ιαβητική νεφροπάθεια και υπέρταση

ιαβητική νεφροπάθεια και υπέρταση Μιχάλης ούμας Παθολόγος Β ΠΠ Κλινική ΑΠΘ

Diabetic nephropathy Diabetic nephropathy is irreversible in humans No cases of recovery or cure have been reported in the literature Once the clinical signs of nephropathy have become manifest, the natural course is inexorably progressive to death The rate of progression is accelerated in the later stages Kussman et al. Jama 1976

"ΘΑΥΜΑΖΩ ΤΙΣ ΚΑΤΑΚΤΗΣΕΙΣ ΤΙΣ ΕΠΙΣΤΗΜΗΣ, ΥΠΟΚΛΙΝΟΜΑΙ, ΟΜΩΣ, ΜΕ ΕΟΣ ΜΠΡΟΣΤΑ ΣΤΗΝ ΑΠΕΡΑΝΤΩΣΥΝΗ ΟΣΩΝ ΘΑ ΜΕΙΝΟΥΝ Α ΙΕΡΕΥΝΗΤΑ. GOETHE 3

Diabetic nephropathy and Hypertension

Ορισμός Μία μικροαγγειακή επιπλοκή του σακχαρώδη διαβήτη που χαρακτηρίζεται από μικρολευκωματινουρία και προοδευτική επιδείνωση της νεφρικής λειτουργίας.

Type 1 Diabetic Epidemiology 25-45% will develop diabetic nephropathy 80-90% with microalbuminuria will progress to overt diabetic nephropathy in 5-10 years nearly 100% with gross proteinuria will progress to ESRD in 7-10 yrs Type 2 Diabetic 50% will have microalbuminuria at the time of presentation probably secondary to HTN 10-20% with microalbuminuria will progress to overt nephropathy

Diabetes: The Most Common Cause of ESRD Primary Diagnosis for Patients Who Start Dialysis Other Glomerulonephritis No. of dialysis patients (thousands) 700 600 500 400 300 200 100 Diabetes 50.1% 10% 243,524 13% Hypertension 27% 281,355 520,240 r 2 =99.8% No. of patients Projection 95% CI 0 1984 1988 1992 1996 2000 2004 2008 United States Renal Data System. Annual data report. 2000.

Υπέρταση σε χρόνια νεφρικά νοσήματα Hypertension Prevalence (%) 80 70 60 50 40 30 20 10 0 MCN CIN IgA MGN APKD DN MPGN FSGN MCN=minimal change nephropathy CIN=chronic interstitial nephritis IgA=IgA nephropathy MGN=membranous glomerulonephritis APKD=adult-onset polycystic kidney disease DN=diabetic nephropathy MPGN=membranoproliferative glomerulonephritis FSGN=focal segmental glomerulonephritis Smith MC and Dunn MJ, in Hypertension. Laragh JH, Brenner BM. Raven Press; 1995:2081-2101.

Sleep and his half-brother Death (Hypnos and Thanatos) by John William Waterhouse (1874)

Natural history

Diabetics with Macroalbuminuria are More Likely to Die than Develop ESRD The United Kingdom Prospective Diabetes Study (approx. 5000 Type 2 Diabetics) Newly diagnosed, predominantly white, medically treated No albuminruia 2.0% Microalbuminruia 2.8% Macroalbuminruia 2.3% Elevated Serum Creatinine 1.4% 3.0% 4.6% 19% C V D E A T H Adler et al. Kid Int, 2003

What are Diabetics with Nephropathy Dying From? Stroke Myocardial Infarction Heart Failure Sudden Death

Diabetes and Cardiovascular Disease Diabetics have similar risk of CVD as non-diabetic with existing CVD. Diabetics with renal disease RR CVD 30 25 20 15 10 has CVD risk that is 6-7 fold that of diabetic without renal disease. 5 0 1st Qtr No DM, No CVD No DM, + CVD + DM, no CKD +DM, + CKD

Pathophysiology

Stages of Diabetic Nephropathy GFR 180 160 140 120 100 80 60 40 20 0 II I III IV V 0 5 10 15 20 25 30 Duration of Diabetes

