Identify Diabetic Kidney Disease Burden pathophysiology and evaluation

Identify Diabetic Kidney Disease Burden, pathophysiology and evaluation of diabetic kidney disease Andrew S Narva, MD, FACP, FASN Theresa A Kuracina, MS, RD, CDE

Objectives • Review the association of kidney function with estimated glomerular filtration rate (e. GFR); and kidney damage with urine albumin-tocreatinine ratio (UACR). • Recognize abnormal urine albumin (albuminuria) as a continuous risk factor for kidney disease progression in diabetes. • Define the basic evaluation of kidney disease. • Articulate the interventions (medications, lifestyle, diet) that may reduce albuminuria. Slide 2 of 53

Risk factors for Chronic Kidney Disease (CKD) • Diabetes • Hypertension • Family history of kidney disease • Cardiovascular disease • Obesity • Acute kidney injury Slide 3 of 53

Kidney ANATOMY and Physiology Slide 4 of 53

Kidneys and the Collecting System • Kidneys • Ureters • Bladder • Urethra Slide 5 of 53

The Nephron • Glomerulus • Proximal tubule • Loop of Henle • Distal tubule • Collecting duct Slide 6 of 53

The Kidneys Maintain Balance • They have a regulatory function: § Control composition and volume of blood § Maintain stable concentrations of inorganic anions such as sodium (Na), potassium (K), and calcium (Ca) § Maintain acid-base balance • They have an excretory function: § Remove metabolic wastes § Including nitrogenous waste § Produce urine Slide 7 of 53

The Kidneys Have Other Functions • Their hormonal function affects many systems: § Produce renin for blood pressure control § Produce erythropoietin which stimulates marrow production of red blood cells § Activate 25(OH)D to 1, 25 (OH)2 D (active vitamin D) needed for bone health • They have metabolic functions: § Gluconeogenesis § Metabolize drugs and endogenous substances (e. g. , insulin) Slide 8 of 53

CKD Is Reduced Kidney Function and/or Kidney Damage • CKD • Kidney function • Glomerular filtration rate (GFR) < 60 m. L/min/1. 73 m 2 for > 3 months with or without kidney damage AND/OR • Kidney damage • > 3 months, with or without decreased GFR, manifested by either • Pathological abnormalities • Markers of kidney damage, i. e. , proteinuria (albuminuria) • Urine albumin-to-creatinine ratio (UACR) > 30 mg/g Reference: Kidney International Supplements, 2013; 3(1): 5 -14 Slide 9 of 53

Diagnosing Kidney Disease I. Assess KIDNEY FUNCTION Slide 10 of 53

What is the GFR? • The GFR is equal to the sum of the filtration rates in all of the functioning nephrons. • GFR is not routinely measured in clinical settings. • An estimation of GFR (e. GFR), using serum creatinine level, gives a rough measure of the number of functioning nephrons. Slide 11 of 53

What is the GFR? • Cardiac output (CO) = 6 L/min • x 20% of CO goes to kidneys = 1. 2 L/min • x Plasma is 50% blood volume = 600 m. L/min • x Filtration Fraction of 20% = 120 m. L/min Slide 12 of 53

Estimating Equations for e. GFR • The Modification of Diet in Renal Disease (MDRD) and CKD Epidemiology (CKD-EPI) equations are most widely used for estimating GFR. • The variables include serum creatinine (Scr), age, race, and gender. • MDRD e. GFR = 175 x (Scr) -1. 154 x (age) -0. 203 x (0. 742 if female) x (1. 212 if African American) • CKD-EPI e. GFR = 141 × min (Scr /κ, 1)α × max (Scr /κ, 1)-1. 209 × 0. 993 age × (1. 018 if female) × (1. 159 if African American) • The estimate is normalized to body surface area. Slide 13 of 53 References: Levey et al. Ann Intern Med. 1999; 130: 461– 470; Levey et al. Ann Intern Med. 2009: 150: 604– 612.

