Finding the Sweet Spot: Renal Diabetic Management and Dosing

Finding the Sweet Spot: Renal Diabetic Management and Dosing Amy Mosman, PA-C SLU Division of Nephrology Disclosures: none Objectives 1) Identify the types of albumin and normal vs. abnormal levels 2) Highlight albumin testing and lab deviations with emphasis on patient care 3) Discuss methods of decreasing proteinuria with an eye on the outcome of CKD progression 4) Using sample patients, discuss who/when/how to treat the proteinuric diabetic patient Alexis 24 y/o obese female here to establish care. No PMH. Strong FH of DM, HTN, CKD PE: 132/78, 240 lbs, no edema, no sx Labs: SCr 0.9mg/dL, UA + albuminuria, A1C 6.8% Worried if she has DM, HTN, and CKD What is the next step? A. Stage her CKD B. Reassure her that the albuminuria and A1C are not significant C. Repeat the UA in 6 weeks and if present quantify* D. Refer for kidney biopsy E. Refer to endocrinologist

Stages of CKD 2002 KDIGO CKD Guidelines, AJKD Supplement, 2002 Stages of CKD 2013 KDIGO 2012 Clinical Practice Guideline for the Evaluation and Management of CKD, Kidney International, Jan 2013, Vol 3, Issue 1

Trends in adjusted* ESRD incidence rate (per million/year), by primary cause of ESRD, in the U.S. population, 1996-2014 USRDS 2016 Annual Report, Vol 2, ESRD, Ch1 Estimated prevalence of self-reported kidney disease by state (%), 2014 USRDS 2016 Annual Report, Vol 1, CKD, Ch1 Ralph 35 y/o male with Hx HTN and DM well controlled with meds X 10 years. Father had CKD 2/2 ESRD requiring dialysis 2/2 HTN and DM. Ralph is worried he is at increased risk for developing CKD and needing dialysis PE: 120-125/70 X 3 readings, no edema, no SOB What is your next step? A. Refer for more lab work* B. Refer to kidney biopsy C. Add ACEi or ARB D. Refer for genetic testing APOL1

CKD Risk Factors Diabetic Hypertensive/CVD Older age (>60y/o) Recurrent UTI Kidney stones History of AKI Polycystic Kidney Disease Genetics Autoimmune disease: Lupus, Sjogrens, RA, MCTD Family history of CKD Neoplasm: multiple myeloma, Wilms, kidney cancer Previous transplant Previous kidney donor 1. KDOQI guidelines 2002 2. http://www.uspreventiveservicestaskforce.org/uspstf/uspsckd.htm CKD Screening & Evaluation Screening: Renal function panel (S Cr, albumin) Proteinuria assay UA with microscopy Follow up with: Renal Ultrasound Blood borne Pathogens (at least once) Vitamin D, ipth CKD Screening for Proteinuria Urine Protein to Creatinine ratio Used when you expect higher degrees of proteinuria Usually lab gives you a Random Total Protein (mg/dl), Random Creatinine (mg/dl) Protein/Creatinine = UPCR Usually represented as g/g (0.5 g/g, 2 g/g, etc) Urine Albumin to Creatinine ratio More accurate when there is <1-2 g proteinuria; BEST SCREENING LAB Usually lab gives you Random Albumin (mcg/ml), Random Creatinine (mg/dl), and UACR Usually represented as mg/g 24 hour urine - Gold Standard?

