Avances en nefroprotección en la enfermedad renal diabética Cómo prevenir sus complicaciones y cómo tratarlas

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Avances en nefroprotección en la enfermedad renal diabética Cómo prevenir sus complicaciones y cómo tratarlas Jesus Egido, MD, PhD Catedrático y Director, Departamento de Medicina.

1 Avances en nefroprotección en la enfermedad renal diabética Cómo prevenir sus complicaciones y cómo tratarlas Jesus Egido, MD, PhD Catedrático y Director, Departamento de Medicina. Universidad Autónoma Jefe del Servicio de Nefrología e Hipertensión Director, Laboratorio de Patología Renal, Vascular y Diabetes Hospital Universitario Fundación Jimenez Díaz. Madrid 20 de Enero de 2017

2 Trends in the occurrence of diabetes-related complications from 1990 to 2010 in US Gregg EW et al. N Engl J Med, 2014;370:

DKD is the most frequent cause of ESRD USRDS 2014 data

28 DM 44% Hypertension; 28 More effective therapy for

Data System, 2014 USRDS annual data report: An overview

3 DKD is the most frequent cause of ESRD USRDS 2014 data We are failing to treat diabetic kidney disease Other; 28 DM 44% Hypertension; 28 More effective therapy for diabetic kidney diseases needed United States Renal Data System, 2014 USRDS annual data report: An overview of the epidemiology of kidney disease in the United States. National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, 2014.

4 Approaches to improving outcomes related to diabetic kidney disease Albuminuria reduction

5 Recommendations for glycemic, blood pressure and lipid control for adults with diabetes. KDOQI,KDIGO and ADA ( 2007,2012 and 2016) most Glycemic control: HbA1C Around 7% to reduce the risk of micro and macro vascular complications and to prevent episodes of hypoglycemia Around 8% in patients with comorbidities including advanced DKD Blood pressure control: In patients with diabetes and normoalbuminuria 140/90-80 mmhg microalbuminuria 130/80 mmh Lipid control :LDL-c 100mg/dL: All adults patients over 50 years with CKD should be treated with a statin or a statin plus ezetimibe regardless of their LDLc

6 Intensive vs conventional glucose therapy on Albuminuria in patients with diabetes and CKD. A KDOQI review Patients with type 1 or 2 diabetes; from 2003 to 2010; 5 studies (n =27,159) A Systematic Review for a KDOQI Clinical Practice Guideline Am J Kidney Dis :

7 EDIC: Early Glycemic Control Reduces Long-term Risk of Impaired GFR Risk reduction with intensive therapy 50% (95% CI 18-69; p=0.006) DCCT/EDIC Research Group. N Engl J Med 2011;365:

8 Nearly 60% of patients with type 2 diabetes are NOT achieving the ADA HbA1c target. Schatz. Diabetes Care 2016;39:

9 Sites of action of glucose-lowering agents Tahrani, AA et al. Nat Rev Endocrinol.2016 Oct;12(10):566-92

10 Approaches to improving outcomes related to diabetic kidney disease Albuminuria reduction

11 Drug-Induced Reduction in Albuminuria Is Associated with Subsequent Renoprotection A Meta-Analysis Lambers Heerspink et al.j Am Soc Nephrol 26: , 2015

12 Approaching the treatment of albuminuria in T2D STANDARD TREATMENT Body weight reduction Up-titration of RAS or dual treatment Sodium restriction and /or addition of diuretics Mineralcorticoid receptor antagonists DRUGS DECREASING PROTEINURIA IN SMALL/LIMITED TRIALS Pentoxifylline Vitamin D receptor activators Allopurinol SELECTED TRIALS IN PHASE 3 OR NOVEL APPROACHES Novel mineralcorticoid receptor antagonists :Finerenone Specific endothelin receptor antagonists: Atrasentan (SONAR) Anti-inflammatory drugs: CCR2 inhibitors, JAK inhibitors

