chronic renal insufficiency catherine m clase division of nephrology mcmaster university

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