View
222
Download
5
Category
Preview:
Citation preview
Diabetes, Anemia and Chronic Kidney Disease
Josephine Carlos-Raboca,M.D., F.P.S.E.M., Endocrinology, Diabetes and Metabolism
Makati Medical Center
OUTLINE
Defining Chronic Kidney Disease(Diabetic Renal Disease)
Pathophysiology of Anemia in CKD Effects of Anemia of CKD Benefits of Early Treatment of Anemia Clinical Trials with Epoietin beta Conclusion
What is Chronic Kidney Disease(CKD) ?
Definition ofChronic Kidney Disease (CKD)
CKD in early stages is characterised by kidney damage and level of kidney function
CKD in later stages is defined as an estimated glomerular filtration rate (eGFR) for at least 3 months of
– eGFR <60 mL/min/1.73m2
Stages of CKD are ranked by classifying severity of disease with declining eGFR and kidney damage
CKD is a serious complication of diabetes mellitus
NKF K/DOQI Clinical Practice Guidelines 2002: Am J Kidney Dis 2002; 39 (2 Suppl 1): S17-S31
Diagnosis of Kidney FunctioneGFR
eGFR can be more accurately predicted from variables such as age, gender, race and body sizes with sCr – Commonly used prediction equations
• Cockcroft-Gault uses sCr, age, weight and sex• MDRD (Modification of Diet in Renal Disease) in its simplest
form uses sCr, age, sex and race
eGFR is a better indicator of renal function than sCr alone
eGFR easily determined from routine analyses
Reviewed by Agarwal. Am J Kidney Dis 2005; 455:610-613
Glomerular Filtration Rate
Where Constant is 1.23 for men and 1.04 for women
GFR in mg/dL
GFR in umol/l
Stages of CKD by Glomerular Filtration Rate (GFR)
Stage DescriptionGFR
(mL/min/1.73m2)
1Kidney damage† with
normal or GFR≥90
2 Mild GFR 60−89
3 Moderate GFR 30−59
4 Severe GFR 15−29
5 Kidney failure <15 or dialysis
NKF-K/DOQI. Am J Kidney Dis. 2002;39(Suppl 1):S1-S266
†Kidney damage is defined by the National Kidney Foundation as ‘pathologic abnormalities or markers of damage, including abnormalities in blood or urine tests or imaging studies’
Symptoms of CKD
Diabetic kidney disease and anaemia
Anaemia is prevalent in people with diabetic kidney disease and is largely unrecognised and untreated
Anaemia occurs earlier in diabetic kidney disease than is commonly recognised
Anaemia worsens with declining kidney function .
Astor et al. Arch Intern Med. 2002;162:1401-1408
Anaemia develops early in CKD
NHANES III– 15,419 non-institutionalised adults over the age of 20
– Prevalence of anaemia (KDOQI) increased from 1% at glomerular filtration rate of 60 ml/min to 9% at 30 ml/min and 33% at 15 ml/min
Astor et al, Arch Int Med 2002; 162: 1401-1408
Hb
(g/d
L)
Glomerular filtration rate (ml/min)
5
10
15
20
60 30 15
Hb (men)Hb (women)
Aetiology of anaemia
Red Blood Cell (RBC) Production
2 000 000 cells/sec
120 000 000 cells/min
173 000 000 000 cells/day
RBC parameterNormal values in adults
Men Women
Hb (g/dL) 15.7±1.7 13.8±1.5
Haematocrit (%) 46.0±4.0 40.0±4.0
RBC count (x1012/L) 5.2±0.7 4.6±0.5
Adapted from Williams et al. In: Williams’ Hematology. 5th ed. 1995;8-15
Defining Anemia
Guideline Definition of Anemia
European Best Practice Guidelines (EBPG) 2004 Anemia Guideline
<12.0 g/d: in males and postmenopausal females;
<11.0 g/dL in premenopausal females and prepubertal patients
Kidney Disease Outcomes Quality Initiative (KDOQI) 2006 Anemia Guideline
<13.5 g/dL males
<12.0 g/dL females
Potential causes of anaemia in chronic kidney disease
Shortened red blood cell survival Iron deficiency Malnutrition and other deficiencies Chronic inflammation Decreased erythropoietin production Inhibition of erythropoiesis
The Lifecycle of the RBC
EXCRETIONMacrophage in spleen, liver or red bone marrow
Globin
Amino acids
Heme
Biliverdin
Bilirubin
Fe
Bilirubin
Circulation120 days
Fe3+ Transferrin
Ferritin and haemosiderin
Liver
Erythropoiesis in bone marrow
Erythropoietin (EPO)
Produced predominantly by peritubular fibroblasts in the kidneys and released in response to anaemia and hypoxia
