Search

Merkel cell carcinoma (MCC) is an aggressive, highly metastatic, cutaneous neuroendocrine malignancy with poor prognosis. Here, we describe a MCC excision specimen with a rare case of tumor-associated amyloid deposition in the absence of residual tumor cells. A 72-year-old man presented with a lesion of 5-6 months' duration on his left elbow, clinically thought to be a ganglion cyst. The biopsy specimen revealed a Stage IIA MCC with classic histomorphologic and immunophenotypic findings, with tumor extending to the tissue edges. The patient underwent wide local excision with negative margins and a negative sentinel lymph node biopsy. Although the patient did not receive any presurgical chemotherapy, immunotherapy, or targeted therapy, the re-excision specimen showed only amphophilic, feathery deposits that were salmon-pink with Congo red stain and further confirmed as amyloid by electron microscopy; there were no residual carcinoma cells. Amyloid deposition in MCC has been described in rare case reports. Our case was extraordinary in that there was only amyloid deposition and an associated granulomatous reaction, without identifiable MCC cells. This case demonstrates that amyloid deposition may be evidence of a prior MCC at the site of a prior procedure and may warrant careful evaluation for residual MCC.

Nephrotoxicity is a rather frequent side effect of vancomycin treatment. Attributes of vancomycin nephrotoxicity (VN) are well documented, including its clinical manifestations and renal morphologic changes. However, VN has not been emphasized as the cause of acute kidney injury (AKI) in the renal transplant setting. We report the first 3 such cases. In each of these cases, AKI developed concurrently with vancomycin treatment and resolved after its cessation. As compared with the general population, VN in the renal transplant setting displayed some unusual clinical behaviors. Its development was rather capricious, being noted in some but not every episode of vancomycin treatment, even in the same individual. AKI developed gradually in conjunction with protracted vancomycin treatment, in contrast to a precipitous course in the nontransplant setting. However, renal transplant biopsies showed typical features of VN in each case. VN is an unusual but now well-documented cause of AKI in renal transplant recipients. VN in this setting may display some atypical features, setting it apart from that in the general population. However, renal transplant biopsy changes are characteristic and are amenable to a definitive diagnosis.

Background: Systemic lupus erythematosus (SLE) represents a principal prototype of a multisystemic autoimmune disease with the participation of both cell- and antibody-mediated mechanisms causing significant renal impairment. A renal biopsy diagnosis is the gold standard for clinical renal disease in SLE, which includes a broad range of indications. Summary: Renal disease in SLE can involve glomerular, tubulointerstitial, and/or vascular compartments, none of which are mutually exclusive. In most instances, the basic pathogenetic mechanism involves tissue deposition of immune complexes and/or cell-mediated mechanisms, identified by light microscopy, immunohistochemical methods, and electron microscopy (EM), evoking intraglomerular proliferative, inflammatory, and other tissue responses. These produce a spectrum of histologic lesions, depending on the participation of a wide range of clinical triggers, namely, genetic, serological, and immunological factors, correlating with their underlying pathogenetic potential. In addition to light and immunofluorescence microscopy, EM in this setting facilitates an accurate diagnosis, assesses disease activity, delineates subclasses, differentiates from primary forms of non-lupus renal lesions, identifies organized deposits, and rarely, identifies other forms of nonimmune complex lesions such as podocytopathies, amyloidosis, and thrombotic microangiopathy. Key Messages: EM findings that are distinctive for most of the renal lesions in SLE include immune complex and nonimmune complex diseases as well as overlapping entities. Routine ultrastructural examination not only provides significant diagnostic and prognostic information from both initial and repeat renal biopsies from lupus patients but also contributes toward the understanding of the underlying pathophysiology of the disease process.

Introduction Vancomycin nephrotoxicity is frequent and may be due to drug-induced acute tubular necrosis (ATN) or tubulointerstitial nephritis (TIN). Vancomycin-associated tubular cast (VTC) was recently described and may represent a novel cause of vancomycin nephrotoxicity. However, much is still unknown about VTC. Materials and Methods Thirty-seven kidney biopsy specimens from patients who were treated with vancomycin and developed acute kidney injury (AKI) were found among a total of 4673 biopsy samples between 2010 and 2019. These biopsy specimens were subjected to light microscopy, immunofluorescence, electron microscopy, and immunolocalization for vancomycin, uromodulin, myoglobin, tubular segment–specific markers, and examined for VTCs. The findings were correlated with the clinical course. Results VTCs displayed precipitated vancomycin casts in a background of uromodulin; the casts were limited to the distal tubules, and always associated with a background of more diffuse renal injury (ATN or TIN). The diagnosis of vancomycin nephrotoxicity was made in in 28 of 37 patients. VTC was noted in 25 of 28 biopsy samples from patients diagnosed with vancomycin nephrotoxicity and in one of nine biopsy samples from patients without this diagnosis. Vancomycin nephrotoxicity was diagnosed in 25 of 26 patients whose biopsy specimens showed VTC, but in only 3 of 11 patients without VTC in the biopsy samples. Conclusions VTC displays a characteristic morphologic profile amenable to ready recognition in biopsy specimens. It results from coprecipitation of vancomycin and uromodulin. It facilitates the biopsy diagnosis of vancomycin nephrotoxicity. It may have a nephrotoxic effect superimposing on and independent from the ATN or interstitial nephritis in the pathogenesis of vancomycin nephrotoxicity., Graphical abstract

Introduction Incidental IgA deposits in donor kidneys have unknown sequelae and may predate clinical kidney disease if primed by adverse immunologic or hemodynamic stimuli or may remain dormant. Methods The presence of incidental IgA in post-implantation (T0) biopsies from living (LDK) and deceased donor (DDK) kidneys, and its relationship to post-transplant patient and graft outcomes was investigated in an ethnically diverse US population at a large transplant center. Results Mesangial IgA was present in 20.4% of 802 T0 biopsies; 13.2% and 24.5% of LDK and DDK, respectively. Donors with incidental IgA deposits were more likely to have hypertension and be of Hispanic or Asian origin. Intensity of IgA staining was 1+ (57.3%), 2+ (26.8%), or 3+ (15.8%) of the T0 IgA+ biopsies. Mesangial pathology correlated with higher-intensity IgA staining with less clearance on follow-up (53.8%) versus 79.2% without mesangial pathology. IgA cleared in 91%, 63%, and 40% of follow-up biopsies with 1+, 2+, and 3+ IgA staining, respectively. Early post-transplant rejection and rejection-related graft loss occurred more frequently in IgA+ kidney recipients; however, 5-year kidney function and graft survival were comparable to kidneys without IgA. Conclusion This first and largest report of incidental IgA in T0 biopsies of LDK and DDK in a US ethnically diverse population demonstrated no adverse association between the presence of IgA in donor kidneys and graft or patient survival. Whether IgA in donor kidneys represents latent IgA nephropathy (IgAN) is uncertain; nevertheless, living donors who demonstrate IgA on T0 biopsy deserve careful follow-up., Graphical abstract

