New biological targets for CKD- MBD: From the KDOQI to the

New biological targets for CKD- MBD: From the KDOQI to the KDIGO Guillaume JEAN, MD. Centre de Rein Artificiel, 42 avenue du 8 mai 1945, Tassin la Demi-Lune, France. E-mail : guillaume-jean-crat@wanadoo.fr

Introduction From 2003 to 2009 the recommendations were the Kidney Disease: Outcomes Quality Improvement (KDOQI) for mineral metabolism abnormalities. Biological targets and therapeutic strategies have been defined precisely and were used by nephrologists and in all clinical trials and observatories. In 2009, the new recommendations were released with the Kidney Disease: Improving Global Outcomes (KDIGO).

Grading differences KDIGO

KDOQI Grading evidence Highest quality Randomized controlled trials Matched controlled trials Prospective nonrandomized/nonmatched controlled trials Retrospective nonrandomized/nonmatched controlled trials KDIGO

NEW TARGET FOR PHOSPHATAEMIA

New KDIGO target 4.1.1. In patients with CKD stages 3 5, we suggest maintaining serum phosphorus in the normal range (2C). In patients with CKD stage 5D, we suggest lowering elevated phosphorus levels toward the normal range (2C). Normal values for phosphaetamia 0,81 1,45 mmol/l (2,5 4,5 mg/dl) KDIGO

EVIDENCE? Risque Relatif de Mortalité (RR) KDOQI 1.50 1.25 1.00 +2 % 0.4-1.5 1.5-1.8 1.8-2.1 2.1-2.5 2.5-5.4 Phosphorémie (mmol/l) +39 % +18 % Phosphorémie mmol/l Adapted from Block GA, et al. Am J Kidney Dis. 1998;31:607-617.

Observational data in the USA 2,5 mmol/l KDIGO GA Block et al. J Am Soc Nephrol 2004,15:2208.

Phosphataemia and survival in the DOPPS study <0,6 mmol > 2,2 mmol > 3 mmol KDIGO Tentori et al; AJKD 2008: 52: 519-

Phosphocalcic Metabolism and 1 year Survival (French cohort Photograph) Age (yr) 1.04 1.04-1.05 <0.0001 Gender F/M 0.78 0.65-0.94 0.010 CV history 1.57 1.28-1.93 <0.0001 Diabetes 1.23 1.00-1.50 0.048 BMI (kg/m2) 0.96 0.94-0.98 <0.0001 Low serum P 1.27 1.03-1.57 0.029 High serum P 1.05 0.84-1.32 0.668 Low serum PTH 1.08 0.86-1.34 0.512 High serum PTH 1.11 0.89-1.38 0.369 Low serum Ca 0.95 0.77-1.18 0.656 High serum Ca 1.37 1.08-1.74 0.009 Hemoglobin (g/l) 0.88 0.82-0.94 <0.0001 Albumin (g/l) 0.92 0.91-0.94 <0.0001 N = 4,937. Models were adjusted for age, sex, BMI, diabetes, history of CV disease, serum albumin, hemoglobin, and baseline serum levels of total calcium, phosphorus and PTH. Patients with recent parathyroidectomy (less than 6 months) were excluded from the analysis. D Fouque et al, WCN, Milan, 2009

Causes of hyperphosphataemia: Excess protein intake (> 1,2 g/kg/j) Excess phosphate intake (> 1000 mg/j) Inadequate dialysis removal : time, frequency, efficiency Inadequate phosphate binding: timing, dosage, side effects, compliance Excess active vitamin D (+ adynamic bone disease) Secondary hyperparathyroidism GA. Block et al, Am J Kidney Dis 2000,35:1226.

Phosphate intake is linked with protein intake Protein intake (g/kg/jour) Phosphate intake (mg) >1.2 1353 ± 253 1.0 1.2 1052 ± 219 0.8 1.0 936 ± 217 0.6 0.8 831 ± 142 <0.6 599 ± 105 Rufino M, et al. Nephrol Dial Transplant. 1998;13:65 67.

The amount of phosphorus removal depends on clearance, frequency and treatment time. Gotch et al;blood Purif 2003, 21:51-57.

Achieving the old target KDOQI 60 1,13 1,78 mmol/l 50 Relative frequency (%) 40 30 20 16% 54% 29% 10 0 0 1 2 3 ARNOS Rhône-Alpes, D. Fouque et al, 2005 Ph KDOQI

70% of dialysis patients in the USA were hyperphosphataemic in the 90s 25% Patients Above Normal Percentage of Patients 20% 15% 10% 5% 0% 0.32-0.94 0.97-1.26 1.29-1.58 1.61-1.91 1.94-2.23 2.26-2.55 Serum Phosphorus (mmol/l) 2.58-2.87 CMAS (1990) mean = 2.00 DMMS (1993) mean = 2.00 2.91-3.20 3.23-5.49 Block GA, et al. Am J Kidney Dis. 1998;31:607 617.

