Search

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).

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.

BACKGROUND AND AIMS Acute Kidney Injury (AKI) is characterized by a rapid deterioration of kidney function. Recently, we showed that tubular epithelial cells (TC) respond to AKI by triggering polyploidy, a condition in which a normally diploid cell acquires additional sets of chromosomes. Polyploidy offers several advantages, but in the kidney the biological significance of polyploidization remains unclear. In this study we hypothesized that polyploidy (i) is the predominant cellular response early during AKI and (ii) that is an adaptive stress response required to maintain a residual kidney function assuring survival. METHOD To address these hypotheses, we employed in vivo transgenic models based on the Fluorescence Ubiquitin Cell Cycle Indicator (FUCCI) technology in combination with YAP1 downregulation. In these models, mice were subjected to unilateral ischemia reperfusion injury (IRI) or glycerol-induced rhabdomyolysis to induce AKI. Polyploid cells have been then characterized by single cell-RNA sequencing analysis, cell sorting, FACS analysis, super-resolution and transmission electron microscopy. RESULTS After AKI, YAP1 is activated triggering TC polyploidization. Polyploid TC increase in parallel to massive cell death triggered by AKI suggesting that polyploidization could be a means to escape cell death. Indeed, we found that polyploid TC tends to accumulate genome instability and survive, while diploid TC do not. Of note, virtually all dying cells were cycling cells based on the Fucci2aR reporter suggesting that TC death occurred during the S or G2/M phase. As polyploid TC increase immediately following AKI, they may be required to survive injury and damage by sustaining renal function. In order to evaluate the functional role of polyploid cells during AKI, we generated mice where YAP1 is knocked-out specifically in TC (YAP1ko mice). Indeed, after AKI, YAP1ko mice showed a reduced number of polyploid cells, worsened kidney function and a dramatic reduction of mouse survival, proving that polyploidization is required to survive AKI. CONCLUSION We demonstrated that (i) after AKI TC accumulate genome instability and die or become polyploidy; (ii) TC polyploidy is essential to preserve residual kidney function immediately after AKI.

BACKGROUND AND AIMS Crescentic glomerulonephritis (crescentic GN) encompasses a group of diverse disorders characterized by the presence of massive hyperplasia of parietal epithelial cells (PEC) as the main histopathological lesion at kidney biopsy. It is associated with a rapid decline in kidney function. Typically, crescent formation is the consequence of diverse upstream pathomechanisms involving the specific activation of PEC. PEC normally reside peacefully along Bowman capsule and represent in part renal progenitor cells (RPC). Previous studies observed RPC markers in crescents from patients with different types of glomerulonephritis. Similarities between stem cell niches of bone marrow and kidney, prompted us to hypothesized that crescents result from monoclonal expansion of a single RPC clone conceptually similar to monoclonal diseases originating from hematopoietic stem cells. According to this analogy, we further hypothesized that drugs known to cure monoclonal disease of the hematopoietic stem cells by enforcing their terminal differentiation could also attenuate crescentic glomerulonephritis. METHOD To address this hypothesis, we established a crescentic GN disease model in a conditional transgenic mouse based on the mT/mG and the Confetti reporter that allows lineage tracing and clonal analysis of RPCs. Animals were treated with known pharmacological inhibitors of clonal stem cell proliferation in myeloproliferative disorders. Crescentic lesions were characterized by super-resolution STED microscopy. Finally, we employed single cell RNA sequencing of human renal progenitor cultures to identify the immature progenitor subset-generating crescent in human to identify putative new biomarkers of crescentic GN to validate in biopsy of patients. RESULTS We observed that the crescentic lesions originated from the clonal expansion of single RPC, thus suggesting a clonal stem cell disorder. Therefore, we administrated a series of drugs known to ameliorates myeloproliferative neoplasms to our crescentic GN mouse model as potential therapeutic agents. Treatment with one of the compounds induced a reduction in both proteinuria and crescent formation. STED super-resolution imaging of glomeruli showed that this compound turned the uncontrolled hyperplasia of a specific immature PEC subset into a controlled differentiation into podocytes thereby restoring the injured glomerular filtration barrier. Moreover, delayed drug administration still induced proteinuria remission and avoided long-term development of chronic kidney disease (CKD), an effect associated to a continued generation of new podocytes and crescent regression over time. Single cell RNA sequencing of human RPC identified a new marker of the crescent-generating progenitor cells. Expression of this marker in biopsies of patients with crescentic GN associated with progression toward end stage kidney disease. Treatment of human PEC with the drug that in in vivo experiments showed a therapeutic effect on crescentic GN reduced proliferation of the immature progenitor subset promoting their differentiation into podocytes. CONCLUSION These results demonstrate that glomerular hyperplastic lesions derive from clonal amplification of a RPC subset and that shifting proliferation to podocyte differentiation reverses improves clinical outcome and avoid CKD.

