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    Predicting graft survival in paediatric kidney transplant recipients using machine learning
    (Springer , 2024) Aksoy, Gulsah Kaya; Akcay, Huseyin Gokhan; Adar, Mehtap; Koyun, Mustafa; Comak, Elif; Akman, Sema; Department of Industrial Engineering; Department of Industrial Engineering; College of Engineering
    Background Identification of factors that affect graft survival in kidney transplantation can increase graft survival and reduce mortality. Artificial intelligence modelling enables impartial evaluation of clinician bias. This study aimed to examine factors that affect the survival of grafts in paediatric kidney transplantation through the use of machine learning. Methods A retrospective review was conducted on records of paediatric patients who underwent kidney transplantation between 1994 and 2021 and had post-transplant follow-up > 12 months. The nearest neighbour method was used to impute missing fields from a total of 48 variables in the dataset. Models including Naive Bayes, logistic regression, support vector machine (SVM), multi-layer perceptron, and XGBoost were trained to predict graft survival. The study used 80% of the patients for training and the remaining 20% for testing. Modelling success was evaluated based on accuracy and F1 score metrics. Results The study analysed 465 kidney transplant recipients. Of these, 56.7% were male. The mean age at transplantation was 12.08 +/- 5.01 years. Of the kidney transplants, 73.1% (n = 339) were from living donors, 34.5% (n = 160) were pre-emptive transplants, and 2.2% (n = 10) were second-time transplants. The machine learning model identified several features associated with graft survival, including antibody-mediated rejection (+ 0.7), acute cellular rejection (+ 0.66), eGFR at 3 years (+ 0.43), eGFR at 5 years (+ 0.34), pre-transplant peritoneal dialysis (+ 0.2), and cadaveric donor (+ 0.2). The successes of the logistic regression and SVM models were similar. The F1 score was 91.9%, and accuracy was 96.5%. Conclusion Machine learning can be used to identify factors that affect graft survival in kidney transplant recipients. By expanding similar studies, risk maps can be created prior to transplantation.
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    The role of PSMA PET/CT in predicting downgrading in patients with Gleason score 4+4 prostate cancer in prostate biopsy
    (Springer, 2024) N/A; Aykanat, İbrahim Can; Kordan, Yakup; Seymen, Hülya; Köseoğlu, Ersin; Özkan, Arif; Esen, Barış; Tarım, Kayhan; Kulaç, İbrahim; Falay, Fikri Okan; Gürses, Bengi; Baydar, Dilek Ertoy; Canda, Abdullah Erdem; Balbay, Mevlana Derya; Demirkol, Mehmet Onur; Esen, Tarık; School of Medicine; Koç University Hospital
    Background To investigate the predictable parameters associated with downgrading in patients with a Gleason score (GS) 8 (4+4) in prostate biopsy after radical prostatectomy. Methods We retrospectively analyzed 62 patients with a GS of 4+4 on prostate biopsy who underwent robotic radical prostatectomy between 2017 and 2022. Results 38 of 62 (61.2%) were downgraded. In multivariable logistic regression model, Ga-68 prostate-specific membrane antigen (PSMA) positron-emission tomography (PET)/computed tomography (CT) SUV max was independent predictor of downgrading (OR 0.904; p = 0.011) and a Logistic Regression model was constructed using the following formula: Y = 1.465-0.95 (PSMA PET/CT SUV max). The model using this variable correctly predicted the downgrading in 72.6% of patients. The AUC for PSMA PET/CT SUV max was 0.709 the cut off being 8.8. A subgroup analysis was performed in 37 patients who had no other European Association of Urology (EAU) high risk features. 25 out of 37 (67.5%) were downgraded, and 21 of these 25 had organ confined disease. Low PSMA SUV max (<8.1) and percentage of GS 4+4 biopsy cores to cancer bearing cores (45.0%) were independently associated with downgrading to GS 7. Conclusion PSMA PET/CT can be used to predict downgrading in patients with GS 4+4 PCa. Patients with GS 4+4 disease, but no other EAU high risk features, low percentage of GS 4+4 biopsy cores to cancer bearing cores, and a low PSMA PET/CT SUV max are associated with a high likelihood of the cancer reclassification to intermediate risk group.
