11/9/2006 1
Chronic Kidney Disease:Definitions and Optimal Management
Jai Radhakrishnan, MDAssoc Professor of Clinical Medicine
College of Physicians & Surgeons of Columbia University, New York, NY
2
Objectives
Definition of CKDPrevalence and Scope of CKDOptimal management
Delaying progressionTreatment of ComorbiditiesTransition to End Stage Renal Disease
Kidney Disease Outcomes Quality InitiativeK/DOQI
http://www.kidney.org/
3
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=160/90Laboratory
creatinine 1.5mg/dL Hb=10g/dLUrine exam 1+ proteinTchol 220, LDL 138, HDL 40, TG 150
How severily compromised is her renal function?Is she being optimally managed?
4
Chronic >3 months
Kidney Damage Hematuria/AlbuminuriaBiopsyAbnormal imaging tests
Glomerular Filtration Rate < 60ml/min
Definitions and Stages of Chronic Kidney Disease
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Good news NO MORE 24-HOUR URINES!
Spot urines are adequate.
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Quantification of Proteinuria(positive dipstick):
Normal Abnormal
24 H Urine Protein < 300mg/24h >300mg/24h
Urine SPOTprotein/
Creat. ratio (mg/gm)
< 200mg/g >200mg/g
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Quantification of Proteinuria:(Negative Dipstick)
Normal “Micro”-albuminuria
Urine AER(μg/min) < 20 20 - 200
Urine AER(mg/24h) < 30 30 - 300
Spot albumin/Cr# ratio (mg/gm)
< 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
Swedko PJ…Arch Intern Med. 2003;163:356-360
27% referred to neprhologist
85% incompletely evaluated
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Methods of Estimating GFRInulin/iothalamate clearance “GOLD STANDARD”Creatinine Clearance (24 h urine)Equations base on serum creatinine
Cockroft-GaultMDRD
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Modification of Diet in Renal Disease Study Group. Ann Intern Med 130:461-470, 1999
MDRD equation for predicting GFR
MDRD not validated in:•Diabetic kidney disease•serious comorbid conditions•normal persons •> 70 years old
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www.nephron.com www.medcalc.com
90 60 30 15GFR
Stage
1 2 3 4 5
Renal Replacement
ComplicationsEvident
ComplicationsPossible
Other markers kidney disease: proteinuria, hematuria, anatomic
K/DOQI CKD StagingK/DOQI CKD StagingRequires 2 or more GFR, 3 or more months apartRequires 2 or more GFR, 3 or more months apart
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Objectives
Definition of CKDPrevalence and Scope of CKDOptimal management
Delaying progressionTreatment of ComorbiditiesTransition to End Stage Renal Disease
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Incidence & Prevalence of ESRD
USRDS 2004
15
19.2
5.9
5.3
7.6
0.4
0.3
0 5 10 15 20 25
Total
Stage 1 (albuminuria)
Stage 2 (GFR 60-89)
Stage 3 (GFR 30-59)
Stage 4 (GFR 15-29)
Stage 5 (GFR <15 or ESRD)
Number (in Millions)
Prevalence of CKD: NHANES III
Coresh J.. Am J Kidney Dis. 2003 Jan;41(1):1-12.
16
Median age by race/ethnicity
USRDS 2004
17
44.4
26.6
9.9
2.3 3.9 3.3 2.07.6
0
20
40
60
Diabetes Hyper- Glomerulo- Secondary Interstitial Cystic/ Neoplasms/ Miscel-tension nephritis GN/ Vascu- Nephritis Hereditary/ Tumors laneous
litis Pyelo- CongenitalNephritis
USRDS 1999
Etiology of ESRD
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Objectives
Definition of CKDPrevalence and Scope of CKDOptimal management
Delaying progressionTreatment of ComorbiditiesTransition to End Stage Renal Disease
Kidney Disease Outcomes Quality InitiativeK/DOQI
http://www.kidney.org/
19
What can be done to slow progression of renal disease?
