Peranan Epoetin Beta pada Pasien Anemia Renal Dr. Ian Effendi Nungtjik, SpPD-KGH SMF Ilmu Penyakit Dalam Sub Bagian Ginjal – Hipertensi RS Moh Hoesin – FK Universitas Sriwijaya PALEMBANG

ANEMIA Laki-laki: Hb < 14 g/dl Perempuan: Hb < 12 g/dl Source : WHO

Anemia pada Penyakit Ginjal Kronik (Anemia Renal) Pasien PGK tahap akhir ( Cuci Darah ) Orang sehat Pasien PGK Anaemia is the most important persistent manifestation of CRF, and is a serious and very common consequence of the disorder. The clinical symptoms of anaemia of CRF are similar to those for anaemia from other causes. In untreated patients with CRF, decreased renal function correlates with increasing severity of anaemia. A reduced Hb concentration is usually detected when kidney functions falls to 25–30% of normal. In healthy males and females, the normal ranges for haemoglobin (Hb) are 14–16g/dL and 12–14g/dL, respectively. As renal function decreases during the predialysis phase, Hb concentrations can fall profoundly, without the appearance of overt anaemia symptoms, e.g. to Hb levels of approximately 11g/dL. All too frequently, at the time CRF patients enter a dialysis programme, they will have symptomatic anaemia with Hb concentrations of the order of 8–9g/dL. A normochromic, normocytic anaemia is present in the vast majority of patients with CRF. This anaemia arises principally from deficiency of erythropoietin (EPO), although other factors may contribute. The direct consequences of EPO deficiency, reduced tissue oxygen supply and consumption, lead to increased cardiac output with cardiac enlargement and left ventricular hypertrophy, decreased cognition and sexual function, as well as disturbed endocrine and immune function. These abnormalities dramatically reduce quality of life in patients with CRF and decrease survival rates. Fortunately, the administration of recombinant human erythropoietin (rHuEPO) results in a dramatic increase in Hb and reversal of the symptoms of anaemia. It should also be noted that the anaemia of chronic uraemia may also present as a microcytic anaemia in some HD patients due to underlying aluminium intoxication. Hb: pria: 14–16 g/dL wanita: 12–14 g/dL Hb: < 11 g/dL Hb: 7–9 g/dL

Penyebab Anemia Renal Defisiensi eritropoietin Anemia 90% dibentuk di ginjal Hyperparatiroidisme sekunder Defisiensi Besi Anemia Inflamasi / Infeksi Hemoglobinopati Masa hidup eritrosit pendek

RBC DEVELOPMENT

Hb dan Eritropoietin: Anemia pada PGK kidney 2 peripheral Hb transport peritubular hypoxia capacity cells DAMAGED serum EPO O precursor cells 2 In patients with CKD the ability of the kidney to produce sufficient erythropoietin is reduced. CKD is characterised by progressive destruction of renal mass, irreversible sclerosis and loss of nephrons over a period of months to many years, causing irreparable damage to the renal apparatus essential for erythropoietin production. This leads to insufficient production of erythroid precursors, reduced RBC replenishment, and an overall reduction in oxygen transport capability. transport capacity erythroblasts ANAEMIA Hb erythrocytes reticulocytes INSUFFICIENT 6

Kapan Anemia Mulai Timbul Pada PGK? Onset anemia : Laju filtrasi glomerulus (LFG) : < 60 mL/menit Manifestasi anemia : LFG < 40 mL/menit

Anemia Develops Early and Increase as Levels of CKD Severity Progress 100 N = 1658 Hgb Values 62 15 10 80 11-12 g/dL 43 8 15 10-11 g/dL 60 Anemia Prevalence (%) <10 g/dL 40 20 8 17 14 9 5 20 <2 2-2.9 3-3.9 ≥4 Creatinine (mg/dL) Chronic Kidney Disease (CKD) Progression Hgb = hemoglobin. Kausz et al. Dis Manage Health Outcomes. 2002;10:505-513.