Renal cell carcinoma (RCC) occurring in the setting of end-stage renal disease (ESRD) shows unique clinicopathological characteristics. The two most frequent types of ESRD-associated RCC are acquired cystic kidney disease-associated renal cell carcinoma (ACKD-RCC) and clear-cell papillary renal cell carcinoma (ccpRCC). Other types of RCC also occur in ESRD, albeit with different frequencies from the non-ESRD general population. The histological features of RCC do not vary in the setting of ESRD vs. non-ESRD, yet other findings, such as multifocality and multiple tumor types, are more frequent in ESRD. Studies have generated novel and important knowledge of the etiology, epidemiology, diagnosis, treatment, immunophenotype, and molecular characteristics of ESRD-associated RCC. Knowledge of these data is important for both pathologists and other physicians who may encounter ESRD patients with RCC. This review presents a comprehensive summary and update of the literature on RCC in ESRD, with a focus on the two most frequent types, ACKD-RCC and ccpRCC.

Since activated macrophages express a functional folate receptor β (FRβ), targeting this macrophage population with folate-linked drugs could increase selectivity to treat inflammatory diseases. Using a macrophage-mediated anti-glomerular basement membrane (anti-GBM) glomerulonephritis (GN) in WKY rats, we investigated the effect of a novel folic acid-aminopterin (AMT) conjugate (EC2319) designed to intracellularly deliver AMT via the FR. We found that treatment with EC2319 significantly attenuated kidney injury and preserved renal function. Kidney protection with EC2319 was blocked by a folate competitor, indicating that its mechanism of action was specifically FRβ-mediated. Notably, treatment with methotrexate (MTX), another folic acid antagonist related to AMT, did not protect from kidney damage. EC2319 reduced glomerular and interstitial macrophage infiltration and decreased M1 macrophage recruitment but not M2 macrophages. The expression of CCL2 and the pro-fibrotic cytokine TGF-β were also reduced in nephritic glomeruli with EC2319 treatment. In EC2319-treated rats, there was a significant decrease in the deposition of collagens. In nephritic kidneys, FRβ was expressed on periglomerular macrophages and macrophages present in the crescents, but its expression was not observed in normal kidneys. These data indicate that selectively targeting the activated macrophage population could represent a novel means for treating anti-GBM GN and other acute crescentic glomerulonephritis.

We herein report a 46-year-old man with diabetes who developed acute kidney injury and oliguria after receiving vancomycin to treat his foot infection. Renal biopsy revealed typical features of advanced diabetic nephropathy as well as features of acute vancomycin nephrotoxicity. Several changes typical for acute vancomycin nephrotoxicity, but hitherto not adequately described, were seen. There was an element of acute tubulointerstitial injury associated with frequent tubular casts consisting of typical hyaline casts, pale glassy material suggestive of uromodulin, and distinctive features suggestive of vancomycin deposition. Coprecipitation of vancomycin and uromodulin was confirmed by immunostain. Electron microscopic study showed features supportive for the diagnosis of diabetic nephropathy and distinctive concentric appearance of vancomycin tubular casts within the fibrillary background of uromodulin. The patient’s renal function improved rapidly after cessation of vancomycin and initiation of steroid therapy, suggesting that vancomycin-associated tubular injury is potentially reversible over time with proper management.

Lupus nephritis is a common manifestation of systemic lupus erythematosus (SLE). IgA nephropathy is a common type of primary glomerulonephritis. Renal manifestations in SLE patients are often due to lupus nephritis; however, renal diseases unrelated to lupus nephritis are rarely reported. While crescentic IgA nephropathy with rapid clinical progression is rare, its development in patients with SLE in the absence of lupus nephritis is even more unusual. A 74-year-old woman with a history of SLE without known renal involvement, chronic kidney disease stage IIIa, congestive heart failure, hypertension, and type 2 diabetes mellitus presented with acute kidney injury. Her creatinine continued to rise rapidly. Renal biopsy revealed mesangial proliferative glomerulonephritis with crescent formation. Immunofluorescent staining showed IgA and C3 mesangial deposition and absence of C4 and C1q, consistent with IgA nephropathy. She received a course of methylprednisolone and plasmapheresis. Unfortunately, her renal function continued to deteriorate, and she was started on hemodialysis which was continued after hospital discharge. This case illustrates crescentic IgA nephropathy without lupus nephritis as the cause of acute kidney injury in a patient with SLE. It highlights the observation that renal diseases other than lupus nephritis can develop in SLE patients.

Chronic kidney disease (CKD) induces the failure of arteriovenous fistulas (AVFs) and promotes the differentiation of vascular adventitial GLI1-positive mesenchymal stem cells (GMCs). However, the roles of GMCs in forming neointima in AVFs remain unknown. GMCs isolated from CKD mice showed increased potential capacity of differentiation into myofibroblast-like cells. Increased activation of expression of PDGFRA and hedgehog (HH) signaling were detected in adventitial cells of AVFs from patients with end-stage kidney disease and CKD mice. PDGFRA was translocated and accumulated in early endosome when sonic hedgehog was overexpressed. In endosome, PDGFRA-mediated activation of TGFB1/SMAD signaling promoted the differentiation of GMCs into myofibroblasts, extracellular matrix deposition, and vascular fibrosis. These responses resulted in neointima formation and AVF failure. KO of Pdgfra or inhibition of HH signaling in GMCs suppressed the differentiation of GMCs into myofibroblasts. In vivo, specific KO of Pdgfra inhibited GMC activation and vascular fibrosis, resulting in suppression of neointima formation and improvement of AVF patency despite CKD. Our findings could yield strategies for maintaining AVF functions., Hedgehog signaling regulates PDGFRA in vascular adventitial mesenchymal stem cells to promote neointima formation in arteriovenous fistula in chronic kidney disease.