Release is modulated through the sympathetic nervous system (ß-adrenergic receptors)
Anaemia associated with EPO deficiency usually occurs at a glomerular filtration rates below 35-40 ml/min but may occur at higher levels in diabetic kidney disease
Regulation of ErythropoiesisFeedback loop
Erythropoietin
RBCsErythroid marrow
CirculatingRBCs
Kidney
Adapted from Erslev & Beutler. In: Williams’ Hematology. 5th ed. 1995;425-441
O2
Erslev & Besarab. Kidney Int. 1997;51:622-630
GM-CSFIL-3, IGF-1SCF
Erythropoietin
Stage 1: CD-34 Stage 2: Erythron
Stem cell pool
Progenitor cellsBFU-E, CFU-E
Mature cellsPrecursor cellserythroblasts
The Role of Erythropoietin in Erythropoiesis
Erythropoietin Receptor
508 amino acids, 66–78 kDa glycoprotein
Located on erythroid progenitor cell surface
Approximately 1000 erythropoietin receptors per cell
Expression– primarily on CFU-E– small numbers on BFU-E– no receptors present once
cells become reticulocytes
Membrane
JAK2P JAK2 P
P
P
P
P
EPO
Target genes
STAT
STAT
Hb O2transportcapacity
peripheral hypoxia
kidneyperitubular cells
serum EPO
precursor cells
erythroblasts
reticulocytes erythrocytesHb
O2transportcapacity
Hb and Erythropoietin: the Anaemic Patient with CKD
DAMAGED
INSUFFICIENT
ANAEMIA
Diabetes and Anaemia
Diabetes
Hyperglycaemia ↓Serum EPO response
RBC abnormalities ↓ RBC survival
Anaemia
Nephropathy (35%) CKD
Neuropathy (50%) ↓Serum EPO level
Anaemia in CKD: Summary
The hormone erythropoietin is the physiological regulator of RBC production and lifespan
In individuals with CKD, damage to the kidney compromises erythropoietin production
Anaemia correlates with the severity of CKD
Effects of anaemia in diabetic renal disease?
The risk of coronary heart disease in people with diabetes is 2-4x higher than the general population and the risk of cerebrovascular disease up to 5x higher
The risks of cardiovascular disease develop early in the course of chronic kidney disease and are increased by diabetes
Combination of anaemia and chronic kidney disease substantially increases stroke risks
Anaemia predicts left ventricular mass, left ventricular dilation, heart failure and death
Reciprocal Relationship :Renal Anemia, Diabetes &
CVD
Cardiovascular disease in early chronic kidney disease
HDFP study1
– subjects with serum creatinine >150 µmol/L vs. < 150 µmol/L OR for death after 8 years 2.2
Framingham study2
– increased incidence of cardiovascular disease in those with renal insufficiency
Canadian multicenter cohort3
– incidence of cardiovascular disease already 35.2% in those with glomerular filtration rate >50 ml/min and rose to 45.3% in those with glomerular filtration rate <25 ml/min
1. Shulman et al Hypertension 1989; 13(5):I80-932. Culleton et al Kidney Int 1999; 56: 2214-22193. Levin et al, Am J Kidney Dis 1999; 34: 125
Anaemia in CKD
Anaemia in CKD induces– increased cardiovascular (CV) workload leading to
left ventricular hypertrophy (LVH)
– reduced exercise capacity
– fatigue
Anaemia in CKD is linked with– increased CV morbidity and mortality
Framingham study, N = 6223
0
5
10
15
20
25
ECG LVH CHD CHF CVD
Culleton et al Kidney Int 1999; 56: 2214-2219
8% mild CRF (males serum creatinine 136-265, females 120-265 µmol/L)
Percentage (%)
No renal insufficiencyChronic renal insufficiency
ECG LVH=echocardiogram left ventricular hypertrophyCHD=coronary heart diseaseCHF=congestive heart failureCVD=cardiovascular disease
CKD and Anaemia Increase the Risk of CHFStage 5 CKD patients on dialysis (n=433)
At start of dialysis– 31% had CHF
– 19% had angina
– 14% had coronary artery disease
On dialysis, for each 1 g/dL fall in Hb– 42% increased risk of LVH
– 18% increased risk of CHF
– 14% increased risk of death
1. Foley et al. Kidney Int. 1995;47:186-1922. Foley et al. Am J Kidney Dis. 1996;28:53-61
The Cardio-Renal Anaemia SyndromeA vicious circle
