Nefropatia Diabética: Estratégias de tratamento Alvimar Gonçalves Delgado Serviço e Disciplina de Nefrologia - HUCFF Faculdade de Medicina UNIVERSIDADE FEDERAL DO RIO DE JANEIRO

Evolução clínica da nefropatia no diabetes tipo 2 20-40% de diabéticos não tratados evoluem para ND Clínica: Proteinúria Redução progressiva da TFG Elevado risco de DCV JCI, 116 (2): 288-296, 2006.

A proteinúria é o mais importante fator de progressão das doenças renais.

Albuminúria como marcador de risco predominante em diabéticos tipo 2: Lições do RENAAL Kidney International (2004) 65, 2309–2320

Albuminúria como marcador de risco predominante em diabéticos tipo 2: Lições do RENAAL Kidney International (2004) 65, 2309–2320

N Engl J Med 358; 23: 2503-2505, 2008.

Baseline creatinine >1.5 mg/dL IECAs são mais renoprotetores que terapia convencional no Diabetes tipo I 100 75 50 25 Baseline creatinine >1.5 mg/dL % com Duplicação Da Creatinina basal Placebo n=202 P<.001 Captopril n=207 1 2 3 4 Years of follow-up Lewis EJ, et al. N Engl J Med. 1993;329(20):1456-1462. www.hypertensiononline.org

Maior renoproteção dos IECAs em relação à terapêutica convencional da HAS no DM tipo 1 2 -4 -6 -8 40 20 -20 -40 -60 P<.001 Redução da pressão arterial média(mmHg) % de variação da proteinúria NS Placebo Captopril Placebo Captopril www.hypertensiononline.org Lewis EJ, et al. N Engl J Med. 1993;329(20):1456-1462.

Events per patient group (%) MICRO-HOPE : efeito do ramipril na evolução de diabéticos tipo II com microalbuminúria RR=17% P=0.03 RR=24% P=0.004 NS RR=24% P=0.03 Events per patient group (%) NS MICRO-HOPE Events Per Patient Group for Secondary Endpoints In addition to having a positive impact on the primary combined endpoint of myocardial infarction, stroke, or cardiovascular death, the relative risk reductions for the secondary endpoints of total mortality, revascularization, and overt nephropathy also proved to be significant for ramipril compared to placebo. Relative risk was reduced by 24% for total mortality (P=0.004), by 17% for revascularization (P=0.03), and by 24% for overt nephropathy (P=0.03). Reference: Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy. Heart Outcomes Prevention Evaluation Study Investigators. Lancet. 2000;355(9200):253-259. Total mortality Revascularization Overt nephropathy* Heart failure† Unstable angina† *Based on positive 24h urine collection or albumin/creatinine ratio 36 mg/mmol †Requiring hospital admission RR=Relative risk reduction NS 0.05 www.hypertensiononline.org HOPE Study Investigators. Lancet. 2000;355:253-259.

IRMA II: Incidência de progressão de micro para macroalbuminúria P<0.001 for difference between 300 mg irbesartan group and placebo Placebo 150 mg of irbesartan Incidence of Diabetic Nephropathy (%) 300 mg of irbesartan 3 6 12 18 22 24 Months of Follow-up Parving HH, et al. N Engl J Med. 2001;345(12):870-878. ©2001 Massachusetts Medical Society. All rights reserved. www.hypertensiononline.org

Efeito dos ARAs na evolução da nefropatia Strategies that Impact Progression of CKD: ARBs in Type 2 Diabetics with CKD Efeito dos ARAs na evolução da nefropatia diabética tipo II RENAAL 30 20 Placebo RR = 28% % With ESRD p = 0.002 Losartan 10 12 24 36 48 Months Hypotheses about therapeutic strategies to reduce progression of CKD were rigorously tested by randomized controlled trials, like the RENAAL study. Even though the efficacy of angiotensin blockade was established in type I DM, the medical community felt it was important determine whether ARBs could slow progression of CKD in type II DM. Placebo (n) 762 715 610 347 42 Losartan (n) 751 714 625 375 69 RR = relative risk RENAAL = Reduction of End points in NIDDM with the Angiotensin II Receptor Antagonist Losartan ARB = Angiotensin II Receptor Blocker CKD = chronic kidney disease Brenner BM, et al. N Engl J Med. 2001;345(12):861-869.

