Chronic Kidney Disease

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Jeremy Dean
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, Albuquerque, NM Definition of Chronic Kidney Disease

1 Chronic Kidney Disease Current state of management in Primary Care. Jayant Kumar, MD Renal Medicine Assoc., Albuquerque, NM Definition of Chronic Kidney Disease AJKD 2002: 39(2) Stages of Chronic Kidney Disease AJKD 2002: 39(2) 1

2 Prevalence of ESRD has been rising steadily USRDS ADR, 2007 Awareness of Early-Stage CKD Is Low in the US Population Albuminuria: < < < Sex: F M egfr: *Proportion of patients who were told they had weak or failing kidneys, egfr (ml/min/1.73 m 2 ). Coresh et al. J Am Soc Nephrol. 2005:16: The Johns Hopkins University School of Medicine. Diabetes and hypertension are leading causes of kidney failure Incident ESRD rates, by primary diagnosis, adjusted for age, gender, & race. USRDS ADR,

3 61 2 20 F W 1.3 56 3 55 F B 1.3 55 3 50 F W 1.3 46 3 *B = black; W = all ethnic groups other than black.

3 AJKD 2002: 39(2) Why Estimate GFR From SCr, Instead of Using SCr for Kidney Function? Age Gender Race SCr (mg/dl) egfr (ml/min/1.73 m 2 ) CKD Stage 20 M B* M W M W F W F B F W *B = black; W = all ethnic groups other than black. GFR calculator available at: Accessed 3/28/05. Stages of CKD: A Clinical Action Plan AJKD 2002: 39(2) 3

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USRDS ADR, 2007 Diabetes (DM) and hypertension (HTN) often coexist in CKD Distribution of CKD, HTN, & diabetic patients

5 Incidence varies widely by race and ethnicity Af Am Rate per million population N Am Hispanic Asian Non-Hispanic White Incident ESRD patients; rates adjusted for age & gender. USRDS ADR, 2007 Diabetes (DM) and hypertension (HTN) often coexist in CKD Distribution of CKD, HTN, & diabetic patients in Medicare population, USRDS ADR, 2006 CKD is disproportionately costly Distribution of costs for CKD, HTN, & diabetic patients in Medicare population, USRDS ADR,

6 26 million Americans have CKD or albuminuria Coresh, et al., 2007 But few are aware of it even those with egfr less than 30 Coresh, et al., 2007 CKD is prevalent in CVD Patients With CKD (%) 23% 33% 46% CAD CrCl 60 ml/min AMI GFR <60 ml/min CHF GFR 60 ml/min Ix, et al., 2003; Anavekar, et al., 2004; Shlipak, et al.,

408 non-diabetic CKD patients (mean initial GFR=39, mean initial age=52 year old) Levey, et al.

7 In addition to ESRD, CKD leads to CVD Adjusted Hazard Ratio egfr Adjusted* hazard ratio for CVD events Go, et al., 2004 People with CKD do progress to kidney failure especially those middle-aged and younger Long term (7 year) follow up of 408 non-diabetic CKD patients (mean initial GFR=39, mean initial age=52 year old) Levey, et al., 2006 Younger people with CKD are more likely to develop ESRD before death Copyright 2007 American Society of Nephrology Annual mortality by age group and egfr. O'Hare,

We can have an impact on progression of CKD Intensive glycemic control lessens progression from microalbuminuria in Type 1 diabetes goal in Type 2 is less clear - DCCT, 1993 - ACCORD, 2008

, 2001 Blood pressure below 130/80 is beneficial - Sarnak, et al.

