Maria Eugênia F Canziani Manejo da Anemia na DRD Maria Eugênia F Canziani UNIFESP

“50 - 80% dos pacientes com Doença Renal Crônica se tornam anêmicos ” Nephron 2000, 85:2 J Am Soc Nephrol 2002, 13:504 Hemoglobina < 13 g/dL Hemoglobina < 11 g/dL

Estudo multicêntrico PUC, UFJF, UERJ, USP, UNIFESP n= 401 , Cl cr= 34.8 ± 17.5ml/min Hb < 12g/dL Hb < 11g/dL Pacientes (%) Canziani ME e col ,JBN 2006, 28:86

Prevalência de anemia em DM vs pop.geral (NHANESIII) Hb < 11g/dL DM NHANES III Thomas M, Diabetes Care, 2003, 26(4):1164

Impacto da DM na concentração de HG na DRC n= 336 DM / 1846 nDM DM nDM p< 0.01 Ravanam R, Diabetologia, 2007, 50(1):26

Pac. HD com hemoglobina < 11g% por região % pacientes Jan 2006 – Censo SBN

Vanrenterghem Y. NDT. 2004;19(S5):54

Cr >2mg/dL anemia 60% vs 29%

 DRC - Anemia normocrômica normocítica   da produção de EPO  deficiência ferro e folatos  toxinas urêmicas, inflamação  perdas  hiperparatiroidismo  drogas (ACE, ARBs) NDT 2002 17(suppl5):32

Inflamação Altera sensibilidade das cels progenitoras à EPO Promove apoptose de eritroblastos imaturos  absorção e disponibilização de ferro  Hepicidina

 dano tubulointersticial   da produção de EPO  alterações hemodinâmicas + consumo de O2 co-transporte Na-Glicose   [ ] glicose no túbulo proximal  HIPOXIA  hiperglicemia   “hipoxia inducible factors”  inflamação – doença microvascular  sangramento GI relacionadas à DM  deficiência de ferro  drogas (ACE, ARBs)

todos os estágios da DRC Anemia – freqüente todos os estágios da DRC nas diferentes terapias Anemia causa multifatorial  EPO, Fe, inflamação, DM.... Conseqüências ?

Anemia e risco de morte Amostra Medicare 1,1 milhão de pacientes, seguimento de 2 anos, ajustados para idade, sexo e raça Esse gráfico mostra que em uma amostra populacional de 1.1 milhao de pacientes do Sistema Medicare dos EUA que o risco relativo de mortalidade em 2 anos em pacientes com mais de 65 anos. Observamos que quanto mais doenças o paciente tem maior é o seu risco relativo de mortalidade em 2 anos de seguimento.

 Hb vs sobrevida em pacientes pré-diálise 1.00 0.95 Hb ≥13.0 g/dL 0.90 Probabilidade de sobrevida 12-12.9 g/dL 0.85 The relationship between Hb levels and patient survival was assessed in a large cohort of patients (n=3028) with GFR <60 mL/min per 1.73 m2, who were not yet on dialysis (Levin et al 2006). Hb level at time of referral was a statistically independent predictor of survival (RR=0.875 for every 1.0 g/dL, 95% CI: 0.835-0.917, P=0.0001). 0.80 11-11.9 g/dL 0.75 <10 g/dL 10-10.9 g/dL Log-rank test: P=0.0001 0.70 0 3 6 9 12 15 18 21 24 27 31 33 37 Meses do resultado da Hb Levin et al. NDT 2006;21:370-377 Levin A et al. Haemoglobin at time of referral, prior to dialysis, predicts survival: as association of haemoglobin with long-term outcomes. Nephrol Dial Transplant. 2006;21: 370-377.

Anemia  risco de progressão – Diálise n=1513, DM Pac. em diálise (%) 60 50 40 30 20 10 Quartil da Hb no Baseline (g/dL) Q1: 6.8-11.3 Q2: 11.3-12.5 Q3: 12.5-13.8 Q4: 13.8-18.0 Q1 (n=378)* Q2 (n=377)* Q3 (n=363)* Anemia has been found to be a contributing factor for the progression of CKD to dialysis (Kuriyama et al 1997). The relationship between baseline Hb levels and progression of diabetic nephropathy was studied in 1513 patients (Mohanram et al 2004). Anemia was found to be an independent predictor for progression of CKD to dialysis. The proportion of patients progressing to dialysis was significantly higher for those in the first, second and third Hb quartiles compared with those in the fourth quartile. Q4 (n=395) 0 1 2 3 4 Time (years) *P<0.05 versus Q4 Mohanram et al. Kidney Int. 2004;66:1131-1138 Kuriyama S et al. Reversal of anemia by erythropoietin therapy retards the progression of chronic renal failure, especially in nondiabetic patients. Nephron. 1997;77:176-85. Mohanram A et al. Anemia and end-stage renal disease in patients with type 2 diabetes and nephropathy. Kidney Int. 2004;66:1131-1138.

