chronic renal insufficiency catherine m clase division of nephrology mcmaster university
DESCRIPTION
Size of the problem - ESRD New to ESRD Canada 1996: 3332 patients Growing at about 10% annually In CRI in nephrology clinics Rate of loss GFR ~ 6 mL/min/y Initiation of dialysis ~ 8 mL/minTRANSCRIPT
Chronic Renal Insufficiency
Catherine M ClaseDivision of NephrologyMcMaster University
Objectives
Review the epidemiology of CRI Describe progression of CRI
Evidence-based strategies to minimize progression
Be aware of the interaction between CRI and CVD
Describe reasons for referral to nephrologists Discuss rationale/evidence
Size of the problem - ESRD New to ESRD
Canada 1996: 3332 patients Growing at about 10% annually
In CRI in nephrology clinics Rate of loss GFR ~ 6 mL/min/y Initiation of dialysis ~ 8 mL/min
Size of the problem - CRI
10% of men and 2% of women have Cr>133 µmol/L
11 million in US Jones et al. Am J Kidney Dis 1998;32:992
~1 million in Canada
Referral is mandatory
Diagnostic uncertainty Treatment of specific diseases Rapidly rising creatinine (20% increase over
days to months)
Optimization of management
Prevention of progression Optimization of transition to ESRD Management of metabolic complications of
CRI Management of comorbidity
cardiac diabetic other
Optimization of management
Prevention of progression Optimization of transition to ESRD Management of metabolic complications of
CRI Management of comorbidity
cardiac diabetic other
Rates of progression in referred populations are variable
Multivariate risks for progression
HTN Proteinuria
Hypertension
Achieved BP control Intensive blood pressure control
MDRD 1994 MAP 92 mmHg vs. 107 mmHg; 98 mmHg vs. 113
mmHg renal outcomes: no difference
HOT study 1998 DBP <80 mmHg vs. 85 mmHg vs. 90 mmHg CV outcomes: no difference
Optimal blood pressure control: diabetics and nondiabetics
Major CV events MI Stroke CV death0
5
10
15
20<90 mmHg<85 mmHg<80 mmHg
p=0.50
p=0.05 p=0.74 p=0.49
Even
ts/1
000
pt-y
ears
Hot study 1998
Hypertension in patients with diabetes
UKPDS 1998 150/85 mmHg vs. 180/105 mmHg significant differences
death stroke microvascular disease
HOT study (subgroup) 1998 DBP <80 mmHg vs. 85 mmHg vs. 90 mmHg significant differences
CV events CV death
Tight control of blood pressure in patients with diabetes
Major CV events MI Stroke CV death0
10
20
30
<90 mmHg<85 mmHg<80 mmHg
HOT study 1998
p=0.005
p=0.11 p=0.34 p=0.016
Even
ts/1
000
pt y
ears
Hypertension Volume control
sodium restriction diuretics
Drug class HANE 1997
hydrochlorothiazide, atenolol, nitrendipine, enalapril
similar efficacy & tolerability Isolated systolic hypertension Proteinuria
ACE inhibition
Diabetic nephropathy Collaborative Study Group 1993
Any chronic renal failure REIN study 1997, 1998 meta-analysis Giatras 1997 proteinuria
increased effectiveness Normotensive normoalbuminaemic type II DM
Ravid 1998
ARB in DMN
Study Population Intervention Outcome Effect
Lewis HTN, >900mg proteinuria (mean
Cr 147 µmol/L)
Irbesartan up to 300 mg vs. Amlodipine vs. placebo
Doubling Cr, or ESRD, or Cr>600, or
death
At 3y, 30% in irbesartan vs
38% in amlodipine or
placebo, P<0.05, NNT 13
Brenner (RENAAL)
>300mg microalb or >500mg
proteinuria, and Cr 115-265 µmol/L (mean Cr 170
µmol/L)
Losartan 100 mg vs.
placebo
Doubling Cr, ESRD, death
At 4y, 43% in losartan, ve.
47% in placebo, P<0.05, NNT 28
Parving 20-200 µg/min albuminuria, Cr
<133 µmol/L (mean Cr 89 µmol/L)
Irbesartan 300 mg vs.