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. Summary 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.

Purpose: Diagnosis of spinal infection (SI) is challenging and usually requires multiple tests. We aimed to perform a systematic review and a bivariate meta-analysis on the diagnostic role of 18F-FDG PET/CT in patients with SI. Methods: A comprehensive literature search of studies published through February 2019 in PubMed/MEDLINE and Cochrane library databases was carried out. Studies investigating the diagnostic performance of 18F-FDG PET/CT in patients with SI were eligible for inclusion in the qualitative analysis. For the quantitative analysis, pooled sensitivity, specificity, positive and negative likelihood ratio (LR+ and LR−) and diagnostic odds ratio (DOR) of 18F-FDG PET/CT in patients with suspected SI were calculated on a per examination-based analysis. Pooled data were presented with 95% confidence intervals (95% CI). Results: Twenty-six articles (833 patients) using 18F-FDG PET/CT were eligible for the qualitative analysis. Twelve studies (396 patients) were selected for the meta-analysis. Overall, 18F-FDG PET/CT demonstrated a very good diagnostic performance in patients with SI and several studies underlined the value of 18F-FDG PET/CT in assessing the response to treatment. The bivariate meta-analysis on 18F-FDG PET/CT in patients with suspected SI provided the following results: sensitivity 94.8% (95% CI 88.9–97.6%) and specificity 91.4% (95% CI 78.2–96.9%). The pooled LR+, LR− and DOR were 4.7 (95% CI 2.9–7.7), 0.11 (95% CI 0.07–0.16) and 63.4 (95% CI 28.9–139), respectively. No significant heterogeneity or publication bias was found. Conclusion: 18F-FDG PET/CT demonstrated a very good diagnostic performance in patients with SI and can be used in patients in which MRI cannot be performed or is non-diagnostic or inconclusive. Several studies underlined the value of 18F-FDG PET/CT in assessing the response to treatment in patients with SI. Overall, larger multicentre and prospective studies and cost-effectiveness analyses are warranted.

Cardiovascular (CVS) infections are associated with high morbidity and mortality. Early diagnosis is crucial for adequate patient's management, as early treatment improves the prognosis. Hardly they are diagnosed on the basis of a single symptom, sign or diagnostic test, being a multidisciplinary discussion in addition to the integration of clinical signs, microbiology data and imaging data necessary in many cases. The application of multimodality imaging, including molecular imaging techniques has improved the sensitivity to detect infections involving heart valves and vessels and implanted cardiovascular devices while also allowing for early detection of septic emboli and metastatic infections before these become clinically apparent. In this chapter, we describe the role of WBC SPECT/CT and [18F] FDG PET/CT in most clinically relevant CVS infections including dedicated imaging acquisition protocols, specific imaging reading and interpretations criteria, emphasizing the need of a specific reference framework within a Cardiovascular Multidisciplinary Team Approach to select the best test or combination of tests for each specific clinical situation.

Infective endocarditis is associated with high morbidity and mortality. Early diagnosis is crucial for adequate patient's management, as early treatment improves the prognosis. Hardly diagnosed on the basis of a single symptom, sign or diagnostic test. Rather, the diagnosis requires a multidisciplinary discussion in addition to the integration of clinical signs, microbiology data and imaging data. The application of multimodality imaging, including molecular imaging techniques has improved the sensitivity to detect IE, also allowing for early detection of septic emboli and metastatic infections before these become clinically apparent. In this chapter, we will describe the main epidemiological, clinical and diagnostic challenges in IE with particular regard to the role of WBC SPECT/CT. In addition, the needs of proper hybrid equipment, dedicated imaging acquisition protocols, specific expertise for imaging reading and imaging interpretations in this field are discussed, emphasizing the need of a specific reference framework within a Cardiovascular Multidisciplinary Team Approach.