13 Short-Term Changes after a Weight Reduction Intervention in Advanced Diabetic Nephropathy Six obese individuals with advanced diabetic nephropathy (estimated GFR,40 ml/min per 1.73 m2, urine albumin excretion >30 mg/d). 12% reduction in weight (12 weeks) 36% reduction in albuminuria Significant reduction in serum creatinine Friedman et al. Clin J Am Soc Nephrol 8: 2013

Randomized controlled trials of RAAS blockade at the various stages of progression of diabetic nephropathy RAAS blockade is the cornerstone of treatment with chronic

14 Randomized controlled trials of RAAS blockade at the various stages of progression of diabetic nephropathy RAAS blockade is the cornerstone of treatment with chronic kidney disease and particularly in diabetic kidney disease ACEI or ARB: decrease albuminuria and preserve GFR Roscioni, S. S. et al. Nat. Rev. Nephrol. 10, ;2014

15 Comparative efficacy and safety of blood pressure-lowering agents in adults with diabetes and kidney A network metaanalysis. Palmer SC, et al: Lancet 2015; 385: studies comprising 43,256 participants, mostly with T2D and CKD - Compared with placebo, end-stage renal disease was significantly less likely after dual treatment with an ARB and an ACE inhibitor - Any benefits of combined ACE inhibitor and ARB treatment need to be balanced against potential harms of hyperkalemia and acute kidney injury. Incidence, Severity, and Outcomes of AKI Associated with Dual Renin-Angiotensin System Blockade. Clin J Am Soc Nephro,2016 Nov Dual RAAS blockade for kidney failure: hope for the future. Lancet 2015 May RAS blockade: Nephroprotection by dual RAS blockade--a welcome back Nat Rev Nephrol Sep

16 Effects of sodium restriction and hydrochlorothiazide on RAAS blockade efficacy in CKD (diabetic nephropathy) A randomised clinical trial Kwakernaak et al Lancet Diabetes Endocrinol 2014; 2:

Diverse diuretics regimens differentially enhance the anti-albuminuric effect of RAS blockers in patients with CKD Effects of diuretics on albuminuria and proteinuria A

17 Diverse diuretics regimens differentially enhance the anti-albuminuric effect of RAS blockers in patients with CKD Effects of diuretics on albuminuria and proteinuria A significant correlation was found between the UACR reduction and GFR and blood pressure changes. Morales et al Kidney International advance online publication, 26 August 2015

18 Spironolactone Add-On for Preventing or Slowing the Progression of Diabetic Nephropathy: A Meta-Analysis Adding spironolactone led to significantly lower urinary protein/albumin concentrations Jing Hou, MS et al. Clin Ther Sep;37(9): e10

7.8 years of intensified, multifactorial treatment Cumulative mortality cardiovascular or death endpoint 160 patients with type 2 diabetes with

19 7.8 years of intensified, multifactorial treatment Cumulative mortality cardiovascular or death endpoint 160 patients with type 2 diabetes with microalbuminuria Mortality Intensive CV events A median of 7.9 years of gain of life The increase in lifespan is matched by time free from incident cardiovascular disease.

20 Approaching the treatment of albuminuria in T2D STANDARD TREATMENT Body weight reduction Up-titration of RAS blockers depending on blood pressure Sodium restriction and /or addition of diuretics Mineralcorticoid receptor antagonists DRUGS DECREASING PROTEINURIA IN SMALL/LIMITED TRIALS Pentoxifylline (around 17%),Navarro-González, et al. JASN 2015 Vitamin D receptor activators (6 to 16%) Allopurinol (8-12%) SELECTED TRIALS IN PHASE 3 OR NOVEL APPROACHES Novel mineralcorticoid receptor antagonists :Finerenone Specific endothelin receptor antagonists: Atrasentan (SONAR) Anti-inflammatory drugs: CCR2 inhibitors, JAK inhibitors

