REFERENCES - Custodiol HTK · 2016-02-10 · 13) deBoer J, DeMeester J, Smits, JMA et al., Eurotransplant randomized multicenter kidney graft preservation study comparing HTK with

Please see accompanying Prescribing Information.

© 2015 Essential Pharmaceuticals, LLC ESS 2015-1 01/15

• REFERENCES •1) Custodiol HTK Solution PI available at http://www.custodiol.com/

prescribing-info/

2) Erhard J, Lange R, Scherer R, et al. Comparison of histidine-tryptophan-ketogluterate (HTK) solution versus University of Wisconsin (U of W) solution for organ preservation in human liver transplantation. A prospective, randomized study. Transplant Int. 1994; 7:177-181

3) Fridell JA, Mangus RS, Tector AJ. Clinical experience with histidine-tryptophan-ketogluterate solution in abdominal organ preservation; a review of recent literature. Clin Transplant 2008 DOI: 10.1111/j.1399-0012.2008.00958.

4) Gebhard MM, Kirlum HJ, Schlegel C. Organ preservation with the solution HTK. In: Hess UJ, de Hemptinne B, eds. Organ Preservation with HTK and U of W Solution: Update on Clinical Use and Experimental Studies. Lengerich, Germany: Pabst Science Publishers; 1999:75-87

5) Welling TH, Heidt DG, Englesbe MJ, et al., Biliary complications following liver transplantation in the model for end-stage liver disease era: effect of donor, recipient and technical factors. Liver Transpl. 2008 14:73-80

6) Ringe B, Braun F, Moritz M, Zeldin G, Soriano H, Meyers W. Safety and efficacy of living donor liver preservation with HTK solution. Transplant Proc. 2005; 37:316-319.

7) Mangus RS, Fridell JA, Vianna RM et al. Comparison of histidine-tryptophan-ketogluterate solution and University of Wisconsin in Extended Criteria Liver Donors. Liver Transplantation 2008 14:365-373

8) Heidenhein C, Pratschke J, Puhl G., et al. Incidence of and risk factors for ischemic-type biliary lesions following orthotopic liver transplantation. Transplant Intl. 2009 ISSN 0934-0874

9) O’Callaghan JM, Morgan RD, Knight SR, et al., The effect of preservation solutions for storage of liver allografts on transplant outcomes. A systematic review and meta-analysis. Annals of Surgery 2014:46-55

10) Lynch RJ, Kubus J, Chenault RH, et al., Comparison of histidine-tryptophan-ketogluterate and University of Wisconsin preservation in renal transplantation. American Journal of Transplantation. 2008;8:567-573

11) Rofaiel G., Bakthavatsalam R., Dick A., et al., HTK and U of W are more efficacious and cost effective than LR for the preservation of live donor kidneys. ATC Annual Meeting 2012 Poster Session, Kidney Transplantation

12) Argawal A, Murdock P, Fridell JA. Comparison of histidine-tryptophan-ketogluterate (HTK) solution and University of Wisconsin in prolonged cold preservation of kidney allografts. Transplantation. 2006;81-480-482

13) deBoer J, DeMeester J, Smits, JMA et al., Eurotransplant randomized multicenter kidney graft preservation study comparing HTK with U of W and Euro-Collins. Transplant Int 1999 12:447-453

14) Schneeberger S, Biebl M, Steurer W, et. Al., A prospective randomized multicenter trial comparing histidine-tryptophan-ketogluterate versus University of Wisconsin perfusion solution in clinical pancreas transplantation. Transplant Int. 2008 ISSN 0934-0874

15) Reddy KS, Moss A, Mekeel K et al., Pancreas Transplantation using HTK preservative: Is it a cautionary tale? ATC 2009 Poster Session June 1, 2009 Exhibit Hall C

16) Paushter DH, Meirigeng Q, Danielson KK et al., Histidine-tryptophan-ketogluterate and University of Wisconsin solution demonstrated equal effectiveness in the preservation of human pancreata intended for islet isolation: A large scale, single-center experience. Cell Transplantation 2013 Vol 22 pp 1113-1121

For more information, e-mail us at [email protected] or call 1-844-Ess-Prod (377-7763)

Visit our websites at www.custodiol.com www.essentialpharma.com


100 Princeton South Corporate Center Suite 140 Ewing, NJ 08628 ORGAN

PRESERVATION SOLUTION

kidney liver

pancreas

• TRULY READY TO USE •




prescribing-info/





















kidney liver

pancreas


CUSTODIOL® HTK SOLUTION Custodiol ® HTK Solution is intended for perfusion and flushing of donor liver, kidney, pancreas (and heart) prior to

removal from the donor for preserving these organs during hypothermic storage and transport to the recipient. It is based on the principal of inactivating organ function by withdrawal of extracellular sodium and calcium, together with intense buffering of the extracellular space by means of histidine/histidine HCI, so as to prolong the period for which the organs will tolerate interruption of blood and oxygen.

