1

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...

2

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

3

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

4

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.

5

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

6

BloodBlood Dialysis FluidDialysis Fluid

SOLUTES, WATERSOLUTES, WATER

Dialysis Membrane

7

New Eng J Med, 1997

8

Tissue-Blood Equilibration

To dialyzer

Blood Tissue

9

Peritoneal Dialysis

Peritoneal Membrane

10

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

12

Peritoneal Dialysis

Effect on Ultrafiltration of changes in dialysate volume, dwell time, and [glucose]

HDPD

HD

13

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

20

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

21

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

23

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

24

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

25

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