Renal Papillary Research Articles

NSAIDs and Kidney Health: A Review of the Silent Threat to Renal Function

Nonsteroidal anti-inflammatory medications (NSAIDs) are frequently recommended to treat rheumatologically and inflammatory diseases as well as to relieve pain. Acute kidney injury (AKI), chronic kidney disease (CKD), acute interstitial nephritis, and renal papillary necrosis are among the serious renal hazards that NSAIDs are linked to, despite their effectiveness, particularly in people who already have kidney disease or those using NSAIDs long-term or at high doses. This umbrella review consolidates evidence from multiple meta-analyses and systematic reviews to clarify the nephrotoxic potential of NSAIDs. The review reveals that NSAID use, including both traditional and selective COX-2 inhibitors, is linked to a 50% to 70% increased risk of AKI and CKD. Adverse effects are primarily related to intrarenal vasculature disruption, glomerular damage, and sodium imbalance. Although some NSAIDs offer specific renal protections, overall, the harm often outweighs the benefits. Further research is needed to better understand these risks, especially the molecular mechanisms underlying NSAID-induced kidney damage and to identify at-risk populations. This understanding will aid in balancing the therapeutic benefits of NSAIDs against their potential renal risks, ensuring safer clinical use.

Combatting cellular immortality in cancers by targeting the shelterin protein complex

Shelterin proteins (TERF1, TERF2, TPP1, TINF2, POT1) protect telomeres, prevent unwarranted repair activation, and regulate telomerase activity. Alterations in these proteins can lead to cancer progression. This study uses an in-silico approach to examine shelterin in tumour samples across various cancers, employing mutation plots, phylogenetic trees, and sequence alignments. Network pharmacology identified TERF1 as an essential shelterin protein and transcription factors RUNX1, CTCF, and KDM2B as potential biomarkers due to their interactions with miRNAs and shelterin proteins. We performed MCODE analysis to identify subnetworks of ncRNAs interacting with the shelterin proteins. Shelterin expression predicted patient survival in 24 cancer types, with TERF1, TERF2, TINF2, and POT1 significantly expressed in testicular, AML, prostate, breast and renal cancers, respectively, and TPP1 in AML and skin cancer. Spearman and Pearson's analyses showed significant correlations of TERF1 across cancers, with near-significant correlations for all five proteins in different cancer datasets like breast cancer, kidney renal papillary and lung squamous cell carcinoma, skin cutaneous melanoma, etc.,. Shelterin expression correlated with patient survival in breast, renal, lung, skin, uterine, and gastric cancers. Insights into TPP1-associated glycans highlighted glycosylated sites contributing to tumorigenesis. This study provides molecular signatures for further functional and therapeutic research on shelterin, highlighting its potential as a target for anti-cancer therapies and promising prospects for cancer prognosis and prediction.

Sustainable chemometric analysis of tension headache drugs in the presence of nephrotoxic impurities

A three-drug combination of caffeine, aspirin and paracetamol is widely prescribed as a first-line treatment for tension headaches and migraine attacks. Being of easy access as an over-the-counter medication, renal papillary necrosis may be caused if large doses are taken chronically. Moreover, several toxic impurities such as p-aminophenol and p-hydroxy acetophenone may be formed during the synthesis or storage of paracetamol. These impurities are classified as nephrotoxic and teratogenic materials which obliges pharmaceutical companies to develop cost-effective methodologies for their detection along with paracetamol itself. During the current study, multivariate chemometric-assisted spectrophotometric models namely; Partial Least Squares, Genetic Algorithm-Partial Least Squares and Multivariate Curve Resolution-Alternating Least Squares were developed for assaying and resolving the complex spectral overlap of the ternary combination in the presence of the nephrotoxic impurities; p-aminophenol and p-hydroxy acetophenone. A comparison was held between the three models where the optimized Genetic Algorithm-Partial Least Squares and Multivariate Curve Resolution-Alternating Least Squares models reduced the root mean square by 18.1%, 21.7%, 20.0%, 43.9% and 11.5% and 31.5%, 32.6%, 39.3%, 54.6% and 37.9% for caffeine, aspirin, paracetamol, p-aminophenol and p-hydroxy acetophenone, respectively. Panadol® migraine tablets were successfully analyzed using the constructed models without interference from the excipients. A statistical comparative analysis and greenness evaluation were carried out using two assessment tools including the “Green Analytical Procedure Index” and the “Analytical Greenness metric”. Also, the “Whiteness Analytical Chemistry tool” using the RGB12 model and the Blueness Applicability Grade Index were applied. Greener quadrants and a high score of 0.74 for the greenness tools were achieved with accepted statistical parameters regarding t and f values. Also, the high scores of the Blueness Applicability Grade Index and RGB12 metrics of 90 and 98.3, respectively confirmed the method's wide practicality and utility. Although other chemometric methods were reported for assaying the ternary combination, our developed method was the only one that incorporated toxic impurities during the analysis along with implementing greenness, whiteness and blueness assessments to ensure the method's sustainability.

