Diabetes and Kidney Disease Alessia Fornoni, MD PhD Professor of Medicine Chief, Katz Family Division of Nephrology and Hypertension Director, Peggy and Harold Katz Family Drug Discovery Center University of Miami School of Medicine Disclosures I am vice President and CSO of L&F Health LLC L&F Health LLC and affiliated companies have a patent estate covering some of the topics being presented L&F Health LLC has consulting agreements with and/or has received honoraria from Hoffman La Roche, Genentech, Mesoblast, Bristol Myers Squibb, Abbvie, Jenssen, Boehringer Ingelheim, Astra Zeneca, Pfizer, Mallinkrodt, Chemocentryx, Dimerix, Variant Pharmaceutical. Variant Pharmaceuticals, Inc. has licensed worldwide rights to develop and commercialize hydroxypropyl beta cylodextrin for treatment of kidney disease from L&F Research Objectives Definition and screening for DKD 2018 Treatment guidelines New approaches to patients risk stratification Objectives Definition and screening for DKD 2018 Treatment guidelines New approaches to patients risk stratification 1
DKD yearly updates DKD remains the most common cause of ESRD ESRD prevalence (per M) 1992 ESRD prevalence by cause 2014 2014 Page S105: Microvascular complications Diabetes Care, 2018, Supplement 1 USRDS 2010-2016 Prevalence of Diabetic Kidney Disease (DKD) DKD and yearly risk of death > 5000 Type 2 Diabetes patients Yearly risk associated CVD risk protection needs early implementation deboer JAMA 2011; 305: 2532 Adler et al, Kidney International, 2003;63:225 2
Kidney disease is among the top causes of death Natural progression of DKD in T1D 277 patients Type 1 DM f/u 18 yrs 75% ESRD at 20 years Murray et al NEJM 2013; 369: 5 Early biomarkers are missing Copyright 2004 BMJ Publishing Group Ltd. Early Detection and Treatment are Essential Hovind, P. et al. BMJ 2004;328:1105 Natural progression of DKD in T2D Screening for DKD 30% At diagnosis if HTN 12% 10,290 members of a managed care organization with HTN and T2D (Kayser Permanente) ACR at baseline and with at least 2 additional determinations over time, 7 1/2 years follow up yearly follow up, Level of evidence B Vupputuri S et al, Diabetes Res Clin Pr, 91: 246, 2011 ADA recommendations, Diabetes Care, January 2017 3
DIABETES with: Definition of DKD ACR & Progression to ESKD Abnormal urine albumin excretion >30 mg/24 hours >30 mg/g creatinine (preferred) >20 µg/min and/or diabetic glomerular lesions and/or loss of glomerular filtration rate (CKD-EPI preferred) ADA recommendations, Diabetes Care, January 2018 White: F Black: M Babazono Diabetes Care 2009; 32: 1518 Proteinuria and GFR: risk factors for ESRD Albuminuria and kidney failure risk Risk calculator: kidneyfailurerisk.com Shahinfar S et al, Kidney Int: S48-S51, RENAAL Baseline Characteristics Chronic Kidney Disease Prognosis Consortium 721357 participants 30 countries Tangri N et al, JAMA. 2016 Jan 12;315(2):164-74 4
Risk stratification Is testing for albuminuria enough? 1 1 1 1 1 2 2 3 3 3 4 4 2 2 3 3 4 4 Numbers indicate the suggested number of visits/year KDIGO 2012, Kidney International, Issue 1, 2013 Albuminuria and DKD progression in T1D: DCCT/EDIC >20 years follow up Normoalbuminuric DKD progression in T2D Severe albuminuria was a strong predictor of risk of developing sustained egfr <60 ml/min/1.73 m 2 11.4% 51% NA Screening with AER alone would have missed 24% of cases of sustained impaired egfr 5102 UKPDS patients with T2D Normal albuminuria and creatinine at baseline Molitich et al, Diabetes Care, 2010; 33:1536-43, DCCT-EDIC f/u Ravi Retnakaran et al. Diabetes 2006;55:1832-1839, UKPDS 74 5
