Download - Chronic Kidney Disease (CKD) Stages
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Chronic Kidney Disease (CKD)Stages
• Stage 1 GFR > 90 (evidence of renal disease)
• Stage 2 GFR 60-89• Stage 3 GFR 30-59• Stage 4 GFR 15-29• Stage 5 GFR <15 (including ESRD)
CHRONIC KIDNEY DISEASETreatment Options
•• AntiAnti--HypertensivesHypertensives•• DiureticsDiuretics•• Diabetic controlDiabetic control•• Phosphate binders, Calcium, Vitamin D3Phosphate binders, Calcium, Vitamin D3•• Erythropoietin, IronErythropoietin, Iron•• Sodium BicarbonateSodium Bicarbonate•• A.C.E. Inhibitor, AII Receptor BlockerA.C.E. Inhibitor, AII Receptor Blocker•• Dietary restrictionsDietary restrictions
–– Potassium, Sodium, Water, Protein, etc...Potassium, Sodium, Water, Protein, etc...
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END-STAGE RENAL DISEASEDefinition
•• Irreversible reduction in intrinsic renal Irreversible reduction in intrinsic renal function function belowbelow that which can be that which can be compensated for by any adjustments in diet compensated for by any adjustments in diet or medications, such that there is or medications, such that there is continuingcontinuingaccumulationaccumulation of nitrogenous waste of nitrogenous waste products, sodium, potassium, water, and /or products, sodium, potassium, water, and /or acid, ...leading to intractable clinical illness acid, ...leading to intractable clinical illness (uremia).(uremia).
Causes of End-Stage Renal Disease
• Diabetes > 40%• Hypertension 27.2%• Glomerulonephritis 12.4%• Cystic Diseases 2.9%• Interstitial Nephritis 2.8%• Collagen Vascular Diseases 2.1%• Obstructive Uropathy 1.9%
USRDS, 2001
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End-Stage Renal Disease
Treatment Options(Renal Replacement Therapy)
• Dialysis– Hemodialysis– Peritoneal Dialysis
• Renal Transplantation– Cadaver Donor– Living Donor
Indications for Renal Indications for Renal Replacement TherapyReplacement Therapy
•• Intractable volume overloadIntractable volume overload•• HyperkalemiaHyperkalemia•• Anorexia, Nausea, Vomiting, GastritisAnorexia, Nausea, Vomiting, Gastritis•• Lethargy, Seizures, ComaLethargy, Seizures, Coma•• PericarditisPericarditis•• Bleeding due to platelet dysfunctionBleeding due to platelet dysfunction
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December 31st point prevalent counts, by ESRD Treatment Modality - USRDS 2001
1990 1991 1992 1993 1994 1995 1996 1997 1998 1999
Num
ber o
f pat
ient
s (th
ousa
nds)
0
50
100
150
200
250
HemodialysisPeritoneal dialysisTransplant
28%
67%
5%
Incident & prevalent ESRD patient counts, by modality
Incident ESRD patients & December 31 point prevalent patients.
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Number of incident & point prevalent ESRD patients
projected to 2010
1984 1986 1988 1990 1992 1994 1996 1998 2000 2002 2004 2006 2008 2010
Num
ber o
f pat
ient
s (in
thou
sand
s)
0
100
200
300
400
500
600
700
IncidenceR2=99.8%
Point prevalenceR2=99.7%
ProjectionNumber of patients
95% Confidence interval
326,217
372,407
661,330
86,82598,953
172,667
USRDS 2000
DialysisBasic Principles
- CONVECTION- Movement of solutes across a semi-permeable membrane carried in the bulk movement of water (hydrostatic pressure, “ultrafiltration”)
- DIFFUSION- Movement of solutes across a semi-permeable membrane down their concentration gradient
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BloodBlood Dialysis FluidDialysis Fluid
SOLUTES, WATERSOLUTES, WATER
Dialysis Membrane
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New Eng J Med, 1997
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Tissue-Blood Equilibration
To dialyzer
Blood Tissue
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Peritoneal Dialysis
Peritoneal Membrane
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Hemodialysis vs Peritoneal Dialysis
• Rapid correction of metabolic, fluid imbalance – Blood flow 400ml/min– Dialysate flow 500 ml/min
• Cardiovascular instability• Angio-access required• Three times weekly• Better clearance of small
molecules
• Gradual correction of metabolic, fluid imbalance– Dialysate 2L/ 6 hours– Blood flow ??
