Hyperpolarised 13C-MRI metabolic and functional imaging: an emerging renal MR diagnostic modality.

Magnetic resonance imaging (MRI) is a well-established modality for assessing renal morphology and function, as well as changes that occur during disease. However, the significant metabolic changes associated with renal disease are more challenging to assess with MRI. Hyperpolarized carbon-13 MRI is an emerging technique which provides an opportunity to probe metabolic alterations at high sensitivity by providing an increase in the signal-to-noise ratio of 20,000-fold or more. This review will highlight the current status of hyperpolarised 13C-MRI and its translation into the clinic and how it compares to metabolic measurements provided by competing technologies such as positron emission tomography (PET).This study was funded by Aarhus University Research Foundation and Karen Elise Jensen Foundation

Organ-specific metabolic profiles of the liver and kidney during brain death and afterwards during normothermic machine perfusion of the kidney

We investigated metabolic changes during brain death (BD) using hyperpolarized magnetic resonance (MR) spectroscopy and ex vivo graft glucose metabolism during normothermic isolated perfused kidney (IPK) machine perfusion. BD was induced in mechanically ventilated rats by inflation of an epidurally placed catheter; sham-operated rats served as controls. Hyperpolarized [1-13C]pyruvate MR spectroscopy was performed to quantify pyruvate metabolism in the liver and kidneys at 3 time points during BD, preceded by injecting hyperpolarized[1-13C]pyruvate. Following BD, glucose oxidation was measured using tritium-labeled glucose (d-6-3H-glucose) during IPK reperfusion. Quantitative polymerase chain reaction and biochemistry were performed on tissue/plasma. Immediately following BD induction, lactate increased in both organs (liver: eµd0.21, 95% confidence interval [CI] [−0.27, −0.15]; kidney: eµd0.26, 95% CI [−0.40, −0.12]. After 4 hours of BD, alanine production decreased in the kidney (eµd0.14, 95% CI [0.03, 0.25], P <.05). Hepatic lactate and alanine profiles were significantly different throughout the experiment between groups (P <.01). During IPK perfusion, renal glucose oxidation was reduced following BD vs sham animals (eµd0.012, 95% CI [0.004, 0.03], P <.001). No differences in enzyme activities were found. Renal gene expression of lactate-transporter MCT4 increased following BD (P <.01). In conclusion, metabolic processes during BD can be visualized in vivo using hyperpolarized magnetic resonance imaging and with glucose oxidation during ex vivo renal machine perfusion. These techniques can detect differences in the metabolic profiles of the liver and kidney following BD

Remote ischaemic conditioning and early changes in plasma creatinine as markers of one year kidney graft function-A follow-up of the CONTEXT study

Background Ischaemia-reperfusion injury in kidney transplantation leads to delayed graft function (DGF), which is associated with reduced long term graft function. Remote ischaemic conditioning (RIC) improved early kidney graft function in a porcine model of donation after brain death and was associated with improved long-term cardiac outcome after myocardial ischaemia. This randomised, double-blinded trial evaluated the effect of RIC on kidney graft outcome in the first year, and examined the predictive value of a new measure of initial kidney graft function, i.e. the estimated time to a 50% reduction in plasma creatinine post-transplantation (tCr50). Methods A total of 225 patients undergoing deceased donor kidney transplantation were randomised to RIC or a sham procedure performed prior to kidney reperfusion. Up to four repetitive cycles of five minutes of leg ischaemia and five minutes of reperfusion were given. GFR, plasma creatinine, cystatin C and neutrophil gelatinase associated lipocalin (NGAL) were measured at three and twelve months and estimated GFR was calculated using four different equations. Other secondary outcomes were identified from patient files. Results RIC did not affect GFR or other outcomes when compared to the sham procedure at three or twelve months. tCr50 correlated with one year graft function (p Conclusion RIC during deceased donor kidney transplantation did not improve one year outcome. However, tCr50 may be a relevant marker for studies aiming to improve graft onset

Elevated plasma free thiols are associated with early and one-year graft function in renal transplant recipients

Background Reduced free thiols in plasma are indicative of oxidative stress, which is an important contributor to ischaemia-reperfusion injury (IRI) in kidney transplantation leading to kidney damage and possibly delayed graft function (DGF). In a post-hoc, exploratory analysis of the randomised controlled CONTEXT trial, we investigated whether higher (i.e. less oxidised) plasma levels of free thiols as a biomarker of reduced oxidative stress are associated with a better initial graft function or a higher GFR. Methods Free thiol levels were measured in plasma at baseline, 30 and 90 minutes after reperfusion of the kidney as well as at Day 1, Day 5 and twelve months after kidney transplantation in 217 patients from the CONTEXT study. Free thiol levels were compared to the kidney graft function measured as the estimated time to a 50% reduction in plasma creatinine (tCr50), the risk of DGF and measured GFR (mGFR) at Day 5 and twelve months after transplantation. Results Higher levels of free thiols at Day 1 and Day 5 are associated with higher mGFR at Day 5 (pConclusion Higher levels of plasma free thiols at Day 1 and Day 5, which are reflective of lower levels of oxidative stress, are associated with better early and late graft function in recipients of a kidney graft from deceased donors. Trial registration ClinicalTrials.gov Identifier:NCT01395719

ARA290, a non-erythropoietic EPO derivative, attenuates renal ischemia/reperfusion injury

BACKGROUND: In contrast with various pre-clinical studies, recent clinical trials suggest that high dose erythropoietin (EPO) treatment following kidney transplantation does not improve short-term outcome and that it even increases the risk of thrombotic events. ARA290 is a non-erythropoietic EPO derivative and does not increase the risk of cardiovascular events, but potentially has cytoprotective capacities in prevention of renal ischemia/reperfusion injury. METHODS: Eight female Dutch Landrace pigs were exposed to unilateral renal ischemia for 45 minutes with simultaneous cannulation of the ureter of the ischemic kidney. ARA290 or saline was administered by an intravenous injection at 0, 2, 4 and 6 hours post-reperfusion. The animals were sacrificed seven days post-reperfusion. RESULTS: ARA290 increased glomerular filtration rate during the observation period of seven days. Furthermore, ARA290 tended to reduce MCP-1 and IL-6 expression 15 minutes post-reperfusion. Seven days post-reperfusion ARA290 reduced interstitial fibrosis. CONCLUSIONS: The improvement in renal function following renal ischemia/reperfusion and reduced structural damage observed in this study by ARA290 warrants further investigation towards clinical application