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Annals of Biomedical Engineering (! 2010)DOI: 10.1007/s10439-010-0228-7 Hypothermic Machine Perfusion of Kidney Grafts: Which Pressure is Preferred? B. M. DOORSCHODT,1 M. C. J. M. SCHREINEMACHERS,2 M. BEHBAHANI,3 S. FLORQUIN,2 J. WEIS,4 M. STAAT,5 1Institute for Laboratory Animal Science and Experimental Surgery, RWTH-Aachen University, Pauwelsstr. 30, 52074 Aachen, Germany; 2Department of Pathology, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands; 3Chair for Computational Analysis of Technical Systems, RWTH-Aachen University, Schinkelstr. 2, 52062 Aachen, Germany; 4Institute of Neuropathology, RWTH-Aachen University, Pauwelsstr. 30, 52074 Aachen, Germany; and 5Institute of Bioengineering and Biomechanics Laboratory, Aachen University of Applied Sciences, Heinrich-Mußmann-Str. 1, 52428 Ju¨lich, Germany (Received 27 April 2010; accepted 26 November 2010) Associate Editor Stefan Jockenhoevel oversaw the review of this article.
Abstract—To assess the effect of the perfusion pressure (PP) during machine perfusion (MP) on the preservation quality ofkidney grafts, we compared mean PPs of 25 and 30 mmHg Currently, hypothermic machine perfusion (MP) is using a porcine autotransplantation model. After assessment gaining ground as the preservation method of choice of the microcirculation, animals underwent left nephrectomy.
for kidney grafts since the first large clinical random- Thereafter, kidneys were washed out followed by 20 h of MPat 25 mmHg (MP25, n = 7) or 30 mmHg (MP30, n = 7) ized study demonstrated a beneficial effect of MP over using a novel MP system for hypothermic pulsatile perfusion.
cold storage The benefit of MP is probably that After MP preservation, the contralateral kidneys were it ensures a uniform distribution of preservation fluid removed and the preserved kidneys heterotopically auto- throughout the organ, which is better than a single transplanted. Ten minutes after reperfusion, the microcircu- flush.Although MP provides favorable preservation lation was reassessed. Seven days posttransplant, animalswere euthanized and the kidney grafts removed for histolog- quality over CS, it remains a more complex and ical analysis. MP using a mean PP of 25 mmHg resulted in expensive procedure. Therefore, simple CS preserva- higher capillary blood flow after reperfusion. In the MP30 tion is still the preservation method of choice. Inter- group, 6 out of 7 animals survived, whereas in the MP25 estingly, in addition to the favorable results of MP group all animals survived. Overall, improvement in recovery regarding renal function, recently, two studies on the of renal function and a better preservation of structuralintegrity were seen in the MP25 group compared to the MP30 cost-effectiveness of MP as a preservation method for group. Using a novel system for hypothermic MP, a mean PP kidney grafts demonstrated that MP is preferable to of 25 mmHg is preferred over a mean PP of 30 mmHg.
CS since it adds substantial value, not only from afunctional perspective but foremost from a cost- Keywords—Perfusion pressure, Preservation, Transplanta- effective perspective.Therefore, it is expected that MP will gain a wider clinical acceptance in the nearfuture.
Nowadays, three MP systems are commercially available; The LIFEPORT (Organ Recovery SystemsInc., Des Plaines, IL, USA), the RM3 (Waters Medical Perfusion pressure Systems LLC, Plymouth, MN, USA), and the KIDNEY Machine perfusion ASSIST (Organs Assist BV, Groningen, the Nether- lands). These systems are used in combination withKPS-1 (Organ Recovery Systems Inc., IL, USA) which Address correspondence to R. H. Tolba, Institute for Laboratory is currently the only commercially available MP solu- Animal Science and Experimental Surgery, RWTH-Aachen Uni- tion. In the MP systems, the mean perfusion pressure versity, Pauwelsstr. 30, 52074 Aachen, Germany. Electronic mail: (PP) with which the perfusion medium is provided to the This study was performed at the House of Experimental Therapy, organ can be altered by the operator. In a survey of 12 University Clinic of Bonn, Sigmund-Freud-Str. 25, 53105 Bonn, organ procurement organizations in the US which used Germany and in part at the affiliations mentioned above.
