Atul Bagul

Randomized clinical trial of laparoscopic versus open donor nephrectomy

This randomized controlled trial was designed to determine the safety and efficacy of laparoscopic donor nephrectomy (LDN) in comparison with short‐incision open donor nephrectomy (ODN).

The relative effects of warm and cold ischemic injury in an experimental model of nonheartbeating donor kidneys.

Background. Ischemia reperfusion injury (I/R) leads to delayed graft function and remains an important problem in renal transplantation. The aim of this experimental study was to assess the effects of warm (WI) and cold ischemia (CI) in models of heartbeating (HBD) and controlled/uncontrolled nonheartbeating donor (NHBD) kidneys. Methods. A reperfusion model utilizing cardiopulmonary bypass technology was used to perfuse isolated porcine kidneys with autologous blood after the following conditions: 0 min WI + 2 h cold storage (CS); 0 min WI + 18 h CS; 10 min WI + 2 h CS; 10 min WI + 18 h CS; 25 min WI + 2 h CS; 25 min WI + 18 h CS. Renal function was measured over a period of 3 hr. Results. Renal functional parameters were not significantly different between 0, 10, 25 WI with 2 h CS [AUC creatinine (Cr) decrease of 1057±177, 1102±260, and 1245±143 &mgr;mol/L h, P=0.338; AUC creatinine clearance (CrCl) of 37.7±15.8, 36.2±21.7, 19.8±9.1 ml/min/100 g h, P=0.099]. After 18 h CS, renal function was severely impaired in the 10 and 25 WI groups compared to 0 min WI [AUC Cr of 2156±401, 2287±148, 1563±395 &mgr;mol/L h, P=0.037; AUC CrCl of 2.2±1.7, 1.5±1.5, 21.7±13.4 ml/min/100 g h, P=0.007). Conclusion. Warm ischemia of up to 25 min was only detrimental to renal function when kidneys were subsequently preserved in cold storage for 18 hr. This data suggests that limiting the cold storage period is of paramount importance when transplanting kidneys subjected from nonheartbeating donors.

A comparison of hypothermic machine perfusion versus static cold storage in an experimental model of renal ischemia reperfusion injury.

Introduction. There is increasing support for the use of hypothermic machine perfusion (HMP) in an attempt to reduce preservation injury. However, experimental evidence is needed to further examine the effects of HMP on renal ischemia reperfusion injury. Methods. Porcine kidneys were subjected to 10 min of warm ischemia followed by 18 hr of static cold storage with hyperosomolar citrate (HOC), histidine-tryptophan-ketoglutarate (HTK), or University of Wisconsin (UW) solutions or 18 hr HMP with Kidney Perfusion Solution using the Lifeport perfusion system. Renal function, oxidative damage, and morphology were assessed during 3 hr of reperfusion with autologous blood using an isolated organ perfusion system. Results. During reperfusion, intrarenal resistance was significantly lower in the HMP group compared with HOC and UW (area under the curve; HMP 3.8±1.7, HOC 9.1±4.3, UW 7.7±2.2, HTK 5.6±1.9 mm Hg/min; P=0.006), and creatinine clearance was significantly higher compared with the UW group (area under the curve creatinine clearance; HMP 9.8±7.3, HOC 2.2±1.7, UW 1.8±1.0, HTK 2.1±1.8 mL/min/100 g; P=0.004). Tubular function was significantly improved in the HMP group (P<0.05); however, levels of lipid peroxidation were significantly higher (P=0.005). Conclusion. HMP demonstrated a reduced level of preservation injury compared with the static techniques resulting in improved renal and tubular function and less tubular cell inflammation during reperfusion.

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.

Effects of arterial pressure in an experimental isolated haemoperfused porcine kidney preservation system

Normothermic preservation provides metabolic support to an ischaemically damaged organ before use as a kidney transplant. Optimal conditions for ex vivo preservation have not yet been established. This study examined the effects of arterial pressure on renal preservation using isolated haemoperfused kidneys.

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).

