Diabetic Nephropathy Larry Lehrner, Ph.D.,M.D.

Diabetic Nephropathy Larry Lehrner, Ph.D.,M.D. llehrner@ksosn.com Commercial Support Acknowledgement: There is no outside support for this activity Financial Disclosure: stocks > 50,000 Bayer, J&J, Norvartis,Novo Nordisk, Pfizer, Sanofi

Diabetic Nephropathy Presentation Outline Definition of DN Classification of CKD Mechanisms for the Development of DN Goals of Treatment and Literature Confusion Primary Care Treatment of DN Improved Clinical Outcomes Future References/Major Studies Summary- for your reading pleasure at home

Definition of Diabetic Nephropathy Persistent albuminuria (>300 mg/24 hr or 200 µg/min) is the hallmark of diabetic nephropathy that can be diagnosed clinically if the following additional criteria are fulfilled presence of diabetic retinopathy and absence of clinical or laboratory evidence of other kidney or renal tract disease. This clinical definition of diabetic nephropathy is valid in types 1 and 2 diabetes (pg 1283) only 50% to 60% of proteinuric type 2 diabetic patients have retinopathy. (pg 1300) Brenner and Rector's The Kidney, 39, 1283-1321.e14 Diabetic kidney disease is usually a clinical diagnosis made based on the presence of albuminuria and/or reduced egfr in the absence of signs or symptoms of other primary causes of kidney damage. The typical presentation of diabetic kidney disease is considered to include a long-standing duration of diabetes, retinopathy, albuminuria without hematuria, and gradually progressive kidney disease. However, signs of CKD may be present at diagnosis or without retinopathy in type 2 diabetes, and reduced egfr without albuminuria has been frequently reported in type 1 and type 2 diabetes and is becoming more common over time as the prevalence of diabetes increases in the U.S. American Diabetes Association- Diabetes Care Volume 40, Supplement 1, January 2017

Definition of Diabetic Nephropathy prevalence of albuminuria in patients with T2DM decreased from about 21% in 1988-1994 to 16% in 2009-2014, despite a rise in the prevalence of reduced egfr CJASN 12:1366-1373,2017

DM Nephropathy Not Just a Glomerular Disease Diabetic Classic Kimmelstiel-Wilson nodule Thickened renal arterial wall

Pathologic Classification of DM Nephropathy

Pathologic Classification of DM Nephropathy IFTA = Interstitial fibrosis and tubular atrophy

Estimating GFR- Cr, Age, Race, Sex The MDRD GFR is an estimate of the glomerular filtration rate (GFR) using serum creatinine and demographic factors. It has not been studied extensively in populations that are not white or black. It relies on a stable creatinine and may be less accurate for GFR values above 60. simplified MDRD equation by Levey, et. al. egfr = 186*(0.742 if female)*(1.212 if Black)*creatinine -1.153 *age -0.203 The CKD-EPI GFR is an estimate of the glomerular filtration rate (GFR) using serum creatinine and demographic factors. It is a relatively new equation proposed to be superior to the MDRD GFR equation. The CKD-EPI equation by Levey, et. al.: egfr = 141 x min(scr/k, 1) a x max(scr/k, 1) -1.209 x 0.993 Age x 1.018 [if female] x 1.159 [if black] Scr is serum creatinine, k is 0.7 for females and 0.9 for males, a is -0.329 for females and - 0.411 for males, min indicates the minimum of Scr/k or 1, and max indicates the maximum of Scr/k or 1 Levey AS, Greene T, Kusek J, Beck GJ, Group MS: A simplified equation to predict glomerular filtration rate from serum creatinine [Abstract]. J Am Soc Nephrol 11: A0828, 2000 Levey et al.a new equation to estimate glomerular filtration rate. Ann Intern Med 2009;150:604-612

CKD Stages < 30 mg/day 30-300 mg/day > 300 mg/day < 20 ug/min 20-200 ug/min > 200 ug/min UAE ACR Albumin/min

Pathogenic processes in DN and potential targeting strategies under clinical investigation. Bioorganic & Medicinal Chemistry Letters Volume 26, Issue 18, 15 September 2016, Pages 4394-4402

Potential Mechanisms for the Development of DM Nephropathy A Target Rich Environment Journal of Advanced Research Volume 8, Issue 4, July 2017, Pages 363-373

What Do Most Studies Evaluate? A Specific Organ System such as Cardiac or Renal For Renal Studies What Are the Usually Measured End Points? Proteinuria Doubling of Serum Creatinine Development of ESRD What do we Really Want to Accomplish with Treatment of Diabetes Improve morbidity Improve mortality