! 2010 Biomedical Engineering Society DOORSCHODT et al.
MP for kidney preservation, a variety of PPs were GmbH, Ulm, Germany), all administered intrave- nously (IV) by means of a butterfly cannula inserted Although Moers et al. applied a fixed systolic PP of into an external marginal ear vein and maintained after 30 mmHg in the aforementioned clinical trial, other intubation by mechanical ventilation with isoflurane.
clinical and preclinical investigators applied different Thereafter, the right internal jugular vein was cannu- mean PPs. In a study comparing CS and MP for the lated with a PE (polyethylene) catheter for infusion preservation of kidney grafts using a porcine kidney and daily collection of blood samples. After the autotransplantation model, Nicholson et al.applied assessment of the microcirculation at four pre-defined a mean arterial PP of 60 mmHg. Treckmann et locations on the renal surface using a combined laser applied a systolic PP of 40–50 mmHg, whereas Doppler and flowmetry system (oxygen-to-see, O2C Maathuis et aldemonstrated that a PP of 30/20 mmHg system, LEA Medizintechnik, Giessen, Germany), a provided favorable results over 60/40 mmHg.
left nephrectomy was performed. Immediately there- Recently, a new MP system with a gas pressure- after, kidneys were washed out ex vivo using 500 mL of driven perfusion pump has been developed for hypo- POLYSOL (Doorzand Polysol B.V., Amsterdam, The thermic pulsatile perfusion of kidney This Netherlands) at 4 "C at a hydrostatic pressure of system is used in combination with POLYSOL, a new 100 cm H2O followed by weighing of the grafts.
low viscosity solution (cP at 5 "C: 1.8 vs. 2.5 of KPS-1)which has been developed for washout and hypother- mic MP and CS preservation of abdominal organs.
POLYSOL demonstrated favorable results in CS kid- Subsequently, kidneys were connected to the MP ney preservation as demonstrated by an improved microcirculatory status and improved graft functi Amsterdam, The Netherlands) for a 20 h period. The The aim of this study was to assess the effect of the PP features of the AIRDRIVE MP system have been during hypothermic MP preservation of kidney grafts.
described in detail previously.Oxygen pressure gener- To this end, pulsatile perfusion preservation at a mean ated by a 2 L medical oxygen cylinder is used to propel PP of 25 mmHg was compared to MP at a PP 30 mmHg a pulsatile membrane pump and to actively oxygenate using a porcine kidney autotransplantation model.
the perfusion medium during perfusion at 4 "C. Forthis study, the mean PP of the pressure-controlled MPsystem was preset according to the group assigned, MATERIALS AND METHODS MP25 or MP30. The mean PP was calculated by the Animals and Experimental Protocols onboard electronic control system from continuousrecordings of the pressure sensor and defined as the All experiments were performed in accordance mean area under the pressure curve during 10 pump with the German legislation governing animal studies cycles. For in line recording of the PP, a temperature following the Principles of Laboratory Animal Care compensated and calibrated silicon pressure sensor (NIH publication, 85–23, revised 1985). Kidneys were was used (MPX2010GST1, Freescale Semiconductor, retrieved from female German landrace pigs, weighing Chandler, AZ, USA) which has a full scale span 24.9 ± 4.1 kg (mean ± SD). This study describes two pressure hysteresis of ±0.1% and temperature hyster- groups, both representing a different PP during MP, esis of ±0.5%. The perfusion flow was calculated in MP at 25 mmHg (MP25, n = 7) and MP at 30 mmHg real time by the amount of pump strokes per minute (MP30, n = 7). Randomization of the groups was times the stroke volume of 12 mL (±2%). Perfusion performed using a roulette wheel.
parameters, flow and renal resistance (mmHg/mL/(100 g) kidney weight), were continuously monitored.
Surgical Procedures Kidney weights after 20 h MP were recorded.