Pathology Expansion of mesangial matrix with diffuse and nodular glomerulosclerosis (Kimmelstiel-Wilson nodules) Thickening of glomerular and tubular BM Arteriosclerosis and hyalinosis of afferent and efferent arterioles Tubulointerstitial fibrosis Σπάνια γίνονται πια βιοψίες νεφρού

Pathogenesis Exposure to the diabetic milieu Hyperglycemia Induce mesangial expansion and injury Increased activity of growth factors Activation of cytokines Formation of ROS accumulation of advanced glycosylation endproducts in tissues Accumulation of ECM components, such as collagen Genetic predisposition to or protection from diabetic nephropathy

Risk Factors Hyperglycemia Hypertension Microalbuminuria Ethnicity Male gender Family history Cigarette smoking

Most Common Cause of Failing to Reduce Proteinuria with ACE Inhibitor or ARB High SALT intake (>5 grams/day) DeZeeuw D et.al Kidney Int., 1989, Mishra SI et.al, Curr Hypertens Rep, 2005

Detection Prevention

Diabetic Nephropathy Improving Outcomes in Diabetic Nephropathy Prevention of Cardiovascular Events Prevention of End-Stage Renal Disease

Primary care physicians have the most frequent contact with diabetic patients and therefore have the greatest potential to favorably affect their health

How are we doing? Studies show that primary care physicians screen only 20% of their diabetic patients for diabetic nephropathy

e-gfr Cockcroft-Gault GFR = (140-ηλικία) x (Βάρος kg) x (0.85 για γυναίκες) / (72 x κρεατινίνη) MDRD egfr = 186 x (κρεατινίνη) -1.154 x (ηλικία) -0.203 x (0.742 εάν ) x (1.210 για αφροαμερικανούς) http://www.mdcalc.com http://clinicalculator.com/english/nephrology/cockroft/cc.htm

Κρεατινίνη: 1.6 mg/dl GFR 122 ml/min/1.73 m 2

Κρεατινίνη: 1.6 mg/dl GFR 22 ml/min/1.73 m 2

Παράμετρος Urine AER ( g/min) Urine AER (mg/24h) Urine albumin/ Cr # ratio (mg/gm) Ορισμοί Μικρολευκωματινουρίας & Λευκωματινουρίας Φ.Τ Mικρολευκωματ ινουρία Λευκωματινουρία < 20 20-200 >200 < 30 30-300 >300 < 30 30-300 >300 AER=Albumin excretion rate CR # =creatinine

Συσχέτιση χρόνιας νεφρικής βλάβης και μικρολευκωματουρίας. I-Demand project 927 subjects renal dysfunction: 38.5% of pts microalbuminuria N=233 (25.3%) 134 (14.5%) 99 (10.7%) 122 (13.2%) egfr 60 ml/min N=221 (24.0%) Parving et al, Kidney Int 2006

Treatment

Η σημασία της πρώιμης αντιμετώπισης

American Society of Hypertension Bakris, JASH 2010

Primary Composite End Point* (%) 60 40 20 Intensive Multiple Risk Factor Management Patients with Type 2 Diabetes and Microalbuminuria N=160; follow-up = 7.8 years Conventional Therapy Intensive Therapy 12 24 36 48 60 72 84 96 Months of Follow-up Adapted from Gæde P et al. N Eng J Med. 2003;348:383-393 20% Absolute Risk Reduction Aggressive treatment of : Microalbuminuria with ACEIs, ARBs, or combination Hypertension Hyperglycemia Dyslipidemia Secondary prevention of CVD Primary composite endpoint: conventional therapy (44%) and intensive therapy (24%). * Death from CV causes, nonfatal myocardial infarction, coronary artery bypass grafting, percutaneous coronary intervention, nonfatal stroke, amputation, or surgery for peripheral atherosclerotic artery disease. Behavior modification and pharmacologic therapy. 2006. American College of Physicians. All Rights Reserved.

