Nefropatia2 Dbt

Nefropata Diabtica

Consideraciones en el Manejo Clnico

Carlos [email protected]

Servicio de Nefrologa y Programa de Trasplantes RenalesHospital Privado - Centro Mdico de Crdoba

Mortalidad anual segn los estados de Nefropata DiabticaAdler et al. Kidney Int. 2003;63:225-232.No nefropataMicroalbuminuriaMacroalbuminuriaElevada creatinina plasmtica o terapia de reemplazo renal1.4% (1.3% to 1.5%)3.0% (2.6% to 3.4%)4.6% (3.6% to 5.7%)19.2% (14.0% to 24.4%)

DIABETES COMO CAUSA DE INSUFICIENCIA RENAL CRNICA TERMINAL EN ARGENTINA 0510152025303519961997199819992000200120022003200420052006PORCENTAJESINTRA, Incucai 2007

Hospital Privado-Centro Mdico de Crdoba: perodo 1997-2003SUPERVIVENCIA EN HEMODIALISIS

Source: Kidney Disease Outcome Quality Initiative of the National Kidney Foundation.RECOMENDACIONESIndividuos a riesgo de Enf. Renal Crnica

Diabticos Hipertensos Enf Autoinmunes Infec. Sistmicas Mayores de 60 aos Historia fliar enf. Renal Reduccin masa renal Antec. de IRA

CASO CLINICO

Mujer, 57 aosDiabtica tipo 2 (15 aos de diagnstico)HTA (10 aos de diagnstico)Refiere controles de PA en casa de 120/80Nunca tabacoBMI: 31Probable SAOS (en estudio)Sin retinopata Control previo hace 6 meses

PA: 155/95Sin edemas

Creatinina: 1.10 mg/dl (previa 0.88 mg/dl)Indice Albmina/Creatinina urinaria: 28 mg/gK: 5.4 mEq/lHb glicosilada: 9.4%LDL: 155 mg/dlHDL: 35 mg/dlTriglicridos: 225 mg/dlOrina completa: normal

Medicacin: Enalapril 10 mg/da, Atorvastatina 10 mg/da, Metformina 850 mg c/12 hs

Tiene esta paciente cada de la funcin renal?Es necesario una recoleccin de orina de 24 hs? El control de la presin arterial debera ser optimizado? El valor de K srico impide seguir utilizando IECAs o ARA II? La optimizacin del control metablico mejorara la salud renal ? Pudo haberse prevenido la aparicin del compromiso renal? Es necesario interconsultar a un nefrlogo?

Source: Kidney Disease Outcome Quality Initiative of the National Kidney Foundation.RECOMENDACIONESwww.kidney.org/professionals/kdoqi/gfr_calculator.cfm

Estimacin del Clearance de Creatinina:Ecuacin de Cockroft-Gault Desarrollada en 249 hombrescon creatinina estable

Sobrestimacin del ClCr en:

1) vegetarianos2) obesos3) malnutridos4) edematosos 5) Bajos FG

(140-edad) x peso(72 x S.Creat.) (x 0.85 en mujeres)Datos de 176 pacientes estudiados en el Hospital Privado Centro Mdico de Crdoba

Levey et al., Ann Int Med, 1999Ecuacin MDRD: Generacin de las variables

Levey et al., Ann Int Med, 1999Ecuacin MDRD: RendimientoPuede subestimar el FG en ERC estadio 1

Puede sobrestimar el FG en ERC estadios 4-5

4 Estudios en pacientes con ERC: diferencias medias encontradas: -5,5 ml/min hasta +0.9 ml/min/1.73m2

Levey et al., N Eng J Med 2006Ecuacin MDRD: Limitaciones Relacionadas a la calibracin de la creatinina

En poblacin con FG > 60 ml/min

En pacientes con IRA

En diabticos con hiperfiltracin

En poblacin oriental (otras etnias?)