Morbidade e Mortalidade Progressão Anemia – associada  Qualidade de vida DCV Morbidade e Mortalidade Progressão Eschbach e col. Ann Intern Med 1989, 111:992 Nissenson AJKD 1992, 20(S1):S21 Levin e col. AJKD, 1999,34:125 Ma e col. J Am Soc Nephrol 1999, 10 (3):610 Foley e col. KI 2000, 58:1325 Al-Ahmad e col. J Am Coll Cardiol 2001,38:955 London e col. 2002, 40:539 Ofsthun e col KI 2003, 63:1908 Collins e col. NDT 2003,18 (S2):2 Weiner e col- J Am Soc Nephrol 2005, 16:1803 Manejo ?

(not intentionally >13 g/dL) (upper limit individualised) Diretrizes para Anemia KDOQI 2007 update 11-12 g/dL (not intentionally >13 g/dL) EBPG >11 g/dL (upper limit individualised) EBPG >11 g/dL (upper limit not defined) KDOQI 11-12 g/dL DOQI 11-12 g/dL KDOQI ≥11 g/dL (caution >13 g/dL) SBN 11-12 g/dL 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 Since 1997, a number of clinical guidelines for the management of anaemia have been developed. The guidelines have evolved as evidence has accumulated and a better understanding has been reached of the benefits of correcting Hb in specific patient groups, for example in patients with comorbid conditions such as heart disease and diabetes. There are still some notable discrepancies between guidelines intended for different regions. The National Kidney Foundation Kidney Disease Outcomes Quality Initiative (NKF-K/DOQI) is expected to publish an update to its 2006 guidelines in 2007. Locatelli et al. Nephrol Dial Transplant 2004;19(Suppl 2):1-43 NKF-KDOQI. AJKD 2001;37(Suppl 1):S182-238; NKF-KDOQI. AJKD 2006; 47(Suppl 3):S11-145 CARI. www.cari.org.au/dialysis_bht_updating.php, 2005 Renal Association. www.renal.org/Standards/Renal Standards_2002b.pdf, 2002 CSN. http://csnscn.ca/local/files/guidelines/CSN-Guidelines-1999.pdf, 1999 CSN 11-12 g/dL CARI 11-12 g/dL CVD 12-14 g/dL no CVD UK RA >10 g/dL CARI >11 g/dL CVD 12-14 g/dL no CVD CARI 11-12 g/dL CVD 12-14 g/dL no CVD UK NICE 10.5-12.5 g/dL 10-12 g/dL in children <2yr CVD=cardiovascular disease

Como tratar ? MEE Ferro causas - perdas? JBN 2000,22, 3(Supl5):28 NDT 2004,19 (Suppl2):39 AJKD 2006, 47, 5 (Suppl3):S33

 Eritropoetina (Eprex, Eritina, Eritromax, Hemax, Eritropoetina – Agentes estimulante da eritropoiese  Eritropoetina (Eprex, Eritina, Eritromax, Hemax, Hemoprex, Hemotin, Recormon, Timax)  Darbopoetina (Amgen) - TREAT  CERA (Roche)  Eritropoetina via EV – SC

Ciclo do ferro 5-10% 75% 10-20% Absorção de ferro 1-2 mg/dia GV Transferrina 10-20% perda de ferro 1-2 mg/dia Ferritina

 Ferro  Avaliação estoques de ferro  ferritina (estoque)  sat. da transferrina- TSAT (ferro disponível)  % céls hipocromicas, Hb do reticulócito JBN 2000,22, 3(Supl5):28 NDT 2004,19 (Suppl2):39 AJKD 2006, 47, 5 (Suppl3):S33

