OBJECTIVE:Tertiary lymphoid tissue (TLT) has been described as germinal center-like lymphoid structures composed of a dendritic network, mixed lymphocytes, and high endothelial venules in internal organs. A recent study indicates that TLT can be seen in up to 19% of protocol renal transplant biopsies. We hypothesize that CD21 staining can identify dendritic cells in TLT so that borderline changes are not overdiagnosed. METHODS:CD21 immunostaining was initially used for identifying TLT in multiple internal organs as a quality control. Subsequently, 34 transplant renal biopsies (TRB) with borderline changes were reviewed and stained for CD21 to reveal the incidence of overdiagnosed borderline changes in our database. The second study was to further explore the presence of CD21 immunostaining in a set of 10 renal transplant biopsies from patients with serum donor-derived cell-free DNA (ddcfDNA). RESULTS:Routine hematoxylin and eosin (H.E.) staining showed TLT with isolated germinal center-like structures and smooth-rounded borders. CD21 staining highlighted wavy dendritic cells forming a lacy-like network within TLT in quality control cases. Of 34 TRB with borderline changes, five cases were retrospectively found to have TLT on routine sections and CD21 staining highlighted the dendritic cell network, thus confirming the presence of TLT in the biopsies, indicating an incidence of overdiagnosed borderline changes at 14.7% (5/34). The true borderline changes showed infiltrative lymphocytes (< 25%) with mild tubulitis, in the absence of TLT. In the second study, only one case (1/10) showed positive CD21 staining, confirming the presence of TLT, but ruling out borderline changes. CONCLUSIONS:TLT represents reactive changes that should not be considered as cellular rejection or borderline changes. Immunohistochemical staining of CD21 is a more reliable method than morphology to confirm TLT, thus helping to rule out TLT in uncertain aggregates of lymphocytes in TRB.

BACKGROUND:C3 glomerulopathy (C3G) is a rare type of glomerular disease characterized by predominant deposits of C3 complement. Although dominant C3 immunofluorescent (IF) staining has become well known as a diagnostic criterion, the findings of electron microscopy (EM) are not well specified. The goal of this study was to scrutinize the characteristic features of C3 deposits on EM and to correlate with C3 IF staining patterns. METHODS:We examined the EM images of a cohort of 24 cases of C3G (22 C3 dominant glomerulonephritis [C3GN] and 2 dense deposit disease [DDD]) to determine their characteristic features when compared to a cohort of patients with immune complex-mediated glomerulonephritis. RESULTS:In our patients with C3G, the C3 deposits were present in all three glomerular compartments (mesangial, subendothelial, and subepithelial spaces) and they had the following features: (1) Smear pattern of C3 deposits along glomerular basement membranes (GBM) and subepithelial spaces; (2) C3 deposits were mostly lighter in gray colors as opposed to the dark black appearance of immune complex deposits (ICD); (3) C3 aggregates revealed smooth contours with a homogeneous fine granular appearance when compared to the humpy and bumpy appearance of ICD, and (4) C3 deposits rarely showed either retraction artifacts around the deposits or vacuolization within the GBM or mesangial areas. CONCLUSIONS:In our cohort, C3 deposits exhibit reproducible EM features that are well correlated with clinical data and dominant C3 staining by IF and are different from ICD upon securitized review.

Paired box 8 (PAX8) and Wilms' tumor 1 (WT1) of cap mesenchyme play important roles in tubular epithelial transition and podocyte maturation of the kidney. Parietal epithelial cells (PEC) progenitors demonstrate activity of these two factors in mature glomeruli. PECs can be activated into spindle cell crescents in crescentic glomerulonephritis (CreGN) or into podocyte hyperplasia in collapsing glomerulopathy (ColGN) based on histologic evidence. The study aimed to use PAX8 and WT1 stains to demonstrate the two transitional processes of mesonephros/metanephros and aberrant in CreGN, and ColGN. Immunohistochemical (IHC) stains for both PAX8 and WT1 were performed in fetal mesonephros/metanephros, adult negative controls, CreGN, and ColGN. Expressive patterns of PAX8 and WT1 in mesonephros/early fetal kidneys, adult kidneys, and aberrant glomerular changes were evaluated. PAX8 showed continuous nuclear expression in the parietal epithelium of mesonephros/metanephros, adult kidneys, & primordial podocytes, and consistent positivity in all renal tubules. WT1 showed strong nuclear and cytoplasmic expression within mature podocytes at all stages, despite some staining of WT1 in parietal epithelium. Cellular crescents and hyperplastic podocytes were strongly positive for PAX8, and only weakly positive in the nuclei of WT1. Our data support that PAX8+ PEC involve in mesenchymal-epithelial transition (MET) in renal tubules, a possible induction of early podocyte development, and aberrant epithelial proliferation of CreGN and ColGN. In addition, WT1 is fully devoted to podocyte maturation and is also partially involved in the aberrant epithelial proliferation of the two glomerular diseases.