0408012016020004080120160200y = 0.471 x + 36.029r = 0.560n = 413MDRD (ml/min/1.73m2)Clearance Plasmtico de Iohexol (ml/min/1.73m2)Gaspari et al. 2005Subestimacin del FG con MDRD en Sujetos Diabticos Tipo 2

Estimacin del FG en Diabticos Influencia del Control MetablicoRigellau V et al. Diabetes Care 2006Deteccin de FG < 60 ml/min

Criterion Standard

When screening tests are positive, measurement of protein excretion in a 24-hour collection has been the longstanding gold standard for the quantitative evaluation of proteinuria.GUIDELINE 5. ASSESSMENT OF PROTEINURIAAmerican Journal of Kidney Diseases,Vol 39, No 2, Suppl 1 (February), 2002An alternative method for quantitative evaluation of proteinuria is measurement of the ratio of protein or albumin to creatinine in an untimed spot urine specimen. These ratios correct for variations in urinary concentration due to hydration and provide a more convenient method of assessing protein and albumin excretion than that involved with timed urine collections.

Por qu es necesario conocer la proteinuria de nuestros pacientes?

La proteinuria es una caracterstica comn de las nefropatas crnicas

Mayor proteinuria se asocia con mayor riesgo de enfermedad renal crnica

Mayor proteinuria se asocia con mayor velocidad en la prdida del filtrado glomerular

La proteinuria se asocia con aumento en el riesgo CV

Source: Kidney Disease Outcome Quality Initiative of the National Kidney Foundation.

Koopman N, et al .Nephrol Dial Transplant 1989Ritmo circadiano de la proteinuria:Importancia en el Indice P/C

60Kg70Kg80Kg

Robdy R, et al. Am J Kidney Dis, 1995Indice P/C como indicador de Proteinuria de 24 hs:Diabticos con Nefropata

Incerti et al.Nephrol Dial Transplant 2005Indice A/C como indicador de Albuminuria de 24 hs:Screening de Microalbuminuria en Diabticos tipo 2 (531 pacientes)

INDICATIONS FOR INITIAL TREATMENT AND GOALS FOR ADULT HYPERTENSIVE DIABETIC PATIENTSGoal (mmHg) < 130< 80

Behavioral therapy 130-139 80-89alone(maximum 3 months) then add pharmacologic treatment

Behavioral therapy + 140 90pharmacologic treatmentSystolicDiastolic American Diabetes Association, Diabetes Care 2004

RAS-IWITHDRAWAL FROM CLINICAL TRIALS ON RAS INHIBITORS BECAUSE OF SEVERE HYPERKALEMIA non RAS-IDiabetic nephropathyNon-diabetic nephropathyAverallLewis et al., N Engl J Med, 1993Lewis et al; N Engl J Med, 2001RENAAL, N Engl J Med, 2001Total Kamper et al., Am J Hypertens, 1992Hannedouche et al., Br Med J, 1994Maschio et al., N Engl J Med, 1994GISEN, Lancet, 1997 Ruggenenti et al., Lancet, 1998Total 3/20711/5799/751 23/1531 (1.6%)0/352/525/3001/780/998/564 (1.4%)

31/2101 (1.5%)0/2025/11362/7627/2100 (0.3%)0/352/483/2831/881/877/521 (1.3%)14/2621 (0.6%)In patients with chronic renal disease, ACE inhibitors usually increase serum K+ by 0.3 - 0.5 mEq/L, but induce severe hyperkalemia in no more than 1% to 2 % of cases

Incidencia de macroalbuminuriaCambio en la albuminuria Parving et al., N Engl J Med, 200120150105150 mgPlacebo%14.9 %9.7 %300 mg5.2 %Irbesartan100-30-10-20150 mgPlacebo%9 %- 6 %300 mgIrbesartan- 30 %p = 0.006NNT: 5NNT: 11EL BLOQUEO DEL SRAA SE ASOCIA CON MENOR PROGRESIN HACIA LA MACROPROTEINURIA