Steno 2 study: Extended Follow up: Effect of a multi factorial vascular protective strategy on total mortality 60 50 HR = 0.54 (0.32 0.88) p = 0.015 Conventional therapy Total mortality (%) 40 30 20 10 END OF TRIAL Intensive therapy 0 1 2 3 4 5 6 7 8 9 10 11 12 13 Years of follow up Gaede 2008. 33

Blood pressure control

Blood Pressure Control and Rate of Renal Decline in Diabetic Nephropathy Parving et al. (1983 Lancet) Ten Type 1 Diabetics followed before (mean of 29 months) and after initiation of antihypertensives (mean 39 months) Antihypertensive agents were metoprolol, hydralazine, furosemide or thiazide BP fell from 144/97 mmhg before treatment to 128/84 mmhg with treatment Albumin excretion rate decreased from 977 mg/min before treatment to 433 mg/min with treatment

Ελάττωση έκπτωσης νεφρικής λειτουργίας -ΑΠ MAP (mmhg) 95 98 101 104 107 110 113 116 119 0 GFR (ml/min/year) -2-4 -6-8 -10-12 -14 130/85 140/90 r = 0.69; P < 0.05 Untreated HTN Bakris GL, et al. Am J Kidney Dis. 2000;36(3):646-661.

ACCORD????

Σακχαρώδης ιαβήτης Bakris, JASH 2010

Multiple Antihypertensive Agents Are Needed to Achieve Target BP No. of antihypertensive agents Trial Target BP (mm Hg) 1 2 3 4 UKPDS DBP <85 ABCD DBP <75 MDRD MAP <92 HOT DBP <80 AASK MAP <92 IDNT SBP <135/DBP <85 ALLHAT SBP <140/DBP <90 DBP, diastolic blood pressure; MAP, mean arterial pressure; SBP, systolic blood pressure. Bakris GL et al. Am J Kidney Dis. 2000;36:646-661. Lewis EJ et al. N Engl J Med. 2001;345:851-860. Cushman WC et al. J Clin Hypertens. 2002;4:393-404.

Σακχαρώδης ιαβήτης Bakris, JASH 2010

Normoalbuminuria Normotension

Αντικρουόμενα δεδομένα Επιβράδυνση της εμφάνισης μικρολευκωματουρίας στη μελέτη του Ravid Ann Intern Med 1998 Δεν υπάρχουν ευνοϊκά αποτελέσματα στη μελέτη DIRECT Ann Intern Med 2009, καθώς και στη μελέτη του Mauer N Engl J Med 2009. Στην πρώτη μελέτη τα επίπεδα της πίεσης και του λευκώματος στα ούρα ήταν υψηλότερα από τις άλλες.

Normoalbuminuria Hypertension

- Κατάλληλη χρονική στιγμή χορήγησης; Αρχικά στάδια Σ ; Εμφάνιση ΜΛ; Οι ΑΜΕΑ προλαβαίνουν τη ΜΛ σε ασθενείς με Σ τύπου 2 20 Ασθενείς με ΜΛ (%) 15 10 5 P =,01 Χωρίς ΑΜΕΑ ΑΜΕΑ (Τραντολαπρίλη) Ν=1204 ασθενείς με υπέρταση, Σ τύπου 2 και φυσιολογικό AER 0 0 6 12 18 24 30 36 42 48 Παρακολούθηση (μήνες) Ruggeneti et al. N Engl J Med 2004;351:541-51 For the Bergami Nephrological Complication Trial (BENEDICT) Investigators 47

ROADMAP Haller, NEJM 2011

Microalbuminuria or Low-grade proteinuria

ARBs vs placebo or Ca-antagonists Albuminuria Kunz, Ann Intern Med 2008

ARBs vs ACE-inh Albuminuria Kunz, Ann Intern Med 2008

Parving, NEJM 2001 Microalbuminuria DM pts UA IRMA II 20 % change in urinary albumin excretion 10 0-10 -20-30 -40 150 mg of irbesartan Placebo 300 mg of irbesartan -50 0 3 6 12 18 22 24 Months of Follow-up *P<0.001 for difference between both irbesartan groups and placebo

Microalbuminuria DM pts Renal progression IRMA II Incidence of Diabetic Nephropathy (%) Placebo (n) Irbesartan 150 mg (n) Irbesartan 300 mg 20 15 10 5 0 P<0.001 for difference between 300 mg irbesartan group and placebo Placebo 0 3 6 12 18 22 24 Months of Follow-up 201 201 164 154 139 195 195 167 161 148 194 194 180 172 159 150 mg of irbesartan 300 mg of irbesartan 129 142 150 36 45 49 Parving, NEJM 2001

Angiotensin-Receptor Blockade versus Converting Enzyme Inhibition in Type 2 Diabetes and Nephropathy-RESULTS Baseline GFR 91 ml/min Barnett AH et.al N Engl J Med 2004;351:1952-1961. 2006. American College of Physicians. All Rights Reserved.