Normoalbuminuric DKD Prevalence of low GFR and normoalbuminuria Natural history of albuminuria MacIsaac Kidney Int 2014; 86: 50 MacIsaac, Kidney Int 2014; 86: 50 Nephrology referral and biopsy egfr<30 cc/min/1.73m 2 at diagnosis CKD care and referral for renal replacement strategies ADA QDOQI Worsening proteinuria despite treatment Loss of egfr> 1cc/min/1.73m 2 /month Active urine sediment Absence of retinopathy biopsy >30% reduction in egfr after initiation of ACEi/ARB Refractory hypertension Limitation of clinically indicated kidney biopsies Often the diagnosis In clinically indicated kidney biopsies differs from DKD Protocol kidney biopsies are needed to understand the disease ADA recommendations, Diabetes Care, January 2018 NKF QDOQI guidelines for diabetes, AJKD 2014 Gonzalez Suarez ML, Thomas DB, Barisoni L, Fornoni A., World J Diabetes, 2013 6
Albuminuria and T2D: pathologic heterogeneity NEAR NORMAL HISTOLOGY (C1) 30 % TYPICAL DIABETIC NEPHROPATHY (C2) 30 % (a) Both normal and totally destroyed glomeruli (b) Severe arteriolohyalinosis NON-SPECIFIC FINDINGS (C3) 40 % Change in GFR (%) in patients with T2D and albuminuria % GFR/year +10 0-10 (n=33, 4 year follow-up) * C3 C1 C2 Fioretto et al. Diabetologia 1998;41:233-236 (c) Tubulointerstitial fibrosis -20 * p<0.05, C2 vs C1 ja C3 Nosadini et al. Diabetes 2000;49:476-484 GBM thickening can predict decline in kidney function in T1D with NA Podocytopathy in early DKD in T2D Caramori M L et al. JASN 2013;24:1175-1181 Pagtalunan ME et al, JCI, 99: 342-348, 1997 Meyer TW et al, Diabetologia, 42:1341-1344 7
Podocytopathy in DKD in T1D Podocyte detachment occurs in T1D correlates with AER and loss of GFR Fraction of peripheral GBM covered by intact foot processes White K E et al. Diabetes 2002;51:3083-3089 Toyoda M et al, Diabetes, 2007, 56: 2155 Objectives Definition and screening for DKD 2017 Treatment guidelines New approaches to patients risk stratification Prevention and treatment of DKD American Diabetes Association recommendations 2018 Level of evidence A: control BP with appropriate agents (goal <140/90mmHg, <130/80 if high risk for CVD) control glycemia (A1C about 7%, personalized) control dyslipidemia (LDL goal <70-100 mg/dl) counsel about smoking cessation education Level of evidence B: protein intake to 0.8 mg/kg/day (more if dialysis) ADA recommendations, Diabetes Care, January 2018 8
Prevention and treatment of DKD JNC7 versus ACC/AHA 2017 American Diabetes Association recommendations 2018 Level of evidence A: control BP with appropriate agents (goal <140/90mmHg, <130/80 if high risk for CVD) control glycemia (A1C about 7%, personalized) control dyslipidemia (LDL goal <70-100 mg/dl) counsel about smoking cessation education Level of evidence B: protein intake to 0.8 mg/kg/day (more if dialysis) ADA recommendations, Diabetes Care, January 2018 ACC/AHA recommendations Nov 13 2017 Recommendations for the treatment of hypertension in DKD Metabolic and hemodynamic factors in DKD ADA recommendations, Diabetes Care, January 2018 Bakris, AJKD, 36:646, 2000 9
