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
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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.
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.
perfusate biomarkers 8
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.
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.