OBJECTIVE:Immuno-checkpoint inhibitors (CPIs) such as PD-1/PD-L1 inhibitors have shown positive effects in treating various metastatic carcinomas but can cause complications like kidney dysfunction. This study aimed to determine if T lymphocytes were the dominant inflammatory cells in CPI-associated acute interstitial nephritis (AIN), graded using a modified Banff criteria for renal transplant cellular rejection. METHODS:20 renal biopsies from 18 patients with acute kidney injury following CPI treatment for metastatic carcinomas were evaluated. Infiltrating lymphocytes were stained for CD3 (T lymphocytes) and CD20 (B lymphocytes). AIN was graded using a modified Banff criteria for borderline changes and acute cellular rejection (ACR). RESULTS:In 14 biopsies, typical AIN was dominated by CD3-positive T lymphocytes and a small percentage of B lymphocytes, with minimal eosinophils or plasma cells. There were one grade 3 AIN, four grade 2 AIN, and nine grade 1 AIN cases. Six biopsies without AIN showed either chronic thrombotic microangiopathy (TMA, n=1) or acute tubular injury (ATN, n=5). Following renal biopsies diagnosing AIN, nine out of 14 patients (64.3 %) experienced clinical improvement with steroid treatment. CONCLUSION:This study indicates that nephrotoxicity due to CPI treatment is characterized by T lymphocyte-mediated AIN, with the majority being grade 1 AIN according to the modified Banff criteria. Most patients showed some renal functional recovery in response to steroid treatment.

Kidney Injury Molecule-1 (KIM-1) has emerged as a significant biomarker and mechanistic player in kidney pathology, particularly in acute kidney injury (AKI). Normally absent in healthy kidney proximal tubules, KIM-1 becomes upregulated specifically along the proximal tubule cells' surface in response to acute injury, reflecting the differential vulnerability of convoluted versus straight proximal tubules. Functionally, KIM-1 aids proximal tubules in clearing apoptotic cells and moderating inflammatory responses, thereby helping to prevent excessive immune activation during the early stages of injury. Clinically, KIM-1 is a sensitive, non-invasive biomarker for detecting proximal tubular injury, allowing for assessment in urine, plasma samples, and tissue biopsies in AKI. However, if tubular injury persists without repair, prolonged KIM-1 expression can drive chronic inflammatory responses and interstitial fibrosis, leading to chronic kidney disease (CKD). In addition, KIM-1's role may extend further into promoting tubular dedifferentiation, potentially contributing to renal cell carcinoma under certain conditions. Over the past two decades, KIM-1 research has reshaped our understanding of kidney pathophysiology and immunology, spanning acute injury responses to chronic disease progression. This review aims to provide an updated synthesis of recent findings, highlighting KIM-1's role across the spectrum of renal injury and repair.

In TFE3 translocation renal cell carcinoma (RCC), rearrangements involving the TFE3 gene can lead to overexpression of the TFE3 transcription factor. This upregulation increases lysosomal activity and autophagy, which in turn contributes to tumor cell proliferation. Although TFE3 translocation RCC is one of the more extensively studied RCC subtypes, other genetic abnormalities, such as gene copy number alterations, may also play a role in disease development. Accordingly, this study aimed to more precisely categorize TFE3-altered RCC variants using fluorescence in situ hybridization (FISH), while also evaluating their histopathological characteristics and clinical behavior. In this retrospective study spanning the past 9 years, 16 cases of renal cell carcinoma (RCC) were examined for TFE3 gene alterations using FISH. The cohort was divided into two groups: TFE3-altered RCC cases as the positive group (n = 6) and TFE3-negative RCC cases as the negative group (n = 10). TFE3 alterations, tumor pathology, and clinical outcomes were systematically evaluated. The age of patients with TFE3-altered RCC ranged from 6 to 70 years old. There were five female patients and one male patient, which is consistent with the known female predominance of this RCC subtype. The TFE3 alterations observed in this cohort included: TFE3 gene rearrangement (n = 1), TFE3 gene rearrangement with copy number gain (n = 1), copy number gain of intact TFE3 gene (n = 3), and copy number loss of TFE3 gene (n = 1). Clinical outcomes varied, with some patients experiencing poor prognoses, including the development of distant metastases. Our data show that TFE3 alterations in RCC span a range of genetic events, from gene rearrangements to copy number variations, as determined by FISH. These TFE3-altered RCCs in adults may be associated with unfavorable outcomes, underscoring the value of FISH in both diagnosing and refining our understanding of TFE3-altered RCC.