Reversin de la ND con el Tx de PancreasFioretto P, et al. N Eng J Med 1998

DCCT Research Group N Eng J Med 1993INCIDENCIA DE MICRO Y MACROALBUMINURIACON CONTROL METABLICO INTENSIVO

MACRORetinopata Basal NORetinopata Basal SIMICROMACROMICRO

ADVANCE Collaborative Group. N Eng J Med 2008CONTROL METABLICO INTENSIVO Y EVENTOS VASCULARES: (11.000 Diabticos tipo 2)

0 0.80-0.60Relative Risk (95% CI) Eventos Macro Incidencia Nefropata -0.80

THE BENEDICT TRIALPatients

End point

Target HbA1C

Target BP1,204 subjects with type 2 diabetes, high blood pressure and normal urinary albumin excretion

Progression to microalbuminuria

< 7.0 %*

120/80 mmHg** ADA guidelines, Diabetes Care 1998Ruggenenti et al., N Eng J Med, 2004

Study designOvernight UAE

Blood pressure and routine laboratory testsRAS inhibitors withdrawalRandomisation061218243036monthsRUN-INTREATMENT PERIODweeksndCCBs withdrawalTrandolapril (2mg/d)Verapamil S.R. (240 mg/d)Trandolapril (2mg/d) plus Verapamil S.R. (180 mg/d)PlaceboRuggenenti et al., N Eng J Med, 2004

708090100110120130140150160036912151821242730333639424548Systolic Diastolic Arterial Blood Pressure (mmHg) Follow-up (months)VerapamilTrandolaprilTrandolapril plus VerapamilPlaceboBlood pressure according to treatment groupRuggenenti et al., N Eng J Med, 2004

0510150612182430364248Follow-up (months)Placebo(30 events)Trandolapril plus verapamil(17 events)300

300249

229232

214217

203210

187201

176192

164162

136115

89Cumulative Incidenceof Microalbuminuria (%)No. at Risk

Trandolapril plus VerapamilPlacebo A.F. (95 % C.I.) = 0.39 (0.19 - 0.80) p = 0.01Ruggenenti et al., N Eng J Med, 2004

0 5 10150612182430364248Cumulative incidence of microalbuminuria (%)Follow-up (months)301

300254

229237

214224

203207

187198

176188

164149

136104

89No. at Risk

Trandolapril

Placebo Placebo(30 events)Trandolapril (18 events)A.F. (95 % C.I.) = 0.47 (0.26 - 0.83) p = 0.01NNT: 8 Ruggenenti et al., N Eng J Med, 2004

Cumulative incidence of microalbuminuria (%)303

300234

229210

214202

203189

187181

176174

164134

136 98

89No. at Risk

Verapamil

Placebo 0 5 1015Placebo(30 events)Verapamil(36 events)Ruggenenti et al., N Eng J Med, 2004

Ravid et al., Ann Intern Med 1998EFFECTS OF ENALAPRIL (10 mg/day) IN NON-OBESE SUBJECTS WITHTYPE 2 DIABETES, NORMAL BLOOD PRESSURE ANDNORMOALBUMINURIA11010510095900123456Mean Blood Pressure (mmHg)Years403020100UAE (mg/24 h)Enalapril (n=77)Placebo (n=79)*** p < 0.05 vs. enalapril

DERIVACION PRECOZ VS TARDIAKinchen et al. An Inter Med 2002, 137

MORTALIDAD Y DERIVACION TARDIAKazmi et al. NDT 2004, 19, 1808

TRASPLANTE Y DERIVACION TARDIACass et al. AJKD 2003, 42, 1043

SITUACION CLINICA DEL PACIENTE CON IRC AL MOMENTO DE DERIVACION AL NEFROLOGOEXPERIENCIA EN UN HOSPITAL POLICLINICOServ. de Nefrologa. Hosp. Privado-Centro Mdico de CrdobaCarrera de Posgrado en NefrologaUniv. Catlica de Crdoba. Argentina

