Key Points: This slide deck is divided into three primary hyperlinked sections: Overview on secondary hyperparathyroidism (HPT) Bone and mineral consequences.

Folgen für den Knochen- und Mineralhaushalt vs
Folgen für den Knochen- und Mineralhaushalt vs. kardiovaskuläre Folgen bei sekundärem HPT Key Point: • This disease state presentation provides an overview of information on secondary hyperparathyroidism (HPT) and the rationale and value for treating this disorder in patients on dialysis. © 2012 Amgen Inc. Alle Rechte vorbehalten.

Key Points: This slide deck is divided into three primary hyperlinked sections: Overview on secondary hyperparathyroidism (HPT) Bone and mineral consequences of secondary HPT Cardiovascular consequences of secondary HPT Folgen für den Knochen- und Mineralhaushalt vs. kardiovaskuläre Folgen bei sekundärem HPT Überblick zum sekundären Hyperparathyreoidismus (HPT) Folgen des sekundären HPT für Knochen- und Mineralhaushalt Abnormale Laborwerte Fraktur Parathyreoidektomie Kardiovaskuläre Folgen des sekundären HPT Verkalkung und linksventrikuläre Hypertrophie Kardiovaskulär bedingte Hospitalisierung und Mortalität

Überblick zum sekundären HPT
Key Point: • This section of the presentation provides a brief overview on secondary HPT, including: (a) secondary HPT as an integral component of chronic kidney disease-metabolic bone disorder (CKD-MBD), (b) potential consequences of secondary HPT, (c) association between the progression of chronic kidney disease (CKD) and changes intact parathyroid hormone (iPTH) levels, and (d) costs associated with secondary HPT. Überblick zum sekundären HPT

Sekundärer HPT ist ein wesentlicher Bestandteil der “Chronic Kidney Disease-Mineral and Bone Disorder” (CKD-MBD) Abnormale Knochen-morphologie: Umsatz Mineralisierung Volumen Längenwachstum Festigkeit Gefäßverkalkung Weichteilverkalkung Arterielle Steifigkeit Erhöht: PTH Phosphat FGF-23 alkalische Phosphatase Erniedrigt: 1,25(OH)2D3 Calcium Sekundärer HPT Knochen- erkrankung Verkalkung Abnormale Laborwerte Key Point: • Secondary HPT is an integral component of CKD-MBD and, if left unchecked, leads to a worsening of laboratory abnormalities, parathyroid hyperplasia, bone disease, and calcification.1 Background Information: • CKD-MBD is a systemic disorder of mineral and bone metabolism due to CKD. KDIGO® defines CKD-MBD as the manifestation of one or a combination of the following1: Abnormalities in PTH, calcium, phosphorus, fibroblast growth factor (FGF-23), alkaline phosphatase, and vitamin D (collectively referred to as disordered mineral metabolism) are common in patients with CKD. KDIGO® recommends monitoring serum levels of calcium, phosphorus, PTH, and alkaline phosphatase activity beginning in CKD stage 3. Abnormalities in bone turnover, mineralization, volume, linear growth, or strength arise secondary to disordered mineral metabolism and secondary hyperparathyroidism. Vascular or other soft-tissue calcification. The diagnosis of CKD–MBD includes the detection of extraosseous calcification, including arterial, valvular, and myocardial calcification. It is generally well recognized that the prevalence of calcification increases with progressively decreasing kidney function and is greater than that in the general population. KDIGO® = Kidney Disease: Improving Global Outcomes. KDIGO® is a registered trademark of the National Kidney Foundation, Inc. Reference: 1. Kidney Disease: Improving Global Outcomes (KDIGO) CKD–MBD Work Group. KDIGO clinical practice guideline for the diagnosis, evaluation, prevention, and treatment of chronic kidney disease–mineral and bone disorder (CKD–MBD). Kidney Int. 2009; 76 (Suppl 113): S1–S130. FGF-23 = Fibroblasten-Wachstumsfaktor 23. Kidney Disease: Improving Global Outcomes (KDIGO) CKD–MBD Work Group. Kidney Int. 2009;76 (Suppl 113):S1–S130.

Folgen von sekundärem HPT und CKD-MBD
Knochen- und Mineralhaushalt Abnormale Laborwerte Fraktur Parathyreoidektomie Kardiovaskulär Kardiovaskuläre Verkalkung und linksventrikuläre Hypertrophie Kardiovaskulär bedingte Hospitalisierung und Mortalität Key Points: • Not surprisingly, there are consequences to CKD-MBD that results from long standing mineral disturbances that occur as the kidneys fail and the adaptive/pathophysiologic response of the parathyroid glands. • Potential bone and mineral consequences include laboratory abnormalities, fracture, and parathyroidectomy. • Potential cardiovascular consequences include cardiovascular calcification, left ventricular hypertrophy, hospitalization, and mortality.

Folgen der CKD-MBD für den Knochen- und Mineralhaushalt
Key Point: • This section of the presentation reviews the bone and mineral consequences of CKD-MBD. Folgen der CKD-MBD für den Knochen- und Mineralhaushalt

Knochen und Mineralhaushalt
Folgen der CKD-MBD für den Knochen- und Mineralhaushalt: Abnormale Laborwerte Folgen von sekundärem HPT und CKD-MBD für den Knochen- und Mineralhaushalt Knochen und Mineralhaushalt Abnormale Laborwerte Fraktur Parathyreoidektomie Key Point: • This section of the presentation reviews the association between CKD-MBD and laboratory abnormalities.

Folgen der CKD-MBD für den Knochen- und Mineralhaushalt: Abnormale Laborwerte
Bei CKD-Patienten kommt es schon früh zu einer Erhöhung der PTH-Spiegel Page 32, col 1, lines 5-8 and 16-36 Querschnittsanalyse von 1814 dialysepflichtigen und nicht-dialysepflichtigen Patienten mit Niereninsuffizienz (Juni bis Oktober 2004) 100 Calcium < 8,4 mg/dl Phosphat > 4,6 mg/dl iPTH > 65 pg/ml Page 34, figure 4 80 60 Patienten (%) 40 Main Point: • Nearly 60% of patients with GFR levels < 60 mL/min/1.73 m2 have elevated iPTH levels that meet the criteria for CKD-MBD.1 Background Information: • The Study for Evaluation of Early Kidney Disease (SEEK) is a prospective, community-based, observational, noninterventional, cohort study of the prevalence of abnormalities in iPTH, calcium, and phosphorus in patients with CKD.1 • The SEEK analysis shown on this slide represents a cross-sectional assessment of blood samples drawn from 1,814 patients between June 2004 and October • Results showed an increase in the prevalence of iPTH levels > 65 mg/dL across declining eGFR levels. High iPTH levels were observed in 12% of those with an eGFR > 80 mL/min/1.73 m2, 17% of those with an eGFR of 70 to 79 mL/min/1.73 m2, 21% of those with an eGFR between 60 and 69 mL/min/1.73 m2, and 56% of those with an eGFR < 60 mL/min/1.73 m2. By the time eGFR levels decrease to less than 20 mL/min/1.73 m2, approximately 85% of patients have iPTH levels above 65 pg/mL.1 • Serum calcium and phosphorus levels were typically normal until eGFR fell below 40 mL/min/1.73 m2. As eGFR continued to decline, there was a progressive increase in the percentage of patients exhibiting low calcium levels (< 8.4 mg/dL) and high phosphorus levels (> 4.6 mg/dL).1 Reference: 1. Levin A, Bakris GL, Molitch M, et al. Prevalence of abnormal serum vitamin D, PTH, calcium, and phosphorus in patients with chronic kidney disease: results of the study to evaluate early kidney disease. Kidney Int. 2007;71:31-38. 20 Page 34, figure 4 > 80 79–70 69–60 59–50 49–40 39–30 29–20 < 20 Page 32,col 1, lines 5-8, 21-22, and page 37, col 1, lines (n = 61) (n = 117) (n = 230) (n = 396) (n = 355) (n = 358) (n = 204) (n = 93) eGFR (ml/min/1,73 m2) Page 32,col 1, lines 5-8, 16 and 25-26 eGFR = geschätzte glomeruläre Filtrationsrate. Nach: Levin A, et al. Kidney Int. 2007;71:31-38. Page 34, figure 4, extrapolated from graph Page 32, col 2, lines 33-41 Page 31, col 1, lines 15-16 Page 34, figure 4 7

Erhöhte PTH-Spiegel waren bei Dialysepatienten mit mit einem erhöhten Mortalitätsrisiko assoziiert Page 2214, figure 5, multivariable Nicht-adjustiert 2,0 Page 2213, Figure 4, multivariable Case-mix 0,0 0,6 0,8 1,0 1,2 1,4 1,6 1,8 Referenzgruppe Case-mix & MICS N ~ (95%-KI) N = Page 2311, Figure 1, multivariable * 1,5 Relatives Mortalitätsrisiko (n = ) Page 2212, Figure 3, multivariable Gesamtmortalität (Hazard Ratio) Note that P values are not cited in paper and are therefore not documented Key Points: This study identified associations between increases in PTH, Ca x P, serum calcium, and serum phosphorus and the risk of death in a sample of 40,583 patients on hemodialysis.1 Background: Data were analyzed from the Fresenius Medical Care North American Patient Statistical Profile system. All patients were on thrice-weekly hemodialysis as of January 1, 1998 and had at least one determination of calcium and phosphorus during the last three months of Serum calcium values were corrected for albumin concentrations.1 Categories for laboratory values were stratified a priori as follows: four categories of iPTH (<150, 150–300, 300–600, and > 600 pg/mL); 12 categories of Ca x P in 5 mg2/dL2 increments from < 30 to ≥ 80 mg2/dL2; Eight categories of calcium in 0.5 mg/dL increments from < 8.0 to ≥ 11.0 mg/dL; and 8 categories of phosphorus in 1.0 mg/dL increments from < 3.0 to > 9.0 mg/dL.1 Multivariable analyses were adjusted for age, gender, race or ethnicity, diabetes, dialysis vintage, body weight, urea reduction ratio, serum albumin, creatinine, predialysis blood urea nitrogen, bicarbonate, cholesterol, hemoglobin, ferritin, and aluminum.1 The adjusted results showed that elevations of PTH (≥ 600 pg/mL), Ca x P (≥ 50 mg2/dL2), and serum phosphorus (≥ 5.0 mg/dL) were associated with significantly increased relative risk of death compared with referent ranges (150–300 pg/mL for iPTH, 40–45 mg2/dL2 for Ca x P, and 4.0–5.0 mg/dL for phosphorus).1 The significantly increased mortality risk observed in patients with an iPTH ≥ 600 pg/mL was largely driven by patients with an iPTH ≥ 900 pg/mL.1 The association between corrected serum calcium and relative risk of death was linear (lower risk at lower calcium concentrations) on multivariable analysis. Additional analyses determined that the relationship between calcium and relative risk of death was independent of PTH level or phosphorus level.1 Kalantar-Zadeh and colleagues analyzed prospectively collected data from a historic cohort of 58,058 maintenance hemodialysis (HD) patients for any associations between survival and markers of mineral metabolism. Investigators evaluated baseline values and longitudinal changes over 2 years in serum phosphorus, calcium, and PTH to determine whether associations between these baseline and/or time-dependent values and mortality were seen as compared to the respective reference groups (the group with a hazard ratio (HR) of 1.0).1 • Levels of PTH below those recommended in the 2003 KDOQI™ guidelines (< 150 pg/mL) were also associated with an increased risk of death. Further, a fall or rise in serum calcium > 0.6 mg/dL, or an excessive change in serum phosphorus in 6 months was associated with higher death risk in patients whose baseline value was within the 2003 KDOQI™-recommended range.1 • The data analyzed were collected between July 1, 2001 and June 30, 2003 from a historical cohort of all maintenance HD patients from virtually all DaVita dialysis clinics in the US. For this study, all repeated measure laboratory data within a given calendar quarter were averaged to give a quarterly mean value; therefore, up to eight values were available over the 2-year study period.1 KDOQI™ is a trademark of the National Kidney Foundation, Inc. Reference: Kalantar-Zadeh K, Kuwae N, Regidor DL, et al. Survival predictability of time-varying indicators of bone disease in maintenance hemodialysis patients. Kidney Int. 2006;70: 1. Block GA, Klassen PS, Lazarus JM, Ofsthun N, Lowrie EG, Chertow GM. Mineral metabolism, mortality, and morbidity in maintenance hemodialysis. J Am Soc Nephrol. 2004;15: Page 2208, col 1, lines 4-12 1 Page 2208, col 2, lines and page 2209, col 1, lines 1-4 < 150 150–300 300–600 > 600 0,9 Plasma-PTH1 (pg/ml) 400– 499,9 500– 599,9 600– 699,9 ≥ 700 < 100 100– 199,9 200– 299,9 300– 399,9 Intaktes Serum-PTH2 (pg/ml) Page 2209, col 1, line 38 Zeitabhängiges Cox-Modell. MICS = “Malnutrition-Inflammation-Cachexia Syndrome”. Page 2209, col 1, lines 34-47 1. Nach: Block GA, et al. J Am Soc Nephrol. 2004;15: 2. Nach: Kalantar-Zadeh K, et al. Kidney Int. 2006;70:771–780. Page 2211, Figure 1, legend Page 2216, col 1, lines 52-55 Page 2211, col 2, lines and page 2212, Figure 3 PTH on page 2214, Figure 5 Ca x P on page 2213, Figure 4 Phosphorus on page 2211, Figure 1 Note that P values are not cited in paper and significance is therefore not documented Page 2213, col 1, lines 7-16