Adapted from Silverberg et al. Kidney Int Suppl. 2003;(87):S40-S47
CKD Anaemia
Hypoxia
Sympathetic activity
TNF-α
Renal vasoconstriction
Uraemia
Fluid retention
Serum EPO production Apoptosis
Hypoxia
Cardiacoutput
CHF=congestive heart failure
CHF
Anaemia, chronic kidney disease and risk of stroke – the ARIC study, n = 13,716
Community based cohort, 9 yr follow up
– mean age 54.1 ± 5.7, mean Hb 13.9, 10.6% diabetic
– 15 percent Cr Cl < 60 ml/min, mean blood pressure 120/71
– 85 percent Cr Cl ≥ 60 ml/min, mean blood pressure 121/74
– Use of anti-hypertensives 24.6% & 23.5%
Lower Cr Cl associated with higher crude stroke rate
– Cr Cl < 60 ml/min, stroke rate 3.7
– Cr Cl ≥ 60 ml/min, stroke rate 2.06
Abramson et al, Kidney Int 2003; 64: 610-615
ARIC study – influence of anaemia (WHO)
Str
oke
rat
e
Abramson et al, Kidney Int 2003; 64: 610-615
0
2
4
6
8
10
12
Total sample Anaemic group Nonanaemic group
Cr Cl ≥ 60 ml/minCr Cl < 60 ml/min
2.06
3.7
1.52
10.53
2.122.85
Hospitalisation Risk Increases with Hb <11 g/dLDialysis patients
1.16 1.091.00 1.01
1.55
0.0
0.5
1.0
1.5
2.0
<8 8−9.99 10−10.99 11−11.99 ≥12
P=0.77P<0.0001 P=0.001 P=0.05
n=7998
Pisoni et al. Am J Kidney Dis. 2004;44:94-111
RR of hospitalisation
Hb level (g/dL)
Summary : CKD and CVD
The association between chronic kidney disease and all forms of cardiovascular disease begins early in the evolution of chronic kidney disease, anaemia significantly amplifies this association
Cardiovascular events and mortality in chronic kidney disease are increased in patients with diabetic kidney disease and are closely related to anaemia
Why do we treat renal anaemia?
Subjective1
– well-being– life satisfaction– happiness– psychological affect
Objective1
– energy level– functional ability– activity level– health status
Others– cardiac status2
– blood transfusions3
– hospitalisation4
– mortality5
1. Evans et al J Am Med Soc. 1990; 263:825-8302. Winearls Nephrol Dial Transplant 1995; 10(suppl10):3-93. Fellner et al Kidney Int; 1993; 44:1309-13154 Churchill et al Clin Nephrol 1995; 43:184-1885. US Renal Data System 1998
Epoetin improves quality of life in predialysis patients
83 predialysis patients entered into a parallel-group, open-label clinical trial and randomised to – epoetin
– no treatment
Epoetin treatment significantly improved anaemia and– energy
– physical function
– home management
– social activity
– cognitive function
Revicki et al Am J Kidney Dis 1995; 25: 548-554
Correction of anaemia improves left ventricular hypertrophy in dialysis patients
22 dialysis patients studied by echocardiogram before and after correction of their anaemia with epoetin
Hb increased at least 3.0 g/dL over baseline
Correction of anaemia produced:– decrease in left ventricular mass (p = 0.0004)
– decrease in left ventricular end-diastolic volume (p <0.0001)
Adapted from Silverberg et al. Can J Cardiol 1990; 6: 1-4
Building the evidence: Mortality & hospitalisation
Collins et al1
– Relative risk of death and/or hospitalisation lowest at Hct levels of 36-39%
Fink et al2
– Pre-dialysis epoetin treatment leads to a relative risk of mortality of 0.8 (n=4866, 1107 epoetin)
1. Collins et al J Am Soc Nephrol November 20012. Fink et al Am J Kidney Dis 2001;37:348-355
Mortality and haematocrit level: First year follow up, all dialysis patients
USRDS prevalent patients 1994-1997
Haematocrit
0
50
100
150
200
250
300
350
400
<30 30 - <33 33 - <36 36+
Deaths per 1000 patient
years
Diabetes mellitus
No diabetes mellitus
Duration of Hb <11 g/dL Increases Mortality RiskDialysis patients
1.001.10 1.12
1.32
1.52
1.82
0
1
2
0 1−20 21−40 41−60 61−80 81−100
Time with Hb <11 g/dL over 2 years (%)
Ofsthun et al. Nephrol Dial Transplant. 2005;20(Suppl 5):v261 (abstract MP204)
Relative mortality risk
* ***
****
n=41 919
*P<0.05; **P<0.001
Levin et al. Nephrol Dial Transplant. 2006;21:370-377
0 3 6 9 12 15 18 21 24 27 31 33 37
