Chronic Kidney Disease: Definitions and Optimal Management

Jai Radhakrishnan, MD
Assoc Professor of Clinical Medicine College of Physicians & Surgeons of Columbia University, New York, NY

11/9/2006

Objectives
Definition of CKD Prevalence and Scope of CKD Optimal management
Delaying progression Treatment of Comorbidities Transition to End Stage Renal Disease

Kidney Disease Outcomes Quality Initiative K/DOQI http://www.kidney.org/

Case
A 78 year old Caucasian female patient presents to her PCP for a routine physical. She has been told of mild HTN but takes no medications. BP=160/90 Laboratory
creatinine 1.5mg/dL Hb=10g/dL Urine exam 1+ protein Tchol 220, LDL 138, HDL 40, TG 150

How severily compromised is her renal function? Is she being optimally managed?
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Definitions and Stages of Chronic Kidney Disease

Chronic >3 months Kidney Damage
Hematuria/Albuminuria Biopsy Abnormal imaging tests

Glomerular Filtration Rate < 60ml/min

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Good news

NO MORE 24HOUR URINES! Spot urines are adequate.

Quantification of Proteinuria (positive dipstick):

Normal
24 H Urine Protein Urine SPOT protein/ Creat. ratio (mg/gm)

Abnormal

< 300mg/24h

>300mg/24h

< 200mg/g

>200mg/g

Quantification of Proteinuria: (Negative Dipstick)

Normal
Urine AER (g/min) Urine AER (mg/24h) Spot albumin/ Cr# ratio (mg/gm)

Microalbuminuria 20 - 200 30 - 300

< 20 < 30

< 30

30 - 300
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Serum Creatinine Is an Inadequate Screening Test for Renal Failure in Elderly Patients
S. Creatinine > 1.7mg/dL

27% referred to neprhologist 85% incompletely evaluated

Swedko PJArch Intern Med. 2003;163:356-360

Methods of Estimating GFR

Inulin/iothalamate clearance GOLD STANDARD Creatinine Clearance (24 h urine) Equations base on serum creatinine
Cockroft-Gault MDRD

MDRD equation for predicting GFR

MDRD not validated in: Diabetic kidney disease serious comorbid conditions normal persons > 70 years old

Modification of Diet in Renal Disease Study Group. Ann Intern Med 130:461-470, 1999
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www.nephron.com

www.medcalc.com

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K/DOQI CKD Staging

Requires 2 or more GFR, 3 or more months apart

GFR

90

60

30
Complications Possible

15
Complications Evident Renal Replacement

Other markers kidney disease: proteinuria, hematuria, anatomic

3 Stage

Objectives
Definition of CKD Prevalence and Scope of CKD Optimal management
Delaying progression Treatment of Comorbidities Transition to End Stage Renal Disease

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Incidence & Prevalence of ESRD

USRDS 2004

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Prevalence of CKD: NHANES III

Stage 5 (GFR <15 or ESRD) Stage 4 (GFR 15-29) Stage 3 (GFR 30-59) Stage 2 (GFR 60-89) Stage 1 (albuminuria) Total 0 5 10 15 5.3 5.9 19.2 20 25 0.3 0.4 7.6

Number (in Millions)

Coresh J.. Am J Kidney Dis. 2003 Jan;41(1):1-12.

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Median age by race/ethnicity

USRDS 2004

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Etiology of ESRD
60
44.4

40
26.6

20
9.9 2.3 3.9 3.3 2.0
Miscellaneous
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7.6

Diabetes

Hypertension

Glomerulo- Secondary Interstitial Cystic/ Neoplasms/ nephritis GN/ Vascu- Nephritis Hereditary/ Tumors litis PyeloCongenital Nephritis

USRDS 1999

Objectives
Definition of CKD Prevalence and Scope of CKD Optimal management
Delaying progression Treatment of Comorbidities Transition to End Stage Renal Disease

Kidney Disease Outcomes Quality Initiative K/DOQI http://www.kidney.org/

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What can be done to slow progression of renal disease?