SITUACION CLINICA AL MOMENTO DE DERIVACION AL NEFROLOGOCRITERIOS DE INCLUSIONPrimera visita al nefrlogo.TFG (Cockorff) < 60 ml/min.Caracteristicas basales al momento de la derivacinnEdad (aos)Sexo (M / F)6357,7 17,345 /18

02468101214161820CONSULTORIOEXTERNOINTERNADON PtesLUGAR DE LA 1 CONSULTA AL NEFRLOGO52,9 %47,1 %

FACTORES COMORBIDOSDIABETES

MEDICAMENTOS ANTI- HTA EN DIABETESFACTORES COMORBIDOSSINO%SINOIECA - ARA

DIURETICOS

01020304050607080

FACTORES COMORBIDOSAnemiaDislipemiaIAM / ATCACVICCE. HepticasVascular perifricaTabaquismo

14 (37,8)17 (70,8)14 (37,8)8 (26,6)2 (6,9)1 (3,7)6 (21,4)9 (32,1)

PatologaN (%)

DATOS BIOQUIMICOSCreatinina, mg/dlUrea, mg/dlAc Urico, mg/dlHTO, %HB, g/dlX DS2,9 2,1100 53,46,8 2,037,3 6,312,1 1,8Rango0,9 11,720 2423,9 10,728,9 51,08,3 15,4

DATOS BIOQUIMICOSNIVELES DE CREATININA05101520253035404550< 1,51,5 - 3,0> 3,0%Creat, mg/dl

00,511,522,533,544,55GMNPKDNAEOTROSNTIDBTDATOS BIOQUIMICOSNIVELES DE CREATININA SEGN ETIOLOGIA

Complicaciones de la Insuficiencia Renal Crnica

NHANES III: J Am Soc Nephrol 13: 504510, 2002

Calcificaciones coronarias en DiabticosCAC < 10CAC 10-100CAC 101-400 CAC > 4000102030405060708090%Kramer H et al, J Am Soc Nephrol 2005

CASO CLINICO

Varn, 66 aosDiabtico tipo 2 (20 aos de diagnstico)IAM a los 50 aosFumador 30 cig/da desde los 18 aosBMI: 28Retinopata diabtica proliferativa (laser bilateral)Control previo hace 1 ao

PA: 165/105Edema MMII ++

Creatinina: 3.5 mg/dl (previa 2.8 mg/dl)Indice Protenas/Creatinina urinaria: 2.7 g/gK: 4.8 mEq/lHb glicosilada: 8.5%LDL: 145 mg/dlHDL: 48 mg/dlTriglicridos: 290 mg/dlOrina completa: Prot +++, Gluc ++, Hemoglobina +

Medicacin: Losartn 100 mg/da, Hidroclorotiazida 25 mg/da, Atenolol 50 mg/da, Atorvastatina 20 mg/da, AAS 100 mg/da, Insulinoterapia

Cul sera el esquema hipotensor a utilizar ?Es de utilidad usar IECAs o ARA II ante esta funcin renal? Cul es superior entre ambas categorias? La asociacin de IECAs con ARA II es til? Existen otros tratamientos que aporten beneficio? Es posible pensar en el Trasplante renal en un paciente diabtico?