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    Survival benefit of nephroureterectomy in systemic therapy exposed metastatic upper tract urinary urothelial carcinoma patients
    (Springer, 2024) Morra, Simone; Incesu, Reha-Baris; Scheipner, Lukas; Baudo, Andrea; Jannello, Letizia Maria Ippolita; Siech, Carolin; de Angelis, Mario; Tian, Zhe; Creta, Massimiliano; Califano, Gianluigi; Colla Ruvolo, Claudia; Saad, Fred; Shariat, Shahrokh F.; Chun, Felix K. H.; de Cobelli, Ottavio; Musi, Gennaro; Briganti, Alberto; Ahyai, Sascha; Carmignani, Luca; Longo, Nicola; Karakiewicz, Pierre I.; N/A; Tilki, Derya; School of Medicine
    Background It is unknown whether the stage of the primary may influence the survival (OS) of metastatic upper tract urothelial carcinoma (mUTUC) patients treated with nephroureterectomy (NU) and systemic therapy (ST). We tested this hypothesis within a large-scale North American cohort. Methods Within Surveillance Epidemiology and End Results database 2000-2020, all mUTUC patients treated with ST+NU or with ST alone were identified. Kaplan-Maier plots depicted OS. Multivariable Cox regression (MCR) models tested for differences between ST+NU and ST alone predicting overall mortality (OM). All analyses were performed in localized (T1-T2) and then repeated in locally advanced (T3-T4) patients. Results Of all 728 mUTUC patients, 187 (26%) harbored T1-T2 vs 541 (74%) harbored T3-T4. In T1-T2 patients, the median OS was 20 months in ST+NU vs 10 months in ST alone. Moreover, in MCR analyses that also relied on 3 months' landmark analyses, the combination of ST+NU independently predicted lower OM (HR 0.37, p < 0.001). Conversely, in T3-T4 patients, the median OS was 12 in ST+NU vs 10 months in ST alone. Moreover, in MCR analyses that also relied on 3 months' landmark analyses, the combination of ST+NU was not independently associated with lower OM (HR 0.85, p = 0.1). Conclusions In mUTUC patients, treated with ST, NU drastically improved survival in T1-T2 patients, even after strict methodological adjustments (multivariable and landmark analyses). However, this survival benefit did not apply to patients with locally more advanced disease (T3-T4).
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    Uncovering the penile clock: expression of molecular clock proteins in human penile cavernous tissue
    (Korean Soc Sexual Medicine and Andrology, 2024) Alkan, Ilter; Bozkurt, Muammer; Canat, Halil Lutfi; N/A; Durkut, Begüm; Uçak, Melike; Özenci, Çiler Çelik; Koç University Research Center for Translational Medicine (KUTTAM); Graduate School of Health Sciences; School of Medicine
    Purpose: To evaluate the expression of core molecular clock genes/proteins in penile cavernous tissue from healthy male subjects and to determine whether their expression has circadian variation. Materials and Methods: Corpus cavernosum biopsy samples were obtained from 10 healthy males with penile deviation or fracture who underwent surgical intervention during the day and night. The daytime group (n=5) underwent corpus cavernosum tissue sampling during zeitgeber time (ZT) 8-12, while the nighttime group (n=5) underwent sampling during ZT 20-24. The expression and localization of BMAL1, CLOCK, PER1, PER2, PER3, CRY1, and CRY2 proteins were analyzed using immunohistochemistry and quantified using H-score analysis. RT-qPCR analysis was performed to assess the expression of core molecular clock genes in the corpus cavernosum tissue of 5 additional daytime patients. Results: The expression of core molecular clock proteins was detected in vascular endothelial cells (VECs) and smooth muscle cells (SMCs) in corpus cavernosum during daytime and nighttime. BMAL1 exhibited the most significant nuclear expression during daytime in both cell types, whereas its expression decreased significantly at night. In VECs, a significant decrease in the nuclear expression of CRY1 was observed at night. In SMCs, a significant decrease in the cytoplasmic expression of PER3 was observed at night. The expression patterns of the core molecular clock genes were ascertained through a RT-qPCR analysis. Conclusions: Our research provides compelling evidence that core molecular clock genes are distinctly expressed in penile tissue in humans. Furthermore, we observed the expression of molecular clock proteins within the VECs and SMCs of the corpus cavernosum, with BMAL1 being the most prominently expressed. The discovery of core molecular clock genes in penile tissue, as well as proteins within the SMCs and VECs of the corpus cavernosum, introduces the potential significance of the molecular clock mechanism in the physiology of penile erection.
