Andrzej G. Baranski

Lectin complement pathway gene profile of donor and recipient determine the risk of bacterial infections after orthotopic liver transplantation

Infectious complications after orthotopic liver transplantation (OLT) are a major clinical problem. The lectin pathway of complement activation is liver‐derived and a crucial effector of the innate immune defense against pathogens. Polymorphisms in lectin pathway genes determine their functional activity. We assessed the relationship between these polymorphic genes and clinically significant bacterial infections, i.e., sepsis, pneumonia, and intra‐abdominal infection, and mortality within the first year after OLT, in relation to major risk factors in two cohorts from different transplant centers. Single‐nucleotide polymorphisms in the mannose‐binding lectin gene (MBL2), the ficolin‐2 gene (FCN2), and the MBL‐associated serine protease gene (MASP2) of recipients and donors were determined. Recipients receiving a donor liver in the principal cohort with polymorphisms in all three components i.e., MBL2 (XA/O; O/O), FCN2+6359T, and MASP2+371A, had a cumulative risk of an infection of 75% as compared to 18% with wild‐type donor livers (P = 0.002), an observation confirmed in the second cohort (P = 0.04). In addition, a genetic (mis)match between donor and recipient conferred a two‐fold higher infection risk for each separate gene. Multivariate Cox analysis revealed a stepwise increase in infection risk with the lectin pathway gene profile of the donor (hazard ratio = 4.52; P = 8.1 × 10−6) and the donor‐recipient (mis)match genotype (hazard ratio = 6.41; P = 1.9 × 10−7), independent from the other risk factors sex and antibiotic prophylaxis (hazard ratio > 1.7 and P < 0.02). Moreover, patients with a lectin pathway gene polymorphism and infection had a six‐fold higher mortality (P = 0.9 × 10−8), of which 80% was infection‐related. Conclusion: Donor and recipient gene polymorphisms in the lectin complement pathway are major determinants of the risk of clinically significant bacterial infection and mortality after OLT. (HEPATOLOGY 2010;)

Early Renal Ischemia‐Reperfusion Injury in Humans Is Dominated by IL‐6 Release from the Allograft

The pathophysiology of ischemia/reperfusion (I/R) injury is complex, and current knowledge of I/R injury in humans is incomplete. In the present study, human living‐donor kidney transplantation was used as a highly reproducible model to systematically study various processes potentially involved in early I/R injury. Unique, direct measurements of arteriovenous concentration differences over the kidney revealed massive release of interleukin (IL)‐6 in the first 30 minutes of graft reperfusion and a modest release of IL‐8. Among the assessed markers of oxidative and nitrosative stress, only 15(S)‐8‐iso‐PGF2α was released. When assessing cell activation, release of prothrombin factor 1 + 2 indicated thrombocyte activation, whereas there was no release of markers for endothelial activation or neutrophil activation. Common complement activation complex sC5b‐9 was not released into the bloodstream, but was released into urine rapidly after reperfusion. To investigate whether IL‐6 plays a modulating role in I/R injury, a mouse experiment of renal I/R injury was performed. Neutralizing anti‐IL‐6 antibody treatment considerably worsened kidney function. In conclusion, this study shows that renal I/R in humans is dominated by local IL‐6 release. Neutralization of IL‐6 in mice resulted in a significant aggravation of renal I/R injury.

Reduced quality of life in living kidney donors: association with fatigue, societal participation and pre-donation variables

Health related quality of life (HRQoL) of living kidney donors on average is good, but some donors experience a low HRQoL after donation. This study assessed the prevalence of reduced HRQoL and explored associations with pre‐ and post‐donation variables. 316 donors (response rate 74%) who donated a kidney between 1997 and 2009 filled in a questionnaire. HRQoL was measured using the Short‐Form 36; fatigue using the Multidimensional Fatigue Inventory; societal participation using the Utrecht Scale for Evaluation of Rehabilitation‐Participation. Donors on average had better HRQoL than the general population. However, 12% had a reduced physical (PCS) and 18% a reduced mental (MCS) HRQoL. Donors with reduced HRQoL reported greater fatigue (Pu2003<u20030.01), lower societal participation (Pu2003<u20030.01) and showed a trend towards statistical significance in experiencing more donor–recipient relationship changes (Pu2003=u20030.07). Prior to donation, donors with reduced PCS had a higher BMI (Pu2003<u20030.05) and more often smoked (Pu2003<u20030.05). Donors with reduced MCS had higher expectations (Pu2003<u20030.05). Reduced HRQoL is associated with higher BMI, smoking and higher expectations prior to donation. These results may be used to develop a screening instrument to select donors at high risk for reduced HRQoL.