INTRODUCTION

CUSTODIOL® HTK SOLUTION• Low Viscosity(2)

• Low Potassium content safe for systemic absorption(2)

• Low Sodium(3)

• No Starch • Buffered with histidine and histidine HCI

• Doubles buffering capacity in transplanted organs which moderates drop pH(4)

• Protects against edema(4)

• Lower Biliary complications(5)(8)

• No Flush needed(1)

HTK (Custodiol®) UW (ViaSpan®)____________________________________________________________________________________________________________Composition K+ low K+ high____________________________________________________________________________________________________________Viscosity (1°C) High: 6.2 cP 2.0 cP, ~water____________________________________________________________________________________________________________Flow Higher:x3 Lower____________________________________________________________________________________________________________Cooling Faster Slower____________________________________________________________________________________________________________Additives Ready-to-use Several: fresh GSH____________________________________________________________________________________________________________Filters (<1–5 μm) No Yes: particles 3-25->100 μm____________________________________________________________________________________________________________Flushing Prior to Implant No Yes____________________________________________________________________________________________________________Adverse events None Cardiovascular complications____________________________________________________________________________________________________________In situ protection Heart, kidney, No liver

cP–centipoise

Organ Preservation Solutions: Major Clinical Differences(6)

EXTENDED CRITERIA DONORS In a study comparing HTK and U of W in a large number of SCD and ECD livers, the authors concluded that HTK and U of W are not clinically distinguishable in the large sample of liver transplants. However, HTK may be protective against biliary complications. Kaplan-Meier graft survival curves failed to demonstrate a significant difference in SCD or ECD livers.(7)

LIVER TRANSPLANTATION

A recent study concluded that Ischemic-type biliary lesions (ITBL) account for a major part of patients’ morbidity and mortality after orthotopic liver transplantation (OLT). This study retrospectively evaluated 1843 patients.(8)

Organs that were perfused with University of Wisconsin (U of W) solution developed ITBL significantly more often than Histidine- Tryptophane-Ketogluterate (HTK) perfused organs (P=0.036).(8)

The authors of this study mentioned that the clinical consequences of this study for their institution have been the strict limitation of CIT to <10h and the exclusive use of HTK solution.(8)

In a meta-analysis and systematic review on the effect of preservation solutions for liver transplant, the authors concluded there was no good evidence of any difference in outcomes when comparing HTK and either University of Wisconsin solution or Celsior(9)

0 50 150 350250100 200 300Days graft survival

0.0

0.2

0.4

0.6

0.8

1.0

Cum

Sur

viva

l

Preservation Solution

HTK-censored+U of W-censored+

U of WHTK

Kaplan-Meier graft survival for donor liver allografts from SCDs preserved in HTK (n = 111) or U of W

(n = 98) preservation solution (log rank P = 0.14)

Early dysfunction comparing HTK with U of W solution in randomized controlled trials(9)

Kaplan-Meier graft survival for donor liver allografts age 60 years and older preserved in HTK (n = 40) or U of W

(n = 30) preservation solution (log rank P = 0.13).

Erhard 1994

Meine 2006

Brolese 2008

Fixed E�ects Model for All Studies

nHTK U of W

N

0

Author and Year

30 30

1

1

6

6

2

37 65

148 74

n N

0.33 [0.01, 7.87]

0.29 [0.04 , 2.34]

1.50 [0.31 , 7.25]

0.73 [0.23 , 2.35]

Relative Risk (log scale)0.10 1.00 10.00

Relative Risk [95% CI]

Erhard 1994

Meine 2006

Brolese 2008

Fixed E�ects Model for All Studies

nHTK U of W

N

0

Author and Year

30 30

1

1

6

6

2

37 65

148 74

n N

0.33 [0.01, 7.87]

0.29 [0.04 , 2.34]

1.50 [0.31 , 7.25]

0.73 [0.23 , 2.35]

Relative Risk (log scale)0.10 1.00 10.00

Relative Risk [95% CI]

Forest plot shows relative risk comparing U of W and HTK in randomized controlled studies (<1 favors HTK). Q =1.78, p = .041

0 50 150 350250100 200 300Days graft survival

0.0

0.2

0.4

0.6

0.8

1.0

Cum

Surv

ival

Preservation Solution

HTK-censored+U of W-censored+

U of WHTK

LIVING DONOR DATAIn a study comparing HTK and U of W in Renal Transplantation, the authors concluded HTK demonstrated similar

efficacy to U of W in terms of patient and graft survival. (10)

HTK was associated with a significant risk reduction on the incidence of DGF

• Graft survival did not significantly differ by preservation solution but in living donor patients, HTK showed a trend toward improved long-term graft survival over U of W solution

KIDNEY TRANSPLANTATION

HTK versus U of W for Renal Transplant

In a study looking at cost effectiveness of preservation solutions in live donor kidneys, it was shown that HTK is superior to LR for preventing DGF, HTK and U of W are more cost effective than LR and LRD in transplantation. (11)

Months after transplantation

Effect of initial graft function of graft survival in the U of W-HTK study

The multivariate analysis of the U of W-HTK study showed that the kind of preservation solution used was not associated with INF. But four other factors were indeed associated with INF: donor age, donor cause of death, re-transplantation and cold ischemic period(13)