8 We can have an impact on progression of CKD Intensive glycemic control lessens progression from microalbuminuria in Type 1 diabetes goal in Type 2 is less clear - DCCT, ACCORD, 2008 Antihypertensive therapy with ACE Inhibitors or ARBs lessens proteinuria and progression - Giatras, et al., Psait, et al., Jafar, et al., 2001 Blood pressure below 130/80 is beneficial - Sarnak, et al., 2005 Incidence of ESRD has leveled off, perhaps because of better use of preventive measures Rate per million population Incident ESRD patients; rates adjusted for age, gender & race. USRDS ADR, 2007 Adherence to treatment guidelines room for improvement The percentage of diabetic CKD patients receiving ACE-Is/ARBs has been slow to improve Percent of patients USRDS ADR,

9 2 simple tests will identify CKD in adults egfr - Estimated GFR from serum creatinine using the MDRD equation UACR - Urine albumin to creatinine ratio on a spot urine sample 24-hour urine collections are NOT needed - Diabetics should be tested once a year. Others at risk can be tested less frequently as long as normal. Estimation of GFR in children MDRD estimating equation is not applicable to children Updated Schwartz formula provides reasonable estimate in children with mild-moderate CKD (GFR ml/min/1.73 m 2 ) Updated Schwartz Formula egfr = k * Ht/S cr Where k=0.4, Ht in cm and S cr in mg/dl and measured by enzymatic methodology Caveats to egfr An estimate based on population data--not the patient s actual GFR Not reliable when used with patients: with GFR above 60 ml/ min/1.73 m 2 with rapidly changing creatinine levels (e.g., acute renal failure in the ICU) with extremes in muscle mass, e.g. cachexia or paraplegia under age 18 8

10 Diabetes The Leading Cause of Kidney Failure Increased Mortality in Patients With Diabetes and CKD: 2-Year Clinical Outcomes Patients (%) DM, - CKD DM, +CKD Medical Cohort DM, + CKD No Events ESRD, CKD Stage 5 Death CKD identified as ICD-9-CM diagnosis code, includes CKD from diabetes, hypertension, obstructive uropathy, and other diagnosis codes reported on USRDS ESRD registration forms. DM = diabetes mellitus; ESRD = end-stage renal disease; ICD-9-CM = International Statistical Classification of Diseases, 9th Revision, Clinical Modification. Collins et al. Kidney Int. 2003;64(suppl 87):S24-S The Johns Hopkins University School of Medicine. 6.1 Proteinuria Predicts Stroke and CHD Events in Patients With Type 2 Diabetes Prot <150 mg/l Prot mg/l Prot >300 mg/l Survival Curves for CV Mortality Overall: P<0.001 Incidence (%) P< Follow-Up (mo) 0 Stroke CHD Events CHD = coronary heart disease; Prot = urinary protein excretion; CV = cardiovascular. Miettinen et al. Stroke. 1996;27: The Johns Hopkins University School of Medicine. 9

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12 Evidence for Effects of Good Glycemic Control on Complications, Including Nephropathy Trial Complication DCCT A1C: (9 7%) N = 1441 Kumamoto (9 7%) N = 110 UKPDS (8 7%) N = 5102 Retinopathy 76% 69% 17-21% Nephropathy 54% 70% 24-33% Neuropathy 60% DCCT = The Diabetes Control and Complications Trial. DCCT Study Group. N Engl J Med. 1993;329: ; Ohkubo. Diabetes Res Clin Prac. 1995;28: ; UKPDS Study Group. Lancet. 1998;352: The Johns Hopkins University School of Medicine. Hypertension The Second Leading cause of Kidney Failure Recommendations for BP and RAS Management in CKD Patient Group Goal BP (mm Hg) First Line Adjunctive + Diabetes <130/80 ACE-I or ARB Diuretics then CCB or BB Diabetes + Proteinuria <130/80 ACE-I or ARB Diuretics then CCB or BB Diabetes Proteinuria <130/80 No specific preference: Diuretics then ACE-I, ARB, CCB, or BB EXPECT TO NEED TO USE 3+ AGENTS TO ACHIEVE GOALS Recommendations largely consistent across JNC 7, ADA, and K/DOQI BP = blood pressure; RAS = renin angiotensin system; CCB = calcium channel blocker; BB = -blocker; JNC 7 = The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. ADA. Diabetes Care. 2005;28(suppl 1); Chobanian et al. JAMA. 2003;289: ; Kidney Disease Outcomes Quality Initiatives (K/DOQI). Am J Kidney Dis. 2004;43(5 suppl 1):S1-S The Johns Hopkins University School of Medicine. 10