Role of BP in DKD Role of ACEi to treat DKD % of patients with endpoints % 50 40 30 20 10 0 Risk reduction of 51% P=0.006 Captopril 25mg x 3 Placebo Captopril 1 2 3 4 * dialysis, transplant, death Time (year) Type I DM (207 captopril and 202 placebo) Proteinuria>500 mg/24 h Bakris GL, AJKD, 36:646, 2000 Creat <2.5 mg/dl Significant effect of captopril on blood pressure The Collaborative Study Group, NEJM, 329:1456, 1993 Role of ARB to treat DKD ACEi vs CCB in primary prevention of DKD with mild hypertension Incidence of diabetic nephropathy (%) 20 15 10 5 0 Placebo Irbesartan 150 mg Irbesartan 300 mg 0 3 6 12 18 22 24 Time (months) P<0.001 P=NS 1715 pt type 2 DM + HTN Irb 300 mg vs amlo 10 mg vs placebo End points: doubling creatinine ESRD death F/u 2.6 years -3.3 mmhg mean BP in tx vs placebo 1204 patients, type 2 DM IDNT trial, NEJM 345:851, 2001 IRMA-2. Parving et al. N Engl J Med 2001;345:870-8 Primary end point: persistent MA BENEDICT, NEJM, 251:1941, 2004 10
ARB vs placebo in primary prevention of DKD with normal BP ACEi or ARB? Prospective, multicentered, double-blind study 250 patients with type 2 DM and DN Telmisartan 80 mg vs enalapril 20 mg. Five year follow-up Primary end-point: change in iohexol GFR Secondary end-points: creat, UAE, BP no difference! 3326/1905 (type 1/type2) patients. Normotensive with normoalbuminuria Candesartan versus placebo (significant effect on BP) 4.7 years follow up Primary end point: development of MA Secondary: Change in UAER Bilius R et al, DIRECT, Annals of internal medicine, 2009; 151:11-20 Barnett AH, NEJM, 351:1952, 2004 ACEi or ARB? Is there a role for ACEi/ARB combination in DKD in type 2 DM? ON TARGET ADA 2017: Type 1 DM with HTN and albuminuria: ACEi Type 2 DM with HTN and microalbuminuria: either ACEi or ARBs Type 2 DM with HTN and overt nephropathy: ARBs When not tolerated, substitute one for the other BP -2.4/1.4 mmhg BP -0.9/0.6 mmhg 25620 patients with CV disease or high risk diabetes Follow up for 5 years Primary renal outcome: dialysis, x2 creat, death Combination not supported ADA recommendations, Diabetes Care, January 2017 Mann J et al, ONTARGET trial, The Lancet, 2008, 372: 547-562 11
Aldosterone antagonism in DN Aldosterone antagonism in DKD Randomized trial 59 patients with type 2 DM + macroalbuminuria On ACEi or ARB 25-50 mg spironolactone x 1 year Figure 3. Percentage change in median UACR from baseline to week 12, by quartile of baseline estimated glomerular filtration rate (egfr) and treatment group J Hyperten, 2006, 24:2285 Epstein, M. et al. Clin J Am Soc Nephrol 2006;1:940-951 Aldosterone antagonism in DKD: phase 2b with finerenone ARTS-DN ARTS-DN Japan Prevention and treatment of DKD American Diabetes Association recommendations 2017 Level of evidence A: control BP with appropriate agents (goal <140/90mmHg, <130/80 if high risk for CVD) control glycemia (A1C about 7%, personalized) control dyslipidemia (LDL goal <70-100 mg/dl) counsel about smoking cessation education Level of evidence B: protein intake to 0.8 mg/kg/day (more if dialysis) JAMA 2015, 314:884 Journal of Diabetes and Its Complications 2017 31, 758-765DO ADA recommendations, Diabetes Care, January 2017 12