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.

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.

Funding Acknowledgements Type of funding sources: None. Aim Recently hypermetabolisms of the spleen and/or bone marrow has been proposed as an indirect sign of infective endocarditis (IE), useful to reinforce the suspicion of IE in the absence of any other infectious, inflammatory, or malignant disease. The purpose of this study is to determine whether hypermetabolisms of the spleen and/or bone marrow are indirect signs of bacteremia rather than of IE, specifically. Materials and Method In this work we retrospectively evaluated a series 240 patients who performed between January 2015 to December 2020 [18F]FDG PET/CT (Discovery 710 GE) for suspected infection. In particular, 80 pts had infections from different origin and a positive blood culture (PBC), 80 pts presented localized infection, but negative blood culture (IDBCN) and 80 pts were classified as definite IE (IED) according to the 2015 ESCcriteria. [18F]FDG SUVmax SUVmean in bone marrow, spleen and liver were measured drawind a 14 cm3 regions of interest (ROIs) positioned close to the centers of the spleen and of the right liver lobe, but excluding abscess and/or ischemic lesions., as previously described (Caroline Boursier et al. ; Jordy P.Pijl et al.). BM SUVmax and SUVmean was obtained from ROIs placed on the bodies of each of the five lumbar vertebrae, excluding any damaged vertebra. BM to liver SUV ratios (BLR) and spleen to liver SUV ratios (SLR) were calculated. Kruskal-Wallis tests and the Dunn’s test procedure for multiple comparison were performed using JMP Statistical Discoverytm. Results No significant difference among the three groups of SUVmax/mean or in SLR were found. Nevertheless, by grouping patients for the presence of positive blood culture (142 pts) or negative blood culture (98 pts), irrespectively from the final diagnosis a significant associations of SLR was found (p = 0.0070). No significant associations were found with BLR. Conclusions Based on our data SLR in seems to represent an indirect signs of bacteremia, rather than IE.

Diagnosis of spondylodiscitis (SD) may be challenging due to the nonspecific clinical and laboratory findings and the need to perform various diagnostic tests including serologic, imaging, and microbiological examinations. Homogeneous management of SD diagnosis through international, multidisciplinary guidance would improve the sensitivity of diagnosis and lead to better patient outcome. An expert specialist team, comprising nuclear medicine physicians appointed by the European Association of Nuclear Medicine (EANM), neuroradiologists appointed by the European Society of Neuroradiology (ESNR), and infectious diseases specialists appointed by the European Society of Clinical Microbiology and Infectious Diseases (ESCMID), reviewed the literature from January 2006 to December 2015 and proposed 20 consensus statements in answer to clinical questions regarding SD diagnosis. The statements were graded by level of evidence level according to the 2011 Oxford Centre for Evidence-based Medicine criteria and included in this consensus document for the diagnosis of SD in adults. The consensus statements are the result of literature review according to PICO (P:population/patients, I:intervention/indicator, C:comparator/control, O:outcome) criteria. Evidence-based recommendations on the management of adult patients with SD, with particular attention to radiologic and nuclear medicine diagnosis, were proposed after a systematic review of the literature in the areas of nuclear medicine, radiology, infectious diseases, and microbiology. A diagnostic flow chart was developed based on the 20 consensus statements, scored by level of evidence according to the Oxford Centre for Evidence-based Medicine criteria. This consensus document was developed with a final diagnostic flow chart for SD diagnosis as an aid for professionals in many fields, especially nuclear medicine physicians, radiologists, and orthopaedic and infectious diseases specialists.