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    Kidney transplantation in children and adolescents with C3 glomerulopathy or immune complex membranoproliferative glomerulonephritis: a real-world study within the CERTAIN research network
    (Springer, 2024) Patry, Christian; Webb, Nicholas J. A.; Feisst, Manuel; Krupka, Kai; Becker, Jan; Bald, Martin; Antoniello, Benedetta; Gulhan, Bora; Hogan, Julien; Kanzelmeyer, Nele; Ozkaya, Ozan; Buescher, Anja; Sellier-Leclerc, Anne-Laure; Shenoy, Mohan; Weber, Lutz T.; Fichtner, Alexander; Hoecker, Britta; Meier, Matthias; Toenshoff, Burkhard; Bilge, İlmay;  ; School of Medicine;  
    BackgroundComplement 3 glomerulopathy (C3G) and immune complex membranoproliferative glomerulonephritis (IC-MPGN) are ultra-rare chronic kidney diseases with an overall poor prognosis, with approximately 40-50% of patients progressing to kidney failure within 10 years of diagnosis. C3G is characterized by a high rate of disease recurrence in the transplanted kidney. However, there is a lack of published data on clinical outcomes in the pediatric population following transplantation.MethodsIn this multicenter longitudinal cohort study of the Cooperative European Paediatric Renal Transplant Initiative (CERTAIN) registry, we compared the post-transplant outcomes of pediatric patients with C3G (n = 17) or IC-MPGN (n = 3) with a matched case-control group (n = 20).ResultsEleven of 20 children (55%) with C3G or IC-MPGN experienced a recurrence within 5 years post-transplant. Patients with C3G or IC-MPGN had a 5-year graft survival of 61.4%, which was significantly (P = 0.029) lower than the 5-year graft survival of 90% in controls; five patients with C3G or IC-MPGN lost their graft due to recurrence during this observation period. Both the 1-year (20%) and the 5-year (42%) rates of biopsy-proven acute rejection episodes were comparable between patients and controls. Complement-targeted therapy with eculizumab, either as prophylaxis or treatment, did not appear to be effective.ConclusionsThese data in pediatric patients with C3G or IC-MPGN show a high risk of post-transplant disease recurrence (55%) and a significantly lower 5-year graft survival compared to matched controls with other primary kidney diseases. These data underscore the need for post-transplant patients for effective and specific therapies that target the underlying disease mechanism.Graphical abstractA higher resolution version of the Graphical abstract is available as Supplementary information
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    The role of antimicrobial polypeptides for the predicting of urinary tract infection: UTILISE study
    (Springer, 2023) Yıldırım, Zeynep Yuruk; Afonso, Alberto Caldas; Akil, Ipek; Aksu, Bagdagul; Alpay, Harika; Atmis, Bahriye; Aydog, Ozlem; Bakkaloglu, Sevcan; Bayazit, Aysun Karabay; Bayram, Meral Torun; Bulut, Ipek Kaplan; Comak, Elif; Kasap-Demir, Belde; Delebe, Ozlem Cam; Bilge, İlmay;  ; School of Medicine;  
    [No abstract available]
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    Application of HLA molecular mismatch algorithms to predict primary alloimmunity risk and rejection in paediatric kidney transplantation
    (Springer, 2023) Kim, Jon Jin; Fichtner, Alexander; Copley, Hannah; Krupka, Kai; Pape, Lars; Toenshoff, Burkhard; Kosmoliaptsis, Vasilis; Süsal, Caner; Koç Üniversitesi Organ Nakli İmmünoloji Araştırma Mükemmeliyet Merkezi (TIREX) / Transplant Immunology Research Centre of Excellence (TIREX); School of Medicine; Koç University Hospital
    [No abstract available]
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    Assessment of HLA incompatibility at the molecular compared to antigenic HLA level enables better prediction of graft function deterioration in paediatric kidney transplantation
    (Springer, 2023) Kim, Jon Jin; Fichtner, Alexander; Copley, Hannah; Susal, Caner; Krupka, Kai; Pape, Lars; Burkhard, Toenshoff; Kosmoliaptsis, Vasilis; Süsal, Caner; Koç Üniversitesi Organ Nakli İmmünoloji Araştırma Mükemmeliyet Merkezi (TIREX) / Transplant Immunology Research Centre of Excellence (TIREX); School of Medicine; Koç University Hospital
    [No abstract available]
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    Clinicopathologic correlations of urinary proteomic and metabolomic analysis in patients with renal aa amyloidosis and membranous nephropathy
    (Oxford Univ Press, 2023) Ozbek, Deniz Aral; Koc, Sila; Yet, Idil; Kablan, Sevilay; Uner, Meral; Lay, Incilay; Yıldırım, Tolga; Yılmaz, Seref Rahmi; Altun, Bulent; Küçük, Nazlı Ezgi Özkan; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM);  ;  
