Therapeutic golas in the treatment of CKD-MBD

Therapeutic golas in the treatment of CKD-MBD Hemodialysis clinic Clinical University Center Sarajevo Bantao, 04-08.10.2017, Sarajevo Abbvie Satellite symposium 06.10.2017

Chronic Kidney Disease Mineral and Bone Disorder CKD-MBD A systemic disorder of mineral and bone metabolism due to CKD, with abnormalities in one or more of the following areas : Laboratory: Ca, P, PTH, or vitamin D metabolism Bone: turnover, mineralization, volume, linear growth or strength Calcification: of vessels or other soft tissue CKD-MBD begins early in the course of CKD and is under-diagnosed Moe SM, et al. Kidney Int 2006;69:1945 53.

Chronic Kidney Disease Mineral and Bone Disorder Serum levels of parathyroid hormone (PTH), 25-hydroxyvitamin D, and 1,25 dihydroxyvitamin D were present in patients with a glomerular filtration rate (egfr) of <60mL / min / 1.73m2. Significant changes in serum levels of calcium and phosphate can be seen with egfr <40mL / min. Between CKD-MBD and adverse outcomes (diseases and mortality of cardiovascular disease (CVD) and progressive HBB) there are strong associations. Eddington et al. Clin J Am Soc Nephrol. 2010 Dec;5(12):2251-7. doi: 10.2215/CJN.00810110. Epub 2010 Aug 5.

Etiology - potential risk factors for susceptibility and initiation of CKD CKD is associated with old age and is linked with diabetes, hypertension, obesity and CVD. Over time, hyperglycaemia damages the blood vessels in the glomerulus the key structure in the kidney involved in filtering blood; this is called diabetic nephropathy and is the leading cause of end stage renal disease (ESRD). Long term hypertension also damages the small vessels of the kidney. Early detection and management of these conditions are a key strategy for countering the public health threat of CKD. National Kidney Foundation. Am J Kidney Dis 2002;39 (2 Suppl 1):S1-266.

Chronic kidney disease (CKD) is characterized by progressive loss of kidney function over time CKD ultimately leads to kidney failure, cardiovascular (CV) complications and death and as such has become a global public health problem. At the very advanced stages patients often receive either dialysis or transplant both associated with major clinical, patient an economic burdens. However, early treatment can slow the progression of CKD, prevent or delay the complications of decreased kidney function, and reduce the risk of cardiovascular disease (CVD).

The Rates of Death, Cardiovascular Events and Hospitalizations Increase as the egfr Declines Go AS. et al. N Engl J Med 2004; 351: 1296 305.

Morbidity in patients with CKD Cardiovascular disease Vessel calcification Left ventricular hypertrophy Unregulated function RAS system Bones and minerals Changes of absorption in the intestine Increased regeneration of bone (osteoblastic activity) Increased bone resorption (osteoclast activity) Changes in the immune system and other Elevated markers of inflammation Increased frequency of infections Progressive proteinuria Cozzolino M, Ketteler M, Zehnder D. The vitamin D system: a crosstalk between the heart and kidney. Eur J Heart Fail. 2010; 12(10):1031-41.

Secondary hyperparathyroidism One of the most common complications in patients with chronic renal failure Hyperparathyroidism indicates an enhanced function of one or more parathyroid glands SHPT is characterized by: Increased serum concentration of ipth Abnormality of serum calcium and phosphorus Abnormality in vitamin D concentration

Pathophysiology of SHPT - Consequence of Reduced Kidney Function PTH = parathyroid hormone

The Progression of SHPT in CKD: Parathyroid Growth Becomes Irreversible Adapted from Yano S, Sugimoto T, Tsukamoto T. Association of decreased calcium-sensing receptor expression with proliferation of parathyroid cells in secondary hyperparathyroidism. Kidney International 2000 58(5):1980-1986. Tominaga Y, Kohara S, Namii Y. Clonal Analysis of Nodular Parathyroid Hyperplasia in Renal Hyperparathyroidism. World Journal of Surgery. 1996 20(7):744-752.

