Prostate cancer detection and complications of MRI-targeted prostate biopsy using cognitive registration, software-assisted image fusion or in-bore guidance: a systematic review and meta-analysis of comparative studies.

BACKGROUND: Three primary strategies for MRI-targeted biopsies (TB) are available: Cognitive TB (COG-TB), MRI-US Fusion TB (FUS-TB), and In Bore TB (IB-TB). Despite nearly a decade of practice, a consensus on the preferred approach is lacking, with previous studies showing comparable PCa detection rates among the three methods. METHODS: We conducted a search of PubMed, EMBASE, PubMed, Web of Science, and Scopus databases from 2014 to 2023, to identify studies comparing at least two of the three methods and reporting clinically significant PCa (csPCa) detection rates. The primary and secondary outcomes were to compare the csPCa and insignificant prostate cancer (iPCa, ISUP GG 1) detection rates between TB techniques. The tertiary outcome was to compare the complication rate between TB techniques. Detection rates were pooled using random-effect models. Planned sensitivity analyses included subgroup analysis according to the definition of csPCa and positive MRI, previous biopsy status, biopsy route, prostate volume, and lesion characteristics. RESULTS: A total of twenty studies, involving 4928 patients, were included in the quantitative synthesis. The meta-analysis unveiled comparable csPCa detection rates among COG-TB (0.37), FUS-TB (0.39), and IB-TB (0.47). iPCa detection rate was also similar between TB techniques (COG-TB: 0.12, FUS-TB: 0.17, IB-TB: 0.18). All preplanned sensitivity analyses were conducted and did not show any statistically significant difference in the detection of csPCa between TB methods. Complication rates, however, were infrequently reported, and when available, no statistically significant differences were observed among the techniques. CONCLUSIONS: This unique study, exclusively focusing on comparative research, indicates no significant differences in csPCa and iPCa detection rates between COG-TB, FUS-TB, and IB-TB. Decisions between these techniques may extend beyond diagnostic accuracy, considering factors such as resource availability and operator preferences. Well-designed prospective studies are warranted to refine our understanding of the optimal approach for TB in diverse clinical scenarios.

External Validation of the IMPROD-MRI Volumetric Model to Predict the Utility of Systematic Biopsies at the Time of Targeted Biopsy.

Background: The aim of this study was to validate externally a nomogram that relies on MRI volumetric parameters and clinical data to determine the need for a standard biopsy in addition to a target biopsy for men with suspicious prostate MRI findings. Methods: We conducted a retrospective analysis of a prospectively maintained database of 469 biopsy-naïve men who underwent prostate biopsies. These biopsies were guided by pre-biopsy multiparametric Magnetic Resonance Imaging (mpMRI) and were performed at two different institutions. We included men with a PIRADSsv 2.1 score from 3 to 5. Each patient underwent both an MRI-ultrasound fusion biopsy of identified MRI-suspicious lesions and a systematic biopsy according to our protocol. The lesion volume percentage was determined as the proportion of cancer volume on MRI relative to the entire prostate volume. The study's outcomes were iPCa (Gleason Grade Group 1) and csPCa (Gleason Grade Group > 1). We evaluated the model's performance using AUC decision curve analyses and a systematic analysis of model-derived probability cut-offs in terms of the potential to avoid diagnosing iPCa and to accurately diagnose csPCa. Results: The nomogram includes age, PSA value, prostate volume, PIRADSsv 2.1 score, percentage of MRI-suspicious lesion volume, and lesion location. AUC was determined to be 0.73. By using various nomogram cut-off thresholds (ranging from 5% to 30%), it was observed that 19% to 58% of men could potentially avoid undergoing standard biopsies. In this scenario, the model might miss 0% to 10% of diagnosis of csPCa and could prevent identifying 6% to 31% of iPCa cases. These results are in line with findings from the multi-institutional external validation study based on the IMPROD trial (n = 122) and the MULTI-IMPROD trial (n = 262). According to DCA, the use of this nomogram led to an increased overall net clinical benefit when the threshold probability exceeded 10%. Conclusions: This study supports the potential value of a model relying on MRI volumetric measurements for selecting individuals with clinical suspicion of prostate cancer who would benefit from undergoing a standard biopsy in addition to a targeted biopsy.

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.

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).

Urinary Biomarkers for Diagnosis and Prediction of Acute Kidney Allograft Rejection: A Systematic Review.