Background and Aims Rapidly progressive glomerulonephritis (RPGN) encompasses a group of diverse disorders characterized by the presence of massive hyperplasia of parietal epithelial cells (PEC) as the main histopathological lesion at kidney biopsy. It is associated with a rapid decline in kidney function referred to altogether as rapidly progressive glomerulonephritis. Typically, crescent formation is the consequence of diverse upstream pathomechanisms involving the specific activation of PEC. PEC normally reside peacefully along Bowman capsule and represent in part renal progenitor cells (RPC). Previous studies observed RPC markers in crescents from patients with different types of glomerulonephritis. Similarities between stem cell niches of bone marrow and kidney, prompted us to hypothesized that crescents result from monoclonal expansion of a single RPC clone conceptually similar to monoclonal diseases originating from hematopoietic stem cells. According to this analogy, we further hypothesized that drugs known to cure monoclonal disease of the hematopoietic stem cells by enforcing their terminal differentiation could also attenuate crescentic glomerulonephritis. Method To address this hypothesis, we established a RPGN disease model in a conditional transgenic mouse based on the mT/mG and the Confetti reporter that allows lineage tracing and clonal analysis of RPCs. Animals were treated with known pharmacological inhibitors of clonal stem cell proliferation in myeloproliferative disorders. Crescentic lesions were characterized by super-resolution STED microscopy. Finally, we employed single cell RNA sequencing of human renal progenitor cultures to identify the immature progenitor subset-generating crescent in human to identify putative new biomarker(s) of RPNG to validate in biopsy of patients. Results We observed that the crescentic lesions originated from the clonal expansion of single RPC, thus suggesting a clonal stem cell disorder. Therefore, we administrated a series of drugs known to ameliorates myeloproliferative neoplasms to our RPGN mouse model as potential therapeutic agents. In particular, treatment with one of the compounds induced a reduction in both proteinuria and crescent formation. 3D confocal microscopy and STED super-resolution imaging of glomeruli showed that this compound turned the uncontrolled hyperplasia of a specific immature PEC subset into a controlled differentiation into new podocytes thereby restoring the injured glomerular filtration barrier. Single cell RNA sequencing of human renal progenitor cultures identified a new marker of the crescent-generating progenitor cells. Expression of this marker in biopsies of patients with rapidly progressive glomerulonephritis associated with progression toward end stage kidney disease. Treatment of human PEC with the drug that in in vivo experiments showed a therapeutic effect on RPGN reduced proliferation of the immature progenitor subset promoting their differentiation into podocytes. Conclusion These results demonstrate that glomerular hyperplastic lesions derive from clonal amplification of a RPC subset and that shifting proliferation to podocyte differentiation reverses crescent formation and improves clinical outcome.

Background and Aims Acute kidney injury (AKI) is a global health concern with an incidence of 13.3 million patients per year, and increasing. AKI is recognized as an important risk factor for the development of chronic kidney disease (CKD). A crucial aspect for successful renal recovery after AKI is an efficient proliferative response of surviving tubular epithelial cells (TECs). Recently, we established a murine model in which the functional and histological recovery of a single kidney, injured by ischemia, is enhanced by removal of the unharmed contralateral kidney; a phenomenon termed nephrectomy-induced recovery. The renal epithelial reparative response in this unique physiological model has not been investigated, yet can provide new insights in unlocking the inherent regenerative potential of the renal epithelium. Method AKI was induced in R26RtdTomato and PAX2/Confetti mice by left unilateral ischemia/reperfusion (UIRI) for 21 min at 34°C, after which either right nephrectomy (Nx) or no Nx was performed 3 days later. Mice were euthanized 6 weeks and 28 days after UIRI, respectively. At week 6, kidneys were weighted and renal function was assessed by serum creatinine. At 28 days, renal tissue of Pax2/Confetti mice was collected to perform renal progenitor cell lineage tracing experiments by immunofluorescence and confocal microscopy. Results When nephrectomy was performed after UIRI, left kidney-to-body weight ratio did not change significantly over time, whereas, when no nephrectomy was performed, left kidney-to-body weight ratio gradually declined from 7,84 ± 0,48 mg/dl at day 3 till 3,26 ± 0,51 mg/dl at week 6, indicating severe atrophy in the injured left kidney. This loss of renal mass was associated with a significant increase in serum creatinine (1,76 ± 0,13 mg/dl) as compared to control (0,21 ± 0,12 mg/dl), whereas with nephrectomy, renal function fully restored. Clonal analysis in PAX2/Confetti mice revealed that nephrectomy after UIRI led to a significant increase in proliferating (i.e. clonogenic) Pax2+ progenitor cells, resulting in more multicellular clones as compared to un-nephrectomized controls. Conclusion Nephrectomy after UIRI overcomes chronic loss of renal mass and function within the investigated 6-week time frame. This study is the first to demonstrate that nephrectomy stimulates clonal expansion of renal progenitor cells in an injured kidney, beyond that observed for spontaneous repair after UIRI. Insight in the signaling mechanisms may reveal new therapeutic approaches to incite the inherent renal regeneration potential.