Das Mortalitätsrisiko hängt mit der Anzahl der erreichten Therapieziele* zusammen Drei Ziele Zwei Ziele Ein Ziel Keine Ziele 1,51 Danese, page 1426, Figure 2 1,39 1,37 1,35 1,21 1,20 1,15 Relatives Mortalitätsrisiko (95%-KI) 1,00 Danese, page 1423, abstract, lines 3-4 and page 1426, figure 2 Main Points: • Danese and colleagues evaluated whether concurrent achievement of the 2003 KDOQI™ targets for bone metabolism and disease was associated with lower mortality as compared to achievement of fewer targets in 22,937 incident hemodialysis patients treated over a 2-year period.1 • Achieving the three main 2003 KDOQITM targets for iPTH, calcium, and phosphorus was associated with the lowest risk of death and achieving none with the highest risk. The increase in risk for having any single target out of range was similar across iPTH, calcium, and phosphorus.1 Background Information: • Study subjects were randomly selected from a pool of patients initiating hemodialysis at Fresenius Medical Care-North America (FMCNA, Lexington, MA) facilities between July 1, 2000 and June 30, Patients were included in the study if they survived more than 3 months after initiation of hemodialysis. Results were adjusted for age, sex, race, body mass index, hemoglobin, blood pressure, albumin, urea reduction ratio, transferrin saturation, and diabetes.1 KDOQI™ is a trademark of the National Kidney Foundation, Inc. Reference: Danese MD, Belozeroff V, Smirnakis K, Rothman KJ. Consistent control of mineral and bone disorder in incident hemodialysis patients. Clin J Am Soc Nephrol. 2008;3: All Alle iPTH and P iPTH und P iPTH and Ca iPTH und Ca Ca and P Ca und P P iPTH Ca None Keins (Referenz) Danese, page 1426, Figure 2 Definition der Gruppen nach zu Studienbeginn erreichten Zielen N = KDOQI™ ist ein Markenzeichen der National Kidney Foundation, Inc. *Die Therapieziele basierten auf den KDOQI™-Leitlinien von 2003: PTH 150 bis 300 pg/ml, Ca innerhalb des Normalbereichs (insbesondere im Hinblick auf das untere Ende von 8,4 bis 9,5 mg/dl), Phosphat 3,5 bis 5,5 mg/dl und Ca x P < 55 mg2/dl2. Danese, page 1426, Figure 2 Nach: Danese MD, et al. Clin J Am Soc Nephrol. 2008;3: Danese, page 1424, col 2, lines 5-13

Zeit außerhalb des Zielbereichs für PTH, Calcium und Phosphat und Mortalitätsrisiko Anzahl der Quartale innerhalb des Zielbereichs im ersten Jahr (% Patienten in Kategorie) PTH Calcium Phosphorus Phosphat Danese, page 1427, figure 4 Main Points: • In a retrospective study by Danese and colleagues, sustained achievement of the KDOQI™ target for iPTH, calcium, or phosphorus for four quarters during the first year of dialysis was associated with the lowest risk of subsequent death.1 • Conversely, achieving a target for ≤ 1 quarter was associated with the highest risk in a subset of patients treated over a 2-year period.1 Background Information: The ‘time in target’ analysis included 17,828 patients initiating hemodialysis at Fresenius Medical Care-North America (FMCNA, Lexington, MA) facilities between July 1, 2000 and June 30, 2002 who survived at least 12 months, and 26,879 person-years of follow-up (excluding the first year of hemodialysis). A Cox proportional hazards model was used to estimate the association between the time in target for PTH, calcium, and phosphorus during the first year of dialysis and the risk of death.1 Results were adjusted for age, sex, race, body mass index, hemoglobin, blood pressure, albumin, urea reduction ratio, transferrin saturation, and diabetes.1 KDOQI™ is a trademark of the National Kidney Foundation, Inc. Reference: Danese MD, Belozeroff V, Smirnakis K, Rothman KJ. Consistent control of mineral and bone disorder in incident hemodialysis patients. Clin J Am Soc Nephrol. 2008;3: Danese, page 1424, col 1, lines 8-16 and page 1426, col 1, lines 28-30 Danese, page 1424, col 1, lines 48-54, and col 2, lines 5-13 and lines 53-55 N = Beurteilt wurde die Anzahl der Quartale der Patienten, die im ersten Jahr unter Dialyse die PTH-, Calcium- und Phosphat-Zielwerte erreichten. Die Patienten wurden anschließend über 3 Jahre beobachtet. Nach: Danese MD, et al. Clin J Am Soc Nephrol. 2008;3: Danese, page 1424, col 2, lines 5-13 and lines 53-55

Cinacalcet in der Behandlung von sekundärem HPT bei Dialysepatienten
Welche Daten zur potenziellen Wirkung von Cinacalcet auf abnormale Laborwerte bei Dialysepatienten mit sekundärem HPT sind verfügbar? Key Point: This section of the slide deck addresses the question: What data are available on the potential effect of cinacalcet on fracture in patients on dialysis with secondary HPT?

Phase-III-Studien mit Cinacalcet: Senkung der Laborparameter
iPTH Serum-Ca 700 10,2 Kontrolle Mimpara® Kontrolle Mimpara® 10,0 600 9,8 500 9,6 400 9,4 9, 2 Medianes iPTH (pg/ml) 300 Medianes Serum-Calcium (mg/dl) 9,0 200 Behandlungsziel 150–300 pg/ml 8,8 8,6 Behandlungsziel 8,4–9,5 mg/dl 100 8,4 8,2 B 2 4 6 8 10 12 14 16 18 20 22 24 26 B 2 4 6 8 10 12 14 16 18 20 22 24 26 n=471 n=663 n=410 n=547 Woche n=366 n=473 n=471 n=663 n=412 n=555 Woche n=368 n=471 Serum-P Ca x P 6,4 Kontrolle Mimpara® 65 Kontrolle Mimpara® 6,2 6,0 60 5,8 55 5,6 5,4 Medianes Ca x P (mg2/dl2) 50 Medianes Serum-Phosphat (mg/dl) 5,2 5,0 45 4,8 Behandlungsziel 3,5–5,5 mg/dl Behandlungsziel <55 mg2/dl2 4,6 40 B 2 4 6 8 10 12 14 16 18 20 22 24 26 B 2 4 6 8 10 12 14 16 18 20 22 24 26 n= 471 n= 663 n=409 n=547 Woche n=363 n=466 Woche n=471 n=662 n=408 n=545 n=363 n=466 Moe S et al. Kidney Int 2005;67:

Knochen- und Mineralhaushalt
Folgen der CKD-MBD für den Knochen- und Mineralhaushalt: Fraktur Folgen von sekundärem HPT und CKD-MBD für den Knochen- und Mineralhaushalt Knochen- und Mineralhaushalt Abnormale Laborwerte Fraktur Parathyreoidektomie Key Point: • This section of the presentation reviews the association between CKD-MBD and fracture.

Folgen der CKD-MBD für den Knochen- und Mineralhaushalt: Fraktur
Störungen des Knochen- und Mineralstoffwechsels sind bei CKD-Patienten mit einem erhöhten Frakturrisiko assoziiert Renale Osteodystrophie (ROD) manifestiert sich typischerweise bei Patienten mit fortgeschrittener CKD (Stadien 3-5D) ROD geht mit einem Verlust an struktureller Integrität, erhöhter Brüchigkeit der Knochen und Frakturen einher Die Prävalenz von Frakturen beträgt bei Dialysepatienten zwischen 10% und 47%, bei den > 50-Jährigen bis zu 50% Die Inzidenz von Hüftfrakturen ist bei Dialysepatienten schätzungsweise 4,4-mal größer als in der Allgemeinbevölkerung Key Point: • Disorders of bone and mineral metabolism are associated with an increased risk of fractures in patients with CKD.1,2 Background Information: • KDIGO® has defined Renal Osteodystrophy as an alteration of bone morphology in patients with CKD. It is one measure of the skeletal component of the systemic disorder of CKD–MBD that is quantifiable by histomorphometry of bone biopsy.1 • Renal osteodystrophy typically manifests in patients with advanced stage CKD (stages 3 through 5D), and is associated with a loss of structural integrity, increased bone fragility, and fractures.1 • Several studies of fracture prevalence and incidence have been reported, with a prevalence from 10% to 47% in general dialysis populations and in approximately half of patients older than 50 years.1 • The incidence rate of hip fractures in all patients who started dialysis in the United States from 1989 to 1996 was 4.4 times higher than that in the residents of Olmstead County. Fractures occur more commonly in elderly patients, in women, in diabetic patients, in those using glucocorticoids, and in those with a longer exposure to dialysis.1,2 KDIGO® is a registered trademark of the National Kidney Foundation, Inc. References: Kidney Disease: Improving Global Outcomes (KDIGO) CKD–MBD Work Group. KDIGO clinical practice guideline for the diagnosis, evaluation, prevention, and treatment of chronic kidney disease–mineral and bone disorder (CKD–MBD). Kidney Int. 2009; 76 (Suppl 113): S1–S130. Alem AM, Sherrard DJ, Gillen DL et al. Increased risk of hip fracture among patients with end-stage renal disease. Kidney Int. 2000;58:396–399. Alem AM, et al. Kidney Int. 2000;58:396–399. Kidney Disease: Improving Global Outcomes (KDIGO) CKD–MBD Work Group. Kidney Int. 2009;76 (Suppl 113):S1–S130.