Pancreas transplantation: advantages of both enteric and bladder drainage combined in a two-step approach.

Abstract: Background: Although there is a tendency to perform enteric drainage of pancreas transplants in simultaneous pancreas–kidney (SPK) transplantation, bladder drainage is still preferable in pancreas transplantation alone (PTA) or after a previous kidney transplantation (PAK). Our hypothesis was that enteric conversion of a bladder drained pancreas is an effective and safe procedure. We studied the complication rate and physiological effects of enteric conversion in patients with primary bladder‐drained SPK transplantation.

Decision making around living and deceased donor kidney transplantation: a qualitative study exploring the importance of expected relationship changes

BackgroundLimited data exist on the impact of living kidney donation on the donor-recipient relationship. Purpose of this study was to explore motivations to donate or accept a (living donor) kidney, whether expected relationship changes influence decision making and whether relationship changes are actually experienced.MethodsWe conducted 6 focus groups in 47 of 114 invited individuals (41%), asking retrospectively about motivations and decision making around transplantation. We used qualitative and quantitative methods to analyze the focus group transcripts.ResultsMost deceased donor kidney recipients had a potential living donor available which they refused or did not want. They mostly waited for a deceased donor because of concern for the donor’s health (75%). They more often expected negative relationship changes than living donor kidney recipients (75% vs. 27%, pu2009=u20090.01) who also expected positive changes. Living donor kidney recipients mostly accepted the kidney to improve their own quality of life (47%). Donors mostly donated a kidney because transplantation would make the recipient less dependent (25%). After transplantation both positive and negative relationship changes are experienced.ConclusionExpected relationship changes and concerns about the donor’s health lead some kidney patients to wait for a deceased donor, despite having a potential living donor available. Further research is needed to assess whether this concerns a selected group.

Surgical injuries of pancreatic allografts during procurement

Marang‐van de Mheen PJ, Hilling DE, Dirkes MC, Baranski AG. Surgical injuries of pancreatic allografts during procurement. u2028Clin Transplant 2011: 25: 737–743.

Flexible Limited Sampling Model for Monitoring Tacrolimus in Stable Patients Having Undergone Liver Transplantation With Samples 4 to 6 Hours After Dosing Is Superior to Trough Concentration

Trough (C0) monitoring is not optimal for therapeutic drug monitoring of tacrolimus. To better estimate systemic exposure of tacrolimus and achieve clinical benefit, an improved therapeutic drug monitoring strategy should be developed. The authors examined which single and combination of time points best estimated the empiric “gold standard” AUC0-12h and developed and validated a new, flexible, and accurate limited sampling model for monitoring tacrolimus in patients having undergone liver transplantation. Twenty-three stable patients with full AUC0-12h were divided into two groups based on area under the concentration-time curve/dose. With multiple regression analysis, limited sampling formulae were derived and population-pharmacokinetic-based limited sampling models were developed and validated. A regression analysis was performed between either area under the concentration-time curves calculated with formulae or models with the reference trapezoidal AUC0-12h. Both formulae and models based on single samples C4-C6 (r2 = 0.94 [MPE/MAPE 0/7]-0.90 [2/8] and 0.97 [0/7]-0.97 [1/5]) showed excellent performance. The calculated area under the concentration-time curve target range for tacrolimus was 90 to 130 h*μg/L. Multiple point sampling performed better, especially when using models (r2 > 0.94). C0 was a less precise predictor of AUC0-12h compared with both formulae and models (r2s 0.68 [5/17] and 0.87 [2/14]). In conclusion, trough concentration monitoring is not an accurate method for assessing systemic exposure to tacrolimus in stable patients having undergone liver transplantation. This new limited sampling model, based on single time points C4-C6, shows excellent performance in estimating the AUC0-12h.

MMP-2 is a disease-modifying gene in primary sclerosing cholangitis

Primary sclerosing cholangitis (PSC) is a chronic inflammatory disease of the bile ducts, frequently necessitating orthotopic liver transplantation (OLT), often accompanied by inflammatory bowel disease (IBD). Matrix metalloproteinases (MMPs) are associated with fibrotic diseases caused by the involvement in tissue remodelling.