Lysinuric protein intolerance (LPI) is an inborn error of cationic amino acid (arginine, lysine, ornithine) transport caused by biallelic pathogenic variants in SLC7A7, which encodes the light subunit of the y+LAT1 transporter. Treatments for the complications of LPI, including growth failure, renal disease, pulmonary alveolar proteinosis, autoimmune disorders and osteoporosis, are limited. Given the early lethality of the only published global Slc7a7 knockout mouse model, a viable animal model to investigate global SLC7A7 deficiency is needed. Hence, we generated two mouse models with global Slc7a7 deficiency (Slc7a7em1Lbu/em1Lbu; Slc7a7Lbu/Lbu and Slc7a7em1(IMPC)Bay/em1(IMPC)Bay; Slc7a7Bay/Bay) using CRISPR/Cas9 technology by introducing a deletion of exons 3 and 4. Perinatal lethality was observed in Slc7a7Lbu/Lbu and Slc7a7Bay/Bay mice on the C57BL/6 and C57BL/6NJ inbred genetic backgrounds, respectively. We noted improved survival of Slc7a7Lbu/Lbu mice on the 129 Sv/Ev × C57BL/6 F2 background, but postnatal growth failure occurred. Consistent with human LPI, these Slc7a7Lbu/Lbu mice exhibited reduced plasma and increased urinary concentrations of the cationic amino acids. Histopathological assessment revealed loss of brush border and lipid vacuolation in the renal cortex of Slc7a7Lbu/Lbu mice, which combined with aminoaciduria suggests proximal tubular dysfunction. Micro-computed tomography of L4 vertebrae and skeletal radiographs showed delayed skeletal development and suggested decreased mineralization in Slc7a7Lbu/Lbu mice, respectively. In addition to delayed skeletal development and delayed development in the kidneys, the lungs and liver were observed based on histopathological assessment. Overall, our Slc7a7Lbu/Lbu mouse model on the F2 mixed background recapitulates multiple human LPI phenotypes and may be useful for future studies of LPI pathology.

We report a colonic adenocarcinoma associated with diffuse submucosal deposition of a peculiar spheroid-type amyloid identified in the colon, terminal ileum, and appendix. A 65-year-old woman with past medical histories of hypertension, and chronic obstructive pulmonary disease, presented to the emergency room with cramping abdominal pain and nausea. A computed tomography (CT) scan of abdomen showed right colonic volvulus. Emergency right hemicolectomy was performed. The specimen showed colonic adenocarcinoma with focal submucosal invasion (pT1) arising from a villotubular adenoma. A diffuse submucosal spheroid-type amyloid deposition (resembling corpora amylacea-like structures with Liesegang ring formation) was identified in the colon, ileum, and appendix. Electron microscopy examination of this unusual spheroidal-type material further confirmed the presence of amyloid fibrils. Analysis by liquid chromatography-mass spectrometry detected AL (lambda) type amyloidosis in this specimen. Tests for monoclonal gammopathy were not performed because patient consent was not obtained. In tissue section evaluation, however, no plasma cell neoplasm was identified. Cases with isolated AL amyloid deposition in the gastrointestinal tract have been reported rarely, and there is no case report of colonic adenocarcinoma associated with primary amyloid deposition in the English literature.

Nonneoplastic renal changes are frequent in nephrectomy specimens for tumor. These changes display a wide morphologic and diagnostic range. They often carry profound clinical implications, but are often underappreciated or even ignored. The renal tissue is normal in about 10% of cases. Among the remainders, arterionephosclerosis and diabetic nephropathy account for the majority. These two diseases also account for most of the clinical significance of the nonneoplastic renal changes and their severity correlates with the renal outcome. A large number of other “medical” renal diseases are also encountered, albeit much less frequently. Their morphology is similar to that of their sporadic counterparts, and perhaps so is their clinical behavior. Large renal cell neoplasms, especially those which are centered in renal medulla or urothelial carcinoma, may be associated with changes in nonneoplastic renal parenchyma due to urine obstruction. Kidneys with end-stage renal disease (ESRD) can give rise to renal cell carcinoma directly, or through an intermediate phase characterized by cystic tubular changes aptly termed acquired cystic kidney disease (ACKD). Thus, ESRD alone or with ACKD is increasingly recognized in nephrectomy specimens for renal tumors. Renal tumors of specific histologic types can be a component of several hereditary syndromes. Several distinctive lesions can develop in the nonneoplastic renal tissue in this context. This chapter details these above changes.

Hereditary renal cell carcinomas (HRCC) comprise about 2–4% of all renal cell carcinomas (RCC). With understanding of molecular basis of RCC, 10 HRCC syndromes have been recognized. All of them exhibit an autosomal dominant inheritance pattern. More common and well-known HRCC syndromes are von Hippel–Lindau (VHL), hereditary papillary RCC, Birt–Hogg–Dube syndrome (BHD), hereditary leiomyomatosis RCC (HLRCC) syndrome, and tuberous sclerosis.

Renal cell carcinoma constitutes 90% of all kidney cancers. Familial/genetic cause accounts for 2–4% of the cases and the rest of them are sporadic. The classification of renal cell carcinoma has been expanded since the first Heidelberg classification in 1997. The recently published 2016 World Health Organization classification has revealed several renal cell carcinoma subtypes according to the molecular and morphological investigations. The complex molecular changes underlying renal cell carcinoma variants and the corresponding familial cancer syndromes still remain the subject of ongoing investigations, especially for the mechanism-based therapeutic approaches. In this section, the molecular pathways and molecular features of each renal cell carcinoma subtype and the corresponding hereditary forms are reviewed.

Deceased diabetic kidneys are increasingly utilized in transplantation. The relationship of donor's history of diabetes to clinical and histological outcomes was examined. Forty-nine diabetic deceased donor kidneys (D-DM) were transplanted into 26 normal (R-N/D-DM) and 23 diabetic recipients (R-DM/D-DM) and compared to 211 diabetic recipients of normal kidneys(R-DM/D-N) and 466 normal recipients of normal kidneys (R-N/D-N). Patient survival at 5 years was 89.7% in R-N/D-N, 96.2% in R-N/D-DM, 80.1% in R-DM/D-N, and a 71.6% in R-DM/D-DM (P = .008). Death-censored graft survival at 5 years was 86.3% in R-N/D-N, 87.4% in R-N/D-DM, 93.5% in R-DM/D-N, and 87.5% in R-DM/D-DM (P = .24). Multivariable regression analysis showed that compared to non-diabetic recipients, diabetic recipients had a 2- to 3-fold increased risk of mortality. In this cohort, there was no impact on death-censored graft survival of diabetic donor status. Only 6 of 26 post-perfusion biopsies showed evidence of diabetic nephropathy (

Renal transplantation is an ever-growing therapeutic option for patients with end-stage renal disease due to lupus nephritis. Outcomes for these patients are comparable to those of patients receiving renal transplantation for other causes. A known complication for these patients is recurrence of lupus nephritis in the renal graft (recurrent lupus nephritis [RLN]). Although disease severity at the time of recurrence is usually milder, a small number of cases have been reported to progress to allograft failure. There is a trend toward preemptive renal transplantation in patients with lupus nephritis, as more favorable outcomes have been observed with this treatment modality. While clinicians usually seek clinical remission of lupus prior to proceeding with renal transplantation, no guidelines are established regarding how often to check for serologic activity of lupus in patients with end-stage renal disease due to lupus nephritis and whether these serologic markers should be taken into account when deciding on the timing of transplantation. We present a case of early RLN co-occurring with acute cellular rejection 15 days after renal transplantation. The patient had been in clinical remission for more than 5 months prior to transplantation but had a rise in anti–double-stranded DNA antibody titers and a decrease in complement C3 level at the time of surgery. Although additional studies are needed to establish the extent to which serologic markers of lupus correlate with renal graft dysfunction, this case suggests hypocomplementemia and high double-stranded DNA antibody titers may be a risk factor for early RLN.

