Renal Progenitors Derived from Urine for Personalized Diagnosis of Kidney Diseases.

BACKGROUND: Chronic kidney disease affects 10% of the world population, and it is associated with progression to end-stage kidney disease and increased morbidity and mortality. The advent of multi-omics technologies has expanded our knowledge on the complexity of kidney diseases, revealing their frequent genetic etiology, particularly in children and young subjects. Genetic heterogeneity and drug screening require patient-derived disease models to establish a correct diagnosis and evaluate new potential treatments and outcomes. SUMMARY: Patient-derived renal progenitors can be isolated from urine to set up proper disease modeling. This strategy allows to make diagnosis of genetic kidney disease in patients carrying unknown significance variants or uncover variants missed from peripheral blood analysis. Furthermore, urinary-derived tubuloids obtained from renal progenitors of patients appear to be potentially valuable for modeling kidney diseases to test ex vivo treatment efficacy or to develop new therapeutic approaches. Finally, renal progenitors derived from urine can provide insights into acute kidney injury and predict kidney function recovery and outcome. KEY MESSAGES: Renal progenitors derived from urine are a promising new noninvasive and easy-to-handle tool, which improves the rate of diagnosis and the therapeutic choice, paving the way toward a personalized healthcare.

Presentation and progression of MPO-ANCA interstitial lung disease.

The association between MPO-ANCA-associated vasculitis (AAV) and interstitial lung disease (ILD) has been well established. Pulmonary fibrosis may coexist with, follow, or even precede the diagnosis of AAV, and its presence adversely affects the prognosis. The optimal approach to investigating ANCA in patients with ILD remains a subject of ongoing debate. Here we aim to describe presentation and progression of MPO-ANCA ILD. We conducted a retrospective evaluation of a cohort of individuals diagnosed with MPO-ANCA ILD, with or without accompanying renal impairment, at the Immunology and Cell Therapy Unit, Careggi University Hospital, Florence, Italy, between June 2016 and June 2022. Clinical records, imaging studies, pathologic examinations, and laboratory test results were collected. Among the 14 patients identified with MPO-ANCA ILD, we observed a significant association between MPO-ANCA titers assessed at the time of ILD diagnosis and renal involvement. Renal impairment in these cases often manifested as subclinical or slowly progressive kidney damage. Interestingly, complement C3 deposits were consistently found in all renal biopsy specimens, thereby suggesting the potential for novel therapeutic targets in managing renal complications associated with MPO-ANCA ILD. The presentation of MPO-ANCA vasculitis as ILD can be the first and only clinical manifestation. MPO-ANCA levels at ILD diagnosis could warn on the progression to renal involvement in patients with MPO-ANCA ILD, hence caution is needed because renal disease can be subclinical or smoldering.

Polyploid tubular cells: a shortcut to stress adaptation.

Tubular epithelial cells (TCs) compose the majority of kidney parenchyma and play fundamental roles in maintaining homeostasis. Like other tissues, mostly immature TC with progenitor capabilities are able to replace TC lost during injury via clonal expansion and differentiation. In contrast, differentiated TC lack this capacity. However, as the kidney is frequently exposed to toxic injuries, evolution positively selected a response program that endows differentiated TC to maintain residual kidney function during kidney injury. Recently, we and others have described polyploidization of differentiated TC, a mechanism to augment the function of remnant TC after injury by rapid hypertrophy. Polyploidy is a condition characterized by >2 complete sets of chromosomes. Polyploid cells often display an increased functional capacity and are generally more resilient to stress as evidenced by being conserved across many plants and eukaryote species from flies to mammals. Here, we discuss the occurrence of TC polyploidy in different contexts and conditions and how this integrates into existing concepts of kidney cell responses to injury. Collectively, we aim at stimulating the acquisition of novel knowledge in the kidney field as well as accelerating the translation of this basic response mechanism to the clinical sphere.

Preparation of Human Kidney Progenitor Cultures and Their Differentiation into Podocytes.