Abstract Introduction/Objective SALL4 has been used to diagnose primary and metastatic germ cell tumors (GCT). However, it is not well established if SALL4 represents an evolving biomarker for GCT during the metastatic processes. Methods/Case Report We studied the fetal expression of SALL4 and a small series of metastatic GCT by comparing SALL4 expression (in all levels of GCT) with OCT3/4 expression (mainly in the early chain of germ cell tumors such as seminoma and embryonal carcinoma). Results (if a Case Study enter NA) First, we found SALL4 expression in Wolffian ducts and their surrounding stromal cells of 4 early embryos (5-7 weeks of gestation), implying that SALL4 may be involved in the early genital structure development. Then we identified 6 cases with metastatic GCT and compared SALL4 with OCT3/4 stains. The original tumors were all positive for both OCT3/4 and SALL4, but 4 out of 6 subsequently metastatic GCT stained positive only for SALL4 but not for OCT3/4. Particularly in case 5, the first two biopsies for metastatic GCT were positive for both biomarkers, but the last metastatic GCT to the gallbladders was positive only for SALL4. Conclusion Our pilot study raises the possibility that metastatic GCT may represent some evolving process to epithelial differentiated neoplasms (via somatic transformation) namely yolk sac tumor and teratoma along the germ cell differentiation chain. Therefore, SALL4 staining becomes a necessary step to avoid the pitfall of misdiagnosing unusual metastatic tumors with a known and unknown history of GCT particularly in male patients.

Abstract Introduction/Objective Monoclonal membranous glomerulopathy (M-MGN) is a rare entity; only two reports are available in the literature. Monoclonal membranous glomerulopathy has been called either monoclonal immunoglobulin deposition disease associated with membranous features in a 3-patient small series report or membranous glomerulopathy with light chain restriction in another larger series with 28 cases. We report M-MGN in a patient with positive serology lupus. Methods/Case Report The patient was a 74-year-old man with hypertension and nephrotic range proteinuria (protein/creatinine ratio at 8.5). His serum creatinine remained normal at 0.6 mg/dL. The patient was positive for double-stranded DNA and ANA at low titer, but had reduced complement C3 and C4. Immunofixation was negative for monoclonal protein. The light microscopy of the renal biopsy revealed thickened loops of glomeruli with mild interstitial nephritis. Immunofluorescent studies showed a positive linear/granular pattern of IgG and lambda but negative kappa staining along the glomerular loops. Electron microscopy revealed smooth contoured stage 2 subepithelial deposits. An outside consultation confirmed our diagnosis and found IgG2 restriction in glomeruli. Electrophoresis revealed no monoclonal protein in the serum. Results (if a Case Study enter NA) NA Conclusion Our patient demonstrated M-MGN with mild interstitial nephritis; the latter may be related to his lupus status. As 30% of patients with M-MGN have either monoclonal serology or B-cell lymphoproliferative disorders, with most having a restricted IgG subtyping, a close follow-up and even chemotherapy for a B-cell clone should be considered.

ContextIgM-dominant immune complex-mediated glomerulonephritis (IgM-dominant ICMGN) is a rare renal entity, characterized by a membranoproliferative pattern by light microscopy, dominant IgM staining by immunofluorescent staining, and subendothelial deposits by electron microscopy. This study was to investigate if some of IgM-ICMGN were associated with autoimmune disorders induced by hydralazine.DesignSeven IgM-dominant ICMGN cases were identified over 8 years. Their pathologic phenotypes and clinical scenarios were analyzed in detail.ResultsPatients' ages ranged from 47 to 87 years old with 5 women and two men. Six of seven patients had drug-induced autoimmune phenomenon (hydralazine-induced positive ANCA and ANA). All of them had renal dysfunction and some proteinuria. Most pathologic features showed a membranoproliferative pattern of glomerulonephritis with dominant IgM deposits at subendothelial spaces. IgM nephropathy (a variant of focal segmental glomerulosclerosis), chronic thrombotic microangiopathy, and cryoglobulinemic glomerulopathy were ruled out in the cases.ConclusionThe hydralazine-induced autoimmune phenomenon can be seen in IgM-dominant ICMGN, which should be classified as a subtype of membranoproliferative glomerulonephritis.