A 1 C: a real measure in CKD? Role of glycemia in type 1 DM and DKD Falsely elevated A1C: Falsely decreased A1C: Intensive treatment With A1c 7.2 Standard treatment With A1c 9.1 Uremic toxins Metabolic acidosis Decreased 1/2 life RBCs Blood transfusions EPO treatment 0-10 -20-30 Retinopathy Severe DR Laser Rx Microalb Severe Microalb Albuminuria Neuropathy May need to change to glycated fructosamine, glycated albumin, variation of A1C or glycosylation gap (based on A1C and fructosamine) Kovesdy CP et al, AJKD 2008, 52: 766 Cohen RM et al, Diabetes Care. 2003 Jan;26(1):163-7 McCarter RJ et al, Diabetes Care. 2004 Jun;27(6):1259-64 -40-50 -60-70 -80-64 -39-51 -54-56 -61 DCCT: 1441 patients with type 1 DM f/u 6.5 years Insulin 3 x day or pump vs conventional (1 or 2 daily insulin injection) Primary prevention/secondary prevention Difference maintained after discontinuation of tx (7 yr follow up) -72 NEJM 1993; 329:977 Role of glycemia in type 2 DM and DKD Role of glycemia in advanced DKD 0-5 -10-15 -20 Treatment with A1c 7.0 Any Diabetes Related Endpoint -12 Microvascular Endpoints Diet with A1c 7.9 Laser Rx Cataract Albuminuria -25-30 -35-40 -25-24 -29-34 UKPDS: 3867 type 2 DM Median age 54 Intensive tx (sulpha or insulin) versus diet End points: any DM related end-point, diabetes related death and all cause mortality F/u 10 years (15 years f/u had no difference in diabetes related death) Lancet 1998; 352: 837-853 Ricks et al., Diabetes 61(30): 708 715, 2012 13
Regression of MA in type 1 DM Regression of MA in type 2 DM 216 Japanese patients with type 2 DM F/u 6 years, 3 periods of 2 years each Regression: 50% reduction MA Remission: back to NA 386 patients with persistent MA Total f/u of 4 periods of 2 years each Regression % Risk defined Reduction as 50% reduction in UAE from one period to the other Perkins, NEJM, 2003;348:2285 % Risk Reduction Araki, Diabetes, 2005;54:2983 A 1 C: how low can we get? A 1 C: how low can we get? 21% relative reduction in nephropathy 11140 patients, standard vs intensive (sulfa + other drugs to achieve A1C less than 6.5). Macro: CV death, MI, stroke Micro: development of alb, x 2 creat, ESRD ADVANCE trial, NEJM, 358:24, 2008 10,251 patients, standard vs intensive (mainly insulin and TZDs). 1/3 patients had prior CV event End point: CV death, MI, stroke Discontinued after 3.5 years f/u for high mortality in intensive arm. ACCORD, NEJM, 358:24, 2008 14
Are all anti-diabetic drugs alike? Legend: MET=Metformin, GLP1 RA= incretins, SGLT2i= glycosuric a, DPP4-i= incretins, AGi=alpha-gluc inhib, TZD=glytazones, Su= sulphanilurea, GLN= glucosaminog, COLSVL= bile acid, BCR=bromocriptin, PRAM=pramlintide Renal Absorption of Glucose and Glucagon Secretion According Glycemia to the and Presence DKD: or drug Absence class of a effect Sodium- Coupled Glucose Transporter Type 2 (SGLT2) Inhibitor. SGLT2 inhibition: is sweet urine the solution? www.aace.com Hattersley AT, Thorens B. N Engl J Med 2015;373:974-976 SGLT2 K Meier inhibitors Analysis of and Two Key DKD: Renal EMPA-REG Outcomes. SGLT2 K Meier inhibitors Analysis of and Two DKD: Key Renal CANVAS Outcomes. trial 39% 46% Worsening Nephropathy: egfr<60 ml/min and/or ACR>300 mg/g Composite outcome: doubling of the serum creatinine initiation of renal-replacement therapy death from renal disease With better A1C and BP control Wanner C et al. N Engl J Med 2016. DOI: 10.1056/NEJMoa1515920 Neal et al, et al. N Engl J Med 2017. 377:644-657 15
