Nierziekten en diabetes

Nierziekten en diabetes Dr. Gerald Vervoort Dept. of General Internal Medicine and Nephrology Radboud University Nijmegen Medical Centre

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Diabetische nefropathie (bij type 1 en type 2 diabetes) Epidemiologie Pathofysiologie Risicofactoren Behandeling SGLT-2 remmers

Epidemiologie Diabetische nefropathie (DNP) (in type 1) wat bepaalt de incidentie en prevalentie van DNP 1. Voorkomen van diabetes mellitus 2. Patient s risk 3. Mortaliteit (alvorens DNP te ontwikkelen)

Epidemiologie Time trends in type 1 diabetes incidence in boys and girls

Epidemiologie % Diab. Nefropathie 100 80 Classical view 60 40 20 0-10 -5 0 5 10 15 20 25 30 Jaren DM Type 2 diabetes Type 1 diabetes

Epidemiologie 8% Cumulative Incidence of End-stage Renal Disease Among Male and Female Patients With Type 1 Diabetes According to Age at Diagnosis of Diabetes.

Epidemiologie

Cumulative incidence Epidemiologie Cumulative incidence of Microalbuminuria 20 15 10 5 0 0 10 20 30 Years since diagnosis DM type 1 DM <1970 1970-1974 1975-1979 1980-1984 1985-1989 1990-1994 1995-1999 >=2000 B. Veldman en G. Vervoort, 2008 (unpublished data)

Pathofysiologie Pathofysiologie Glucose Glucose Polyol pathway Sorbitol Fructose Glucose-6-P Fructose-6-P GFAT Hexosamine pathway Glucosamine-6-P UDP-GlcNAc Glyceraldehyde-3-P NAD + - GAPDH NADH 1,3-diP-glycerate DHAP alpha-glycerol-p DAG PKC PKC pathway Methylglyoxal AGEs AGE pathway O 2 - ROS PARP

Diabetes mellitus Pathofysiologie Hyperglycemia ROS glycolytic intermediates PKC, MAPK Oxidative stress AGEs Intracellulaire signaling NF- AP-1 Sp-1 Transcription factors Growth Factors TGF-, VEGF, IGF-1, CTGF, bfgf Cytokines Pro-coagulant factors PAI-1 Hemodynamic factors NO, AT-II, endothelin ECM accumulation inflammation thrombosis intracapillary pressure celproliferation vasoconstriction permeability ischemia Diabetic Nephropathy

Pathofysiologie Diabetes Hyperglycemie Complicaties Other factors

Pathofysiologie Pathofysiologie Glucose Glucose Sorbitol Fructose Glucose-6-P Fructose-6-P GFAT Glucosamine-6-P UDP-GlcNAc Glyceraldehyde-3-P NAD + - GAPDH NADH 1,3-diP-glycerate DHAP alpha-glycerol-p DAG PKC Methylglyoxal AGEs Glyoxalase I ROS

Pathofysiologie Glyoxalase-I overexpression O. Brouwers et al, Maastricht

Potential new treatment modalities in preventing diabetic angiopathy Aldose reductase inhibitors GFAT inhibitors PKC inhibitors (LY333531) AGE breakers / AGE inhibitors (pimagedine) anti-oxidants TGF-beta inhibitors (ACE-inhibitors) PARP inhibitors vitamin B1 glyoxalase stimulation

Cumulative incidence of persistent microalbuminuria in the DCCT Risk factors

Risk factors Unmet need Cumulative incidence of persistent microalbuminuria in the DCCT

Risk factors

Risk factors ESRD ± 10% x 25% = 3%

Risk factors Risk factors for long-term renal outcome in microalbuminuric pts

Treatment Spironolactone diminishes UAE in type 1 diabetic patients with microalb. * 60% reduction in UAE * 10% hyperkalemia (>5.7 mmol/l) * no change in RR S. Nielsen et al, STENO Denmark

Eplerenone study in microalbuminuric Pts with RR < 130/80 or maximum antiht therapy G.Vervoort, K. Kramers, J. Deinum Preliminary results

Mortality type 1 diabetic Pts. from the FinnDiane study, stratified for the presence and severity of albuminuria (A), estimated GFR (B)

Mortality Mortality risk of type 1 diabetic Pts.