Folgen der CKD-MBD für den Knochen- und Mineralhaushalt: Fraktur
Dialysepatienten haben im Vergleich zur Allgemeinbevölkerung höhere jährliche Frakturraten Analyse von Daten aus DOPPS (Jahre ) und des US Department of Health and Human Services (Jahr 2000) zur Inzidenz von Hüftfrakturen in den USA Jadoul, 1364, Figure 1 and caption Allgemeinbevölkerung DOPPS 8000 Frauen Männer 6667 7000 6000 Jadoul, page 1360, col 2, lines and page 1361, Table 3, last line on PTH > 900 5000 Jahresinzidenz von Hüftfrakturen, pro Patienten 4000 3136 3280 Key Point: As shown on this slide, annual hip fracture rates are higher in hemodialysis patients compared with the general United States population.1 Elevated PTH levels (> 900 pg/mL) have been associated with a 72% increased risk of new fracture of any time compared with PTH levels of 150 to 300 pg/mL.1 Background Information: The general population incidence estimates are from the US Department of Health and Human Services, Centers for Disease Control, National Center for Health Statistics, National Hospital Discharge Survey, year The DOPPS incidence estimates are based on a period-prevalent sample of patients and hospital admissions for hip fractures, years The Dialysis Outcomes Practice Patterns Study (DOPPS) conducted an analysis of DOPPS II data (2002 to 2004), including an assessment of the association between PTH levels and the risk for fracture. The analysis included data from 320 dialysis facilities from 12 countries. Among 8,162 patients with evaluable data, PTH levels > 900 pg/mL were associated with a 72% increase in the relative risk for new fracture of any type compared with PTH levels of 150 to 300 pg/mL (relative risk = 1.72; 95% CI = ; P = 0.03).1 Reference: Jadoul M, Albert JM, Akiba T, et al. Incidence and risk factors for hip or other bone fractures among hemodialysis patients in the Dialysis Outcomes and Practice Patterns Study. Kidney Int. 2006;70: 3000 2439 2000 1470 1538 1190 985 1000 535 559 690 320 526 100 312 Jadoul, 1364, Figure 1 and caption 30 40 200 55-64 65-74 75-84 85+ 45-54 55-64 65-74 75-84 85+ Altersgruppe Nach: Jadoul M. Kidney Int. 2006;70: Jadoul, page 1360, col 2, lines and page 1361, Table 3, last line on PTH > 900

Das Frakturrisiko ist vom PTH-Spiegel abhängig
Folgen der CKD-MBD für den Knochen- und Mineralhaushalt: Fraktur Das Frakturrisiko ist vom PTH-Spiegel abhängig Monozentrische Kohortenstudie mit 462 Hämodialysepatienten von April 2003 bis März 2008 Note that the abstract states that there were 485 patients but the baseline characteristics table (pg 347) and data reporting include data for 462 patients—this is the number used as the N for the study PTH < 150 pg/ml (P < 0,01) PTH 150 bis 300 pg/ml PTH > 300 pg/ml (P < 0,001) 100 90 80 Wahrscheinlichkeit des frakturfreien Überlebens (%) 70 Key Point: In a study published after the KDIGO® analysis, PTH levels were associated with the increased risk of fracture observed in patients with CKD.1 Background Information: This single-center cohort study retrospectively assessed the occurrence of fracture in 485 hemodialysis patients from April 2003 to March A Kaplan-Meier survival analysis was used to calculate the hazard ratio for fractures associated with three PTH groups: (a) PTH < 150 pg/mL, (b) PTH 150 to 300 pg/mL, and (c) PTH > 300 pg/mL.1 Data were adjusted for age, gender, dialysis vintage, and diabetes.1 Both lower (< 150 pg/mL: HR = 3.47, P < 0.01, n = 148) and higher PTH (> 300 pg/mL; HR = 5.88, P < , n = 141) were associated with a significantly greater risk of fracture compared with a PTH of 150 to 300 pg/mL (n = 173).1 KDIGO® is a registered trademark of the National Kidney Foundation, Inc. Reference: 1. Iimori S, Mori Y, Akita W, et al. Diagnostic usefulness of bone mineral density and biochemical markers of bone turnover in predicting fracture in CKD stage 5D patients—a single-center cohort study. Nephrol Dial Transplant. 2012;27: 60 50 12 24 36 48 60 Beobachtungszeitraum (Monate) Iimori S, et al. Nephrol Dial Transplant. 2012;27:

Überleben von Dialysepatienten nach Hüftfraktur
Folgen der CKD-MBD für den Knochen- und Mineralhaushalt: Fraktur Überleben von Dialysepatienten nach Hüftfraktur Kaplan-Meier-Schätzer des Überlebens (Gesamtmortalität) nach Hüftfraktur Mittalhenkle, pg 675, Figure A Überleben Keine Fraktur Fraktur Key Points: Fractures are associated with an increased risk of all-cause mortality in patients on dialysis.1,2 Background Mittalhenkle and colleagues used data from the United States Renal Data System (USRDS) to retrospectively analyze whether hip fractures in dialysis patients also confer an increase in risk for all-cause and/or cardiovascular mortality. Data were obtained from USRDS, for patients initiating dialysis between May 1, 1995 and December 21, Hip fracture patients were matched to non-fracture controls by age, history of cardiovascular disease, and dialysis duration. Patients were considered at risk from time of hip fracture (or corresponding start time for matched controls) to the first of either death, loss to follow-up, or end of study (December 31, 2000).1 The final sample size included 7,636 fracture patients and 22,896 non-fracture controls. Overall, 4,901 deaths were observed over 6,324 patient-years among those who had a hip fracture (774.9 deaths per 1,000 patient-years) compared with 9,836 deaths over 27,310 person-years among those without a hip fracture (360.2 deaths per 1,000 patient-years).1 As seen in the figure on this slide, Kaplan-Meier survival curves for all-cause mortality demonstrated a 1-year survival rate in dialysis patients after hip fracture of approximately 50% (IRR = 2.15). Median survival time for patients with hip fracture was 289 days (95% CI:275, 302) compared with 714 days (95% CI 697, 732) for those without a hip fracture. Hip fracture was also associated with a 26% greater risk of cardiovascular events and a 91% greater risk for cardiovascular mortality in patients with a history of cardiovascular disease (CVD).1 In a separate study, a similar impact on all-cause mortality was observed following long-bone fracture in 11,136 prevalent hemodialysis patients from the Dialysis Morbidity and Mortality Study (DMMS) Waves 3 and 4 (observational study initiated by USRDS).2 Of the 11,136 patients, 7,179 were studied longitudinally. Mortality rates of per 1,000 patient-years were seen in the dialysis patients after long-bone fracture versus per 1,000 patient-years in the overall dialysis population evaluated) (HR = 1.95). In this analysis, long-bone fractures were common in hemodialysis patients, and were associated with older age, female gender, Caucasian race, diabetes as a cause of CKD 5, lower body mass index, and lack of renal transplantation. Long-bone fracture occurrences were associated with higher than expected rates of cardiovascular disease, pulmonary embolism, major infections, and death.2 References: Mittalhenkle MD, Gillen DL, Stehman-Breen CO. Increased risk of mortality associated with hip fracture in the dialysis population. Am J Kidney Dis. 2004;44: Kaneko TM, Foley RN, Gilbertson DT, Collins AJ. Clinical epidemiology of long-bone fractures in patients receiving hemodialysis. Clin Orthoped Rel Research. 2006;457: N = Dialysepatienten mit Fraktur N = Dialysepatienten ohne Fraktur Nach: Mittalhenkle A, et al. Am J Kidney Dis. 2004;44:

Welche Daten zur potenziellen Wirkung von Cinacalcet auf das Frakturrisiko bei Dialysepatienten mit sekundärem HPT sind verfügbar? Key Point: This section of the slide deck addresses the question: What data are available on the potential effect of cinacalcet on fracture in patients on dialysis with secondary HPT?

Auswirkung der Cinacalcet-Gabe auf das Frakturrisiko
Key Point: • Cinacalcet significantly reduced the risk of fracture in patients with secondary HPT on dialysis.1 Background Information: • Cunningham and colleagues undertook a combined analysis of safety data from four similarly designed randomized, double-blind, placebo-controlled, clinical trials enrolling 1,184 subjects (697 cinacalcet and 487 control) with ESRD and uncontrolled secondary HPT (defined as an iPTH level ≥ 300 pg/mL). Cinacalcet or placebo was administered to patients receiving standard care for hyperphosphatemia and secondary HPT (ie, phosphate binders and vitamin D).1 • The studies included one 12-month phase 2 trial and three 6-month phase 3 trials. The study design, including study drug dosing, was similar across all studies. For those receiving cinacalcet, doses ranged from 30 to 180 mg/day, with doses titrated every 3 to 4 weeks, if necessary. Subjects receiving vitamin D at baseline generally continued at the same dose throughout the trial (although reductions were permitted for albumin-adjusted serum calcium ≥ 11 mg/dL, serum phosphorus ≥ 6.5 mg/dL, or Ca x P ≥ 70 mg2/dL2).1 • As shown on this slide, fracture rates were lower in the cinacalcet group compared with the placebo group (3.2 versus 6.9 per 100 subject-years, respectively). The relative risk of fractures was significantly reduced in the cinacalcet group (relative risk = 0.46, 95% CI to 0.95).1 • In the control group there were 7 fractures of the lower extremities (him, femur, tibia, etc.), and 13 other fractures (ribs and upper extremities). Corresponding data for the cinacalcet group were 11 fractures of the lower extremities and 1 other fracture. Due to the larger number of subjects randomized to cinacalcet, the fracture rate was approximately 50% lower in the cinacalcet group.1 Reference: 1. Cunningham J, Danese M, Olson K, Klassen P, Chertow GM. Effects of the calcimimetic cinacalcet HCl on cardiovascular disease, fracture, and health-related quality of life in secondary hyperparathyroidism. Kidney Int. 2005;68: Auswirkung der Cinacalcet-Gabe auf das Frakturrisiko Gepoolte Analyse von Sicherheitsdaten aus 4 randomisierten, doppelblinden, placebokontrollierten Studien mit ähnlichem Design 1,00 0,95 Wahrscheinlichkeit der Ereignisfreiheit 0,90 P = 0,04 0,85 0,80 Placebo Cinacalcet 0,75 Woche 4 8 12 16 20 24 28 32 36 40 44 48 52 Placebo n = 487 470 445 419 404 383 367 314 136 132 120 117 112 109 Cinacalcet n = 697 656 614 574 554 513 485 392 132 131 125 115 110 106 Alle Patienten erhielten eine Standardtherapie mit Phosphatbindern und Vitamin D, falls verordnet. Cunningham J, et al. Kidney Int. 2005;68: Post-hoc Analyse von prospektiven, randomisierten, Placebo-kontrollierten Phase-3-Studien.

