Chronic Kidney Disease for the Primary Care Physician in What do the Kidneys do? CKD in the US

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1:25-2:25pm Managing Chronic Kidney Disease in 2019 SPEAKERS Adriana Dejman, MD Chronic Kidney Disease for the Primary Care Physician in 2019 Adriana Dejman, MD Assistant Professor of Clinical

1 1:25-2:25pm Managing Chronic Kidney Disease in 2019 SPEAKERS Adriana Dejman, MD Chronic Kidney Disease for the Primary Care Physician in 2019 Adriana Dejman, MD Assistant Professor of Clinical Medicine Katz Family Division of Nephrology and Hypertension University of Miami Miller School of Medicine What do the Kidneys do? Eliminate the nitrogenous waste products of metabolism (urea, creatinine) Maintain balance for water and electrolytes (Na +, phos, K +, H+, etc.) Endocrine activity (Vitamin D, erythropoietin, renin, prostaglandins) Produce vasoactive compounds (i.e., prostaglandins, nitric oxide, angiotensin II, endothelin) CKD in the US The 9 th leading cause of death ~26 million adults estimated to have CKD ~80,000 patients receive a new diagnosis of CKD annually >500,000 patients receive maintenance dialysis to sustain life Medicare spending for CKD > $64 billion 2015 $34 billion dollars spent on ESRD care Centers for Medicare and Medicaid Services (CMS). Medicare & Medicaid Statistical Supplement: 2013 Edition. Statistics Data and Systems/Statistics Trends and Reports/MedicareMedicaidStatSupp/2013.html. Accessed July 12, 2017.

2 Definition Kidney damage for >3 months, as defined by structural or functional abnormalities of the kidney, with or without decreased GFR, manifest by either, Pathological abnormalities of the kidney i.e. abnormal imaging tests of the kidneys ( i.e. ultrasound) Or Markers of kidney damage, including abnormalities in the composition of the blood or urine i.e. albuminuria Or GFR <60 ml/min/1.73m 2 for > 3 months, with or without markers of kidney damage This definition is INDEPENDENT of the cause of CKD Chapter 1: Definition an Classification of CKD. Kidney In Suppl (2011). 2013; 3(1):19. GFR Diagnosis Structural CKD Albuminuria It is the average filtration rate of each single nephron x # nephrons in both kidneys. Affected by age, sex, body size, physical activity, medications, diet. Normal: 120 & 130 ml/min/1.73m2 (young women and men respectively). Lesley A., Levey A. Chapter 3. NKF Primer on Kidney Disease: Assessment of Glomerular Filtration Rate in Acute and Chronic Settings. 6th Edition, Measurement of GFR egfr calculation for Determination of CKD In AKI, the serum creatinine is used for diagnosis and classification In CKD, the GFR is used for diagnosis and classification Collect a 24 hour urine sample Time consuming Inaccurate Inconvenient Use a mathematical formula to immediately estimate it : egfr Lesley A., Levey A. Chapter 3. NKF Primer on Kidney Disease: Assessment of Glomerular filtration Rate in Acute and Chronic Settings. 6th Edition, hour urine for creatinine clearance Cockcroft and Gault formula (140 age)*wgt (Kg) / (72 * SCr) MDRD Formula 186 * cr (mg/dl ) * age.203 * (if black) *.742 (if female) CKD EPI Formula (only formula for GFR > 60) (creatinine/0.9) (0.993) age ( 166 if black) x (female) Lesley A., Levey A. Chapter 3. NKF Primer on Kidney Disease: Assesment of Glomerular filtration Rate in Acute and Chronic Settings. 6th Edition, 2014.

Estimation of GFR Important concepts For any given serum creatinine Males have a higher GFR than females Younger patients have a higher GFR than older patients Black patients have a higher GFR than

NKF Primer on Kidney Disease: Assessment of Glomerular filtration Rate in Acute and Chronic Settings. 6th Edition, 2014.

Damage Urine sediment abnormalities (tubular cells/casts) Electrolyte and urine abnormalities caused by tubular disorders ( i.e., RTA, Fanconi s, DI) History of kidney transplantation Normal Cystic Scarred/Contracted Lesley A.

