Marek Karczewski

Secukinumab, a human anti-IL-17A monoclonal antibody, for moderate to severe Crohn's disease: unexpected results of a randomised, double-blind placebo-controlled trial

Objective The authors tested whether the anti-interleukin (IL)-17A monoclonal antibody secukinumab was safe and effective for the treatment of active Crohns disease. Design In a double-blind, randomised, placebo-controlled proof-of-concept study, 59 patients with moderate to severe Crohns disease (Crohns Disease Activity Index (CDAI) ≥220 to ≤450) were assigned in a 2:1 ratio to 2×10 mg/kg intravenous secukinumab or placebo. The primary end point, addressed by Bayesian statistics augmented with historical placebo information, was the probability that secukinumab reduces the CDAI by ≥50 points more than placebo at week 6. Ancillary analyses explored associations of 35 candidate genetic polymorphisms and faecal calprotectin response. Results 59 patients (39 secukinumab, 20 placebo, mean baseline CDAI 307 and 301, respectively) were recruited. 18/59 (31%) patients discontinued prematurely (12/39 (31%) secukinumab, 6/20 (30%) placebo), 10/59 (17%) due to insufficient therapeutic effect (8/39 (21%) secukinumab, 2/20 (10%) placebo). Fourteen serious adverse events occurred in 10 patients (seven secukinumab, three placebo); 20 infections, including four local fungal infections, were seen on secukinumab versus none on placebo. Primary end point analysis estimated <0.1% probability (∆CDAI (SD) =33.9 (19.7), 95% credible interval −4.9 to 72.9) that secukinumab reduces CDAI by ≥50 points more than placebo. Secondary area under the curve analysis (weeks 4–10) showed a significant difference (mean ΔCDAI=49; 95% CI (2 to 96), p=0.043) in favour of placebo. Post hoc subgroup analysis showed that unfavourable responses on secukinumab were driven by patients with elevated inflammatory markers (CRP≥10 mg/l and/or faecal calprotectin≥200 ng/ml; mean ΔCDAI=62; 95% CI (−1 to 125), p=0.054 in favour of placebo). Absence of the minor allele of tumour necrosis factor-like ligand 1A was strongly associated with lack of response measured by baseline-adjusted changes in calprotectin at week 6 (p=0.00035 Bonferroni-corrected). Conclusions Blockade of IL-17A was ineffective and higher rates of adverse events were noted compared with placebo. Clinical trial registration This trial was registered at ClinicalTrial.gov with the number NCT01009281.

Urologic De Novo Malignancies After Kidney Transplantation: A Single Center Experience

INTRODUCTION Urologic cancers are the second or third most common malignancies in renal transplant (RT) recipients. This study sought to determine the incidence of and identify possible risk factors for urologic malignancies among patients who underwent transplantation at our center. METHODS This retrospective, single-center cohort included 836 patients who underwent transplantation from 1994 to 2011 who remained under our care. A review of their medical records revealed 63 subjects with de novo cancer, including 21 with urologic malignancies (2.5%). We analyzed demographic and clinical data of cancer versus noncancer patients with differences considered to be significant at P < .05. RESULTS The urologic malignancies included renal cell carcinoma (n = 13), prostate cancer (n = 5), and bladder transitional cell carcinoma (n = 3). The mean follow-up time was 10 ± 3.9 years. The mean age at diagnosis was 54 ± 7.4 years and the mean time from transplantation was 4 ± 3.3 years. The mortality rate among group was 19.0%. The analysis did not show significant differences in demographic or clinical characteristics between the groups, except for the prevalence of male gender and smoking status among the cancer cohort. No significant differences were observed for other suspected risk factors, including immunosuppressive protocols, time of pretransplantation dialysis, and age. CONCLUSIONS The development of urologic malignancies is an early event, frequently observed within 4-5 years after transplantation. Therefore, this period should be considered for routine urologic cancer screening.

The role of simulation to support donation after circulatory death with extracorporeal membrane oxygenation (DCD-ECMO)

Maintaining the viability of organs from donors after circulatory death (DCD) for transplantation is a complicated procedure, from a time perspective in the absence of appropriate organizational capabilities, that makes such transplantation cases difficult and not yet widespread in Poland. We present the procedural preparation for Poland’s first case of organ (kidney) transplantation from a DCD donor in which perfusion was supported by extracorporeal membrane oxygenation (ECMO). Because this organizational model is complex and expensive, we used advanced high-fidelity medical simulation to prepare for the real-life implementation. The real time scenario included all crucial steps: prehospital identification, cardiopulmonary resuscitation (CPR), advanced life support (ALS); perfusion therapy (CPR-ECMO or DCD-ECMO); inclusion and exclusion criteria matching, suitability for automated chest compression; DCD confirmation and donor authorization, ECMO organs recovery; kidney harvesting. The success of our first simulated DCD-ECMO procedure in Poland is reassuring. Soon after this simulation, Maastricht category II DCD procedures were performed, involving real patients and resulting in two successful double kidney transplantations. During debriefing, it was found that the previous simulation-based training provided the experience to build a successful procedural chain, to eliminate errors at the stage of identification, notification, transportation, donor qualifications and ECMO organ perfusion to create DCD-ECMO algorithm architecture.