Cinacalcet war mit einer Minderung des Risikos inzidenter Hüftfrakturen assoziiert
Analyse von Daten aus dem Japanese Renal Data Registry zur Ermittlung der Inzidenz von Hüftfrakturen unter Hämodialysepatienten, die mindestens ein Jahr lang Cinacalcet erhielten, gegenüber gematchten Kontrollpatienten ( ) Adjustierte Hazard Ratio der inzidenten Hüftfraktur 0,1 0,2 0,3 0,5 0,7 1 2 3 5 7 10 0,81 [0,61; 1,07] 0,94 [0,67; 1,29] 0,51 [0,27; 0,9] 0,78 [0,53; 1,13] 0,8 [0,52; 1,2] 1,15 [0,7; 1,84] 0,65 [0,45; 0,92] 0,64 [0,41; 0,97] 0,76 [0,47; 1,2] Hazard Ratio (95%-KI) < 6,0 P (mg/dl) ≥ 6,0 < 10 Ca (mg/dl) Baseline-Strata ≥ 10 Key Point: • In this retrospective analysis, administration of cinacalcet for 1 to 2 years was associated with a decreased risk for incident hip fracture.1 Background Information: • Fujii and colleagues analyzed the data from the Japanese Renal Data Registry to assess the incidence of hip fracture among 6,137 hemodialysis patients receiving cinacalcet for at least one year matched with 12,274 control patients, and whether cinacalcet therapy was associated with a reduction in the incidence of hip fracture. The study included data from 2007 through • Hazard ratios were adjusted for age, Cr, albumin, body mass index, and Kt/V, which were significantly different between controls and the cinacalcet group at the end of • The hazard ratio for incident hip fracture in patients receiving cinacalcet therapy for 1 to 2 years was 0.81 (95% CI 0.61 to 1.07, P = 0.143). In subgroup analyses of those with a high risk for bone fracture (ie, iPTH > 180 pg/mL, phosphorus > 6 mg/dL, or body mass index < 22) cinacalcet therapy for 1 to 2 years significantly reduced the risk of incident hip fractures.1 Reference: 1. Fujii N, Hamano T, Taniguchi M, et al. CINACALCET REDUCES THE INCIDENCE OF HIP FRACTURE IN HEMODIALYSIS PATIENTS WITH HYPERPARATHYROIDISM, HYPERPHOSPHATEMIA OR LOW BMI. presented at ERA-EDTA 2011, Prague, Czech Republic. Abstract SuO011 iPTH (pg/ml) <180 ≥ 180 < 22,0 BMI (kg/m2) ≥ 22,0 Zugunsten von Cinacalcet Nicht zugunsten von Cinacalcet P = Phosphat; Ca = Calcium; iPTH = intaktes Parathormon; BMI = Body Mass Index; KI = Konfidenzintervall. Fujii N, et al. presented at ERA-EDTA 2011, Prague, Czech Republic. Abstract SuO011

Knochen und Mineralhaushalt
Folgen der CKD-MBD für den Knochen- und Mineralhaushalt: Parathyreoidektomie Folgen von sekundärem HPT und CKD-MBD für den Knochen- und Mineralhaushalt Knochen und Mineralhaushalt Abnormale Laborwerte Fraktur Parathyreoidektomie Key Point: • This section of the presentation reviews the association between CKD-MBD and parathyroidectomy.

PTH -Spiegel/ Schweregrad der Erkrankung Fortschreiten der Hyperplasie
Folgen der CKD-MBD für den Knochen- und Mineralhaushalt: Parathyreoidektomie Nebenschilddrüsenhyperplasie trägt in bedeutendem Maß zum Fortschreiten der Erkrankung bei Frühe Nodularität Diffuse Hyperplasie Nodulär Einzelner Knoten PTH -Spiegel/ Schweregrad der Erkrankung Monoklonal: VDR CaR Polyklonal: Fortschreiten der Hyperplasie Sekretion Synthese Minuten Stunden/Tage Wochen/Jahre Adaptiv Pathologisch FGFR1 Klotho Normal Tominga Y, et al. Semin Surg Oncol. 1997;13: 78,A,1; 80,B,3; 82,A,fig 3. Rodriguez M, et al. Am J Physiol Renal Physiol. 2005;288: F258,A,fig 4; F257,B,3. Komaba H, et al. Kidney Int. 2010;77: 234,A,2; 234,A,2. Fukuda N, et al. J Clin Invest. 1993;92: 1440,A, fig 4; 1440,B,4; 1437,A,2. Rodriguez M, et al. Am J Physiol Renal Physiol. 2005;288: F257,B,3; F258,A, fig 4; F258,A,2; fig 4. Key Point: • As parathyroid hyperplasia progresses, the parathyroid glands respond by increasing the number of cells (cell proliferation) and size (hypertrophy/gland enlargement) of cells available to produce PTH.1 Background Information: • In early renal failure, a reduced number of CaRs, VDRs, FGFR1, and Klotho may be present in the parathyroid cells.1,2 The greatest reduction in CaRs, VDRs, FGFR1, and Klotho is seen in patients with nodular hyperplasia.1,2 It is not clear why the downregulation occurs, as the cause and effect have not been established.1 • The abnormal growth of the parathyroid glands can be defined as1: Diffuse hyperplasia (polyclonal growth), Nodular growth (monoclonal growth) within diffuse hyperplastic tissue, or Diffuse monocloncal hyperplasia (adenoma or single nodule) References: Rodriguez M, Nemeth E, Martin D. The calcium-sensing receptor: a key factor in the pathogenesis of secondary hyperparathyroidism. Am J Physiol Renal Physiol. 2005;288:F253-F264. Komaba H, Goto S, Fujii H, et al. Depressed expression of Klotho and FGF receptor 1 in hyperplastic parathyroid glands from uremic patients. Kidney Int. 2010;77: Gogusev J, et al. Kidney Int. 1997;51: 332,A,fig 3. Fortschreitende Nebenschilddrüsenhyperplasie ist gekennzeichnet durch erhöhte Zellularität und Größe der Drüse sowie Knotenbildung Bargman JM, et al. In: Harrison’s Principles of Internal Medicine. 17th ed Chapter 274: pdf11,A,4. Nach: Rodriguez M, et al. Am J Physiol Renal Physiol. 2005;288:F253-F264. Nach: Komaba H, et al. Kidney Int. 2010;77:

KDIGO®-Empfehlung zur Parathyreoidektomie:
Folgen der CKD-MBD für den Knochen- und Mineralhaushalt: Parathyreoidektomie Bei Patienten, die auf medikamentöse/pharmakologische Therapie nicht ansprechen, kann eine Parathyreoidektomie erforderlich sein KDIGO®-Empfehlung zur Parathyreoidektomie: „Bei Patienten mit CKD des Stadiums 3-5D mit schwerem sekundärem HPT, die auf medikamentöse/pharmakologische Therapie nicht ansprechen, empfehlen wir eine Parathyreoidektomie.“ Die KDIGO®-Leitlinien stellen außerdem fest, dass bei den meisten Patienten nach einer Parathyreoidektomie eine Verbesserung der biochemischen Parameter eintritt aufgrund eines Mangels an randomisierten kontrollierten Studien mit medikamentöser versus chirurgischer Therapie des sekundären Hyperparathyreoidismus ein Vergleich dieser beiden Managementstrategien nur schwer möglich ist Key Point: • Parathyroidectomy may be required in patients who fail to respond to medical/pharmacological therapies.1 Background Information: • KDIGO® states that, “In patients with CKD stages 3-5D with severe secondary HPT who fail to respond to medical/pharmacological therapy, we suggest parathyroidectomy.” This recommendation was graded as a 2B recommendation.1 Level 2 recommendations are awarded if the strength of evidence is weak. KDIGO® states that the majority of patients would want to follow the recommended course of action, but many would not. Different choices will be appropriate for different patients. The Grade B is awarded if the quality of evidence supporting the recommendation is moderate.1 • The KDIGO® guidelines also note that1: Most patients who undergo parathyroidectomy exhibit an improvement in biochemical parameters. Owing to a lack of randomized controlled trials of medical versus surgical therapy of secondary hyperparathyroidism, these management strategies are difficult to compare. KDIGO® = Kidney Disease: Improving Global Outcomes. KDIGO® is a registered trademark of the National Kidney Foundation, Inc. Reference: 1. Kidney Disease: Improving Global Outcomes (KDIGO) CKD–MBD Work Group. KDIGO clinical practice guideline for the diagnosis, evaluation, prevention, and treatment of chronic kidney disease–mineral and bone disorder (CKD–MBD). Kidney Int. 2009; 76 (Suppl 113): S1–S130. KDIGO® ist eingetragenes Markenzeichen der National Kidney Foundation, Inc. Kidney Disease: Improving Global Outcomes (KDIGO) CKD–MBD Work Group. Kidney Int. 2009;76 (Suppl 113):S1–S130.

Adjustierte Hazard Ratio für Parathyreoidektomie
Folgen der CKD-MBD für den Knochen- und Mineralhaushalt: Parathyreoidektomie Main Point: • Higher PTH levels are associated with a progressively increased risk of parathyroidectomy.1 Background Information: • Data from the retrospective Waves 1, 3, and 4 of the Dialysis Morbidity and mortality Study datasets were linked to Medicare claims data to identify associations of parathyroidectomy. The dialysis Morbidity and Mortality study was a historical cohort study of a random sample of one of every 5 U.S. patients on hemodialysis who were alive on December 31, Data abstraction began in 1995 and continued for 3 years. The final study cohort was 10,588 patients.1 • The figure on this slide shows the association between the risk for parathyroidectomy and the adjusted hazards ratio for parathyroidectomy. As shown, higher levels of PTH were associated with a stepwise increase in the risk for parathyroidectomy. The authors suggest that this stepwise increase in risk suggests that a single-threshold management approach may not be ideal.1 Reference: 1. Slinin Y, Foley RN, Collins AJ. Clinical epidemiology of parathyroidectomy in hemodialysis patients: the USRDS waves 1, 3, and 4 study. Hemodial Int. 2007;11:62-71. Höhere PTH-Spiegel sind mit einem höheren Parathyreoidektomie-Risiko assoziiert Retrospektive Analyse von Medicare-Daten sowie der Waves 1, 3 und 4 der Dialysis Morbidity and Mortality Study (DMMS), erhoben an Hämodialyse-Patienten innerhalb eines mittleren Beobachtungszeitraums von 3,6 Jahren P < 0,0001 Adjustierte Hazard Ratio für Parathyreoidektomie P < 0,0001 P = 0,0002 P = 0,0139 PTH (pg/ml) Slinin Y, et al. Hemodial Int. 2007;11:62-71. 24

Beobachtungszeitraum (Monate) Adjustierte Hazard Ratio für Mortalität
Folgen der CKD-MBD für den Knochen- und Mineralhaushalt: Parathyreoidektomie In den ersten drei Jahren nach Parathyreoidektomie besteht ein erhöhtes Mortalitätsrisiko Retrospektive Analyse von Daten aus der Dialysis Morbidity and Mortality Study, Waves 1, 3 und 4, sowie von Medicare-Erstattungsdaten zur Identifikation von inzidenten Parathyreoidektomien unter Hämodialyse-Patienten innerhalb eines mittleren Beobachtungszeitraums von 3,6 Jahren Beobachtungszeitraum (Monate) Adjustierte Hazard Ratio für Mortalität 3,0 2,5 2,0 1,5 1,0 0,5 12 24 36 48 60 72 84 96 Main Point: • The adjusted hazard ratio for mortality is increased markedly during the first year following parathyroidectomy, and remains elevated for 3 years. A lower risk of mortality is observed starting in year 4 following parathyroidectomy.1 Background Information: • Data from the retrospective Waves 1, 3, and 4 of the Dialysis Morbidity and mortality Study datasets were linked to Medicare claims data to identify associations of parathyroidectomy. The dialysis Morbidity and Mortality study was a historical cohort study of a random sample of one of every 5 U.S. patients on hemodialysis who were alive on December 31, Data abstraction began in 1995 and continued for 3 years. The final study cohort was 10,588 patients.1 • The figure on this slide shows the mortality hazards ratios associated with parathyroidectomy using 12-month interval Poisson regression, adjusted for baseline patient characteristics.1 • A similar analysis used observational data from the USRDS examined data from 4,558 hemodialysis or peritoneal dialysis patients undergoing a first parathyroidectomy between January 1, 1998 and December 31, Parathyroidectomy was associated with higher short-term and lower long-term mortality rates. Compared with matched control patients, those who underwent parathyroidectomy had a significantly higher adjusted relative risk for mortality during the first 30 days following parathyroidectomy (adjusted RR 2.72, 95% CI 2.12, 3.48, P < 0.001) and 30 to 90 days following parathyroidectomy (adjusted RR 1.45, 95% CI 1.23, 1.72, P < 0.001). Survival curves between the 2 groups crossed 587 days following parathyroidectomy.2 References: Slinin Y, Foley RN, Collins AJ. Clinical epidemiology of parathyroidectomy in hemodialysis patients: the USRDS waves 1, 3, and 4 study. Hemodial Int. 2007;11:62-71. Kestenbaum B, Andress DL, Schwartz SM, et al. Survival following parathyroidectomy among United States dialysis patients. Kidney Int. 2004;66: Slinin Y, et al. Hemodial Int. 2007;11:62-71.

