Herbert Maier

Lipocalin-2 Regulates the Inflammatory Response During Ischemia and Reperfusion of the Transplanted Heart

Ischemia and reperfusion (IR) are known to negatively affect early allograft function following solid organ transplantation. Lipocalin‐2 (Lcn‐2) has been described as a marker and potential positive modulator of acute inflammation during these processes. Using a heterotopic murine heart transplant model we previously found that IR resulted in a pronounced upregulation of Lcn‐2 mRNA in the heart at 12 (22.7‐fold increase) and 24 h (9.8‐fold increase) of reperfusion. We now confirm this increase at the protein level and provide evidence for infiltrating polymorphonuclear cells as the primary source of Lcn‐2 protein. Lcn‐2 levels are increased 6.6‐fold at 12 h, 11.4‐fold at 24 h and 6.4 fold at 48 h after reperfusion. In Lcn‐2−/− grafts the number of infiltrating granulocytes is reduced by 54% (p < 0.05) at 2 h, 79% (p < 0.01) at 12 h, 72% (p < 0.01) at 24 h and 52% (p < 0.01) at 48 h after reperfusion compared to Lcn‐2+/+ grafts, without any differences in cardiomyocyte apoptosis. These data suggest a function of Lcn‐2 in the initiation of the inflammatory response. Moreover, an increase in Lcn‐2 is not only restricted to the transplanted heart, but is also observed in the kidney, hinting at a possible involvement of Lcn‐2 in the systemic response to IR.

Combined pancreas-kidney transplantation for patients with end-stage nephropathy caused by type-2 diabetes mellitus.

Background Simultaneous pancreas-kidney (SPK) transplantation is widely accepted as an optimal therapeutic option for patients with type 1 diabetes mellitus (T1DM) and end-stage renal disease, but the indication for patients with type 2 diabetes mellitus (T2DM) is still controversially discussed. Methods Twenty-one T2DM recipients of a first combined pancreas-kidney graft performed at our center during a 9-year period were retrospectively analyzed with regard to demographic characteristics; cardiovascular risk factors; surgical, immunological, and infectious complications; and patient and graft survivals and compared with T1DM recipients (n=195) and 32 T2DM patients who received a kidney transplant alone (KTA) during the same period. Results Patient survival at 1 and 5 years was 96.9% and 91.6% for the T1DM group, 90.5% and 80.1% for the T2DM group, and 87.1% and 54.2% for the T2DM KTA group, respectively (P<0.001). Actuarial pancreas graft survival for SPK recipients at 1 and 5 years was calculated to be 92.6% and 80.7% for the T1DM group and 81.0% and 75.9% for the T2DM group, respectively (P=0.19). Kidney allograft survival at 5 years was 83.6% for T1DM, 80.4% for T2DM, and 52.7% for T2DM KTA (P<0.0001). Multivariate analysis adjusting for donor and recipient age, secondary complications of diabetes, body mass index, waiting time, cold ischemic time, delayed graft function, and coronary risk factors showed that differences did not remain statistically significant. Conclusion Favorable results can be achieved with SPK transplantation in type 2 diabetics with a low coronary risk profile. A high cardiac death rate impacts results of KTA and calls for stringent selection.

Lipocalin‐2 as mediator of chemokine expression and granulocyte infiltration during ischemia and reperfusion

Lipocalin‐2 (Lcn2) expression contributes to ischemia and reperfusion injury (IRI) by enhancing pro‐inflammatory responses. The aim of this work was to elucidate the regulation of Lcn2 during hypoxia and its effects on the expression of key chemokines and adhesion molecules. Lcn2 wt and Lcn2−/− mice were used in a heterotopic heart transplantation model. Quantitative RT‐PCR was applied for chemokine gene expression analysis. Reporter gene studies were used to elucidate the regulation of the Lcn2 promoter by hypoxia. HIF‐1β expression led to a 2.4‐fold induction of the Lcn2 promoter. Apart from an earlier onset of granulocyte infiltration in the Lcn2 wt setting after 2 h of reperfusion compared with the Lcn2−/− setting (P < 0.013), exogenous application of recombinant Lcn2 revealed a trend toward increase of granulocyte infiltration. Analyzed chemokines were expressed significantly higher in the Lcn2 wt setting at 2 h of reperfusion (P ≤ 0.05). The number of apoptotic cells observed in Lcn2−/− grafts was significantly higher than in the Lcn2 wt setting. Our results indicate that Lcn2 affects granulocyte infiltration in the reperfused graft by modulating the expression of chemokines, their receptors and the apoptotic rate.