Achieving the new target KDIGO 60 1.45mmol/ l 56% 50 0.8 mmol/l Relative frequency (%) 40 30 20 38% 10 12% 0 0 1 2 3 Ph KDIGO 2009

Questions What is the better day for biological sampling? 1st day of the week, mid-week? Morning, evening, nighttime? Circadian cycle and dietary intake? What is «lowering toward the normal range»? some pitfalls: Lowering phosphataemia from 3.5 to 2.5 mmol/l may seems enough Being happy with malnourish patient with phosphataemia at 1 mmol/l

Normal phosphataemia? Phosphataemia mmol Case n 1 Case n 2 Case n 3 1,1 1,1 1,1 Calcaemia mmol/l 2.45 2.45 2.45 Albumin g/l 29 42 38 PTH pg/ml 89 289 156 B-ALP µg/l 8 18 13 npcr g/kg/j 0.7 1.5 1.2 Kt/V 1.2 1.7 2.7 Session time 3 x 4h 3 x 4h 3 x 8 h Caco3 mg/j 0 4500 0 Alfacalcidol µg/s 0 3 0 BMI kg/m² 19 29 23 Age years 82 49 65

Conclusion on phosphataemia target (Tend to) normalizing phosphataemia would help (theoretically) in decreasing CV mortality (calcification), but this is not based on any data. Normalizing phosphataemia needs to: Decrease protein intake Increase phosphate binder dosage Increase dialysis (time/frequency) Increase medical cost, limited by compliance Post-dialysis hypophosphataemia (< 0.5 mmol/l) may be harmful (neuromuscular, osteomalacia)

NEW PTH TARGET

High turnover for PTH 150-200 pg/ml

Low turnover for PTH < 60 pg/ml

PTH and «The optimal target level of PTHi in CKD is not know due to limitation of data available and the emerging consensus that those target levels may be lower than currently thought» PTHi diagnose adynamic bone disease when < 60 pg/ml and high turnover bone disease when > 150-200 pg/ml Eknoyan, AJKD 2003 KDOQI

KDIGO target for PTH 4.2.3. In patients with CKD stage 5D, we suggest maintaining ipth levels in the range of approximately two to nine times the upper normal limit for the assay (2C). 130-585 pg/ml (Roche Elecsys ) We suggest that marked changes in PTH levels in either direction within this range prompt an initiation or change in therapy to avoid progression to levels outside of this

KDIGO: relationship between PTH levels and the risk for fractures

KDIGO: relationship between PTH levels, Bone ALP and bone turnover

PTHi Bone turnover relationship in the 90s KDOQI From: Q. QI, AJKD, 1995,26,4:622.

Relationship between coronary calcifications and low PTH and calcium carbonate Caractéristiques cliniques Score de calcification 0 1 2 3 4 Age 41 48,5 54 66 63 p 0,001 Adaptation de Guérin, NDT,2000 Ancienneté en 52 81 85 101 107 dialyse (mois) Ca. élé t (CaCO3) 1,35 (3,3) 1,35 (3,3) 1,5 (3,4) 1,8 (3,75) 2,18 (5,5) Tabagisme (Paquets/Année) 5 11 5 17 17 Fibrinogène (g/l) 4 4,2 4,25 5 5,1 CRP (mg/l) 5,2 7 6,4 12 13 PTH (pg/ml) 360 410 480 220 240 HyperCa (%) 8 10 18 36 42 Ca.P (mmol2/l2) 4,4 4,54 4,57 4,14 4,64 0,001 0,001 0,01 0,001 0,001 0,047 0,034 NS

Low PTH level is associated with arterial calcification GM London et al: e. JASN 2004,15:1943.