Das Risiko einer Hüftfraktur kann nach Parathyreoidektomie erhöht sein
Folgen der CKD-MBD für den Knochen- und Mineralhaushalt: Parathyreoidektomie Das Risiko einer Hüftfraktur kann nach Parathyreoidektomie erhöht sein Analyse von Daten aus der Dialysis Outcomes Practice Patterns Study an Hämodialyse-Patienten mit oder ohne anamnestisch bekannte Parathyreoidektomie ( ) Jadoul, page 1360, table 2, and page 1359, col 1, lines (for P value) Adjustierte Odds Ratio für Hüftfraktur Key Point: Parathyroidectomy is associated with an increased risk of hip fracture in patients on hemodialysis.1 Background Information: The Dialysis Outcomes Practice Patterns Study (DOPPS) conducted an analysis of DOPPS II data (2002 to 2004), including an assessment of the association between a history of hip fracture and prior parathyroidectomy. The analysis included data from 320 dialysis facilities from 12 countries.1 Medical record abstraction performed by facility staff was used to obtain baseline data and the occurrence of parathyroidectomy and hip fracture. Data were available for 8,978 patients.1 Patients with a prior parathyroidectomy (n = 610) had a 70% increased risk for a history of hip fracture compared with those who had not had a parathyroidectomy (adjusted odds ratio = 1.70; 95% CI , P = 0.02).1 Results were controlled for the effects of facility clustering and adjusted for age, gender, race, body mass index, years on dialysis, prior transplant, nursing home status, need for assistance in walking, phosphorus, calcium, albumin, PTH, and bicarbonate levels, and 15 comorbid conditions.1 Adynamic bone disease is becoming increasingly common in patients on dialysis. Typically associated with low PTH levels, the disease has been ascribed to over suppression of PTH due to parathyroidectomy, the aggressive use of vitamin D, or chronic positive calcium balance. The main concerns are related to the inability of bone to contribute to mineral homeostasis in the absence of kidney function, and the risk of hip fracture.2 References: Jadoul M, Albert JM, Akiba T, et al. Incidence and risk factors for hip or other bone fractures among hemodialysis patients in the Dialysis Outcomes and Practice Patterns Study. Kidney Int. 2006;70: National Kidney Foundation. K/DOQI Clinical Practice Guidelines for Bone Metabolism and Disease in Chronic Kidney Disease. Am J Kidney Dis. 2003;42(suppl 3):S1-S202. P = 0,02 Jadoul, page 1358, col 1, lines 6-8 Jadoul, page 1365, col 1, lines 40-45, col 2, lines 1-3, and page 1360, table 2 (note that the patient population for the PTX and hip fracture analysis included only 8,978 patients) Jadoul M, et al. Kidney Int. 2006;70: Jadoul, page 1360, table 2, for factors, and table caption explaining that odds ratios were adjusted for these factors Jadoul, page 1360, table 2, and page 1359, col 1, lines (for P value) NKF, KDOQI page S125, col 2, lines 19-39

Hypokalzämie tritt mit einer Häufigkeit von > 80% auf
Folgen der CKD-MBD für den Knochen- und Mineralhaushalt: Parathyreoidektomie Hypokalzämie nach Parathyreoidektomie erfordert proaktives Monitoring und Management Hypokalzämie tritt mit einer Häufigkeit von > 80% auf Mögliche durch Hypokalzämie bedingte unerwünschte Ereignisse sind: Tetanie Krampfanfälle Frakturen Arrhythmien und Mortalität Zur Aufrechterhaltung des Calciumspiegels ist häufig Calcium- und Vitamin-D-Supplementierung erforderlich Die Calciumspiegel müssen engmaschig überwacht werden Die Notwendigkeit der Calciumgabe ist typischerweise unmittelbar nach einer Parathyreoidektomie am größten Key Points: • Hypocalcemia may occur following parathyroidectomy, and proactive monitoring and management are required.1-3 Background Information: • In an analysis of calcium needs in the early post-parathyroidectomy period, Viaene and colleagues retrospectively assessed calcium needs in 42 patients on dialysis who underwent successful subtotal parathyroidectomy, including biochemical indices of mineral metabolisms within a time frame of 4 weeks before and 6 weeks after surgery.1 Transient hypocalcemia was observed in 83% of the patients.1 • Hypocalcemia is associated with potentially serious adverse events, including tetany, seizures, fractures, arrhythmias, and mortality.1-3 • Calcium and vitamin D supplementation are often required following parathyroidectomy to maintain calcium levels. Calcium levels need to be monitored closely since calcium requirements typically vary over time (and are generally highest in the period immediately following parathyroidectomy).1-3 References: Viaene L, Evenepoel P, Bammens B, Claes K, Kuypers D, Vanrenterghem Y. Calcium requirements after parathyroidectomy in patients with refractory secondary hyperparathyroidism. Nephron Clin Pract. 2008;110:c80-c85. Gür S, Yilmaz H, Tüzüner S, Aydin AT, Süleymanlar G. Fractures due to hypocalcemic convulsion. Int Orthopaedics. 1999;23: National Kidney Foundation. Clinical Practice Guidelines for Bone Metabolism and Disease in Chronic Kidney Disease. Am J Kidney Dis. 2003;42(suppl 3):S1-S201. Viaene L, et al. Nephron Clin Pract. 2008;110:c80-c85. Gür S, et al. Int Orthop. 1999;23(5): National Kidney Foundation. Am J Kidney Dis. 2003;42(suppl 3):S1-S201.

Schwerer rezidivierender sekundärer HPT Rezidivierender sekundärer HPT
Folgen der CKD-MBD für den Knochen- und Mineralhaushalt: Parathyreoidektomie Hyperparathyreoidismus kann nach Parathyreoidektomie fortbestehen oder erneut auftreten Retrospektive Analyse von 20 CKD-Patienten, die einer totalen Parathyreoidektomie unterzogen wurden, zur Beurteilung des Wiederauftretens von sekundärem HPT über einen medianen Zeitraum von 46,8 Monaten % Patienten Key Point: • Hyperparathyroidism can persist or reoccur following parathyroidectomy.1 Background Information: • This single-center study assessed predictors of recurrent secondary HPT among 20 patients on dialysis who received total parathyroidectomy over a 10-year period.1 • Patients were followed for a median of 46.8 months (range months).1 • During follow-up, fifteen patients (75%) had detectable iPTH levels (ie, > 10 pg/mL), seven (35%) had recurrent secondary HPT (ie, iPTH > 62 pg/mL), and three (15%) had severe recurrent secondary HPT (ie, iPTH > 300 pg/mL).1 • The occurrence of recurrent secondary HPT was predicted by the duration of dialysis dependency post-parathyroidectomy (a measure of the overall exposure to uremic stimulus to parathyroid hyperplasia), and the degree of early hypocalcemia (possibly reflecting the adequacy of operative parathyroid ablation).1 Reference: 1. Stratton J, Simcock M, Thompson H, Farrrington K. Predictors of recurrent hyperparathyroidism after total parathyroidectomy in chronic renal failure. Nephron Clin Pract. 2003;95:c15-c22. Schwerer rezidivierender sekundärer HPT Messbare PTH-Spiegel Rezidivierender sekundärer HPT Rezidivierender sekundärer HPT = iPTH > 62 pg/ml Schwerer rezidivierender sekundärer HPT = iPTH > 300 pg/ml Stratton J, et al. Nephron Clin Pract. 2003;95:c15-c22.

Welche Daten zur potenziellen Wirkung von Cinacalcet auf die Notwendigkeit einer Parathyreoidektomie bei Dialysepatienten mit sekundärem HPT sind verfügbar? Key Point: This section of the slide deck addresses the question: What data are available on the potential effect of cinacalcet on parathyroidectomy in patients on dialysis with secondary HPT?

Wirkung von Cinacalcet auf das Drüsenvolumen
Mittleres (± SEM) Drüsenvolumen der Nebenschilddrüsen, geschätzt anhand Ultraschalluntersuchung, vor und nach 26 bzw. 52 Wochen Behandlung mit Cinacalcet, stratifiziert anhand des Ausgangsvolumens P = 0,016 P = 0,12 1000 Komaba, page 2309, col 2, Figure 3 900 800 P = 0,048 700 Mittleres Volumen jeder Nebenschilddrüse (mm3) 600 P = 0,055 200 150 Key Point: • In the analysis conducted by Komaba and colleagues, long-term use of cinacalcet led to significant decreases in parathyroid gland volume, regardless of baseline volume.1 Background: • The volume of each parathyroid gland decreased significantly during the study from a mean of 236 ± 272 mm3 at baseline, to 200 ± 266 mm3 at week 26, and 191 ± 252 mm3 at week 52 (P < 0.001).1 • For patients with a baseline parathyroid gland volume < 500 mm3, gland volume was 152 ± 116 mm3, 134 ± 128 mm3, and 132 ± 129 mm3 at baseline, week 26, and week 52, respectively; P = 0.02).1 • For patients with a baseline parathyroid gland volume > 500 mm3, gland volume was 780 ± 357 mm3, 627 ± 468 mm3, and 571 ± 453 mm3 at baseline, week 26, and week 52, respectively; P = 0.01).1 Reference: Komaba H, Nakanishi S, Fujimori A, et al. Cinacalcet effectively reduces parathyroid hormone secretion and gland volume regardless of pretreatment gland size in patients with secondary hyperparathyroidism. Clin J Am Soc Nephrol. 2010;5: 100 50 Komaba, page 2309, col 1, lines 27-30 BL Wk 26 Wk 52 BL Wk 26 Wk 52 Ausgangsvolumen < 500 mm3 (Anzahl der Drüsen = 155) Ausgangsvolumen ≥ 500 mm3 (Anzahl der Drüsen = 155) Komaba, page 2309, col 1, lines 32-34 Komaba, page 2309, col 1, lines 37-39 Nach: Komaba H, et al. Clin J Am Soc Nephrol. 2010;5:

Cinacalcet senkte das Risiko einer Parathyreoidektomie bei Dialysepatienten mit sekundärem HPT
Gepoolte Analyse von Sicherheitsdaten aus 4 randomisierten, doppelblinden, placebokontrollierten Studien mit ähnlichem Design 1,00 0,95 P = 0,0009 0,90 Wahrscheinlichkeit der Ereignisfreiheit 0,85 0,80 Placebo Key Point: • Cinacalcet significantly reduced the risk of parathyroidectomy in patients with secondary HPT on dialysis.1 Background Information: • Cunningham and colleagues undertook a combined analysis of safety data from four similarly designed randomized, double-blind, placebo-controlled, clinical trials enrolling 1,184 subjects (697 cinacalcet and 487 control) with ESRD and uncontrolled secondary HPT (defined as an iPTH level ≥ 300 pg/mL). Cinacalcet or placebo was administered to patients receiving standard care for hyperphosphatemia and secondary HPT (ie, phosphate binders and vitamin D).1 • The studies included one 12-month phase 2 trial and three 6-month phase 3 trials. The study design, including study drug dosing, was similar across all studies. For those receiving cinacalcet, doses ranged from 30 to 180 mg/day, with doses titrated every 3 to 4 weeks, if necessary. Subjects receiving vitamin D at baseline generally continued at the same dose throughout the trial (although reductions were permitted for albumin-adjusted serum calcium ≥ 11 mg/dL, serum phosphorus ≥ 6.5 mg/dL, or Ca x P ≥ 70 mg2/dL2).1 • As shown on this slide, parathyroidectomy rates were lower in the cinacalcet group compared with the placebo group (0.3 versus 4.1 per 100 subject-years, respectively). The relative risk of parathyroidectomy was significantly reduced in the cinacalcet group (relative risk = 0.07, 95% CI to 0.55—a 93% reduction). The median PTH at the time of parathyroidectomy was 1,056 pg/mL (interquartile range of 523 to 1,502).1 • In the control group there were 12 parathyroidectomies in subject years of follow-up. In the cinacalcet group there was 1 parathyroidectomy in subject-years of follow-up.1 Reference: 1. Cunningham J, Danese M, Olson K, Klassen P, Chertow GM. Effects of the calcimimetic cinacalcet HCl on cardiovascular disease, fracture, and health-related quality of life in secondary hyperparathyroidism. Kidney Int. 2005;68 Cinacalcet 0,75 Woche 4 8 12 16 20 24 28 32 36 40 44 48 52 n = 487 475 461 444 426 396 240 153 146 136 134 132 128 411 Placebo n = 697 670 639 601 584 526 275 152 143 137 127 121 552 Cinacalcet Alle Patienten erhielten eine Standardtherapie mit Phosphatbindern und Vitamin D, falls verordnet. Cunningham J, et al. Kidney Int. 2005;68: Post-hoc Analyse von prospektiven, randomisierten, Placebo-kontrollierten Phase-3-Studien.