Cardiovascular infections are associated with high morbidity and mortality. Early diagnosis is crucial for adequate patient’s management, as early treatment improves the prognosis. Cardiovascular infections are difficult to diagnose on the basis of a single symptom, sign, or diagnostic test. Rather, the diagnosis requires a multidisciplinary discussion in addition to the integration of clinical signs, microbiology data, and imaging data. The application of multimodality imaging, including molecular imaging techniques, has improved the sensitivity to detect infections involving heart valves and vessels and implanted cardiovascular devices, while also allowing for early detection of septic emboli and metastatic infections before these become clinically apparent. This chapter describes the main epidemiological, clinical, and diagnostic challenges in infective endocarditis and infections associated with cardiovascular implantable electronic devices, with particular regard to the role of WBC SPECT/CT and [18F]FDG PET/CT in each diagnostic algorithm. In addition, the needs of proper hybrid equipment, dedicated imaging acquisition protocols, specific expertise for imaging reading and imaging interpretations in this field are discussed, emphasizing the need of a specific reference framework within a cardiovascular multidisciplinary team approach.

Simple Summary Kidney cancer is a frequent malignant tumor that accounts for approximately 5% of all cancer incidences. It affects both males and females, but males are twice as likely to develop kidney cancer than females. Evidence shows that this discrepancy takes root in individual differences, such as genetics or pathologies that affect the patient. It is then reflected in the clinical characteristics of the tumors, as males have larger and more aggressive tumors. Understanding the sex- and gender-based differences in kidney cancer is essential to be able to offer patients individualized medicine that would better cover their needs in terms of prevention, diagnosis and treatment. Abstract 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.

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.

Background and Aims Acute Kidney Injury (AKI) is a syndrome characterized by an acute deterioration of renal function. Due to its high prevalence and poor short-term outcomes, AKI represents a global healthcare issue. Many epidemiologic studies have indicated that the development of Chronic Kidney Disease (CKD) features prominently among the numerous long-term complications of AKI. The pathophysiological basis for this phenomenon has remained unclear so far. Recently, we found that tubular epithelial cells (TEC) undergo endoreplication-mediated hypertrophy after AKI. Endoreplications are incomplete cell cycles that lead to the formation of polyploid cells. Physiologically, polyploidy offers several advantages such as rapid adaptation to stress, compensation for cell loss and enhanced cell function. However, as renal epithelial cells are massively lost after AKI, TEC polyploidy may constitute an effective strategy to sustain a temporary functional recovery of the kidney without restoring tissue integrity potentially leading to CKD. Therefore, we hypothesized that: 1) polyploid TEC are an adaptive stress response required to maintain kidney function after AKI; 2) polyploid TEC are involved in the AKI to CKD progression. Method To address these hypotheses, we employed a series of in vitro and in vivo transgenic models based on the Fluorescence Ubiquitin Cell Cycle Indicator (FUCCI) technology to monitor cell cycle phasing in combination with YAP1 overexpression or downregulation. In the in vivo models, YAP1 overexpressing mice and YAP1 knock-out mice were subjected to unilateral ischemia reperfusion injury (IRI) or glycerol-induced rhabdomyolysis to induce AKI. Polyploid cells have been then characterized by single cell-RNA sequencing analysis, cell sorting, super-resolution STED microscopy and transmission electron microscopy in both mouse and human. Results In vitro, human renal tubular cells undergo polyploidization. The fraction of polyploid cells significantly decreases when YAP1 nuclear translocation is blocked, indicating a possible involvement of YAP1 in regulating TEC polyploidy. After AKI in mice, YAP1 expression and nuclear translocation are significantly enhanced. The inhibition of YAP1 following AKI, reduces the number of polyploid cells impairing kidney function and causing a dramatic reduction of mouse survival. In contrast, YAP1 overexpression leads to an increase in the number of polyploid cells even in the absence of kidney damage (healthy mice). Strikingly, these healthy mice, despite having an increased percentage of polyploid cells, present an unexpected decline of renal function suggesting an association between increased polyploidy and CKD development. Indeed, they develop tubulointerstitial fibrosis acquiring a marked senescent phenotype triggering CKD. Isolation of polyploid cells proved that these cells actively transcribe and secrete pro-fibrotic factors thus confirming their role in CKD progression. Conclusion Collectively, these data suggest that: 1) polyploidization after AKI is required to maintain kidney function allowing survival; 2) polyploid cells are pro-fibrotic leading in the long run to CKD progression.