Months from Hb result
Probability of survival
Hb
≥13.0 g/dL
12−12.9 g/dL
11−11.9 g/dL
10−10.9 g/dL
<10 g/dL
Log-rank test: P=0.0001
0.75
0.80
0.85
0.90
0.95
1.00
0.70
Hb Levels Predict Survival Prior to Dialysis InitiationCKD patients not on dialysis
Mean units per patient per 4 weeks
0.6
0.5
0.4
0.3
0.2
0.1
0Pre 4 12 20 28 36 44 52
Weeks
Eschbach et al. Ann Intern Med. 1989:111:992-1000
*
*autologous blood donation ahead of elective hip surgery
Commencement ofanaemia therapy
Anaemia Treatment Greatly Reduces Blood TransfusionsDialysis patients
Building the evidence: delaying progression of chronic renal failure
• 63 patients (serum creatinine > 300 μmol/L, creatinine clearance < 15 mL/min/1.73 m2)
• 20 with Hb < 10 g/dL = study group (epoetin+) 43 with Hb > 10 g/dL= control group
• Significant reduction in rate of progression of chronic renal failure in study group, no change in control group
Jungers et al Nephron Dial Transplant 2001; 16: 307-312
Trials in treatment of CKD anaemia
CREATE trial (Cardiovascular risk Reduction by Early Anaemia Treatment with Epoetin beta)
CHOIR trial (Correction of Haemoglobin and Outcomes In Renal Insufficiency)
ACORD (Anaemia CORrection in Diabetes)
Aims of the studies : to establish whether early intervention– prevents development of left ventricular hypertrophy– reduces cardiovascular mortality and morbidity– delays progression of chronic renal failure– reduces stroke and heart failure related hospitalisations
The CHOIR and CREATE Studies: OverviewCKD patients not on dialysis
CHOIR(n=1432)
CREATE(n=605)
Patient Population Stage 3–4 patients with renal anaemia and not on renal
replacement therapy (RRT)‡
Stage 3–4 CKD patients with renal
anaemia not on RRT§
Duration 16 months700 patients completed trial
48 months476 patients completed trial
Primary Endpoints Composite(death, MI, HF, stroke)
Composite(sudden death, MI, acute HF, CVA, TIA, hosp for angina or arrhythmia, PVD complications)
Hb Targets Group 1: 13.5 g/dL†
Group 2: 11.3 g/dL†
Group 1: 13–15 g/dL Group 2: 10.5–11.5 g/dL
†Original targets before protocol amendment:
• Group 1: 13.0–13.5 g/dL• Group 2: 10.5–11.0 g/dL Singh et al. N Engl J Med. 2006;355:2085-2098
Drüeke et al. N Engl J Med. 2006;355:2071-2084
‡127 and 111 patients in groups 1 and 2, respectively, progressed to RRT during study
§127 and 111 patients in groups 1 and 2, respectively, progressed to RRT during study
CHOIR: Increased Risk of Composite Event with Target Hb 13.5 g/dLStage 3–4 CKD patients
0 3 6 9 12 15 18 21 24 27 30 33 36 39
0.30
0.25
0.20
0.15
0.10
0.05
0.00
Pro
bab
ilit
y o
f co
mp
osi
te e
ven
t
Month
Hb target 13.5 g/dLHb target 11.3 g/dL
Patients at riskGroup 1 715 654 587 520 457 355 270 176 101 72 55 23Group 2 717 660 594 539 499 397 293 182 107 67 44 23
Time to the primary composite endpoint
Events: 125 vs 97HR=1.34 (1.03–1.74)Log rank test P=0.03
Singh et al. N Engl J Med. 2006;355:2085-2098
CREATE: No Significant Difference in Time to First CV EventCKD patients not on dialysis
Time to the primary endpoint of a first cardiovascular event†
†Before censoring of data on patients at the time of initiation of dialysis
100
90
80
70
60
50
40
30
20
10
0
Eve
nt-
free
Su
rviv
al (
%)
0 6 12 18 24 30 36 42 48
MonthPatients at riskGroup 1 301 279 268 249 207 158 97 56 2Group 2 302 286 272 257 223 177 121 61 2
Events: 58 vs 47HR=0.78 (0.53–1.14)Log rank test P=0.20
Hb target 13–15 g/dLHb target 10.5–11.5 g/dL
Drüeke et al. N Engl J Med. 2006;355:2071-2084
The Anaemia CORrection in Diabetes (ACORD) study
The ACORD study is investigating the effects of anaemia correction with subcutaneous epoetin beta on – cardiac structure
– cardiac function In patients with early diabetic nephropathy Primary endpoint
– effect of early anaemia treatment on left ventricular hypertrophy as a cardiovascular risk marker
Hb (g/dl)
16
14
12
10
8
6
16
14
12
10
8