Proportion with primary endpoint IDNT: ARA é melhor que amlodipina e placebo na nefropatia diabética tipo II P=0.02 for irbesartan compared to placebo Proportion with primary endpoint *Composite of a doubling of serum creatinine, end stage renal disease, or death 6 12 18 24 30 36 42 48 54 Months of Follow-up Irbesartan (n) 579 555 528 496 400 304 216 146 65 Amlodipine (n) 565 542 508 474 385 287 187 128 46 Placebo (n) 568 551 512 471 401 280 190 122 53 Lewis EJ, et al. N Engl J Med. 2001;345(12):851-860. ©2001 Massachusetts Medical Society. All rights reserved. www.hypertensiononline.org

IECA + Verapamil: efeito aditivo sobre a Proteinúria em Diabetes tipo II a 1 ano Trandolapril (5.5 mg/d) Verapamil (315 mg/d) Trandolapril (2.9 mg/d) + Verapamil (219 mg/d) n=12 n=11 n=14 -27% -33% Percent reduction -62% * *p <0.001 combination vs either monotherapy Bakris GL, et al. Kidney Int. 1998;54:1283-1289. Reprinted by permission, Blackwell Science, Inc. www.hypertensiononline.org

Efeito do duplo bloqueio (ARA + IECA) sobre a PA e a proteinúria em diabéticos Parving, H-H et al.

Efeito do duplo bloqueio (ARA + IECA) em diabéticos com alto risco vascular (ONTARGET) Lancet 372: 547–53, 2008

Aliskireno Combinado com Losartan em Diabetes Tipo II e Nefropatia Hans-Henrik Parving, M.D., D.M.Sc., Frederik Persson, M.D., Julia B. Lewis, M.D., Edmund J. Lewis, M.D.,and Norman K. Hollenberg, M.D., Ph.D., for the AVOID Study Investigators* N Engl J Med 2008;358:2433-46. Aliskireno pode ter efeitos nefroprotetores independentes dos efeitos da redução da pressão arterial em diabéticos com nefropatia e hipertensão? Figure 2. Changes from Baseline in the Urinary Albumin-to-Creatinine Ratio, Urinary Albumin Excretion Rate, and Blood Pressure According to Study Group. The percentage change from baseline (2 weeks before randomization), in the geometric mean, with 95% confidence intervals, is shown for the ratio of urinary albumin to creatinine (Panel A), overnight urinary albumin excretion rate (Panel B), and mean blood pressure, measured while the patient was seated (Panel C). The data show a dose-dependent effect of aliskiren on albuminuria.

Original Article Kidney International (2009) 75, 72–79; doi:10.1038/ki.2008.528; published online 22 October 2008 Regression of glomerular injury by losartan in experimental diabetic nephropathy Flávio Teles1, Flávia G Machado1, Bianca H Ventura1, Denise M A C Malheiros1, Clarice K Fujihara1, Luís F F Silva1 and Roberto Zatz1

A importância do controle da pressão arterial.