3 Estimation of GFR Important concepts For any given serum creatinine Males have a higher GFR than females Younger patients have a higher GFR than older patients Black patients have a higher GFR than Caucasians Clinical application GFR defines and stages CKD, therefore its estimation is needed to detect, evaluate and manage CKD. GFR Structural CKD Albuminuria Lesley A., Levey A. Chapter 3. NKF Primer on Kidney Disease: Assessment of Glomerular filtration Rate in Acute and Chronic Settings. 6th Edition, Markers of Kidney Damage Structural (examples) Multiple renal cysts Kidneys with scars (pyelonephritis) or small size, asymmetry in kidney sizes Presence of only one kidney Other: Markers of Kidney Damage Urine sediment abnormalities (tubular cells/casts) Electrolyte and urine abnormalities caused by tubular disorders ( i.e., RTA, Fanconi s, DI) History of kidney transplantation Normal Cystic Scarred/Contracted Lesley A., Levey A. Chapter 53. NKF Primer on Kidney Disease: Staging and Management of Chronic Kidney Disease. 6th Edition, Lesley A., Levey A. Chapter 53. NKF Primer on Kidney Disease: Staging and Management of Chronic Kidney Disease. 6th Edition, 2014.

Structural Albuminuria >30mg/day Independent of GFR or structural defects GFR CKD Albuminuria Collection method: spot ratio UACR (mg/d) A1: <30 mg/d A2: 30 300 mg/d A3: >300 mg/d Evaluate CKD risk

4 Structural Albuminuria >30mg/day Independent of GFR or structural defects GFR CKD Albuminuria Collection method: spot ratio UACR (mg/d) A1: <30 mg/d A2: mg/d A3: >300 mg/d Evaluate CKD risk factors Start measures to reduce CVD risk RAAS blockade and treat BP to goal Treat Nephrotic Sd. if present Lesley A., Levey A. Chapter 53. NKF Primer on Kidney Disease: Staging and Management of Chronic Kidney Disease. 6th Edition, Levey A. et al. The definition, classification, and prognosis of chronic kidney disease: a KDIGO Contraversies report. Kidney Int. 2011; 80:17 Outcomes of CKD Kidney Outcomes CKD progression (GFR decline and worsening albuminuria) GFR: + Albuminuria: +++ We recommend that CKD is classified based on cause, GFR category, and albuminuria category. Staging of CKD National Kidney Foundation Classification of Chronic Kidney Disease GFR: 90 ml/min/ Normal or high G1 GFR: ml/min/ Mildly decreased G2 GFR: ml/min/ Mildly to moderately decreased G3a Complications (Current and Future) CVD and mortality GFR: +++ Albuminuria: +++ GFR: ml/min/ Moderately to severely decreased G3b GFR: ml/min/ Severely decreased G4 GFR: <15 ml/min/ Kidney failure G5 Lesley A., Levey A. Chapter 53. NKF Primer on Kidney Disease: Staging and Management of Chronic Kidney Disease. 6th Edition, M van der Velde et al.: Lower egfr and higher albuminuria as risk factors for mortality. Kidney International (2011) 79, KDIGO 2012 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. Kidney International Supplements (2013) 3, 5 14; doi: /kisup

5 Rationale for GFR <60 ml/min/1.73 m 2 Rationale for GFR <60 ml/min/1.73 m 2 Rate of decline 0.1 cc/min/yr < 40 years old Rate of decline 0.8 cc/min/yr > 40 years old L. Wesson, Physiology of the Human Kidney, Grune & Stratton, New York, NY, USA, M van der Velde et al.: Lower egfr and higher albuminuria as risk factors for mortality. Kidney International (2011) 79, Age standardized Rate per 100 person yr Rate of Death from Any Cause Rationale for GFR categories <15 Estimated GFR, ml/min/ Rate of Cardiovascular Events <15 Estimated GFR, ml/min/ Rate of Hospitalization <15 Estimated GFR, ml/min/ Prognosis of CKD by GFR and Albuminuria Categories: KDIGO 2012 Green: Low risk (no CKD if no other markers of kidney disease) Yellow: Moderately increased risk Orange: High risk Red: Very high risk AS Go, et al. New Engl J Med 2004; 351:1296 KDIGO 2012 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. Kid Int Supplements (2013) 3, 5 14.