21 Open-label, not placebo-controlled, Pentoxifylline 1200 mg/d on top of RAS blockade 169 patients randomized 70 year-old, egfr 37+/- 12 ml/min, UAE 1100 mg/d;24months egfr egfr UAE Juan F. Navarro-González, et al. JASN 2015

22 JAMA September 1,2015 Volume 314. Number Finerenone -90 days -DM and albuminuria -RAS blockade Improvement in UACR dose dependent Safety: NO increase in hyperkaliemia or AKI Efficacy and Safety of Finerenone in Subjects With Type 2 Diabetes Mellitus and Diabetic Kidney Disease (FIDELIO-DKD).Phase 3 (estimation completion end, May 2019)

Atrasentan reduces albuminuria by 35-42% SONAR: atrasentan phase 3 clinical trial 4000 type 2 diabetic patients stage 2-4 with macroalbuminuria Atrasentan 0.

23 Atrasentan reduces albuminuria by 35-42% SONAR: atrasentan phase 3 clinical trial 4000 type 2 diabetic patients stage 2-4 with macroalbuminuria Atrasentan 0.75 mg or placebo on top of standard of care (+RAAS blockade) Primary endpoint: time to renal composite (doubling of serum creatinine or ESRD) Secondary endpoint: time to CV events Study Of diabetic Nephropathy with AtRasentan An orally active ETA/ETB receptor antagonist ameliorates proteinuria and glomerular lesions in rats with proliferative nephritis.gómez-garre D et al. Kidney Int ;50:962-72

24 Glomerular Cell Crosstalk and the Glycocalyx The structural integrity of a glomerular endothelial glycocalyx is required to prevent albuminuria Atrasentan Reduces Albuminuria by Restoring the Glomerular Endothelial Glycocalyx Barrier in Diabetic Nephropathy. Diabetes,August 2016

Chemokine Receptors Antagonists Completed and published

25 Leukocyte recruitment cascade and the potential drug targets Kreuger J Nat Rev Drug Discov ;15: Chemokine Receptors Antagonists Completed and published Fernandez-Fernandez B et al. Nat Rev Nephrol ;10:

26 The effect of CCR2 inhibitor CCX140-B on residual albuminuria in patients with type 2 diabetes and nephropathy: a randomised trial 332 patients followed for 52 weeks Primary endpoint -2% -11% -18% de Zeeuw D et al,lancet Diabetes Endocrinol Sep;3(9):687-96

27 A Phase 2 Multi-Center Study To Evaluate The Efficacy And Safety Of A Chemokine CCR2/5 Receptor Antagonist In Adults With Type 2 Diabetes And Overt Nephropathy This study has been completed (PF ) and has results,but no publications Percent Reduction From Baseline in Urinary Albumin to Creatinine Ratio (UACR) at Week 12, % in the treated group (n=159) vs 5.2 in placebo (n=51) Structure of CC chemokine receptor 2 with orthosteric and allosteric antagonists.nature,2016 The diverse pocket epitopes that can be exploited to overcome obstacles in drug design.

28 Inflammation in Diabetic Kidney Disease Targeting intracellular signaling High glucose Inflammation Oxidative stress Nrf2 NF- B pathway JAK/STAT pathway Inflammatory cytokines Functional and structural renal changes Chronic Kidney Disease Renal failure Egido J and Gómez-Guerrero C 2017

The JAK/STAT pathway plays a key role in the genesis of

Glucose Stress Activation Inhibition SOCS family

proliferation and differentiation Foam cell formation

proteins Kinase: JAK1, JAK2, JAK3, TYK2 Transcription

29 The JAK/STAT pathway plays a key role in the genesis of renal inflammation and diabetes Angiotensin II Oxidative Glucose Stress Activation Inhibition SOCS family Suppressors of cytokine signaling Cell activation, proliferation and differentiation Foam cell formation Apoptosis Inflammatory gene expression Extracellular matrix proteins Kinase: JAK1, JAK2, JAK3, TYK2 Transcription factor: STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, STAT6 Gómez-Guerrero C and Egido J, 2017