All-cause death hazard ratio The risk of death increases with persistent hypocalcemia or hypercalcemia 3 Time-dependent model with repeated measures. 2 1.5 K/DOQI recommendation 8.4 9.5 mg/dl 1 0.7 <8.0 8.0 8.49 8.5 8.99 9.0 9.49 9.5 9.99 10.0 10.49 10.5 10.99 11.0 Corrected serum calcium (mg/dl) Kalantar-Zadeh et al., Kidney Int 2006;70:771 80

All-cause death hazard ratio The risk of death increases with persistent hypophosphatemia or hyperphosphatemia 4 3 2 Time-dependent model with repeated measures. K/DOQI Preporučene vrijednosti: 3.5 5.5 mg/dl 1 0.7 < 3.0 3.0 to 3.99 4.0 to 4.99 5.0 to 5.99 6.0 to 6.99 7.0 to 7.99 8.0 to 8.99 9.0 Serum phosphorus (mg/dl) Kalantar-Zadeh et al. Kidney Int 2006;70:771 80

KDOQI Clinical practice Clinical management of SHPT - Clinical Practice Guidelines KDOQI Clinical Practice Guidelines for Bone Metabolism and Disease in Chronic Kidney Disease American Journal of Kidney Diseases, Vol 42, No 4, Suppl 3 (October), 2003: p S2 46

GUIDELINE 1. EVALUATOIN OF CALCIUM AND PHOSPHORUS METABOLISM Serum levels of calcium, phosphorus, and intact plasma parathyroid hormone (PTH) should be measured in all patients with CKD and GFR <60 ml/min/1.73 m2. These measurements should be made more frequently if the patient is receiving concomitant therapy for the abnormalities in the serum levels of calcium, phosphorus, or PTH and in transplant recipient. The target range of plasma levels of intact PTH in the various stages of CKD are denoted in the following table: KDOQI Clinical Practice Guidelines for Bone Metabolism and Disease in Chronic Kidney Disease American Journal of Kidney Diseases, Vol 42, No 4, Suppl 3 (October), 2003: p S2

GUIDELINE 3. EVALUATION OF SERUM PHOSPHORUS LEVELS In CKD patients with kidney failure (Stage 5) and those treated with hemodialysis or peritoneal dialysis, the serum levels of phosphorus should be maintained between 3.5 and 5.5 mg/dl (1.13 and 1.78 mmol/l) GUIDELINE 4. RESTRICTION OF DIETARY PHOSPHORUS IN PATIENTS WITH CKD GUIDELINE 5. USE OF PHOSPHATE BINDERS IN CKD GUIDELINE 6. SERUM CALCIUM AND CALCIUM-PHOSPHORUS PRODUCT In CKD Patients With Kidney Failure (Stage 5): Serum levels of corrected total calcium should be maintained within the normal range for the laboratory used, preferably toward the lower end (8.4 to 9.5 mg/dl [2.10 to 2.37 mmol/l]) KDOQI Clinical Practice Guidelines for Bone Metabolism and Disease in Chronic Kidney Disease American Journal of Kidney Diseases, Vol 42, No 4, Suppl 3 (October), 2003: p S2

*GUIDELINE 8B. VITAMIN D THERAPY IN PATIENTS ON DIALYSIS (CKD STAGE 5) Patients treated with hemodialysis or peritoneal dialysis with serum levels of intact PTH levels >300 pg/ml (33.0 pmol/l) should receive an active vitamin D sterol (such as calcitriol, alfacalcidol, paricalcitol, or doxercalciferol) to reduce the serum levels of PTH to a target range of 150 to 300 pg/ml (16.5 to 33.0 pmol/l): When therapy with vitamin D sterols is initiated or the dose is increased, serum levels of calcium and phosphorus should be monitored at least every 2 weeks for 1 month and then monthly thereafter. The plasma PTH should be measured monthly for at least 3 months and then every 3 months once target levels of PTH are achieved KDOQI Clinical Practice Guidelines for Bone Metabolism and Disease in Chronic Kidney Disease American Journal of Kidney Diseases, Vol 42, No 4, Suppl 3 (October), 2003: p S2