e. GFR Estimates the Measured GFR • e. GFR is not the measured GFR. • e. GFR provides an estimate of GFR which is within +/- 30% of the measured GFR in approximately 85% of people. • MDRD and CKD-EPI results are based on serum creatinine levels. • Previous methods to estimate kidney function also are based on serum creatinine. Slide 14 of 53

Creatinine-Based Estimates of Kidney Function have Limitations • Results may be inaccurate with: § Rapidly changing creatinine levels § Example: acute kidney injury • Extremes in muscle mass, body size, or altered diet patterns • Medications that interfere with the measurement of serum creatinine • Use of creatine supplements Slide 15 of 53

Serum Creatinine Alone is Not Adequate • Serum creatinine levels reflect muscle mass, age, sex and race. • A typical “normal” reference range of 0. 6– 1. 2 mg/d. L listed on many lab reports does not account for muscle mass, age, sex and race. • A 28 -year-old African American man with serum creatinine of 1. 2 has an e. GFR > 60. • A 78 -year-old white woman with serum creatinine of 1. 2 has an e. GFR of 43. Slide 16 of 53

Decreased Kidney Function versus Kidney Disease • Estimating equations are less reliable at higher GFR. • Kidney function declines with age. • While there is an association between decreased e. GFR and morbidity, even in elderly, this association does not mean causality. • Use diagnostic terms denoting disease with caution, especially in older people without evidence of kidney damage (e. g. elderly with e. GFR 55). Slide 17 of 53

Kidney Function and e. GFR Decline with Age Reference Table for Population Mean e. GFR from NHANES III Age (years) Mean e. GFR (m. L/min/1. 73 m 2) 20– 29 116 30– 39 107 40– 49 99 50– 59 93 60– 69 85 70+ 75 In healthy kidney donors the number of glomeruli per kidney decrease 25% by age 60 -69 and GFR declines proportionately. Reference: Coresh et al. Am J of Kidney Dis. 2003; 41(1): 1– 12. Denic et al. J Am Soc Nephrol. 2017; 28(1): 313– 320. Slide 18 of 53

Explaining GFR Slide 19 of 53

Diagnosing Kidney Disease II. Kidney damage Slide 20 of 53

Urine Albumin is a Marker for Kidney Damage • An abnormal urine albumin level is a marker for glomerular disease, including diabetes. • Urine albumin is a marker for cardiovascular disease and is a hypothesized marker of generalized endothelial dysfunction. • May be associated with increased mortality. Slide 21 of 53

Damaged Kidneys Allow More Albumin to Cross the Filtration Barrier into the Urine • Increased glomerular permeability allows albumin and other proteins to cross the glomerulus into the urine. • Higher levels of protein which exceed the tubule’s capacity to reabsorb that protein may exacerbate kidney damage through injury to the tubules. Slide 22 of 53

Use Urine Albumin-to-Creatinine Ratio (UACR) for Urine Albumin Assessment • UACR uses a spot urine sample. • In adults, ratio of urine albumin to creatinine is used to estimate 24 hour albumin excretion. • Ratio is between two measured substances (not dipstick). • UACR < 30 mg/g is generally the most widely used cutoff for “normal. ” https: //www. niddk. nih. gov/health-information/professionals/clinical-tools-patient-educationoutreach/quick-reference-uacr-gfr Slide 23 of 53

UACR Quantifies All Levels of Urine Albumin • UACR is a continuous variable. • The term albuminuria describes all levels of urine albumin. The modifiers micro and macro are going out of use. • The term microalbuminuria has been used to denote § 30 mg/g – 300 mg/g • The term macroalbuminuria has been used to denote § > 300 mg/g Slide 24 of 53

Which Urine Test to Use? • Dipstick § Semi-quantitative, screening only § Affected by urine concentration, highly variable § Detection of urine albumin > 300 mg/day (1+ approximates albumin excretion of 30 mg/day) • Urine protein/creatinine ratio § All proteins, not just albumin • Urine albumin-to-creatinine ratio (UACR) § Other common names for UACR include microalbumin, urine albumin, albumin-tocreatinine ratio or microalbumin/creatinine ratio. Slide 25 of 53