ARBs and ACEi combination

Αθροιστική δράση των ΑΜΕΑ και ARB σε ασθενείς με Ν ΣΑΠ ΑΠ Λευκωματουρία (mg/24ωρο) 1050 850 650 450 250 50 ΕΦ Βαλσαρτάνη Μπεναζεπρίλη Μπεναζεπρίλη Και τα 2 ΑΦ ΑΠ (mmhg mmhg) 150 140 130 120 110 100 90 80 70 60 50 ΕΦ Βαλσαρτάνη Και τα 2 ΑΦ Jacobsen et al. J Am Soc Nephrol 2003;14:992-99 57

ARBs - ACEi combo Albuminuria Kunz, Ann Intern Med 2008

ARBs or ACEi combo Albuminuria Kunz, Ann Intern Med 2008

Co-operate trial Nakao, Lancet 2003

Co-operate trial Lancet 2009

Tobe, Circulation 2011 ONTARGET sub-analysis CKD - Albuminuria Renal events GFR>60 GFR<60 Normoalbuminuria 1.18 1.40 Microalbuminuria 1.20 1.04 Macroalbuminuria 0.81 1.63 Mortality GFR>60 GFR<60 Normoalbuminuria 1.12 1.15 Microalbuminuria 1.07 1.09 Macroalbuminuria 0.82 0.78 No CV or renal benefit even in pts with low GFR and/or albuminuria

ARBs or ACEi combo Benefit according to albuminuria levels REIN study, Kidney International 2003

Direct renin inhibitors

Aliskiren provides significantly greater reductions in UACR compared with placebo 65 Mean change from baseline in UACR at Month 6 (%) 5 2 n=289 0 n=287 5 10 15 20 18 * Optimal treatment + aliskiren 300 mg Optimal treatment + placebo Parving H-H, et al. 2007 (AVOID) Parving H-H, et al. 2008 (AVOID)

Spironolactone

Spironolactone -Albuminuria Mehdi, JASN 2009

Spironolactone and ARBs or ACEi combo Albuminuria Bomback, Am J Hypertens 2009

Advanced Diabetic Nephropathy

ACE-I is More Renoprotective than Conventional Therapy in Type 1 Diabetes (Total N = 409) % with Doubling of Baseline Creatinine 0 25 50 75 Captopril Conventional therapy 100 Baseline creatinine > 1.5 mg/dl Decrease in Mean Blood Pressure (mm Hg) - 2 0-2 -4-6 0 1 2 3 4 % Reduction in Proteinuria - 40-20 0-20 - 40 P <.001-8 NS - 60 Lewis et al. N Engl J Med. 1993;329:1456-1462.

CKD, albuminuria - RENAAL Doubling of Serum Creatinine, ESRD, and/or Death 50 (16% ) 47.1% Patients (%) 46 42 38 43.5% 34 P =.02 30 Losartan Placebo (Adapted from Brenner B, et al. N Engl J Med. 2001)

RENAAL ARB Reduction of Renal Failure 16% 25% 28% 20% Brenner BM et al, N Eng J Med 345:861, 2001

CKD, albuminuria - IDNT Doubling of Serum Creatinine, ESRD, and/or Death 45 40 20% - irb vs. pla 23% - irb vs. aml 41.1% 39.0% Patients (%) 35 30 25 * 32.6% 20 Irbesartan Amlodipine Placebo *P =.02 vs. placebo; P =.006 vs. amlodipine. (Adapted from Lewis E, et al. N Engl J Med. 2001)

IDNT ARB Reduction of Renal Failure 20% 23% 33% Lewis EJ et al, N Eng J Med 345:851, 2001

ALTITUDE Διαβητικοί τύπου ΙΙ Λευκωματουρία Μικρολευκωματινουρία και ΧΝΑ στάδιο ΙΙΙ Καρδιαγγειακή και νεφρική νόσο Αλισκιρένη vs placebo Νεφρικά και καρδιαγγειακά τελικά σημεία

ιαβητική νεφροπάθεια: Take Home Message Lower blood pressure < 130 / 80 mmhg Reducing Proteinuria Inhibition of Renin-Angiotensin System Multiple risk factor intervention Glycemia Dyslipidemia Physical activity Aspirin Smoking cessation

Αρχίζει από τον άρρωστο Συνεχίζεται με τον άρρωστ άρρωστo και Τελειώνει στον άρρωστο

Percentage of Adults with Diabetes Who Achieved Recommended Goals of Cardiovascular Risk Factors in NHANES NHANES III NHANES IV 50 % 40 30 20 10 Saydah S et.al JAMA 2004;291:335 0 HbA1c<7% BP <130/80 mmhg TC <200 mg/dl Good Control

Future???

