Sisätaudit. Tampereen yliopisto ja TAYS

Transkriptio

1 Kalsimimeetit nefrologiassa Sisätautilääkäripäivät Ilkka Pörsti Sisätaudit Tampereen yliopisto ja TAYS

2 Normal mineral metabolism traditional view Ca 2+ Ca 2+ reabsorption PO 3 excretion Kidneys 4 PTH Calcitriol Normal Ca 2+ Parathyroid glands Bone Ca 2+ PO 4 3 Release Brown EM. In: The Parathyroids Basic and Clinical Concepts 2 nd ed Bilezikian JP et al. (eds)

3 SHPT, Ca and P in CKD 1814 patients with estimated GFR (MDRD) Elevated P and reduced Ca are poor markers for diagnosing elevated PTH Suppression of 1!-OHase: reduced renal mass, resistance to PTH, reduced 25OH-D, high P, acidosis, i uremic toxins, FGF-23 * * Levin, et al. Kidney Int 2007;71:31 38 Andress D. Kidney Int 2006;69:33 43

4 SHPT: major cause of morbidity and mortality in renal disease Hyperphosphataemia p p Extraskeletal and vascular calcification Increased mortality, particularly cardiovascular Renal osteodystrophy Osteitis fibrosa vs. adynamic and mixed bone disorder Insulin resistance and glucose intolerance Atherosclerosis, coronary heart disease Disturbed lipoprotein p metabolism,! VSMC [Ca] i,! Ca-Phos deposition in the vessel wall Hypertension Reduced vasodilatation, impairment of vascular reactivity Aggravation of renal anemia bone marrow fibrosis Ineffective erythropoiesis - EPO resistance! Goodman and Quarles Kidney Int 2008; 74: ; Kovesdy CP et al. Kidney Int 2008;73:

5 SHPT: major cause of morbidity and mortality in renal disease Neurotoxicity cognitive function, dysphoria, poor concentration capacity, etc. Immune dysfunction Increased susceptibility to infection, partly due to defective leukocyte function Intracellular Ca 2+! Reduced ATP content Sexual dysfunction Uraemic myopathy - fatigue Uraemic cardiomyopathy Changes in contraction, poor energy metabolism and impaired energy utilization, fibrosis, myocardial calcium deposition, mitral annular calcification BP independent wall thickening in intramyocardial arteries Pruritus, bone and joint pain, irritability " Goodman and Quarles Kidney Int 2008; 74: ; Kovesdy CP et al. Kidney Int 2008;73:

6 Vascular calcification in dialysis patients Severe ectopic calcinosis 52 year-old man Hemodialysis for 11 years PTH 1489 pg/ml Low BMD Vascular calcification Systolic hypertension Left ventricular hypertrophy Reduced d coronary perfusion Significant predictor of mortality NEJM 349(12): 293, 2003

7 SHPT associated with higher mortality (CV) in predialysis men with CKD male US veterans with CKD and were not on dialysis Multivariable regression spline model, adjusted for age, race, BMI, smoking status, Charlson comorbidity index, diabetes mellitus, estimated GFR (MDRD), serum levels of calcium, phosphorus, albumin and cholesterol, proteinuria, and the use of activated vitamin D (with vitamin D use hazard ratio was 0.28, CI ), ACE inhibitors, statins and calcium-containing medications Kovesdy CP, et al. Kidney Int 2008;73:

8 CKD 3-5 targets CKD stage GFR ml/min Pi mmol/l PTH pg/ml (pmol/l) Ca (Alb korj) mmol/l 25OH-D3 ng/ml (nmol/l) >30 (4-8) (>75*) >30 (8-12) (>75*) 5 < >30 (16-33) (>75*) *Norm. HUSlab > 40 nmol/l # K/DOQI guidelines AJKD (4) Suppl. 3 Kidney Disease Outcomes Quality Initiative

9 CKD 3-5 targets Kidney CKD Disease: GFR Improving Pi PTH Global Outcomes Ca 25OH-D3 (KDIGO) stage ml/min mmol/l pg/ml (Alb korj) ng/ml In patients with CKD stages (pmol/l) 3 5 not on dialysis, mmol/l the (nmol/l) optimal PTH 3 level is not known >30 (4-8) (>75*) CKD stage 5D, we suggest maintaining i i ipth levels l in the range 4 of approximately two to nine times the upper normal >30 limit for the assay (8-12) (>75*) 5 < >30 (16-33) (>75*) Kidney International 2009; 76, Suppl 113 *Norm. HUSlab > 40 nmol/l $ K/DOQI guidelines AJKD (4) Suppl. 3 Kidney Disease Outcomes Quality Initiative