DOQI criteria / criteria for use / Parikalcitol / Zemplar PTH 150-300 pg/ml Calcium 2,10-2,37 mmol/l Phosphorus 1,13-1,78 mmol/l CaxP < from 55PTH 150-300 pg/ml Age over 18 years Dialysis 12 hours a week Expected continuity of dialysis treatment Calcium <2.6 mmol / l Phosphorus <1.9 mmol / l CaxP <5.0 mmol2 / l2 PTH> 1.5-3.0x upper limit of normal National Kidney foundation, Inc 2003 Posljednji odobreni sažetak karakteristika lijeka Zemplar

MECHANISM OF ACTION Paracalcitol (ZEMPLAR ) is a synthetic, biologically active calcitriol analog of vitamin D, which contains modifications in the side chain (D2) and ring A (19- nor), which allows it to selectively activate the vitamin D receptor (VDR). The latest approved summary of the drug caracteristics ZEMPLAR

Parikalcitol (Zemplar ) Pharmacodynamic properties Mechanism of action: Paracalcitol selectively enhances the expression of vitamin D receptors in the parathyroid gland, and does not increase the activation of the Vit D receptor in the intestine and lessens the bone resorption. Parikalcitol enhances the expression of Ca-susceptible receptors in the parathyroid gland. In this way, by inhibiting proliferation in the parathyroid gland and by reducing the synthesis and secretion of the parathyroid hormone (PTH), it lowers the PTH level with minimal influence on Ca and P. Parikalcitol has 1/3 of the ability to reduce secretion PTH versus calcitriol, but it only has 1/10 its ability to increase serum concentrations of Ca and P.

GOALS OF TREATMENT IN SHPT AN OVERVIEW OF TREATMENT OPTIONS

Importance of Early Treatment of SHPT VDR activation levels are disrupted early on in CKD, before changes in PTH can be observed. Guidelines advocate treatment for SHPT as early as stage 3 (<60 ml/min/1.73m2) to: Correct VDR activation deficiency Restore and preserve normal Ca and P equilibrium Prevent bone and CV complications Reduce albuminuria If SHPT patients are left untreated they may develop parathyroid hyperplasia which can lead to resistance to medical therapy. Benefits of treating SHPT early with VDR activators in comparison to no therapy include: Prevention of the development of SHPT resistance Improved survival Reduced healthcare costs

Treatment Goals in SHPT The following interventions are available for managing SHPT: The goal of treatment for SHPT is to control PTH levels without impacting levels of Ca and P This is predominantly achieved through restoring VDR activation

What are the Treatment Options?

An overview of the Treatment Options

Zemplar - Selective VDRa Parikalcitol effectively reduces PTH with minimal effect on Ca and P 3-month Treatment with IV Paricalcitol is Associated with Minimal Increase in Ca and P in Stage 5 CKD Patients on Hemodialysis The values for normalized serum calcium (upper lines) and serum phosphorus (lower lines) during the I2 wk of study in placebo and paricalcitol-treated groups. p < 0.05. Martin KJ, et al. J Am Soc Nephrol 1998;9:1427 32.

Parikalcitol Zemplar Selective 1,2 - selectively regulates VDR activation leading to optimal treatment Treatment with parikalcitol leads to significantly less expression of VDR in the intestines compared with calcitriol. 1. Slatopolsky et al., Am J Kidney Dis 1998;32:S40-47, 26 2. Sprague et al. Kidney Int 2003;63:1483-1490 26

Parikalcitol is effective for long-term treatment Study Design 13-month, open, multicentre study of patients with ESRD on hemodialysis (n = 164) Primary objective: reduction of ipth with reduced impact on calcium, phosphorus and Ca x P levels in an acceptable range over a period of 13 months The initial dose of paracalcitol was 0.04-0.24 μg / kg in the first week, 2-3 times a week, titrated to a maximum of 40 μg until the end of the study. Lindberg J, et al. Clin Nephrol 2001;56:315 23.