Phosphorylation of dynamin-related protein 1 (Drp1) represents an important regulatory mechanism for mitochondrial fission. Here, we established the role of Drp1 serine 600 (Drp1S600) phosphorylation in mitochondrial fission in vivo and assessed the functional consequences of targeted elimination of the Drp1S600 phosphorylation site in the progression of diabetic nephropathy (DN). We generated a knockin mouse in which S600 was mutated to alanine (Drp1S600A). We found that diabetic Drp1S600A mice exhibited improved biochemical and histological features of DN along with reduced mitochondrial fission and diminished mitochondrial ROS in vivo. Importantly, we observed that the effect of Drp1S600 phosphorylation on mitochondrial fission in the diabetic milieu was stimulus dependent but not cell type dependent. Mechanistically, we show that mitochondrial fission in high-glucose conditions occurs through concomitant binding of phosphorylated Drp1S600 with mitochondrial fission factor (MFF) and actin-related protein 3 (Arp3), ultimately leading to accumulation of F-actin and Drp1 on the mitochondria. Taken together, these findings establish the idea that a single phosphorylation site in Drp1 can regulate mitochondrial fission and progression of DN in vivo and highlight the stimulus-specific consequences of Drp1S600 phosphorylation in mitochondrial dynamics.

Despite the presence of many studies on the role of mechanistic target of rapamycin (mTOR) in cardiorenal tissues, the definitive role of mTOR in the pathogenesis of renal injury subsequent to ischemia-reperfusion (IR) remains unclear. The aims of the current study were to characterize the role of mTOR in normal kidney function and to investigate the role of mTOR activation in IR-induced kidney injury. In euvolemic anesthetized rats, treatment with the mTOR inhibitor rapamycin increased blood pressure (121±2 to 144±3 mmHg; P

A2A adenosine receptors (A2ARs) are endogenous inhibitor of inflammation. Macrophages that are key effectors of kidney disease progression express A2ARs. We investigated the role of A2ARs in kidney inflammation in a macrophage-mediated anti-glomerular basement membrane reactive serum-induced immune nephritis in A2AR-deficient mice. Sub-threshold doses of glomerular basement membrane-reactive serum induced more severe and prolonged kidney damage with higher levels of proinflammatory cytokines and greater accumulation of inflammatory cells in A2AR(-/-) mice than wild-type (WT) mice. To investigate the role of macrophage A2AR in progressive kidney injury, glomerulonephritis was induced in CD11b-DTR transgenic mice. Macrophages were selectively depleted in the established phase of the disease and reconstituted with macrophages from WT or A2AR-deficient mice and then treated with an A2AR agonist. In mice receiving WT macrophages and treated with an A2AR agonist, the glomerular cellularity, crescent formation, sclerotic glomeruli, and tubulointerstitial injury were significantly reduced compared with the control group. In contrast, in mice reconstituted with A2AR-deficient macrophages and treated with an A2AR agonist, the kidney injury was more severe with increased deposition of collagen I, III, and IV. These findings suggest that disruption of the protective A2AR amplifies inflammation to accelerate glomerular damage and endogenous macrophage A2ARs are essential to protect from progressive kidney fibrosis.

Despite dose-limiting nephrotoxicity concerns, polymyxin B has resurged as the treatment of last resort for multidrug-resistant Gram-negative bacterial infections. However, the pharmacokinetic, pharmacodynamic, and nephrotoxic properties of polymyxin B still are not thoroughly understood. The objective of this study was to provide additional insights into the overall biodistribution and disposition of polymyxin B in an animal model. Sprague-Dawley rats were dosed with intravenous polymyxin B (3 mg/kg of body weight). Drug concentrations in the serum, urine, bile, and tissue (brain, heart, lungs, liver, spleen, kidneys, and skeletal muscle) samples over time were assayed by a validated methodology. Among all the organs evaluated, polymyxin B distribution was highest in the kidneys. The mean renal tissue/serum polymyxin B concentration ratios were 7.45 (95% confidence interval [CI], 4.63 to 10.27) at 3 h and 19.62 (95% CI, 5.02 to 34.22) at 6 h postdose. Intrarenal drug distribution was examined by immunostaining. Using a ratiometric analysis, proximal tubular cells showed the highest accumulation of polymyxin B (Mander's overlap coefficient, 0.998) among all cell types evaluated. Less than 5% of the administered dose was recovered in urine over 48 h, but all 4 major polymyxin B components were detected in the bile over 4 h. These findings corroborate previous results that polymyxin B is highly accumulated in the kidneys, but the elimination likely is via a nonrenal route. Biliary excretion could be one of the routes of polymyxin B elimination, and this should be further explored. The elucidation of mechanism(s) of drug uptake in proximal tubular cells is ongoing.

The value of histochemical analysis in the diagnosis of medical renal diseases has long been known, and its use continues currently. Depending on the particular disorder in question, a variety of "special" stains may be applied to renal biopsies. These include the periodic acid-Schiff, Masson trichrome, Jones, von Kossa, Verhoeff-van Gieson, Congo Red, and toluidine blue methods, among others. This review considers the application of such techniques in the assessment of vascular, glomerular, and tubulointerstitial lesions of the kidney.

Summary Knowledge on renal involvement in kidney donors with diabetes, that is, diabetic nephropathy (DN), is limited. During the 7 years (2010-2017), 921 postperfusion biopsies were performed for living donors (14%) or deceased donors (86%). The Renal Pathology Society classification schema for DN (class 0-IV) was used. Biopsies with light microscopic changes of DN (at least class IIa) were selected for study. Eleven biopsies (1.2%) showed DN, all from deceased donors (class IIa in 8, class IIb in 2, and class III in 1 biopsy). The glomerular basement membrane thickness ranged from 439 ± 52 to 725 ± 82 nm. These biopsies also displayed arterionephrosclerosis. They were from 9 deceased donors (fulfilling clinical criteria for acceptance in all, diabetes ;[>6 years] in 8, hypertension in 6, and proteinuria [1+] in all). Follow-up biopsies (5-342 weeks after transplant) showed DN of the same class (7 biopsies), probably progression (1), or progression (3). At follow-up (15-416 weeks), all recipients were alive. One graft was lost at 76 weeks because of progressive DN. The other 10 grafts were functioning, but the serum creatinine reached 2.0 to 2.7 mg/dL in 5 of them. Although diabetes is frequent in kidney donors, donor-related DN is unusual. It is observed only in deceased donors, but the risk factors for its development are not known. Donor-related DN may be stable or progress. Whether it resolves, especially for DN in early phase, remains unknown. It may adversely impact the graft outcome with a magnitude proportional to the severity of the tissue injury in the postperfusion biopsies.