Hypertension control ACE-Inhibitors/A2R-BlockersBlood sugar controlModerate protein restriction
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Early Aggressive Antihypertensive Treatment in Diabetic Nephropathy (n=10)
Parving HH... Lancet 1:1175-1179, 1983
144/97
128/84
Albuminuria GFR Decline
metoprolol, hydralazine, and furosemide or thiazide
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Meta Analysis: Lower Mean BP Results in Slower Rates of Decline in GFR in Diabetics and Non-Diabetics
9595 9898 101101 104104 107107 110110 113113 116116 119119
r = 0.69; P < 0.05
MAP (mmHg)
GFR
(mL/
min
/yea
r)
130/85 140/90
UntreatedHTN
00
--22
--44
--66
--88
--1010
--1212
--1414
Bakris GL, et al. Am J Kidney Dis. 2000;36(3):646-661. www.hypertensiononline.org
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Blood Pressure Targets
Clinical Status BP GoalHypertension(no diabetes or renal disease)
<140/90 mmHg(JNC 7)
Diabetes Mellitus <130/80 mmHg(ADA, JNC 7)
Renal Diseasewith proteinuria >1 gram/24 hours, or diabetic kidney disease
<130/80 mmHg<125/75 mmHg
(NKF)
Chobanian AV et al. JAMA. 2003;289:2560–2571.American Diabetes Association. Diabetes Care. 2002;25:134–147.National Kidney Foundatrion. Am J Kidn Dis. 2002;39(suppl 1):S1–S266.
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SCORECARD: Awareness, Treatment and Control of Blood Pressure 1976-2000 (JNC-VII)
01020304050607080
1976-1980 1988-1991 1991-1994 1999-2000
AwarenessTreatmentControl
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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 Agentsto Reduce CVD Risk
and Reach Blood Pressure Target
Diabetic Kidney Disease
Nondiabetic Kidney Disease with Urine Total
Protein-to-Creatinine Ratio ≥200 mg/g
ACE inhibitoror ARB
Diuretic preferred, then BB or CCB
Nondiabetic Kidney Disease with Spot Urine
Total Protein-to-Creatinine ratio <200
mg/g
Diuretic preferred, then ACE inhibitor, ARB, BB
or CCB
Kidney Disease in Kidney Transplant Recipient
CCB, diuretic, BB, ACE inhibitor, ARB
None preferred
<130/80
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Angiotensin II: Role in Renal InjuryAngiotensin II: Role in Renal Injury
Angiotensin II
AT1RAT2R
NF-κB
TNFR1
TNFR2
Angiotensinogen
Fibroblasts
Proliferation and differentiation
Matrix
FIBROSIS
Inflammation
Cellular adhesion molecules
Tubule cells
TNF-α
+ +
Profibrotic cytokines
www.hypertensiononline.org
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ACE-I: Preventing Microalbuminuriain 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/dTrandolapril alone 2 mg/dVerapamil SR 240mg/d alone Placebo
The target blood pressure=120/80 mm Hg.The primary end point: development of persistent microalbuminuria
N Engl J Med. 2004 Nov 4;351(19):1941-51.
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ACE-I/ARB in Diabetic Nephropathy
REFERENCE POPULATION Drug/Duration
Viberti et alJAMA 1994; 271: 275-9
92 DM-1 Non- HTNMicroalbuminuria
Captopril3 years
Collaborative Study Grp.N E J M 1993 Nov 11;329(20):1456-62.
419 DM-1UVPr> 0.5g
Captopril3 years
RENAALN E J M. 2001;345:861–869
1513 DM-2UVPr >0.9g, Cr 1-3
Losartan3.4 years
IRMA 2N E J M. 2001;345:870–888.
