1. Progression & Prevention of Chronic Kidney Disease

2. Definition of CKD Structural or functional abnormalities of the kidneys for >3 months, as manifested by either: 1. Kidney damage, with or without decreased GFR, as defined by pathologic abnormalities markers of kidney damage, including abnormalities in the composition of the blood or urine or abnormalities in imaging tests 2. GFR <60 ml/min/1.73 m 2, with or without kidney damage

3. Stages in CKD StageDescription GFR (ml/min/1.73 m 2 ) 1 Kidney Damage with Normal or  GFR  90 2 Kidney Damage with Mild  GFR 60-89 3 Moderate  GFR 30-59 4 Severe  GFR 15-29 5Kidney Failure< 15 or Dialysis GFR estimated from serum creatinine using MDRD Study equation based on age, gender, race and calibration for serum creatinine. For Stage 1 and 2, kidney damage estimated by spot albumin-to-creatinine ratio  17 mg/g in men or  25 mg/g in women in two measurements.

4. Prevalence of Abnormalities at each level of GFR *>140/90 or antihypertensive medicationp-trend < 0.001 for each abnormality

5. CKD death Stages in Progression of Chronic Kidney Disease and Therapeutic Strategies ComplicationsComplications Screening for CKD risk factors CKD risk reduction; Screening for CKD Diagnosis & treatment; Treat comorbid conditions; Slow progression Estimate progression; Treat complications; Prepare for replacement Replacement by dialysis & transplant NormalNormal Increased risk Kidney failure DamageDamage  GFR

6. Age-Standardized Rates of Death from Any Cause (Panel A) and Cardiovascular Events (Panel B), According to the Estimated GFR among 1,120,295 Ambulatory Adults Go, A, et al. NEJM 351: 1296

7. Clinical Practice Guidelines for the Detection, Evaluation and Management of CKD

8. Definition of ESRD vs Kidney Failure ESRD is a defined term that indicates chronic treatment by dialysis or transplantation Kidney Failure: GFR < 15 ml/min/1.73 m 2 or on dialysis.

9. Importance of Proteinuria in CKD

10. Albuminuria as a Risk Factor for CVD in PREVEND Hillege HL et al. Circulation 2002: 106: 1777-1782 PREVEND = Prevention of Renal and Vascular Endstage Disease trial

11. Progression of Kidney Disease related to level of proteinuria and blood pressure lowering in MDRD (Modification of Diet in Renal Disease) Study Petersen. Annals of Internal Medicine. 1995

12. Classification of CKD by Diagnosis Diabetic Kidney Disease Glomerular diseases (autoimmune diseases, systemic infections, drugs, neoplasia) Vascular diseases (renal artery disease, hypertension, microangiopathy) Tubulointerstitial diseases (urinary tract infection, stones, obstruction, drug toxicity) Cystic diseases (polycystic kidney disease) Diseases in the transplant (Allograft nephropathy, drug toxicity, recurrent diseases, transplant glomerulopathy)

13. Retarding Progress of Chronic Kidney Disease

14. Early treatment can make a difference 100 10 0 No Treatment Current Treatment Early Treatment 47911 Time (years) Kidney Failure GFR (mL/min/1.73 2 )

15. Primary Goals of CKD Care To prevent cardiovascular events and death Heart Attacks Congestive Heart Failure Sudden Cardiac Death Stroke To prevent the progression of CKD to Kidney Failure or ESRD To prevent complications of CKD To prepare for dialysis/transplantation in a timely manner

16. Clinical Action Plan A Clinical Action Plan should be developed for each patient, based on the stage of CKD Patients with CKD should be evaluated to determine: –Diagnosis –Comorbid Conditions –Severity, assessed by level of kidney function –Complications, related to level of kidney function –Risk for loss of kidney function –Risk for cardiovascular disease Review of medications should be performed at all visits. Self-management behaviors should be incorporated into the treatment plan at all stages of chronic kidney disease.