Life Cycle of Diabetic Nephropathy in T1DM and 3 Points of Intervention A2- microalbuminuria to A3- Macroalbuminuria (diabetic nephropathy) A3- macroalbuminuria (DN) to ESRD Type 1 DM Changing nomenclature A1-normoalbuminuria to A2- microalbuminuria microalbuminuria = moderately increased albuminuria (A2) macroalbuminuria = severely increased albuminuria (A3)

Potential Issues with Studies T1DM vs. T2DM What phase is being studied- primary prevention, secondary prevention, tertiary prevention Only about 30% of diabetic patients develop DN- thus in primary prevention studies about 70% of enrolled patients will NOT develop the disease no matter the treatment. Need for better biomarkers of which patients are at risk for DN Sex differences- young males worse outcomes. Estrogen protective? Is the study drug s mechanism of action independent of glycemic and/or BP control

Is Albuminuria an Appropriate Surrogate Marker of Renoprotection? Albuminuria Is an Appropriate Therapeutic Target in Patients with CKD: The Pro View Clin J Am Soc Nephrol. 2015 Jun 5; 10(6): 1079 1088. reduction in albuminuria observed during the first months of treatment with these drugs correlates with the degree of long-term renal protection: the larger the initial reduction in albuminuria, the lower the risk of ESRD during treatment. In addition, in treated patients, residual albuminuria is again the strongest risk marker for renal disease progression. These observations combined provide a strong argument that albuminuria is an appropriate therapeutic target in patients with CKD Albuminuria is Not an Appropriate Therapeutic Target in Patients with CKD: The Con View Clin J Am Soc Nephrol. 2015 Jun 5; 10(6): 1089 1093. combining renin-angiotensin system therapies decreases albuminuria without significant clinical benefit but with increased risk of adverse events albuminuria has not jumped the hurdle needed to be accepted as a surrogate end point or target for treatment. Primum non nocere, first do no harm.

Primary Care Treatment Make the Dx of DN When to Test For Albuminuria T1DM- 5 years after Dx of DM (sooner if poor control and/or hypertensive) T2DM- upon Dx of DM Disease-a-Month Volume 61, Issue 9, September 2015, Pages 378-386 https://doi.org/10.1016/j.disamonth.2015.07.002

Primary Care Make the Dx of DN If you do not look for a disease you will never find it vol 1 Figure 2.3 Trends in percent of patients with testing of urine albumin (a) in Medicare 5% sample (aged 65+ years) patients without a diagnosis of CKD, by year from 2005 to 2015 (a) Medicare 5% Data Source: Special analyses, Medicare 5% sample aged 65 and older with Part A & B coverage in the prior year and Optum Clinformatics patients aged 22-64 years. Tests tracked during each year. Abbreviations: CKD, chronic kidney disease; DM, diabetes mellitus; HTN, hypertension. 2017 Annual Data Report Volume 1 CKD, Chapter 2 22

Primary Care Treatment Make the Dx of DN The lack of albuminuria does not exclude DN When to Test For egfr egfr T2DM T1DM Ø 90 yearly at Dx then yearly starting at year 5 Ø 60-89 yearly yearly Ø 30-59 q3 months q3 months Ø 15-30 q6-8 weeks q6-8 weeks Ø <15 q4 weeks q4 weeks My opinion

Primary Care Make the Dx of DN If you do not look for a disease you will never find it Figure 2.3 Trends in proportion of patients (b) serum creatinine testing, by year, among Medicare patients aged 65+ WITHOUT a diagnosis of CKD, 2000-2013 (b) Serum Creatinine Data Source: Special analyses, Medicare 5 percent sample, aged 65 and older with Part A & B coverage in the prior year. Tests tracked during each year. Abbreviations: CKD, chronic kidney disease; DM, diabetes mellitus; HTN, hypertension. USRDS Vol 1, CKD, Ch 2 2015

Primary Care Treatment- General Measures Ø Weight Loss Ø Smoking Cessation Ø Modest Protein Restriction 0.8 mg/kg Ø Lipid Management Ø Uric Acid Management Ø Acidosis Management Journal of Advanced Research Volume 8, July 2017 pg 363-373 J Diabetes Res. 2015; 2015: 801348 doi: 10.1155/2015/801348 Canadian Journal of Diabetes Volume 39, Issue 3, June 2015, Pages 239-246 BMC Nephrol. 2015; 16: 58. doi: 10.1186/s12882-015-0047-z

Primary Care Treatment Glycemic Control and BP Control

Primary Care Treatment- BP Hypertension Common DM comorbidity Major risk factor for ASCVD & microvascular complications Antihypertensive therapy reduces ASCVD events, heart failure, and microvascular complications. Cardiovascular Disease and Risk Management: Standards of Medical Care in Diabetes - 2018. Diabetes Care 2018; 41 (Suppl. 1): S86-S104