Osteopontin (OPN) is a pro-and anti-inflammatory molecule that simultaneously attenuates oxidative stress. Both inflammation and oxidative stress play a role in the pathogenesis of glomerulonephritis and in the progression of kidney injury. Importantly, OPN is highly induced in nephritic kidneys. To characterize further the role of OPN in kidney injury we used OPN−/−mice in antiglomerular basement membrane reactive serum-induced immune (NTS) nephritis, an inflammatory and progressive model of kidney disease. Normal wild-type (WT) and OPN−/−mice did not show histological differences. However, nephritic kidneys from OPN−/−mice showed severe damage compared with WT mice. Glomerular proliferation, necrotizing lesions, crescent formation, and tubulointerstitial injury were significantly higher in OPN−/−mice. Macrophage infiltration was increased in the glomeruli and interstitium in OPN−/−mice, with higher expression of IL-6, CCL2, and chemokine CXCL1. In addition, collagen (Col) I, Col III, and Col IV deposition were increased in kidneys from OPN−/−mice. Elevated expression of the reactive oxygen species-generating enzyme Nox4 and blunted expression of Nrf2, a molecule that inhibits reactive oxygen species and inflammatory pathways, was observed in nephritic kidneys from OPN−/−mice. Notably, CD11b diphteria toxin receptor mice with NTS nephritis selectively depleted of macrophages and reconstituted with OPN−/−macrophages showed less kidney injury compared with mice receiving WT macrophages. These findings suggest that in global OPN−/−mice there is increased inflammation and redox imbalance that mediate kidney damage. However, absence of macrophage OPN is protective, indicating that macrophage OPN plays a role in the induction and progression of kidney injury in NTS nephritis.

Neointima formation is a major contributor to arteriovenous fistula (AVF) failure. We have previously shown that activation of the Notch signaling pathway contributes to neointima formation by promoting the migration of vascular smooth muscle cells (VSMCs) into the venous anastomosis. In the current study we investigated the mechanisms underlying the dedifferentiation and migration of VSMCs, and in particular the role of bone marrow-derived fibroblast specific protein 1 (FSP-1)(+) cells, another cell type found in models of vascular injury. Using VSMC-specific reporter mice, we found that most of the VSMCs participating in AVF neointima formation originated from dedifferentiated VSMCs. We also observed infiltration of bone marrow-derived FSP-1+ cells into the arterial anastomosis where they could interact with VSMCs. In vitro, conditioned media from FSP-1+ cells stimulated VSMC proliferation and phenotype switching. Activated Notch signaling transformed FSP-1(+) cells into type I macrophages and stimulated secretion of cytokines and growth factors. Pretreatment with a Notch inhibitor or knockout of the canonical downstream factor RBP-Jκ in bone marrow-derived FSP1(+) cells decreased FSP1(+) cell infiltration into murine AVFs, attenuating VSMC dedifferentiation and neointima formation. Our results suggest that targeting Notch signaling could provide a new therapeutic strategy to improve AVF patency.

HIV-positive individuals are at increased risk for kidney disease, including HIV-associated nephropathy, non-collapsing focal segmental glomerulosclerosis, immune-complex kidney disease, and comorbid kidney disease, as well as kidney injury resulting from prolonged exposure to antiretroviral therapy or from opportunistic infections. Clinical guidelines for kidney disease prevention and treatment in HIV-positive individuals are largely extrapolated from studies in the general population, and do not fully incorporate existing knowledge of the unique HIV-related pathways and genetic factors that contribute to the risk of kidney disease in this population. We convened an international panel of experts in nephrology, renal pathology, and infectious diseases to define the pathology of kidney disease in the setting of HIV infection; describe the role of genetics in the natural history, diagnosis, and treatment of kidney disease in HIV-positive individuals; characterize the renal risk-benefit of antiretroviral therapy for HIV treatment and prevention; and define best practices for the prevention and management of kidney disease in HIV-positive individuals.

We characterize invasive urothelial carcinoma (UC) exhibiting urothelial basal cell immunohistochemical markers. Consecutive invasive UCs were immunostained with CK20 and urothelial basal cell markers, cytokeratin 5 (CK5)/CD44. Immunostaining for CK5 and CD44 was scored as follows: positive for staining of more than 25% thickness of the epithelial nest or epithelium and low for lesser immunoreactivity. Invasive urothelial carcinoma (UC) exhibiting positive CK5/CD44 staining was designated as basal-like UC (BUC). In this study, of 251 invasive UC (pT1 in 57% and pT2-4 in 43%), BUC accounted for 40% of cases (accounting for most pT2-4 UC) and often presented as non-papillary UC without previous history of UC. In addition, BUC exhibited uniform nuclei with lesser degree of atypia than non BUC and decreased or negative cytokeratin 20 reactivity. Nested and microcystic variants of UC immunohistochemically stained as BUCs. Invasive non-BUCs were often papillary with marked cytologic atypia and pleomorphism, and accounted for most pT1 UC. The rates of perivesical invasion, lymph node and distant metastases were higher for BUC than non-BUC. All nine cases with absent/minimal residual in situ UC in 102 radical cystectomy specimens were from invasive non-BUC. BUC is distinguished from non-BUC due to this aggressive behavior, distinct immunohistochemical profile, and predominant non-papillary architecture. Our findings are consistent with recent studies identifying a subtype of muscle-invasive UC with molecular expression of basal cell and luminal cell molecular profiles. Our study further supports categorizing invasive UCs into these subtypes with different biological behaviors, possibly contributing to better therapeutic strategies.

With the increasing utility of hematopoietic stem cell transplantation (SCT) as a treatment for cancer and noncancerous disorders, more challenges and complications associated with SCT have emerged. Renal injury immediately after transplant is common and well understood, but long-term renal injury is becoming more evident. Chronic graft-versus-host disease (GVHD) is a known long-term complication of SCT, and membranous nephropathy (MN) is emerging as the most common cause of SCT-associated glomerular pathology. In this case report, we present a patient who developed features of anti-PLA2R antibody-negative MN following autologous SCT. The renal injury responded well to steroids and further response to rituximab therapy was noted, suggesting antibody-mediated autoimmune glomerular disease. We also present a review of the literature on autologous GVHD and the role of T and B cells in induction of autoimmunity by SCT.