Animals were premedicated with ketamine (90 mg/ kg, Parke-Davis GmbH, Berlin, Germany), xylazine (10 mg/kg, Bayer Vital GmbH, Leverkusen, Ger- Twenty hours after left nephrectomy, the contra- many), and atropine (10 lg/kg, Bremer Pharma lateral kidney was removed, followed by immediate GmbH, Warburg, Germany) administered intramus- heterotopic transplantation of the preserved kidney.
cularly (IM). General anesthesia was induced by The renal artery was anastomosed end-to-end to the midazolam (0.5 mg/kg, Roche GmbH, Grenzach- right renal artery and the renal vein end-to-side to the Wyhlen, Germany), and fentanyl (12.5 lg/kg, Janssen- inferior vena cava. Before completion of the arterial Cilag GmbH, Neuss, Germany), muscle relaxation was anastomosis, a bolus of 3,000 IU of heparin was achieved by pancuronium (0.2 mg/kg, Ratiopharm injected to prevent vascular thrombosis. Following Perfusion Pressures During Machine Perfusion of Kidneys reperfusion, 250 mL of 20% glucose was administered from 0 to 5: 0 = no abnormality, 1 = mild, lesions intravenously to induce osmotic diuresis. The ureter affecting up to 10% of the field, 2 = moderate lesions, was cannulated with a PE tube (CH 10) to allow free affecting 10–25%, 3 = severe, affecting 25–50%, outflow of urine through an ureterocutaneostomy. Ten 4 = very severe, affecting 50–75%, and 5 = extensive minutes after reperfusion, the renal microcirculation damage, involvement of more than 75% of the field.
was reassessed. Postoperatively, the animals were Immunohistochemical staining of paraffin sections allowed free access to water and were supplemented for von Willebrand factor (vWF) was performed as with 1 L of 0.9% NaCl infusion IV. Ranitidine 50 mg follows. After heat-mediated antigen retrieval by pre- IV (Sigma–Aldrich Chemie GmbH) was administered treatment in a pressure cooker for 20 min, sections daily and postoperative analgesia was provided every were incubated with rabbit polyclonal anti-vWF anti- 6–8 h with Tramadol (1 mg/kg IM) (Sigma-Aldrich serum (ab6994, Abcam, Cambridge, UK) at a con- Chemie GmbH) for up to 72 h after transplantation.
centration of 1:200 for 30 min at room temperature, Ampicillin 500 mg (Sigma-Aldrich Chemie GmbH) and subsequently incubated with biotinylated goat- was administered IV perioperatively as well as on a anti-rabbit antiserum, peroxidase-conjugated strepta- daily basis during follow-up. Also, Aspirin 500 mg IV vidin, and diaminobenzidine, and finally counter- (Bayer AG, Leverkusen, Germany) was given twice daily for the entire period of follow-up. Animals were endothelial cells was determined semiquantitatively on observed for 7 days after transplantation with daily a scale of 0–3 for the following features: 0 = no assessment of renal function. Creatinine clearance was staining above background immunoreactivity in non- calculated from 24 h urine production and serum cre- endothelial cells, 1 = minor staining, 2 = moderate atinine ((urine creatinine 9 24 h volume)/(serum cre- staining, 3 = prominent staining.
atinine 9 24 9 60 min)). At day 7 posttransplant, thetransplanted kidney was removed for histologicalevaluation and animals were euthanized by injection of T61 IV (Hoechst Roussel Vet, Wiesbaden, Germany).
Data are expressed as mean ± SD. Statistical anal- ysis of kidney weights as well as MP parameters were Noninvasive Assessment of Renal Microcirculation performed using the repeated measurements analysis The O2C combined Laser Doppler and flowmetry of variance (RM ANOVA) followed by the Bonferroni device was used to evaluate the microcirculation non- posttest. Significant differences of the renal microcir- invasively. Prior to left nephrectomy and 10 min after culatory measurements at different time points within reperfusion, capillary blood flow (flow, arbitrary units, the groups were assessed using the Mann–Whitney AU) and capillary blood flow velocity (velocity, AU) U test. For renal function, area under the curve (AUC) were simultaneously recordedat 2 and 8 mm tissue was calculated individually using the GraphPad Prism depths. At four predefined locations on the renal sur- 5.0 statistics package (GraphPad Software, San Diego, face (cranially, medially, caudally, and laterally), CA, USA). Statistical significance of differences measurements were performed for 30 s each, to pre- was assessed using the Mann–Whitney U test. A vent the influence of regional heterogeneity and tem- p value < 0.050 was considered statistically significant.
poral blood flow variations.