Parving H-H et al, Am J Kidney Dis 22, 1993

Meta Análise: Menor PA média resulta em declínio mais lento da TFG em diabéticos e não-diabéticos 95 98 101 104 107 110 113 116 119 r = 0.69; P < 0.05 MAP (mmHg) GFR (mL/min/year) 130/85 140/90 Untreated HTN -2 -4 -6 -8 -10 -12 -14 Meta Analysis: Lower Mean BP Results in Slower Rates of Decline in GFR in Diabetics and Non-Diabetics Hypertension and renal parenchymal disease are closely interrelated. Arterial hypertension accelerates renal disease and hastens the progression to end stage renal failure. Recent studies have firmly established the importance of blood pressure reduction as a means to slow the progression of different forms of renal parenchymal injury. For diabetic or non-diabetic nephropathy, the higher the blood pressure the greater the renal risk. The beneficial impact from achieved control of mean arterial pressure (MAP) is demonstrated in this slide, which shows a meta-analysis of the 9 major clinical trials in diabetic and non-diabetic renal diseases. The GISEN Group, Klahr, and Moschio studies are those in non-diabetic subjects. The higher the MAP the faster the GFR declines; the better the control of MAP the slower the GFR declines.   References: Bakris GL, Mangrum A, Copley JB, Vicknair N, Sadler R. Effect of calcium channel or beta-blocker on the progression of diabetic nephropathy in African Americans. Hypertension. 1997;29(3):744-750. Bakris GL, Williams M, Dworkin L, Elliott WJ, Epstein M, Toto R, Tuttle K, Douglas J, Hsueh W, Sowers J. Preserving renal function in adults with hypertension and diabetes: a consensus approach. National Kidney Foundation Hypertension and Diabetes Executive Committees Working Group. Am J Kidney Dis. 2000;36(3):646-661. Randomised placebo-controlled trial of effect of ramipril on decline in glomerular filtration rate and risk of terminal failure in proteinuric, non-diabetic nephropathy. The GISEN group (Gruppo Italiano di Studi Epidemiologici in Nefrologia). Lancet. 1997;349(9069):1857-1863. Herbert LA, Bain RP, Verme D, Cattran D, Whittier FC, Tolchin N, Rohde RD, Lewis EJ. Remission of nephrotic range proteinuria in type 1 diabetes. Collaborative Study Group. Kidney Int. 1994;46(6):1688-1693. Klahr S, Levey AS, Beck GJ, Caggiula AW, Hunsicker L, Kusek JW, Striker G. The effects of dietary protein restriction and blood-pressure control on the progression of chronic renal failure. N Eng J Med. 1994;330(13):877-884. Lebovitz HE, Wiegmann TB, Cnaan A, Shahinfar S, Sica DA, Broadstone V, Schwartz SL, Mengel MC, Segal R, Versaggi JA, et al. Renal protective effects of enalapril in hypertensive NIDDM:Role of baseline albuminuria. Kidney Int Suppl. 1994;Suppl 45:150-155. Parving HH, Hommel E, Damkjaer Nielsen M, Giese J. Effect of captopril on blood pressure and kidney function in normotensive insulin dependent diabetics with nephropathy. BMJ. 1989;299(6698):533-536. Viberti G, Morgensen CE, Groop LC, Pauls JF. Effect of captopril on progression to clinical proteinuria in patients with insulin-dependent diabetes mellitus and microalbuminuria. JAMA. 1994;271(4):275-279. Parving HH, et al. Br Med J. 1989. Moschio G, et al. N Engl J Med. 1996. Viberti GC, et al. JAMA. 1993. Bakris GL, et al. Kidney Int. 1996. Klahr S, et al. N Eng J. Med 1994. Bakris GL. Hypertension. 1997. Hebert L, et al. Kidney Int. 1994. The GISEN Group. Lancet. 1997. Lebovitz H, et al. Kidney Int. 1994. Bakris GL, et al. Am J Kidney Dis. 2000;36(3):646-661. Reprinted by permission, Harcourt Inc. www.hypertensiononline.org

Recomendações de Pressão Arterial Alvo para pacientes com DM ou Doença Renal Organization Year Systolic BP Diastolic BP American Diabetes Association 2001 <130 <80 National Kidney Foundation 2000 Canadian Hypertension Society 1999 British Hypertension Society <140 WHO & International Society of Hypertension <85 Joint National Committee (JNC VI) 1997 www.hypertensiononline.org