Mortality Chronic kidney disease is the dominant contributor to excess mortality in type 1 diabetes. Consequently, if you have type 1 diabetes, prevention of chronic kidney disease is currently the best way to reduce your risk of a premature death. Type 1 diabetes pts lose 3 years of their life mainly due to renal disease.

Epidemiologie Diabetische nefropathie (DNP) in type 2 diabetes wat bepaalt de incidentie en prevalentie van DNP 1. Voorkomen van diabetes mellitus 2. Patient s risk 3. Mortaliteit (alvorens DNP te ontwikkelen)

Epidemiologie 350.000.000

Epidemiologie

Epidemiologie Kaplan-Meier plots of proportion of patients with microalbuminuria, macroalbuminuria, reduced creatinine clearance (CrCl), doubling of plasma creatinine, or any one of these, after diagnosis of type 2 diabetes. Retnakaran R et al.

Epidemiologie EASD 2011 Finnish study in type 2 diabetes 20 yrs follow-up 332000 pts 105000 died = 30% 941 developed ESRD = 0,3%!! Factor 100!!! Let op: incidentie ESRD > for younger people 2-3%

Epidemiologie Natuurlijk beloop van diabetische nefropathie Diabetes mellitus Functionele veranderingen Structurele veranderingen Bloeddruk stijging Microalbuminurie Proteinurie kreatinine stijgt Nierfunctieverlies 10-15 jr

Epidemiologie 50% of Pts with GFR< 60 ml/min are normoalbuminuric Are albuminuric and GFR decreased people different??

P. Fioretto

Epidemiologie Albuminuria or renal impairment Albuminuria Renal impairment (systolic) RR UAE Creatinine Ethnicity Male Increased waist circumference LDL cholesterol Smoking Female Decreased waist circumference Age Prognostic importance??

Albuminuria increases CV death more than GFR-decrease

Epidemiology/Treatment New data from the ADVANCE trial after 5 yr follow up intensive glucose lowering treatment (HbA1c <6,5%) risk ESRD HR 0.35 (0.15-0.83) risk renal death HR 0.85 (0.45-1.63) ESRD and/or renal death HR 0.64 (0.38-1.08) doubling of creatinine NS

Epidemiology/Treatment New data from the ADVANCE trial Significant predictors for renal events egfr UAE (systolic) RR HbA1c Diabetic retinopathy Male sex Level of formal education ROC curve, 0.83 (95% CI, 0.80-0.87)

Epidemiology/Treatment Initial ARB-induced decrease in albuminuria predicts long term renal outcome in DMT2 with microalbuminuria post-hoc analysis of IRMA-2 2 yr follow up 531 microalb. subjects Initial change in UAE was independently associated with egfr slope; The more UAE reduction the less egfr decline, irrespective of blood pressure Hellemons, Groningen

Decline in egfr from 6 to 24 months for groups of UAE and SBP change in 531 type 2 diabetic patients with microalbuminuria. Hellemons M E

Treatment What about blood pressure New guidelines??? <140/90 (130/80)? Niet diastolisch <70-75 mmhg Niet systolisch <110 mmhg

SGLT-2 inh. SGLT-2 remmers ( gliflozines ) dapagliflozin canagliflozin BI 10773 TS-071 ipragliflozin sergliflozin LX4211 (combined SGLT-2 and SGLT-1 inhibitor)

SGLT-2 inh.

SGLT-2 inh. GFR 100 ml/min ~ glucose 10 mmol/l ~ 1440 mmol glucose ~ 250 gram glucose

SGLT-2 inh. Dapagliflozin and/or metformin in treatment-naïve T2DM patients; 24 week trial; n=638 MET DAPA 10mg DAPA 10mg + MET HbA1c (%) -1.44-1.45-1.98* FPG (mmol/l) -1.93-2.58# -3.35* Weight (kg) -1.36-2.73# -3.33* Urinary tract infection Genital infection 4.3% 11% 7.6% 2.4% 12.8% 8.5% Langste follow-up DAPA: 2 yr

SGLT-2 inh. Ipragliflozin in Japanese type 2 patients: BRIGHTEN Study Phase 3 study; 16 weeks follow-up HbA1c FPG Body weight Baseline 8.32 9.7 67.18 IPRA -0.76-2.2-2.36 Placebo +0.47 +0.3-0.89 Difference -1.23-2.5-1.47-3.2 mmhg RR

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