17. Management of Patients with Chronic Kidney Disease

18. RENAL INJURY Reduction in nephron mass Glomerular capillary hypertension Increased glomerular permeability to macromolecules Increased filtration of plasma proteins Proteinuria Excessive tubular protein reabsorption Tubulointerstitial inflammation RENAL SCARRING PROGRESSIVE RENAL DAMAGE: The Final Common Pathway Increased BP

19. NonmodifiableModifiable Patient characteristics associated with increased rate of GFR decline African American race Male gender Older age Lower baseline level of kidney function Higher level of proteinuria Higher BP Poor glycemic control Smoking

20. GUIDELINE 13. LOSS OF KIDNEY FUNCTION IN CKD Interventions to slow the progression should be considered in all patients with CKD Interventions proven to be effective include: 1. Strict glucose control in diabetes; 2. Strict blood pressure control; 3. ACEI and ARBs Interventions that may be effective, but studies are inconclusive, include: 1. Dietary protein restriction; 2. Lipid-lowering therapy; 3. Partial correction of anemia. Attempts should be made to prevent acute renal failure: Volume depletion; IV contrast; Some antibiotics (for example, aminoglycosides and amphotericin B); NSAIDs, including COX 2 inhibitors; Other drugs: ACEI, ARBs, calcineurin inhibitors Obstruction. eGFR should be obtained at least yearly in CKD, and more often in patients with: GFR <60 mL/min/1.73 m2; Fast GFR decline in the past Risk factors for faster progression; Ongoing treatment to slow progression; Exposure to risk factors for acute GFR decline.

21. Slowing Progression The Earlier, the Better…

22. Interventions that delay progression of CKD: ACEI and ARBs Mechanisms –Lower systemic blood pressure –Lower glomerular capillary blood pressure and protein filtration –Reduce AT II mediated cell proliferation and fibrosis Should be employed in all proteinuric kidney diseases!

23. RENAL INJURY Reduction in nephron mass Glomerular capillary hypertension Increased glomerular permeability to macromolecules Increased filtration of plasma proteins Proteinuria Excessive tubular protein reabsorption Tubulointerstitial inflammation RENAL SCARRING PROGRESSIVE RENAL DAMAGE: The Final Common Pathway Increased BP ACEI ARB ACEI ARB ACEI ARB

24. Interventions that delay progression of CKD: ACEI and ARBs Diabetic Kidney Disease –ACEI or ARB in all diabetic patients with microalbuminuria –ACEI (alt ARB) for Type 1 Diabetics with macroalbuminuria –ARB (alt. ACEI) in Type 2 Diabetics with macroalbuminuria Nondiabetic Kidney Disease –ACEI/ARB recommended in all proteinuric (>200 mg/g Cr on spot urine) patients with CKD –May tolerate creatinine rise of 35% above baseline –<130/80 is goal –3 or more drugs may be required! One will probably be a diuretic (thiazide first, then loop) –ACEI and ARB may be used in combination -KDOQI Guideline 8, Table 110 -JNC 7, 2003 http://www.nhlbi.nih.gov/guidelines/hypertension/express.pdf

25. -HTN is both a cause and a complication of CKD. -HTN may develop early during the course of CKD and is associated with adverse outcomes—in particular, faster loss of kidney function and development of CVD. -Blood pressure should be closely monitored in all patients with chronic kidney disease. -Treatment of high blood pressure in CKD should include specification of target BP levels, nonpharmacologic therapy, and specific antihypertensive agents for the prevention of progression of kidney disease and development of cardiovascular disease. Controlling Hypertension GUIDELINE 7. ASSOCIATION OF LEVEL OF GFR WITH HYPERTENSION

26. Pathogenic Mechanisms of High Blood Pressure in CKD Pre-existing essential hypertension Extracellular fluid volume expansion Renin-agniotensin aldosterone system stimulation Increased sympathetic activity Alteration in endothelium-derived factors(NO/endothelin) Increased body weight Erythropoietin administration PTH secretion/hypercalcemia calcified arterial tree renal vascular disease and renal artery stenosis