Hypertension control ACE-Inhibitors/A2R-Blockers Blood sugar control Moderate protein restriction

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Early Aggressive Antihypertensive Treatment in Diabetic Nephropathy (n=10)

144/97

Albuminuria

GFR Decline

128/84

metoprolol, hydralazine, and furosemide or thiazide

Parving HH... Lancet 1:1175-1179, 1983

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Meta Analysis: Lower Mean BP Results in Slower Rates of Decline in GFR in Diabetics and Non-Diabetics
MAP (mmHg)
95 0 -2 -4 -6 -8 Untreated HTN 98 101 104 107 110 113 116 119

GFR (mL/min/year)

r = 0.69; P < 0.05

-10 -12 130/85 -14 140/90

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Bakris GL, et al. Am J Kidney Dis. 2000;36(3):646-661.

www.hypertensiononline.org

Blood Pressure Targets

Clinical Status
Hypertension (no diabetes or renal disease) Diabetes Mellitus Renal Disease with proteinuria >1 gram/24 hours, or diabetic kidney disease

BP Goal
<140/90 mmHg (JNC 7) <130/80 mmHg (ADA, JNC 7) <130/80 mmHg <125/75 mmHg (NKF)

Chobanian AV et al. JAMA. 2003;289:25602571. American Diabetes Association. Diabetes Care. 2002;25:134147. National Kidney Foundatrion. Am J Kidn Dis. 2002;39(suppl 1):S1S266.

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SCORECARD: Awareness, Treatment and Control of Blood Pressure 1976-2000 (JNC-VII)

80 70 60 50 40 30 20 10 0 1976-1980 1988-1991 1991-1994 1999-2000

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Awareness Treatment Control

Clinical Practice Guidelines for Management of Hypertension in CKD

Type of Kidney Disease Blood 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 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-toCreatinine ratio <200 mg/g Kidney Disease in Kidney Transplant Recipient

<130/80

Diuretic preferred, then ACE inhibitor, ARB, BB or CCB None preferred CCB, diuretic, BB, ACE inhibitor, ARB
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Angiotensin II: Role in Renal Injury

Angiotensin II
+ Angiotensinogen Fibroblasts AT1R AT2R TNFR1 TNFR2 + TNF- Tubule cells Cellular adhesion molecules Inflammation

NF-B Profibrotic cytokines Matrix

Proliferation and differentiation

FIBROSIS

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www.hypertensiononline.org

ACE-I: Preventing Microalbuminuria in Type 2 Diabetes (Benedict Study)

1204 subjects with type 2 DM, HTN and normal urine albumin. Treatment with at least three years of Trandolapril 2 mg/d + verapamil (SR180mg/d Trandolapril alone 2 mg/d Verapamil SR 240mg/d alone Placebo The target blood pressure=120/80 mm Hg. The primary end point: development of persistent microalbuminuria

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N Engl J Med. 2004 Nov 4;351(19):1941-51.

ACE-I/ARB in Diabetic Nephropathy

REFERENCE
Viberti et al
JAMA 1994; 271: 275-9

POPULATION
92 DM-1 Non- HTN Microalbuminuria 590 DM-2, HTN Microalbuminuria 332 DM-2 Microalbuminuria 419 DM-1 UVPr> 0.5g 1715 DM-2 UVPR>0.5g 1513 DM-2 UVPr >0.9g, Cr 1-3

Drug/Duration
Captopril 3 years Usual AHTN vs Valsartan 2 years Valsartan vs Amlodipine 24 weeks Captopril 3 years Irbesartan vs Amlodipine 2.6 years Losartan 3.4 years

IRMA 2
N E J M. 2001;345:870888.

MARVAL
Circulation. 2002;106:672678

Collaborative Study Grp.

N E J M 1993 Nov 11;329(20):1456-62.

IDNT
N Engl J Med. 2001 Sep 20;345(12):851-60.