Fever of unknown origin (FUO) is a prolonged febrile status without a known etiology despite accurate evaluation and diagnostic testing. It can be due to infection (21–54%), malignancies (6–31%), and/or inflammatory diseases (13–24%). Infection can be diagnosed in about 69.2% of the cases by noninvasive methods. Radiological imaging modalities (US, CT, and MRI) are often the first diagnostic imaging in the workup of patients with FUO. However, in order to identify the site of infection as the cause of FUO, it is often necessary to use nuclear medicine imaging, such as 67Ga-citrate scintigraphy, labeled autologous leukocyte (WBC) scintigraphy, or [18F]FDG PET/CT. The 67Ga-citrate scan shows quite low sensitivity (67%) and specificity (78%) for infectious diagnosis of FUO. Labeled WBC scintigraphy has higher sensitivity (60–85% and 96% for 111In-oxine-WBC and for 99mTc-HMPAO-WBC, respectively) and specificity (78–94% for 111In-oxine-WBC and 92% for 99mTc-HMPAO-WBC, respectively). By mirroring glucose metabolism, [18F]FDG accumulates equally well into inflammatory and neoplastic cells; this feature constitutes the pathophysiologic basis to perform [18F]FDG PET/CT in patients with FUO. The main advantages of [18F]FDG PET/CT are the high-quality imaging, short time consuming, and high diagnostic accuracy, especially in the spine and in chronic low-grade infections. Because of its high negative-predictive value, [18F]FDG PET/CT is considered the diagnostic procedure of choice for patients with FUO with low or intermediate probability of infection. Labeled WBC scintigraphy is instead the diagnostic procedure of choice in patients with FUO with high probability of infectious origin.

Infection and inflammation of bone can be acute, subacute or chronic depending on time of symptom appearance and clinical manifestation. Some microorganisms more often induce chronic osteomyelitis than others. Infection is often associated with inflammation, particularly in acute and sub-acute forms, but bone inflammation is not necessarily associated with an infection, as in the case of aseptic prosthesis loosening. According to the main site of anatomical location, bone infections can be divided into three distinct groups: infection of peripheral bone, infection of the axial skeleton, and infection of joint(s). Table 3.1 summarizes the main clinical indications and usefulness of radionuclide imaging procedures in patients with bone infection.

Background and Aims Acute kidney injury (AKI) is a global health concern. If not lethal in the acute phase, AKI is considered reversible based on the capacity of surviving tubular cells (TECs) to re-enter cell cycle. However, even mild AKI episodes carry a substantial risk of developing chronic kidney disease (CKD). The pathophysiological basis for this phenomenon remains unclear. Recently, we demonstrated that tubular epithelial cells (TECs) can undergo endoreplication-mediated hypertrophy after AKI. Endoreplications are incomplete cell cycles that lead to the formation of polyploid cells. As polyploid cells can provide increased cell function without restoring tissue integrity, we hypothesized that this mechanism is essential to survive AKI but it can be potentially maladaptive. Method To address this hypothesis, we employed a series of in vitro and in vivo transgenic models based on the Fluorescence Ubiquitin Cell Cycle Indicator (FUCCI) technology to monitor cell cycle phasing in combination with YAP1 overexpression or downregulation. In the in vivo models, YAP1 overexpressing mice and YAP1 knock-out mice were subjected to unilateral ischemia reperfusion injury (IRI) or glycerol-induced rhabdomyolysis to induce AKI. Polyploid cells have been then characterized by microarray analysis, cell sorting, super-resolution STED microscopy and transmission electron microscopy. Results In vitro, human renal tubular cells undergo polyploidization. The fraction of polyploid cells significantly decreases when YAP1 nuclear translocation is blocked, suggesting a possible involvement of YAP1 in regulating TEC polyploidization. After AKI in mice, the inhibition of YAP1 significantly reduces the number of polyploid cells and worsens kidney function resulting in a dramatic decrease of mouse survival. In contrast, YAP1 overexpression leads to an increase in the number of polyploid cells up to 20% of all TECs, further confirming the role of YAP1 in controlling TEC polyploidization. In YAP1 overexpressing mice, electron microscopy and STED analysis revealed the presence of both mononucleated and binucleated polyploid cells. Strikingly, these mice appear to be more prone to develop tubulointerstitial fibrosis acquiring a marked senescent phenotype along with significant decline in renal function thus suggesting an association between polyploidization and CKD development. Indeed, isolation of polyploid cells proved that these cells actively transcribe and secrete pro-fibrotic and senescent factors confirming their role in CKD progression. Conclusion These data suggest that: 1) polyploidization after AKI is required to preserve renal function in the acute phase of damage and it is essential for survival 2) polyploid cells are pro-fibrotic and senescent leading in the long run to the progression of AKI to CKD.

