Monika Kaushik

Carbon monoxide protects against ischemia-reperfusion injury in an experimental model of controlled nonheartbeating donor kidney.

Background. CO-releasing molecule-3 (CORM-3) is a transitional metal carbonyl that liberates carbon monoxide under appropriate conditions. Carbon monoxide exerts effects on intracellular apoptotic and inflammatory pathways, which suggest a role in reducing the effects of renal ischemia/reperfusion (I/R) injury. This study investigated the effects of CORM-3 administered at the time of reperfusion in a model of controlled nonheartbeating donor kidneys. Methods. Porcine kidneys (n=4) were subjected to 10 min warm ischemia and 18 hr cold storage (CS) and then treated as follows: CORM-3 (50, 100, 200, and 400 &mgr;M doses), iCORM-3 (inactive carbon monoxide-releasing molecule, 50 &mgr;M), and control (no further intervention). Renal hemodynamics and function were then measured during 3-hr reperfusion with autologous blood using an isolated organ-perfusion system. Results. CORM-3 at a concentration of 50 &mgr;M improved renal blood flow (RBF) compared with the iCORM and control groups (area under the curve 774±19 vs. 448±88 vs. 325±70, respectively, P=0.002). CO-releasing molecule-3 at a concentration of 50 &mgr;M also improved renal function during reperfusion with a greater area under the curve for creatinine clearance (CORM-3: 14±6 vs. iCORM: 3.3±0.1 vs. control: 2.2±2 mL/min, P=0.006) and higher urine output (CORM-3: 793±212 vs. iCORM: 368±72 vs. control: 302±211 mL, P=0.01). CO-releasing molecule-3 at a concentration of 100 &mgr;M exerted similar effects. Treatment with CORM-3 at higher doses (200 and 400 &mgr;M) led to poor renal hemodynamics and function after reperfusion. Conclusion. Low-dose CORM-3 significantly ameliorates the effects of ischemia/reperfusion in a porcine model of controlled nonheartbeating donor kidney transplantation.

Comparison of right and left laparoscopic live donor nephrectomy

To compare the anatomy and function of right and left kidneys retrieved by laparoscopic live donor nephrectomy (LDN).

Biomarkers of oxidative damage to predict ischaemia-reperfusion injury in an isolated organ perfusion model of the transplanted kidney.

Ischaemia-reperfusion (IR) injury is known to be a risk factor influencing both short and long-term graft function following transplantation. The pathophysiology of IR injury is suggested to involve elevated reactive oxygen species production resulting in oxidative damaged cellular macromolecules. The objective of this study was to evaluate oxidative damage following IR using an isolated organ perfusion model of the transplanted kidney, in order to determine a simple, preferably non-invasive biomarker for IR injury. Porcine kidneys were retrieved with 10 or 40 min warm ischaemic (WI) time and haemoperfused for 6 h on an isolated organ perfusion machine. ELISA was used to detect carbonyls, 8-isporostane and 8-hydroxy-2′-deoxyguanosine, representing protein, lipid and DNA damage respectively in pre and post reperfusion samples of plasma, urine and biopsy material. Plasma carbonyl and 8-isporostane and were significantly increased in the 40 min group compared to pre-perfusion (0.96 ± 0.10 vs. 0.62 ± 0.06, P < 0.001 and 1.57(1.28–4.9) vs. 0.36(0.09–0.59), P < 0.05). The levels also correlated with creatinine clearance used to determine renal function (r = − 0.6150, P < 0.01 and r = − 0.7727, P < 0.01). The results of this study suggest both plasma carbonyl and 8-isporostane to be reliable biomarkers to predict the level IR injury.

Application of nitric oxide and carbon monoxide in a model of renal preservation.

Nitric oxide and carbon monoxide exert vasodilatory effects that minimize ischaemia–reperfusion injury. An isolated porcine kidney model was used to assess the effects of administering the nitric oxide donor sodium nitroprusside (SNP) and carbon monoxide‐releasing molecule (CORM) 3 during a period of warm preservation followed by reperfusion.

Health-related quality of life after living donor nephrectomy: a randomized controlled trial of laparoscopic versus open nephrectomy.

Background. The aim of this study was to compare patient-reported health status and quality of life after randomization to laparoscopic donor nephrectomy (LDN) or short-incision open donor nephrectomy (ODN). Methods. Live kidney donors were randomized in a 2:1 ratio to LDN (n=56) or ODN (n=28). Health-related quality of life was assessed using the Short Form 36 questionnaire preoperatively and at 6 weeks postdonation. Results. Postoperative morphine requirement was lower in the LDN group (median [range], 59 [6–136]) versus ODN group (90 [35–312] mg; P=0.001). Norm adjusted physical components scores decreased significantly at 6 weeks in both the LDN and ODN groups. The bodily pain domain score of physical components score at 6 weeks returned to baseline in the laparoscopic group (86.4±19.8 vs. 81.8±15.9; P=0.2277) but not in the open group (87.3±18.3 vs. 69.0±25.0; P=0.05). The mental component score decreased in the ODN group (53.5±7.6 vs. 45.3±10.1; P=0.0084) but returned to baseline 6 weeks after LDN (53.8±6.5 vs. 51.9±7.2; P=0.2931). Conclusions. Donors undergoing laparoscopic nephrectomy reported less bodily pain in the first 6 weeks postdonation, and this was associated with an improved mental health component of quality of life compared with ODN (51.9±7.2 vs. 45.3±10.1; P=0.0009).