Μελλοντικές θεραπείες διαβητικής νεφροπάθειας Αναστολείς ουροτενσίνης Αποτυχία Hypertension 2011 Γλυκοζαμινογλυκάνες Suledoxide (Αποτυχία στη μελέτη SUN-micro-trial) Αναστολείς πρωτεϊνικής κινάσης C Ruboxistaurin (Αντικρουόμενα αποτελέσματα stop) Αναστολείς AGEs (advance glycation end-products) Pimagedine (Αποτελεσματικά αλλά μη-ασφαλής) Pyridoxamine (Επιτυχία σε φάση ΙΙ)

Doumas, Int J Hypertens 2011 ιέγερση καρωτιδικών τασεο-υποδοχέων Programming System Baroreflex Activation Leads Implantable Pulse Generator

Sympathetic Innervations and Hypertension Doumas, Am J Cardiol 2010

BP control was maintained long-term Peet, Am J Surg 1948

Grimson, Ann Surg 1941

Doumas, Current Opinion Nephrology Hypertension 2011

Renal sympathetic denervation Circulation, 2011

Renal sympathetic denervation J Hypertension, 2011

Νεφρική συμπαθητική απονεύρωση Μελλοντικά πρωτόκολλα New Catheter Design Completed two animal studies Large in house data base Studies in diabetic nephropathy Feasibility Human study Coming Soon ARSENAL study Ablation-induced Renal Sympathetic denervation trial RSD in CKD VA protocol

Ευχαριστώ πολύ για την προσοχή σας 91

Παράμετρος Urine AER ( g/min) Urine AER (mg/24h) Urine albumin/ Cr # ratio (mg/gm) Ορισμοί Μικρολευκωματινουρίας & Λευκωματινουρίας Φ.Τ Mικρολευκωματ ινουρία Λευκωματινουρία < 20 20-200 >200 < 30 30-300 >300 < 30 30-300 >300 AER=Albumin excretion rate CR # =creatinine

ΧΡΟΝΙΑ ΝΕΦΡΙΚΗ ΝΟΣΟΣ (ΧΝΝ) ΣΤΑ ΙΑ Στάδιο Περιγραφή GFR ml/min/1,73m 2 1 Νεφρική βλάβη με κφ ή GFR 90 2 Νεφρική βλάβη με ήπια GFR 60-89 3 Μέτρια GFR 30-59 4 Σοβαρή GFR 15-29 5 Νεφρική ανεπάρκεια < 15 NFK. K/DOQI, AJKD 2002; 39 (Suppl 1)

Definitions

Epidemiology

Prevalence of CKD by Stage of Disease Stage Definition # in millions % of population 1 Albuminuria, GFR > 90 ml/min ~ 6.0 3.3 2 GFR 60-89 5.3 3.0 3 GFR 30-59 7.6 4.3 4 GFR 15-39.4 0.2 5 GFR < 15.3 0.1 NHANES III (1988 1994, USRDS 1998

ιαβητική νεφροπάθεια: Take Home Message 1 Η κυριότερη αιτία ΧΝΑ Χαρακτηρίζεται από αυξημένη αποβολή λευκώματος στα ούρα, επιδείνωση της νεφρικής λειτουργίας και υπέρταση Μεγάλη αύξηση των ΚΑ επεισοδίων Οι ασθενείς είναι πιθανότερο να πεθάνουν παρά να φθάσουν σε ΧΝΑ

Take Home Message Diabetic nephropathy is progressive kidney disease Most common cause of ESRD in the US More likely to die than progress to ESRD Multi-risk factor intervention is critical Lowering blood pressure with RAAS blockade is critical Combinations of ACEi or ARB with MRA or DRIs sensible No long term efficacy or safety data Prevent cardiovascular morbidity and mortality