Exogenous Lipocalin 2 Ameliorates Acute Rejection in a Mouse Model of Renal Transplantation

Lipocalin 2 (Lcn2) is rapidly produced by damaged nephron epithelia and is one of the most promising new markers of renal injury, delayed graft function and acute allograft rejection (AR); however, the functional importance of Lcn2 in renal transplantation is largely unknown. To understand the role of Lcn2 in renal AR, kidneys from Balb/c mice were transplanted into C57Bl/6 mice and vice versa and analyzed for morphological and physiological outcomes of AR at posttransplantation days 3, 5, and 7. The allografts showed a steady increase in intensity of interstitial infiltration, tubulitis and periarterial aggregation of lymphocytes associated with a substantial elevation in serum levels of creatinine, urea and Lcn2. Perioperative administration of recombinant Lcn2:siderophore:Fe complex (rLcn2) to recipients resulted in functional and morphological amelioration of the allograft at day 7 almost as efficiently as daily immunosuppression with cyclosporine A (CsA). No significant differences were observed in various donor–recipient combinations (C57Bl/6 wild‐type and Lcn2−/−, Balb/c donors and recipients). Histochemical analyses of the allografts showed reduced cell death in recipients treated with rLcn2 or CsA. These results demonstrate that Lcn2 plays an important role in reducing the extent of kidney AR and indicate the therapeutic potential of Lcn2 in transplantation.

Pancreatic Graft Survival Despite Partial Vascular Graft Thrombosis due to Splenocephalic Anastomoses

Thrombotic complications following pancreas transplantation are still the most common cause of nonimmunologic graft loss. The aim of this study was to analyze pancreatic graft function after partial arterial graft thrombosis and the investigation of the pancreatic arterial anatomy with regard to intraparenchymal anastomoses. We retrospectively analyzed the data for 175 consecutive pancreas transplants performed between January 2002 and October 2007. Selective Y‐graft angiography was performed in 10 and rubber‐milk injection in 5 fresh pancreas specimens. Thrombosis of one leg of the Y‐graft was diagnosed in 18 (10.3%) patients. Only one of these patients with thrombosis of the splenic artery required exogenous insulin. Sufficient graft perfusion was demonstrated in all of the remaining grafts. One graft was lost due to acute rejection. In all specimens angiography showed an excellent perfusion of the pancreaticoduodenal arcade, even after selective cannulation of the splenic artery. Arterial collaterals between the gastroduodenal, splenic artery and the superior mesenteric artery were demonstrated. Our results demonstrate that global perfusion of the pancreatic graft and sufficient graft function is sustained after the thrombotic occlusion of one branch of the Y‐graft by a complex system of intraparenchymal anastomoses. These anatomical findings may have consequences for resection strategies in pancreas surgery.

Upregulation of Neutrophil Gelatinase-Associated Lipocalin in Colorectal Cancer Predicts Poor Patient Survival: Reply

Background Lipocalin-2 (Lcn-2) is expressed in human neutrophils and epithelial cells, particularly in the presence of inflammation or cancer. It was shown to be highly expressed in various human cancers. Increased protein levels were associated with decreased survival of patients with breast or gastric cancer. The main focus of this work was to analyze the implication of Lcn-2 up-regulation in the genesis of colon cancer.

Acellular porcine cross-linked dermal collagen may be a valuable graft for pelvic floor reconstruction after extended resection.