A long-term study of the effectiveness of Parikalcitol and the rapid reduction in Efficient 1 elevated levels of ipth n = 35 * Base serum phosphorus value> 7.0 mg / dl 1. Llach et al. Am J Kidney Dis. 2001;38(5 suppl):s45-s50. 2. Lindberg J, et al. Clin Nephrol 2001;56:315 23.

ipth response and dosing of Paricalcitol in patients with initial ipth levels greater than 800 pg /ml or 600-800 pg /ml Llach F, Yudd M. Paricalcitol in dialysis patients with calcitriol-resistant secondary hyperparathyroidism. Am J Kidney Dis. 2001 Nov;38(5 Suppl 5):S45-50.

Parikalcitol improves the quality of life Descriptive cohort analysis of patients on HD (n = 16) reported that HRQoL in patients with SHPT significantly improved after treatment with parikalcitol. The study applied the SF-36 questionnaire before treatment and after 4 months of continuous administration of IV paricalcitol (mean dose: 5.06 mcg), with a significant improvement in total scores at the end of the study (70 vs. 84; p<0.0006), with the exception of physical function, improvements were seen in all domains over time SF36 Changes by domain over time Arango J. Paricalcitol's effect on hemodialyzed patient's quality of life. Presented at the American Society of Nephrology Conference 2009 PUB508.

Efficacy of paricalcitol versus ns-vdr activators Paricalcitol versus calcitriol in the treatment of SHPT In a double-blind, randomized, multicentre study were randomized 263 HD patients with Ca P product < 75 and a PTH level 300 pg/ml to receive either paricalcitol or calcitriol in a doseescalating fashion for up to 32 weeks Results: Paricalcitol-treated patients achieved a 50% reduction from baseline PTH significantly faster than citriol-treated patients (P0.025) and achieved a mean reduction of PTH into a desired therapeutic range (100 to 300 pg/ml) at approximately week 18, whereas the calcitriol-treated patients, as a group, were unable to achieve this range. Moreover, paricalcitol-treated patients had significantly fewer sustained episodes of hypercalcemia and/or increased Cax P product than calcitriol patients (P 0.008) Sprague SM, Llach F, Amdahl M, Taccetta C, Batlle D. Paricalcitol versus calcitriol in the treatment of secondary hyperparathyroidism. Kidney International 2003;63(4):1483-1490.

Patients treated with parikalcitol had significantly fewer episodes of hypercalcaemia and / or increased Ca x P products vs patients treated with calcitriol Adapred from: Sprague SM, Llach F, Amdahl M, Taccetta C, Batlle D. Paricalcitol versus calcitriol in the treatment of secondary hyperparathyroidism. Kidney International 2003;63(4):1483-1490.

Benefits to survive parikalcitol vs ns-vdra Teng et al. 2003 compared the 36-month survival rates among patients undergoing long-term HD, receiving treatment with paricalcitol IV (n=29.021) or calcitriol IV (n=38.378) The all-cause mortality rate among patients receiving paricalcitol IV was 3,417 per 19,031 person-years (0.180 per person-year), as compared with 6,805 per 30,471 person-years (0.223 per person-year) among those receiving calcitriol (p <0,001) The difference in survival was significant at 12 months and increased with time (p <0,001) At 12 months, Ca and P levels had increased by 6.7% and 11.9%, respectively, in the paricalcitol group, as compared with 8.2% and 13.9%, respectively, in the calcitriol group (p <0,001) The two-year survival rate among patients who switched from calcitriol to paricalcitol was 73.0%, as compared with 64.0% among those who switched from paricalcitol to calcitriol (p = 0,04) The findings from this study suggest that paricalcitol has survival advantage over calcitriol in HD patients Teng M, et al. N Engl J Med 2003;349:446 56

Survival (%) Parikalcitol Zemplar Preventive 1 - proven better survival than CV complications compared to therapy with calcitriol. 100 90 80 70 60 50 40 30 20 10 0 0 5 1 0 A 16% higher survival rate on parikalcitol 1 5 2 0 Month Parikalcitol n = 29,021 Kalcitriol n = 38,378 P<0.001 nakon 1 g. 2 5 3 0 3 5 4 0 1. Teng et al., N Engl J Med. 2003; 349:446-456.. 34

Efficient. Selective. Preventive.