Irbesartan 150 mg vs.
placebo
>200 µg/min albuminuria
At 2y, 5% in 300 mg, 10% in 150 mg and 18% in
placebo, P<0.05, NNT (300 mg) 8
New Engl J Med 2001;345:851 & 861 & 870
ACE inhibition & ARBs
Adverse effects precipitation of ARF
monitoring usually reversible
hyperkalaemia dietary intervention diuretics K binding resins
Dietary protein restriction
MDRD 1993 1.3 vs. 0.58 g/kg/day; 0.58 vs. 0.28 g/kg/day
(+KA) selected, well-nourished patients intensive dietary counselling nutritional parameters
weight, arm circumference, % body fat albumin
no difference in rate of loss GFR
Nutrition Spontaneous reduction in protein intake, independent
of dietary advice, with advancing CRI Cross-sectional studies
Ikizler et al. J Am Soc Nephrol 1995;6:1386 Pollock et al. J Am Soc Nephrol 1997;8:777
Nutrition
Malnutrition independent predictor of death in ESRD
Bloembergen et al. Kidney Int 1996;50:557 Struijk et al. Perit Dial Int 1994;14:121 Churchill et al. J Am Soc Nephrol 1996;7:198 Blake et al. J Am Soc Nephrol 1993;3:1501 Maiorca et al. Nephrol Dial Transplant
1995;10:2295 Jassal et al. Nephrol Dial Transplant
1996;11:1052
Optimization of management
Prevention of progression Optimization of transition to ESRD Management of metabolic complications of
CRI Management of comorbidity
cardiac diabetic other
How early are patients referred before ESRD? 39% of HD patients and 27% of PD patients are
referred <4 months prior to ESRD USRDS Wave 2. Am J Kidney Dis 1997;30:S67
<1 1-3 4-12 >40
25
50
75HDPD
Months Pre-ESRD
Perc
ent o
f Pat
ient
s
How early are patients referred?
Canada, 1998-1999 Consecutive patients new to ESRD Multicentre, N=238 35% first saw a nephrologist within 3 months
of starting dialysis Curtis et al. Submitted
Referral time
Effects on mortality morbidity access: Collins 1997 modality: Bloembergen 1997 quality of life: Jones 1998
Morbidity Early Late p
Ratcliffe 1984 Complications prolonging hospital stay (%) 9 70 <0.001
Campbell 1989 Hospital stay (days) 9 30 ?
Jungers 1993 Initial hospitalization (days) 5.8 34.5 <0.0001
Ifundu 1996 Hospital stay (days) 12 25 <0.002
Sakai 1997 Hospital stay (days) 47 31 0.008
Gøranson 2001 Hospital stay (days) 7 31 <0.0001
Mortality
Ratcliffe 1984 Survival (%) 97 87 ?
Campbell 1989 1 y survival (%) 94 61 ?
Eadington 1994 2 y survival, patients with high comorbidity
(%) 44 31 <0.01
Survival and referral time
0
25
50
75
100LateEarly
% m
orta
lity
Ratcliffe 1984 Campbell 1989 Eadington 19940
25
50
75
100EarlyLate
% S
urvi
val
How early should patients be referred to observe these benefits?