Lois 65 y/o with HTN, HLD, DM PMH: retinopathy, nephropathy, neuropathy PE: 150/88, trace edema, RRR, CTA Labs: SCr 2.3mg/dL (GFR 29ml/min), K 4.5 BUN 45, BG 142, A1C 6.5%, UACR 1700mg/g Meds: glargine (Lantus), lispro (Humalog), lisinopril, furosemide (lasix), atorvastatin What adjustments would you make to her management? A. None, she is stable B. Increase the lispro C. Increase the lisinopril* D. Increase the atorvastatin Proteinuria BEST PREDICTOR OF PROGRESSION Check at least annually in DM patients to screen Check every 6-12 months in CKD patients Goal: as low as possible Ideally <0.5 g/g Partial remission: 0.2-2 g/g Complete remission: <0.2 g/g Albuminuria As Risk Factor The relationship between magnitude of proteinuria reduction and the risk of ESRD: Results of the AASK study of kidney disease and hypertension Ach Intern Med 2001 Proteinuria and Rate of Change in Kidney Function in a Community Based Population, JASM 2013 The Progression of CKD: A 10-year population-based study of the effects of gender and age. KI 2006 Combining GFR and albuminuria to classify CKD improves prediction of ESRD, JASN 2009 Alberta Kidney Disease Network: Relation between kidney function, proteinuria, and adverse outcomes, JAMA 2010

Renin-Angiotensin-Aldosterone System (RAAS) Inhibition of RAAS: leads to less proteinuria 1. ACEIs Block conversion of angiotensin I Renin to angiotensin II Increase availability of Angiotensin I Angiotensinogen bradykinin ACE 2. ARBs Selectively antagonize angiotensin II May also modulate the effects of angiotensin II breakdown products + Angiotensin II Aldosterone RAAS inhibition provides nephroprotection independent of blood pressure lowering Weir MR. Clin Ther. 2007;29(9):1803-1824. Main Diabetic CKD Goals Blood Pressure Control ACCORD: 140/90 SPRINT: 120/80 KDIGO: <140/90, <130/80 with proteinuria Keep the patient and the med list in mind! Glycemic Control Proteinuria Reduction CVD management Kills more than CKD SHARP trial: Vytorin benefits CKD patients Lipid panel less indicative of true CV risk - set it and forget it Name of the Game: Slow it down, delay progression of CKD! Sherman 55 y/o with family history of HTN and DM BP trending up into the 140-165/85-90 range S Cr 1.6mg/dL (GFR 58) & UACR 400mg/g Which of the following is the best HTN medication for Sherman? A. Loop diuretics B. Thiazide diuretics C. ACE inhibitors* D. ARB inhibitors* E. Calcium channel blockers F. Beta blockers

Rose 74 y/o routine visit, PMH: PVD, HL, HTN, Meds: metoprolol, HCTZ, amlodipine, ASA, atorvastatin PE: 168/98, home 150-160s Labs: SCr 1.2mg/dL, UACR 50mg/dL, GFR 56ml/min 2 weeks ago, lisinopril added for BP/UACR lowering F/U labs: 2 weeks later reveal SCr 1.4mg/dL with K 5.4mEq/L. BP 150/90 What is the cause of the rise in SCr? A. Medication induced AIN B. Renovascular Disease (RAS) C. Rhabdomyolysis from statins D. Usual rise from ACE inhibitor* E. Essential hypertension Rose 74 y/o routine visit PMH: PVD, HL, HTN, Meds: metoprolol, HCTZ, amlodipine, ASA, atorvastatin PE: 168/98, home 150-160s Labs: SCr 1.2mg/dL, UACR 50mg/dL, GFR 56ml/min 2 weeks ago, lisinopril added for BP/UACR lowering F/U labs: 2 weeks later reveal SCr 1.4mg/dL. BP 150/90 Acceptable rise in SCr due to RAAS What is the cause of the rise in SCr? is 20-25% A. Medication induced AIN B. Renovascular Disease (RAS) C. Rhabdomyolysis from statins D. Usual rise from ACE inhibitor E. Essential hypertension Fred 81 y/o poorly controlled DM x 20 years, bilateral BKA, often forgets meds, has passing acquaintance with diabetic diet, has issues w/ exercise due to chronic leg ulcers Labs: A1C historically 11.5-12% most recent A1C 7.5%, GFR 20ml/min Meds: metformin, lisinopril, furosemide, ASA, atorvastatin Why is his A1C closer to goal now? A. McDonald's has changed their menu B. A1C is not reliable at lower GFRs* C. He doubled his metformin D. He has taken up marathon running