Kidney diseases are a global health concern. Modeling of kidney disease for translational research is often challenging because of species specificities or the postmitotic status of kidney epithelial cells that make primary cultures, for example podocytes. Here, we report a protocol for preparing primary cultures of podocytes based on the isolation and in vitro propagation of immature kidney progenitor cells subsequently differentiated into mature podocytes. This protocol can be useful for studying physiology and pathophysiology of human kidney progenitors and to obtain differentiated podocytes for modeling podocytopathies and other kidney disorders involving podocytes.

Polyploid tubular cells initiate a TGF-ß1 controlled loop that sustains polyploidization and fibrosis after acute kidney injury.

Polyploidization of tubular cells (TC) is triggered by acute kidney injury (AKI) to allow survival in the early phase after AKI, but in the long run promotes fibrosis and AKI-chronic kidney disease (CKD) transition. The molecular mechanism governing the link between polyploid TC and kidney fibrosis remains to be clarified. In this study, we demonstrate that immediately after AKI, expression of cell cycle markers mostly identifies a population of DNA-damaged polyploid TC. Using transgenic mouse models and single-cell RNA sequencing we show that, unlike diploid TC, polyploid TC accumulate DNA damage and survive, eventually resting in the G1 phase of the cell cycle. In vivo and in vitro single-cell RNA sequencing along with sorting of polyploid TC shows that these cells acquire a profibrotic phenotype culminating in transforming growth factor (TGF)-ß1 expression and that TGF-ß1 directly promotes polyploidization. This demonstrates that TC polyploidization is a self-sustained mechanism. Interactome analysis by single-cell RNA sequencing revealed that TGF-ß1 signaling fosters a reciprocal activation loop among polyploid TC, macrophages, and fibroblasts to sustain kidney fibrosis and promote CKD progression. Collectively, this study contributes to the ongoing revision of the paradigm of kidney tubule response to AKI, supporting the existence of a tubulointerstitial cross talk mediated by TGF-ß1 signaling produced by polyploid TC following DNA damage.NEW & NOTEWORTHY Polyploidization in tubular epithelial cells has been neglected until recently. Here, we showed that polyploidization is a self-sustained mechanism that plays an important role during chronic kidney disease development, proving the existence of a cross talk between infiltrating cells and polyploid tubular cells. This study contributes to the ongoing revision of kidney adaptation to injury, posing polyploid tubular cells at the center of the process.

A Clinical Workflow for Cost-Saving High-Rate Diagnosis of Genetic Kidney Diseases.

SIGNIFICANCE STATEMENT: To optimize the diagnosis of genetic kidney disorders in a cost-effective manner, we developed a workflow based on referral criteria for in-person evaluation at a tertiary center, whole-exome sequencing, reverse phenotyping, and multidisciplinary board analysis. This workflow reached a diagnostic rate of 67%, with 48% confirming and 19% modifying the suspected clinical diagnosis. We obtained a genetic diagnosis in 64% of children and 70% of adults. A modeled cost analysis demonstrated that early genetic testing saves 20% of costs per patient. Real cost analysis on a representative sample of 66 patients demonstrated an actual cost reduction of 41%. This workflow demonstrates feasibility, performance, and economic effect for the diagnosis of genetic kidney diseases in a real-world setting. BACKGROUND: Whole-exome sequencing (WES) increases the diagnostic rate of genetic kidney disorders, but accessibility, interpretation of results, and costs limit use in daily practice. METHODS: Univariable analysis of a historical cohort of 392 patients who underwent WES for kidney diseases showed that resistance to treatments, familial history of kidney disease, extrarenal involvement, congenital abnormalities of the kidney and urinary tract and CKD stage ≥G2, two or more cysts per kidney on ultrasound, persistent hyperechoic kidneys or nephrocalcinosis on ultrasound, and persistent metabolic abnormalities were most predictive for genetic diagnosis. We prospectively applied these criteria to select patients in a network of nephrology centers, followed by centralized genetic diagnosis by WES, reverse phenotyping, and multidisciplinary board discussion. RESULTS: We applied this multistep workflow to 476 patients with eight clinical categories (podocytopathies, collagenopathies, CKD of unknown origin, tubulopathies, ciliopathies, congenital anomalies of the kidney and urinary tract, syndromic CKD, metabolic kidney disorders), obtaining genetic diagnosis for 319 of 476 patients (67.0%) (95% in 21 patients with disease onset during the fetal period or at birth, 64% in 298 pediatric patients, and 70% in 156 adult patients). The suspected clinical diagnosis was confirmed in 48% of the 476 patients and modified in 19%. A modeled cost analysis showed that application of this workflow saved 20% of costs per patient when performed at the beginning of the diagnostic process. Real cost analysis of 66 patients randomly selected from all categories showed actual cost reduction of 41%. CONCLUSIONS: A diagnostic workflow for genetic kidney diseases that includes WES is cost-saving, especially if implemented early, and is feasible in a real-world setting.