Differential expression of cytoprotective and apoptotic genes in an ischaemia‐reperfusion isolated organ perfusion model of the transplanted kidney

The optimal kidney preservation system and methods to ameliorate reperfusion injury are major factors in accomplishing successful graft function following transplantation. Ischaemia and reperfusion lead to cellular stress and the adaptive response may include the activation of genes involved in cellular protection and/or cell death by apoptosis. We investigated the expression of cytoprotective heme oxygenase‐1 (HO‐1), anti‐apoptotic Bcl‐2 and pro‐apoptotic Bax after 6 h isolated organ perfusion in porcine kidneys that had been given 10 and 40 min warm ischaemic time. The level of HO‐1 was shown to be significantly higher in the 10‐min warm ischaemic group compared with 40‐min group (0.90 ± 0.03 vs. 0.83 ± 0.03; P = 0.002). The levels of HO‐1 showed a significant positive correlated with parameters of renal function, creatinine clearance, and renal blood flow and urine output (AUC; r = 0.8042, P = 0.03; r = 0.6028, P = 0.04; r = 0.6055, P = 0.04), demonstrating a possible protective role of this gene in this model of renal transplantation.

Effects of erythropoietin on ischaemia/reperfusion injury in a controlled nonheart beating donor kidney model

Erythropoietin (EPO) has been shown to have an anti‐apoptotic action and has the potential to protect against ischaemia/reperfusion injury. This study investigated the effect of high dose EPO (5000 U), administered as a bolus at the onset of reperfusion and at the onset of cold storage in a model of controlled nonheart beating donors kidneys. Porcine kidneys(n = 6) were subjected to 10min warm ischaemia and preserved as follows: Group 1:16 h Cold storage +2 h Normothermic perfusion (16 h CS + 2 h NP) Group 2:16 h CS + 2 h NP + EPO given at the onset of reperfusion Group 3:18 h CS (static hypothermic storage) Group 4:18 h CS + EPO given at the onset of cold storage Haemodynamic and functional parameters were assessed during 3‐h reperfusion using autologous blood. Renal blood flow improved in Groups 1 and 2 vs. Groups 3 and 4 though no difference was noted between Groups 3 and 4 (563 ± 119 vs. 491 ± 95 vs. 325 ± 70 vs. 418 ± 112, respectively; P = 0.012). Total urine output showed no difference between Groups (271 ± 172 vs. 359 ± 184 vs. 302 ± 21 vs. 421 ± 88; P = 0.576). Percentage serum creatinine fall at 3 h was significantly better in Groups 1 and 2 vs. Group 3 (64 ± 17 vs. 60 ± 11 vs. 44 ± 13 vs. 52 ± 8; P = 0.04). Fractional‐excretion of sodium was significantly lower for Groups 1 and 2 vs. Group 3 and 4 (17 ± 14 vs. 18 ± 9 vs. 49 ± 21 vs. 45 ± 16 respectively; P = 0.002). There was significant improvement in oxygen consumption in Groups 2 vs. Groups 3 and 4 (P = 0.037) (39 ± 10 vs. 46 ± 10 vs. 24 ± 12 vs. 24 ± 7 respectively). EPO added at the time of reperfusion improved oxygen consumption when added to NP in comparison to static hypothermic storage but did not exert any other major benefits.

Abstract P1-14-15: Recent experience of neoadjuvant chemotherapy according to breast cancer subtype: experience from a large United Kindgom teaching hospital

INTRODUCTION: The most recent United Kingdom (NICE, 2009) guidelines recommend neoadjuvant chemotherapy as the most appropriate initial treatment for locally advanced breast cancer followed by mastectomy. Neoadjuvant chemotherapy should also be offered to patients with early breast cancer who are considering breast conserving surgery that is not advisable at presentation. However, the evidence base is still gathering. This study reviews the recent experience of neoadjuvant chemotherapy in a large United Kingdom breast unit according to breast cancer subtype. METHODS: Retrospective chart review of patients who received neoadjuvant chemotherapy for breast cancer at University Hospitals of Leicester between January 2008 and March 2011. Patients were identified from the unit database. Breast cancers were typed according to immunehistochemical marker profile: luminal A (ER or PR positive, HER2 negative), luminal B (ER or PR positive, HER2 positive), triple negative (ER and PR negative, HER2 negative), and HER2 positive (ER and PR negative, HER2 positive). RESULTS: Of 2,489 new patients with breast cancer seen during the study period, 153 patients received neoadjuvant chemotherapy. 20 patients had lobular-type cancers, and the remaining 133 patients had ductal- or mixed-type histology. 101 patients had locally advanced disease and 52 patients presented as early breast cancer. 24 of all patients (15 %) achieved complete pathological response. 18 patients (12 %) never proceeded to surgery, eight of whom died during the study period. In total to date, 23 patients (15 %) have died including one death due to complications from chemotherapy. Of 120 patients initially scheduled for mastectomy, the tumor was downsized in 26 patients (22 %) so that they were able to undergo breast conserving surgery (BCS), with margins involved in six patients. The outcome of neoadjuvant chemotherapy according to breast cancer subtype is presented (Tables 1 and 2). CONCLUSIONS: In our experience, patients receive neoadjuvant chemotherapy for breast cancer for a variety of indications. Compared to our standard population of breast cancer patients, early mortality remains relatively high, particlularly in the hormone receptor negative subtypes. BCS conversion rates were similar across breast cancer subtypes, but BCS was less likely to be successful in the Luminal A group. Luminal A cancers were also significantly less likely to achieve pCR after neoadjuvant chemotherapy. Breast cancer subtype should be taken into account when scheduling patients for neoadjuvant chemotherapy. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-14-15.