Confirm High UACR • There is significant variation within individuals. • Diagnosis of kidney injury requires confirmation with a second test. Slide 26 of 53

Risk Factors for Albuminuria Known risks • • Diabetes Hypertension Smoking Obesity Possible risks • High sodium intake • High protein intake • Inflammation Transient increases may be due to: • Episodic hyperglycemia • Exercise within 24 hrs. • Fever • Urinary tract infection References: De Jong et al. Kidney International. 2004; 66: 2109– 2118; Tuttle et al. Diabetes Care; 2014: 37: 2864– 2883 Slide 27 of 53

Lowering UACR may Lower Risk of Progression Reference: De Zeeuw et al. Kidney Int 2004; 65(6): 2309– 2320. Slide 28 of 53

Interventions for Reducing Urine Albumin • Control blood pressure • Reduce sodium intake • Achieve good control of diabetes early; may help prevent albuminuria • Reduce weight, if obese • Reduce protein intake, if excessive • Achieve tobacco cessation Slide 29 of 53

Explaining Urine Albumin Slide 30 of 53

Natural History of Diabetic Nephropathy: Hyperglycemia Causes Hyperfiltration, Followed by Albuminuria and Decreased GFR Reference: Adapted from Friedman, 1999 Slide 31 of 53

Hyperglycemia is Associated with Hyperfiltration • The initial response to hyperglycemia is an increase in GFR, or hyperfiltration, followed by a slow decline. • The increased pressure and flow within the glomerular capillary may damage the nephrons. • Diabetic kidney disease (DKD) is generally, but not always, associated with progressive albuminuria. References: Molitch et al. Diabetes Care 2010; 33(7): 1536– 1543; Retnakaran et al. Diabetes 2006; 55(6): 1832– 1839. Slide 32 of 53

Prevalence of Diabetes; United States 2011 -2014 National Health and Nutrition Examination Survey CDC National Diabetes Statistics Report, 2017 Slide 33 of 53

Prevalence of Diabetic Kidney Disease (DKD) Among Adults with Diabetes; United States, 2005 -2008 Adapted from: De Boer et al. JAMA 2011; 305: 2532– 2539 Slide 34 of 53

10 -Year Mortality in Type 2 Diabetes in the United States Mortality in persons without diabetes or kidney disease *Standardized to age, sex, and race of study population Adapted from: Afkarian et al. J Am Soc Nephrol 2013. 24: 302– 308 Slide 35 of 53

Diabetes is the Leading Cause of ESRD, Followed by Hypertension Reference: USRDS Annual Data Report (NIDDK, 2016) Slide 36 of 53

Trends in ESRD Prevalence by Modality, 1980 -2015 Reference: USRDS Annual Data Report (NIDDK, 2017) Slide 37 of 53

ESRD is Very Costly Reference: USRDS Annual Data Report (NIDDK, 2017) • • • Hemodialysis $ 26. 7 billion ($88, 195 per patient) Peritoneal Dialysis $ 2. 1 billon ($75, 140 per patient) Transplantation $ 3. 3 billion ($34, 800 per patient) ESRD data do not include Medicare Part D cost Slide 38 of 53 Reference: USRDS Annual Data Report (NIDDK, 2017)

Once CKD is Identified, Further Evaluation Is Needed and Often Includes: • Basic panel including glucose, creatinine, blood urea nitrogen, electrolytes, albumin, calcium and phosphorus • Fasting lipid panel • Complete blood count • Complete urinalysis • Screening serologies • Renal ultrasound • Dilated retinal exam • A 1 C • Additional data may include iron studies, 25(OH) vitamin D and intact parathyroid hormone (i. PTH) Slide 39 of 53

Diabetes Is the Most Likely Cause of CKD IF: • Albuminuria is present. • Diabetic retinopathy is present. • The patient has diabetes of at least 10 years duration. However, kidney disease in diabetes may manifest differently in different people. In the future, individualized treatment may be guided by kidney biopsy and advanced biochemical or genetic testing. Am J Kidney Dis. 2012; 60(5): 850 -886 Clin J Am Soc Nephrol. 2017; 12(9): 1544 -1547 Slide 40 of 53