Figure 1. Pathophysiological Mechanisms Underlying Anemia of Chronic Disease. In Panel A, the invasion of microorganisms, the emergence of malignant cells, or autoimmune dysregulation leads to activation of T cells (CD3+) and monocytes. These cells induce immune effector mechanisms, thereby producing cytokines such as interferon-{gamma} (from T cells) and tumor necrosis factor {alpha} (TNF-{alpha}), interleukin-1, interleukin-6, and interleukin-10 (from monocytes or macrophages). In Panel B, interleukin-6 and lipopolysaccharide stimulate the hepatic expression of the acute-phase protein hepcidin, which inhibits duodenal absorption of iron. In Panel C, interferon-{gamma}, lipopolysaccharide, or both increase the expression of divalent metal transporter 1 on macrophages and stimulate the uptake of ferrous iron (Fe2+). The antiinflammatory cytokine interleukin-10 up-regulates transferrin receptor expression and increases transferrin-receptor-mediated uptake of transferrin-bound iron into monocytes. In addition, activated macrophages phagocytose and degrade senescent erythrocytes for the recycling of iron, a process that is further induced by TNF-{alpha} through damaging of erythrocyte membranes and stimulation of phagocytosis. Interferon-{gamma} and lipopolysaccharide down-regulate the expression of the macrophage iron transporter ferroportin 1, thus inhibiting iron export from macrophages, a process that is also affected by hepcidin. At the same time, TNF-{alpha}, interleukin-1, interleukin-6, and interleukin-10 induce ferritin expression and stimulate the storage and retention of iron within macrophages. In summary, these mechanisms lead to a decreased iron concentration in the circulation and thus to a limited availability of iron for erythroid cells. In Panel D, TNF-{alpha} and interferon-{gamma} inhibit the production of erythropoietin in the kidney. In Panel E, TNF-{alpha}, interferon-{gamma}, and interleukin-1 directly inhibit the differentiation and proliferation of erythroid progenitor cells. In addition, the limited availability of iron and the decreased biologic activity of erythropoietin lead to inhibition of erythropoiesis and the development of anemia. Plus signs represent stimulation, and minus signs inhibition. Weiss, G. N Eng J Med 2005; 352:1011-1023.

Iron Sucrose US Clinical Trials Group – KI 2006, 70(6):1188 Ferro EV vs. Oral Resp.cumulativa ( Hb >1g/dL)  Ferritina (ng/mL)  estoque Iron Sucrose US Clinical Trials Group – KI 2006, 70(6):1188

Tratamento Eritropoetina Ferro ALVO de Hb?

Maior Hb melhor sobrevida Fresenius Medical Care, North America (n=44.550) 100 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 patients surviving 90 Methods A longitudinal study of haemodialysis patients in Fresenius Medical Care-North America facilities was performed. Selection was restricted to patients in the census for 6 consecutive months from July 1, 1998 through June 30, 2000. Patient mean haemoglobin and other covariates measured during the initial 6 months were related to survival, number of hospitalizations, and length of stay over the subsequent 6 months of follow-up. Results Patients with haemoglobin <9 g/dL had an adjusted relative risk of death of 2.11 compared to those patients with 11 </= haemoglobin < 12 g/dL (P < 0.0001). The adjusted relative risk of death was 0.84 for 12 </= haemoglobin < 13 g/dL (P = 0.007). These data suggest there is no increased risk of mortality associated with haemoglobin above the current recommended values. Both number of hospitalizations and length of stay decreased as haemoglobin increased. Patients with haemoglobin >/=13 g/dL had an adjusted length of stay of 9.6 days compared to 10.9 days for those with 11 </= haemoglobin < 12 g/dL (P < 0.0001). Conclusions These data indicate the relative risk of death and hospitalization are inversely associated with haemoglobin levels, with no apparent additional risk associated with haemoglobin levels> 12 g/dL. 80 15 30 45 60 75 80 105 120 135 150 165 180 Follow-up time, days Maior Hb melhor sobrevida Ofsthun et al. Kidney Int 2003;63:1908-14

All cause mortality hazard ratio 12000 5 11–12.9 g/dL Unadjusted 10000 3 8000 All cause mortality hazard ratio Number of patients 1 6000 n=58 058 incident and prevalent patients 4000 1 2000 0.8 <9 Hb level (6 mos) ≥14 9.0-9.4 9.5-9.9 10.0-10.4 10.5-10.9 11.0-11.4 11.5-11.9 12.0-12.4 12.5-12.9 13.0-13.4 13.5-13.9 Regidor et al. J Am Soc Nephrol. 2006;17:1181-91

CREATE CHOIR Besarab e cols. NEJM 339:584, 1998 Singh e col. N Engl J Med 2006,355 (20):2085 CHOIR Drueke e col. N Engl J Med 2006,355 (20):2071 CREATE