The risk of macrovascular and microvascular complications in type 2 diabetes is strongly associated with blood pressureUKPDS (36): BMJ 2000;321:412-419

Rate/1000 person/year25

20

15

10

5

0 P

Peterson JC et al. Ann Intern Med, 1995Mean glomerular filtration rate (GFR) decline and achieved follow-up blood pressureModification of Diet in Renal Disease study840 patients with non-diabetic proteinuric nephropathies

Jafar TH et. Ann Intern Med, 2003Relative risk for kidney disease progression based on current level of SBP and current proteinuria11 randomized, controlled trials comparing the efficacy of antihypertensive regimens with or without ACE inhibitorsn = 1860 patients

The decrease in risk for each 10 mm Hg reduction of SBP for macro and microvascular complicationsUKPDS (36): BMJ 2000;321:412-419

ACE inhibitors versus dihydropyridine calcium channel blockers in diabetic patients012963%ABCD trial

470 Hipertensive patients5 years follow upMI: secondary end point

NisoldipineEnalapril016128%4AmlodipineFosinoprilFACET trial

380 Hipertensive patients3.5 years follow upCombined End Point: MI, stroke, angina

CAPPP study: ACE inhibitor therapy associated withreduction in endpoints : Diabetic vs Total populationHansson L , et al. Lancet 1999

EFFECTS ON RAMIPRIL ON CARDIOVASCULAR AND MICROVASCULAR OUTCOMES IN 3.577 PATIENTS WITH TYPE 2 DIABETES ENROLLED IN THE HOPE STUDY

THE MICRO-HOPE STUDY

- age > 55 years no clinical proteinuria previous cardiovascular event or at least one other cardiovascular risk factorHOPE Study Investigators, Lancet, 2002

0 25%- 50%THE MICROHOPE STUDYRelative Risk (95% CI)Combined Myocardial infarction Stroke Cardiovascular death Total mortality Revascularization Overt nephropathyClinical outcomes for Ramipril and placebo groupPrimary outcomesSecondary outcomes - 25%HOPE Study Investigators, Lancet, 2002

ATENOLOL AND CAPTOPRIL IN REDUCING RISK OF MACRO AND MICROVASCULAR COMPLICATIONS: UKPDS 39UKPDS (39) BMJ, 1998 - 1148 hypertensive type 2 diabetic patientsMyocardial infarction, sudden death, stroke, peripheral vascular disease and renal failureLess tight BP control: 154/87Captopril: 144/83Atenolol: 143/81

Cardiovascular morbidity and mortality in patients with diabetes in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): Inclusion criteria

Design

Treatment

Follow-up

Main end point- Diabetes (both types)- Hypertension SBP: 160 - 200 mmHg and/or DBP: 95 - 115 mmHg- Left ventricular hypertrophy

- Randomized, double blind

- Losartan (50 - 100 mg/day) n = 586- Atenolol (50 - 100 mg/day) n = 609

- 4.7 1.1 years

Combined cardiovascular mortality, stroke, miocardial infarctionLindholm et al., Lancet, 2002

Blood pressure and metabolic control were comparable in the two treatment groups throughout the whole study periodLingholm et al., Lancet, 2002

0-2-4-6-8-10-12-14GFR (ml/min/year)9598113110107104101119116130/85140/90Untreated HTNr = 0.69; p < 0.05MAP (mmHg)Parving et al., Br Med J, 1989Viberti et al., JAMA, 1993Hebert et al., Kidney Int, 1994Lebovitz et al., Kidney Int, 1994Bakris et al., Kidney Int, 1996Bakris et al., Hypertension, 1997Klahr et al., N Engl J Med, 1993Maschio et al., N Engl J Med, 1996GISEN Group, Lancet, 1997Bakris et al., Am J Kidney Dis, 2000DiabetesNon-diabetes

Cul sera el esquema hipotensor a utilizar ?Es de utilidad usar IECAs o ARA II ante esta funcin renal? Cul es superior entre ambas categorias? La asociacin de IECAs con ARA II es til? Existen otros tratamientos que aporten beneficio? Es posible pensar en el Trasplante renal en un paciente diabtico?