Context.— Monoclonal gammopathy of renal significance (MGRS) is a relatively new concept for patients with renal monoclonal protein deposition (RMPD) (except monoclonal cast nephropathy) and has been used as a reason for nephrologists to obtain a bone marrow biopsy (BMB). It takes a team of pathologists and clinicians to determine when RMPD at our institution can be defined as MGRS. Objective.— To identify the proportion of various subtypes of tentative MGRS diagnosed by renal biopsy that can be confirmed as final MGRS after BMB. Design.— One hundred thirty kidney biopsies with variants of RMPD were identified during the past 10 years. Biopsy cases with known myeloma, B-cell lymphoma, or monoclonal cast nephropathy were separated as a heavy-burden group. The remaining biopsies with RMPD were considered tentative MGRS. Their BMB and clinical indices were further analyzed to determine the final percentage of MGRS diagnoses. Results.— Among the 130 renal paraprotein deposition cases, 44 (33.8%) were categorized as the heavy-burden group. In the remaining 86 cases, 33 (38.4%) with subsequent identification of myeloma (>10% of monoclonal plasma cells) or lymphoma in BMB were further considered as heavy-burden cases. Eighteen cases (18 of 86; 20.9%) did not receive follow-up BMB; thus, no further analysis was performed. BMBs diagnosed as either nonmalignant (no plasma cells; 8 of 86 cases; 9.3%) or premalignant (<10% plasma cells; 27 of 86 cases; 31.4%) were confirmed to be final MGRS (35 of 86; 40.7%). Conclusions.— The data indicate that BMB is an important element in the confirmation of MGRS.

Abstract Introduction/Objective Nephroblastoma/Wilms tumor is a common renal tumor primarily observed in children, and its occurrence in adults is exceedingly rare. This rarity contributes to the diagnostic challenges encountered in adults. Here, we present a case of a 32-year-old male diagnosed with biphasic nephroblastoma/Wilms tumor in the kidney, with liver and lung metastases. Methods/Case Report A 32-year-old male, without significant past medical history, presented with the chief complaint of abdominal pain for 2-3 weeks. Imaging studies revealed a substantial 17.5 cm kidney lesion accompanied by numerous lung and liver lesions. A liver biopsy indicated a small blue cell tumor, morphologically and immunophenotypically, (positive WT1) resembling nephroblastoma, with a strong suspicion of metastasis. Subsequent kidney biopsy confirmed a small blue cell malignant tumor demonstrating biphasic features, including blastema and epithelial components forming tubular structures similar to the liver biopsy, predominantly showing the blastemal component. The renal tumor biopsy supported the diagnosis of nephroblastoma. Despite chemotherapy, the patient passed away two months after the initial liver tumor biopsy. Results (if a Case Study enter NA) NA Conclusion Diagnosing nephroblastoma in adults poses significant challenges, particularly when initial presentations involve metastases. The occurrence of pediatric tumors in adulthood, though rare, should be considered in the diagnostic process after exhausting other possibilities. It is also important to note that the clinical presentation of pediatric tumors in adults may deviate from typical patterns. While Wilm’s tumor commonly presents as a painless, palpable abdominal mass in pediatric cases, adults may exhibit abdominal pain as the predominant symptom, as present in our case.

Abstract Introduction/Objective Hemangioblastomas are indolent brain tumors consisting histologically of atypical stromal cells and a large number of blood vessels lined by endothelial cells. The tumors are often associated with either von Hippel- Lindau (VHL) syndrome or sporadic mutation of VHL genes. As CA9 is a marker of the hypoxic inducible factor-alpha1 cascade, its overexpression has been well known to present in clear cell renal cell carcinoma that involves the mutation of VHL gene. A few studies demonstrate overexpression of CA9 in hemangioblastomas, but not in other primary brain tumors such as gliomas and meningioma. Our two cases were used to determine if positive CA9 and negative PAX8 immuno-stains were useful markers to support the diagnosis of hemangioblastomas. Methods/Case Report One patient was a 50-year-old man and the other patient was a 75-year-old man. Two lesions were identified in the cerebellum with typical appearance of vascular channels intermingled with atypical stromal cells showing clear cell cytoplasm. The endothelial cells were positive for CD34 and ERG. The stromal cells were weakly positive for inhibin but negative for the endothelial markers GFAP, pancytokeratin and PAX8, ruling out primary glioma and metastatic clear cell renal carcinoma. The atypical stromal cells with clear cytoplasm in both tumors, however, showed strong and diffuse membranous staining for CA9 (3+). The overall findings supported the morphologic diagnosis of hemangioblastomas in both patients. Results (if a Case Study enter NA) NA Conclusion Our preliminary data indicates that positive CA9 and negative PAX8 stains are a useful pair of markers to support a diagnosis of hemangioblastoma and differentiate them from metastatic clear cell renal cell carcinoma. Additionally, CA9 can help confirm the diagnosis of hemangioblastoma when inhibin is weak or nearly negative.