6
Early intervention
Target Hb: 13–15 g/dl
Standard treatment
Target Hb: 10.5–11.5 g/dl
Inclusion:Hb 10.5–13.0 g/dlCreatinine clearance ≥30 ml/min
m
f
Time
n = 160
Randomisation
ACORD: Study design
Maintaining the Right Hb RangeSummary
Efficacy of SC epoetin beta confirmed by Hb response according to different Hb targets both in CREATE and ACORD
Complete Hb correction improves QoL and was not associated with any consistent hazard
Trend towards decrease in LVMI with complete anaemia correction among those with higher baseline LVMI
– In CREATE and ACORD annual CV event rate lower than expected from previous studies
Prospective international randomised trials (CREATE, ACORD) show no added benefit of complete Hb correction to 13-15 g/dL on CV outcome measures and CKD progression
– But it may still be beneficial as CV event rates were low
European recommendations for optimising treatment of renal anaemia
Indication for start of epoetin therapy:– repeated Hb measurements <11g/dL
– after exclusion of non-renal causes of anaemia (bleeding, nutritional deficiencies, hypothyroidism, iron deficiency, haemolysis)
Target haemoglobin: – general: Hb >11 g/dL (no upper limit)
– in CHD: Hb 11-12 g/dL Administration of epoetin:
– SC dosing preferred; IV dosing also an option in HD patients
– the goal is to increase Hb levels by 1–2 g/dL per month
van Ypersele de Strihou Nephrol Dial Transplant 1999; 14 (suppl 2): 37-45
Iron stores
Target– serum ferritin > 100 g/l (aim for 200-500)
– hypochromic red blood cell count < 10%, TSAT > 20% (aim for < 2.5% & 30-40%)
Level B Treatment strategies
– predialysis and CAPD oral intravenous
– HD will need intravenous
Level B
How should epoetin be administered to predialysis patients with diabetes and
anaemia?
EBPG & KDOQI recommend epoetin treatment for anaemia due to CKD when Hb < 11 g/dL
Hb correction should be gradual to avoid:– exacerbation of hypertension– increased viscosity with adverse haemodynamics
Guidelines recommend an increase of Hb 0.5 g/dL every 2 weeks
Common practice suggest a target Hb of 11–12 g/dL (or ?12-13 g/dL)
RECORMON DOSING GUIDE for CKD Patients with Renal Anemia:
Correction Phase
Subcutaneous Administration Intravenous Administration
60 IU/kg Body weight per week 120 IU/kg Body Weight per Week
Dosage maybe increase every 4 weeks by 60IU/kg BW/wk if the increase in PCV is <0.5 volume % per week or <0.5 g/dL Hb every 2 weeks.
Dosage maybe increase every 4 weeks by 120IU/kg BW/wk if the increase in PCV is <0.5 volume % per week or <0.5g/dL Hb every 2 weeks.
Maintenance Phase:
Dose can be reduced to 50% or adjusted at intervals of one or two weeks individually for the patients to maintain target Hb and Hct.
The clear differencesEpeotin Beta Recormon Epoetin alpha
Half life SC 12-28 hoursIV 4-12 hours
SC 12-18 hoursIV 4-6 hours
Stabilizers GlycinePoylsorbate 20UreaCalcium ChlorideComplex of 5 amino acids
GlycinePolysorbate 80
Storage and handling
2-8 degrees centigrade can be removed from refrigeration and store at 25 degrees centigrade for a single period of up to 3 days Can tolerate shaking
2-8 degrees at all timesCan not tolerate shaking
Tolerability Almost pain free at the injection site
With pain at the injection site
Dose Recommendation(Correction)
60 IU/kg Body weight/wk 100 IU/kg Body Weight /wk
Shelf Life (PFS) 24 months 18 months
Conclusions
Anaemia is prevalent in diabetic kidney disease and occurs earlier than is commonly recognised
Proven benefits of treatment of anaemia with epoetin (± intravenous iron) include– improved quality of life and performance status– regression of left ventricular hypertrophy– reduced transfusion requirements
Potential benefits of early anaemia treatment include– reduced cardiovascular mortality and morbidity– delayed progression of chronic renal failure– reduced stroke and heart failure related hospitalisations
Thank you
Recommended