    Background and Aims AA Amyloidosis is a multisystemic amyloidosis subtype that develops on the background of various chronic inflammatory etiologies. Urinary omics studies have become a promising tool for elucidating pathophysiology and prognosis of glomerular diseases. However, no urinary omics analysis has been performed focusing on renal AA amyloidosis in literature to the best of our knowledge. Our main aim in this study is to perform a comparative urine proteomic and metabolomic analysis of recently diagnosed renal AA amyloidosis and to investigate the correlation of bioinformatic results with clinical and pathological data. Method Urine samples of 8 recently diagnosed AA amyloidosis (AA), 8 membranous nephropathy (MN) and 6 healthy control group patients were collected before kidney biopsy procedure. Proteomic analyzes were performed with nLC/Q-TOF MS/MS and metabolomic analyzes were performed by GC/MS in all patients. Biopsy specimens were scored according to glomerulosclerosis (G), tubular atrophy (TA) and interstitial fibrosis (IF) grades by two pathologists. Raw spectroscopic data was analyzed using MaxQuant and MS-DIAL programs for proteomic and metabolomic studies, respectively. Statistical analysis of the differences in molecules between study groups were performed with ANOVA and HSD-Tukey tests. Principal component (PCA) and heatmap analyzes were made in R language, while gene ontology (GO), network and functional enrichment analysis of bioinformatic results were performed with PANTHER, STRING and MetaboAnalyst databases. Results In comparison between AA and MN groups, median eGFR values tend to be lower in the AA group (67.6 vs 112 ml/min/1.73 m2 respectively, p = 0.08). Median 24-hour urine protein levels did not show statistically significant difference (9499 vs 9512 mg/day respectively, p = 0.9). Percentage of patients with moderate/severe IF/TA was higher and G score was tend to be in AA group compared to MN group (p values 0.02 and 0.07 for IF/TA and G scores, respectively). As a result of proteomic analysis, a total of 859 proteins were determined. Statistical analysis showed 51 proteins that were significantly differ in AA group compared to the control group. GO and functional enrichment analyzes showed that statistically most significant sub-domains were mainly related with cell-cell adhesion (Figure 1 & 2). In comparative analysis between AA and MN patients, uromodulin (UMOD) was lower in the AA group than in the MN group (log2FC -3.37), whereas ribonuclease 1 (RNASE1) and α-1-microglobulin/bikunin precursor protein (AMBP) were higher in the AA group (log2FC 3.41 and 3.07, respectively). In Spearman correlation analyzes, significant negative correlations were demonstrated between UMOD-proteinuria (r = -0.48, p = 0.03) and between AMBP-eGFR (r = -0.69, p = 0.003) variables. Metabolomic analysis showed 9 metabolites that were significantly different between AA and other study groups. Myo-inositol and urate were higher in AA group compared to MN group, while D-mannitol and N-acetylglutamate were higher in AA group compared to the control group. Significant positive correlation independent of GFR was detected between RNASE1 and urate (r = 0.63, p = 0.01).
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    Glomerular hyperfiltration as a therapeutic target for CKD
    (Oxford Univ Press, 2024) Covic, Adrian; Ortiz, Alberto; Tuttle, Katherine R.; Kanbay, Mehmet; Bakır, Çiçek Nur; Çöpür, Sidar;  ; School of Medicine;  
    The global burden of chronic kidney disease (CKD) is high and increasing. Early diagnosis and intervention are key to improve outcomes. Single-nephron glomerular hyperfiltration is an early pathophysiologic manifestation of CKD that may result in absolute glomerular hyperfiltration, i.e. a high glomerular filtration rate (GFR), or be associated with normal or low GFR because of nephron loss (relative glomerular hyperfiltration). Even though compensatory glomerular hyperfiltration may contribute to maintain kidney function after the loss of kidney mass, the associated increased glomerular capillary pressure and glomerular and podocyte size drive podocyte loss, albuminuria and proximal tubular overload, contributing to CKD progression. In this regard, all kidney protective drugs in clinical use so far, from renin-angiotensin system blockers to mineralocorticoid receptor blockers to sodium-glucose co-transporter 2 inhibitors to tolvaptan, induce an early dip in glomerular filtration that is thought to represent reversal of hyperfiltration. As glomerular hyperfiltration may be present early in the course of kidney disease, its recognition may provide an effective intervention window that may predate current criteria based on high albuminuria or loss of GFR. Nevertheless, there is no diagnostic method with high sensitivity and specificity to identify single-nephron glomerular hyperfiltration, except when it leads to obvious absolute glomerular hyperfiltration, as observed in the early stages of diabetic kidney disease when nephron mass is still preserved. We now review the concept of glomerular hyperfiltration as an indicator of CKD risk, including definitions, challenges in diagnosis and evaluation, underlying pathophysiological mechanisms, potential therapeutic approaches and unanswered questions.