We hypothesize that cystic structures in metastatic papillary thyroid carcinoma (PTC) develop along the framework of lymphatic channels. To investigate this phenomenon, different categories of PTC were immunostained for D2-40 and TTF1. In this study, reactivity for D2-40 was considered as positive when there is membranous staining as often seen in lymphatic endothelial cells. Thirty cases of PTC with lymph node metastasis or with potential for lymphatic invasion and 20 cases metastatic PTC in lymph nodes were reviewed and found to show double/mosaic immunoreactivity for TTF1/D2-40 in 40-100% of cases. PTC metastasis in lymph nodes with cysts and some branching lymphatic-like channels lined by follicular cells with or without nuclear features of PTC were diffusely reactive to TTF1, and focally to D2-40. For primary and metastatic PTC, focal membranous D2-40 reactivity was also demonstrated in cysts or cleft linings. For25 thyroid neoplasms with no known potential for lymphatic invasion, there was no such immunoreactivity. The mosaic or double immunoreactivity for TTF1/D2-40 suggests lymphatic cancerization and possible endothelial mimicry of follicular cells. Mosaic/double immunoreactivity is helpful to detect the hidden pattern of lymphatic invasion masquerading as 'benign-appearing' follicles and supports our hypothesis of malignant cells developing along the lymphatic framework.

We determined the likelihood that transurethral resection biopsy of the prostatic urethra adjacent to the verumontanum would detect prostatic involvement of urothelial carcinoma in patients with bladder carcinoma.We compared precystectomy transurethral resection biopsy specimens of the prostatic urethra with those of the matched radical cystoprostatectomy in 272 patients with urothelial carcinoma of the bladder. All prostates were evaluated by whole mount step sections.Prostatic involvement by urothelial carcinoma was detected by transurethral resection biopsy or radical cystoprostatectomy in 101 patients (37.1%). Transurethral resection biopsy detected urothelial carcinoma in 72 cases with 71.3% sensitivity and 100% specificity. The overall accuracy of transurethral resection biopsy to detect urothelial carcinoma of the prostate was 89% (positive and negative predictive values 100% and 86%, respectively). Invasive prostatic urothelial carcinoma arising from the prostatic urethra was detected by transurethral resection biopsy in 21 of 26 patients (81%) while prostatic carcinoma in situ was detected in 39 of 52 (75%). Transurethral resection biopsy detected prostatic invasive urothelial carcinoma resulting from transmural invasion of a bladder tumor in 4 of 15 patients.Prostatic involvement by urothelial carcinoma of the bladder was found in 37.1% of patients. Transurethral resection biopsy missed most tumors resulting from transmural invasion of the bladder primary lesion. Carcinoma in situ and invasive urothelial carcinoma arising from the prostatic urethra were detected in most cases. Transurethral resection biopsy of the prostatic urethra can complement staging and support clinical decision making with respect to neoadjuvant chemotherapy and planning for an orthotopic neobladder.

Sarcoid-like (SL) granulomas have been previously described in association with malignant tumors. These granulomas appear to be tumor-related but are not indicative of systemic sarcoidosis, and hence are referred to as SL reactions. These SL reactions can be seen within the primary tumor, its vicinity, or in uninvolved sites such as the spleen, bone marrow, skin, and/or regional lymph nodes draining the tumor. It is a widely held view that SL granulomas are caused by soluble antigenic factors, shed by tumor cells or released due to tumor necrosis. SL reactions reported in Hodgkin lymphoma have been associated with a better prognosis. SL granulomas are thought to play an important role in the host's defenses against metastatic extension. SL granulomas have been reported in approximately 4.4% of carcinomas. Isolated cases of renal cell carcinoma (RCC) with SL granulomas have been reported with questionable prognostic significance. We identified 11 cases of RCCs with SL granulomas. Interestingly, all cases had abundant clear cell cytoplasm (10 clear cell RCC cases and 1 clear cell papillary RCC). We propose that this clear, abundant cytoplasm of the tumor cells with high content of glycogen and lipids may trigger granuloma formation akin to that seen in seminomas with SL granulomas. To date, this is the largest case series of RCCs with SL granulomas.

Mesoamerican nephropathy is a devastating disease of unknown etiology that affects mostly young agricultural workers in Central America. An understanding of the mechanism of injury and the early disease process is urgently needed and will aid in identification of the underlying cause and direct treatment and prevention efforts. We sought to describe the renal pathology in Mesoamerican nephropathy at its earliest clinical appearance in prospectively identified acute case patients in Nicaragua. We considered those with elevated (or increased at least 0.3 mg/dL or 1.5-fold from baseline) serum creatinine, leukocyturia, and either leukocytosis or neutrophilia for inclusion in this biopsy study. Renal tissue was obtained by ultrasound-guided biopsy for examination by light, immunofluorescence, and electron microscopy. All 11 individuals who underwent renal biopsy showed tubulointerstitial nephritis, with varying degrees of inflammation and chronicity. Interstitial cellular infiltrates (predominantly T lymphocytes and monocytes), mostly in the corticomedullary junction; neutrophilic accumulation in the tubular lumens; largely preserved glomeruli; few mild ischemic changes; and no immune deposits were noted. The acute components of tubulointerstitial nephritis were acute tubular cell injury, interstitial edema, and early fibrosis. Chronic tubulointerstitial nephritis included severe tubular atrophy, thickened tubular basement membrane, and interstitial fibrosis. Thus, renal histopathology in Mesoamerican nephropathy reveals primary interstitial disease with intact glomeruli.

Despite dose-limiting nephrotoxic potentials, polymyxin B has reemerged as the last line of therapy against multidrug-resistant Gram-negative bacterial infections. However, the handling of polymyxin B by the kidneys is still not thoroughly understood. The objectives of this study were to evaluate the impact of renal polymyxin B exposure on nephrotoxicity and to explore the role of megalin in renal drug accumulation. Sprague-Dawley rats (225 to 250 g) were divided into three dosing groups, and polymyxin B was administered (5 mg/kg, 10 mg/kg, and 20 mg/kg) subcutaneously once daily. The onset of nephrotoxicity over 7 days and renal drug concentrations 24 h after the first dose were assessed. The effects of sodium maleate (400 mg/kg intraperitoneally) on megalin homeostasis were evaluated by determining the urinary megalin concentration and electron microscopic study of renal tissue. The serum/renal pharmacokinetics of polymyxin B were assessed in megalin-shedding rats. The onset of nephrotoxicity was correlated with the daily dose of polymyxin B. Renal polymyxin B concentrations were found to be 3.6 ± 0.4 μg/g, 9.9 ± 1.5 μg/g, and 21.7 ± 4.8 μg/g in the 5-mg/kg, 10-mg/kg, and 20-mg/kg dosing groups, respectively. In megalin-shedding rats, the serum pharmacokinetics of polymyxin B remained unchanged, but the renal exposure was attenuated by 40% compared to that of control rats. The onset of polymyxin B-induced nephrotoxicity is correlated with the renal drug exposure. In addition, megalin appears to play a pivotal role in the renal accumulation of polymyxin B, which might contribute to nephrotoxicity.