10 Therapeutic Strategies for SHPT Control phosphate Control Adjust vitamin i D calcium levels or give VDRA Control PTH levels Goodman WG. Kidney Int. 2001;59:

11 Ca 2+ reseptori (CaR CaR) Cloning and characterization of an extracellular Ca 2+ - sensing receptor from bovine parathyroid Brown EM et al. Nature 1993; 366: Ca 2+ toimii hormonin kaltaisena välittäjänä, vaikutus Ca 2+ - reseptorin välityksellä sekunneissa minuuteissa Aktivoijia: iji Ca 2+, Mg 2+ trivalentit yhdisteet (heikompia kuin Ca 2+ : gadolinium, lantanium, alumiini) polykationiset yhdisteet (neomysiini, gentamysiini) CaR: PTH erityksen säätely - lisäkilpirauhanen CaR: munuaisen tubulustoiminnan säätelijä tubuluksissa useissa eri kohdissa aistii sekä systeemistä tä että virtsan [Ca 2+ ]

12 Ca 2+ -reseptori: lisäkilpirauhasen ja munuaisen lisäksi useissa kudoksissa Coburn and Maung Current Opinion in Nephrology and Hypertension 2000; 9:

13 H Sinakalseetti F 3 C N Me HCl Ca 2+ -reseptorin allosteerinen modulaattori lisää Ca 2+ aistivan reseptorin herkkyyttä solunulkoiselle Ca 2+ :lle Käyttöaihe nefrologiassa: loppuvaiheen munuaistautiin liittyvän SHPT:n hoitoon dialyysipotilaille i ill Käyttö osana kokonaishoitoa, johon tarpeen mukaan sisältyy fosfaatinsitojia ja D-vitamiinireseptoria aktivoivia valmisteita Hyperparatyreoosin hoito Sinakalseetti VDR aktivaatio (D-vitamiini / parikalsitoli) Kalsiumin ja fosfaatin tason optimointi (fosfaatinsitojat) Ca-suolat, sevelameeri, lantaanikarbonaatti tti Ei ole käyttöaihe: SHPT kroonista munuaistautia sairastavilla potilailla, jotka eivät ole dialyysihoidossa

14 Ca 2 + -receptor a member of the superfamily of G-protein-coupled receptors Cinacalcet M F 3 C H N Me HCl Agonist binding (Ca, Mg, Al, Gd) Activation of second messengers Suuri solunulkoinen aminoterminaalinen osa; serpentiinimäinen solukalvo-osa (7); solunsisäinen osa, jossa 3 silmukkaa ja karboksiterminaalinen osa

15 Sinakalseetti Sivuvaikutuksia melko vähän: sinakalseetti vs. placebo Pahoinvointi 31 % 19% Hoidon keskeytymisetk 5 % 1 % Oksentelu 27% 15% Hoidon keskeytymiset 4 % 1 % Lisäksi yli 1% saa seuraavia: huimaus, parestesia, ihottuma, lihaskipu, heikotus, hypokalsemia, testosteronipitoisuuden lasku Sinakalseetti i pienentää plasman kalsiumpitoisuutta i i 6 kk tutkimuksessa vapaan testosteronin pitoisuuden laskun mediaani: sinakalseetti a 31,3 %, lume 16,3 % Metaboloituu osittain CYP3A4, CYP1A2 välityksellä CYP3A4 estäjiä ketokonatsoli, itrakonatsoli, telitromysiini, vorikonatsoli, ritonaviiri; indusoija rifampisiini CYP1A2 estäjiä esim. fluvoksamiini, siprofloksasiini Voimakas CYP2D6:n estäjä, j joka metaboloi mm. sauraavia: flekainidi, propafenoni, metoprololi, desipramiini, nortriptyliini, klomipramiini

16 With disease progression, the ability of calcium and vitamin D to regulate PTH is limited PTH PTH! VDR / CaR " disease progression Rodriguez M et al. Am J Physiol Renal Physiol. 2005;288:F253 F265

17 With disease progression, the ability of calcium and vitamin D to regulate PTH is limited 5-fold increase in plasma PTH is the maximal secretory response of parathyroids to hypocalcemia in normal volunteers CKD: non-suppressible component of PTH secretion is increased (that is not regulated by calcium) PTH PTH! VDR / CaR Goodman and Quarles Kidney International 2008; 74: " disease progression Rodriguez M et al. Am J Physiol Renal Physiol. 2005;288:F253 F265