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.

Cardiovascular infections are associated with high morbidity and mortality. Early diagnosis is crucial for adequate patient management, as early treatment improves the prognosis, hardly diagnosed on the basis of a single symptom, sign or diagnostic test. Rather, the diagnosis requires a multidisciplinary discussion in addition to the integration of clinical signs, microbiology data and imaging data. The application of multimodality imaging, including molecular imaging techniques, has improved the sensitivity to detect infections involving heart valves and vessels and implanted cardiovascular devices while also allowing for early detection of septic emboli and metastatic infections before these become clinically apparent. In this chapter, we describe data supporting the use of a multimodality and multidisciplinary approach to cardiovascular infections. In particular, the role of WBC SPECT/CT and [18F]FDG PET/CT in most prevalent and clinically relevant cardiovascular infections is discussed.

INTRODUCTION: Radiolabelled autologous white blood cells (WBC) scintigraphy is being standardized all over the world to ensure high quality, specificity and reproducibility. Similarly, in many European countries radiolabelled anti-granulocyte antibodies (anti-G-mAb) are used instead of WBC with high diagnostic accuracy. The EANM Inflammation & Infection Committee is deeply involved in this process of standardization as a primary goal of the group. AIM: The main aim of this guideline is to support and promote good clinical practice despite the complex environment of a national health care system with its ethical, economic and legal aspects that must also be taken into consideration. METHOD: After the standardization of the WBC labelling procedure (already published), a group of experts from the EANM Infection & Inflammation Committee developed and validated these guidelines based on published evidences. RESULTS: Here we describe image acquisition protocols, image display procedures and image analyses as well as image interpretation criteria for the use of radiolabelled WBC and monoclonal antigranulocyte antibodies. Clinical application for WBC and anti-G-mAb scintigraphy is also described. CONCLUSIONS: These guidelines should be applied by all nuclear medicine centers in favor of a highly reproducible standardized practice.

Cardiovascular infections are associated with high morbidity and mortality. Early diagnosis is crucial for adequate patient management, as early treatment improves the prognosis. The diagnosis cannot be made on the basis of a single symptom, sign, or diagnostic test. Rather, the diagnosis requires a multidisciplinary discussion in addition to the integration of clinical signs, microbiology data, and imaging data. The application of multimodality imaging, including molecular imaging techniques, has improved the sensitivity to detect infections involving heart valves and vessels and implanted cardiovascular devices while also allowing for early detection of septic emboli and metastatic infections before these become clinically apparent. In this review, we describe data supporting the use of a Multimodality, Multitracer, and Multidisciplinary approach (the 3M approach) to cardiovascular infections. In particular, the role of white blood cell SPECT/CT and [F-18]FDG PET/CT in most prevalent and clinically relevant cardiovascular infections will be discussed. In addition, the needs of advanced hybrid equipment, dedicated imaging acquisition protocols, specific expertise for image reading, and interpretation in this field are discussed, emphasizing the need for a specific reference framework within a Cardiovascular Multidisciplinary Team Approach to select the best test or combination of tests for each specific clinical situation. (C) 2018 Elsevier Inc. All rights reserved.