Influence of donor and recipient gender as well as selected factors on the five-year survival of kidney graft.

UNLABELLED The aim of the study was to determine the impact of the gender of renal allograft donor and recipient on the graft function over a 5-year follow-up period. MATERIAL AND METHODS The 154 kidney grafts from 77 donors transplanted into recipients of both genders. Two study groups were formed: one group consisted of male donors, while the other consisted of female donors. The recipients in each of the groups consisted of a pair, one male and one female. RESULTS 71% of grafts survived the five-year period in the group of male and female recipients when the donor was male; in case of female donors, the rate was 62.5%. Depending on the gender of the donor and the recipient, the rates of grafts with five-year survival were as follows: 79.2% for male donors and female recipients (MF); 62.5% for male donors and male recipients (MM). The difference between both groups was not statistically significant. In the case of female donors and male recipients (FM), the five-year survival rate was 58.3%, while in female donors and female recipients, the five-year survival rate was 64.1%. CONCLUSIONS Grafts from male donors show a trend towards better five-year survival compared to grafts from female donors. The highest five-year survival rate was observed when the donor was male and the recipient was female; the lowest rate was observed for female donors and male recipients.

Pretransplant urine cytokine pattern predicts acute kidney rejection.

Acute rejection (AR) remains a major problem after kidney transplantation and crucial determinant of long-term graft function. Potent mediators of alloimmune response leading to AR are cytokines. To further explore the relation between cytokine pattern and frequency of AR episodes we analyzed Th1/Th2 cytokine concentrations in the urine of 44 patients prior to the kidney transplantation. During the 6-month period following the transplantation AR was diagnosed in 11 patients. Urine samples were collected 1day before the transplantation. Samples were cytometrically tested for concentrations of IL-2, IL-4, IL-5, IL-10, IFN-gamma and TNF-alpha. Analysis showed significantly higher pretransplant concentrations of IFN-gamma (P > .001), TNF-alpha (P < .05) and IL-10 (P < .001) in the urine of patients with diagnosed AR. No significant differences in the concentrations of IL-2, IL-4, IL-5 between the two groups were observed. Elevated pretransplant concentrations of urine IFN-gamma and TNF-alpha in AR patients, not accompanied by higher concentrations of IL-2, may suggest an ongoing undetected and local, non-specific Th1 immune response, capable of amplifying the alloimmune response in the early phase postsurgery. While higher concentrations of IL-10 can partially result from activation of monocytes/macrophages, and partially from peripheral regulatory mechanisms controlling the ongoing immune reaction.

Using simulation to create a unique regional ECMO program for the Greater Poland region

Background: “ECMO for Greater Poland” is a program being developed to serve the 3.5 million inhabitants of the Greater Poland region (Wielkopolska) based on an approach already implemented in the USA1 or Qatar.2,3Method: The program is complex and takes full advantage of the ECMO perfusion therapy opportunities to save the life of patients in the Greater Poland region. The main implementation areas are: – treatment of patients with hypothermia;4 – treatment of reversible severe respiratory failure;5 – treatment of acute intoxication resulting in cardiorespiratory failure6 or other critical conditions resulting in heart failure; – in the absence of response to treatment and eventual death, and with donor authorization, there is possible organ transplantation from a non-heart beating donor (NHBD) to another patient.7 This led to the development of a program for donation after circulatory death (DCD). Study: The program will help to put in place a Medical Rescue System including ECMO (Figure 1). It requires training in specialized resuscitation, perfusion, and transplantation teams in the implementation of this “ECMO rescue chain”. The main strength of the program is the widespread use of extracorporeal perfusion. All program arms in the use of ECMO should be implemented in parallel to maximize its positive impact.Figure 1. Organizational model of “ECMO for Greater Poland” – “ECMO rescue chain” scheme divided into three stages: prehospital, hospital/perfusion, and transplantation. As this organizational model is complex and expensive, we used high-fidelity medical simulation to prepare for the real-life implementation of our ECMO program. During 4 months, we performed scenarios including: – “ECMO for DCD” which includes: prehospital identification, CPR ALS (cardiopulmonary resuscitation advanced life support), perfusion therapy (CPR-ECMO or DCD-ECMO), inclusion and exclusion criteria matching, mechanical chest compression, transport, DCD confirmation, and donor authorization, the veno-arterial (VA) cannulation of a mannequins artificial vessels, and starting on-scene organ perfusion.7 – “ECMO for INTOXICATION” which includes: hospital identification (Department of Toxicology), poisoning treatment, CPR ALS, mechanical chest compression, VA cannulation, for the implementation of ECMO therapy and transport to another hospital (Department of Cardiac Surgery).6 – “ECMO for RRF” (reversible respiratory failure) which includes: hospital identification (Regional Department of Intensive Care) – inclusion and exclusion criteria matching, ECMO team transport (80 km), therapy confirmation, veno-venous cannulation for the implementation of perfusion therapy, and return transport (80 km) with ECMO to another hospital in a provincial city (Clinical Department of Intensive Care), where the veno-venous (VV) ECMO therapy was continued for the next 48 hours.5 The training programs, in a short time, resulted in a team being appropriately trained to successfully undertake the complex procedures. Soon after these simulations, Maastricht category II DCD procedures were performed involving real patients and resulting in two double successful kidney transplantations, for the first time in Poland. One month later, we treated two hypothermia patients and, for the first time in the region, also treated on ECMO an adult patient with reversible respiratory failure. Conclusions: The “ECMO for Greater Poland” program will allow the use of perfusion therapy for the inhabitants of Wielkopolska in a comprehensive manner, covering all critical disease states, by what appears to be a unique regional program in Poland. The full-scale, high-fidelity simulation enabled standardized training and testing of new, commonly, and rarely used procedures, and facilitated clinicians’ skills development.