Kenapa Anemia Harus di Obati? LVH , prediktor peny. KV Perawatan RS  Kapasitas aerobik  Fs. Kognitif  Kualitas hidup  Morbiditas  Mortalitas  Prognosis PGK buruk

Serum EPO production Apoptosis Renal vasoconstriction The Cardio-Renal Anaemia Syndrome suatu lingkaran patofisiologi yang saling mempengaruhi Hypoxia CKD Anaemia Serum EPO production Apoptosis Cardiacoutput Fluid retention Renal vasoconstriction Uraemia Sympathetic activity TNF-α Hypoxia Cardiac disease, CKD and anaemia are interconnected in a complex way, termed the cardio-renal anaemia syndrome. In a patient with anaemia, associated hypoxia leads to peripheral vasodilatation, decreased vascular resistance and reduced blood pressure. To maintain blood pressure, peripheral vasoconstriction, heart rate and stroke volume are all increased through elevated sympathetic activity. However, this also leads to renal vasoconstriction, resulting in a reduction of blood flow to the kidney, a reduction in glomerular filtration rate (GFR) and renal ischemia. This can be aggravated further by the renin-angiotensin aldosterone system. The outcome is fluid retention (Anand et al 1993) and an increase in plasma volume, which causes left ventricular hypertophy (LVH), leading to necrosis and apoptosis of myocardial cells. Excessive renin, angiotensin, and aldosterone can also destroy cardiac cells directly (Katz 1994; Johnson & Dell’Italia 1996). The result is congestive heart failure (CHF). Levels of tumour-necrosis factor-alpha (TNF-) are increased in CHF. Increased production of cytokines such as this has been implicated in the development of renal anaemia (Torre-Amione et al 1999), and may also worsen the anaemia in patients with CKD and CHF, completing a vicious cycle of disease progression. CHF CHF=congestive heart failure Adapted from Silverberg et al. Kidney Int Suppl. 2003;(87):S40-S47 Anand IS et al. Pathogenesis of oedema in chronic severe anaemia: studies of body water and sodium, renal function, haemodynamic variables, and plasma hormones. Br Heart J. 1993;70:357-362. Johnson DB, Dell’Italia LJ. Cardiac hypertrophy and failure in hypertension. Curr Opin Nephrol Hypertens. 1996;5:186-191. Katz AM. The cardiomyopathy of overload: an unnatural growth response in the hypertrophied heart. Ann Intern Med. 1994;121:363-371. Torre-Amione G et al. An overview of tumor necrosis factor alpha and the failing human heart. Curr Opin Cardiol 1999;14:206-210. Silverberg DS et al. Erythropoietin should be part of congestive heart failure management. Kidney Int Suppl. 2003;(87):S40-S47 11

Koreksi Anemia dengan EPO Dapat Memperlambat Progresifitas PGK 100 n = 108 80 60 Cumulative renal survival rate (%) 40 p = 0.0024 p = 0.3111 In two animal experiments have shown that the correction of anaemia with EPO accelerated the progression of renal disease by increasing the blood pressure and the blood viscosity. In humans, however, the effect of rhEPO on residual renal function is a matter of controversy. In this prospective study by Kuriyama and colleagues the effects of rhEPO therapy on baseline creatinine and cumulative renal survival rates were evaluated in 108 predialysis patients. The 73 patients with a significant anaemia (Hct <30%) were randomly assigned to two groups (1 and 2): Group 1: anaemia (Hct <30%), no rhEPO therapy (n = 31) Group 2: anaemia (Hct <30%), rhEPO therapy (n = 42) 35 predialysis patients with non severe or moderate anaemia (Hct >30%) were recruited as untreated, nonanaemic controls: Group 3: no anaemia (Hct >30%), no rhEPO therapy (n = 35) Care was taken in these patients to stabilise and minimise the effects of clinical factors known to modify renal function including blood pressure, ACE inhibitor therapy, and amount of dietary protein.The degree of control was comparable among the three groups. rhEPO therapy retarded the progression of renal failure. The survival of renal function, which was measured as doubling of creatinine in a follow-up of 36 months, was significantly increased in the rhEPO-treated anaemic patients (group 2), as well as in the untreated nonanaemic control patients (group 3), compared to the untreated nonanaemic patients (group 1). While the maximal benefit was observed in nondiabetic patients (nondiabetic patients in group 2), the benefit was also clearly visible in predialysis diabetic patients treated with rhEPO. This study provides the evidence that renal anaemia is a factor in the progression of end-stage renal failure. The reversal of anaemia by treatment with rhEPO can retard this progression of renal failure. Kuriyama S, Tomonari H, Yoshida H, Hashimoto T, Kawaguchi Y, Sakai O. Reversal of anemia by erythropoietin therapy retards the progression of chronic renal failure, especially in nondiabetic patients. Nephron 1997; 77: 176-185. p = 0.0003 20 Hct <30%, treated with rhEPO Hct >30%, untreated Hct <30%, untreated 5 10 15 20 25 30 35 40 Months of follow-up Adapted from Kuriyama S et al. Nephron 1997; 77: 176-185. DOD/0307-04