Kardiovaskuläre Folgen der CKD-MBD
Key Point: • This section of the presentation reviews the cardiovascular consequences of CKD-MBD. Kardiovaskuläre Folgen der CKD-MBD

Folgen von sekundärem HPT und CKD-MBD
Kardiovaskuläre Folgen der CKD-MBD: Verkalkung und linksventrikuläre Hypertrophie Folgen von sekundärem HPT und CKD-MBD Kardiovaskulär Verkalkung und linksventrikuläre Hypertrophie Kardiovaskulär bedingte Hospitalisierung und Mortalität Key Point: • This section of the presentation reviews the association between CKD-MBD, calcification, and left ventricular hypertrophy.

Risikofaktoren für vaskuläre und kardiale Verkalkung bei CKD-Patienten
Kardiovaskuläre Folgen der CKD-MBD: Verkalkung und linksventrikuläre Hypertrophie Risikofaktoren für vaskuläre und kardiale Verkalkung bei CKD-Patienten Traditionell Alter Diabetes mellitus Hypertonie Dyslipidämie Rauchen Nicht-traditionell Abnahme der Nierenfunktion Zeit unter Dialyse Störungen des Mineralstoffwechsels Hyperparathyreoidismus Hyperphosphatämie Veränderter Vitamin-D-Stoffwechsel Erhöhte FGF-23-Spiegel Entzündung und oxidativer Stress Osteogene Faktoren Key Point: A wide variety of traditional and nontraditional risk factors may contribute to vascular and cardiac calcification in patients with CKD.1 Background Information: Traditional risk factors for vascular and cardiovascular calcification include: (a) age, (b) diabetes mellitus, (c) hypertension, (d) dyslipidemia, and (e) smoking.1 Nontraditional risk factors for vascular and cardiovascular calcification include: (1) kidney function decline, (b) dialysis vintage, (c) disorders of mineral metabolism (including hyperparathyroidism, hyperphosphatemia, changes in vitamin D metabolism, and elevated levels of FGF-23), (d) inflammation and oxidative stress, (e) increased expression of osteogenesis factors (including core binding factor a 1 and runt-related transcription factor 2), and decreased expression of fetuin A.1 Reference: Kendrick J, Chonchol M. The role of phosphorus in the development and progression of vascular calcification. Am J Kidney Dis. 2011;58: Nach: Kendrick J, et al. Am J Kidney Dis. 2011;58:

Kardiovaskuläre Folgen der CKD-MBD: Verkalkung und linksventrikuläre Hypertrophie
Die Prävalenz der Koronarverkalkung steigt mit abnehmender Nierenfunktion Drei unabhängige Studien zeigen, dass bei der Mehrzahl der Dialysepatienten eine Koronarverkalkung vorliegt.* Koronarverkalkung Prävalenzrate (%) Key Point: • Coronary artery calcification is common in all stages of CKD, and increases in prevalence as kidney function declines.1-3 Background Information: • Coronary artery calcification (CAC) is regarded as an index of the severity of atherosclerotic vascular disease, and may predict future adverse cardiovascular events in patients on dialysis. Russo and colleagues assessed the prevalence of coronary artery calcification in 85 patients with CKD not yet on dialysis. Spiral computed tomography demonstrated coronary artery calcification in 40% of patients. Calcium scores were less than 100 in 12 patients, 101 to 400 in 12 patients, 401 to 1,000 in 6 patients, and > 1,000 in 4 patients.1 • Spiegel and colleagues used electron beam computed tomography to assess the prevalence of vascular and coronary calcification in 129 subjects who were new to dialysis. Overall, 36% had no artery calcification (0 calcium score), while 64% had some degree of calcification. Thirty-four percent of subjects had coronary calcification scores greater than the 90th percentile for age and gender.2 • Raggi and colleagues conducted a cross-sectional analysis of 205 prevalent patient on hemodialysis in which cardiac calcification was assessed using electron beam tomography. Overall, 83% of subjects had evidence of coronary calcification. The median coronary artery calcium score was 595 (interquartile range of 76 to 1,600). The extent of coronary calcification was more pronounced with older age, male gender, white race, diabetes, longer dialysis vintage, and higher serum concentrations of calcium and phosphorus.3 References: 1. Russo D, Palmiero G, De Blasio AP, Balletta MM, Andreucci VE. Coronary artery calcification in patients with CRF not undergoing dialysis. Am J Kidney Dis. 2004;44: 2. Spiegel DM, Raggi P, Mehta R, et al. Coronary artery calcifications in patients new to dialysis. Hemodial Int. 2004;8: 3. Raggi P, Boulay A, Chasan-Taber S, et al. Cardiac calcification in adult hemodialysis patients: a link between end-stage renal disease and cardiovascular disease. J Am Coll Cardiol. 2002;39: Prä-Dialyse Inzidente Dialyse Prävalente Dialyse n = 851 N = 1292 N = 2053 *Das Vorliegen einer Koronarverkalkung wurde festgestellt, wenn durch Elektronenstrahl- oder Spiral-Computertomographie arterielle oder Klappenverkalkung nachgewiesen werden konnte. Nach: Russo D, et al. Am J Kidney Dis. 2004;44: Nach: Spiegel DM, et al. Hemodial Int. 2004;8: Nach: Raggi P, et al. J Am Coll Cardiol. 2002;39:

Höhere PTH-Spiegel waren mit ausgedehnterer Koronarverkalkung assoziiert Analyse von Koronarverkalkungs-Scores bei 197 Dialysepatienten P < 0,01 zwischen den Gruppen Koronarverkalkungs-Score (HE) Key Point: • Background Information: Coen and colleagues studied the association between serum PTH levels and coronary calcification in a cohort of 197 hemodialysis patients in Italy. They also provided data on the relationship between PTH and phosphorus.1 Patients were divided into groups of intact PTH levels, 0 to 150,150 to 300, 300 to 600, and > 600 pg/mL.1 Mean serum phosphorus levels were measured at each iPTH category.1 The difference in terms of coronary calcification scores among the groups of PTH was significant (P < 0.01). There was a progressive increase of the average value from group 0 to 150 pg/mL to group > 600 pg/mL, with pathological, nevertheless lower levels, in the 0 to 150 pg/mL group.1 No prominent association between low PTH serum levels and the severity of coronary calcium deposits in hemodialysis patients was found.1 Coen and colleagues point out that increased levels of PTH were associated with hypercalcemia and hyperphosphatemia, and should be considered a major risk factor for coronary calcification and cardiac events.1 Reference: 1. Coen G, Manni M, Mantella D, et al. Are PTH serum levels predictive of coronary calcifications in haemodialysis patients? Nephrol Dial Transplant. 2007;22: (n = 40) (n = 51) (n = 54) (n = 52) iPTH-Gruppen (pg/ml) *Statistisch signifikanter (ANOVA) progressiver Anstieg der Durchschnittswerte nach iPTH-Gruppen HE = Hounsfield-Einheit, bestimmt durch Messung des Agatston-Score Coen G, et al. Nephrol Dial Transplant. 2007;22:

Der Koronarverkalkungs-Score ist bei Hämodialyse-Patienten ein unabhängiger Prädiktor der Mortalität Analyse von Koronarverkalkungs-Scores als Prädiktor der Mortalität bei 166 Hämodialyse-Patienten zwischen Oktober 2001 und September 2007 100 CAC 0 Ereignisrate: 11,1% (2/18) 80 CAC 1-100 Ereignisrate: 18,7% (9/48) 60 Ereignisfreies Überleben (%) CAC Ereignisrate: 32,1% (9/28) 40 CAC ≥ 400 Ereignisrate: 41,7% (30/72) 20 Key Point: • Coronary artery calcification is associated with an increased risk for mortality in patients on hemodialysis.1 Background Information: • Shantouf and colleagues examined data from a cohort of maintenance hemodialysis patients who participated in the prospective Nutritional and Inflammatory Evaluation of Dialysis Patients Study and underwent cardiac computed tomography. The analysis assessed the relationship between coronary artery calcium (CAC) scores and event-free survival across four CAC groups, including: (a) CAC = 0, (b) CAC = 1 to 100, (c) CAC = 101 to 400, and (d) CAC ≥ 400.1 • Patients who who had undergone cardiac computed tomomography and participated in the study from October 1, 2001 to September 30, 2006 were evaluated. Mortality was followed up to September 30, 2007 (n = 166).1 • At the end of the follow-up period there were 50 deaths among the 166 participants, including 30 deaths in the CAC ≥ 400 group and 2 deaths among the CAC = 0 group. Subjects with no evidence of CAC had higher event-free survival rates (88.9%) than those with CAC scores ≥ 400 (58.3%).1 • Compared with subjects with a CAC score of 0, there was a significantly greater risk of death for those with a CAC scores of 101 to 400 (HR = 8.5; 95% CI = , P = 0.02) or ≥ 400 (HR = 13.3; 95% CI = , P = 0.01).1 Reference: 1. Shantouf RS, Budoff MJ, Ahmadi N, et al. Total and individual coronary artery calcium scores as independent predictors of mortality in hemodialysis patients. Am J Nephrol. 2010;31: 12 24 36 48 60 72 Beobachtungszeitraum (Monate) Anzahl Patienten bei einem bestimmten CAC-Score CAC 0 18 16 15 10 9 5 3 CAC 1-100 48 42 35 26 6 1 CAC 28 21 17 8 2 CAC 400+ 72 59 44 Nach: Shantouf RS, et al. Am J Nephrol. 2010;31:

Gefäßverkalkung und Störungen des Mineralstoffwechsels gehen mit der Entwicklung einer LVH einher Gefäß- verkalkung Steifigkeit DBD SBD Pulswellen- geschwindig- keit LV Nachlast LVH Koronar- perfusion Key Points: • As shown on the next three slides, left ventricular hypertrophy leads has been associated with increases in calcification, pulse wave velocity, and iPTH levels. • This slide shows the relationship between changes in arterial wall, blood pressure, coronary perfusion, and cardiac remodeling in patients with CKD, leading to LVH.1 Background Information: • It has been estimated that LVH is present in approximately 75% of patients with CKD by the time they progress to end-stage renal disease. LVH is the strongest independent predictor of cardiovascular mortality in patients with CKD, and has been been associated with the development of arrhythmias, sudden death, heart failure, and ischemic heart disease.1 • The etiology of LVH is multifactorial. Contributing factors may include calcification, increased pulse-wave velocity, mineral metabolism disorders (including hypocalcemia, hyperphosphatemia, low serum vitamin D levels, and secondary hyperparathyroidism), pressure and volume overload, increased asymmetric dimethylarginine, oxidative stress, hyperhomocysteinemia, and endothelial dysfunction.1 Reference: 1. Taddei S, Nami R, Bruno RM, Quatrini I, Nuti R. Hypertension, left ventricular hypertrophy and chronic kidney disease. Heart Fail Rev. 2011;16: LVH ist mit der Entwicklung von Arrhythmien, plötzlichen Todesfällen, Herzinsuffizienz und Ischämie assoziiert Nach: Taddei S, et al. Heart Fail Review. 2011;16:

Verkalkung und erhöhte Pulswellengeschwindigkeit können zur linksventrikulären Hypertrophie beitragen Querschnittsanalyse von 49 Hämodialyse-Patienten mithilfe von CT-Scan und M-Mode-Echokardiographie 100 120 140 160 180 200 220 240 260 280 1000 LVMI (g/m2) PWG (cm/s) r = 0,439 P = 0,0014 1500 2000 2500 3000 3500 4000 4500 r = 0,467 P = 0,0006 AVI (%) 100 120 140 160 180 200 220 240 260 280 10 20 30 40 50 60 70 80 90 Key Points: • Calcification and elevated pulse wave velocity may contribute to left ventricular hypertrophy.1 Background Information: • This cross-sectional analysis evaluated the effect of calcification and elevated pulse wave velocity on left ventricular hypertrophy in 49 patients on hemodialysis. The aortic calcification index (ACI) was quantified morphometrically by CT scan, and the left ventricular mass index (LVMI) was estimated by M-mode echocardiography.1 • To assess pulse wave velocity, occlusion and monitoring cuffs were placed snugly around both sides of the upper and lower extremities, with patients in the supine position. Pressure waveforms of the brachial and tibial arteries were then recorded after 15 minutes of bed rest using an automatic waveform analyzer. The best 10 consecutive pulses were analyzed, and the average PWV from the heart to the posterial tibial artery was calculated by dividing the distance by the time interval. Two measurements were performed in each leg and the average value was used for the analysis (expressed in centimeters/second).1 • LVMI correlated positively with systolic blood pressure (r = 0.421, P = ), PWV (r = 0.439, P = , and ACI (r = 0.467, P = ).1 The latter two parameters are shown on this slide. • The authors conclude that their results suggest that left ventricular hypertophy is associated with hypertension, increased arterial stiffness, and the extent of vascular calcification in patients on hemodialysis. Vascular calcification, which alters the pulsatile dynamics and thereby contributes to an increase in left ventricular load, was identified as the most important contributor to the development of LVH.1 Reference: 1. Nitta K, Akiba T, Uchida K, et al. Left ventricular hypertrophy is associated with arterial stiffness and vascular calcification in hemodialysis patients. Hypertens Res. 2004;27:47-52. PWG = Pulswellengeschwindigkeit; AVI = Aorten-Verkalkungs-Index. LVMI = linksventrikulärer Masseindex; cm/s = Zentimeter/Sekunde Nach: Nitta K, et al. Hypertens Res. 2004;27:47-52.

Sekundärer HPT ist mit LVH assoziiert
Kardiovaskuläre Folgen der CKD-MBD: Verkalkung und linksventrikuläre Hypertrophie Sekundärer HPT ist mit LVH assoziiert N = 130 Patienten unter Hämodialyse1 N = 41 Patienten unter Hämodialyse2 20 40 60 80 100 120 90 150 180 210 240 iPTH (pg/ml) LVMI 400 800 1.200 1.600 2.000 50 200 250 300 LVM-Index (g/m2) PTH > 280 pg/ml PTH pg/ml PTH < 100 pg/ml Alle Patienten: r = 0,34, P = 0,03 PTH > 280 pg/ml: r = 0,62, P = 0,003 r = 0,415 P ≤ 0,0001 Key Point: • Secondary HPT is associated with left ventricular hypertrophy in patients on hemodialysis.1,2 Background Information: • Al-Hilali and colleagues prospectively evaluated the relationship between left ventricular hypertrophy and secondary hyperparathyroidism in 130 patients on maintenance. All patients underwent M-mode echocardiography. Left ventricular mass (LVM) was calculated by using Devereux’s formula, and was indexed for body surface area (LVMi)). As shown on the right hand graphic on this slide, LVMi values correlated positively with iPTH (r = 0.415, P ≤ ).1 • Similarly, Randon and colleagues evaluated the association between LVMI and iPTH in 41 patients on hemodialysis. Patients underwent Doppler echocardiogram evaluation, with LVM calculated according to the modified cube formula proposed by Devereux and colleagues, and LVMI calculated by dividing LVM by body surface area. Patients were subsequently stratified into three groups according to serum iPTH levels: (a) iPTH < 100 pg/mL (n = 10), (b) iPTH 100 to 280 pg/mL (n = 10), and (c) iPTH > 280 pg/mL (n = 21). As shown on the right hand graphic on this slide, LVMi values correlated postively with iPTH among all patients (r = 0.34, P = 0.03). In a subsequent analysis of iPTH subgroups, a significant association was only observed among patients in the highest iPTH group (r = 0.62, P = 0.003). In multivariate analysis, after adjustment for age, hemoglobin, body mass index, and blood pressure, the only independent predictor of LVMi was the PTH level.2 References: 1. Al-Hilali N, Hussain N, Ataia AI, Al-Azmi M, Al-Hell B, Johny KV. Hypertension and hyperparathyroidism are associated with left ventricular hypertrophy in patients on hemodialysis. Indian J Nephrol. 2009;19: 2. Randon RB, Rohde LE, Comerlato L, Ribeiro JP, Manfro RC. The role of secondary hyperparathyroidism in left ventricular hypertrophy of patients under chronic hemodialysis. Braz J Med Biol Res. 2005;38; LVM = linksventrikuläre Hypertrophie. 1. Nach: Al-Hilali N, et al. Indian J Nephrol. 2009;19: 2. Nach: Randon RB, et al. Braz J Med Biol Res. 2005;38;

Adjustierte Cox-Überlebenskurven
Kardiovaskuläre Folgen der CKD-MBD: Verkalkung und linksventrikuläre Hypertrophie LVH ist bei Dialysepatienten mit einem erhöhten Mortalitätsrisiko assoziiert Analyse des Effekts der LVH hinsichtlich der Mortalität bei 2584 inzidenten Dialysepatienten aus der Dialysis Morbidity and Mortality Study, Wave 2 1,0 Keine LVH 0,8 Adjustierte Cox-Überlebenskurven LVH 0,6 0,4 100 200 300 400 500 600 700 Zeit (Tage) Bei Patienten mit LVH betrug das erhöhte Mortalitätsrisiko 61% nach 1 Jahr (P < 0,01), % nach 2 Jahren (P < 0,05) und 29% nach 3 Jahren (P < 0,01) Die Daten wurden zu Studienbeginn für Alter, Geschlecht und ethnische Abstammung adjustiert. Nach: Stack AG, et al. Am J Kidney Dis. 2002;40:

Welche Daten zur potenziellen Wirkung von Cinacalcet auf Verkalkung und linksventrikuläre Hypertrophie bei Dialysepatienten mit sekundärem HPT sind verfügbar? Key Point: This section of the slide deck addresses the question: What data are available on the potential effect of cinacalcet on cardiovascular disease in patients on dialysis with secondary HPT?

Zugunsten der Cinacalcet-Gruppe Zugunsten der Kontrollgruppe
Endpunkt-Ergebnisse aus ADVANCE: Medianer Behandlungsunterschied, alle Prüfzentren Agatston-Score Volumen-Score Zugunsten der Cinacalcet-Gruppe Zugunsten der Kontrollgruppe Koronarien gesamt Thoraxaorta Aortenklappe Main Points: This forest plot graph illustrates the median treatment differences between the cinacalcet group and the control group (95% CI) in percent of progression of vascular calcification for each of the 4 sites assessed, using both Agatston (Primary Analysis) and Volume (Additional Analysis) scores.1 The analysis shown in this graph describes the magnitude of the effect size between the two treatment groups using median percent change values (95% CI). Data do not represent a simple analysis of variance between the group means. Differences between treatment groups were compared using a generalized Cochran-Mantel-Haenszel (CMH) test on ranks, stratified by CAC score at randomization. The stratum-adjusted median differences and corresponding 95% confidence intervals were determined by inverting the CMH test and conducting a numerical search.1 A statistically significant difference was not observed for the primary endpoint of percent change from baseline in Total CAC score at week 52 using Agatston scoring.1 For all calcification endpoints evaluated, there were consistent differences between treatment groups with regard to attenuated progression of cardiovascular calcification.1 References 1Data on file, Amgen; [ADVANCE CSR ; March 30, 2010]. Mitralklappe -90 -80 -70 -60 -50 -40 -30 -20 -10 10 20 30 Nach Stratum adjustierter medianer Behandlungsunterschied, 95%-KI (% Veränderung der Verkalkung) Der Koronarverkalkungs-Gesamtscore (Agatston-Methode) war der primäre Endpunkt. Der Unterschied zwischen den Gruppen war statistisch nicht signifikant. Primärer und sekundärer Endpunkt basierten auf der Agatston-Methodik. Die Volumen-Scores gehörten zu einem zusätzlichen Analyseset. Log-transformierte Daten. Nach: Raggi P, et al. Nephrol Dial Transplant. 2011;26:

Wirkung von Cinacalcet auf den linksventrikulären Masseindex
Prospektive 12-monatige Analyse der Pulswellengeschwindigkeit in der Aorta und der Masse des linken Ventrikels vor und nach Behandlung mit Cinacalcet bei 21 Hämodialyse-Patienten P = 0,063 P = 0,03 LV Masseindex (g/m2) Pulswellengeschwindigkeit Aorta (m/sg) Key Point: • In this analysis, cinacalcet therapy was associated with a significant reduction in aortic pulse wave velocity (a marker of aortic stiffness). There was also a trend toward reducing ventricular mass index.1 Background Information: • Bonet and colleagues conducted a prospective, observational study of 21 patients on dialysis who were assessed at baseline and after at least a year of cinacalcet therapy. The mean daily dose of cinacalcet was 35 mg (range 30 to 60 mg).1 • There was a notable reduction trend in left ventricular mass index (from ± 39.4 g/m2 to ± 31.8 g/m2), although it did not achieve statistical significance (P = 0.063).1 • Aortic pulse wave velocity decreased significantly after 12 months of cinacalcet, from 9.35 ± 1.83 m/sg to 8.66 ± 1.86 m/sg, P = 0.03).1 • The authors conclude that there is a possibility that cinacalcet reduces arterial stiffness in patients with secondary HPT after 12 months of treatment. Prospective, randomized clinical trials are needed to confirm these preliminary findings.1 Reference: 1. Bonet J, Bayés B, Fernández-Crespo P, Casals M, López-Ayerbe J, Romero R. Cinacalcet may reduce arterial stiffness in patients with chronic renal disease and secondary hyperparathyroidism—results of a small-scale, prospective, observational study. Clin Nephrol. 2011;75: Studien-beginn Beobachtungs-zeitraum Studien-beginn Beobachtungs-zeitraum Bonet J, et al. Clin Nephrol. 2011;75:

Kardiovaskuläre Folgen von sekundärem HPT und CKD-MBD
Kardiovaskuläre Folgen der CKD-MBD: kardiovaskulär bedingte Hospitalisierung u. Mortalität Kardiovaskuläre Folgen von sekundärem HPT und CKD-MBD Kardiovaskuläre Folgen Verkalkung und linksventrikuläre Hypertrophie Kardiovaskulär bedingte Hospitalisierung und Mortalität Key Point: • This section of the presentation reviews the association between CKD-MBD, cardiovascular hospitalization, and mortality.