Spondylodiscitis is an infection of the vertebral body or disc and may also involve the epidural space, posterior elements, and paraspinal soft tissues. It is a cause of morbidity and mortality, and warrants early diagnosis and prompt treatment. Diagnosis can be difficult because of nonspecific signs and symptoms. Magnetic resonance imaging is sensitive and specific and is the imaging modality of choice for spondylodiscitis. Gadolinium contrast can show the extent of soft tissue and bone phlegmon and abscess. The test is less useful for evaluating treatment response. When magnetic resonance imaging cannot be performed or is not diagnostic, radionuclide imaging is a useful alternative. Although bone scintigraphy frequently is used as a screening test, false-negative results can occur, especially in the elderly. This test is not useful for detecting soft tissue infections that accompany or mimic spondylodiscitis. Gallium-67 citrate improves the specificity of the bone scan, can detect infection earlier than the bone scan, may be more sensitive, especially in elderly patients, and identifies accompanying soft tissue infection. Performing SPECT and SPECT/CT improves accuracy. The 2- to 3-day delay between radiopharmaceutical administration and the relatively poor image quality are significant disadvantages of gallium-67. Indium-111 biotin, alone or in combination with streptavidin, accurately diagnoses spondylodiscitis; unfortunately, this agent is not widely available. Currently, 18F-FDG imaging is the radionuclide test of choice for spondylodiscitis. The procedure, which is completed in a single session, is sensitive, has a high negative predictive value, and reliably differentiates degenerative from infectious vertebral body end plate abnormalities. In comparative investigations, 18F-FDG has outperformed bone and gallium-67 imaging. Preliminary data suggest that 18F-FDG may be able to provide an objective means to measure response to treatment. Gallium-68 citrate and 99mTc-radiolabeled antimicrobial peptides have been investigated, but their role in spondylodiscitis has yet to be established.

Soft tissues infections frequently present with nonspecific signs and symptoms. The diagnosis and evaluation of extension of soft tissues infection may be tricky. Diagnostic imaging is mandatory to evaluate the extension of infection disease, the response to the antibiotic treatment, and the potential relapse of disease. Radiologic imaging is composed of ultrasound that is widely available and can be easily and early performed, Computed Tomography (CT) and Magnetic Resonance (MRI).

Imaging infections with radiolabeled WBC requires precise strategies in order to differentiate them from sterile inflammatory conditions. Indeed, radiolabeled neutrophil, when injected into peripheral veins, has a peculiar biodistribution characterized by a short transit through the lungs (usually 30–60 min), followed by rapid accumulation into liver, spleen, and bone marrow with slow migration into infection sites. This migration process is slower in chronic, low-degree infections and faster in acute, high-degree infections, and it is believed that it is driven by the local production of chemotactic factors.

Increasing evidence has demonstrated the bidirectional link between acute kidney injury (AKI) and chronic kidney disease (CKD) such that, in the clinical setting, the new concept of a unified syndrome has been proposed. The pathophysiological reasons, along with the cellular and molecular mechanisms, behind the ability of a single, acute, apparently self-limiting event to drive chronic kidney disease progression are yet to be explained. This acute injury could promote progression to chronic disease through different pathways involving the endothelium, the inflammatory response and the development of fibrosis. The interplay among endothelial cells, macrophages and other immune cells, pericytes and fibroblasts often converge in the tubular epithelial cells that play a central role. Recent evidence has strengthened this concept by demonstrating that injured tubules respond to acute tubular necrosis through two main mechanisms: The polyploidization of tubular cells and the proliferation of a small population of self-renewing renal progenitors. This alternative pathophysiological interpretation could better characterize functional recovery after AKI.

Diagnosis of spinal infection (SI) is challenging and usually requires multiple tests. We aimed to perform a systematic review and a bivariate meta-analysis on the diagnostic role ofA comprehensive literature search of studies published through February 2019 in PubMed/MEDLINE and Cochrane library databases was carried out. Studies investigating the diagnostic performance ofTwenty-six articles (833 patients) using

Bone tissue is a specialized form of connective tissue, to which mineralization of the extracellular matrix confers remarkable hardness and strength. It fulfills three main functions