Reduccin de la MAP (mm Hg) 2

0

- 2

- 4

6

8

40

- 20

0

- 20

40

60 % Reduccin de la ProteinuriaP 1.5 mg/dlLewis et al. N Engl J Med. 1993NS

ESRD012243648Months% with eventp=0.002Risk Reduction: 28%PL- 1513 type 2 diabetes - Age 31-70 years- Alb/Cr ratio >300 mg/g, - S Creat 1.3-3.0 mg/dL,RENAAL Reduction of Endpoints in NIDDM with the AII Antagonist LosartanNNT: 32

RENAALESRD by Baseline Level of Serum Creatinine012243648Months% with eventsCr< 2.0 mg/dL 2.0 mg/dLRR: 31% 26%p=0.0450.029L (+CT)sCr < 2.0 mg/dL sCr 2.0 mg/dLP (+CT)482/280463/252424/186254/9333/933/933/933/933/933/9482/269468/246429/196269/10651/1851/1851/1851/1851/1851/18sCr (mg/dL)

Cul sera el esquema hipotensor a utilizar ?Es de utilidad usar IECAs o ARA II ante esta funcin renal? Cul es superior entre ambas categorias? La asociacin de IECAs con ARA II es til en Nefropata DBT? Existen otros tratamientos que aporten beneficio? Es posible pensar en el Trasplante renal en un paciente diabtico?

IECAs o ARAII en Nefropata Diabtica: DETAIL studyBarnett et al., N Eng J Med, 2004 250 type 2 diabetic patients

Mild-moderate hypertensive

Albuminuria < 1000 /min

80% microalbuminuric

- S Creat. 1.01 mg/dl

CANDESARTAN AND LISINOPRIL MICROALBUMINURIA (CALM) STUDYAdjusted risk reduction (at 24 weeks) in SBP, DBP, and urinary A/C ratio in 197 type 2 diabetics with hypertension and microalbuminuriaMogensen et al., Br Med J, 2000

Jacobsen et. al. J Am Soc Nephrol 2003ADDITIVE EFFECT OF ACE INHIBITION AND ANGIOTENSIN II RECEPTOR BLOCKADE

- Crossover studyType 1 DM Overt nephropathyTreatment: PlaceboBenazepril 20 mg/dayValsartan 80 mg/dayCombination (full doses)50150100 mmHgPlaceboBlood Pressure0BenazeprilValsartanCombination1000500mg/24 hsPlaceboAlbuminuria0BenazeprilValsartanCombination

Rossing et. al. Diabetes Care 2005BENEFICIAL EFFECTS OF ADDING SPIRONOLACTONE TO ANTIHIPERTENSIVE TREATMENT IN TYPE 2 DIABETES NEPHROPATHY

Crossover study: (8 weeks per period)

- Spironolactone 25 mg/day vs.

- Placebo

-20 patients with type 2 DM

-Overt nephropathy

-Full doses of inhibition on RASS0.51.51.0(g/24 hours)PlaceboSpironolactoneAlbuminuria0p < 0.001

EFFECT OF LIPID REDUCTION ON THE PROGRESSION OF RENAL DISEASE: GFRFried et al., Kidney Int, 2001Meta analysis of studies with statins, fibrates and probucol Treatment worseTreatment betterSmulders et al., 1997Aranda et al., 1994Rayner et al., 1996 Thomas et al., 1993Nielsen et al., 1993Tonolo et al., 1993Buemi et al., 1999Hommel et al., 1992Scanferla et al., 1991Lam et al., 1995Olbricht et al., 1999Nishimuria et al.,1999TOTAL

15161718192121243443118362

p = 0.008Difference in GFR decline (ml/min/month)-5-3-11357TrialsN of patientsDifference in change of GFR (95% CI)

INTERACTION BETWEEN THE RENIN-ANGIOTENSIN SYSTEM AND STATINSANG IANG IIAT2AT1ACEACE-inhibitorsOther districtsAIIRASTATINSTranscription factors (rho, rac, rab...)NF-kB- Chemoattraction, adhesion, inflammation- proliferation, differentiation, sclerosis- increased ROS production- endothelial dysfunctionLDL, VLDLsdLDL

Tonelli M, et al. J Am Soc Nephrol 16: 37483754, 2005.

