less than 60 mmHg however
the Eurotransplant trial the perfusion pressure was set at 30 mmHg for the
kidneys that had MP 8.
Machine perfusion flow
rate 8
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Several studies have demonstrated that the higher the
flow rate was (at a given perfusion pressure) the better the results were with
regards to immediate function, DGF, duration of dysfunction, post-operative
creatinine and length for urine output to exceed 2Lt / day 54. There was
further confirmation of the correlation between the flow rate and the
proportion of kidneys immediately functioning and those with primary non-function.
54, 55. Moreover, another team reported a case of immediate non-function in a
MP graft with optimal perfusion pressures and biomarkers levels but with low
flow rate in order to support the importance of it 56. Newcastle viability
criteria suggested flow rate of > 25 ml/min/100 g of tissue 8.
Resistance
indices 8
It has been shown that
rising resistance to flow in MP is related to a not desirable outcome. 57 It
was also confirmed in trials with human renal grafts when they studied the
resistive index and its correlation with instant function rate versus delayed
graft function 58. There is a number of studies with empirical use of
different values for renal resistance as a predictor of graft response /
outcome. An interesting analysis of the Eurotransplant RCT showed that renal
resistance is a predicting factor of graft outcome and especially DGF and graft
survival which also may have prognostic power 59.
Machine
perfusate biomarkers 8
The
main focus of this field of research is to identify special biomarkers of the
perfusate and their correlation with urine output that could be used for
assessment of kidney’s viability while being preserved with MP. The majority is
based on experimental models using animals and so far, evidence is
controversial. In general, high such
enzyme levels within the perfusate indicate an increased extent of cellular
damage which may mean higher risk of PNF 60. In an extension of the
Eurotrasplant RCT where they analysed in depth the levels of certain biomarkers
of the perfusate they showed that there was a relationship between increased
levels of those enzymes and greater flow resistance and eventually kidneys that
had delayed graft function. However, they failed to find any correlation of the
above with the primary non-function 61. It is expected these biomarkers to be
embedded in clinical viability scores compared to isolated use. The current
research is concentrated on alanine aminopeptidase, lactate dehydrogenase
(LDH), glutathione S-transferase (GST), N-acetyl-?-DGlycosaminidase, aspartate
aminotransferase (AST) and heart-type fatty acid binding protein 8.
It
has been affirmed that a-glutathione
is one of the most
reliable pre-transplant renal perfusate markers in predicting the transplant outcome via anticipating the
primary non-function versus function or even immediate versus DGF 62.
According to the Newcastle criteria
for viability testing GST: <100 iu/100g of kidney/litre
perfusate in standard organ recovery is advised. Lactate dehydrogenase (LDH) is one of the markers of cellular
injury, although it is non-specific. There was an expectation that LDH in
kidneys during MP might show the degree of cellular damage due to ischaemia.
This was not confirmed though in a recent study 63.
Alanine
aminopeptidase is one of the peptidases with role in cell regulation that can
be found in renal cells. 61, 64. When renal tubular injury occurs, it is
excreted in the urine. This has been studied as a potential marker of renal
viability (measured pre-transplantation and predicting post transplantation
outcome). Few experimental protocols in porcine have shown a remarkable
relationship between levels of alanine aminopeptidase in the urine and warm
ischaemia time 64. Despite this in human NHBD kidney protocols researchers
failed to reveal alanine aminopeptidase correlation with primary non-function or
delayed function etc.
Aspartate aminotransferase is an enzyme
present in hepatic and renal parenchymal cells. Among other markers it has also
been investigated in MP protocols as a potential predictor of outcome 61. Most
of this research focused in liver however some evidence exists for kidney transplants.
Higher levels of aspartate aminotransferase in MP kidneys' perfusate are
associated with acute parenchymal cellular injury and greater risk of delayed
graft function. Lastly, heart-type fatty
acid binding protein obviously as its name suggests it is present primarily in
the heart. However, in smaller concentrations it can be found in skeletal
muscle or the distal renal tubules. 65 The main focus of research is its
correlation with myocardial damage. As a result, its use in MP protocols
requires further study. However, it has been demonstrated that higher levels of
it were present in perfusate of NHBD grafts that subsequently showed DGF. This
might support its use as a prognostic factor 61.
Interestingly
enough, research has shown that there is influence of the perfusion solution on
renal graft viability assessment. Wilson et al demonstrated that initial
machine perfusion viability testing and mainly levels of those biomarkers are
directly dependent on the perfusion solution used. For example, HTK-perfused
kidneys were heavier with higher levels of GST levels but reduced mitochondrial
injury secondary to ischaemia when compared to Marshall's hypertonic citrate
(HOC) 66.
Imaging
guided viability assessment
-
Doppler
ultrasonography and renal scintigraphy (pre-retrieval
/ pre-transplantation)
Radionuclide studies may be helpful in quantifying
perfusion and function without causing harm to the precious graft 67. Their main role is important in
identification of potential complication following transplantation. However,
there are attempts to use these as a viability tool pre-retrieval and as well
as while MP the kidney. There is no doubt that ultrasonography with coloured
Doppler is the most common modality used. It is the first step on assessment of
graft dysfunction. However, radionuclide scintigraphy may add significant
information such as real time functional status 68, 69. Technically, acquisition of scintigraphic
images is performed with use of a gamma camera detector. Technetium-99m-labelled
mercaptoacetyltriglycine (Tc-99m MAG3) is often used and administered IV. This
molecule is cleared by the proximal tubules with minimal filtration 70. Therefore,
it is a tubular secretion agent ideal for the functional assessment of the
kidney (pre or post-transplant).
Research for use of above for viability assessment is in early stages. However,
I assume that their role might be beneficial.
-
Dynamic
MRI using the Ktrans technique (pre-retrieval / pre-transplantation)
Contrary
to Doppler ultrasonography and renal scintigraphy
which are most commonly use to assess transplant function and complications.
Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) has the ability
to differentiate it from any residual renal
function of native kidneys. It evaluates signal dynamics during the flow of
contrast medium through the renal cortex, medulla
and collecting system 71. Although used post transplantation etc this
technique to my understanding may constitute a non-invasive modality of
determination of the viability of kidneys transplants
pre-transplantation and while on MP.
Biopsy parameters
viability assessment
Research on use of histological
examination in order to assess organs' quality primarily comes from ECD as
compared to DCD organs. Most of the available knowledge is based on protocols
designed to match organs with impaired functional status to dual kidney transplantation
72. There are few scoring systems which are well validated such as the Banff,
CADI, MAPI, and Pirani ones 72, 73, 74. These have been demonstrated that
they have improved predictive value for impaired graft function at one-year
when compared to other clinical scoring systems without use of histological
parameters. Scoring systems combining donor blood pressure and creatinine
values with histological examination findings offer the highest predictive
value. However, this means large, formalin based biopsy samples. At present
there are no predictors of primary non-function based on histology findings 16.
Moreover, there are several pitfalls of evaluation of kidneys by biopsy 75.
One of them is the sampling error related to interobserver variability,
overestimation, need for large sample etc. Also, there are time issues too as
this means prolongation of cold ischaemic time. The whole process of using
formalin, then paraffin etc might take up to 4-5 hrs 76 and this makes any
benefit of biopsy guided decision making less attractive from increasing the
cold ischaemic time 77.