Tubular cell polyploidy protects from lethal acute kidney injury but promotes consequent chronic kidney disease.

Acute kidney injury (AKI) is frequent, often fatal and, for lack of specific therapies, can leave survivors with chronic kidney disease (CKD). We characterize the distribution of tubular cells (TC) undergoing polyploidy along AKI by DNA content analysis and single cell RNA-sequencing. Furthermore, we study the functional roles of polyploidization using transgenic models and drug interventions. We identify YAP1-driven TC polyploidization outside the site of injury as a rapid way to sustain residual kidney function early during AKI. This survival mechanism comes at the cost of senescence of polyploid TC promoting interstitial fibrosis and CKD in AKI survivors. However, targeting TC polyploidization after the early AKI phase can prevent AKI-CKD transition without influencing AKI lethality. Senolytic treatment prevents CKD by blocking repeated TC polyploidization cycles. These results revise the current pathophysiological concept of how the kidney responds to acute injury and identify a novel druggable target to improve prognosis in AKI survivors.

Differentiation of crescent-forming kidney progenitor cells into podocytes attenuates severe glomerulonephritis in mice.

Crescentic glomerulonephritis is characterized by vascular necrosis and parietal epithelial cell hyperplasia in the space surrounding the glomerulus, resulting in the formation of crescents. Little is known about the molecular mechanisms driving this process. Inducing crescentic glomerulonephritis in two Pax2Cre reporter mouse models revealed that crescents derive from clonal expansion of single immature parietal epithelial cells. Preemptive and delayed histone deacetylase inhibition with panobinostat, a drug used to treat hematopoietic stem cell disorders, attenuated crescentic glomerulonephritis with recovery of kidney function in the two mouse models. Three-dimensional confocal microscopy and stimulated emission depletion superresolution imaging of mouse glomeruli showed that, in addition to exerting an anti-inflammatory and immunosuppressive effect, panobinostat induced differentiation of an immature hyperplastic parietal epithelial cell subset into podocytes, thereby restoring the glomerular filtration barrier. Single-cell RNA sequencing of human renal progenitor cells in vitro identified an immature stratifin-positive cell subset and revealed that expansion of this stratifin-expressing progenitor cell subset was associated with a poor outcome in human crescentic glomerulonephritis. Treatment of human parietal epithelial cells in vitro with panobinostat attenuated stratifin expression in renal progenitor cells, reduced their proliferation, and promoted their differentiation into podocytes. These results offer mechanistic insights into the formation of glomerular crescents and demonstrate that selective targeting of renal progenitor cells can attenuate crescent formation and the deterioration of kidney function in crescentic glomerulonephritis in mice.

Alternative Nuclear Imaging Tools for Infection Imaging.

PURPOSE OF REVIEW: Cardiovascular infections are serious disease associated with high morbidity and mortality. Their diagnosis is challenging, requiring a proper management for a prompt recognition of the clinical manifestations, and a multidisciplinary approach involving cardiologists, cardiothoracic surgeons, infectious diseases specialist, imagers, and microbiologists. Imaging plays a central role in the diagnostic workout, including molecular imaging techniques. In this setting, two different strategies might be used to image infections: the first is based on the use of agents targeting the microorganism responsible for the infection. Alternatively, we can target the components of the pathophysiological changes of the inflammatory process and/or the host response to the infectious pathogen can be considered. Understanding the strength and limitations of each strategy is crucial to select the most appropriate imaging tool. RECENT FINDINGS: Currently, multislice computed tomography (MSCT) and nuclear imaging (18F-fluorodeoxyglucose positron emission tomography/computed tomography, and leucocyte scintigraphy) are part of the diagnostic strategies. The main role of nuclear medicine imaging (PET/CT and SPECT/CT) is the confirmation of valve/CIED involvement and/or associated perivalvular infection and the detection of distant septic embolism. Proper patients' preparation, imaging acquisition, and reconstruction as well as imaging reading are crucial to maximize the diagnostic information. In this manuscript, we described the use of molecular imaging techniques, in particular WBC imaging, in patients with infective endocarditis, cardiovascular implantable electronic device infections, and infections of composite aortic graft, underlying the strength and limitations of such approached as compared to the other imaging modalities.