Noninvasive tools for diagnosis or prediction of acute kidney allograft rejection have been extensively investigated in recent years. Biochemical and molecular analyses of blood and urine provide a liquid biopsy that could offer new possibilities for rejection prevention, monitoring, and therefore, treatment. Nevertheless, these tools are not yet available for routine use in clinical practice. In this systematic review, MEDLINE was searched for articles assessing urinary biomarkers for diagnosis or prediction of kidney allograft acute rejection published in the last five years (from January 1, 2015 to May 31, 2020). This review follows the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines. Articles providing targeted or unbiased urine sample analysis for the diagnosis or prediction of both acute cellular and antibody-mediated kidney allograft rejection were included, analyzed, and graded for methodological quality with a particular focus on study design and diagnostic test accuracy measures. Urinary C-X-C motif chemokine ligands were the most promising and frequently studied biomarkers. The combination of precise diagnostic reference in training sets with accurate validation in real-life cohorts provided the most relevant results and exciting groundwork for future studies.

Acute kidney injury promotes development of papillary renal cell adenoma and carcinoma from renal progenitor cells.

Acute tissue injury causes DNA damage and repair processes involving increased cell mitosis and polyploidization, leading to cell function alterations that may potentially drive cancer development. Here, we show that acute kidney injury (AKI) increased the risk for papillary renal cell carcinoma (pRCC) development and tumor relapse in humans as confirmed by data collected from several single-center and multicentric studies. Lineage tracing of tubular epithelial cells (TECs) after AKI induction and long-term follow-up in mice showed time-dependent onset of clonal papillary tumors in an adenoma-carcinoma sequence. Among AKI-related pathways, NOTCH1 overexpression in human pRCC associated with worse outcome and was specific for type 2 pRCC. Mice overexpressing NOTCH1 in TECs developed papillary adenomas and type 2 pRCCs, and AKI accelerated this process. Lineage tracing in mice identified single renal progenitors as the cell of origin of papillary tumors. Single-cell RNA sequencing showed that human renal progenitor transcriptome showed similarities to PT1, the putative cell of origin of human pRCC. Furthermore, NOTCH1 overexpression in cultured human renal progenitor cells induced tumor-like 3D growth. Thus, AKI can drive tumorigenesis from local tissue progenitor cells. In particular, we find that AKI promotes the development of pRCC from single progenitors through a classical adenoma-carcinoma sequence.

A Disposable Passive Microfluidic Device for Cell Culturing.

In this work, a disposable passive microfluidic device for cell culturing that does not require any additional/external pressure sources is introduced. By regulating the height of fluidic columns and the aperture and closure of the source wells, the device can provide different media and/or drug flows, thereby allowing different flow patterns with respect to time. The device is made of two Polymethylmethacrylate (PMMA) layers fabricated by micro-milling and solvent assisted bonding and allows us to ensure a flow rate of 18.6 µl/ℎ - 7%/day, due to a decrease of the fluid height while the liquid is driven from the reservoirs into the channels. Simulations and experiments were conducted to characterize flows and diffusion in the culture chamber. Melanoma tumor cells were used to test the device and carry out cell culturing experiments for 48 hours. Moreover, HeLa, Jurkat, A549 and HEK293T cell lines were cultivated successfully inside the microfluidic device for 72 hours.

Reverse Phenotyping after Whole-Exome Sequencing in Steroid-Resistant Nephrotic Syndrome.

BACKGROUND AND OBJECTIVES: Nephrotic syndrome is a typical presentation of genetic podocytopathies but occasionally other genetic nephropathies can present as clinically indistinguishable phenocopies. We hypothesized that extended genetic testing followed by reverse phenotyping would increase the diagnostic rate for these patients. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: All patients diagnosed with nephrotic syndrome and referred to our center between 2000 and 2018 were assessed in this retrospective study. When indicated, whole-exome sequencing and in silico filtering of 298 genes related to CKD were combined with subsequent reverse phenotyping in patients and families. Pathogenic variants were defined according to current guidelines of the American College of Medical Genetics. RESULTS: A total of 111 patients (64 steroid-resistant and 47 steroid-sensitive) were included in the study. Not a single pathogenic variant was detected in the steroid-sensitive group. Overall, 30% (19 out of 64) of steroid-resistant patients had pathogenic variants in podocytopathy genes, whereas a substantial number of variants were identified in other genes, not commonly associated with isolated nephrotic syndrome. Reverse phenotyping, on the basis of a personalized diagnostic workflow, permitted to identify previously unrecognized clinical signs of an unexpected underlying genetic nephropathy in a further 28% (18 out of 64) of patients. These patients showed similar multidrug resistance, but different long-term outcome, when compared with genetic podocytopathies. CONCLUSIONS: Reverse phenotyping increased the diagnostic accuracy in patients referred with the diagnosis of steroid-resistant nephrotic syndrome.

Molecular Mechanisms of the Acute Kidney Injury to Chronic Kidney Disease Transition: An Updated View.

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.