27. Relationship between BP and progression of diabetic nephropathy. BP, albumin excretion rate, and GFR in patients with type 1 DMs randomly assigned to a reduction in MAP of 10 mm Hg using metoprolol at 100 to 400 mg/d, hydralazine at 50 to 200 mg/d, and furosemide at 80 to 500 mg/d versus no antihypertensive therapy. Solid circles represent the treated group. Open circles represent the control group. Vertical lines represent standard error. Study was stopped earlier in the control group because of faster decline in GFR. Reprinted with permission. 253 253 BP vs. Time Controls AER vs. Time GFR vs. Time Controls

28. Relationship between MAP and GFR decline (Non-diabetic Pts). Mean GFR decline and achieved follow-up BP in MDRD Study A (patients with baseline GFR 25 to 55 mL/min/1.73 m 2 ). Regression lines relating the estimated mean GFR decline over 3 years to mean follow-up MAP for groups of patients defined according to baseline proteinuria. Within each group, a 3-slope model was used with break points at 92 and 98 mm Hg. Reprinted with permission. 255 255 “Nephrotic”

29. JNC-7 recommends a goal blood pressure of <130/80 mm Hg for individuals with high blood pressure and CKD. http://www.nhlbi.nih.gov/guidelines/hypertension/express.pdf

30. Clinical Practice Guidelines for Management of Hypertension in CKD Type of Kidney DiseaseBlood Pressure Target (mm Hg) Preferred Agents for CKD, with or without Hypertension Other Agents to Reduce CVD Risk and Reach Blood Pressure Target Diabetic Kidney Disease <130/80 ACE inhibitor or ARB Diuretic preferred, then BB or CCB Nondiabetic Kidney Disease with Urine Total Protein-to-Creatinine Ratio  200 mg/g Nondiabetic Kidney Disease with Spot Urine Total Protein-to-Creatinine ratio <200 mg/g None preferred Diuretic preferred, then ACE inhibitor, ARB, BB or CCB Kidney Disease in Kidney Transplant Recipient CCB, diuretic, BB, ACE inhibitor, ARB

31. PopulationBP GoalNondrug RxDrug RX CKD + >200mg/g <130/80Reduce saltACEI/ARB Prot/Cr RatioBMI≤25 kg/m2Then diuretic Mod EtOHThen BB or CCB Stop Smoking Exercise CKD + no proteinuria<130/80SameThiazide/Loop Then ACEI/ARB Then BB or CCB Recommendations for Controlling HTN in Non-Diabetic CKD KDOQI Table 118, Guideline 9

32. Interventions that delay progression of CKD: Strict Glycemic Control 80% Type I DM with microalbuminuria develop DN in 10-15years, 50% to ESRD –DCCT, benefit of tight control in reducing occurrence subclinical and overt DN(40-60%) 20-40% Type II DM with microalbuminuria develop DN, 20% to ESRD –UKPDS 33, 25% reduction in microvascular events –Kumamoto –Steno Type 2, 73% reduction in clinical proteinuria

33. Interventions that delay progression of CKD: Strict Glycemic Control Recommended Therapy: HgbA 1c < 7% Additional information in 2001 ADA Clinical Practice Guidelines www.diabetes.org/clinicalrecommendations/Supple ment101/S3.htm

34. Management of Patients with Chronic Kidney Disease

35. When to Expect Complications…

37. Anemia and CKD Anemia usually develops during the course of chronic kidney disease and may be associated with adverse outcomes. Anemia is one of the modifiable complications of CKD. All individuals with hemoglobin (Hb) levels lower than physiologic norms are considered anemic.  Erythropoietin deficiency is the primary cause of anemia of CKD.  The NKF recommends that evaluation for anemia should occur when GFR <60 mL/min/1.73 m 2 ; measurement should include Hb level.  Anemia should be treated according to the K/DOQI TM guidelines for anemia of CKD.