Histological Analysis At euthanization, renal tissue specimens were fixed Animal weights did not differ between the groups in neutral 10% buffered formalin and embedded in (MP25, 23.5 ± 4.6 kg; MP30, 26.3 ± 3.2 kg; p = paraffin. Tissue injury was assessed on periodic acid- 0.201). All animals demonstrated normal renal func- Schiff (PAS) stained 4 lm-thick sections by scoring tion before the start of the experiments (serum creati- glomerular damage (shrinking), tubular damage, infil- nine; MP25, 1.09 ± 0.14 mg/dL; MP30, 1.13 ± 0.10 tration of inflammatory cells, interstitial edema and mg/dL; p = 0.565). Cold ischemic times (CITs) necrosis. Tubular damage was defined as dilatation, of the groups were comparable (CIT, MP25, 20:32 h ± denudation of the tubular basement membrane and 0:06; MP30, 20:28 h ± 0:17; p = 0.158). Also, times vacuolization. Injury of each specimen was graded to required for both anastomoses were comparable the extent of region involvement in 10 randomly cho- between the groups (MP25, 00:41 ± 0:08 min; MP30, sen, nonoverlapping fields (original magnification, 00:40 ± 0:08 min; p = 0.847). At the end of the 9400). Injury was scored by a pathologist blinded for 500 mL washout, all kidneys showed a macroscopi- the groups using a semi-quantitative score on a scale cally asanguinous effluent.
DOORSCHODT et al.
Kidney weights after washout did not differ between or the resistance as: the groups (MP25, 66.0 ± 11.8 g; MP30, 72.3 ± 12.5 g; p = 0.369). Also, repeated measurement anal- ysis of kidney weights after washout and after MPpreservation, did not differ between the groups (RM For reasons of clarity we assumed that the vessel is a ANOVA kidney weights, p = 0.209).
single duct with constant diameter. Using the meanflow at 10 h we estimated the shear stress on theendothelial wall as follows: MP25: 25 mmHg = 3.33306 kPa Data on perfusion parameters per 100 g kidney weight are shown in Fig. Analysis of perfusion flow showed a trend towards higher flow rates in the MP30 MP30: 30 mmHg = 3.99967 kPa group, though not significant (RM ANOVA, MP25vs. MP30, p = 0.068, Fig. a). Overall, intravascular resistance did not differ between the groups (RM ANOVA, MP25 vs. MP30, p = 0.419, Fig. The resistance per 100 g kidney weight is a function of the geometry of the vessel and the viscosity of blood or Perfusion Dynamics the perfusion medium. The flow and renal resistance The Hagen–Poiseuille law states that the volume should be constant if the geometry and viscosity are un- Q through a vessel with diameter d and length changed. When we assume that the viscosity is the same L is related to the pressure drop Dp by the equation in both situations and the change of L can be neglected,we may conclude that the difference of the pressure drop produces a change in diameter of the vessels leading to the following ratio of the both values of the resistance.
where l is the dynamic viscosity of the fluid.
Blood is a two-phase fluid so that l is not strictly constant but may decrease in vessels with diametersbetween 10 and 300 lm with decreasing diameters due We can express this as an additional stretch k pro- to the Fa˚hræus–Lindqvist effect. It occurs because duced in the vessel by increasing the pressure from 25 erythrocytes move towards the center of the vessel leaving plasma at the wall of the vessel. Introducing the laminar resistance: MP25 ¼ 1:092 ¼ 1:022 This corresponds to an additional Green–Lagrange the pressure drop can be expressed by the equation: " 1 ¼ 0:022 ¼ 2:2% (a, b) Machine perfusion parameters. (a) Perfusion flow recorded during 20 h MP per 100 g kidney weight. (b) Intra- vascular resistance during 20 h MP per 100 g kidney weight.
