Predicting Tacrolimus Exposure in Kidney Transplanted Patients Using Machine Learning

Tacrolimus is one of the cornerstone immunosup-pressive drugs in most transplantation centers worldwide following solid organ transplantation. Therapeutic drug monitoring of tacrolimus is necessary in order to avoid rejection of the transplanted organ or severe side effects. However, finding the right dose for a given patient is challenging, even for experienced clinicians. Consequently, a tool that can accurately estimate the drug exposure for individual dose adaptions would be of high clinical value. In this work, we propose a new technique using machine learning to estimate the tacrolimus exposure in kidney transplant recipients. Our models achieve predictive errors that are at the same level as an established population pharmacokinetic model, but are faster to develop and require less knowledge about the pharmacokinetic properties of the drug

PERANG SALIB III (Faktor Penyebab, Peran dan Perjuangan Shalahuddin Al Ayyubi)

M. Iqbal Hasby A. 1411315000. PERANG SALIB III (FAKTOR PENYEBAB, PERAN DAN PERJUANGAN SHALAHUDDIN AL AYYUBI). Skripsi. Jurusan Sejarah Kebudayaan Islam. Fakultas Adab Dakwah. IAIN Syekh Nurjati Cirebon. 2016. Perang Salib merupakan sebuah peristiwa peperangan yang terjadi dalam kurun waktu kurang lebih dua ratus tahun (1096-1292 M), yang mempertemukan Umat Islam dan Kristen Eropa demi mendapatkan kekuasaan atas wilayah Baitul Maqdis (Yerusalem). Dalam serangkaian Perang Salib ini telah memunculkan peran seorang tokoh yang cukup berjasa besar peranannya dalam mempertahankan Baitul Maqdis (Yerusalem), dia adalah seorang raja dan pahlawan umat Islam yaitu Shalahuddin Al Ayyubi. Sesuai dengan latar belakang yang telah di ungkapkan di atas, di sini penulis mencoba menguraikan rumusan masalah mengenai latar belakang perang salib dan sejauh mana peran dan perjuangan Shalahuddin Al Ayyubi dalam peristiwa Perang Salib, yang dirumuskan ke dalam pembahasan terkait latar belakang terjadinya perang salib serta peran dan perjuangan yang dimunculkan oleh Shalahuddin Al Ayyubi dalam peristiwa Perang Salib tersebut. Peristiwa ini memfokuskan pembahasannya pada peran penting seorang Shalahuddin dalam mempertahankan Baitul Maqdis (Yerusalem) saat Perang Salib III (1096 s/d 1198 M) sehingga tetap di dalam kekuasaan Umat Muslim. Untuk metode penelitian ini penulis menggunakan pendekatan Library Research dengan menggunakan metode heuristik, di mana setelah sumber-sumber informasi terkait diperoleh, berikutnya dilakukan kritik dan verivikasi kemudian dibuat alur yang logis dengan penafsiran-penafsiran agar apa yang penulis tulis memiliki alur cerita sejarah yang runtut dengan metode historiografi. Dari hasil penelitian tersebut dapat ditarik sebuah kesimpulan bahwa Perang Salib terjadi kurang lebih selama 200 tahun yang memperebutkan wilayah (Baitul Maqdis/Yerusalem) yang diangap suci oleh 3 agama besar (Yahudi, Kristen dan Islam) karena faktor Agama, faktor Politik (Kekuasaan), dan faktor Ekonomi. Shalahuddin Al Ayyubi menjadi tokoh yang paling dikenal dalam peristiwa Perang Salib ini, peran dan perjuangannya yang cukup berarti demi mempertahankan Baitul Maqdis (Yerusalem) dari serangan Pasukan Salib Eropa. Kata Kunci : Perang Salib, Shalahuddin Al Ayyubi, Peran dan perjuanga

Low level of MAp44, an inhibitor of the lectin complement pathway, and long-term graft and patient survival; a cohort study of 382 kidney recipients

© 2016 The Author(s). Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background: Higher incidence of malignancy and infectious diseases in kidney transplant recipients is related to immunosuppressive treatment after transplantation and the recipient’s native immune system. The complement system is an essential component of the innate immunity. The aim of the present study was to investigate the association of effector molecules of the lectin complement pathway with graft and patient survival after kidney transplantation. Methods: Two mannan-binding lectin (MBL) associated proteases, MASP-2 and MASP-3 (activators of the lectin pathway) and two MBL-associated proteins, MAp44 and MAp19 (inhibitors of the lectin pathway) were measured at the time of transplantation in 382 patients (≥17 years old) transplanted in 2000–2001. The cohort was followed until December 31, 2014. Data on patient and graft survival were obtained from the Norwegian Renal Registry. Cox proportional hazard regression models were performed for survival analyses. Results: Low MAp44 level (1st versus 2–4 quartile) was significantly associated with overall mortality; HR 1.52, 95 % CI 1.08–2.14, p = 0.017. In the sub analyses in groups below and above median age (51.7 years), low MAp44 as a predictor of overall mortality was statistically significant only in recipients of ≤51.7 years; HR 2.57, 95 % CI 1.42–4.66, p = 0.002. Furthermore, low MAp44 was associated with mortality due to infectious diseases; HR 2.22, 95 % CI 1.11–4.41, p = 0.023. There was no association between MASP-2, MASP-3 or MAp19 levels and patient mortality. No association between any measured biomarkers and death censored graft loss was found. Conclusions: Low MAp44 level at the time of transplantation was associated with increased overall mortality in kidney recipients of median age of 51.7 years or below and with mortality due to infectious diseases in the whole patient cohort after nearly 14-years of follow up after transplantation. No associations between other effector molecules; MASP-2, MASP-3 or MAp19 and recipient mortality were found, as well as no association of any biomarker with death censored graft loss