Renal Papillary Neoplasms – Concordance Rate between Diagnosis on Fine-Needle Biopsy (FNB) and Subsequent Resection

Renal Papillary Neoplasms – Concordance Rate between Diagnosis on Fine-Needle Biopsy (FNB) and Subsequent Resection

Investigating hematuria among young Indian adults using MDCT urography.

Hematuria may suggest bladder cancer, renal cell carcinoma, UUT-UCC, or urinary tract stones. Therefore, it is of interest to use Multi-Detector Computed Tomography (MDCT) to determine the cause of hematuria in children and connect MDCT results with cystoscopic and histological findings. The study included 110 young people under 40 with microscopic or macroscopic hematuria. A clinical exam and complete history were recorded. MDCT data from non-contrast and contrast-enhanced scans were properly documented. Histopathological and cystoscopic findings were noted alongside MDCT data when appropriate. The study's typical patient was 26 years old, 66% male. Eighty of the cases had hematuria as the cause. In 66 of 80 individuals, renal or ureteric calculi were the most common clinically relevant outcomes. There were four renal and four UB masses. Two cases of renal papillary necrosis and four of pyelonephritis/renal abscess were identified. MDCT diagnosed renal and vesical masses 100% accurately. MDCT can diagnose and treat hematuria, especially in young men, according to one study. The findings emphasize clinical awareness and targeted diagnosis. Further research is needed to determine hematuria causes and prevention across demographics.

Renal papillary tip biopsy in stone formers: a review of clinical safety and insights.

Alexander Randall first published renal papillary tip findings from stone formers in 1937, paving the way for endoscopic assessment to study stone pathogenesis. We performed a literature search to evaluate the safety of papillary tip biopsy and clinical insights gained from modern renal papillary investigations. A search on the topic of renal papillary biopsy provided an overview of Randall's plaques (RP), classification systems for renal papillary grading, and a summary of procedure type, complications, and outcomes. Within 26 identified manuscripts, 660 individuals underwent papillary tip biopsy percutaneously (n = 562), endoscopically (n = 37), or unspecified (n = 23). Post-operative hemoglobin changes were similar to controls.One individual (0.2%) reported fever > 38°, and long-term mean serum creatinine post-biopsy (n = 32) was unchanged. Biopsies during ureteroscopy or PCNL added ~20-30min of procedure time. Compared to controls, papillary plaque-containing tissue had upregulation in pro-inflammatory genes, immune cells, and cellular apoptosis. Urinary calcium and papillary plaque coverage were found to differ between RP and non-RP stone formers, suggesting differing underlying pathophysiology for these groups. Two renal papillary scoring systems have been externally validated and are used to classify stone formers. Overall, this review shows that renal papillary biopsies have a low complication profile with high potential for further research. Systematic adaption of a papillary grading scale, newer tissue analysis techniques, and the development of animal models of Randall's plaque may allow further exploration of plaque pathogenesis and identify targets for prevention therapies in patients with nephrolithiasis.

Discovery and Validation of Survival-Specific Genes in Papillary Renal Cell Carcinoma Using a Customized Next-Generation Sequencing Gene Panel.