KAPLAIN-MEYER KIDNEY ALLOGRAFTIn a study comparing HTK and U of W in Renal Trans-plantation, the authors concluded HTK demonstrated similar efficacy to U of W in terms of patient and graft survival.(10)

0.6

0.8

1.0

Cum

ulat

ive

Surv

ival

Months0.00 10.00 20.00 30.00 40.00 50.00

U of WHTK

Deceased donor

HR = 1.100 (95% Cl = 0.632-1.981

Preservative

0.6

0.8

1.0

Cum

ulat

ive

Surv

ival

Months0.00 10.00 20.00 30.00 40.00 50.00

U of WHTK

Living donor

HR = 1.001 (95% Cl =0.558- 1.794)

Preservative

0

50

60

70

80

90

100

12 24 36

Gra

ft S

urvi

val (

%)

Months After Transplant

P = 0.0005

P=0.001

x

xxx

x x

x

xxxx

xxxxxx

x x x x x x xx x x x

x xxx xxxxxx ....

x

HTK-IGF (n=189)HTK-INF (n=102)U of W-IGF (n=187)U of W-INF (n=94)

In a study by Argarwal et at., is was found that HTK is not inferior to U of W (as previously suggested by other authors) and may in fact be better protection for the prevention of delayed graft function compared to U of W solution(12)

NON LIVING DONOR DATAIn a randomized multi-center study on kidney graft preservation comparing HTK with U of W and Euro Collins, the authors concluded HTK is comparable to U of W in its preservative abilities(13)

Figures A & B - Survival after transplant using either U of W or HTK organ preservation solution. The hazard ratio refers to the risk of graft loss when HTK solution was used compared to U of W solution.

Figure A.

Figure B.

A recent study prospectively evaluated early graft function in clinical pancreas transplantation after organ perfusion with HTK versus U of W. This prospective, randomized study, in concordance with the findings of previous retrospective comparisons of pancreas per-fusion with HTK versus U of W solution demonstrated equally good patient and graft survival for both preser-vation fluids. HTK solution appears to be equally suit-able as U of W solution for in situ perfusion and organ preservation in clinical pancreas transplantation(14)

The study was designed as a phase III study for Germany.(14)

PANCREAS TRANSPLANTATION

PANCREAS TRANSPLANTATION USING HTK PRESERVATION: IS IT A CAUTIONARY TALE?(15)

This study looks at pancreas transplant outcomes. The authors performed 115 PTXs (simultaneous kidney PTX (SKPTs) and 28 solitary PTX’s (SPTs) in 114 patients between July 2003 and September 2008(15)

Outcomes in HTK v U of W Group

Normal endocrine function (no need for exogenous insu-lin) for patients with organs perfused with HTK (n = 27)

versus U of W (n = 41) solution during the first 6 months after pancreas transplantation (mo, months).

HTK (n=75) U of W (n=39) P Value_______________________________________________30 day P 93% 95% NS graft survival _______________________________________________1 yr 89% 85% NS actual P graft survival (for pts w 1 yr FU)_______________________________________________1 yr 95% 100% NS actual K graft survival (for pts w 1 yr FU)

HTK

U of W

0

20

40

60

80

100

Full

panc

reas

func

tion(

%)

day 1 day 3 day 10 day 20 3 months 6 months

P=1.00P = 0.453 P=0.428 P=0.728 P=0.406 P=1.00

Conclusion – There is no difference in the kidney and pancreas graft survival rates between HTK and U of W preservation solutions in PTX recipients with cold isch-emia times up to 15 hrs. (15)

A recent study compared the effectiveness of HTK and U of W in the preservation of human pancreata intended for islet isolation. The authors concluded HTK and U of W possess equal capacity to prevent cellular edema throughout the pancreas procurement and isolation process.(16)

The quality of pancreas flush and preservation is one of the most important determining factors for the success-ful grafting of both whole pancreata and isolated islets(16)

F3p=0.01

F4p=0.47

F5p=0.08

F6p=0.008

F7p=0.003

F9p=0.02

F8p=0.02

F10p=0.11

F11p=0.34

F12p=0.47

0

20

40

60

80

100

Isle

t Pur

ity [%

]

U of WHTK

Islet purity distribution across purification fractions. The number of isolations analyzed was 95 and 157 for HTK and U of W, respectively. Data was expressed as percentages and adjusted for age, sex, BMI, CIT and enzyme. Sample size ranged from 167-249 across frac-tions. Statistical significance was set at p<0.01.

The distribution of islet purity across fractions also served as an indicator of purification outcome and an indirect measurement of cellular edema. Within the top fraction (>69%), the islet purity distribution was similar between the HTK and U of W groups. However within the middle fraction (40-69%), a significantly higher puri-ty was observed in fractions 6 and 7 if the HTK group.(16)

PANCREAS TRANSPLANTATION




prescribing-info/





















kidney liver

pancreas


Documents

REFERENCES - Custodiol HTK · 2016-02-10 · 13) deBoer J, DeMeester J, Smits, JMA et al., Eurotransplant randomized multicenter kidney graft preservation study comparing HTK with