SELF-ASSESSMENT: COULD THIS BE KIDNEY DISEASE DUE TO DIABETES? Slide 41 of 53

Could This Be Kidney Disease Due to Diabetes? 65–year–old man with DM 2 for 25 years and Retinopathy He may have diabetic kidney disease: he has long term diabetes, and both retinopathy and albuminuria. Slide 42 of 53

Could This Be Kidney Disease Due to Diabetes? 69–year–old Woman with DM 2 for 15 years, without Retinopathy, Lupus for 4 years Probably not, she has normal urine albumin and no retinopathy. Slide 43 of 53

Could This Be Kidney Disease Due to Diabetes? 28–year–old woman with DM 1 for 9 years, Retinopathy for 4 years She may have diabetic kidney disease: she has both retinopathy and albuminuria. Slide 44 of 53

Could This Be Kidney Disease Due to Diabetes? 40–year–old woman with history of GDM, DM 2 for 5 years, background Retinopathy She may have diabetic kidney disease: she has very high levels of albuminuria. Slide 45 of 53

Key Issues in Managing DKD • Ensure the diagnosis is correct § Assess UACR and e. GFR • Implement appropriate therapy • Monitor progression • Screen for CKD complications • Educate the patient about DKD • Prepare appropriately for kidney failure Slide 46 of 53

Much of the Necessary Care May be Managed in the Primary Care Setting • Many CKD interventions are similar to those for diabetes care. • Other key interventions include co-morbidity screening. • Timing of nephrology referral varies depending on patient status and provider experience. § Lack of appropriate care is associated with more rapid progression, worse health status at time of dialysis initiation, higher mortality after starting dialysis, and decreased access to transplant. • Refer to a Registered Dietitian who is familiar with CKD for Medical Nutrition Therapy. Slide 47 of 53

Considerations for Nephrology Referral • Prepare for renal replacement therapy, especially when e. GFR is less than 30. • Assist with diagnostic challenges. • Rapid decrease of e. GFR. • Assist with therapeutic challenges related to CKD complications such as blood pressure, anemia, abnormal mineral metabolism and bone disorders, hyperkalemia, hyperphosphatemia, malnutrition, and secondary hyperparathyroidism. • Assist with acute kidney injury. Slide 48 of 53

Identify Diabetic Kidney Disease (DKD) • Albuminuria may be the first sign of DKD. • • Confirm abnormal levels. Recommend annual urine and blood tests. • Check UACR to assess kidney damage. • • A spot urine sample can be used. A normal level is less than 30 milligrams per gram. • Check e. GFR to assess kidney function. • • • Serum creatinine, age, gender and race are needed. An e. GFR less than 60 identifies kidney disease. An e. GFR less than 15 identifies kidney failure. Slide 49 of 53

https: //www. niddk. nih. gov/health-information/professionals/clinical-to -patient-education-outreach/explain-kidney-test-results Slide 50 of 53

Congratulations! You learned how to identify kidney disease using GFR and UACR. https: //www. niddk. nih. gov/-/media/Files/Health-Information/Communication. Programs/NKDEP/kidney-test-results-508. pdf Slide 51 of 53

NKDEP Tools to Share with Other Providers • Quick Reference on GFR and UACR in Evaluating Patients with Diabetes for Kidney Disease: https: //www. niddk. nih. gov/health-information/professionals/clinicaltools-patient-education-outreach/quick-reference-uacr-gfr • Identify & Manage Patients with CKD: https: //www. niddk. nih. gov/healthinformation/communication-programs/nkdep/identify-manage-patients • Nephrology Referral form: https: //www. niddk. nih. gov/healthinformation/communication-programs/nkdep/identify-manage-patients/manageckd/collaborate-nephrologist Slide 52 of 53

Congratulations! You have completed module 1 Slide 53 of 53