Papillary renal cell carcinoma (PRCC), the second most common kidney cancer, is morphologically, genetically, and molecularly heterogeneous with diverse clinical manifestations. Genetic variations of PRCC and their association with survival are not yet well-understood. This study aimed to identify and validate survival-specific genes in PRCC and explore their clinical utility. Using machine learning, 293 patients from the Cancer Genome Atlas-Kidney Renal Papillary Cell Carcinoma (TCGA-KIRP) database were analyzed to derive genes associated with survival. To validate these genes, DNAs were extracted from the tissues of 60 Korean PRCC patients. Next generation sequencing was conducted using a customized PRCC gene panel of 202 genes, including 171 survival-specific genes. Kaplan-Meier and Log-rank tests were used for survival analysis. Fisher's exact test was performed to assess the clinical utility of variant genes. A total of 40 survival-specific genes were identified in the TCGA-KIRP database through machine learning and statistical analysis. Of them, 10 (BAP1, BRAF, CFDP1, EGFR, ITM2B, JAK1, NODAL, PCSK2, SPATA13, and SYT5) were validated in the Korean-KIRP database. Among these survival gene signatures, three genes (BAP1, PCSK2, and SPATA13) showed survival specificity in both overall survival (OS) (p = 0.00004, p = 1.38 × 10-7, and p = 0.026, respectively) and disease-free survival (DFS) (p = 0.00002, p = 1.21 × 10-7, and p = 0.036, respectively). Notably, the PCSK2 mutation demonstrated survival specificity uniquely in both the TCGA-KIRP (OS: p = 0.010 and DFS: p = 0.301) and Korean-KIRP (OS: p = 1.38 × 10-7 and DFS: p = 1.21 × 10-7) databases. We discovered and verified genes specific for the survival of PRCC patients in the TCGA-KIRP and Korean-KIRP databases. The survival gene signature, including PCSK2 commonly obtained from the 40 gene signature of TCGA and the 10 gene signature of the Korean database, is expected to provide insight into predicting the survival of PRCC patients and developing new treatment.

Urinary tract mycosis masquerading as renal papillary necrosis post-COVID: A case report

Urinary tract mycosis is more often seen in hospitalized patients than in community-acquired ones. Funguria is common but becomes invasive and life-threatening in immunosuppressed patients such as with diabetes mellitus, post-transplant, chronic antibiotic usage, cancer chemotherapy, and long-term steroids. In the last 2 years, the world has witnessed one of its worst pandemics with the COVID-19 infection, killing millions of people. Deaths have been due to the virus or secondary complications thereafter. Secondary fungal infections, especially those caused by mucormycosis, have been on the rise, the majority of which have been reported from India. The rhino-cerebral-pulmonary form is the most common, followed by isolated case reports of gastrointestinal, cutaneous, and musculoskeletal mucormycosis. Isolated renal and urinary tract mycosis in COVID-19 is an extremely rare association. We report a case of a middle-aged man with fairly well-controlled diabetes who received steroids for COVID-19 infection and, about 8 weeks later, presented with non-invasive mixed mycosis of the urinary tract that was managed conservatively without any surgical intervention.

Pachymic acid activates TP53INP2/TRAF6/caspase-8 pathway to promote apoptosis in renal cell carcinoma cells.

While pachymic acid (PA), a key component of Poria cocos (Schw.), has demonstrated anti-tumor effects in lung, breast, and pancreatic cancers, its impact on renal cell carcinoma (RCC) is unclear. This study evaluated the effect of PA on proliferation, migration, and apoptosis in human renal cancer A498 and ACHN cells as well as in cancer xenograft mice using wound scratch test, Western blotting, and co-immunoprecipitation assays. In a dose- and time-dependent manner, PA exhibited significant inhibition of RCC cell proliferation, migration, and invasion, accompanied by the induction of apoptosis. Additionally, PA upregulated the expression of tumor protein p53-inducible nuclear protein 2 (TP53INP2) and tumor necrosis factor receptor-associated factor 6 (TRAF6), which were downregulated in renal papillary and chromophobe carcinoma, resulting in inhibited tumor growth in mice. PA treatment elevated cleaved-caspase 3 and 8, and PARP levels, and facilitated TP53INP2 and TRAF6 binding to caspase 8, promoting its ubiquitination. Molecular docking revealed interactions between PA and TP53INP2, TRAF6. In summary, PA inhibits RCC development by upregulating TP53INP2 and promoting TRAF6-induced caspase 8 ubiquitination, activating apoptotic pathways.