Stanniocalcin-1 is an intracrine protein; it binds to the cell surface, is internalized to the mitochondria, and diminishes superoxide generation through induction of uncoupling proteins. In vitro, stanniocalcin-1 inhibits macrophages and preserves endothelial barrier function, and transgenic overexpression of stanniocalcin-1 in mice protects against ischemia-reperfusion kidney injury. We sought to determine the kidney phenotype after kidney endothelium-specific expression of stanniocalcin-1 small hairpin RNA (shRNA). We generated transgenic mice that express stanniocalcin-1 shRNA or scrambled shRNA upon removal of a floxed reporter (phosphoglycerate kinase-driven enhanced green fluorescent protein) and used ultrasound microbubbles to deliver tyrosine kinase receptor-2 promoter-driven Cre to the kidney to permit kidney endothelium-specific shRNA expression. Stanniocalcin-1 mRNA and protein were expressed throughout the kidney in wild-type mice. Delivery of tyrosine kinase receptor-2 promoter-driven Cre to stanniocalcin-1 shRNA transgenic kidneys diminished the expression of stanniocalcin-1 mRNA and protein throughout the kidneys. Stanniocalcin-1 mRNA and protein expression did not change in similarly treated scrambled shRNA transgenic kidneys, and we observed no Cre protein expression in cultured and tyrosine kinase receptor-2 promoter-driven Cre–transfected proximal tubule cells, suggesting that knockdown of stanniocalcin-1 in epithelial cells in vivo may result from stanniocalcin-1 shRNA transfer from endothelial cells to epithelial cells. Kidney-specific knockdown of stanniocalcin-1 led to severe proximal tubule injury characterized by vacuolization, decreased uncoupling of protein-2 expression, greater generation of superoxide, activation of the unfolded protein response, initiation of autophagy, cell apoptosis, and kidney failure. Our observations suggest that stanniocalcin-1 is critical for tubular epithelial survival under physiologic conditions.

Congo red stain apple-green birefringence under polarized light is the most popular method for detecting amyloid; however, it has limitations. The goal of this study was to evaluate if examination of Congo red stain by fluorescent microscopy (FM) significantly enhances the diagnostic yield. Congo red-stained tissue sections were retrospectively and prospectively examined by light microscopy (LM) with and without polarizer and by FM using the Texas red filter and results by each method compared. Congo red-stained amyloid recognized by LM was unequivocally and easily identified by FM in each of 48 cases. In 22 of them, FM either confirmed the presence of a small amount of amyloid or lead to a definitive diagnosis, which was otherwise missed. Eight cases with Congo red-negative by LM were also negative by FM. In 8 cases with a false-positive Congo red stain, FM still detected the signal in 5, but it was absent in 3 cases. In conclusion, Congo red fluorescence improves the diagnostic yield of LM for both positive and negative cases.

Membranous glomerulonephritis (MGN) is a very significant kidney disease. It is one of the frequent causes of heavy protein excretion in urine. MGN is thought to be an immune-mediated disease caused by glomerular deposition of antigen-antibody complexes. The pathogenic antigen, however, has been an enigma until recently. It was discovered in 2009 that phospholipase A2 receptor (PLA2R), a normal transmembrane protein in podocyte plasma membrane, is the antigen causing MGN. Within 5 yr of its discovery, this seminal finding has leaded to novel insights into the treatment of this disease including diagnosis, therapy, and prediction of outcome. This finding also paves the way for fundamental studies on how and why autoimmunity against PLA2R develops. The discovery of PLA2A as the cause of “idiopathic” MGN after a half century of speculation, followed by further fundamental insights with such an expedient and successful application in patient care, embodies the elegance of science at its junction with society. This perspective traces the story of this remarkable discovery.

Objective: It was the aim of this study to determine the utility of PAX2 and PAX8 in cytology effusions with metastatic tumor. Study Design: PAX2 and PAX8 immunohistochemical staining was performed on cell blocks of 89 pleural, pericardial and peritoneal effusions with benign diagnoses (18 cases), or secondary to renal cell carcinoma (RCC; 9 cases), müllerian carcinoma (21 cases) or non-müllerian carcinoma (41 cases). Results: PAX2 stained 0% (0/18) of controls, 100% (8/8) of RCCs, 35% (7/20) of müllerian carcinomas, and 2% (1/41) of non-müllerian carcinomas. PAX8 stained 6% (1/18) of control cases, 100% (9/9) of RCC cases, 100% (20/20) of müllerian carcinomas, and 5% (2/41) of non-müllerian carcinomas. PAX2 was 35% sensitive and 95% specific for müllerian carcinoma and 100% sensitive and 95% specific for RCC. PAX8 was 100% sensitive and 95% specific for müllerian carcinoma and 100% sensitive and 95% specific for RCC. Conclusions: PAX8 is more sensitive than PAX2 for metastatic effusions from müllerian carcinomas (100 vs. 35%), while also having a higher intensity of staining than PAX2. However, PAX2 and PAX8 are both highly sensitive and specific for RCCs. PAX2 and PAX8 are valuable diagnostic markers for metastatic müllerian carcinomas and RCCs in effusion cytology. PAX8 is superior for carcinomas of müllerian origin.

Background. Cancer patients are particularly vulnerable to drug-induced kidney injury during their chemotherapy. Whereas the direct nephrotoxic effects of these drugs are well recognized, that of tubulointerstitial nephritis (TIN) is less well known, underdiagnosed and often reported only as a functional tubular disorder. The diagnosis of acute TIN is important because of its insidious onset with tubular dysfunction, its potential reversibility if detected early and the possibility of its response to steroid treatment. Methods. We performed a literature review (44 cases) and reviewed our institutional biopsy register (12 cases) of patients on cancer chemotherapy with documented TIN. Biopsies were considered in three groups: acute TIN, chronic TIN and acute on chronic TIN. The outcomes that were evaluated were recovery of kidney function, development of chronic kidney disease and onset of end-stage renal disease (ESRD). Results. Ifosfamide, BCG, tyrosine kinase inhibitors and premetrexed were the most commonly implicated drugs. Ifosfamide and premetrexed were associated with worst outcomes. Recovery of kidney function was better in acute TIN (ATIN) (29%) with fewer progressing to ESRD (12.9%) than with chronic TIN (7.6% recovery, 15.3% ESRD). Steroid use appeared to favorably alter outcomes in ATIN (40% recovery) compared with conservative treatment (18.75% recovery). Peak serum creatinine, age, gender and type of malignancy did not influence outcomes. Conclusions. As a potentially reversible lesion that can respond to withdrawal of the suspected agent, and in some cases to a short course of steroid therapy, it is important to consider ATIN in the differential diagnosis of all cases of acute kidney injury in cancer patients on chemotherapy.