• Respiratory embarrassment
• Peritoneal access• Daily treatments• Loss of albumin• Better clearance of
“middle molecules”
Factors determining the clearance of substances by dialysis
• Molecular size• Protein binding• Relative concentration (tissue vs blood vs dialysate)• Membrane characteristics (“pore size”)• Blood flow (QB)• Dialysate flow (QD)
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Relative ConcentrationsBlood Dialysate SolutionGlucose < Dextrose
Na+ = Na+
K+ > K+
HCO3 - < HCO3 -
Ca++ < Ca++
Phos >>> Ø
Urea >>> Ø
Creatinine >>> Ø
Hemodialysis: Solute Clearance
Effect of blood flow and solute size
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Peritoneal Dialysis
Effect on Ultrafiltration of changes in dialysate volume, dwell time, and [glucose]
HDPD
HD
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Risk of first all-cause hospitalization, by URRfig 5.26, incident hemodialysis patients, 1998, adjusted for age, gender,
comorbidity, disease severity, & hct, stratified on diabetic status
<60 60-<65 65-<70 70-<75 75+
Rel
ativ
e ris
k
0.6
0.8
1.0
1.2
1.4
* p < 0.001^ p < 0.01~ p < 0.05
*
USRDS, 2001
“High Intensity” Hemodialysis (Improved Outcomes in Hemodialysis)
Variables• Increased duration
– Same frequency, longer treatments• 3 x /week x 6-8 hours
• Increased frequency– Daily short treatments
• 6-7 x/week x 2-2.5 hours
• Increased frequency and duration– Daily (Nocturnal), longer treatments
• 6-7 nights/week x 8 hours
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End-Stage Renal Disease
Treatment Options(Renal Replacement Therapy)
• Dialysis– Hemodialysis– Peritoneal Dialysis
• Renal Transplantation– Deceased Donor– Living Donor
Renal TransplantationRenal Transplantation
•• Single kidney from the donor implanted into the Single kidney from the donor implanted into the iliac fossa of the recipient.iliac fossa of the recipient.
•• Renal artery and vein are anastamosed to the Renal artery and vein are anastamosed to the (external) iliac artery and vein, respectively. The (external) iliac artery and vein, respectively. The ureter is implanted into the bladder.ureter is implanted into the bladder.
•• The recipients native kidneys are not removed.The recipients native kidneys are not removed.•• Major barrier to success is immunologic.Major barrier to success is immunologic.
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Renal Transplantation (2)Renal Transplantation (2)
•• AdvantagesAdvantages (vs Dialysis)(vs Dialysis)–– Better renal function (gfr 40Better renal function (gfr 40--80 ml/min)80 ml/min)–– No further need for dialysis No further need for dialysis –– Complete correction of fluid and electrolyte Complete correction of fluid and electrolyte
abnormalitiesabnormalities–– Improved quality of lifeImproved quality of life–– Improved longevity (for comparable patients)Improved longevity (for comparable patients)
•• DisadvantagesDisadvantages–– ““LifelongLifelong”” immunosuppressionimmunosuppression–– Possible rejection (likely eventual allograft failure)Possible rejection (likely eventual allograft failure)
Renal TransplantationRenal TransplantationUSA USA -- 20052005
•• 17,000 transplants17,000 transplants–– 55% Deceased Donor55% Deceased Donor–– 45% Living Donor45% Living Donor
•• Living Related DonorsLiving Related Donors•• Living UnLiving Un--related donors (spouses, friends)related donors (spouses, friends)
•• Waiting List Waiting List –– 70,00070,000