Candida-Associated Renal Papillary Necrosis Following Severe COVID-19 Infection

Candida-associated renal papillary necrosis is rare. The few cases described previously were secondary to candidemia, especially in immunocompromised hosts. We describe two patients who presented with hydroureteronephrosis and were diagnosed with candida-associated renal papillary necrosis. Both patients had a history of severe COVID-19 infection within the past year and had been treated with immunosuppressants. Both patients underwent double J stenting and anti-fungal treatment with fluconazole. One patient recovered completely, while the other patient who had chronic kidney disease stage 4 at diagnosis progressed to dialysis-dependent renal failure later following an episode of bacterial sepsis. The incidence of candida-associated renal papillary necrosis may reflect the immunomodulatory effects of COVID-19, immunosuppressants, or a combination of both.

23 Navigating Drug-Induced Acute Interstitial Nephritis and Renal Papillary Necrosis in a Renal Transplant Recipient

23 Navigating Drug-Induced Acute Interstitial Nephritis and Renal Papillary Necrosis in a Renal Transplant Recipient

Abstract 3681: Transcribed ultraconserved regions are associated with survival in multiple tumor types

Abstract Ultraconserved regions (UCRs), encompassing 481 genomic segments identical across humans, mice, and rats, and conserved in other species, are distributed across all human chromosomes except 21 and Y. Over 90% of these regions, termed transcribed ultraconserved regions (T-UCRs) are expressed in at least one human tissue. Although extensively studied in the context of cancer since their discovery, the prognostic significance of T-UCRs in a pan-cancer context has not been explored. For this, TCGA data extracted from the TANRIC platform was utilized, differential expression and survival analysis was performed on different tumor types. Our analysis revealed that approximately 300 UCRs were expressed in the majority of the 20 tumor tissues. Additionally, it was noted that all examined tumor tissues expressed a higher number of UCRs compared to their non-tumor counterparts. Through t-distributed stochastic neighbor embedding (t-SNE) analysis, UCR expression patterns could distinguish primary tumor origins and types. Regarding the prognostic value, we identified 100 (20,8%) T-UCRs associated with disease-specific survival (DSS) and 102 (21.2%) T-UCRs associated with progression-free interval (PFI). Those T-UCRs are particularly important in the survival outcomes of kidney renal clear cell carcinoma (KIRC) and low-grade gliomas (LGC). In addition, we verified that uc.44, uc.48, uc.135, uc.144, uc.153, uc.217, uc.255, uc.256, uc.344, uc.357, uc.390, uc.427 and uc.436 were associated with survival of more than one tumor. Particularly, uc.135 high expression was associated with poor prognosis in Kidney Renal Papillary Cell Carcinoma (KIRP) and LGC, and good prognosis in KIRC. Uc.135 are mapped on MECOM gene, coding an oncoprotein acting as transcriptional regulator and involved in apoptosis, proliferation, and cell differentiation. Our findings suggest that analysis of T-UCRs expression have the potential to be used as predictive biomarkers and can help in studying the mechanisms and specific roles of the highlighted T-UCRs in cancer. Citation Format: Ana Carolina Rodrigues, Douglas Adamoski, Daniela F. Gradia, Jaqueline Carvalho de Oliveira. Transcribed ultraconserved regions are associated with survival in multiple tumor types [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3681.

Ferroptosis-Related lncRNA to Predict the Clinical Outcomes and Molecular Characteristics of Kidney Renal Papillary Cell Carcinoma.