Molecular Mechanisms and Biomarkers Associated with Chemotherapy-Induced AKI.

Acute kidney injury (AKI) is a life-threatening condition characterized by a rapid and transient decrease in kidney function. AKI is part of an array of conditions collectively defined as acute kidney diseases (AKD). In AKD, persistent kidney damage and dysfunction lead to chronic kidney disease (CKD) over time. A variety of insults can trigger AKI; however, chemotherapy-associated nephrotoxicity is increasingly recognized as a significant side effect of chemotherapy. New biomarkers are urgently needed to identify patients at high risk of developing chemotherapy-associated nephrotoxicity and subsequent AKI. However, a lack of understanding of cellular mechanisms that trigger chemotherapy-related nephrotoxicity has hindered the identification of effective biomarkers to date. In this review, we aim to (1) describe the known and potential mechanisms related to chemotherapy-induced AKI; (2) summarize the available biomarkers for early AKI detection, and (3) raise awareness of chemotherapy-induced AKI.

The role of prehospital ultrasound in reducing time to definitive care in abdominal trauma patients with moderate to severe liver and spleen injuries.

BACKGROUND: The role of prehospital focused assessment sonography for trauma (FAST) is still under debate and no definitive recommendations are available in actual guidelines, moreover, the availability of ultrasound machines in emergency medical services (EMS) is still inhomogeneous. On the other hand, time to definitive care is strictly related to survival in bleeding trauma patients. This study aimed at investigating if a positive prehospital FAST in abdominal trauma patients could have a role in reducing door-to-CT scan or door-to-operating room (OR) time. METHODS: This retrospective observational study included all the patients affected by an abdominal trauma with an abdominal abbreviated injury score ≥ 2 and a spleen or liver injury admitted to Maggiore Hospital Carlo Alberto Pizzardi, a level 1 trauma centre between 2014 and 2019. Prehospital and emergency department (ED) clinical and laboratory variables were collected, as well as in-hospital times during the diagnostic and therapeutic pathways of these patients. RESULTS: 199 patients were included in the final analysis. Of these, 44 had a prehospital FAST performed and in 27 of them, peritoneal free fluid was detected in the prehospital setting, while 128 out of 199 patients had a positive ED-FAST. Sensitivity was 62.9% (95% CI: 42.4%-80.6%) and specificity 100% (95% CI: 80.5% - 100%). Patients with a positive prehospital FAST reported a significantly lower door-to-CT or door-to-OR median time (46 vs 69 min, p < 0.001). Prehospital hypotension and Glasgow coma scale, first arterial blood lactate, ISS, age, positive prehospital and ED FAST were inserted in a stepwise selection for a multivariable Cox proportional regression hazards model. Only ISS and prehospital FAST resulted significantly associated with a reduction in the door-to-CT scan or door-to-operating theatre time in the multivariable model. CONCLUSION: Prehospital FAST information of intraperitoneal free fluid could significantly hasten door-to-CT scan or door-to-operating theatre time in abdominal trauma patients if established hospital response protocols are available. LEVEL OF EVIDENCE: III, (Therapeutic / Care Management).

Role of Multimodal Imaging in Patients With Suspected Infections After the Bentall Procedure.