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Renal TransplantationRenal TransplantationColumbia University Medical CenterColumbia University Medical Center
•• 199 Transplants 2005199 Transplants 2005–– 93 (47%) Deceased Donor93 (47%) Deceased Donor–– 106 (53%) Living Donor106 (53%) Living Donor
•• 65% Living Related donor65% Living Related donor•• 35% Living35% Living--Unrelated Donor (Spousal, Friends)Unrelated Donor (Spousal, Friends)
Allograft ImmunogenicityAllograft Immunogenicity
•• MMajor ajor HHistocompatibility istocompatibility CComplex (MHC)omplex (MHC)encoded proteinsencoded proteins
•• HLA antigensHLA antigens–– Class IClass I (HLA A,B (HLA A,B -- all nucleated cells)all nucleated cells)–– Class IIClass II (HLA DR (HLA DR -- APCAPC’’s, B cells, endothelial s, B cells, endothelial
cells, renal tubular epithelial cells)cells, renal tubular epithelial cells)
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CoCo--stimulatory molecules, receptors stimulatory molecules, receptors
MHC + alloantigenMHC + alloantigen
AlloAllo--Immune ActivationImmune Activation
APC(Self/Allo)
T cell Antigen T cell Antigen receptorreceptor
ILIL--22
CD3 complexCD3 complex
T cell
calcineurin
ILIL--2 receptor2 receptor
mTOR
AntigenAntigen--specificspecificActivatedActivatedCytotoxic T cellsCytotoxic T cells
AntibodyAntibody--producing B cellsproducing B cells
T cell
Types of Immunosuppressive Medications Used in Renal Transplantation
• Corticosteroids– Prednisone, Methyl-prednisolone
• Lymphocyte Proliferation/Purine Synthesis Inhibitors– Mycophenolate mofetil, Azathioprine
• Calcineurin Inhibitors– Cyclosporine, Tacrolimus
• mTOR Inhibitors– Sirolimus (rapamycin)
• Anti-Lymphocyte Antibodies– Polyclonal– Monoclonal
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CoCo--stimulatory molecules, receptors stimulatory molecules, receptors
MHC + alloantigenMHC + alloantigen
Sites of Action of Immunosuppressive Medications
APC
T cell receptorT cell receptor
ILIL--22
CD3 complexCD3 complex
T cell
calcineurin
ILIL--2 receptor2 receptor
mTOR
SteroidsSteroids SteroidsSteroids MycophenolateMycophenolate
Cyclosporine, TacrolimusCyclosporine, Tacrolimus AzathioprineAzathioprine
SirolimusSirolimus
Maintenance Immunosuppressive Maintenance Immunosuppressive RegimensRegimens
Triple TherapyTriple Therapy
Cyclosporine/ +Cyclosporine/ + MycophenolateMycophenolate ++ PrednisonePrednisoneTacrolimusTacrolimus
Cyclosporine/ + Cyclosporine/ + SirolimusSirolimus ++ PrednisonePrednisoneTacrolimusTacrolimus
SirolimusSirolimus ++ MycophenolateMycophenolate ++ PrednisonePrednisone
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Current Renal Transplant Survival Rates
1 yr 5 yr 10 yr
• Deceased donor 89 % 66% 50%
• Living Donor 95 % 79% 65%
SRTR 2005 data
10
100
Years Posttransplant
Perc
ent
Gra
ft S
urvi
val (
Log)
20
30
40
60
80
0 5 10 15 20 25
70-74 (3,155)
75-79 (3,575)
80-84 (5,035)
85-89 (7,479)
90-94 (12,793)
95-99 (18,683)
95-9990-9485-8980-8475-7970-74
17.714.412.013.113.8 13.5
T1/2
Living Donors
0 5 10 15 20 25
95-99 (37,241)
90-94 (36,458)
85-89(28,889)
80-84(13,772)
75-79(9,017)70-74(5,985)
CadaverDonors
10.99.07.76.76.87.2
T1/2
Cecka, Clinical Transplants 2000 (p. 2)
Kidney Graft Survival Rates
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Cecka, Clinical Transplants 2001 (p.4)
Living Donor Graft Survival According to Donor Relationship (1988-2000)
0
20
40
60
80
100
0 2 4 6 8 10Years Posttransplant
Per
cen
t G
raft
Su
rviv
al
HLA-IdParentmm SibOtherSpouseUnrelOffspring
n t 1/25,6768,448
11,1622,5313,0572,1135,610
22.212.314.014.014.513.612.5
Donor
Per
cen