Kid Int Supplements (2013) 3, 63 72 Conceptual Model of Chronic Kidney Disease

6 Causes of CKD in the US KDIGO 2012 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. Kid Int Supplements (2013) 3, Conceptual Model of Chronic Kidney Disease Complications or Death Management of CKD Normal Increased risk DAMAGE GFR ESRD Death Asymptomatic Levey et al AJKD 2009: S4 Symptoms

7 Stages in Progression of Chronic Kidney Disease and Therapeutic Strategies Normal Screening for CKD & CKD risk reduction Increased risk Primary Prevention DAMAGE GFR Diagnosis & Treatment Treat comorbidities to decrease mortality & to slow progression; Treat complications Prepare for RRT Secondary Prevention Complications or Death ESRD Replacement by dialysis & transplant Death Tertiary Prevention Risk Factors for the Development of Progression of Kidney Disease MODIFIABLE Proteinuria HTN AKI Obesity HLD Smoking High protein diet Metabolic acidosis Hyperphosphatemia Hyperuricemia NON MODIFIABLE Male gender Older age Family Hx of DM, CKD, ESRD Low birth weight Cause (e.g., Diabetic Kidney Disease) AA or Native American Race Lesley A., Levey A. Chapter 52. NKF Primer on Kidney Disease: Pathophysiology of Chronic Kidney Disease. 6th Edition, Trends in prevalence of recognized CKD, by race, among Medicare patients aged 65+, Black Race as a Risk Factor for CKD To survive Trypanosomiasis in Africa, a mutation had to occur on chromosome 22 Affects the gene for Apolipoprotein L1 This mutation confers resistance to Trypanosomiasis However.. Mutation present in 35% of people of Black Race in the U.S. Data Source: Special analyses, Medicare 5 percent sample. Abbreviation: CKD, chronic kidney disease; Af Am, African American; Native Am, Native American. Mutation leads to progressive scarring and injury to the kidney especially when exposed to Hypertension or Diabetes Slide courtesy of Dr WL Kupin

Initial Evaluation of Patients with CKD Obtain serum creatinine to calculate egfr (estimated GFR by a mathematical formula as compared to measuring a creatinine clearance) Measure albumin/creatinine

8 Initial Evaluation of Patients with CKD Obtain serum creatinine to calculate egfr (estimated GFR by a mathematical formula as compared to measuring a creatinine clearance) Measure albumin/creatinine ratio in first AM (morning sample) or random urine Examine the urine sediment for RBCs, WBCs, and cellular casts Imaging study of kidneys Ultrasound (always!) Serum electrolytes (Na, K, Cl, HCO 3,) and chemistries (calcium, phosphorous) Check hemoglobin Measure parathyroid hormone level (PTH) Key Issues in the Management of Chronic Kidney Disease Treat any reversible causes of renal dysfunction (i.e. volume depletion, AKI) Prevent or slow the progression of disease Treat the complications of kidney failure Prepare the patient for renal replacement therapy (i.e., dialysis or transplantation) Reversible Factors Contributing to a Temporary Reduction in Kidney Function (AKI) Management of progression and complications of CKD Dehydration and/or volume depletion Overuse of diuretics Accelerated hypertension Heart failure with poor renal perfusion Nephrotoxic substances (IV contrast, NSAIDs) Urinary tract infection/obstruction

9 Progression of Kidney Disease Despite the many diseases that can initiate kidney injury, there appears to be a limited number of common final pathways for kidney disease progression. A general theme of many of these pathways is that adaptive changes in the nephron may lead to maladaptive long term consequences The effort of the kidney to correct a low GFR may eventually lead to progression of renal failure MALAdaptations to CKD The maintenance of the volume and composition of the ECF is the primary function of the kidneys and is remarkably well preserved until late in the course of CKD Nephron hypertrophy and hyperfunction combine to compensate for the loss of functioning nephrons There is no capacity to generate new nephrons/tubules after embryogenesis No Hyperplasia just Hypertrophy! Whittier, W and Lewis, E. Chapter 52. NKF Primer on Kidney Disease: Pathophysiology of Chronic Kidney Disease. 6th Edition, Whittier, W and Lewis, E. Chapter 52. NKF Primer on Kidney Disease: Pathophysiology of Chronic Kidney Disease. 6th Edition, Intact Nephron Hypothesis GFR 100 cc/min 1 million nephrons Loss of 50% of nephrons Loss of 50% of nephrons GFR 50 cc/min 500,000 nephrons GFR 75 cc/min 500,000 nephrons Compensatory Hyperfiltration Increased Renal Afferent Vasodilation PGE2/PGI2, NO Increased Renal Efferent Vasoconstriction Angiotensin II Increased Intraglomerular Pressure BUN 10 mg/dl BUN 20 mg/dl BUN 15 mg/dl Increased single nephron GFR!!! Increased stretch on glomerular capillaries Glomerular growth (hypertrophy) Normal What should happen in CKD! What really happens in CKD Increased single nephron GFR