Kidney renal papillary cell carcinoma (KIRP) is a highly heterogeneous type of kidney cancer, resulting in limited effective prognostic targets for KIRP patients. Long non-coding RNAs (lncRNAs) have emerged as crucial regulators in the regulation of ferroptosis and iron metabolism, making them potential targets for the treatment and prognosis of KIRP. In this study, we constructed a ferroptosis-related lncRNA risk score model (FRM) based on the TCGA-KIRP dataset, which represents a novel subtype of KIRP not previously reported. The model demonstrated promising diagnostic accuracy and holds potential for clinical translation. We observed significant differences in metabolic activities, immune microenvironment, mutation landscape, ferroptosis sensitivity, and drug sensitivity between different risk groups. The high-risk groups exhibit significantly higher fractions of cancer-associated fibroblasts (CAFs), hematopoietic stem cells (HSC), and pericytes. Drugs (IC50) analysis provided a range of medication options based on different FRM typing. Additionally, we employed single-cell transcriptomics to further analyze the impact of immune invasion on the occurrence and development of KIRP. Overall, we have developed an accurate prognostic model based on the expression patterns of ferroptosis-related lncRNAs for KIRP. This model has the potential to contribute to the evaluation of patient prognosis, molecular characteristics, and treatment modalities, and can be further translated into clinical applications.

Comprehensive Analyses Revealed Eight Immune Related Signatures Correlated With Aberrant Methylations as Prognosis and Diagnosis Biomarkers for Kidney Renal Papillary Cell Carcinoma.

Kidney renal papillary cell carcinoma (KIRP) is a common type of renal cell carcinoma. DNA methylation plays an important role in the development of several cancers. The aim of our study was to identify differentially expressed genes associated with abnormal DNA methylation as biomarkers for predicting the outcome of KIRP. We downloaded KIRP methylation data, RNA sequencing (RNAseq) data, and their corresponding clinical information from the Cancer Genome Atlas (TCGA) database. ChAMP and DEGseq2 packages in R software were used to screen differentially methylated probes (DMPs) and differentially expressed genes (DEGs). Univariate and multivariate Cox regression analyses were used to identify suitable immune related genes correlated with aberrant methylations as prognosis biomarkers. We identified 8 DEGs (Cysteine And Glycine Rich Protein 1 [CSRP1], major histocompatibility complex, Class II, DM Beta [HLA-DMB], LIF Receptor Subunit Alpha [LIFR], Leukotriene B4 receptor 2 [LTB4R2], Mitogen-Activated Protein Kinase Kinase Kinase 14 [MAP3K14], Nuclear Receptor Subfamily 2 Group F Member 1 [NR2F1], Secreted And Transmembrane 1 [SECTM1], and Vimentin [VIM]) that were independently associated with the overall survival (months) (OS) of KIRP. The time dependent area under the curve (AUC) for each receiver operating characteristic (ROC) of the risk assessment model at 1, 3, 5, and 10-years reached 0.8415, 0.8131, 0.7873, and 0.7667. The risk assessment model was correlated with several immune cells and factors. The AUC value of the diagnosis model using those 8 DEGs reached 0.99. The risk assessment model constructed by those 8 DEGs was well able to predict the prognosis and diagnose of KIRP. However, whether the prognosis and diagnosis model could be applied in clinical practice requires further study.

Primary Extra Renal Papillary Renal Cell Carcinoma Masquerading as A Metastatic Carcinoma: A Unique Case with Dual Malignancies

A 50-year-old male presented with abdominal pain, pain during defaecation, constipation, bleeding per rectum for 2 months. Colonoscopy showed an ulcero-proliferative growth, that is 2.5 cm from anal verge. Further PET-CT confirmed the growth in the lower rectum with mesorectal fat stranding and an irregular, lobulated, encapsulated solid-cystic mass in right perinephric fat, separated from the kidney (suggestive of metastasis), with intact bilateral kidneys. Biopsy of the rectum revealed an adenocarcinoma and biopsy of right perinephric mass revealed a papillary neoplasm. Following which abdominoperineal resection with perinephric mass excision was performed, due to encapsulation of mass. Histopathological evaluation and further immunohistochemistry performed was positive for vimentin, AMACR, CD10 and negative for other markers to rule out metastasis of either. This led to the diagnosis of synchronous primaries i.e., Extra-renal papillary renal cell carcinoma and adenocarcinoma of rectum.