KDOQI Goals in 2014 Evidence that intensive treatment has an effect on loss of glomerular filtration rate (GFR) is sparse* 2.1: We recommend a target HbA1c of 7.0% to prevent or delay progression of the microvascular complications of diabetes, including DKD. (1A) 2.2: We recommend not treating to an HbA1c target of <7.0% in patients at risk of hypoglycemia. (1B) 2.3: We suggest that target HbA1c be extended above 7.0% in individuals with co-morbidities or limited life expectancy and risk of hypoglycemia. (2C) *NKF-KDIGO Clinical Practice Guideline for Diabetes and CKD, Guideline 2: Management of Hyperglycemia and General Diabetes Care in CKD, AJKD, Vol 60, #5, Nov 2012 Sadie 85 y/o Type 2 DM, HTN, CKD. Meds: metformin 1000mg BID Labs: Scr 1.7mg/dl (historical 1.3mg/dL), egfr 31ml/min, A1C 7.0% What is the next step in management of DM? A. Decrease metformin* B. Discontinue metformin C. Add insulin D. Discontinue metformin and start insulin Metformin Dosing SCr Race Age egfr CKD Stage Male 1.5 Male 1.5 African American 17 78 2 African American 70 54 3a Female 1.5 white 17 50.7 3a Female 1.5 white 70 35 3b GFR using CKD-EPI equation

Metformin in CKD Now approved by the FDA for lower GFR s Non-Insulin Agents & CKD/Dialysis Incretin mimetics - not recommended for moderate/severe renal impairment (late stage 3 and onward) Hypoglycemia is the largest concern for lower GFR s Incretins and SGLT-2 Inhibitors DPP-4 inhibitors - have showed reductions in albuminuria and Victoza - cardioprotection and renoprotection in the LEADER trial SGLT-2 - have demonstrated ability to decrease BP, weight, uric acid, and albuminuria beyond what can be explained by its glycemic effect

SGLT-2 Inhibition EMPA-REG: ~7000 diabetics empagliflozin vs placebo Similar use of ACE/ARB in both groups Initial drop in GFR seen in empagliflozin group (wk 1-4), then later showed stable GFR with empagliflozin vs declining GFR with placebo Significant relative risk reduction in progressing albuminuria CANATU-SU: >1000 diabetics canagliflozin vs glimepiride Initial drop in egfr, then stabilized & declines slower with canagliflizin at either dose Canagliflozin significantly reduced albuminuria, mostly with patients who started with positive UACR Results were independent of A1c reductions SGLT2 inhibition for CKD, not DM?? JASN August 2016 Canagliflozin Slows Progression of Renal Function Decline Independently of Glycemic Effects. Heerspink, et, al, JASN August 2016 CKD and Insulin All types are safe and effective for All Stages of CKD Basal Insulin is VERY easy to dose in CKD Basal Insulin with Oral Medications is fine CKD Patients including Dialysis may use pumps Dosing Requirements decrease with decreasing Kidney Function Decreasing Dosing Requirements are NOT logarithmic no matter what you may have read...