Consequences of CKD Other Complications of CKD Intraglomerular Hypertension Glomerular Hypertrophy Short Term Adaptive Benefits Improves GFR Improves GFR Long Term Maladaptive Consequences

10 Consequences of CKD Other Complications of CKD Intraglomerular Hypertension Glomerular Hypertrophy Short Term Adaptive Benefits Improves GFR Improves GFR Long Term Maladaptive Consequences Progressive glomerular scarring Progressive glomerular scarring Cardiac and vascular disease (CVD) Medication dosage Patient safety Infections Hospitalizations Increased ammoniagenesis Prevents Acidosis Progressive interstitial scarring Hypertension in CKD Patients Blood Pressure Goals in CKD Highly Debatable but this is the current KDIGO (2012) recommendation: BP goal 140/90 in CKD without albuminuria Lower BP target of 130/80 for pts with CKD and albuminuria (>30 mg/day) ACC/AHA HTN guidelines JACC,2018:e

in Promoting Compensatory Hyperfiltration CKD Entire glomerulus increases in size Compensatory Hyperfiltration Angiotensin II mediated efferent constriction is the most essential component for

11 Hypertension in CKD Patients The majority of CKD patients are hypertensive and require > 2 drugs to achieve goal BP. Most patients with CKD 3 5 require dietary Na + restriction and a diuretic due to the volume component to their HTN ACC/AHA HTN guidelines JACC,2018:e PGE2 / NO Importance of RAAS Activation in Promoting Compensatory Hyperfiltration CKD Entire glomerulus increases in size Compensatory Hyperfiltration Angiotensin II mediated efferent constriction is the most essential component for increasing intraglomerular pressure and increasing single nephron GFR in CKD Blocking or inhibiting Angiotensin II is of major importance Effect of Inhibition of RAAS in CKD Prevention of Intra glomerular Hypertension Glomerular Hypertrophy Reduces progressive fibrosis and scarring (reduces glomerulosclerosis)

12 Postulated Mechanisms of ACEI/ARB Renoprotection Control of systemic and glomerular pressure Decrease of mesangial deposition of macromolecules Decreased proteinuria/tubule interstitial injury Inhibition of release of TGB b, etc. Inhibition of procollagen formation Slowing Progression of CKD is Possible ACEIs and ARBs are mainstays of therapy Aggressive treatment of hypertension is needed: SBP< 130 & DBP< 80 mmhg with presence of albuminuria Proteinuria should be monitored and the dose of RAAS inhibition increased as needed to maximize the anti proteinuric effect even if the BP is well controlled Yes! BUT!!!! Isn t the GFR going to fall with the use of an ACEI/ARB? Glomerular hyperfiltration is Mal adaptive!! Preventing hyperfiltration will reduce the GFR in the short term but will prevent progressive scarring Patients on ACEI/ARB do experience a slight increase in creatinine but it will stabilize and progressive disease will be prevented (reduced) This is a critical concept!!!

13 Progression of Diabetic Nephropathy The Irbesartan Diabetic Nephropathy Trial (IDNT): ARB better than placebo/ccb Intact Nephron Hypothesis 3.52 ml/min/1.73m2/year 3.76 ml/min/1.73m2/year 2.34 ml/min/1.73m2/year 1 million nephrons 500,000 nephrons 500,000 nephrons Slight early decrease in GFR on ACEI/ARB GFR 100 cc/min GFR 75 cc/min GFR 65 cc/min yearly GFR decline 5 cc/min GFR 25 cc/min After 10 years GFR 45 cc/min After 10 years yearly GFR decline 2 cc/min Slower rate of yearly decline in GFR on ACEI/ARB Evans NDT 2012:2255 Normal Compensatory Hyperfiltration ACEI/ARB Take Home Points CKD EPI is the preferred estimating formula to establish and stage CKD. Early CKD referral to the nephrologist GFR 60 and/or UACR >30mg/g. Albuminuria is correlated with increased mortality. Goal BP for a CKD patient with albuminuria is <130/80 mmhg. ACEI and ARBs are the mainstay of therapy in patients with CKD to slow down its progression.

QUICK REFERENCE FOR HEALTHCARE PROVIDERS

QUICK REFERENCE FOR HEALTHCARE PROVIDERS KEY MESSAGES 1 SCREENING CRITERIA Screen: Patients with DM and/or hypertension at least yearly. Consider screening patients with: Age >65 years old Family history of stage 5 CKD or hereditary kidney disease