590 DM-2, HTNMicroalbuminuria
Usual AHTN vs Valsartan2 years
MARVALCirculation. 2002;106:672–678
332 DM-2Microalbuminuria
Valsartan vs Amlodipine24 weeks
IDNTN Engl J Med. 2001 Sep 20;345(12):851-60.
1715 DM-2UVPR>0.5g
Irbesartan vs Amlodipine2.6 years
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ACE-I/ARB in Non-Diabetic Renal Disease
REFERENCE POPULATION Drug/Duration
AIPRI N Engl J Med 1996; 334: 939
REINKidney Int 1998; 53: 1209-16. Lancet 1999; 354: 359-64
AASKJAMA. 2001 Jun 6;285(21):2719-28JAMA. 2002;288(19):2421-31
1094 AA ptsHTN, GFR 20-65ml/min
Amlodipine vs.Ramipril vs Metoprolol
Praga MJASN. 2003 Jun;14(6):1578-83.
Wei AKidney Int. 2003 Oct;64(4):1462-71.
44 HIVANCreatiinine<2.0
Fosinopril5.1 years
583 CRI (DM/Non DM)
Benazepril3 years
352 CRI +/-Nephroticproteinuria
Ramipril2 years
44 IgAN Enalapril~6 years
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SCORECARD: ACE-I/ARB Use in Proteinuric Patients
32% 26%
91% 85%
0%10%20%30%40%50%60%70%80%90%
100%
1997 2005
DIABETESNO DIABETES
McClellan WM, et al. Am J Kidney Dis. 1997 Mar;29:368-75Nephrology Dialysis Transplantation 2005 20(6):1110-1115 .
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Diabetes Control and Complications Trial
1441 patients with IDDM 726 without retinopathy at base line (the primary-prevention 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 TrialPrevention of Microalbuminuria
Microalbuminuria reduced by 39 percent (95 % C.I.=21 – 52 %)
DCCT Research Group. N Engl J Med 1993;329:977-86.
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Albuminuria(urinary albumin > 300 mg/24h) reduced by 54%) (95% C.I. 19 – 74%)
DCCT Research Group. N Engl J Med 1993;329:977-86.
Diabetes Control and Complications Trial Prevention of Macroalbuminuria
33ukpds
UKPDS: MicroalbuminuriaUKPDS: MicroalbuminuriaUrine albumin >50 mg/L
0.890.830.880.760.670.70
0.240.0430.130.000620.0000540.033
BaselineThree yearsSix yearsNine yearsTwelve yearsFifteen years
RR p 0.5 1 2
Relative Risk& 99% CI
Favoursconventional
Favoursintensive
<
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HOPE TRIAL:Predictive Variables for CV Death, MI, and Stroke
Variable Hazard Ratio
Microalbuminuria 1.59
Creatinine > 1.4 mg/dL 1.40
CAD 1.51
PVD 1.49
Diabetes Mellitus 1.42
Male 1.20
Age 1.03
Waist-Hip Ratio 1.13
Mann JFE, et al. Ann Intern Med. 2001;134(8):629-636. www.hypertensiononline.org
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Go, A. S. et al. N Engl J Med 2004;351:1296-1305
Go AS.. NEJM, 351:1296-1305, 2004
Chronic Kidney Disease and the Risks of Death, Cardiovascular Events, and Hospitalization
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Risk Factors for CVDTRADITIONAL
AgeMale genderMenopauseFamily historyHypertensionSmokingLow HDL, high LDLDiabetesInactivity, ObesityLVH
NON TRADITIONAL CaxPO4 productAnemiaInflammationHypoalbuminemia
“REVERSE” EPIDEMIOLOGYLow cholesterolLow body weightLow 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
AnemiaRenal OsteodystrophyHyperlipidemia
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What is the prevalence of anemia in CKD ?Is the pt’s GFR too good to explain anemia?