Thymoglobulin and Its Use in Renal Transplantation: A Review

Thymoglobulin (Thymoglobulin®; Genzyme, Cambridge, Mass., USA) is a polyclonal antibody which has been used in the field of transplantation over the last four decades. With an initial hesitancy, it is widely used now in the prevention and treatment of rejection following renal transplantation. Thymoglobulins lack of nephrotoxic properties (unlike calcineurin inhibitors) may potentiate it to be a very useful induction therapy during the early days following transplantation, particularly in a donation after circulatory death programme. More recently its role in conjunction with inhibitors of terminal complement activation has been shown to be beneficial in cross-match-positive transplantation. This review article consolidates up-to-date available evidence to address the therapeutic role of thymoglobulin in immunological tolerance, ischemia perfusion, live donor transplantation, delayed graft function, prevention and treatment of rejection, graft survival and post-transplant lymphoproliferative disorder following renal transplantation.

Normothermic versus hypothermic ex vivo flush using a novel phosphate-free preservation solution (AQIX) in porcine kidneys.

BACKGROUND The initial flush of an organ is important to remove any cellular components from the microcirculation before storage. The aim of this study was to assess graft function after an ex vivo warm flush with a novel non-phosphate buffered preservation solution AQIX RS-I (AQIX) compared with a traditional cold flush. METHODS Porcine kidneys were either warm-flushed with AQIX RS-I at 30°C, or cold-flushed at 4°C with University of Wisconsin solution (UW) or hyperosmolar citrate (HOC) preservation solution at a pressure of 100 cmH2O (n = 6). Renal function was measured ex vivo by perfusing the organs with autologous blood at 37°C on an isolated organ perfusion system. RESULTS The AQIX group flushed significantly quicker than the cold stored groups (22 ± 1.8 versus UW 4.9 ± 1.6 versus HOC 10 ± 1.6 mL/min/100g; P = 0.001) and gained less weight than the UW group (19 ± 2.9 versus UW 30 ± 3.4 versus HOC 21% ± 7.7%; P = 0.025). The AQIX group also had superior acid-base homeostasis. Functional results, histologic analysis, and ADP: ATP levels were comparable between the groups. CONCLUSION Flushing kidneys with AQIX at 30°C cleared the renal microcirculation of blood more rapidly without any detrimental effects when compared to traditional cold flushing with UW or HOC at 4°C. Warm initial flushing has potential to be developed as part of normothermic renal preservation techniques.

Erythropoietin regulates apoptosis, inflammation and tissue remodelling via caspase-3 and IL-1β in isolated hemoperfused kidneys.

Ischemia reperfusion injury associated with apoptosis and inflammation plays crucial roles in renal transplantation. Erythropoietin provides renoprotection, but its effects and mechanisms on kidney preservation are not fully defined. Porcine kidneys, subjected to 10 min warm ischemia, underwent 16 h cold storage followed by 2 h normothermic hemoperfusion with or without 5000 units/L erythropoietin. Apoptotic cells were increased in tubular lumens and interstitial areas by normothermic perfusion alone, but decreased in tubular areas by additional erythropoietin. Myeloperoxidase+ cells, free cells and cell debris in tubular lumens were gradually increased by cold storage, normothermic perfusion and erythropoietin in normothermic perfusion. Accordingly, caspase-3 activity as well as its active proteins was increased by normothermic perfusion and furthered by erythropoietin. In contrast, macrophage L1 protein positive cells in tubulointerstitial areas, cytokine interleukin (IL)-1β activation, tubular dilation and vacuolation were raised by normothermic perfusion, but all alleviated by erythropoietin, with higher urine output. The migration of myeloperoxidase+ cells with apoptotic features and apoptotic cells with polymorphous nuclei from tubulointerstitial areas into tubular lumens was widely displayed in the kidneys, especially those preserved by erythropoietin in normothermic perfusion. HSP70 protein was enhanced by normothermic perfusion regardless of erythropoietin. In addition, erythropoietin induced a dose-dependent increase in caspase-3 precursor in porcine proximal tubular cells (LLC-PK1) and also stimulated caspase-3 cleavage in cisplatin-treated cells. In conclusion, erythropoietin promotes inflammatory cell apoptosis, drives inflammatory and apoptotic cells into tubular lumens, eventually leads to inflammation clearance, renoprotection and tissue remodelling through caspase-3 and IL-1β in isolated haemoperfused kidneys.

Minimising cold ischaemic injury in an experimental model of kidney transplantation.

Eur J Clin Invest 2011; 41 (3): 233–240