Perfusion Pressures During Machine Perfusion of Kidneys The physiological systolic and diastolic pressures precisely known. However, the estimated ratios repre- are approximately 40 and 30 mmHg, respectively, in sent the expected trends.
pre-capillary arterioles. Changes in diameter fromdiastole and systole depend strongly on the location of Renal Microcirculation the arteries, ranging from 1% for carotid artery to10.8% for main pulmonary artery. Although our Overall, cortical microcirculatory flow at 2 mm tis- simple approximation represents an average effect, it is sue depth postreperfusion was better compared to nevertheless in the range of the physiological values.
cortical microcirculatory flow preretrieval in both the Accepting the effect that the pressure drop expands the MP25 and the MP30 groups. (Capillary blood flow at vessels, we could estimate the effect on wall shear 2 mm, postreperfusion vs. preretrieval, p < 0.001, and Fig. a.) Capillary blood flow values assessed at 8 mm postreperfusion did not differ from capillary blood values preretrieval in both the MP25 and the MP30groups. (Capillary blood flow at 8 mm, postreperfu- With the above assumptions the ratio between shear sion vs. preretrieval, p = 0.565, and p = 0.393, stresses shows a 18.6% reduction brought about by the respectively, Mann–Whitney U test, Fig. All blood 16.7% reduction of the PP from 30 to 25 mmHg.
flow velocity measurements assessed postreperfusion were higher compared to blood flow velocity mea- surements preretrieval at both 2 and 8 mm tissue depths in both the MP25 and MP30 groups. (Blood flow velocity at 2 mm, postreperfusion vs. preretrieval; MP25, p = 0.002 and MP30, p = 0.041; Blood flowvelocity at 8 mm, postreperfusion vs. preretrieval; If the vessel diameter would be unchanged the ratio MP25, p = 0.025 and MP30, p = 0.041, Mann– would appear even more favorable for the MP25 case.
Whitney U test, Fig. Directly after revascularization, macroscopically, both the MP25 and the MP30 grafts showed a The blood flow is nonlinear and therefore the ratios may not be equal in all vessel diameters. The perfusion Follow-up After Transplantation medium finally has to flow through arterioles whichtypically have a diameter of approximately 25 lm so In the MP30 group, 6 out of 7 animals survived that the Fa˚hræus–Lindqvist effect applies. Therefore, 7 days. One animal in the MP30 group was killed at the viscosity and shear stress very near a wall are not postoperative day 2 since it was suffering from renal (a, b) Renal microcirculation. (a) Capillary blood flow values at 2 mm and at 8 mm tissue depths, MP25 and MP30 groups (*p < 0.050, ***p < 0.001). (b) Blood flow velocity values at 2 and at 8 mm tissue depths, MP25 groups and MP30 (*p < 0.050,**p < 0.010).
DOORSCHODT et al.
failure, as demonstrated by rising creatinine levels. In blood urea values in the MP25 group were lower the MP25 group all animals survived 7 days. Survival compared to peak blood urea values in the MP30 did not differ between the groups (Log rank test, group (MP25, 104 ± 99 mg/dL; MP30, 241 ± 136 p = 0.317). Animals surviving the 7 day follow-up mg/dL; p = 0.022). Times to peak blood urea in the after transplantation were included in the postopera- MP25 group were shorter compared to the MP30 tive analyses.
group (MP25, 3.3 ± 2.4 days; MP30, 5.7 ± 0.8 days;p = 0.049). At killing, blood urea values in the MP25group were lower than in the MP30 group (MP25, 75 ± 109 mg/dL; MP30, 197 ± 156 mg/dL; p = 0.022).