18 Cinacalcet improved mineral metabolism in 1136 dialysis patients with SHPT Median ipth (pg/ml) Median serum phosphorous (mg/dl L) Control ipth Cinacalcet 30 to 180 mg once daily, target to achieve a mean ipth!250 pg/ml KDOQI target Median serum calcium (mg/dl) Control 2.4 mmol/l Serum calcium Cinacalcet B B Week Week Serum phosphorous Control 1.76 mmol/l Cinacalcet B Week Median Ca x P (mg 2 /dl 2 ) mmol/l Control 4.2 mmol 2 /l mmol/l 3.1 mmol 2 /l 2 KDOQI target Ca x P Cinacalcet KDOQI target KDOQI target B Week Post hoc analysis of pooled data from phase III clinical trials. ipth, intact parathyroid hormone; Ca x P, calcium-phosphorous produc %# Moe SM et al. Kidney Int 2005;67:

19 ECHO Study: Cinacalcet and target values for mineral metabolism m in real-world clinical practice (1865 patients) The higher the better reduction in PTH Urena et al. Nephrol Dial Transplant 2009; 24:

20 Sinakalseetin teho ja pitkäaikaishoito (n=1) 70- vuotias mies, jolle kroonisen munuaisten vajaatoiminnan vuoksi tehtiin munuaisensiirto vuonna Vuodesta 1993 alkaen dialyysihoidoissa, ih id i aluksi CAPD-hoidossa ja 1/1994 lähtien hemodialyysihoidoissa. ih id i Pitkäaikaiseen loppuvaiheen munuaisten vajaatoimintaan liittyen kehittyi vaikea sekundaarinen hyperparatyreoosi ja renaalinen osteodystrofia. Kalkki- ja D-vitamiinilääkityksestä huolimatta PTH nousi ollen toistuvasti yli 100. Kliinisinä manifestaatioina todettiin vaikeat luustomuutokset ja pehmytosakalkkeumat. Vuonna 2002 potilaalle ll aloitettiin ttii sinakalseetti-lääkitys. lääkit

21 3737 -yr yr-old man on longlong-term hemodialysis with a relapse of secondary hyperparathyroidism PTH > 1500 pg/ml Th: cinacalcet + oral calcitriol + calcium acetate Right radiograph taken 6 months later Zerbi et al. JCEM 2008, 94, 1121

22 Comparison of the key features of treatments for SHPT in CKD 5 effects on PTH, Ca, and P Ca-based phosphate p binder Ca-free phosphate p binder Vitamin D sterols Cinacalcet PTH "" # """ """ Ca!! #!! " P "" ""!! " Ca x P " "!! " Long-term efficacy Sustained, hyper-ca Sustained, not consistent in achiev. KDOQI targets " with disease progression Sustained (rather rarely " with disease progression) Pattern of PTH reduction Slow Weak effect on PTH Gradual Fast (hours)/ oscillating Modified form de Francisco ALM. Expert Opinion Pharmacother 2006;7:

23 Cinacalcet in predialysis CKD stage 3-4 Increase in urinary calcium: CaR action in the kidney - reduced PTH Reduction of 1,25(OH) 2 D 3? - Reduced PTH, increased phosphate No significant changes in 1,25-D or Pi in 9 Tx patients (Transplantation 2008;86: ) Increase in FGF-23? - Increase in serum phosphate Chonchol et al, Am J Kidney Dis 53: ; Evenepoel Kidney Int 2008; 74:

24 Cinacalcet in predialysis CKD stage 3-4 Hyperphosphatemia p p is probably the most worrisome feature of cinacalcet use in patients with stage 3 4 CKD. Jorge B. Cannata-Andía and José L. Fernández-Martín Nature Reviews Nephrology 2009; 6: Problematic selected cases: Post-Tx HPT can be controlled with off-label l use of cinacalcet Increase in urinary calcium: CaR action in the kidney - reduced PTH Reduction of 1,25(OH) 2 D 3? - Reduced PTH, increased phosphate No significant changes in 1,25-D or Pi in 9 Tx patients (Transplantation 2008;86: ) Increase in FGF-23? via an increase in serum phosphate? Chonchol et al, Am J Kidney Dis : ; Evenepoel Kidney Int 2008; 74:

25 Kalsimimeetit nefrologiassa Sinakalseetti tärkeä farmakologinen väline SHPT:n kontrolloinnissa i Käyttö vakiintunutta dialyysipotilailla, joilla SHPT on ongelma Hoitoa ei saa jättää liian myöhään aloitettavaksi Teho säilyy pitkäaikaishoidossa Off label käyttöä jnkv transplantaatiopotilailla, joilla SHPT persistoi Hyperparatyreoosin hoidolla edullinen vaikutus hypofosfatemiataipumukseen Hyöty ei ole kiistaton predialyysivaiheen munuaisten vajaatoimintaa sairastavilla potilailla Fosfaattiretentio on ongelman ydin!