Riesgo* de Insuficiencia Renal Crnica Terminal en Diabeticos segn cuartilos de Hemoglobina< 11.3 11.3 12.5 12.5 13.8 13.8R.R. (95 % C.I.)11.251.52.02.50.5Incremento del riesgoAjustado segn edad, sexo, raza, BMI, tabaquismo, funcin renal, albuminuria, perfil lipdico, calcio, fsforo y PA.RENAAL Study: Kidney International Vol. 66, 2004

REMISSION CLINICTargets:

Blood pressure< 120/80 mmHgProteinuria< 0.3 g/24 hLDL< 100 mg/dlLDL + VLDL< 130 mg/dlHbA1c< 7.5 % (diabetics)Ruggenenti et al., Lancet, 2001

Cul sera el esquema hipotensor a utilizar ?Es de utilidad usar IECAs o ARA II ante esta funcin renal? Cul es superior entre ambas categorias? La asociacin de IECAs con ARA II es til en Nefropata DBT? Existen otros tratamientos que aporten beneficio? Cules son los resultados del Trasplante renal en un diabtico?

1Tiempo (meses)0,2,4,6,8Supervivencia Acumulada0102030405060No DBT 488 375 306 258 209 171 138 DBT 35 24 21 13 11 9 8Logrank: p= 0.6 No DBT DBT SOBREVIDA DEL INJERTO

Tiempo (meses)0,2,4,6,81Supervivencia acumulada0102030405060Logrank: p= 0.9No DBT 488 377 307 258 210 173 141 DBT 35 24 21 13 11 9 8SOBREVIDA DEL PACIENTE No DBT DBT

in assessing the exact amount of proteinuria, the urine P/C ratio may haveunacceptably wide limits of agreement in high protein excretion range.

This slide summarizes the data in the patients with diabetes. It is kind of confusing and hard to read, but it shows you the relative risk, major cardiovascular events--all MIs, all CVAs, cardiovascular mortality, total mortality; the bars represent the difference between the diastolic of 90 versus 85, 85 versus 80. The point is that in several of these major categories, major cardiovascular event, mortality--that in the patients with diabetes, there was a striking degree of protection by achieving the lower blood pressure goal. They found the overall study was somewhat positive. But in many of these studies, the data in the diabetic population was much more strikingly positive. It is kind of a recurring theme in these studies. The one subset that benefits from the most intensive, aggressive therapy are the diabetic patients. So lowering blood pressure is good. Results of the Modification of Diet in Renal Disease study showed that in patients with non-diabetic proteinuric renal disease, targeting treatment at BP levels of 125/75 mmHg or less reduced GFR decline more effectively than if the target was 140/90 mmHg. However, 48% of patients in the lower BP group received ACEi therapy vs 28% in the usual BP group. Thus, the benefit recorded in the low BP group was affected by use of ACEi.A meta-analysis of 11 randomised trials of ACEi therapy in 1860 people with non-diabetic chronic kidney disease showed that systolic BP reduction to less than 120 mmHg did not offer additional renoprotection compared with targets of 120-130 mmHg, and reduction to 110 mmHg or less even accelerated progression of renal disease. ABCD trial: But it doesn't tell us anything about the relative efficacy of the different classes of drugs. So there have now been a couple of studies directly comparing ACE inhibitors versus dihydropyridine calcium channel blockers when it comes to cardiovascular protection. This one and the next study I am going to show you are both published around the same time, in 1998. This was the ABCD trial, which was a prospective, randomized, controlled trial of 470 hypertensive patients with type 2 diabetes, randomized to enalapril or nisoldipine. And this study, I believe, they actually stopped a little bit early because when they looked at fatal or non-fatal MIs, they found a significant difference in that the patients on the calcium channel blocker arm were five times more likely to have a significant event as compared to the patients on the ACE inhibitor. FACET trial: A very similar study, published around the same time--and these will all be discussed again Friday afternoon, was the FACET trial. Different drugs, same design, fosinopril versus amlodipine, a prospective, randomized, control trial of 380 patients followed for 3 1/2 years. When they looked at a combined outcome of acute MI, stroke, or hospitalization for angina, again they found a significant difference, with the ACE providing superior cardiovascular effect. Most cardiologists, as I understand it, are not taking this to mean that calcium channel blockers are bad for the heart; it is just that ACE inhibitors are better. But I think it is starting to be a fairly consistent story here that in patients with diabetes who have a huge cardiovascular risk anyway, ACE inhibitors are kind of a reasonable thing to have in the regimen.