Canadian Clinical Practice GuidelinesCreatinine clearance
Cockcroft-Gault formula
Refer when GFR <30 mL/min Refer when Cr <300 µmol/L
Whichever is worse Mendelssohn CMAJ 1999;161:4
CrCl age weightCr
( )140 ( 1.2 if male)
Referral to nephrologists in Ontario Mailed survey, N=728, 41% response rate
Mendelssohn et al. Arch Intern Med 1995;155:2473
Haematuria Proteinuria Cr >120 Cr >150 Cr >300 Cr >600 Cr >9000
25
50
75
100
Criteria for Referral to Nephrologist
Perc
ent o
f GPs
Modality selection
Late referrals less likely to select PD: Bloembergen 1997
Multidisciplinary education time to requirement of dialysis: Binik 1993
Choice HRQoL on PD: Szabo 1997
Access AVF > PTFE > catheter
25% access at 30 days prior to initiation: USRDS 1997 Woods 1997, Collins 1997
access-related morbidity cost mortality
Assessment Preservation of veins Creation of fistula at GFR 15 - 25 mL/min
Timing of initiation of dialysis
Early dialysis Tattersall 1995 CanUSA 1998 Bonomini 1979 - 1986
Results morbidity mortality rehabilitation
Symptoms at initiation in the elderly: Porush & Faubert 1991
No of Patients (%)Non-specific
Weakness 68 (58)Anorexia, weight loss 72 (61)
Nervous systemEncephalopathy 58 (48)Peripheral neuropathy 8 (7)
GastrointestinalNausea, vomiting 48 (41)Bleeding 12 (10)
CardiovascularVolume overload 19 (16)Pleuropericarditis 2 (2)
Optimization of management
Prevention of progression Optimization of transition to ESRD Management of metabolic complications of
CRI Management of comorbidity
cardiac diabetic other
Anaemia Progressive relative erythropoietin deficiency and
uraemic resistance to erthropoietin Cardiac
In ESRD LV dilatation, CHF, death: Foley 1996 hospitalization, LoS, death: Collins 1997
In CRF LVH: Levin 1996
Quality of life SF-36 (ESRD): Merkus 1997 SIP (CRF): Klang 1996
Treatment of anaemia Erythropoietin
cost regulations monitoring
Iron p.o. (timing) or i.v.
Benefits quality of life
energy, physical functioning no change in GFR, may BP
Target Hgb
Calcium homeostasis
Phosphate retention early not necessarily accompanied by phosphate
1, 25 D3 deficiency
Hypocalcaemia Hyperparathyroidism
Management of calcium homeostasis
Dietary intervention Phosphate binders
Calcium carbonate 1-alphacalcidol
decreases PTH no effect on GFR monitoring
Metabolic acidosis
Malnutrition Metabolic bone disease Treatment
Sodium bicarbonate
Malnutrition
Progressive spontaneous decline in protein intake MDRD 1994, Ikizler 1995, Pollock 1996
Malnutrition at initiation: CanUSA 1996 morbidity mortality
Improves with starting dialysis: CanUSA 1996
Malnutrition
Management dietary intervention
0.8 - 1.3 g/kg/day protein adequate calories
control of acidosis initiation of dialysis
Cockcroft-Gault (mL/min) MDRD equation 7 (mL/min/1.73m2) Couchoud (mL/min/1.73m2)
<20 <30 <40 <20 <30 <40 <30
Any metabolic abnormality *
Sensitivity 45 74 87 70 88 96 91
95% CI 37-54 66-81 81-92 62-77 82-93 91-98 86-95
Haemoglobin <110 g/L
Sensitivity 58 80 90 78 93 98 93
95% CI 48-67 71-86 84-95 70-81 87-97 93-99 88-97
Albumin <35 g/L Sensitivity 38 57 76 61 79 94 83
95% CI 28-49 46-67 66-84 51-71 69-86 87-98 74-90
Bicarbonate <23 mmol/L
Sensitivity 55 76 90 75 87 93 90
95% CI 44-65 65-84 81-95 64-83 78-94 86-97 83-96
Calcium <2.15 mmol/L
Sensitivity 53 75 84 79 89 98 93
95% CI 40-66 63-85 73-92 67-88 79-96 92-100 84-98
Phosphorus >2.1 mmol/L
Sensitivity 100 100 100 100 100 100 100
95% CI 77-100 77-100 77-100 78-100 78-100 78-100 79-100
Phosphorus >1.6 mmol/L
Sensitivity 70 91 100 94 100 100 100
95% CI 57-80 82-97 95-100 86-98 95-100 95-100 95-100