The Most Common Type of Kidney Stone and High Incidence in Males or Female

In the renal calyces and pelvis, mineral deposits known as kidney stones can be found either loosely or firmly attached to the renal papillae. They comprise both crystalline and organic molecules and are produced when the urine is very saturated with a specific mineral. The majority of stones are mostly formed of calcium oxalate, and a lot of these stones form on Randall's plaques on the renal papillary floor, which are made of calcium phosphate. In the first five years after the initial stone episode, charges of up to 50% may recur. There are charges of up to 14.8% and increasing for stone creation. Risk factors for kidney stone development include obesity, diabetes, high blood pressure, and metabolic syndrome. Kidney stones can then lead to hypertension, chronic kidney disease, and end-stage renal disease. Less invasive endourological techniques have replaced open surgical lithotomy for the treatment of symptomatic kidney stones, reducing patient morbidity, increasing stone-free rates, and improving quality of life. Prevention of recurrence requires behavioral and nutritional adjustments in addition to drugs according to the kind of stone. The creation of stronger capsules and the pressing need for recurrence prevention necessitate a greater comprehension of the mechanisms behind stone formation.

Identification and verification of prognostic cancer subtype based on multi-omics analysis for kidney renal papillary cell carcinoma.

Identifying Kidney Renal Papillary Cell Carcinoma (KIRP) patients with high-risk, guiding individualized diagnosis and treatment of patients, and identifying effective prognostic targets are urgent problems to be solved in current research on KIRP. In this study, data of multi omics for patients with KIRP were collected from TCGA database, including mRNAs, lncRNAs, miRNAs, data of methylation, and data of gene mutations. Data of multi-omics related to prognosis of patients with KIRP were selected for each omics level. Further, multi omics data related to prognosis were integrated into cluster analysis based on ten clustering algorithms using MOVICS package. The multi omics-based cancer subtype (MOCS) were compared on biological characteristics, immune microenvironmental cell abundance, immune checkpoint, genomic mutation, drug sensitivity using R packages, including GSVA, clusterProfiler, TIMER, CIBERSORT, CIBERSORT-ABS, quanTIseq, MCPcounter, xCell, EPIC, GISTIC, and pRRophetic algorithms. The top ten OS-related factors for KIRP patients were annotated. Patients with KIRP were divided into MOCS1, MOCS2, and MOCS3. Patients in the MOCS3 subtype were observed with shorter overall survival time than patients in the MOCS1 and MOCS2 subtypes. MOCS1 was negatively correlated with immune-related pathways, and we found global dysfunction of cancer-related pathways among the three MOCS subtypes. We evaluated the activity profiles of regulons among the three MOCSs. Most of the metabolism-related pathways were activated in MOCS2. Several immune microenvironmental cells were highly infiltrated in specific MOCS subtype. MOCS3 showed a significantly lower tumor mutation burden. The CNV occurrence frequency was higher in MOCS1. As for treatment, we found that these MOCSs were sensitive to different drugs and treatments. We also analyzed single-cell data for KIRP. Based on a variety of algorithms, this study determined the risk classifier based on multi-omics data, which could guide the risk stratification and medication selection of patients with KIRP.

New proteins in the differentiation of papillary renal cell carcinoma from clear cell renal cell carcinomas; Importance of DARS2, Reelin and Enkurin

Purpose: The purpose of the present study was to examine the roles of new proteins DARS2, Reelin, and Encurin in the differentiation of Clear-Cell Renal Cell Carcinoma (RCC) and Papillary Renal Cell Carcinoma (RCC). Clear-cell RCC is the most common malignancy of the kidney, and papillary RCC is the second most common malignant malignancy in this respect. They are neoplasms and show similarity to each other, both histologically and morphologically, in some cases. Differential diagnosis is important because treatment approaches and prognoses are different. Although careful histopathological examination and specific immunohistochemical markers are important for diagnosis, there are no specific antibodies that can be used reliably and the search for biomarkers continues in this regard.
 Materials and Methods: A total of 30 Clear-Cell RCC and 30 Papillary RCC cases were included in the present study. Patients were identified retrospectively by reviewing the hospital database and pathological reports. Pathological data were obtained from hospital medical archives and pathology reports.
 Results: It was found that DARS2, Reelin, and Encurin proteins were significantly higher in papillary RCC when compared to clear-cell RCC.
 Conclusion: It was concluded that DARS2, Reelin, and Encurin proteins may be potential biomarkers for the differentiation of Papillary RCC and Clear-Cell RCC.