KDIGO: bone disease according to CKD stage and treatment

Same as in the 21th century KDIGO Baretto et al,kidney Int 2008: 73; 771

Upper limits PTH reference levels are disturbed by vitamin D deficiency Non vitamin D-deficient Souberbielle, J.-C. et al. J Clin Endocrinol Metab 2001;86:3086-3090 Copyright 2001 The Endocrine Society

What is your PTH assay? KDIGO Souberbielle JC, et al;kidney Int 2006;70:345-350

PTH level of 300 pg/ml can be associated with different bone turnover Calcaemia Phosph PTH 25(OH)D B ALP mmol/l mmol/l pg/ml nmol/l µg/l Mild SHPT 2,15 1,7 300 12 27 Adynamic BD 2,5 1,4 300 28 7 Severe HPT 2,6 2 300 39 65

Case N 1 T0 3 mths 6 mths Lowering BT PTH pg/ml 878 478 300 treatment Calcaemia mmol/l 2,36 2,45 2,5 Phosphataemia mmol/l 1,6 1,7 1,8 ALP total UI/ l 120 87 55 Case N 2 PTH pg/ml 69 187 300 Calcaemia mmol/l 2,5 2,45 2,29 Phosphataemia mmol/l 1,9 1,7 1,5 ALP total UI/ l 20 78 159

PTH and mortality in DOPPS < 600 Tentori, AJKD 2008,52:519 KDIGO

PTH and survival in the USA Kalantar-Zadeh et al; Kidney Int 2006.70:771 200-400

Impact of the PTH target in a French population 30 268 ± 293 pg/ml 25 Relative frequency (%) 20 15 10 KDOQI 30% KDIGO 50 % 5 0 0 100 200 300 400 500 600 700 800 900 1000 1100 1200 1300 1400 1500 1600 ARNOS Rhône-Alpes, D. Fouque et al, 2005 PTH pg/ml

Conclusion KDIGO PTH target is wider mainly based on bone turnover criteria (supposed) Consequences: Larger uncertain zone less affected by the assay Needs a dynamic rendition rather than based on a single value Needs of real bone marker (B-ALP) Less adynamic bone disease (increasing the mean value) Less lowering PTH therapies (calcium, calcitriol analogues, cinacalcet) More hyperparathyroidism Which consequences on bone disease, vascular calcification, survival?

NEW CALCIUM TARGET

Evolution of recommendations 2003: Total corrected calcium must be maintained within the normal range for the laboratory (EVIDENCE) preferably toward the lower end (8.4 to 9.5 mg/dl [2.10 to 2.37 mmol/l]). (OPINION) KDIGO In CKD stage 3-5D, we suggest maintaining serum calcium in the normal range (2D, very low evidence). 2009: KDOQI

Factors Associated with Cardiac Calcification in Young Dialysis Patients KDOQI Coronary Calcification No Calcification Factor (N=14) (N=25) P Value Ca intake from calcium binders (mg/day) 6456 ± 4278 3325 ± 1490 0.02 Serum P (mmol/l) 2.2 ± 0.1 2.0 ± 0.4 0.06 Ca P (mmol 2 /L 2 ) 5.3 ± 0.9 4.6 ± 1.0 0.04 Age (years) 26 ± 3 15 ± 5 <0.001 Mean duration of dialysis (years) 14 ± 5 4 ± 4 <0.001 Serum calcium was not significant. 1. Adapted from Goodman WG, et al. N Engl J Med. 2000;342:1478-1483.

Total calcaemia Severe Hypocalcaemia < 1.9 mmol/l Moderate Hypocalcaemia 1.9 2.1 mmol/l Normal calcaemia 2.1 2.55 mmol/l Mild Hypercalcaemia 2.55 3 mmol/l Moderate Hypercalcaemia 3 3,3 mmol/l Severe Hypercalcaemia > 3.3 mmol/l Calcium, Lancet 1998,352:306. KDIGO

Calcium in the body

Calcium references? KDOQI : no reference of ionized Ca Ionized calcium is:«time consuming and money consuming» Better using Formulae: Corrected ca= Tot Ca (mg/dl) + 0,0704 X [34 alb g/l] Corrected ca= Tot Ca + 0,8 x [40 alb]

KDIGO Corrected calcium? Unfortunately, recent data have shown that it offers no superiority over total calcium alone and is less specific than ionized calcium measurements. The Work Group did not recommend that corrected calcium measurements be abandoned at present. Gauci C, J Am Soc Nephrol 2008. 19; 1592

Relationship between PTH and i-calciumi the set-point PTH (%) 110 100 90 80 70 60 50 40 30 20 10 0 0 Set point Severe SHPT Moderate SHPT Normal subject 4 4.4 4.8 5.2 5.6 6.0 6.4 mg/dl 1.0 1.1 1.2 1.3 1.4 1.5 1.6 mmol/l Ionized calcium Adapted, with permission, from Malberti F et al. Nephrol Dial Transplant 1999;14:2398 406

Baseline calcaemia = set-point Malberti, F., M. Farina, et al. (1999). "The PTH calcium curve and the set point of calcium in primary and secondary hyperparathyroidism." Nephrol Dial Transplant 14(10): 2398 406.