Pharmacologic Interventions Treatment for hypertension should include drug classes demonstrated to reduce CV events in patients with diabetes: A ACE Inhibitors Angiotensin receptor blockers (ARBs) Thiazide-like diuretics Dihydropyridine calcium channel blockers e.g. Amlopidine Primary Care Treatment- BP Hypertension/BP Control: Recommendations (5) Cardiovascular Disease and Risk Management: Standards of Medical Care in Diabetes - 2018. Diabetes Care 2018; 41 (Suppl. 1): S86-S104

Hypertension/BP Control: Recommendations (6) Pharmacologic Interventions Multiple-drug therapy is generally required to achieve BP targets. However, combinations of ACE inhibitors and ARBs and combinations of ACE inhibitors or ARBs with direct renin inhibitors should not be used. A Cardiovascular Disease and Risk Management: Standards of Medical Care in Diabetes - 2018. Diabetes Care 2018; 41 (Suppl. 1): S86-S104

Hypertension/BP Control: Recommendations (7) Pharmacologic Interventions An ACE inhibitor or ARB, at the maximumly tolerated dose indicated for BP treatment, is the recommended first-line treatment for hypertension in patients with diabetes and urinary albumin-to-creatinine ratio 300 mg/g creatinine A or 30-299 mg/g creatinine B. If one class is not tolerated, the other should be substituted. B For patients treated with an ACE inhibitor, ARB, or diuretic, serum creatinine/estimated glomerular filtrated rate and serum potassium levels should be monitored at least annually. B Cardiovascular Disease and Risk Management: Standards of Medical Care in Diabetes - 2018. Diabetes Care 2018; 41 (Suppl. 1): S86-S104

Classic Study Showing ACEI is Renoprotecitve NEJM 1993;329:1456-62

ACEI For Renoprotection- CKD Stage is Important NEJM 1993;329:1456-62

Diabetic Kidney Disease (DKD): Recommendations (5) Treatment An ACE inhibitor or an ARB is not recommended for the primary prevention of DKD in patients with diabetes who have normal blood pressure, normal UACR (<30 mg/g creatinine), and normal egfr. B When egfr rate is <60 ml/min/1.73m 2, evaluate and manage potential complications of DKD. E Microvascular Complications and Foot Care: Standards of Medical Care in Diabetes - 2018. Diabetes Care 2018; 41 (Suppl. 1): S105-S118

What is the Optimal BP for Patients with Diabetic Nephropathy?

Most people with diabetes and hypertension should be treated to a systolic BP goal of <140 mmhg and a diastolic BP goal of <90 mmhg.

SJ Taler. N Engl J Med 2018;378:636-644. Classification of Blood Pressure in Adults.*

Synopsis of the 2017 ACC/AHA Hypertension Guideline Table 4. Recommendations for Nonpharmacologic and Pharmacologic Treatment and BP Goals* BP threshold and goal for adults with DM In adults with DM and hypertension, initiate antihypertensive drug therapy at SBP 130 mm Hg (class I recommendation; level of evidence: B-R) or DBP 80 mm Hg (class I recommendation; level of evidence: C-EO) and treat to goal of <130/80 mm Hg (class I recommendation; level of evidence: B-R) AnnInternMed. 2018;168:351-358. doi:10.7326/m17-3203

Primary Care Treatment- Glucose Diabetic Kidney Disease (DKD): Recommendations (2) Treatment Optimize glucose control to reduce the risk or slow progression of DKD. A Optimize blood pressure control to reduce the risk or slow progression of DKD. A For people with nondialysis-dependent DKD, dietary protein intake should be ~0.8 g/kg body weight per day (the recommended daily allowance). For patients on dialysis, higher levels of dietary protein intake should be considered. B Microvascular Complications and Foot Care: Standards of Medical Care in Diabetes - 2018. Diabetes Care 2018; 41 (Suppl. 1): S105-S118

Intensive Glucose Control in T1DM NO Retinopathy A2 Retinopathy A2 A3 A3 N Engl J Med 1993; 329:977-986September 30, 1993DOI: 10.1056/NEJM199309303291401

Summary of Intense Glycemic Control in T2DM Thus, as a whole, the intensity of glycemic control should probably be tempered in patients with T2DM who also have multiple comorbid conditions, with the goal of moderate glycemic control (HbA1C 7 8 %), since the benefits, if any, are hard to achieve, come with risk, and are at best small in magnitude. Intensive glycemic control with HbA1C <7 % should be attempted with extreme caution and only in younger, newly diagnosed patients without comorbidities. Update on Glycemic Control for the Treatment of Diabetic Kidney Disease Curr Diab Rep (2015) 15: 42 DOI 10.1007/s11892-015-0612-7

Intensive Glucose Control in T2DM

CKD Patients Are More Likely to Die Than Progress to ESRD Percentage Who Remained Event-Free vs Death vs Developed ESRD During 5-Year Follow-up % of Patients 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% 15% 16% 10% 7% 28% 64% 63% 75% 20% 1% 46% 20% 24% 10% Stage 1 Stage 2 Stage 3 Stage 4 Disenrolled Event free RRT Died Keith et al. J Am Soc Nephrol. 13:620A, 2002.

