Chronic Renal Insufficiency Catherine M Clase Division of Nephrology McMaster 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

Hypertension in patients with diabetes UKPDS /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

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 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 vs g/kg/day; 0.58 vs 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

How early are patients referred? Canada, 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

Survival and referral time

How early should patients be referred to observe these benefits?

Canadian Clinical Practice Guidelines Creatinine clearance Cockcroft-Gault formula Refer when GFR <30 mL/min Refer when Cr <300 µmol/L Whichever is worse Mendelssohn CMAJ 1999;161:4

Referral to nephrologists in Ontario Mailed survey, N=728, 41% response rate Mendelssohn et al. Arch Intern Med 1995;155:2473

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 mL/min

Timing of initiation of dialysis Early dialysis Tattersall 1995 CanUSA 1998 Bonomini Results  morbidity  mortality  rehabilitation

Symptoms at initiation in the elderly: Porush & Faubert 1991

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 D 3 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 g/kg/day protein adequate calories control of acidosis initiation of dialysis

Cockcroft-Gault (mL/min)MDRD equation 7 (mL/min/1.73m 2 )Couchoud (mL/min/1.73m 2 ) <20<30<40<20<30<40<30 Any metabolic abnormality * Sensitivity % CI Haemoglobin <110 g/L Sensitivity % CI Albumin <35 g/L Sensitivity % CI Bicarbonate <23 mmol/L Sensitivity % CI Calcium <2.15 mmol/L Sensitivity % CI Phosphorus >2.1 mmol/L Sensitivity100 95% CI Phosphorus >1.6 mmol/L Sensitivity % CI PTH >22.8 pmol/L Sensitivity % CI

Cockcroft-Gault (mL/min)MDRD equation 7 (mL/min/1.73m 2 )Couchoud (mL/min/1.73m 2 ) <20<30<40<20<30<40<30 Any metabolic abnormality * Specificity % CI Haemoglobin <110 g/LSpecificity % CI Albumin <35 g/LSpecificity % CI Bicarbonate <23 mmol/L Specificity % CI Calcium <2.15 mmol/LSpecificity % CI Phosphorus >2.1 mmol/L Specificity % CI Phosphorus >1.6 mmol/L Specificity % CI PTH >22.8 pmol/LSpecificity % CI

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 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 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

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