Purpose: This study aimed to assess the diagnostic performances of multimodal imaging [i.e., white blood cell single-photon emission computed tomography/CT (99mTc-HMPAO-WBC SPECT/CT) and 18-fluoride-fluorodeoxyglucose positron emission tomography/CT ([18F]FDG PET/CT)] in patients with suspected infection after the Bentall procedure, proposing new specific diagnostic criteria for the diagnosis. Methods: Between January 2009 and December 2019, we selected within a cardiovascular infections registry, 76 surgically treated patients (27 women and 49 men, median 66 years, and range 29-83 years). All the patients underwent molecular imaging for a suspected infection after the replacement of the aortic valve and ascending aorta according to the Bentall procedure. We analyzed 98 scans including 49 99mTc-WBC and 49 [18F]FDG PET/CT. A total of 22 patients with very early/early suspected infection (<3 months after surgery) were imaged with both the techniques. Positive imaging was classified according to the anatomical site of increased uptake: to the aortic valve (AV), to both the AV and AV tube graft (AVTG) or to the TG, to surrounding tissue, and/or to extracardiac sites (embolic events or other sites of concomitant infection). Standard clinical workup included in all the patients having echocardiography/CT, blood culture, and the Duke criteria. Pretest probability and positive/negative likelihood ratio were calculated. Sensitivity and specificity of 99mTc labeled hexamethylpropylene amine oxime-WBC SPECT/CT (99mTc-HMPAO-WBC SPECT/CT) and [18F]FDG PET/CT imaging were calculated by using microbiology (n = 35) or clinical follow-up (n = 41) as final diagnosis. 99mTc-HMPAO-WBC scintigraphy and [18F]FDG PET/CT findings were compared with 95% CIs by using the McNemar test to those of echocardiography/CT, blood culture, and the Duke criteria. Results: Sensitivity, specificity, and accuracy of 99mTc-HMPAO-WBC were 86, 92, and 88%, respectively, with a slightly higher sensitivity for tube graft infection (TGI) as compared to isolated AV and combined AVTG. Overall, sensitivity, specificity, and accuracy of [18F]FDG PET/CT were 97, 73, and 90%, respectively. In 22 patients with suspected very early and early postsurgical infections, the two imaging modalities were concordant in 17 cases [10 true positive (TP) and 7 true negative (TN)]. [18F]FDG PET/CT presented a higher sensitivity than 99mTc-HMPAO-WBC scan. 99mTc-HMPAO-WBC scan correctly classified as negative three false-positive (FP) PET/CT findings. Conclusion: Our findings supported the use of 99mTc-HMPAO-WBC SPECT/CT and [18F]FDG PET/CT in patients with suspicion infection after the Bentall procedure early in the course of the disease onset to confirm the diagnosis and provide a comprehensive assessment of disease burden through the proposed criteria.

Stimulated Expression of CXCL12 in Adrenocortical Carcinoma by the PPARgamma Ligand Rosiglitazone Impairs Cancer Progression.

Adrenocortical carcinoma (ACC) is a rare malignancy with poor prognosis when metastatic and scarce treatment options in the advanced stages. In solid tumors, the chemokine CXCL12/CXCR4 axis is involved in the metastatic process. We demonstrated that the human adrenocortex expressed CXCL12 and its cognate receptors CXCR4 and CXCR7, not only in physiological conditions, but also in ACC, where the receptors' expression was higher and the CXCL12 expression was lower than in the physiological conditions. In a small pilot cohort of 22 ACC patients, CXCL12 negatively correlated with tumor size, stage, Weiss score, necrosis, and mitotic activity. In a Kaplan-Meier analysis, the CXCL12 tumor expression significantly predicted disease-free, progression-free, and overall survival. In vitro treatment of the primary ACC H295R and of the metastatic MUC-1 cell line with the PPARγ-ligand rosiglitazone (RGZ) dose-dependently reduced proliferation, resulting in a significant increase in CXCL12 and a decrease in its receptors in the H295R cells only, with no effect on the MUC-1 levels. In ACC mouse xenografts, tumor growth was inhibited by the RGZ treatment before tumor development (prevention-setting) and once the tumor had grown (therapeutic-setting), similarly to mitotane (MTT). This inhibition was associated with a significant suppression of the tumor CXCR4/CXCR7 and the stimulation of human CXCL12 expression. Tumor growth correlated inversely with CXCL12 and positively with CXCR4 expression, suggesting that local CXCL12 may impair the primary tumor cell response to the ligand gradient that may contribute to driving the tumor progression. These findings indicate that CXCL12/CXCR4 may constitute a potential target for anti-cancer agents such as rosiglitazone in the treatment of ACC.