RENAAL
N E J M. 2001;345:861869

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ACE-I/ARB in Non-Diabetic Renal Disease

REFERENCE AIPRI
N Engl J Med 1996; 334: 939

POPULATION 583 CRI (DM/Non DM) 352 CRI +/Nephrotic proteinuria 1094 AA pts HTN, GFR 2065ml/min

Drug/Duration Benazepril 3 years Ramipril 2 years

REIN
Kidney Int 1998; 53: 1209-16. Lancet 1999; 354: 359-64

AASK
JAMA. 2001 Jun 6;285(21):271928 JAMA. 2002;288(19):2421-31

Amlodipine vs. Ramipril vs Metoprolol

Enalapril ~6 years Fosinopril 5.1 years
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Praga M
JASN. 2003 Jun;14(6):1578-83.

44 IgAN 44 HIVAN Creatiinine<2.0

Wei A
Kidney Int. 2003 Oct;64(4):1462-71.

SCORECARD: ACE-I/ARB Use in

Proteinuric Patients
100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% 91% 85%

32%

26%

DIABETES NO DIABETES

1997

2005
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McClellan WM, et al. Am J Kidney Dis. 1997 Mar;29:368-75 Nephrology Dialysis Transplantation 2005 20(6):1110-1115 .

Diabetes Control and Complications Trial

1441 patients with IDDM 726 without retinopathy at base line (the primaryprevention cohort) 715 with mild retinopathy (secondary-intervention cohort) Conventional (2 insulin injections/day vs Intensive (insulin pump or > 3 insulin injections/day) mean F/U =6.5 yrs

DCCT Research Group. N Engl J Med 1993;329:977-86.

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Diabetes Control and Complications Trial

Prevention of Microalbuminuria

Microalbuminuria reduced by 39 percent

(95 % C.I.=21 52 %)

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DCCT Research Group. N Engl J Med 1993;329:977-86.

Diabetes Control and Complications Trial

Prevention of Macroalbuminuria
Albuminuria (urinary albumin > 300 mg/24h) reduced by 54%)
(95% C.I. 19 74%)

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DCCT Research Group. N Engl J Med 1993;329:977-86.

UKPDS: Microalbuminuria
Urine albumin >50 mg/L

RR Baseline Three years Six years Nine years Twelve years Fifteen years 0.89 0.83 0.88 0.76 0.67 0.70 0.24

Relative Risk & 99% CI 0.5 1 2

0.043 0.13 0.00062 0.000054 0.033 <

Favours Favours intensive conventional

33 ukpds

HOPE TRIAL:
Predictive Variables for CV Death, MI, and Stroke

Variable Microalbuminuria Creatinine > 1.4 mg/dL CAD PVD Diabetes Mellitus Male Age Waist-Hip Ratio
Mann JFE, et al. Ann Intern Med. 2001;134(8):629-636.

Hazard Ratio

1.59 1.40 1.51 1.49 1.42 1.20 1.03 1.13

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www.hypertensiononline.org

Chronic Kidney Disease and the Risks of Death, Cardiovascular Events, and Hospitalization

Go, A. S. et al. N Engl J Med 2004;351:1296-1305

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Go AS.. NEJM, 351:1296-1305, 2004

Risk Factors for CVD

TRADITIONAL
Age Male gender Menopause Family history Hypertension Smoking Low HDL, high LDL Diabetes Inactivity, Obesity LVH

NON TRADITIONAL
CaxPO4 product Anemia Inflammation Hypoalbuminemia REVERSE EPIDEMIOLOGY
Low cholesterol Low body weight Low blood pressure
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Malnutrition, Inflammation and Atherosclerosis (MIA syndrome)

Stenvinkel P .. Nephrol Dial Transplant. 2000 Jul;15(7):953-60.

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Management of Comorbidities
Anemia Renal Osteodystrophy Hyperlipidemia

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What is the prevalence of anemia in CKD ? Is the pts GFR too good to explain anemia?