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14 ACEI/ARB & Reduced Risk of Rapid GFR Decline, Kidney Failure, or Death AASK (N=1094) RENAAL (N=1513) IDNT (N=1722) -38 Ramipril vs Amlodipine P = Ramipril vs Metoprolol P = Losartan vs Placebo P = Irbesartan vs Placebo Irbesartan P = 0.02 vs Amlodipine P = Wright et al for the AASK Study Group. JAMA. 2002;288: [AASK - African American Study of Kidney Disease and Hypertension] Brenner et al for the RENAAL Study Investigators. N Engl J Med. 2001;345: [RENAAL = Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan] Lewis et al for the Collaborative Study Group. N Engl J Med. 2001;345: [IDNT = Irbesartan in Diabetic Nephropathy Trial.] 2005 The Johns Hopkins University School of Medicine. Relationship Between Achieved BP and GFR MAP = Mean Arterial Pressure* r = 0.69 P< /80 140/90 Untreated Hypertension *MAP = [SBP + (2 DBP)]/3 mm Hg. Summary of 9 studies used in figure. Parving et al. 1989; Viberti et al. 1993; Klahr et al. 1993; Hebert et al. 1994; Lebovitz et al. 1994; Moschio et al. 1996; Bakris et al. 1996; Bakris et al. 1997; GISEN Group Bakris et al. Am J Kidney Dis. 2000;36: The Johns Hopkins University School of Medicine. Anemia Close association with CKD stage 11

15 Anemia Prevalence by CKD Stage NHANES III NHANES Patients With Anemia* (%) CKD Stage *NHANES participants aged 20 y with anemia as defined by WHO criteria: hemoglobin (Hgb) <12 g/dl for women, and Hgb <13 g/dl for men. USRDS 2004 Annual Data Report. The data reported here have been supplied by the USRDS. The interpretation and reporting of these data are the responsibility of the author(s) and in no way should be seen as an official policy or interpretation of the U.S. government. Available at: Accessed 3/28/ The Johns Hopkins University School of Medicine. Anemia Treatment Eligibility Serum Creatinine (2.0 mg/dl or above) or Creatinine Clearance (45 ml/min or below) and Hemoglobin (10g/dl or below) or Hematocrit (30% or below) or Symptoms of anemia Consequences of Anemia in CKD Reduced oxygen delivery to tissues Decrease in Hgb compensated by increased cardiac output Progressive cardiac damage and progressive renal damage 1 Increased mortality risk 2 Reduced quality of life (QOL) 3 Fatigue Diminished exercise capacity Reduced cognitive function Left ventricular hypertrophy (LVH) 4 1. Silverberg et al. Blood Purif. 2003;21: Collins et al. Semin Nephrol. 2000;20: ; 3. The US Recombinant Human Erythropoietin Study Group. Am J Kidney Dis. 1991;18:50-59; 4. Levin. Semin Dial. 2003;16: The Johns Hopkins University School of Medicine. 12

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17 Impact of treatment Risk of ESA use includes increase cardiovascular events like MI/Stroke, worsening HTN and progression of solid tumors Maximize iron stores before using ESA Read the FDA black box warning and consent patients before ESA use ESA use and correction of Hb above 10 decreases transfusion need and hence better chance to get kidney transplant Secondary Hyperparathyroidism An Early and Modifiable Complication of CKD Calcitriol Decline and ipth Elevation as CKD Progresses Calcitriol 1,25(OH) 2 D 3 (pg/ml) CKD Stage million Low-Normal Calcitriol Stage million Stage million Stage 4 300, ipth (pg/ml) High-Normal 65 PTH egfr (ml/min/1.73 m N = ) ipth = intact PTH. Adapted from Martinez et al. Nephrol Dial Transplant. 1996;11(suppl 3): The Johns Hopkins University School of Medicine. 13

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Feedback Loops in SHPT Decreased Vitamin D Receptors and Ca-Sensing Receptors PTH PTH Bone Disease Fractures Serum P Bone pain Marrow fibrosis Erythropoietin resistance Ca ++ 1,25D Calcitriol 25D