Tubular Cell Cycle Response upon AKI: Revising Old and New Paradigms to Identify Novel Targets for CKD Prevention.

Acute kidney injury (AKI) is characterized by a rapid deterioration of kidney function, representing a global healthcare concern. In addition, AKI survivors frequently develop chronic kidney disease (CKD), contributing to a substantial proportion of disease burden globally. Yet, over the past 30 years, the burden of CKD has not declined to the same extent as many other important non-communicable diseases, implying a substantial deficit in the understanding of the disease progression. The assumption that the kidney response to AKI is based on a high proliferative potential of proximal tubular cells (PTC) caused a critical confounding factor, which has led to a limited development of strategies to prevent AKI and halt progression toward CKD. In this review, we discuss the latest findings on multiple mechanisms of response related to cell cycle behavior of PTC upon AKI, with a specific focus on their biological relevance. Collectively, we aim to (1) provide a new perspective on interpreting cell cycle progression of PTC in response to damage and (2) discuss how this knowledge can be used to choose the right therapeutic window of treatment for preserving kidney function while avoiding CKD progression.

Sex and Gender Differences in Kidney Cancer: Clinical and Experimental Evidence.

Sex and gender disparities have been reported for different types of non-reproductive cancers. Males are two times more likely to develop kidney cancer than females and have a higher death rate. These differences can be explained by looking at genetics and genomics, as well as other risk factors such as hypertension and obesity, lifestyle, and female sex hormones. Examination of the hormonal signaling pathways bring further insights into sex-related differences. Sex and gender-based disparities can be observed at the diagnostic, histological and treatment levels, leading to significant outcome difference. This review summarizes the current knowledge about sex and gender-related differences in the clinical presentation of patients with kidney cancer and the possible biological mechanisms that could explain these observations. Underlying sex-based differences may contribute to the development of sex-specific prognostic and diagnostic tools and the improvement of personalized therapies.

State of the art of 18F-FDG PET/CT application in inflammation and infection: a guide for image acquisition and interpretation.

AIM: The diagnosis, severity and extent of a sterile inflammation or a septic infection could be challenging since there is not one single test able to achieve an accurate diagnosis. The clinical use of 18F-fluorodeoxyglucose ([18F]FDG) positron emission tomography/computed tomography (PET/CT) imaging in the assessment of inflammation and infection is increasing worldwide. The purpose of this paper is to achieve an Italian consensus document on [18F]FDG PET/CT or PET/MRI in inflammatory and infectious diseases, such as osteomyelitis (OM), prosthetic joint infections (PJI), infective endocarditis (IE), prosthetic valve endocarditis (PVE), cardiac implantable electronic device infections (CIEDI), systemic and cardiac sarcoidosis (SS/CS), diabetic foot (DF), fungal infections (FI), tuberculosis (TBC), fever and inflammation of unknown origin (FUO/IUO), pediatric infections (PI), inflammatory bowel diseases (IBD), spine infections (SI), vascular graft infections (VGI), large vessel vasculitis (LVV), retroperitoneal fibrosis (RF) and COVID-19 infections. METHODS: In September 2020, the inflammatory and infectious diseases focus group (IIFG) of the Italian Association of Nuclear Medicine (AIMN) proposed to realize a procedural paper about the clinical applications of [18F]FDG PET/CT or PET/MRI in inflammatory and infectious diseases. The project was carried out thanks to the collaboration of 13 Italian nuclear medicine centers, with a consolidate experience in this field. With the endorsement of AIMN, IIFG contacted each center, and the pediatric diseases focus group (PDFC). IIFG provided for each team involved, a draft with essential information regarding the execution of [18F]FDG PET/CT or PET/MRI scan (i.e., indications, patient preparation, standard or specific acquisition modalities, interpretation criteria, reporting methods, pitfalls and artifacts), by limiting the literature research to the last 20 years. Moreover, some clinical cases were required from each center, to underline the teaching points. Time for the collection of each report was from October to December 2020. RESULTS: Overall, we summarized 291 scientific papers and guidelines published between 1998 and 2021. Papers were divided in several sub-topics and summarized in the following paragraphs: clinical indications, image interpretation criteria, future perspectivess and new trends (for each single disease), while patient preparation, image acquisition, possible pitfalls and reporting modalities were described afterwards. Moreover, a specific section was dedicated to pediatric and PET/MRI indications. A collection of images was described for each indication. CONCLUSIONS: Currently, [18F]FDG PET/CT in oncology is globally accepted and standardized in main diagnostic algorithms for neoplasms. In recent years, the ever-closer collaboration among different European associations has tried to overcome the absence of a standardization also in the field of inflammation and infections. The collaboration of several nuclear medicine centers with a long experience in this field, as well as among different AIMN focus groups represents a further attempt in this direction. We hope that this document will be the basis for a "common nuclear physicians' language" throughout all the country. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40336-021-00445-w.