30 JAK expression levels in human diabetic nephropathy correlates with renal function. European Renal cdna Bank N=11 EARLY N=12 PROGRESSIVE Berthier et al Diabetes 58: , 2009 N=12 N=10 EARLY PROGRESSIVE mrna expression of JAKs 1 and 3, and STATs 1 and 3 was increased in patients with DKD compared to normal individuals

31 Baricitinib in Diabetic Kidney Disease A Phase 2, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study 2015 American Diabetes Association (ADA) 129 patients with DKD treated with baricitinib for 6 months Baricitinib an inhibitor of JAK1-2 Baseline 24 UACR was 886 ( ) mg/g. -Baseline egfr (cystatin C) was 49±23 ml/min/1.73 m2 (mean±sd) and did not change in any group. -Inflammatory markers decreased in a dose-dependent manner suggesting an anti-inflammatory mechanism to reduce albuminuria -Anemia occured in 32% with the highest dose

Glomerular area ( m 2 x10 3 ) UAC ( g/ mol)

4 ** *** ** ## 80 60 40 * ** >40% ** # 2 0 C

Mu Non-diabetic mice 16 wks 34 wks 16 wks 34

32 Glomerular area ( m 2 x10 3 ) UAC ( g/ mol) SOCS1 peptide improves renal damage in diabetic mice Control vehicle (C) SOCS1 peptide (S1) Mutant peptide (Mu) 16 weeks 34 weeks 16 weeks 34 weeks 34 weeks PAS staining (quantification) Albuminuria ** *** ** ## * ** >40% ** # 2 0 C S1 C S1 Mu Non-diabetic mice 20 0 C S1 C S1 Mu Non-diabetic mice 16 wks 34 wks 16 wks 34 wks * and P<0.05 vs C # P<0.05 vs Mu Recio et al. JASN. Sept. 2016

Infiltrating leukocytes Cytokine expression F4/80 + macrophages

u.) 16 12 8 4 0 * Ccl2 * # * C S1 C S1Mu 16 34 wks wks * Ccl5 *

wks 5 4 3 2 1 0 Lymphocytes Macrophages *** ** C S1 C S1

33 Cells + /gcs mrna (a.u.) SOCS1 peptide reduces inflammation in diabetic kidneys Infiltrating leukocytes Cytokine expression F4/80 + macrophages CD3 + lymphocytes Vehicle (C) SOCS1 peptide (S1) mrna levels (a.u.) * Ccl2 * # * C S1 C S1Mu wks wks * Ccl5 * # * C S1 C S1Mu wks wks * Tnfα * C S1 C S1Mu wks wks Lymphocytes Macrophages *** ** C S1 C S1 Systemic inflammation Splenic cytokines ifn il-12 tnf il-4 il-10 Vehicle SOCS1 Recio et al. JASN. Sept. 2016

34 Summary -Current nephroprotection (ACEI or ARB) is not enough for many patients -Tremendous interest with the new anti-diabetic drugs,the incretinebased drugs and mainly with SGLT2 inhibitors -Promising clinical trials targeting endothelin receptors (volume overload risk!), and additional trials targeting mineralcorticoid receptors, and different inflammation pathways -It is expected that new drugs, combating DKD in the coming years, can drecrease the burden of this disease

35 Renal, Vascular and Diabetes Research Lab. Fundación Jiménez Díaz. Autónoma University. Madrid.

SLOWING PROGRESSION OF KIDNEY DISEASE. Mark Rosenberg MD University of Minnesota

SLOWING PROGRESSION OF KIDNEY DISEASE Mark Rosenberg MD University of Minnesota OUTLINE 1. Epidemiology of progression 2. Therapy to slow progression a. Blood Pressure control b. Renin-angiotensin-aldosterone