Bioinformatics analysis reveals the potential role of matrix metalloproteinases in immunity and urolithiasis.

The pathogenesis of urolithiasis remains unclear, making the development of medications for treatment and prevention stagnant. Randall's plaques (RPs) begin as interstitial calcium phosphate crystal deposits, grow outward and breach the renal papillary surface, acting as attachment for CaOx stones. Since matrix metalloproteinases (MMPs) can degrade all components of extracellular matrix (ECM), they might participate in the breach of RPs. Besides, MMPs can modulate the immune response and inflammation, which were confirmed to be involved in urolithiasis. We aimed to investigate the role of MMPs in the development of RPs and stone formation. The public dataset GSE73680 was mined to identify differentially expressed MMPs (DEMMPs) between normal tissues and RPs. WGCNA and three machine learning algorithms were performed to screen the hub DEMMPs. In vitro experiments were conducted for validation. Afterwards, RPs samples were classified into clusters based on the hub DEMMPs expression. Differentially expressed genes (DEGs) between clusters were identified and functional enrichment analysis and GSEA were applied to explore the biological role of DEGs. Moreover, the immune infiltration levels between clusters were evaluated by CIBERSORT and ssGSEA. Five DEMMPs, including MMP1, MMP3, MMP9, MMP10, and MMP12, were identified between normal tissues and RPs, and all of them were elevated in RPs. Based on WGCNA and three machine learning algorithms, all of five DEMMPs were regarded as hub DEMMPs. In vitro validation found the expression of hub DEMMPs also increased in renal tubular epithelial cells under lithogenic environment. RPs samples were divided into two clusters and cluster A exhibited higher expression of hub DEMMPs compared to cluster B. Functional enrichment analysis and GSEA found DEGs were enriched in immune-related functions and pathways. Moreover, increased infiltration of M1 macrophages and enhanced levels of inflammation were observed in cluster A by immune infiltration analysis. We assumed that MMPs might participate in RPs and stone formation through ECM degradation and macrophages-mediated immune response and inflammation. Our findings offer a novel perspective on the role of MMPs in immunity and urolithiasis for the first time, and provide potential biomarkers to develop targets for treatment and prevention.

Predicting IHC staining classes of NF1 using features in the hematoxylin channel

Immunohistochemistry (IHC) highlights specific cell types in tissues and traditionally involves antibody staining together with a hematoxylin counterstain. The intensity and pattern of hematoxylin staining differs between cell types and reveals morphological characteristics of cells. Here, we propose that features in the hematoxylin stain can be used to predict IHC labels, such as Neurofibromin (encoded by the gene NF1). The dataset consists of 7.2 million cells from benign and kidney cancer cores in a tissue microarray. Morphology and hematoxylin (H&M) features defined within QuPath are subjected to a clustering analysis in CytoMap. H&M features are also used to train 4 different XGBoost models to predict high, low, and negative NF1 stain classes in benign renal tubules, clear cell (ccRCC), papillary (PRCC), and chromophobe (ChRCC) renal carcinoma. The prediction accuracies of NF1 staining classes in benign, ccRCC, ChRCC, and PRCC range between 70% and 90% with areas under the precision recall curve PRAUCNF1-high = 0.82+0.12, PRAUCNF1-low = 0.62+0.25, and PRAUCNF1-negative = 0.83+0.16. The most important feature for predicting the NF1 class involves the minimum cellular hematoxylin staining intensity. Together, these results demonstrate the feasibility to predict NF1 expression solely from features in hematoxylin staining using open source software. Since the hematoxylin features can be obtained from regular H&E and IHC slides, the proposed workflow has broad applicability.