19 Feedback Loops in SHPT Decreased Vitamin D Receptors and Ca-Sensing Receptors PTH PTH Bone Disease Fractures Serum P Bone pain Marrow fibrosis Erythropoietin resistance Ca ++ 1,25D Calcitriol 25D Systemic Toxicity CVD Hypertension Inflammation Calcification Immunological Renal Failure Ca = calcium; CVD = cardiovascular disease; P = phosphorus. Courtesy of Kevin Martin, MB, BCh The Johns Hopkins University School of Medicine. Bone Loss Correlates With Severity of SHPT in CKD Stages 3 and 4 * * * *P<0.05 compared with patients with PTH in the normal range. Z-Score = comparison to the mean value for women at a similar risk, including age, weight, and ethnicity. Rix et al. Kidney Int. 1999;56: The Johns Hopkins University School of Medicine. Bone-Fracture Rate Increases as CKD Progresses: Fractures in Patients on Dialysis Observed/Expected Incidence of Hip Fracture* Overall Male Relative Risk = 4.4 Female Relative Risk = < Total Age (y) *Ratio of observed incidence of hip fracture in patients with kidney failure to expected incidence of hip fracture in the general population. Adapted from Alem et al. Kidney Int. 2000;58: The Johns Hopkins University School of Medicine. 14

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Cardiovascular Outcomes Worsen With CKD Progression: 3-Y Follow-Up by egfr Levels Estimated Event Rate (%) P<0.001 egfr (ml/min/1.73 m 2 ) 75 60-74 45-59 <45 CHF = congestive heart failure.

21 Cardiovascular Outcomes Worsen With CKD Progression: 3-Y Follow-Up by egfr Levels Estimated Event Rate (%) P<0.001 egfr (ml/min/1.73 m 2 ) <45 CHF = congestive heart failure. Anavekar et al. N Engl J Med. 2004;351: The Johns Hopkins University School of Medicine. Early treatment can make a difference 100 No Treatment Current Treatment Early Treatment GFR (ml/min/ ) 10 Kidney Failure Time (years) What can primary care providers do? Recognize and test at-risk patients Educate patients about CKD and treatment Focus on good glycemic control in people with diabetes For those with CKD: Blood pressure below 130/80 Use an ACE inhibitor or ARB More than one drug is usually required A diuretic should be part of the regimen 15

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23 What can primary care providers do? (Continued) Monitor egfr and UACR Treat cardiovascular risk, especially with smokers and hypercholesterolemia Screen for anemia (Hgb), malnutrition (albumin), metabolic bone disease (Ca, Phos, PTH) Refer to dietitian for nutritional guidance Consult or team with a nephrologist Encourage labs to report estimated egfr and urine albumin/creatinine ratios Nephrology referral suggestions To assist with diagnostic challenge (e.g. decision to biopsy) To assist with therapeutic challenge (e.g. blood pressure) Rapid decay of estimated GFR Most primary kidney diseases, (e.g. glomerulonephridites) Preparation for renal replacement therapy, especially when GFR less than 30 Nephrology referral suggestions, cont. Regardless of when you refer: Obtaining preliminary evaluation (e.g. ultrasound, screening serologies) Providing consultant with patient history including serial measures of renal function 16