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Am J Kidney Dis 34:125-134, 1999

Etiology and Workup of Anemia in Renal Failure

Decreased production
Reticulocyte count Red Blood Cell indices: MCV, RDW Iron Parameters Total iron Iron binding capacity Ferritin Vitamins: Folate\ B12 levels Stools for occult blood Erythropoietin levels not indicated
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Low EPO (renal failure) Nutritional

(Iron, B12, Folate)

Infection, inflammation and malignancy
Blood Loss

Benefits of Correction of Hb
Raising Hematocrit to 30-36% improves: Brain and cognitive function Quality of Life Exercise capacity/muscle function ?LVH ?Survival
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Principles of Anemia Treatment

Erythropoietin
Epoetin alfa :Procrit , Epogen Darbepoietin Alpha: ARANESP

Targets
Hgb=11 to 12 g/dL Hct =33% to 36%

Sufficient iron should be administered to maintain

TSAT of >20%, Serum ferritin level of >100 ng/mL

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Scorecard: Mean monthly hemoglobin (g/dl) at initiation

i l

i l

a l

a l

Incident ESRD patients with a first service date between May 1995 & June 2003; data from Medical Evidence form.
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Treatment of Calcium, Phosphate Levels and Osteodystrophy

AIM: To NormalizeSerum calcium Serum Phosphorus PTH levels

Methods:
Oral Calcium Vitamin D analogs Phosphate binders (sevelamer-Renagel) Calcimimetics (cinacalcet-Sensipar)

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Dyslipidemia in Renal Patients

Am J Kidney Dis. 1998 Nov;32(5 Suppl 3):S142-56

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Atorvastatin in Patients with Type 2 Diabetes Mellitus Undergoing Hemodialysis

Primary end point of cardiovascular death, nonfatal myocardial infarction, and stroke in diabetic hemodialysis pts.

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Wanner, C. et al. N Engl J Med 2005;353:238-248

Management of Dyslipidemia in CKD

NCEP guidelines recommended:
Cholesterol <200 LDL-C <100 HDL-C >45 (M), 55(F) Triglycerides<150

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Preparation for renal replacement

Choice of renal replacement Timely access surgery Timely dialysis initiation

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Preparation for Renal Replacement

When GFR <25ml/min
Renal transplant is treatment of first choice
Workup living donors

If no donors available
List patient on cadaver tx. list Place Angioaccess if HD preferred

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AV access (Target 50% Fistulae)

i l

i l

a l

a l

USRDS 2004

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Patient Survival vs Waiting Time

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Effect of Preemptive Renal Transplant on Allograft Survival

Mange K.N Engl J Med. 2001 Mar 8;344(10):726-31.

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Renal Transplant Waiting List 1993-2002

60,000

Number of Registrations

50,000 40,000 30,000 20,000 10,000 0 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002

Year
Kidney
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Kidney Donors Recovered

1993-2002
6000

# of Donors Recovered

5000 4000 3000 2000 1000 0 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002

Year
Deceased Donor Living Donor
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Awareness/CKD Stage

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Timing Of Nephrology Referral

Patients with chronic kidney disease should be referred to a specialist for consultation and comanagement if:
the clinical action plan cannot be prepared the prescribed evaluation of the patient cannot be carried out the recommended treatment cannot be carried out. In general, patients with GFR <30 mL/min/1.73 m2 should be referred to a nephrologist.

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The timing of specialist evaluation in chronic kidney disease and mortality: Cumulative Mortality

Early: > 12 months Intermediate: 4-12 months Late: <4 months

Kinchen KS.Ann Intern Med 2002 Sep 17;137(6):479-86

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Early Treatment Should Make a Difference

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Brenner, et al., 2001

PCP Must be Engaged

1) 2) 3)

7.6 million people with GFR 30-60 mL/min/1.73 m2 About 5,000 full-time nephrologists Nearly 1,500 new patients per nephrologist Therefore, 7 new patients per day per nephrologist. Obviously not possible.

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Summary: Definition of CKD

Spot urine albumin/microalbumin to creatinine ratio Estimate GFR from serum creatinine using the MDRD prediction equation Note: 24 hour urine collections are NOT needed Diabetics, HTN: should be tested once a year Others at risk: less frequently as long as normal

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Summary Optimal Management of CKD

Treat Comorbidities

Delay Progression
ACE-Inhibitors/ARB BP control (130/85) Blood sugar control ?Protein restriction

Anemia Renal osteodystrophy Hyperlipidemia Cardiovascular disease Nutrition, Acidosis

Preparation for renal replacement Choice of Renal Replacement Timely access surgery Timely dialysis initiation
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www.columbianephrology.org

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