PTH >22.8 pmol/L Sensitivity 61 88 99 85 100 100 100
95% CI 50-72 79-94 93-100 75-92 96-100 96-100 96-100
Cockcroft-Gault (mL/min) MDRD equation 7 (mL/min/1.73m2) Couchoud (mL/min/1.73m2)
<20 <30 <40 <20 <30 <40 <30
Any metabolic abnormality *
Specificity 95 69 45 93 54 30 43
95% CI 87-99 57-79 34-57 85-97 43-65 20-41 32-55
Haemoglobin <110 g/L Specificity 83 59 38 76 44 20 36
95% CI 77-87 53-66 32-44 70-81 37-50 15-25 30-42
Albumin <35 g/L Specificity 72 49 32 65 36 17 28
95% CI 66-77 43-55 26-38 59-71 30-42 12-22 22-33
Bicarbonate <23 mmol/L
Specificity 79 56 36 70 40 16 33
95% CI 74-84 50-62 30-42 64-75 34-46 12-21 27-39
Calcium <2.15 mmol/L Specificity 74 52 33 65 37 16 29
95% CI 69-79 46-58 28-38 60-71 31-42 12-21 24-35
Phosphorus >2.1 mmol/L
Specificity 73 50 31 60 33 14 26
95% CI 68-78 44-55 26-36 55-66 28-38 11-18 22-31
Phosphorus >1.6 mmol/L
Specificity 80 57 37 71 40 17 31
95% CI 75-84 51-63 32-43 65-76 34-46 13-22 26-37
PTH >22.8 pmol/L Specificity 82 55 35 70 39 18 31
95% CI 76-87 48-63 28-43 63-77 32-47 13-25 25-38
Nutrition in unreferred populations
National Health and Nutrition Examination Survey III database
5248 participants over 60y Composite definition of malnutrition Adjusted OR for malnutrition
GFR 30-60 mL/min 1.2 (0.7 – 2.0) GFR <30 mL/min 3.6 (2.0 – 6.6)
Garg et al, submitted
Optimization of management
Prevention of progression Optimization of transition to ESRD Management of metabolic complications of
CRI Management of comorbidity
cardiac diabetic other
Cardiac comorbidity is common
Consecutive prevalent patients with CRI in nephrology clinics, mean GFR 75 mL/min
Previous CVD 38.5% CVD associated with severity of CRI 80% hypertension 43% hyperlipidemia 38% had diabetes mellitus 27% were smokers
Renal insufficiency is an independent CV risk factor
Meta-analysis performed with a fixed effects model. Cardiovascular events included cardiovascular mortality, myocardial infarction or stroke.
A lack of homogeneity was present among studies (P < 0.001).
Adjusted hazard ratio (95% confidence interval) 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5
NHANES I FRAMINGHAM
BRHS
SOLVD
PIUMA CHS HOT
HOPE
POOLED ESTIMATE
1.4 (1.3 – 1.6)
Garg et al. Submitted.
Cardiac comorbidity
Hypertension control Lipid-lowering agents ACE inhibition Beta-blockers ASA Anticoagulation Smoking cessation
Diabetic comorbidity Glycaemic control
DCCT 1993 (type I) UKDPS 1998 (type II)
Hypertension HOT 1998 (subgroup) UKPDS 1998
ACE inhibitors retinopathy (Euclid 1998)
Formalized care of patients with chronic renal failure
Urgent dialysis Hospitalized Outpatient training0
25
50
75
100
Usual nephrological careCRF clinic
% p
atie
nts
Levin 1997
p<0.05 p<0.05
p<0.05
Referral is mandatory
Diagnostic uncertainty Treatment of specific diseases Rapidly rising creatinine (20% increase over
days to months)
Optimization of management
Prevention of progression Optimization of transition to ESRD Management of metabolic complications of
CRI Management of comorbidity
cardiac diabetic other
Role of non-nephrologist
Diagnosis Establish chronicity/progression rate Manage HTN Use ACE, ARB Manage comorbidity Monitor progression Consider referral
When to Refer: Role of Nephrologist Diagnostic uncertainty Rapid progression
GFR < 30mL/min Management of complications Preparation for dialysis
Objectives
Review the epidemiology of CRI Describe progression of CRI
Evidence-based strategies to minimize progression
Be aware of the interaction between CRI and CVD
Describe reasons for referral to nephrologists Discuss rationale/evidence