Effects of β-erythropoietin in patients with CRAS Randomized double-blind controlled study of correction of 51 anemia in patients with moderate or severe CHF with systolic dysfunction, mild-moderate renal insufficiency, & moderate anemia 2 arms: Group A: SC β-epoetin 6000 IU twice weekly Group B: placebo All patients received oral iron Treatments period: 1 year End point: LV dimensions, systolic function, lab assessment (hematological, renal function, BNP level) Palazzuoli et al, Am Heart J, 2007

P value (with respect to baseline intergroup and intragroup) Koreksi anemia dengan β-EPO & besi memperbaiki struktur & fungsi jantung Time 0 month 4 month 12 month P value (with respect to baseline intergroup and intragroup) EPO Group LVDD (mm) 66.8 ± 5.8 66.8 ± 5.7 66 ± 5.4 LVSD (mm) 49.5 ± 4.8 48.3 ± 4.7 46 ± 4.7 <.01 LVM (g/m2) 197.6 ± 16.1 194 ± 16.4 186.1 ± 18.8 LVDV (mL/m2) 104.7 ± 17.7 102.2 ± 16.5 99.3 ± 16.8 LVSV (mL/m2) 74.4 ± 19 69.9 ± 16.1 63.2 ± 17.1 EF (%) 30.1 ± 7.1 32.3 ± 6.1 36.8 ± 6.5 PAPs (mmHg) 39.6 ± 4.7 36.4 ± 3.3 33.8 ± 3.4 Placebo Group 67.5 ± 5.5 68 ± 4.9 68.8 ± 4.9 <.05 50.7 ± 4.9 50.9 ± 4.8 51.6 ± 5.1 192.2 ± 10.7 190.5 ± 10.1 193.1 ± 10.9 101.4 ± 14.1 103.4 ± 14.7 104.7 ± 15 71.1 ± 10.9 71.8 ± 10.2 74.4 ± 10.7 30.9 ± 5.9 30.8 ± 5.6 29.5 ± 6.1 39.4 ± 5.1 38.6 ± 5.1 39 ± 4.7 *LVDD: Left ventricular diastolic diameter, LVSD:LV systolic diameter, LVM: LV mass, LVDV: LV diastolic volume, LVSV: LV systolic volume, EF: ejection fraction, PAP: pulmonary artery pressure

Koreksi anemia dengan β-EPO & besi memperbaiki struktur & fungsi jantung BNP: grup dengan epo mengalami penurunan dibandingkan baseline, tetapi tidak di grup tanpa epo. Cardiac event (rawat inap krn gangguan jantung): grup dengan epo lebih sedikit signifikan Kelas NYHA: grup dengan epo menurun signifikan tetapi tidak pada grup tanpa epo

Terapi anemia meningkatkan ketahanan hidup Survival in Stage 5 CKD Increases with Higher Hb Levels N=44,550 Hb ≥ 13.0 12.0 ≤ Hb <13.0 11.0 ≤ Hb < 12.0 10.0 ≤ Hb < 11.0 9.0 ≤ Hb < 10.0 Hb < 9.0 % of surviving patients 100 90 80 0 15 30 45 60 75 90 105 120 135 150 165 180 Follow-up time, days Ofsthun et al. Kidney Int 2003; 63:1908-14