Overall, posttransplant serum creatinine values in the MP25 group were lower than posttransplant serum nephrectomy and prior to reperfusion did not differ creatinine of surviving animals in the MP30 group between the groups (p = 0.352). Overall, creatinine (AUC serum creatinine, MP25 vs. MP30; p = 0.035, clearances rates in the MP25 group were significantly Fig. Peak serum creatinine levels were comparable higher compared to creatinine clearance rates in the MP30 group (AUC creatinine clearance; MP25 (MP25, 5.5 ± 5.4 mg/dL; MP30, 11.1 ± 2.9 mg/dL; vs. MP30, p = 0.026, Fig. p = 0.051). Times to peak serum creatinine did notdiffer between the groups (MP25, 2.9 ± 2.6 days; Histological Examination MP30, 5.2 ± 1.3 days; p = 0.149). At killing, serumcreatinine levels in the MP25 group were lower com- Overall, tissue injury of grafts in the MP25 group pared to the MP30 group (MP25, 4.0 ± 5.8 mg/dL; was significantly less compared to grafts in the MP30 MP30, 7.4 ± 3.2 mg/dL; p = 0.035).
group (Table ; Fig. ).
Posttransplant blood urea values in the MP25 group These findings were confirmed with the immuno- were lower than posttransplant blood urea values of histochemical staining (Fig. showing increased vWF surviving animals in the MP30 group (AUC blood in the MP30 group (average score 2.1) compared to the urea; MP25 vs. MP30; p = 0.035, Fig. Also, peak MP25 group (average score 1.4).
(a–c) Renal function. (a) Serum creatinine values posttransplant in the MP25 and the MP30 groups (AUC serum creatinine, MP25 vs. MP30, p 5 0.035). (b) Blood urea levels posttransplant in the MP25 and the MP30 groups (AUC blood urea,MP25 vs. MP30, p 5 0.035). (c) Creatinine clearance rates posttransplant in the MP25 and the MP30 groups (AUC creatinineclearance rates, MP25 vs. MP30, p 5 0.026).



Perfusion Pressures During Machine Perfusion of Kidneys deceased kidney grafts, MP holds the potential for atrue comebackIn the first large multi-center, In the early days of kidney transplantation from prospective, randomized clinical trial performed by deceased donors, MP was the only preservation Moers et al.,it was demonstrated that kidney grafts method available.However, for over two decades, the from standard as well as extended criteria donors less cumbersome and inexpensive cold static storage benefit from MP as the risk of delayed graft function method has been the standard for preservation of was significantly reduced.
kidney grafts. Following recent studies showing the A recent preclinical study comparing hypothermic beneficial effect of MP over CS preservation of MP using either a high or low PP with CS, also showedthe advantage of MP over CS for the preservation ofporcine kidney grafts. In addition to better survivaldata when a PP of 30/20 mmHg was applied, less Quantification of morphological data.
damage to the endothelial cells was observed when compared to a PP of 60/40 mmHThe two non-surviving animals in the 60/40 mmHg group revealed Glomerular shrinking diffusely black colored grafts with patent arterial and venous anastomoses suggesting impairment of intra- renal circulation. It was concluded that the PP was of critical importance for transplantation outcome.
Following the aforementioned reports and the Semiquantitative scale: 0 = no injury; 1 = lesions affecting £10% favorable results of the clinical trial in which a PP of of the field; 2 = 10–25%; 3 = 25–50%; 4 = 50–75%; and 5 =involvement of >75% of the field. Data expressed as mean ± SD.
30 mmHg was applied, we investigated whether a (a, b) Light microscopy. (a) MP25 group, well preserved glomerulus, moderate tubular dilatation, and interstitial inflammation (original magnification 320, PAS stain). (b) MP30 group, moderate shrinking of glomerulus, simplification of tubularepithelium, few inflammatory cell infiltrates (original magnification 320, PAS stain).
(a, b) vWF immunohistochemistry. (a) MP25 case: there is only minor immunoreactivity slightly above background of endothelial cells of both small (white arrows) and larger caliber blood vessels (black arrows). Scale bar 5 50 lm. (b) MP30 case:endothelial cells (arrows) of blood vessels of these kidneys often showed a prominent vWF immunoreactivity considerably abovebackground. Scale bar 5 50 lm.