Dear Editor: Muscular pelvic floor defects, which can occur after pelvic tumor resection, require primary repair in order to avoid perineal herniation of abdominal contents. Small defects can be repaired with direct approximation of tissue or with gracilis muscle flaps. For large defects formation of either bilateral gluteus maximus advancement myocutaneous flaps, or transpelvic or transabdominal vertical rectus abdominis myocutaneous flaps is required. When additional support is needed, a synthetic mesh can be used. However, synthetic meshes are prone to complications such as infection and bowel adhesion, erosion, and fistula formation. Nowadays, grafts made of porcine dermis cleared of cells, DNA, and RNA are available (CollaMendTM, C. R. Bard Inc., Cranston, USA; PermacolTM, Tissue Science Laboratories, Aldershot, UK). In these grafts, the collagen fibers are chemically cross-linked, what makes collagen resistant to absorption. The three-dimensional collagen matrix allows cellular in-growth, neovascularization, and rapid integration into the surrounding tissue. Grafts made of porcine dermal collagen (PDC) are more resistant to infection and adhesion formation than synthetic material. We report on a 63-year-old woman who presented with a huge perineal and lower pelvic anal cancer recurrence. The patient had undergone radical hysterectomy and lymphadenectomy followed by radiotherapy for invasive cervical cancer 25 years ago. Five years ago, a squamous cell anal cancer was diagnosed. Due to prior radiotherapy, a limited radiation reserve was available. The patient received 30.4 Gy and chemotherapy and subsequently underwent abdominoperineal excision of the anorectum with formation of a permanent colostomy. The cancer recurrence presented as a deep perineal ulcer, the vagina did not exist any more, urine leaked from a bladder fistula. CT, MRI, and PET scans revealed local resectability, there was no evidence of distant tumor spread. The bladder was widely infiltrated; the tumor reached the pubic bones, however there were no signs of osseous infiltration. The patient was informed about the necessity of total pelvic exenteration. Additionally, she was informed that the implantation of a bioprosthetic graft for pelvic floor reconstruction was planned. Laparotomy was performed in the Lloyd–Davis position. The peritoneum at the entrance to the small pelvis was incised and the dissection followed the pelvic wall down to the coccyx, sparing the ureters and the iliac vessels. The bladder was mobilized; the ureters were transsected close to the bladder. The extent of the tumor required resection of most of the muscular pelvic floor. Tumor resection was completed from the perineal approach and included excision of the coccyx, wide lateral excision of the perineum and transsection of the tissue anteriorly of the ostium of the urethra. The specimen was removed, biopsies taken from four points of the resection margins at the patient’s side microscopically revealed no evidence of residual tumor. Both ureters were anastomosed to an ileum conduit which was diverted in the right lower quadrant of the abdominal wall. The huge pelvic floor defect was closed with an 10.2 cm×15.2 cm elliptic graft of PDC, which was sutured to the sacral fascia, to the residual pelvic Int J Colorectal Dis (2009) 24:357–358 DOI 10.1007/s00384-008-0629-3

Prediction of delayed graft function and long-term graft survival by serum and urinary neutrophil gelatinase-associated lipocalin during the early postoperative phase after kidney transplantation.

Neutrophil gelatinase-associated lipocalin (NGAL) has emerged as an early marker protein for kidney dysfunction in various clinical settings. In this prospective study we evaluated serial changes of serum and urinary NGAL within the first 7 days after kidney transplantation in 170 consecutive recipients. The main focus of this study was to assess the performance of serum and urinary NGAL in the prediction of delayed graft function (DGF) and two-year graft and patient survival. Serum and urine samples of 170 patients undergoing primary kidney transplantation from October 2010 to December 2012 were prospectively collected from day 0 to 7. NGAL was analyzed by ELISA. Multivariate regression models, receiver-operating characteristics (ROC), and areas under ROC curves (AUC) were used to identify predictors of DGF. DGF occurred in 52 patients (30.6%). Serum (AUC = 0.869) and urinary NGAL (AUC = 0.872) on postoperative day (POD) 2 could accurately predict DGF compared to serum creatinine (AUC = 0.619). Multivariate analyses revealed donor age, serum and urinary NGAL significantly associated with DGF (p<0.001). Recipient age was the only significant factor in a cox regression model influencing two-year graft and patient survival. In conclusion, serum and urinary NGAL are early predictors of DGF after kidney transplantation.

Intraoperative complications during VATS lobectomies from conversion to minimally-invasive “trouble-shooting”

The aim of this study was to explore intraoperative complications during video-assisted thoracoscopic surgery (VATS) lobectomy. Vascular and bronchial injuries, after a robust learning curve, can be sometimes successfully managed by VATS. During a VATS lobectomy, it is necessary: to be prepared in potentially dangerous situations; to think about strategies to handle intraoperative complications and to share these strategies with your own staff. Herein we present some videos showing cases where vascular injuries led to conversion and others where a minimally-invasive trouble shooting of intraoperative complications was achieved.

Benefits of a multidisciplinary team approach on a challenging case of bilateral tension pneumothorax

This editorial comment refers to the article “ Multidisciplinary team approach on a case of bilateral tension pneumothorax ” by Li et al ., Journal of Thoracic Disease ( JTD ); Vol. 10, No. 4 (1).