Tahap Penatalaksanaan Anemia Renal Pengkajian anemia Pengkajian status besi Terapi besi (bila ada defisiensi besi) Terapi EPO Penatalaksanan terapi EPO resisten

Pengkajian Anemia Renal

Bagaimana Langkah Pengkajian Anemia Renal ? Cari penyebab anemia : Anamnesis : Perdarahan Laboratorium : * Hb, Ht, L, Trombosit (hitung retikulosit) * Morfologi eritrosit * Analisis status besi * Feses darah samar (occult bleeding)

Pengkajian Status Besi

Pengkajian status besi Kenapa diperlukan ? Prevalensi def. besi pd PGK : 25 - 37% Intake kurang Kehilangan darah : Perdarahan tersembunyi dari saluran cerna (Occult bleeding) Punksi vena : lab Retensi darah (HD) Bila def. besi dikoreksi : Hb  Persiapan terapi EPO

Pengkajian Status Besi : 1. Saturasi transferin (ST) ST = SI / TIBC x 100% Serum Iron (SI)= Kadar besi serum Total iron binding capacity (TIBC)= Kapasitas ikat besi total 2. Feritin serum (FS)

Anemia Renal Status besi cukup Anemia def. besi ST  20% SF  100 ng/mL A. def. besi fungsional A. def. besi absolut ST < 20% FS  100 ng/mL ST < 20% FS < 100 ng/mL Cat : HD : FS ≥ 200 ng/mL

Terapi Besi

KONSENSUS PERNEFRI 2011

Terapi ESA

Kapan Terapi ESA Dimulai? Konsensus PERNEFRI 2011 Indikasi : Hb < 10 g/dL & penyebab anemia lainnya sudah disingkirkan (target HB: 10-12 g/dL, tidak boleh > 13 g/dL) Syarat : Tidak ada anemia defisiensi besi absolut, yaitu: ST <20% dan FS <100 ng/ml (PGK-non-D & PGK-PD), < 200 ng/ml (PGK-HD) Tidak ada infeksi yang berat Kontraindikasi : Hipersensitivitas Keadaan yang perlu diperhatikan: hipertensi & hiperkoagulasi “ Sesuai dengan Konsensus Pernefri 2011, Erithropoetin Stimulating Agen atau Recormon diperlukan bila kadar Hb < 10 g/dL dengan status besi yang cukup serta tidak ada infeksi yang berat” “ Saturasi transferin Normal yaitu minimal 20% & serum feritin minimal 200 ng/ml pada PGK yang menjalani hemodialisa” “ Dan pemberian Erithropoetin bisa bersamaan dengan pemberian cadangan besi”.

Algoritma Terapi ESA – Konsensus PERNEFRI 2011

Rute Pemberian EPO Pre-HD HD CAPD Transplant SC SC / IV

Efikasi meningkat dengan SK Menurunkan “ neositolisis ” Hancurnya eritrosit muda pada saat eritropoietin tidak ada berkurang (mis: diantara dosis epoetin) Memperpanjang “ stimulasi eritropoiesis ” Meningkatnya waktu paruh Kurang efisiennya pemberian IV karena sitokin2 proinflamasi yang menekan eritropoiesis yang diproduksi pada saat HD prolonged half-life of the hormone with subcutaneous administration. Possible mechanisms resulting in greater efficiency with subcutaneous therapy include sustained stimulation of the erythroid progenitor cells, diminished inhibition of erythropoiesis by proinflammatory cytokines, and prevention of neocytolysis, the hemolysis of newly formed red blood cells.