Efeito do tratamento anti-hipertensivo intensivo (I) ou moderado (M) sobre a evolução da proteinúria em diabéticos tipo 2 I M Schrier RW et al, Kidney Int 61, 2002

O rigoroso controle da pressão é mais eficaz que um rigoroso controle glicêmico (UKPDS)

Estratégias para atingir PA < 130 x 80 mmHg Etapa 1: Revisar medicações (AINEs) e eliminar ou minimizar o uso de drogas (incluindo alcool) que aumentam a PA. Etapa 2: Prescrever e insistir no uso de 2 g de sal. Etapa 3: Usar IECAs ou ARAs até a dose máxima. Etapa 4: Usar diuréticos de alça se a TFG for igual ou < 50 ml/min e um tiazídico se TFG > 50 ml/min. Etapa 5: Adicionar um BCC ou BB. Etapa 6: Adicionar um alfa-bloqueador um alfa-agonista de ação central. Etapa 7: Acrescentar hidralazina ou minoxidil.

Outros fatores de importância

PADRÃO DE CONTROLE METABÓLICO

Controle metabólico rigoroso previne o aparecimento de microalbuminúria em diabetes tipo 1. DCCT Research Group. NEJM 329:977, 1993

Novos hipoglicemiantes com ação renal Renal sodium–glucose transport inhibition: role in diabetes mellitus and potential clinical implications (dapagliflozin and sergliflozin) George L Bakris et al, Kidney Int , 2009.

COLESTEROLEMIA

Influência do fumo na progressão da nefropatia diabética (DNID) Chuahirun T et al, Am J Kidney Dis 39 (2), 2002

Influência do genótipo DD na evolução da nefropatia diabética ID e II DD Parving H-H et al, Br Med J 313, 1996

Redução da ingesta protéica e progressão da DRC Diabéticos Não Diabéticos Walker, JD, Bending, JJ, Dodds, RA, et al, Lancet 1989; 2:1411 and Zeller, K, Whittaker, E, Sullivan, L, et al, N Engl J Med 1991; 324:78. Klahr, S, Levey, AS, Beck, GJ, et al, N Engl J Med 1994; 330:877.

Vitamina D e seus metabólitos são nefroprotetores? Renoprotection with vitamin D: Specific for diabetic nephropathy? G Klaus, Kidney Int 2008.

Tratamento intensivo e multifatorial de longa duração Changes in Selected Risk Factors during the Interventional Study and Follow-up Period Tratamento intensivo e multifatorial de longa duração Figure 2. Changes in Selected Risk Factors during the Interventional Study and Follow-up Period. Panel A shows mean ({+/-}SE) values for selected risk factors during the interventional part of the study for all patients (solid lines) and during the follow-up period (dashed lines). In the conventional-therapy group, mean values were obtained at baseline, at 3.8 years, at 7.8 years, and at 13.3 years. At these intervals, the total numbers of patients in both study groups were 160, 149, 130, and 93, respectively. Panel B shows the percentage of patients in each group in whom the treatment goals for the intensive-therapy group were reached at the end of the study. Only one patient (in the intensive-therapy group) reached all five treatment goals at the end of follow-up. To convert the values for cholesterol to millimoles per liter, multiply by 0.02586. To convert the values for triglycerides to millimoles per liter, multiply by 0.01129. LDL denotes low-density lipoprotein. Gaede P et al. N Engl J Med 2008;358:580-591

Tratamento intensivo e multifatorial de longa duração Gaede P et al. N Engl J Med 2008;358:580-591

CONCLUSÕES Os principais fatores modificáveis são a proteinúria e a hipertensão arterial. O curso da doença pode ser modificado por um tratamento anti-hipertensivo rigoroso e rígido controle glicêmico. Os medicamentos que produzem mais efeitos benéficos sobre a proteinúria são os IECAs (tipo I) e/ou ARAs (II) O tratamento deve ser multifatorial e o mais intensivo possível sobre a pressão arterial, a proteinúria, o controle glicêmico e a hiperlipidemia.