t G
raft
Su
rviv
al
0 1 2 3 4 5
01-23-45-6
Years Posttransplant
1009080706050403020100
4,5664,238
10,4354,584
15.512.313.211.0
n T1/2HLAMM
Cecka, Clinical Transplants 2000 (p. 12)1995-1999
Effect of HLA Mismatches on Graft Survival
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Roberts, J. P. et. al. N Engl J Med 2004;350:545-551
Relative Risk of Graft Failure with One or Two Mismatches at Each HLA Locus as Compared with Zero Mismatches
Renal TransplantationMatching Donor and Recipient
• “Essential”– ABO Compatibility– Negative cross-match
• Antibodies reactive with Donor HLA: (Donor lymphocytes + Recipient serum +
Complement---> ? Cytolytic antibodies)
• Desirable– HLA Compatibility
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Survival in ESRD: Dialysis vs. Survival in ESRD: Dialysis vs. TransplantTransplant
Wolfe, et al Wolfe, et al NEJMNEJM, 1999, 1999
Survival: Transplant vs Dialysis
Relative mortality risksDialysis - Wait List (WL) vs non-Wait List: RR 0.43-0.55
Transplant vs WL Dialysis: (1st 2 wks) RR 2 - 5
Transplant vs WL Dialysis: (146 -377 d) RR 1
Transplant vs WL Dialysis: (long-term) RR 0.26 - 0.41
Wolfe et al, USRDS Database, 1998 ASN
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Challenges to Long-Term Success of Renal Transplantation
• Donor Shortage• Chronic Allograft Nephropathy
– Long-term progressive deterioration in renal function
• Patient death– Cardiovascular disease– Complications of Long-term Immunosuppression
• Malignancy• Infection
The US waiting list for deceased donor kidneys - 1992–2001
1992 1993 1994 1995 1996 1997 1998 1999 2000 2001
Waiting listKidneys
SRTR 2002
60,000
50,000
40,000
30,000
20,000
10,000
0
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Time on Dialysis vs Transplant Outcome
Meier-Kreische, et al. KI, 2000
10
100
Years Posttransplant
Perc
ent
Gra
ft S
urvi
val (
Log)
20
30
40
60
80
0 5 10 15 20 25
70-74 (3,155)
75-79 (3,575)
80-84 (5,035)
85-89 (7,479)
90-94 (12,793)
95-99 (18,683)
95-9990-9485-8980-8475-7970-74
17.714.412.013.113.8 13.5
T1/2
Living Donors
0 5 10 15 20 25
95-99 (37,241)
90-94 (36,458)
85-89(28,889)
80-84(13,772)
75-79(9,017)70-74(5,985)
CadaverDonors
10.99.07.76.76.87.2
T1/2
Cecka, Clinical Transplants 2000 (p. 2)
Kidney Graft Survival Rates
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Chronic Allograft Nephropathy
Immunologic– HLA mismatch– Acute rejection
episodes– Prior sensitization
(anti-HLA antibodies)– Inadequate
immunosuppression
Non-immunologic– Donor Organ Quality
• Number of nephrons • Delayed Graft Function/
Ischemia-Reperfusion Injury
– Nephrotoxicity of immunosuppressive drugs
• Cyclosporine, Tacrolimus– Hypertension– Hyperlipidemia– Hyperfiltration– (Recurrent/ De Novo
Disease)
•• Improved (more Improved (more biocompatible) membranesbiocompatible) membranes
•• Improved measures of Improved measures of dialysis adequacydialysis adequacy
•• Alternative dialysis Alternative dialysis schedulesschedules
•• Portable dialysisPortable dialysis•• ““Artificial kidneyArtificial kidney””
•• New/Improved New/Improved Immunosuppressive AgentsImmunosuppressive Agents
•• Molecular Diagnosis of Molecular Diagnosis of RejectionRejection
•• Improved Organ Donation Improved Organ Donation RatesRates
•• XenoXeno--transplantationtransplantation•• Tissue/Organ CultureTissue/Organ Culture•• Tolerance InductionTolerance Induction
Future Perspectives in Renal Future Perspectives in Renal Replacement TherapyReplacement Therapy
DialysisDialysis Renal TransplantationRenal Transplantation