Subkutan – meningkatkan efikasi 10 20 30 40 50 60 70 80 90 Baseline Mean dose (IU/kg/week) 100 Study end* 32% reduction in dose IV SC *Mean study duration = 82.3 days

Perubahan dari IV menjadi SK memperbaiki kontrol tekanan darah Epoetin dose (IU/kg/week) MAP (mmHg) * * MAP = mean arterial pressure *p<0.05, compared with baseline Navarro et al Scand J Urol Nephrol 1995

Efikasi dan kenyamanan Keamanan & tolerabilitas Subkutan tetap menjadi cara pemberian yang paling disarankan berdasarkan berbagai guideline Berdasarkan: Efikasi dan kenyamanan Keamanan & tolerabilitas Cost effectiveness

PEMILIHAN PRODUK ESA

Jenis-jenis epoetin: Epoetin alfa Epoetin beta Cera

Protein + Karbohidrat = glikoprotein Jenis-jenis epoetin: Epoetin alfa Epoetin beta (Recormon) Karbohidrat Protein Protein + Karbohidrat = glikoprotein

Perbedaan Bahan Aktif epoetin beta dan epoetin alfa Perbedaan struktur karbohidrat Epoetin beta dapat mempengaruhi Sifat-sifat Farmakokinetik dan Farmakodinamik Waktu paruh eliminasi yang lebih panjang hingga dapat mengurangi dosis (1 x seminggu atau 1 x 2 minggu) Konsentrasi serum lebih tinggi secara signifikan Respon retikulosit meningkat secara signifikan Sifat-sifat biologik Secara signifikan menunjukkan aktifitas biologik lebih tinggi Storring et al Br J Haematol 1998 Halstenson et al Clin Pharmacol Ther 1991

Respon retikulosit epoetin beta lebih tinggi dibandingkan epoetin alfa Halstenson et al Clin Pharmacol Ther 1991

Perbedaan pada formulasi Epoetin alfa (Branded generic) Epoetin alfa (Original-pre 1998) Epoetin alfa (Original-post 1998) EPOETIN BETA (1990 launch) HSA HSA Polysorbate-80 Polysorbate-20 Glycine Glycine Complex of 5 other amino acids Calcium chloride Urea BERUBAH HSA = human serum albumin

PRCA & Epoetin

Pengalaman Insiden PRCA Perubahan 1 materi saja pada Formulasi Epo Alfa di Eropa pada tahun 1998 Penstabil formulasi HSA diubah menjadi Polysorbate 80 (agregasi) Menurun stabilitasnya Peningkatan imunogenisitas produk? (Pemberian Subkutan Epo-alfa) “Berkaca dari pengalaman terjadinya epidemi kejadian Pure Red Cell Aplasia (terjadinya imunogenisitas terhadap hormon eritropoietin) di sekitar tahun 2000” “Pada tahun 1998, Eprex diharuskan mengubah stabilizernya, yaitu albumin karena dikhawatirkan mengandung virus madcow dengan polysorbat 80 & glisin” Tetapi perubahan tersebut ternyata menurunkan stabilitasnya serta meningkatkan imunogenisitasnya yang ditunjukkan dengan kejadian PRCA terutama jika diberikan secara subkutan. Kejadian ini meningkatkan insiden PRCA pada tahun2 tersebut. Meningkatnya insiden PRCA Schellekens H. et al, Nature Biotechnology June 2006;24:613-614

Cumulative number of PRCA cases Modification of Epoetin alfa Penyebab Epidemi PRCA *188 suspected cases, 121 positive for anti-erythropoietin (EPO) antibodies of 146 tested4 Epoetin alfa-associated cases (outside USA) Epoetin alfa-associated cases (within USA) EPOETIN BETA Cumulative number of PRCA cases Modification of Epoetin alfa formulation outside USA * 200 180 160 140 120 100 80 60 40 20 7 to 1 to 7 to 1 to 7 to 1 to 7 to 1 to 7 to 31 May 31 Oct 12/97 6/98 12/98 6/99 12/99 6/00 12/00 6/01 12/01 02 02 Terjadinya epidemi PRCA berkaitan dengan perubahan formulasi Eprex di luar Amerika. Sedangkan epoetin alfa di Amerika tidak mengalami perubahan formulasi sehingga tidak ada peningkatan kejadian yang signifikan. Hal ini mengindikasikan bahwa formulasi yang baru meningkatkan imunogenisitas dari Eprex. 1Gershon et al NEJM 2002 2Communiqué de l'Agence française de sécurité sanitaire des produits de santé, 18 July 2002 3Roche Safety Database 4Johnson & Johnson Statement 30 Jan 2003