24 Primary care providers First line of defense against CKD Primary care professionals can play a significant role in early diagnosis, treatment, and patient education Therapeutic interventions for diabetic CKD are similar to those required for optimal diabetes care Control of glucose, blood pressure, and lipids A greater emphasis on detecting CKD, and managing it prior to referral, can improve patient outcomes CKD is Part of Primary Care References Anavekar NS, McMurray JJ, Velazquez EJ, Solomon SD, Kober L, Rouleau JL, White HD, Nordlander R, Maggioni A, Dickstein K, Zelenkofske S, Leimberger JD, Califf RM, Pfeffer MA. Relation between renal dysfunction and cardiovascular outcomes after myocardial infarction. New England Journal of Medicine Sep 23;351(13): Coresh J, Selvin E, Stevens LA, Manzi J, Kusek JW, Eggers P, Van Lente F, Levey AS. Prevalence of chronic kidney disease in the United States. Journal of the American Medical Association Nov 7;298(17): Giatras I, Lau J, Levey AS. Effect of angiotensin-converting enzyme inhibitors on the progression of nondiabetic renal disease: a meta-analysis of randomized trials. Angiotensin-Converting-Enzyme Inhibition and Progressive Renal Disease Study Group. Annals of Internal Medicine Sep 1;127(5): Go AS, Chertow GM, Fan D, McCulloch CE, Chi-Yuan H. Chronic Kidney Disease and the Risks of Death, Cardiovascular Events, and Hospitalization. New England Journal of Medicine Sep 23;351(13): Hogg RJ, Furth S, Lemley KV, Portman R, Schwartz GJ, Coresh J, Balk E, Lau J, Levin A, Kausz AT, Eknoyan G, Levey AS; National Kidney Foundation's Kidney Disease Outcomes Quality Initiative. National Kidney Foundation's Kidney Disease Outcomes Quality Initiative clinical practice guidelines for chronic kidney disease in children and adolescents: evaluation, classification, and stratification. Pediatrics Jun;111(6 Pt 1): References Ix JH, Shlipak MG, Liu HH, Schiller NB, Whooley MA. Association between renal insufficiency and inducible ischemia in patients with coronary artery disease: the heart and soul study. Journal of the American Society of Nephrology Dec;14(12): Jafar TH, Schmid CH, Landa M, Giatras I, Toto R, Remuzzi G, Maschio G, Brenner BM, Kamper A, Zucchelli P, Becker G, Himmelmann A, Bannister K, Landais P, Shahinfar S, de Jong PE, de Zeeuw D, Lau J, Levey AS. Angiotensin-converting enzyme inhibitors and progression of nondiabetic renal disease. A meta-analysis of patient-level data. Annals of Internal Medicine Jul 17;135(2): Erratum in: Ann Intern Med 2002 Aug 20;137(4):299. Levey AS, Greene T, Sarnak MJ, Wang X, Beck GJ, Kusek JW, Collins AJ, Kopple JD. Effect of dietary protein restriction on the progression of kidney disease: long-term follow-up of the Modification of Diet in Renal Disease (MDRD) Study. American Journal of Kidney Diseases Dec;48(6): National Diabetes Information Clearinghouse. Diabetes Control and Complications Trial (DCCT). Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, US Department of Health and Human Services; 1993 (NIH Publication No ). Available from: National Kidney Disease Education Program. Manuscript submitted for review National Kidney Foundation. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. American Journal of Kidney Diseases Feb;39(2 Suppl 1):S

25 References O'Hare AM, Bertenthal D, Covinsky KE, Landefeld CS, Sen S, Mehta K, Steinman MA, Borzecki A, Walter LC. Mortality risk stratification in chronic kidney disease: one size for all ages? Journal of the American Society of Nephrology Mar;17(3): Sarnak MJ, Greene T, Wang X, Beck G, Kusek JW, Collins AJ, Levey AS. The effect of a lower target blood pressure on the progression of kidney disease: long-term follow-up of the modification of diet in renal disease study. Annals of Internal Medicine Mar 1;142(5): Shlipak MG, Smith GL, Rathore SS, Massie BM, Krumholz HM. Renal function, digoxin therapy, and heart failure outcomes: evidence from the digoxin intervention group trial. Journal of the American Society of Nephrology Aug;15(8): Stevens LA, Fares G, Fleming J, Martin D, Murthy K, Qiu J, Stark PC, Uhlig K, Van Lente F, Levey AS. Low rates of testing and diagnostic codes usage in a commercial clinical laboratory: evidence for lack of physician awareness of chronic kidney disease. Journal of the American Society of Nephrology Aug;16(8): U.S. Renal Data System, USRDS 2006 Annual Data Report: Atlas of End-Stage Renal Disease in the United States, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, U.S. Renal Data System, USRDS 2007 Annual Data Report: Atlas of End-Stage Renal Disease in the United States, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD,

Classification of CKD by Diagnosis

Classification of CKD by Diagnosis Diabetic Kidney Disease Glomerular diseases (autoimmune diseases, systemic infections, drugs, neoplasia) Vascular diseases (renal artery disease, hypertension, microangiopathy)