38. K/DOQI: Evaluation and Management of Anemia  For Adults with ≥ Stage 3 CKD:  Assess Hemoglobin level  If anemia (HgB ≤ 12)  RBC indices/CBC  Reticulocyte count  Iron studies  Test for occult GI bleeding as indicated  Medical evaluation of comorbid conditions  Erythropoetin levels are usually NOT indicated.

39. Prevention of Uremic Complications: Anemia Therapy Subcutaneous administration of erythropoietin once to thrice weekly (sometimes less). Supplemental oral or IV iron to keep ferritin > 100 and iron saturation >20%. Monthly monitoring of Hgb, iron stores. Monthly adjustments in EPO dose and frequency to meet target Hgb 11-12 g/dl (HCT 33-36%).

40. Bone disease and disorders of calcium and phosphorus metabolism develop during the course of chronic kidney disease and are associated with adverse outcomes. -Patients with GFR <60 mL/min/1.73 m 2 should be evaluated for bone disease and disorders of calcium and phosphorus metabolism. -Patients with bone disease and disorders of bone metabolism should be evaluated and treated—see K/DOQI Clinical Practice Guidelines on Bone Metabolism and Disease in Chronic Kidney Disease (October, 2004). GUIDELINE 10. ASSOCIATION OF LEVEL OF GFR WITH BONE DISEASE AND DISORDERS OF CALCIUM AND PHOSPHORUS METABOLISM

41. Prevention of Uremic Complications: Osteodystrophy Osteitis fibrosis cystica, due to 2 o HPT, is major form of bone disease. Check indices of bone and mineral metabolism at GFR < 60 cc/min/1.73m 2: –iPTH the earliest marker –Hypocalcemia, hyperphosphatemia –Phosphorus control is cornerstone of treatment

42. Prevention of Uremic Complications: Osteodystrophy Therapy Restrict dietary phosphorus to 800- 1,000 mg/d Calcium-based phosphate binders (but not with Vit D!) to combat hypocalcemia and bind phosphorus Assure repletion of Vitamin D 25 Avoid acidosis, HCO 3 > 23 mEq/l

43. Management of Renal Osteodystrophy is Very Complex! http://www.kidney.org/profess ionals/KDOQI/guidelines_bo ne/index.htm

44. Protein energy malnutrition develops during the course of chronic kidney disease and is associated with adverse outcomes. Low protein and calorie intake is an important cause of malnutrition in chronic kidney disease. Patients with GFR <60 mL/min/1.73 m 2 should undergo assessment of dietary protein and energy intake and nutritional status: Guideline 23. Panels of Nutritional Measures for Nondialyzed Patients: "For individuals with CRF (GFR <20 mL/min) protein-energy nutritional status should be evaluated by serial measurements of a panel of markers including at least one value from each of the following clusters: (1) Serum albumin; (2) Edema-free actual body weight, percent standard (NHANES II) body weight, or subjective global assessment (SGA); and (3) Normalized protein nitrogen appearance (nPNA) or dietary interviews and diaries. (Evidence and Opinion)" Guideline 26. Intensive Nutritional Counseling for Chronic Renal Failure: "The nutritional status of individuals with CRF should be monitored at regular intervals." GUIDELINE 9. ASSOCIATION OF LEVEL OF GFR WITH NUTRITIONAL STATUS

45. Prevention of Uremic Complications: Malnutrition Contributors to protein-energy malnutrition(PEM) in CKD: –low protein and calorie intake –metabolic acidosis –resistance to insulin, GH, IGF-1 –proinflammatory cytokines Assessment of nutritional status requires multiple markers to assess protein status, fat stores, body composition and dietary protein and energy intake.

46. Prevention of Uremic Complications: Nutrition Guidelines Protein intake –0.75g/kg/d (RDA) –GFR < 25 cc/min(Stages 4-5) consider 0.6g/kg/d Energy intake –RDA depends on energy expenditure –GFR < 25 cc/min(Stages 4-5) 30-35kcal/kg/d Patients with less than recommended intake need frequent follow-up of nutritional status

47. Prevention of Uremic Complications: Just a Word About Immunizations Don’t forget to continue routine immunizations, e.g. –Tetanus –Pneumococcus –Influenza Hepatitis B –Check for immunity first--ie, hepatitis B sAb, sAg, cAb –Those who are immune or have chronic infection do not need the vaccine. –All others should receive the vaccine. Don’t wait for dialysis! Patients with advanced chronic kidney disease are less likely to gain immunity from the vaccine. Consider for all Stage 3 or greater CKD patients!