K Meier ARB Analysis versus of Two SGLT2 Key Renal inhibitors Outcomes. SGLT2 inhibitors and TG feedback IDNT EMPA-REG Doubling of serum creatinine ESRD Hospitalisation for heart failure All cause mortality 0.78 0.67 0.77 0.92 0.1 0.4 0.7 1.0 1.4 Doubling of serum creatinine ESRD Hospitalisation for heart failure All cause mortality 0.56 0.45 0.65 0.68 0.1 0.4 0.7 1.0 1.4 No difference in incident albuminuria! Courtesy of Dr Per-Henrik Groop % Risk Reduction Other effects? Cherney D et al, CirculationAHA 2013 DN: the gut to kidney connection K Meier Liraglutide Analysis and of Two DKD: Key LEADER Renal Outcomes. trial Time to first renal event: ACR>300, x2 creat, ESRD, renal death The cumulative incidences were estimated with the use of the Kaplan Meier method, and the hazard ratios with the use of the Cox proportionalhazard regression model. The data analyses are truncated at 54 months, because less than 10% of the patients had an observation time beyond 54 months. CI: confidence interval; ESRD: end-stage renal disease; HR: hazard ratio. 9340 T2DM patients 3.8 yrs f/u CKD1 35%, CKD2 42%, CKD3 20% Muskiet et al, Nature Review, 10:88-103, 2014 Mann J et al, NEJM 2017, 377:839-848, 2017l 16
DPP4 K Meier inhibition Analysis of Two and Key DKD: Renal linagliptin Outcomes. Prevention and treatment of DKD American Diabetes Association recommendations 2017 Level of evidence A: control BP with appropriate agents (goal <140/90mmHg, <130/80 if high risk for CVD) control glycemia (A1C about 7%, personalized) control dyslipidemia (LDL goal <70-100 mg/dl) counsel about smoking cessation education 5466 T2D pt 13 trials Sec EP: new onset A 50% egfr loss (CKD-EPI) S creat >250 umol/l Level of evidence B: protein intake to 0.8 mg/kg/day (more if dialysis) ADA recommendations, Diabetes Care, January 2018 Statins do not prevent GFR loss Prevention and treatment of DKD American Diabetes Association recommendations 2017 CARDS study group, Am J Kidney Dis. 2009 Nov;54(5):810-9 Level of evidence A: control BP with appropriate agents (goal <140/90mmHg, <130/80 if high risk for CVD) control glycemia (A1C about 7%, personalized) control dyslipidemia (LDL goal <70-100 mg/dl) counsel about smoking cessation education Level of evidence B: protein intake to 0.8 mg/kg/day (more if dialysis) Haynes R et al. JASN 2014, 25:1825-1833 ADA recommendations, Diabetes Care, January 2017 17
Cigarette smoking and DKD (T1D) Prevention and treatment of DKD American Diabetes Association recommendations 2017 N C E normo micro mild moder moder ESRD HR=ns* for current smokers *Adjusted for duration of diabetes, HbA 1c and hypertension N=non-smokers, C= current smokers, E=Ex-smokers HR=2.39* for current smokers E N C N C E HR=ns* for current smokers Level of evidence A: control BP with appropriate agents (goal <140/90mmHg, <130/80 if high risk for CVD) control glycemia (A1C about 7%, personalized) control dyslipidemia (LDL goal <70-100 mg/dl) counsel about smoking cessation education Level of evidence B: protein intake to 0.8 mg/kg/day (more if dialysis) Feodoroff et al Acta Diabetol 2016 ADA recommendations, Diabetes Care, January 2017 Multifactorial intervention in type 1 DM Smoking A1C MAP 600 patients 20 years follow up ACEi Hovind, P, Diabetes Care, 26: 1258, 2003 18