Report of the first five DCDD pancreas transplants within the Eurotransplant region; excellent results with prolonged first warm ischemia times

Dear Sirs, The success of pancreas transplantation has led to an increased number of pancreas transplantations, which again has led to an increased need for suitable pancreas allografts. This initiated a search for alternative ways to increase the number of pancreas donors. Donation-aftercirculatory-determination-of-death (DCDD) is such an alternative and is a recognized form of transplantation with regard to kidney, liver, and lung transplantation. However, there is limited experience with DCDD in pancreas transplantation [1–6]. A large study with Scientific Registry of Transplant Recipients (SRTR) data showed DCDD-status to have a marginally significant risk (HR 1.39; P = 0.10) compared with a donation-after-brain-death (DBD)-donor [1]. Nevertheless, similar patient survival and graft survival rates between DBD and DCDD-groups at 1-year, 5-years [2,3,6], and even 10-years follow-up [5] have been reported. Results describe higher rate of renal complications such as delayed graft function (DGF) or urinary tract infections [2,3] after DCDD transplantation, however, there were no higher rates in pancreas-related complications [2,5]. Interestingly, these reports are always with rather short 1st warm ischemia times (WITs), ranging from 14 min [4] to 21 min [5]. Within the Eurotransplant region DCDD is only performed in Austria, Belgium, and The Netherlands. In February 2011, the first DCDD pancreas transplantation within the Eurotransplant region was performed in our center. Since then four more DCDD pancreas transplantations were performed. All five allografts were procured from DCDD-donors in The Netherlands. Pancreas allografts were matched and offered via Eurotransplant. Donor, transplant, and recipient characteristics are shown in the Table 1. HTK perfusion-fluid was used in all procedures. All patients were treated with alemtuzumab (Campath) induction-therapy and maintained on duo therapy, consisting of tacrolimus and mycophenalate mofetil. At 1-year follow-up all recipients are alive with optimally functioning pancreas and kidney allografts. There were no perioperative complications. Three pancreas allografts were enteric-drained and two were initially bladder-drained and converted to enteric drainage afterward, according to a two-step protocol [7]. All patients had immediate pancreas function, measured as peroperative lowering of the blood glucose levels, and, except for the fourth recipient, all SPKpatients had immediate kidney function, measured as peroperative diuresis. There were a few long-term complications: the first patient developed moderate interstitial and vascular rejection after 3 months, which was treated with antirejection therapy consisting of methylprednisolone. The third recipient developed a hematoma near the pancreas allograft, for which he was reoperated twice. After 2 months this recipient developed acute kidney insufficiency because of a ureteral stricture caused by a renal BK-infection, for which he was reoperated and reinsertion of the ureter to the bladder was performed. After lowering the immunosuppressive therapy, this recipient developed an interstitial rejection episode of the kidney, which was treated with methylprednisolone. The fourth recipient had a DGF of the kidney, for which he was treated with dialysis on days 2, 3, 4, and 6 postoperatively. After 6 weeks, a CT-scan showed a distal, partial venous thrombosis in the splenic vein, for which anticoagulant therapy (coumarine) was started liberally. The fifth recipient showed acute respiratory insufficiency because of a rhinovirus-infection 2 days after the operation, for which he was shortly admitted to the intensive care unit (ICU). HbA1c-values at 3-months follow-up were normal (mean of 32.6 mmol/mol) and most recent values are still within the normal ranges for all patients. Most of the postoperative complications our recipients experienced are not necessarily directly related to DCDD-allografts. Only DGF of the kidney in the fourth recipient is seen more often after DCDD transplantation [2,3,5]. Although DCDD pancreas transplantation is not a new concept worldwide, only few reports of pancreas transplantation using allografts from DCDD-donors have been published [1–5]. Within Europe, UK-Transplant has the largest series of DCDD pancreas transplantation [8], with

Application of near-infrared fluorescence imaging during modified associating liver partition and portal vein ligation for staged hepatectomy

Therefore, the confusion may be the result of whether one is referring to the procedure (action) or the end result. This leads to the discussion of whether there should be a distinction between a life-saving but temporary procedures (-tomy) or a definitive procedure (-stomy), a stoma that in some cases is never reversed. Although it may be difficult to imagine that these ethymologic-based suggestions will be applied daily to clarify the terminology and give proper meaning to the terms used, our interrogation might also give rise to further discussion as concerns the use of words such as “laparostomy” for the “open abdomen, “urostomy” which refers to a very imprecise communication between the urinary tract and.whatever.