CKD Patients Are More Likely to Die Than Progress to ESRD Percentage Who Remained Event-Free vs Death vs. Developed ESRD During 2-Year Follow-up. Patients had their first Nephrology consult at an outpatient clinic 100% 80% % of Patients 60% 40% 20% 0% 90% 84% 1% 8% 12% No DM, No CKD 4% 68% 11% 61% 18% 20% 22% DM, No CKD No DM, CKD DM, CKD Status at Entry Period Event Free ESRD Death Medicare 5% sample 1996-1997, Two year follow-up, adjusted for age, gender, and race Analysis performed by Minneapolis Medical Research Foundation

vol 2 Figure 1.7 Trends in (a) ESRD incident cases, in thousands, and (b) adjusted* ESRD incidence rate, per million/year, by primary cause of ESRD, in the U.S. population, 1980-2012 (a) Incident Cases IC (b) Incidence Rates IR Data Source: Reference tables A.1, A.2(2). *Adjusted for age, sex, and race. The standard population was the U.S. population in 2011. Abbreviation: ESRD, end-stage renal disease. Simple Mathematical Example- Incident Cases (IC) vs Incident Rate (IR) 1980 2012 Population 1,000,000 5,000,000 New Patients (IC) 1,000 3,750 Incident Rate/Million (IR) 1,000 750 USRDS 2014 Vol 2, ESRD, Ch 1 46

Are SGLT2 Inhibitors Renal Protective Canagliflozin Placebo Total

Remember Is the Patient better off Not are one or two organ systems better off CONCLUSIONS In two trials involving patients with type 2 diabetes and an elevated risk of cardiovascular disease, patients treated with canagliflozin had a lower risk of cardiovascular events than those who received placebo but a greater risk of amputation, primarily at the level of the toe or metatarsal.

Proposed Mechanism Of Action Hyperglycemia & SGLT2 Inhibitors In Diabetics Tubuloglomerular feedback:impact of low salt intake and SGLT2 inhibitors. UF = glomerular ultrafiltrate; SGLT = sodium glucose transporter; PCT = proximal convoluted tubules; DCT = distal convoluted tubule; MD = macula densa; AMP = adenosine monophosphate; VD = vasodilation; AA = afferent arteriole Journal of Advanced Research Volume 8, Issue 4, July 2017, Pages 363-373

Are GLP-1 Agonists Renoprotective?

Proposed Mechanism Of Action DPP-4 GLP-1 --- insulin secretion inflammation Angiotensin II DPP-4 mediated renal fibrosis. DPP4 = dipeptyl peptidase-4; TGFβ = transforming growth factorβ; EndMT = endothelial-mesenchymal transition Journal of Advanced Research Volume 8, Issue 4, July 2017, Pages 363-373

Incretin Dependent Incretin INDEPENDENT

Diabetic Nephropathy Larry Lehrner, Ph.D.,M.D. llehrner@ksosn.com Thank You Commercial Support Acknowledgement: There is no outside support for this activity Financial Disclosure: stocks > 50,000 Bayer, J&J, Norvartis,Novo Nordisk, Pfizer, Sanofi

Review of Potential New Treatments for DN Selected References Therapies on the Horizon for Diabetic Kidney Disease Curr Diab Rep (2015) 15: 111 DOI 10.1007/s11892-015-0685-3 Diabetic nephropathy: What does the future hold? Int Urol Nephrol (2016) 48:99 113 DOI 10.1007/s11255-015-1121-y Mechanistic insight of diabetic nephropathy and its pharmacotherapeutic targets: An update European Journal of Pharmacology Volume 791, 15 November 2016, Pages 8-24 Management of diabetic nephropathy: Recent progress and future perspective Diabetes & Metabolic Syndrome: Clinical Research & Reviews 9 (2015) 343 358 Diabetic nephropathy: landmark clinical trials and tribulations Nephrol Dial Transplant (2016) 31:359-368 doi:10.1093/ndt/gfu411

Approved Treatments for DM Nephropathy Journal of Advanced Research Volume 8, Issue 4, July 2017, Pages 363-373

Major DN Studies Nephrol Dial Transplant (2016) 31: 359 368 doi: 10.1093/ndt/gfu411

Nephrol Dial Transplant (2016) 31: 359 368 doi: 10.1093/ndt/gfu411 Major DN Studies