High-fidelity simulation — the first DCD-ECMO procedure in Poland

Mateusz Puslecki, Marcin Ligowski, Marek Dabrowski, Maciej Sip, Sebastian Stefaniak, Tomasz Klosiewicz, Lukasz Gasiorowski, Marek Karczewski, Tomasz Malkiewicz, Malgorzata Ladzinska, Marcin Zielinski, Aleksander Pawlak, Agata Dabrowska, Piotr Ziemak, Bartlomiej Perek, Marcin Misterski, Slawomir Katarzynski, Piotr Buczkowski, Wojciech Telec, Ilona Kiel-Puslecka, Michal Kiel, Michael Czekajlo, Marek Jemielity Poznan University of Medical Sciences, Department of Cardiac Surgery and Transplantology, Clinical Hospital SKPP, Poznan, Poland Poznan University of Medical Sciences, Department of Rescue and Disaster Medicine, Poznan, Poland Polish Society of Medical Simulation, Poland Poznan University of Medical Sciences, Center for Medical Simulation, Poznan, Poland Poznan University of Medical Sciences, Department of Intensive Care and Pain Treatment, Poznan, Poland Poznan University of Medical Sciences, Department of Transplantology, General, Vascular and Plastic Surgery, Poznan, Poland Poznan University of Medical Sciences, Department of Anesthesiology and Intensive Care, Clinical Hospital H. Święcickiego, Poznan, Poland Voivodeship Emergency Medical Services, Poznan, Poland Poznan University of Medical Sciences, Department of Palliative Medicine, Poznan, Poland ZF RTW, Częstochowa, Poland Hunter Holmes McGuire VA Medical Center, Department of Surgery, Richmond, United States of America Lublin Medical University, Lublin, Poland

Scaffolds from Surgically Removed Kidneys as a Potential Source of Organ Transplantation

End stage renal disease (ESRD) is a common disease, which relates to nearly 600 million people in the total population. What is more, it seems to be a crucial problem from the epidemiological point of view. These facts lead to a further necessity of renal replacement therapy development connected with rising expenditures for the health care system. The aim of kidney tissue engineering is to develop and innovate methods of obtaining renal extracellular matrix (ECM) scaffolds derived from kidney decellularization. Recently, progress has been made towards developing a functional kidney graft in vitro on demand. In fact, decellularized tissues constitute ideal natural scaffolds, due to the preservation of native ECM architecture, as well as of cell-ECM binding domains critical in promoting cell attachment, migration, and proliferation. One of the potential sources of the natural scaffolds is the kidney, which cannot be transplanted immediately after excision.

De novo renal cell carcinoma of native kidneys in renal transplant recipients: a single-center experience.

OBJECTIVES Our study aimed to determine the incidence of de novo renal cell carcinoma in the native kidneys of patients transplanted at our center and to identify possible risk factors. MATERIALS AND METHODS We performed a retrospective, single-center cohort study, which included patients transplanted at the District Hospital in Poznan, Poland, during 1994-2011, among whom 836 were selected. Sixty-three patients with confirmed de novo cancer were found. Of those, 11 had renal cell carcinoma in the native kidney (1.3%) and 2 in the transplanted kidney (0.2%). RESULTS Mean follow-up was 10 ± 3.2 years. Mean age at renal cell carcinoma diagnosis was 52 ± 9.4 years, and mean time from transplant was 3 ± 2.6 years. A statistical analysis showed no significant differences in demographic or clinical characteristics between renal cell carcinoma and noncancer group, except for the prevalence of male sex and smoking in the cancer group (P < .05). CONCLUSIONS Renal cell carcinoma development in the native kidney seems to be an early event, frequently observed within 4 to 5 years after transplant. We believe that kidneys in renal transplant recipients should be routinely screened by ultrasound for early diagnosis.

Ghrelin as a potential molecular marker of adrenal carcinogenesis: In vivo and in vitro evidence

Adrenal tumours belong to one of the most prevalent neoplasms. It is a heterogeneous group with different aetiology, clinical manifestation and prognosis. Its histopathologic diagnosis is difficult and identification of differentiation markers for tumorigenesis is extremely valuable for diagnosis.