48. Management of Patients with Chronic Kidney Disease

49. Patients with CKD, irrespective of diagnosis, are at increased risk of cardiovascular disease (CVD), including coronary heart disease, cerebrovascular disease, peripheral vascular disease, and heart failure. Both “traditional” and “chronic kidney disease related (nontraditional)” CVD risk factors may contribute to this increased risk. -All patients with CKD should be considered in the “highest risk” group for CVD, irrespective of levels of traditional CVD risk factors. -All patients with CKD should undergo assessment of CVD risk factors, including: Measurement of “traditional” CVD risk factors in all patients; Individual decision-making regarding measurement of selected “CKD-related” CVD risk factors in some patients. -Recommendations for CVD risk factor reduction should take into account the “highest-risk” status of patients with chronic kidney disease. GUIDELINE 15. ASSOCIATION OF CHRONIC KIDNEY DISEASE WITH CARDIOVASCULAR DISEASE

50. Cardiovascular Mortality in the General Population and in ESRD Treated by Dialysis 0.01 100 10 1 0.1 Annual mortality (%) 25–3445–5465–74  85 35–4455–6475–84 Male Female Black White Dialysis General population Age (years)

51. The most common cause of death among ESRD patients is CVD Fig 5. Causes of death among period prevalent patients 1997–1999, treated with hemodialysis, peritoneal dialysis, or kidney transplantation. Data are from the USRDS 2001 Annual Data Report (www.usrds.org). Abbreviations: MI, myocardial infarction; HD, heart disease.

52. Modification of Comorbidity: Cardiovascular Disease CVD is the cause of death in 40-50% ESRD patients ESRD CVD mortality rates 15x higher than general population. CVD is leading cause of death in patients with CKD, regardless of stage. –HDFP, pts with Cr> 1.7mg/dl, 58% deaths CV –British Regional Heart Study, 50% deaths CV in patients in upper decile of baseline Cr

55. GFR and relative risk for CVD-related death. Wannamethee 625 : risk is for S Cr  1.5 mg% vs S Cr  1.3 mg%. Culleton 622 : risk is for S Cr  1.5 mg% and  1.4 mg% vs. 1.5 mg% vs  1.5 mg%. Upper limit for SCr was 3.0 mg%. Fried 640 : risk is for S Cr  1.5 mg% versus S Cr  0.9 mg%. Hemmelgarn 642 : risk is for S Cr >2.3 mg/dL vs  2.3 mg/dL. 625 622 637 634 640 642

56. Proteinuria and relative risk for cardiovascular disease. Where possible, results presented are from multivariable analyses. Agewall 650, Ljungman 647 : Unadjusted results shown. Data not available to calculate age or multivariable adjusted risk. 650 647

57. Modification of Comorbidity: Cardiovascular Disease Patients with CKD should be considered highest risk for CVD. Aggressive intervention and management of traditional CV risk factors is indicated. This particularly includes dyslipidemias. –All adults with Stage1-5 CKD should be evaluated for dyslipidemia. –Fasting lipid profile with total cholesterol, LDL, HDL and triglycerides, at baseline, and at least annually.

58. Management of Dyslipidemia in CKD Expert Panel on Detection Evaluation and Treatment of High Blood Cholesterol in Adults. Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA, 2001, 285;2486-2497. http://www.kidney.org/professionals/KDOQI/guidelines_lipids/index.htm

59. Conclusions CKD is a public health problem with poor outcomes and high cost. CKD is underdiagnosed and undertreated. Early CKD detection and intervention may increase opportunities for the prevention of ESRD and of complications of CKD, including death.

60. THANK YOU !