Klotho and Fibroblast Growth Factor 23 Are Independent of Vitamin D, and Unlike Vitamin D, Are Not Associated With Graft- and Patient Survival After Kidney Transplantation

Background: Short-term survival after kidney transplantation is excellent but long-term survival remains suboptimal. The aim of the study was to explore the relationship between soluble α-Klotho (sKlotho) and intact fibroblast growth factor 23 (iFGF23) measured 8 wk and 1 y posttransplant with long-term graft- and patient survival in a cohort of kidney transplant recipients with deficient and nondeficient vitamin D (25[OH]D) levels. Methods: Vitamin D, sKlotho, and iFGF23 were measured 8 wk and 1 y posttransplant in 132 recipients transplanted between November 2012 and October 2013. Results: Of the 132 kidney transplant recipients, 49 had deficient vitamin D levels (<30 nmol/L) and 83 had nondeficient vitamin D levels (≥30 nmol/L) at 8 wk posttransplant. The mean age was 51 y and the median follow-up was 7.4 y. At 1 y posttransplant, vitamin D increased significantly. There were no significant differences in sKlotho or iFGF23 levels between the 2 vitamin D groups neither at 8 wk nor 1 y. sKlotho increased significantly and iFGF23 decreased significantly in the whole cohort. During the follow-up, there were 36 graft losses (27%) and 27 deaths (20%). Ninety-four percent of the transplant recipients with nondeficient vitamin D levels were alive with a well-functioning graft after 5 y using Kaplan-Meier survival estimates, compared with 84% of the patients with deficient vitamin D levels (P = 0.014). Klotho and FGF23 levels did not influence graft- and patient survival. Conclusions: In this nationwide cohort of kidney transplant recipients, long-term graft- and patient survival were significantly better in patients with vitamin D ≥30 nmol/L 8 wk posttransplant compared with those with vitamin D <30 nmol/L. sKlotho levels increased and iFGF23 levels decreased from 8 wk to 1 y posttransplant. Klotho and FGF23 levels were not associated with graft- and patient survival.publishedVersio

Endomyocardial, intralymphocyte, and whole blood concentrations of ciclosporin A in heart transplant recipients

BACKGROUND: In the early phases following heart transplantation a main challenge is to reduce the impact of acute rejections. Previous studies indicate that intracellular ciclosporin A (CsA) concentration may be a sensitive acute rejection marker in renal transplant recipients. The aims of this study were to evaluate the relationships between CsA concentrations at different target sites as potential therapeutic drug monitoring (TDM) tools in heart transplant recipients. METHODS: Ten heart transplant recipients (8 men, 2 women) on CsA-based immunosuppression were enrolled in this prospective single-center pilot study. Blood samples were obtained once to twice weekly up to 12 weeks post-transplant. One of the routine biopsies was allocated to this study at each sampling time. Whole blood, intralymphocyte, and endomyocardial CsA concentrations were determined with validated HPLC-MS/MS-methods. Mann–Whitney U test was used when evaluating parameters between the two groups of patients. To correlate whole blood, intralymphocyte, and endomyocardial CsA concentrations linear regression analysis was used. RESULTS: Three patients experienced mild rejections. In the study period, the mean (range) intralymphocyte CsA trough concentrations were 10.1 (1.5 to 39) and 8.1 (1.3 to 25) ng/10(6) cells in the rejection and no-rejection group, respectively (P=0.21). Corresponding whole blood CsA concentrations were 316 (153 to 564) and 301 (152 to 513) ng/mL (P=0.33). There were no correlations between whole blood, intralymphocyte, or endomyocardial concentrations of CsA (P >0.11). CONCLUSIONS: The study did not support an association between decreasing intralymphocyte CsA concentrations and acute rejections. Further, there were no association between blood concentrations and concentrations at sites of action, potentially challenging TDM in these patients

Systemic inflammation early after kidney transplantation is associated with long-term graft loss: a cohort study

Background: Early graft loss following kidney transplantation is mainly a result of acute rejection or surgical complications, while long-term kidney allograft loss is more complex. We examined the association between systemic inflammation early after kidney transplantation and long-term graft loss, as well as correlations between systemic inflammation scores and inflammatory findings in biopsies 6 weeks and 1 year after kidney transplantation. Methods: We measured 21 inflammatory biomarkers 10 weeks after transplantation in 699 patients who were transplanted between 2009 and 2012 at Oslo University Hospital, Rikshospitalet, Norway. Low-grade inflammation was assessed with predefined inflammation scores based on specific biomarkers: one overall inflammation score and five pathway-specific scores. Surveillance or indication biopsies were performed in all patients 6 weeks after transplantation. The scores were tested in Cox regression models. Results: Median follow-up time was 9.1 years (interquartile range 7.6-10.7 years). During the study period, there were 84 (12.2%) death-censored graft losses. The overall inflammation score was associated with long-term kidney graft loss both when assessed as a continuous variable (hazard ratio 1.03, 95% CI 1.01-1.06, P = 0.005) and as a categorical variable (4th quartile: hazard ratio 3.19, 95% CI 1.43-7.10, P = 0.005). In the pathway-specific analyses, fibrogenesis activity and vascular inflammation stood out. The vascular inflammation score was associated with inflammation in biopsies 6 weeks and 1 year after transplantation, while the fibrinogenesis score was associated with interstitial fibrosis and tubular atrophy. Conclusion: In conclusion, a systemic inflammatory environment early after kidney transplantation was associated with biopsy-confirmed kidney graft pathology and long-term kidney graft loss. The systemic vascular inflammation score correlated with inflammatory findings in biopsies 6 weeks and 1 year after transplantation

A snapshot of European registries on chronic kidney disease patients not on kidney replacement therapy

Non peer reviewe