Am J Kidney Dis 34:125-134, 1999
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Etiology and Workup of Anemia in Renal Failure
Decreased productionLow EPO (renal failure)Nutritional
(Iron, B12, Folate)Infection, inflammation and malignancy
Blood Loss
Reticulocyte countRed Blood Cell indices: MCV, RDWIron Parameters
Total ironIron binding capacityFerritin
Vitamins:Folate\ B12 levels
Stools for occult bloodErythropoietin levels not indicated
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Raising Hematocrit to 30-36% improves:
Brain and cognitive functionQuality of LifeExercise capacity/muscle function?LVH?Survival
Benefits of Correction of Hb
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Principles of Anemia Treatment
ErythropoietinEpoetin alfa :Procrit ® , Epogen® Darbepoietin Alpha: ARANESP ®
TargetsHgb=11 to 12 g/dLHct =33% to 36%
Sufficient iron should be administered to maintain
TSAT of >20%, Serum ferritin level of >100 ng/mL
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lla
illi
lla
illi
Incident ESRD patients with a first service date between May 1995 & June 2003; data from Medical Evidence form.
Scorecard: Mean monthly hemoglobin (g/dl) at initiation
44
Treatment of Calcium, Phosphate Levels and Osteodystrophy
AIM: To Normalize-Serum calciumSerum PhosphorusPTH levels
Methods:Oral CalciumVitamin D analogsPhosphate 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
Wanner, C. et al. N Engl J Med 2005;353:238-248
Primary end point of cardiovascular death, nonfatal myocardial infarction, and stroke in diabetic hemodialysis pts.
47
Management of Dyslipidemia in CKD
NCEP guidelines recommended:Cholesterol <200LDL-C <100HDL-C >45 (M), 55(F)Triglycerides<150
48
Preparation for renal replacementChoice of renal replacementTimely access surgeryTimely dialysis initiation
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Preparation for Renal Replacement
When GFR <25ml/minRenal transplant is treatment of first choice
Workup living donors
If no donors availableList patient on cadaver tx. listPlace Angioaccess if HD preferred
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lla
illi
lla
illi
AV access (Target 50% Fistulae)
USRDS 2004
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Patient Survival vs Waiting Time
52
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
0
10,000
20,000
30,000
40,000
50,000
60,000
1993 1994 1995 1996 1997 1998 1999 2000 2001 2002Year
Num
ber o
f Reg
istr
atio
ns
Kidney
54
Kidney Donors Recovered1993-2002
0
1000
2000
3000
4000
5000
6000
1993 1994 1995 1996 1997 1998 1999 2000 2001 2002Year
# of
Don
ors
Rec
over
ed
Deceased Donor Living Donor
55
56
57
Awareness/CKD Stage
58
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Timing Of Nephrology Referral
Patients with chronic kidney disease should be referred to a specialist for consultation and co-management if:
the clinical action plan cannot be preparedthe prescribed evaluation of the patient cannot be carried outthe 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 monthsIntermediate: 4-12 monthsLate: <4 months
Kinchen KS….Ann Intern Med 2002 Sep 17;137(6):479-86
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Early Treatment Should Make a Difference
Brenner, et al., 2001
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PCP Must be Engaged
1) 7.6 million people with GFR 30-60 mL/min/1.73 m2
2) About 5,000 full-time nephrologists
3) 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”Spot” urine albumin/microalbumin to creatinine ratio
• Estimate GFR from serum creatinine using the MDRD prediction equation
Note: 24 hour urine collections are NOT neededDiabetics, HTN: should be tested once a yearOthers at risk: less frequently as long as normal
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SummaryOptimal Management of CKD
Delay ProgressionACE-Inhibitors/ARBBP control (130/85)Blood sugar control?Protein restriction
Treat ComorbiditiesAnemiaRenal osteodystrophyHyperlipidemiaCardiovascular diseaseNutrition, Acidosis
Preparation for renal replacementChoice of Renal ReplacementTimely access surgeryTimely dialysis initiation
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