Adult polycystic kidney disease (APKD) is a genetic disorder leading to premature renal dysfunction and failure. The prevalence of malignant renal tumors occurring in the APKD setting has been rarely reported. OBJECTIVE:To better characterize malignant renal tumors in nephrectomy specimens of APKD and apply modern pathologic evaluation. METHODS:We reviewed our database of APKD specimens over the past 11 years (from 2012 to 2023) for primary malignant tumors within the kidneys of APKD. RESULTS:Of 48 nephrectomy specimens with APKD evaluated, 10 malignant renal tumors were identified, indicating a prevalence of 20.8 % (10/48). These included three clear cell (cc) renal cell carcinomas (RCC) (ranging from 1 mm to 6.7 cm), three papillary RCCs (2.5, 3.5, and 14 cm with lymph node metastasis), two cases of clear cell papillary (CCP) RCC, one acquired cystic disease (ACD) with associated RCC (4 mm), and one urothelial adenocarcinoma. The urothelial adenocarcinoma was found near a tubulovillous adenoma in a collecting duct and stained positively for GATA3 and Uroplakin-2 but was negative for PAX8 & CDX2. The tumor showed extensive invasion into perirenal fatty tissue and the rectum. Next generating sequencing (NGS) analysis of the tumor showed mutations in TERT, RB1, TP53, ERBB2, and TET1 genes, further supporting its urothelial origin. CONCLUSIONS:We found a prevalence of 20.8%, which was higher than in previous reports of malignant renal tumors in patients who underwent resections for APKD. Renal tumors were mostly from damaged proximal tubular origins (clear cell or papillary RCC), but less commonly were from distal tubular or urothelial cells as well (clear cell papillary RCC and urothelial adenocarcinoma).

Crop growth and development can be impeded by salt stress, leading to a significant decline in crop yield and quality. This investigation performed a comparative analysis of the physiological responses of two maize inbred lines, namely L318 (CML115) and L323 (GEMS58), under salt-stress conditions. The results elucidated that CML115 exhibited higher salt tolerance compared with GEMS58. Transcriptome analysis of the root system revealed that DEGs shared by the two inbred lines were significantly enriched in the MAPK signaling pathway-plant and plant hormone signal transduction, which wield an instrumental role in orchestrating the maize response to salt-induced stress. Furthermore, the DEGs' exclusivity to salt-tolerant genotypes was associated with sugar metabolism pathways, and these unique DEGs may account for the disparities in salt tolerance between the two genotypes. Meanwhile, we investigated the dynamic global transcriptome in the root systems of seedlings at five time points after salt treatment and compared transcriptome data from different genotypes to examine the similarities and differences in salt tolerance mechanisms of different germplasms.

Objective. Various renal cell carcinomas (RCC) are derived from different segments of the renal tubular origin, which determines their morphological and immunohistochemical phenotype and their molecular signaling pathway as a therapeutic target. Most of these tumors utilize the mammalian target of rapamycin (mTOR) pathway to activate pathways involving metabolic and nutritional supplies. Methods. Overexpressed mTOR signals are reported in more than 90% of the most common types of RCC. Many new renal tumor entities have been reported in recent years. Results. Among them, somatic mutations in tuberous sclerosis complex (TSC) result in loss of its normal inhibitory control over mTOR, thus promoting mTOR-associated proliferative activities in several new renal neoplastic entities including RCC with fibromyomatous stroma (RCCFMS), eosinophilic vacuolated tumor, eosinophilic solid & cystic RCC, and low-grade oncocytic tumor. Conclusions. This short review provides a comprehensive correlation of tumor morphology and immunohistochemical phenotype with renal tubular differentiation and their shared mTOR. These essential pieces of knowledge are vital in the diagnosis and clinical management of renal cell neoplasms.

Paneth cell-like granules (PCLG) in clear cell renal cell carcinomas (RCC) have previously been reported but were not found to express neuroendocrine markers. This study was to investigate if the eosinophilic granules (so called PCLG) were enlarged lysosomes. A retrospective review of 72 different renal tumors was conducted which included 42 clear cell RCC, 16 papillary RCC, 6 chromophobe RCC, 5 clear cell papillary RCC, 2 urothelial carcinomas and 1 unclassified RCC. All tumors were evaluated for the eosinophilic granules on hematoxylin and eosin-stained sections. In addition, PAS-D staining, immunohistochemical stains, and electron microscopy were performed. The eosinophilic granules were found in 19