Pure Red Cell Aplasia (PRCA) Suatu kelainan hematologi yang dicurigai terjadi jika: Dengan terapi ESA > 4 minggu ditemukan: Penurunan Hb mendadak 0.5-1 g/dL/minggu atau perlu transfusi 1-2 kali/minggu Hitung lekosit & trombosit normal Hitung retikulosit absolut <10.000/µL Diagnosis pasti: Anti-erythropoietin antibody positif &/atau Erythroid progenitor cells yang berkurang pada biopsi sumsum tulang Konsensus PERNEFRI 2011, Casadevall et al. N Engl J Med 2002; 346: 469–475

Konsekuensi terhadap Epo alfa Apakah pertimbangan dengan Epo alfa mempengaruhi pemberian SK? Pemberian epoetin alfa secara subkutan dikontraindikasikan oleh Badan Otoritas Kesehatan Eropa1,2 Hal ini tidak berlaku untuk produk epoetin yang lain Tidak ada peningkatan insiden PRCA dengan penggunaan subkutan epoetin yang lain Epoetin beta memiliki profil keamanan yang sudah terbukti sejak lama baik untuk subkutan maupun intravena  tidak ada pembatasan penggunaannya secara SK & IV Eckardt & Casadevall NDT 2003 Locatelli F et alNephrology Dialysis Transplant 2004 : Vol. 19 (Suppl 2):ii!-ii47

Tolerabilitas injeksi SK Nyeri pada tempat injeksi SK epoetin beta secara signifikan lebih rendah nyerinya dibandingkan epo alfa SK dengan buffer jenis sitrat & phospat * *p0.001 vs epoetin alfa (phosphate) Visual analog scale (cm) / ( pain scale ) 10 Epoetin alfa (citrate) (phosphate) Epoetin beta Saline 5 Volume kecil : 0,3 ml Jarum kecil tajam : 27G1/2 Veys et al Clin Nephrol 1998

Dosis pada pasien dialisis Produk berbeda, kebutuhan dosis berbeda

Respon Terapi ESA Tidak Adekuat

Beberapa penyebab tidak respon terhadap ESA Inflamasi (tingkat sitokin tinggi) Defisiensi besi & vitamin Fistula graft Dialisis tidak adekuat Wanita muda Hiperparatiroid Status nutrisi buruk Tidak ada residual fungsi ginjal Transplan ginjal gagal DOD/0307-04

Seringkali terapi harus disesuaikan secara individual… Variabilitas Inter-individual dari respon dosis terhadap epoetin adalah 45% hingga 50% Variabilitas umur sel darah merah adalah sekitar 30% DOD/0307-04

Efek Samping Terapi ESA Hipertensi Reaksi hipersensitivitas terhadap EPO PRCA: Pure red cell aplasia. Kejang (Biasanya bila kenaikan Hb terlalu cepat)

Kesimpulan Terapi anemia yang optimal akan memperbaiki outcome pasien QOL yang lebih baik, mengurangi komorbid (mis: penyakit jantung), memperbaiki survival Pemberian secara SK memungkinkan terapi yang lebih optimal Efikasi (kebutuhan dosis lebih kecil) serta tolerabilitas (mis: hipertensi) yang lebih baik daripada IV  Cost effective Sediaan epoetin yang berbeda, mempunyai karakteristik & kebutuhan yang berbeda Epoetin beta Berbeda nyata dalam hal bahan aktif & formulasinya dengan epoetin alfa Formulasi yang optimal sejak awal Profil imunogenisitas yang telah terbukti jangka panjang Tidak pernah dilarang penggunaannya secara SK oleh badan otoritas manapun

TERSEDIA BAGI PASIEN HEMODIALISA BPJS Epoetin beta Recormon 2000 IU / 0,3 ml Prefilled syringes E-Katalog BPJS – JKN Rp. 139.500,- / syringes

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