The Captopril Prevention Project was a fairly large trial, as well. This was a hypertension trial, not specifically a diabetes trial. It was a trial of captopril versus conventional therapy with about 11,000 patients. What they found in the entire group was that there was really no significant difference in the incidence of these various endpoints. But in the diabetic subgroup, which was pretty small--only 600 patients with diabetes, the ACE inhibitor was associated with a significant reduction in most of the endpoints . Some of that data is shown here. The yellow lines are the diabetic subjects, and the orange lines are the total population. As you can see, for the total population as a whole, they all crossed a line of identity, whereas the ACE inhibitor did show a benefit in the diabetic patients. Interestingly in this study and in the HOPE study--both of those studies found that in patients who did not have diabetes going into the study that being on the ACE inhibitor arm reduced your risk of developing diabetes, which I think is very interesting. It has now been shown in two good-sized studies But in micro-HOPE, which was just published, they specifically showed the data from the diabetic subjects. It was quite impressive. This slide shows you reduction in risks. So the higher the bar, the better. The combined outcome, MI, CVA, cardiovascular disease I think that is, and overt proteinuria. As you can see, there was a significant reduction in risk, on the order of about 30 percent for most of these, all of them significant in the diabetic population. So in these type 2 diabetic patients, it appeared as though treatment with ramipril was extremely effective in preventing major cardiovascular disease. It is one of the bigger studies we have out there.

The one possible exception to the story that ACE inhibitors are better is the UKPDS, the gigantic United Kingdom study in patients with type 2 diabetes. They looked at two issues: Tight blood pressure control versus less tight; and then they compared captopril to atenolol. This slide shows you the value of treating blood pressure. In the patients who received better blood pressure control, the relative risk of microvascular disease, microalbuminuria, and retinopathy was significantly reduced. But they found no difference between captopril and atenolol when it came to the incidence of cardiovascular events, etc. So that is kind of the one exception to this otherwise fairly consistent story that ACE inhibitors are superior. But, obviously, atenolol may be a cardioprotective drug, as well

I want to make the point that multiple drugs are needed. This is why we need data on what happens when you use multiple drugs. This slide just shows you the average number of drugs needed to get to goal in a bunch of the big studies. They are not all diabetes studies: UKPDS, ABCD, MDRD, HOT and ASK. As you can see, the number of drugs needed ranges from about 2.8 up to about 3.9. The point is, as you all know from your practice, you need a bunch of drugs. What we don't know is what the combination of drugs will do. Pravastatin 40 mg daily versus placebo. Median follow-up was 64 mo. Stage 2 or early stage 3 CKD and diabetes both are associated with higher cardiovascular risk, and pravastatin reduces cardiovascular event rates in people with neither, one, or both characteristics. Given the high absolute benefit of pravastatin in patient with diabetes and stage 2 or early stage 3 CKD, this population in particular should be targeted for widespread use of statins.

El valor predictivo de la Insuficiencia Renal y microalbuminuria es comparable al de la enfermedad coronaria preexistente y an superior cuando ambas estn asociadas

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