Survival and corrected calcaemia Survival and corrected calcaemia GA Block et al, Mineral metabolism, mortality and morbidity in maintenance hemodialysis. J Am Soc Nephrol 2004,15:2208.

Calcaemia and survival: DOPPS study 2,15 2,5 mmol/l Tentori, AJKD 2008,52:519 KDIGO

KDOQI 50 Relative frequency (%) 40 30 20 44% in the target 2.1 2.37 mmol/l 10 0 0,5 0,8 1,0 1,3 1,5 1,8 2,0 2,2 2,5 2,7 3,0 3,2 3,5 3,7 4,0 ARNOS Rhône-Alpes, D. Fouque et al, 2005 Alb-corrected calc mmol/l

KDIGO 50 40 Relative frequency (%) 30 20 81% in the target 2.1 2.55 mmol/l 10 0 0,3 0,5 0,8 1,0 1,2 1,4 1,7 1,9 2,1 2,4 2,6 2,8 3,0 3,3 3,5 ARNOS Rhône-Alpes, D. Fouque et al, 2005 Calc totale mmol/l

Conclusion We move from a narrow target for albcorrected calcaemia (2.1 to 2.37 mmol/l) to a normal range for total calcaemia with twice more patients achieving the target. Consequences? Less low dialysate calcium? Less non-calcium based phosphate binder? Less SHPT? Less cinacalcet use? More vitamin D? Bone and vascular consequences?

KDOQI strategy: a real pitfall T0 T3 T6 T9 PTH pg/ml 250 390 250 170 Alb-corrected 2.5 2.45 2 2.25 calcaemia Total calcaemia 2.45 2.4 1.9 2.15 mmol/l Phosphataemia 1.8 2 1.7 1.7 mmol/l Ca dialysate mmol 1,5 1.25 1.25 1.5 CacO3 g/day 2g 0 0 2 g Sevelamer mg/day 0 2400 3200 0 Cinacalcet mg/day 0 0 30 30 Un-alpha µg/week 0 0 0 3

With the KDIGO T0 T3 PTH pg/ml 250 220 Corrected 2,5 2,45 calcaemia mmol/l Total calcaemia 2,45 2,4 Phosphataemia mmol/l 1,8 1,5 Ca dialysate 1,5 1,5 CacO3 g/day 1.5 1.5 Lanthanum g/d 0 1 g Cinacalcet 0 0 Un alpha 0 0 Cholecalciferol 100 000 U/mths

MORE RECOMMENDATIONS

KDOQI: native vitamin D In patients with more advanced CKD (Stage 5) and in dialysis patients, it is not established that nutritional replacement with vitamin D (ergocalciferol or cholecalciferol) will be effective since the ability to generate adequate levels of 1,25(OH)2D3 is markedly reduced or is unlikely.

KDIGO and native vitamin D 3.1.3 In patients with CKD stages 3 5D, we suggest that 25(OH)D (calcidiol) levels might be measured, and repeated testing determined by baseline values and therapeutic interventions (2C). We suggest that vitamin D deficiency and insufficiency be corrected using treatment strategies recommended for the general population (2C).

75 100 nmol/l Melamed, M. L.,, et al. (2008). Arch Intern Med 168(15): 1629-

KDIGO and bone markers 3.2.3. In patients with CKD stages 3 5D, we suggest that measurements of serum PTH or bone-specific alkaline phosphatase can be used to evaluate bone disease

Ca x P product 3.1.5. In patients with CKD stages 3 5D, we suggest that individual values of serum calcium and phosphorus, evaluated together, be used to guide clinical practice rather than the mathematical construct of calciumphosphorus product (CaxP) (2D).

Biological target evolution Target Calcaemia Phosphataemia PTH Ca x P Normal range but 1,13 1,78 150 300 < 4,4 preferably toward mmol/l pg/ml mmol²/l² KDOQI the lower end (2,1 2,37 mmol/l ) Normal range (2,1 Toward the 2 9 time the No more 2,55 mmol/l) normal range upper limit of target KDIGO (0,8 1,45 mmol/l) the assay

Take home message The evidence level requirement has increased with the KDIGO, but the level of evidence remains poor. However, most of the recommendations make sense and constitute an improvement of the KDOQI, beyond the targets: The idea of dynamic rather than static interpretation Individualization rather than one size fits all A global approach not based on only one parameter To prevent rather than to cure