Kardiovaskuläre Folgen der CKD-MBD: kardiovaskulär bedingte Hospitalisierung u. Mortalität
Dialysepatienten sind stark von kardiovaskulären Erkrankungen betroffen Kardiovaskulär bedingte Mortalität in der Allgemeinbevölkerung (AB) und bei Patienten mit terminaler Niereninsuffizienz unter Dialyse Jährliche Mortalität (%) 100 10 0,1 0,01 1 AB Männer AB Frauen AB Schwarze AB Weiße Dialyse Männer Dialyse Frauen Dialyse Schwarze Dialyse Weiße 0,001 Alter (Jahre) > 85 25–34 35–44 45–54 55–64 65–74 75–84 Key Points Foley et al analyzed data from the United States Renal Data System (USRDS) and determined that regardless of gender, race (black/white), or age, the annual cardiovascular (CV) mortality was 10 to 20 times higher in dialysis patients compared to the general population.1 {Foley RN, et al. Am J Kidney Dis 1998;32(suppl3): S114,B,2} According to Foley et al, a 25- to 34-year-old dialysis patient has approximately the same annual percentage CV mortality as a ≥ 85-year-old in the general population.1 {Foley RN, et al. Am J Kidney Dis 1998;32(suppl3): S115,Figure 1} 1Foley RN, Parfrey PS, Sarnak MJ. Clinical epidemiology of cardiovascular disease in chronic renal disease. Am J Kidney Dis. 1998;32(suppl 3):S112-S119. Foley RN, et al. Am J Kidney Dis. 1998;32(suppl 3):S112-S119. .

Todesursachen bei Dialysepatienten in den USA (2001-2007)1
Kardiovaskuläre Folgen der CKD-MBD: kardiovaskulär bedingte Hospitalisierung u. Mortalität Kardiovaskuläre Erkrankungen tragen am stärksten zur Mortalität von Dialysepatienten bei Todesursachen bei Dialysepatienten in den USA ( )1 Alle anderen Kardiovaskulär Malignom Zerebrovaskulärer Insult Abbruch Infektion „Wir schlagen vor, dass das National Cholesterol Education Program und andere Gruppen CKD in die Gruppe mit den höchsten Risiko für Empfehlungen zur Prävention, Ermittlung und Behandlung von CVD-Risikofaktoren aufnehmen." — American Heart Association 1. US Renal Data System. USRDS 2011 Annual Data Report: Atlas of End-Stage Renal Disease in the United States 2. Sarnak MJ, et al. Circulation. 2003;108:

Kardiovaskuläre Folgen der CKD-MBD: kardiovaskulär bedingte Hospitalisierung u. Mortalität
Kardiovaskuläre Erkrankungen stellen eine Hauptursache von Hospitalisierung bei prävalenten Dialysepatienten dar USRDS-Analyse der Hospitalisierungsraten HD Peritoneal- dialyse Transplantation Die Rate kardiovaskulär bedingter Hospitalisierungen beträgt 0,55 pro Patientenjahr Höhere Raten kardiovaskulär bedingter Hospitalisierungen pro Patientenjahr sind zu verzeichnen bei: Patienten ≥ 75 Jahre (0,62) Diabetikern (0,60) Afroamerikanern (0,58) Frauen (0,58) Aufnahmen pro 1000 Patientenjahre 532 432 Key Point: • Cardiovascular disease is a major cause of hospitalization and mortality in patients on dialysis. Background Information: • Cardiovascular disease continues to be a major cause of hospitalization in patients on dialysis. As shown in the left hand graphic on this slide, as of 2009 cardiovascular-related hospitalization admissions occurred at a rate of 532/1,000 patient years among patients on hemodialysis, 432/1,000 patient years among those on peritoneal dialysis, and 123/1,000 patient years for those with a kidney transplant. Data are for period prevalent patients with ESRD adjusted for age, gender, race, and primary diagnosis. ESRD patients in 2005 were used as the reference group.1 • As shown in the right hand graphic, cardiovascular disease is also a major cause of mortality in patients on dialysis. As of 2009, cardiovascular-related causes accounted for 82.6 deaths per 1,000 patient years at risk. Data are for prevalent dialysis patients (unadjusted).1 Reference: United States Renal Data System. USRDS 2011 Annual Data Report: Atlas of End-Stage Renal Disease in the United States. Bethesda, MD: National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases; 2011. 123 Jahr US Renal Data System. USRDS 2011 Annual Data Report: Atlas of End-Stage Renal Disease in the United States

Welche Daten zur potenziellen Wirkung von Cinacalcet auf kardiovaskulär bedingte Hospitalisierung und Mortalität bei Dialysepatienten mit sekundärem HPT sind verfügbar? Key Point: This section of the slide deck addresses the question: What data are available on the potential effect of cinacalcet on cardiovascular disease in patients on dialysis with secondary HPT?

Cinacalcet senkte signifikant die kardiovaskulär bedingten Hospitalisierungsraten bei Dialysepatienten mit sekundärem HPT Gepoolte Analyse von Sicherheitsdaten aus 4 randomisierten, doppelblinden, placebokontrollierten Studien mit ähnlichem Design 1,00 0,95 0,90 Wahrscheinlichkeit der Ereignisfreiheit 0,85 Key Point: • Cinacalcet significantly reduced cardiovascular (CV) hospitalization rates in patients with secondary HPT on dialysis.1 Background Information: • Cunningham and colleagues undertook a combined analysis of safety data from four similarly designed randomized, double-blind, placebo-controlled, clinical trials enrolling 1,184 subjects (697 cinacalcet and 487 control) with ESRD and uncontrolled secondary HPT (defined as an iPTH level ≥ 300 pg/mL). Cinacalcet or placebo was administered to patients receiving standard care for hyperphosphatemia and secondary HPT (ie, phosphate binders and vitamin D).1 • The studies included one 12-month phase 2 trial and three 6-month phase 3 trials. The study design, including study drug dosing, was similar across all studies. For those receiving cinacalcet, doses ranged from 30 to 180 mg/day, with doses titrated every 3 to 4 weeks, if necessary. Subjects receiving vitamin D at baseline generally continued at the same dose throughout the trial (although reductions were permitted for albumin-adjusted serum calcium ≥ 11 mg/dL, serum phosphorus ≥ 6.5 mg/dL, or Ca x P ≥ 70 mg2/dL2).1 • As shown on this slide, cardiovascular hospitalization rates were lower in the cinacalcet group compared with the placebo group (15.0 versus 19.7 per 100 subject-years, respectively). Using the Andersen-Gill method, the relative risk of cardiovascular hospitalization was significantly reduced in the cinacalcet group (relative risk = 0.61, 95% CI to 0.86). Results were virtually identical using the conditional model (relative risk = 0.63, 95% CI 0.44 to 0.90).1 • In the control group cardiovascular-related hospitalizations included 29 hospitalizations for ischemic heart disease (including myocardial infarction and angina pectoris), 19 for heart failure, 18 for arrhythmia, 7 for peripheral vascular disease, and 4 for stroke. Corresponding data for the cinacalcet group included 22 hospitalizations for ischemic heart disease, 26 for heart failure, 17 for arrhythmia, 2 for peripheral vascular disease, and 5 for stroke.1 Reference: 1. Cunningham J, Danese M, Olson K, Klassen P, Chertow GM. Effects of the calcimimetic cinacalcet HCl on cardiovascular disease, fracture, and health-related quality of life in secondary hyperparathyroidism. Kidney Int. 2005;68 0,80 Placebo Cinacalcet 0,75 Woche 4 8 12 16 20 24 28 32 36 40 44 48 52 n = 487 Placebo n = 697 Cinacalcet 476 454 430 411 384 339 148 145 132 127 125 122 397 660 629 592 573 515 418 142 140 124 119 538 Alle Patienten erhielten eine Standardtherapie mit Phosphatbindern und Vitamin D, falls verordnet. Cunningham J, et al. Kidney Int. 2005;68: Post-hoc Analyse von prospektiven, randomisierten, Placebo-kontrollierten Phase-3-Studien.

Kardiovask. Mortalität Patienten ohne Cinacalcet Cinacalcet-Patienten
Cinacalcet war bei Dialysepatienten mit sekundärem HPT mit niedrigerer Gesamt- und kardiovaskulärer Mortalität assoziiert Prospektive 26-monatige Beobachtungsanalyse der Wirkung von Cinacalcet auf die Mortalität bei Patienten unter Hämodialyse. Nicht-adjustiert P < 0,0001 für alle Vergleiche mit Patienten, die kein Cinacalcet erhielten Adjustiert* Hazard Ratio (95%-KI) Key Point: • In this study, cinacalcet was associated with significant decreases in all-cause and cardiovascular mortality.1 Background Information: • Block and colleagues conducted a prospectively designed 26-month observational analysis in which they followed 5,976 hemodialysis patients on cinacalcet and 13,210 hemodialysis patients who were not receiving cinacalcet to test the hypothesis that use of cinacalcet in patients with secondary HPT who were on hemodialysis would be associated with improved survival.1 • As shown on this slide, unadjusted and adjusted time-dependent Cox proportional hazards modeling found that all-cause and cardiovascular mortality rates were significantly lower for those treated with cinacalcet that for those who did not receive therapy.1 The unadjusted hazard ratio for cinacalcet patients for all-cause mortality was 0.73 (95% CI 0.68 to 0.78, P < ).1 The adjusted hazard ratio for cinacalcet patients for all-cause mortality was 0.74 (95% CI 0.67 to 0.83, P < ).1 The unadjusted hazard ratio for cinacalcet patients for cardiovascular mortality was 0.78 (95% CI 0.71 to 0.86, P < ).1 The adjusted hazard ratio for cinacalcet patients for cardiovascular mortality was 0.76 (95% CI 0.66 to 0.86, P < ).1 • Data were adjusted for demographic characteristics, comorbidity, hospital days, vascular access, and laboratory information.1 Reference: 1. Block GA, Zaun D, Smits G, et al. Cinacalcet hydrochloride treatment significantly improves all-cause and cardiovascular survival in a large cohort of hemodialysis patients. Kidney Int. 2010;78: Gesamtmortalität Gesamtmortalität Kardiovask. Mortalität Patienten ohne Cinacalcet (n = ) Cinacalcet-Patienten (n = 5.976) *Adjustiert für demographische Merkmale, Komorbidität, Krankenhaustage, Gefäßzugang und Labordaten. Alle Patienten erhielten Vitamin-D-Analoga. Block GA, et al. Kidney Int. 2010;78:

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Key Points: This slide deck is divided into three primary hyperlinked sections: Overview on secondary hyperparathyroidism (HPT) Bone and mineral consequences.

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Key Points: This slide deck is divided into three primary hyperlinked sections: Overview on secondary hyperparathyroidism (HPT) Bone and mineral consequences.

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Präsentation zum Thema: "Key Points: This slide deck is divided into three primary hyperlinked sections: Overview on secondary hyperparathyroidism (HPT) Bone and mineral consequences."— Präsentation transkript:

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