. Treatments Effect on serum concentration receptor Net number of factors suppressing: b Oxalate Calcitriol Bicarbonate sensitization a PTH c Vascular calcification d Ca-OPB Increase Decrease Decrease No change Increase No change 3 0 Sevelamer HCl No change Decrease Not known No change Decrease No change 0 2 (+ 2) e = 4 Lanthanum CO 3 No change Decrease Not known No change Increase No change 2 0 Nicotinamide No change Decrease Not known No change No change No change 1 1 (+ 2) e = 3 Ca-OPB plus sevelamer HCl Increase decrease Ca-OPB plus Increase lanthanum CO 3 decrease Ca-OPB plus nicotinamide Increase decrease Decrease No change No change No change 3 2 (+ 2) e = 4 Decrease No change increase No change 5 0 Decrease No change Increase No change 4 1 (+ 2) e = 3 Increase Increase Increase Increase No change No change 1 4 plus sevelamer HCl plus lanthanum CO 3 plus nicotinamide Cinacalcet a (dialysis patients) Cinacalcet a (predialysis patients) Higher dose Ca-OPB plus cinacalcet a (dialysis patients) Higher dose Ca-OPB plus cinacalcet a (predialysis patients) plus cinacalcet (dialysis patients) plus cinacalcet (predialysis patients) Increase No change Increase Increase Decrease No change 1 2 (+ 2) e = 0 Increase No change Increase Increase Increase No change 3 4 Increase No change Increase Increase No change No change 2 3 (+ 2) e = 1 Decrease Decrease No change No change No change Increase 1 2 Decrease Increase No change No change No change Increase 0 0 No change decrease decrease No change No change decrease No change No change increase increase Increase 5 2 Increase 3 0 No change No change Increase Increase No change Increase 2 2 No change Increase Increase Increase No change Increase 1 3 a Sensitization of calcium receptors by cinacalcet suppresses parathyroid hormone, but lowers serum phosphate levels only in dialysis patients; in predialysis patients, cinacalcet-mediated suppression of parathyroid hormone increases serum phosphate levels. b The net number of factors suppressing parathyroid hormone and vascular calcification is the algebraic sum. c Parathyroid hormone is suppressed by an increase in levels of serum calcium, serum bicarbonate or serum calcitriol, by a decrease in serum phosphate level, and by calcium receptor sensitization. d The risk of vascular calcification is decreased by a reduction in levels of serum calcium, serum phosphate, serum bicarbonate, serum calcitriol or oxalate. e (+ 2) refers to lowering of the LDL cholesterol : HDL cholesterol ratio and C-reactive protein specifically induced by sevelamer and by nicotinamide, two factors that decrease intimal calcification. Note that when the adjective greater is used, the factor change is arbitrarily considered to be twofold. Ca-OPB, calcium-based oral phosphate binder; CO 3, carbonate; HCl, hydrochloride; PTH, parathyroid hormone. JUNE 2006 VOL 2 NO 6 MONGE ET AL. NATURE CLINICAL PRACTICE NEPHROLOGY 333

overexpression of the calcium receptor and activation of vitamin D-1α-hydoxylase. For prevention of vascular calcification, decreased serum phosphorus concentration might be the most potent factor, because a high calcium diet ameliorated aortic calcification in uremic animals, even those overloaded with phosphate. 42 The effect of calcium-based OPBs (at non hypercalcemic doses) on PTH suppression might be enhanced by a non-calcium-based OPB (i.e. sevelamer hydrochloride, lanthanum carbonate, nicotinamide or nicotinic acid [Niaspan ; Kos Life Sciences, Inc., Miami, FL]). We recognize that only sevelamer hydro chloride and, more recently, lanthanum carbonate, have been approved for use in uremic patients. This is despite fears of lanthanum causing long-term toxicity in humans because it accumulates in the bones of uremic patients (although without obvious toxic effects at 4.5 years 64 ) and in the bone and liver of uremic rats. 25,65 The hypophosphatemic effect of nicotinamide and nicotinic acid (Niaspan ), which is mediated by inhibition of intestinal transport of phosphate, as well as their HDL-cholesterol-increasing effects, have been shown in both uremic and nonuremic patients. In nonuremic patients, long-term use of nicotinic acid decreased the risk of coronary heart disease. 66,67 The long-term safety of these two drugs in uremic patients is still to be confirmed, 68 even though their anti-inflammatory potential is great (these drugs decrease poly [ADP-ribose] polymerase activity and expression of nuclear factor kappa B 69,70 ). We suggest that a comparative study of sevelamer and nicotinamide might reveal that nicotinamide is equally as effective as sevelamer at suppressing PTH and preventing calcification, with the advantage of a lower price. Suppression of PTH by can be enhanced without worsening vascular calcifica tion only by combination with a non-calcium-based OPB (e.g. sevelamer hydrochloride, lanthanum or nicotinamide). The net number of PTH-suppressive mechanisms associated with lanthanum is greater than the number induced by sevelamer or nicotinamide (three versus one and two, respectively) but is offset by a greater number of calcificationpromoting factors (four versus zero with sevelamer and one with nicotinamide). None of the regimens that combine with non-calcium-based OPBs seems to be superior to those that combine calcium-based OPBs with non-calcium-based OPBs, in terms of either PTH suppression or prevention of calcification. Cinacalcet plus a higher calcium load from a calcium-based OPB (and from dialysate when increasing the dose of a calcium-based OPB is restricted by gastrointestinal intolerance) seems to be the most efficient strategy for suppressing PTH (five different mechanisms promote PTH suppression in dialysis patients) and for preventing vascular calcification (one mechanism in dialysis patients). This regimen might, however, be the most expensive. According to Manns et al., 71 the mean yearly costs of treatment with CaCO 3, calcium acetate or sevelamer are US$154, $463 and $3,644, respectively, while that of cinacalcet (which has not yet been evaluated) can range according to the dose used (30 mg minimal daily dose to 180 mg maximal daily dose) from $3,552 to $21,336. The cost of controlling dyslipidemia is not included in these estimates; the price of statin treatment to attain the recommended LDL cholesterol : HDL cholesterol ratio must be added for fair comparison with alternative treatments. The final alternative is cinacalcet plus 1αOHvitamin D. This regimen is likely to be less effective than cinacalcet plus calcium-based OPBs as, in dialysis patients, there would be only two PTH-suppressing mechanisms operating (as opposed to five). Two calcification-promoting factors would counteract the one protecting against calcification. CONCLUSION To date, none of the add-on therapies consider ed in the previous section have been compared. As such, no evidence-based advice on their administration can yet be given. Long-term randomized controlled trials incorporating evaluation of hard clinical endpoints should be performed to accurately assess the cost-effective ness of these alternative therapies. We think that the most appropriate comparisons to be performed at the present time would be between the K/DOQI-recommended add-on therapy of plus sevelamer and the three most appealing alternatives (i.e. a calcium-based OPB plus sevelamer or nicotinamide, and cinacalcet plus a higher calcium load provided by a calcium-based OPB and, if necessary, higher dialysate calcium concentrations). Completion of such studies will permit future guidelines to be based not just on opinion, but on evidence. Furthermore, these data will be necessary to justify the increased costs that public or private insurance will have to cover to better treat uremic patients. 334 NATURE CLINICAL PRACTICE NEPHROLOGY MONGE ET AL. JUNE 2006 VOL 2 NO 6

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