Maior dose de EPO < sobrevida 1.8 1.6 1.4 1.2 All-cause mortality hazard ratio 1.0 0.9 Minimally adjusted 0.8 Case-Mix Case-Mix & MICS 0.7 1-5.000 ≥25.000 5.000-10.000 10.000-15.000 15.000-20.000 20.000-25.000 rHuEPO (units/week) Maior dose de EPO < sobrevida Streja E et al. Am J Kidney Dis. 2008; 52(4):727

Estudos ≠ alvos, n0 mínimo 100 pacientes, mínimo 12 meses Mortality and target haemoglobin concentrations in anemic patients with chronic kidney disease treated with erythropoietin: a meta- analysis. Phrommintikul A, Haas SJ, Elsik M, Krum H. Lancet 2007:369 Estudos ≠ alvos, n0 mínimo 100 pacientes, mínimo 12 meses - 5143 pacientes - Os grupos com Hb + altos  > mortalidade, > trombose de acesso FDA exigir que na bula dos MEE Hb 10-12g/dL

Anemia e DRC: que resposta os pac. estão obtendo? Hb 11-12: 38.4% Núm. de pacientes 3000 DOQI target 65.000 pacientes em diálise 98% em uso de EPO 2500 2000 1500 1000 Hb <10: 12.2% Hb <11: 31.5% Hb >12: 30.0% 500 <6.0 6.9 7.9 8.9 9.9 10.9 11.9 12.9 13.9 14.9 15.9 16.9 Hb (g/dL) Adaptado de Lacson et al 2003

Objetivo Avaliar a proporção de pacientes renais crônicos em uso EPO com níveis adequados de hemoglobina (10.5 g/dL-12.5 g/dL); Hb abaixo de 10.5 g/dL 14 – 27 %  20 ± 3.8% Alvo 42 – 61 %  50 ± 5.1% Hb acima de 12.5g/dL 19 – 41 %  30 ± 6.0%

HEMOGLOBIN LEVEL VARIABILITY: ASSOCIATIONS WITH COMORBIDITY, INTERCURRENT EVENTS, AND HOSPITALIZATION Pac HD (n= 152.846), sobreviveram os primeiros 6 meses de 2003  6 padrões BAHA Alto AA 12,5 Hemoglobina, g/dL Nível alvo 11,0 BAHB Baixo 6 meses Ebben JP e cols., 2006; CJASN 1:1205-1210

Padrões de flutuação de HB Objetivo Estudar a variação da hemoglobina dos pacientes em 3 anos; Período (meses) N Padrões de flutuação de HB Baixo Alvo Alto BAHB BAHA AA % 6 01/04-06/04 221 2.3 10.4 31.7 29.4 24.0 07/04-12/04 196 3.6 9.2 20.4 3.1 41.3 22.4 01/05-06/05 188 2.1 6.9 26.6 33.0 29.3 07/05-12/05 172 2.9 6.4 26.2 7.6 35.5 21.5 01/06-06/06 142 12.7 14.8 5.6 40.1 24.6 07/06-12/06 135 . 5.9 18.5 33.3 36.3 12 01/04-12/04 0.5 19.7 26.1 52.7 01/05-12/05 164 1.2 2.4 21.3 29.9 43.9 01/06-12/06 130 0.8 29.2 58.5 36 01/04-12/06 108 2.8 8.3 88.9 2.2% 8.6 % 23 % 4.4% 35.4% 26.3%  89 %

Hospitalização e comorbidades pela flutuação da Hb hemoglobina Baixa No alvo Alta BAHB BAHA AA Admissão Hospitalar (%) 69,2 25,3 29,8 51,1 33,5 54,0 Admissão por infecção (%) 29,5 6,2 7,4 17,6 9,3 17,7 TPH (dias) 29,5 6,2 7,4 17,6 9,3 17,7 Média de comorbidades (n) 29,5 6,2 7,4 17,6 9,3 17,7 TPH=Tempo de permanência hospitalar; BAHB= baixa amplitude, Hb baixa; BAHA= baixa amplitude, Hb alta; AA= ampla amplitude. Ebben JP e cols., 2006; CJASN 1:1205-1210

Kidney Int. 2008; 74(6):695 Anemia na DRC Comorbidades que afetam a resposta eritropoietica Efeitos dos MEE procoagulantes, hipertensão viscosidade, inflamação Outros fatores Fe EV, hiporesposta MEE fatores não conhecidos Aumento da dose para atingir o alvo Aumento do risco de mortalidade Kidney Int. 2008; 74(6):695

Resumo Complicação freqüente na DRC Precoce Multifatorial -  EPO, DM Associada  mortalidade Tratamento – EPO /Ferro Variabilidade - nociva Hb 11-12 g/dL