Multifactorial intervention in type 2 DM Prevention and treatment of DKD 160 patients from Steno2 7.8 years tx + 5.5 yrs f/u Primary end point: death Sec end point: ESRD INTENSIVE: Statin ASA ACEi/ARB Exercise diet American Diabetes Association recommendations 2018 Level of evidence A: control BP with appropriate agents (goal <140/90mmHg, <130/80 only for younger patients) control glycemia (A1C about 7%, personalized) control dyslipidemia (LDL goal <70-100 mg/dl) counsel about smoking cessation education Level of evidence B: protein intake to 0.8 g/kg/day (more if dialysis) Gaede, P, NEJM, 358: 580, 2008 Diabetic Nephropathy Remission and Regression Team Triial (DNETT-Japan) ADA recommendations, Diabetes Care, January 2017 Dietary protein intake in DKD Case Mr JD comes to you with GFR 50 cc/min/1.73m 2 Smoker Obese BP150/90 A1c 11% LDL 150 High protein diet Non smoker Exercise TIW BP130/80 A1c 6.9% LDL 70 Low protein diet Careful protein restriction in CKD 3 and above GFR loss 20 cc/min/year ESRD in 2 year GFR loss 2 cc/min/year ESRD in 20 year Hansen HP et al, Kidney International, 62:220, 2002 IT S UP TO MR JD AND TO YOU! 19
Objectives Is hyperuricemia a predictor of outcome? Definition and screening for DKD 2018 Treatment guidelines New approaches to patients risk stratification 263 patients with type 1 diabetes, 18.1 years f/u Uric acid measured 3 years after onset of diabetes All patients NA at enrollment (23 with macroalbuminuria at f/u) 355 patients with DM and MA Baseline uric acid determination 6 years f/u End points: GFR Cystatin decline albuminuria Awaiting the results of the preventing early renal function loss (PERL) allopurinol study Ficociello et al, Diabetes Care. 2010 Jun;33(6):1337-43. Hovind P et al, Diabetes, 2009 Jul;58(7):1668-71 DKD: role of Vitamin D TNF Receptors 1 and 2 in DKD T1DM T2DM Cumulative risk for CKD>3 in patients with T1D during 12 years of follow-up according to quartile (Q1 Q4) of circulating TNFR2 at baseline. Gohda T and Niewczas M et al, JASN, 23:516-524, 2012 168 consecutive patients in a CKD clinic (28% with DKD) 6 years follow up Baseline Vitamin D adjusted for age, sex, smoking, CRP, albumin, ACE/ARB usage, egfr Ravani P et al, Kidney International (2009) 75, 88 95 (Caucasian Americans, 410 patients) Adapted from Niewczas MA et al., JASN, 2012. (PIMA Native Americans, 193 patients) Adapted from PavkovME et al. KI, 2014. 20
Soluble Urokinase Receptor (supar) supar levels in patients with T1D and DKD 2292 patients Q1: egfr loss of 0.9 cc/min Q4: egfr loss of 4.2 cc/min BASELINE (A) supar (pg/ml) 15000 10000 5000 ** ** ** (B) 4500 4000 3500 3000 supar (pg/ml) Normo-micro (n=10) Normo-normo (n=10) ## 0 Normo Micro Macro Normal GFR 2500 0 2 4 6 8 time (years) (C) supar (pg/ml) 10000 7500 5000 Micro-macro (n=10) Micro-micro (n=10) ## ** (D) Hayek SS et al. N Engl J Med 2015;373:1916-1925. Yoo T, Pedigo C.Fornoni et al., JASN, 2014 2500 0 2 4 6 8 time (years) Role of dyslipidemia in DKD Plasma proteome analysis of patients with type 1 DM and DKD Sacks F M et al. Circulation. 2014;129:999-1008 Anne J Overgaard et al, Proteome Sci. 2010; 8: 4 21
Serum Amyloid A and DKD Plasma metabolomic analysis of patients with type 2 DM and DKD 135 T2D patients DKD stage 3a and severe albuminuria 3.5 years of follow up Outcomes: death and ESRD Dieter BP et al, J Diabetes Complications. 2016 Nov - Dec;30(8):1467-1472 Red circles: Common and stable metabolites Red empty circles: Common metabolites that are not stable Blue: essential amino acids Niewczas et al, Kidney International, 2014, 85:1214 DKD: next generation biomarkers DKD: system biology Fornoni et al, Brenner Rector 11 th Edition, In press Heinzel et al,frontiers in Cell and Developmental Biology, 2014 22
Acknowledgments Questions? Nephrotic Syndrome Study Network 23