From kidney injury to kidney cancer.

Epidemiologic studies document strong associations between acute or chronic kidney injury and kidney tumors. However, whether these associations are linked by causation, and in which direction, is unclear. Accumulating data from basic and clinical research now shed light on this issue and prompt us to propose a new pathophysiological concept with immanent implications in the management of patients with kidney disease and patients with kidney tumors. As a central paradigm, this review proposes the mechanisms of kidney damage and repair that are active during acute kidney injury but also during persistent injuries in chronic kidney disease as triggers of DNA damage, promoting the expansion of (pre-)malignant cell clones. As renal progenitors have been identified by different studies as the cell of origin for several benign and malignant kidney tumors, we discuss how the different types of kidney tumors relate to renal progenitors at specific sites of injury and to germline or somatic mutations in distinct signaling pathways. We explain how known risk factors for kidney cancer rather represent risk factors for kidney injury as an upstream cause of cancer. Finally, we propose a new role for nephrologists in kidney cancer (i.e., the primary and secondary prevention and treatment of kidney injury to reduce incidence, prevalence, and recurrence of kidney cancer).

Comparison of MRI, [18F]FDG PET/CT, and 99mTc-UBI 29-41 scintigraphy for postoperative spondylodiscitis-a prospective multicenter study.

PURPOSE: Postoperative infection still constitutes an important complication of spine surgery, and the optimal imaging modality for diagnosing postoperative spine infection has not yet been established. The aim of this prospective multicenter study was to assess the diagnostic performance of three imaging modalities in patients with suspected postoperative spine infection: MRI, [18F]FDG PET/CT, and SPECT/CT with 99mTc-UBI 29-41. METHODS: Patients had to undergo at least 2 out of the 3 imaging modalities investigated. Sixty-three patients enrolled fulfilled such criteria and were included in the final analysis: 15 patients underwent all 3 imaging modalities, while 48 patients underwent at least 2 imaging modalities (MRI + PET/CT, MRI + SPECT/CT, or PET/CT + SPECT/CT). Final diagnosis of postoperative spinal infection was based either on biopsy or on follow-up for at least 6 months. The MRI, PET/CT, and SPECT/CT scans were read blindly by experts at designated core laboratories. Spine surgery included metallic implants in 46/63 patients (73%); postoperative spine infection was diagnosed in 30/63 patients (48%). RESULTS: Significant discriminants between infection and no infection included fever (P = 0.041), discharge at the wound site (P < 0.0001), and elevated CRP (P = 0.042). There was no difference in the frequency of infection between patients who underwent surgery involving spinal implants versus those who did not. The diagnostic performances of MRI and [18F]FDG PET/CT analyzed as independent groups were equivalent, with values of the area under the ROC curve equal to 0.78 (95% CI: 0.64-0.92) and 0.80 (95% CI: 0.64-0.98), respectively. SPECT/CT with 99mTc-UBI 29-41 yielded either unacceptably low sensitivity (44%) or unacceptably low specificity (41%) when adopting more or less stringent interpretation criteria. The best diagnostic performance was observed when combining the results of MRI with those of [18F]FDG PET/CT, with an area under the ROC curve equal to 0.938 (95% CI: 0.80-1.00). CONCLUSION: [18F]FDG PET/CT and MRI both possess equally satisfactory diagnostic performance in patients with suspected postoperative spine infection, the best diagnostic performance being obtained by combining MRI with [18F]FDG PET/CT. The diagnostic performance of SPECT/CT with 99mTc-UBI 29-41 was suboptimal in the postoperative clinical setting explored with the present study.