http://kdigo.org/home/ https://www.kidney.org https://www.aace.com/ publications/guidelines References 1. Brazie M. National Kidney Foundation Spring Clinical Meetings, April 2011 2. Daugirdas JT. Handbook of Chronic Kidney Disease Management. Philadelphia, PA: Wippincott Williams & Wilkins; 2011. 3. Chertow GM, Beddhu S, Lewis JB, Toto RD, Cheung AK. Managing hypertension in patients with CKD: a marathon, not a SPRINT. JASN. 2016 Jan;27(1):40-3. 4. Cushion WC et al. Effects of intensive blood pressure control in type 2 diabetes: the ACCORD study group. N Engl J Med 2010;362:1575-85. 5. de Boer IH, Kahn SE. SGLT2 inhibitors - sweet success for diabetic kidney disease? J Am Soc Nephrol. 2017 Jan;28(1):7-10. 6. FDA packet inserts (medications). 7. Flynn C, Bakris GL. Noninsulin glucose-lowering agents for the treatment of patients on dialysis. Nature Reviews Nephrology. 2013 Mar; 9: 147-153. 8. Gilbert SJ et al. National Kidney Foundation s Primer on Kidney Diseases. 6th ed. Philadelphia, PA: Elsevier Saunders; 2014. 9. Goff DC Jr, et al. 2013 ACC/AHA guideline on the assessment of cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2013;00:000 000. 10.Gupta D. Contemporary treatment of diabetes. Oral presentation at Saint Louis University Division of Nephrology. March 2017; Saint Louis, MO. 11.Heerspink HJL et al. Canagliflozin slows progression of renal function decline independently of glycemic effects. J Am Soc Nephrol. 2017 Jan;28(1):368-375. 12.James PA et al. 2014 Evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the eighth joint national committee (JNC 8). JAMA. 2013. doi:10.1001/jama.2013.284427 13.Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO 2012 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. Kidney inter., Suppl. 2013; 3: 1-150. 14.Kidney Disease: Improving Global Outcomes (KDIGO) Blood Pressure Work Group. KDIGO Clinical Practice Guideline for the Management of Blood Pressure in Chronic Kidney Disease. Kidney Inter., Suppl. 2012; 2: 337-414. 15.Kidney Disease: Improving Global Outcomes (KDIGO) Lipid Work Group. KDIGO Clinical Practice Guideline for Lipid Management in Chronic Kidney Disease. Kidney Inter., Suppl. 2013; 3: 259 305. 16. Kidney Disease Statistics for the United States. National Institute of Diabetes and Digestive and Kidney Diseases. https://www.niddk.nih.gov/health-information/ health-statistics/pages/kidney-disease-statistics-united-states.aspx. Accessed April 2, 2017. 17.Liles A. Medication Considerations for Patients With Chronic Kidney Disease Who Are Not Yet on Dialysis, Nephrology Nursing Journal 2011 18.Link DK. Chronic kidney disease: new paradigms in diagnosis and management. JAAPA. 2015; 28 (7): 23-28. 19.Making sense of CKD: a concise guide for managing chronic kidney disease in the primary care setting. National Kidney Disease Education Program. July 2014. NIH Publication No. 14-7989. Available at: http://nkdep.nih.gov/resources/ckd-primary-care-guide-508.pdf 20.Mende CW. Diabetes and kidney disease: the role of sodium glucose cotransporter-2 (SGLT-2) and SGLT-2 inhibitors in modifying disease outcomes. Current Medical Research and Opinion. 2017; 33:3, 541-551. 21.Narva A. National Kidney Disease Education Program, NIH, Steering Committee meetings, 2013 22.Navaneethan SD et al. Diabetes control and the risks of ESRD and mortality in patients with CKD [published online ahead of print February 10, 2017]. AJKD. doi: 10.1053/j.ajkd.2016.11.018. 23.Perkovic V et al. Intensive glucose control improves kidney outcomes in patients with type 2 diabetes, Kidney International 2013 Mar;83(3):517-23. 24.Rodby RA. Timed urine collections for albumin and protein: the king is dead, long live the king! Am J Kidney Dis. 2016 Dec;68(6):836-838. 25.Schmitz P. Renal: An Integrated Approach. New York, NY: McGraw Hill; 2012. 26.Sinha AD, Agarwal R. The complex relationship between CKD and ambulatory blood pressure patterns. Advances in Chronic Kidney Disease. 2015(22)2:102-7. 27.Tonelli M, Wanner C and members of KDIGO Lipid Guideline Development Work Group. Lipid management in chronic kidney disease: synopsis of the kidney disease: improving global outcomes 2013 clinical practice guideline. Ann Intern Med. 2014; 160: 182-189. 28.United States Renal Data System. 2016 USRDS annual data report: Epidemiology of kidney disease in the United States. National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, 2016. 29.Wanner C et al. Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med. 2016; 375:323-334. 30.Wright JT et al. A randomized trial of intensive versus standard blood-pressure control: the SPRINT research group. NEJM. 2015; 373(22): 2103-16.