DOORSCHODT et al.
mean PP of 25 mmHg could be advantageous over a shown that intrarenal resistance fell to a baseline level PP of 30 mmHg. The rationale of lowering the PP after 4–6 h, and after this period, the formation of originates from the common regard that pressure edema increased rapidly. Also, from preclinical studies induced endothelial damage is one of the main draw- a time-dependent increase in vascular resistance was backs associated with Also, the feasibility of observed during prolonged hypothermic pulsatile per- the new perfusion solution POLYSOL was evaluated.
By using a similar experimental model as Maathuis Our study did not confirm these phenomena since, et al., parameters of microcirculatory integrity, renal function and morphology were assessed.
remained at a basement level for the duration of the For assessment of the microcirculation, we used the 20 h perfusion period. A steady or decreasing intrare- O2C Laser Doppler and flowmetry system. Major nal resistance is considered a useful indication of graft advantages of the O2C are the possibility to quanti- viability, suggesting preservation of structural integrity tatively assesses the microcirculation and frequent of the endothelium and patency of the vascular measurements. The O2C measures every other second which results in accurate data. A disadvantage of the Recently, experimental preservation studies were method is that it can only measure blood flow at a performed comparing CS to hypothermic MP of warm small location since it is commonly known that graft ischemically damaged kidney grafts. Hosgood et al.
injury can be distributed heterogeneously. To assure applied a mean PP of 30 mmHg whereas in a study by reliable assessment of the microcirculation, we per- our group, a mean PP of 20 mmHg was applied in formed 30 s measurements at four predefined locations order to minimize the possibility of MP induced on the renal surface. The results of our study confirm endothelial injury which is aggravated by warm earlier findings that lowering of the PP is advantageous ischemia.In our study, the ratio between shear since MP using a mean PP of 25 mmHg resulted in a stresses shows a 18.6% reduction brought about by the higher capillary blood flow at 10 min after reperfusion.
16.7% reduction from 30 to 25 mmHg. Hypertension Moreover, histological evaluation showed better pres- is a phenomenon that takes considerable time to pro- ervation of structural integrity in the MP25 group.
voke renal disease. However, at the short time intervals Overall, improvement in recovery of renal function used in this study, we can assume that high wall shear was seen in the MP25 group compared with the MP30 stress rates are the root cause for endothelial damage.
group. The effect of the POLYSOL solution does not Reducing the PP from 30 to 25 mmHg has a beneficial appear to be of importance, since the results of this effect on the wall shear stress. This finding was con- study resemble the results obtained in similar studies using KPS-1.Also, POLYSOL meets the pre- showed increased vWF expression in the MP30 group requisites for an effective MP solution as postulated by compared to the MP25 group. The expression of vWF Belzer et al.; the presence of a colloid, impermeants is known to be higher in renal endothelial cells of and extracellular electrolyte concentration.
patients with hypertension, acute, and chronic renal Before starting this study, we performed a pilot study using mean PP's of 40 and 35 mmHg duringpulsatile perfusion of porcine kidney grafts (data not shown). In contrast to the studies by Nicholson et using a mean PP of 60 mmHg and M(mean In a porcine autotransplantation model, MP of PP approximately 50 mmHg), in our pilot study, none renal grafts with the novel AIRDRIVE MP system of the animals (n = 3) survived the intended 7 day using a mean PP of 25 mmHg is preferred over a mean follow-up after autotransplantation. In all three PP of 30 mmHg. These results corroborate earlier experiments, kidney failure, as demonstrated by a steep studies suggesting a direct effect of the PP applied rise of creatinine levels, was observed resulting in during MP on vascular injury and organ viability.
premature killing of the animals. Histological exami-nation of the grafts showed severe tubular injury andnecrosis in all sections which was considered a result of long-term renal hypertension. Although the mean PPsapplied were lower than human and porcine physio- The authors would like to thank Mario Sitzia, Wei logical pressure levels, endothelial damage is likely to Lai, Mareike Schulz, and Ute Lohmer for their con- occur even at mean PPs of 50–60 mmHg since hypo- tinuous support. This study was in part sponsored by thermia severely increases cell membrane stiffne Doorzand Medical Innovations BV, Amsterdam, The According to Nicholson et al. a period of 6 h perfusion Netherlands (the company ceased operations as per preservation was chosen as previous experience had August 2008).
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