Hemodialysis patients depend on arteriovenous fistulas (AVF) for vascular access. Unfortunately, their 2-yr primary patency rate is only 60% because of AVF clog due to intimal hyperplasia at the venous anastomosis. Chronic kidney disease (CKD) can increase neointima formation by unknown mechanisms. A new AVF mouse model was created, and the mechanisms of CKD on neointima formation in AVFs were investigated. We created AVFs in mice by anastomosing the common carotid artery to the internal jugular vein. CKD was induced [BUN (blood urea nitrogen) in control and CKD mice, 33.3 ± 3.9 vs. 114.2 ± 12.1 mg/dl, P < 0.05]. After 1 day, there was endothelial cell loss and CD41-positive platelet aggregation, especially in the venous anastomosis. An invasion of macrophages and neutrophils peaked at 1 wk after surgery. Neointima formation (smooth muscle cell accumulation and extracellular matrix deposition) increased progressively over 4 wk. Mice with CKD had ∼45% ( P < 0.05) more neointima formation than control mice. CKD decreased vascular endothelial-cadherin expression in endothelial cells and delayed regeneration of the endothelium. CKD also increased inflammatory cells (Mac-2-positive or CD45-positive) in AVFs at 2 wk. Finally, AVFs were “leakier” (increased accumulation of Evans blue) in CKD mice at 7 and 14 days than control mice. We find that CKD increases neointima formation and endothelial barrier dysfunction. We have created a mouse model of AVF with characteristics similar to failed AVFs in patients. The model will allow testing of strategies directed at improving AVF function in CKD patients.

Nephrogenic adenoma is a benign lesion of the urinary tract, particularly the urinary bladder. It is a gross and microscopic mimicker of urothelial neoplasm or metastatic carcinoma. Several histological patterns (tubular, tubulocystic, polypoid, papillary, fibromyxoid) have been recognized, but a flat pattern has not been described. Histologically, nephrogenic adenoma consists of tubules, cysts or papillae lined by flat to polygonal cells with frequent hobnail appearance. The stroma is often edematous or has a granulation tissue-like appearance with acute or chronic inflammation. By immunohistochemistry, nephrogenic adenomas are positive for renal epithelial markers CK7, CD10 and alpha-methylacyl-coenzyme A racemase, and negative for bladder urothelium or prostate markers. Recent studies have shown that nephrogenic adenomas are positive for PAX2 and PAX8. We encountered an interesting case of tubular nephrogenic adenoma with adjacent areas suspicious of flat urothelial atypia. Immunohistochemistry for PAX2 and PAX8 were positive in these areas, unveiling a flat pattern of nephrogenic adenoma. This case prompted us to study 15 cases of nephrogenic adenoma to determine additional instances of flat pattern and to assess the value of PAX2 and PAX8 immunoreactivity to diagnose nephrogenic adenoma. PAX2 and PAX8 immunostaining was positive in 14/15 and 15/15 cases, respectively. The flat pattern was present at least focally adjacent to tubular, polypoid and papillary areas, in 8/15 cases of nephrogenic adenoma. In conclusion, the flat pattern is a common finding in nephrogenic adenomas, but easily under recognized by morphologic examination and may be confused with flat urothelial lesions with atypia. Immunostains for PAX2 and PAX8 are useful in the detection of nephrogenic adenomas and particularly unveil those nephrogenic adenomas with flat pattern.

How the kidney responds to the metabolic cues from the environment remains a central question in kidney research. This question is particularly relevant to the pathogenesis of diabetic nephropathy (DN) in which evidence suggests that metabolic events in podocytes regulate chromatin structure. Here, we show that miR-93 is a critical metabolic/epigenetic switch in the diabetic milieu linking the metabolic state to chromatin remodelling. Mice with inducible overexpression of a miR-93 transgene exclusively in podocytes exhibit significant improvements in key features of DN. We identify miR-93 as a regulator of nucleosomal dynamics in podocytes. miR-93 has a critical role in chromatin reorganization and progression of DN by modulating its target Msk2, a histone kinase, and its substrate H3S10. These findings implicate a central role for miR-93 in high glucose-induced chromatin remodelling in the kidney, and provide evidence for a previously unrecognized role for Msk2 as a target for DN therapy., Podocyte injury is central to kidney dysfunction in diabetic nephropathy. Here the authors show that Msk2 is a target of miR-93 and this interaction mediates pathogenic chromatin remodelling in diabetic nephropathy.

The increasing prevalence of multidrug-resistant Gram-negative infections has led to renewed interest in the use of systemic polymyxin B. However, the nephrotoxic properties of polymyxin B are still poorly understood. The objective of this study was to characterize nephrotoxicity associated with polymyxin B, with an emphasis on examining the impact of dosing frequencies on the onset of nephrotoxicity. Sprague-Dawley rats were divided into two groups and administered the same total daily dose of polymyxin B subcutaneously but with different dosing frequencies (either 20 mg/kg of body weight every 24 h [q24h] or 5 mg/kg q6h). Drug concentrations in renal tissue were compared between the two groups at 24 h. Kidney tissues were harvested at 48 h and compared histologically. Serum creatinine was measured daily for up to 10 days, and nephrotoxicity was defined as a significant elevation in serum creatinine (≥2× baseline). Kaplan-Meier analysis was used to compare the onset of nephrotoxicity. Polymyxin B-induced nephrotoxicity manifested as elevation in serum creatinine and acute tubular necrosis. Extensive injury of the proximal tubules was observed. The lesions were more severe and higher drug concentrations were achieved in the kidneys of the q6h dosing group. The q24h dosing group experienced a more gradual onset of nephrotoxicity, which could be attributed to the lower kidney tissue drug concentrations (48.5 ± 17.4 μg/g versus 92.1 ± 18.1 μg/g of polymyxin B1, P = 0.04). Preferential accumulation of polymyxin B in the kidneys suggests that uptake to renal cells is a nonpassive process and q24h dosing was less nephrotoxic than q6h dosing.

Retroperitoneal sarcoma is a rare tumor accounting for 10 - 15% of all soft tissue malignancies with an incidence of 2.5 per million. Of those, liposarcoma is the most common type of retroperitoneal sarcoma accounting for 41% of cases. It usually presents late with vague symptoms such as abdominal discomfort or palpable mass. Vascular invasion is seen in 18% of retroperitoneal sarcomas but acute renal failure secondary to bilateral renal artery invasion/stenosis by these tumors has never been described yet. In this report, we describe the first case, to our knowledge, in the medical literature and discuss epidemiology, diagnosis, and management. Treatment is primarily surgical and the ability to completely resect the tumor is the most important predictor of survival. Active clinical trials are currently testing the use of adjunct chemotherapy and radiotherapy to improve morbidity and mortality.

PAX2 and PAX8 are transcription factors that are essential in embryonic development of müllerian organs. They may also play a role in tumor development in these organs. The diagnostic utility of PAX2 and PAX8 relative to one another has not been comprehensively studied. Archival tissue samples for normal or non-neoplastic tissue (251), primary epithelial neoplasms (316 for PAX2 and 357 for PAX8), and metastatic epithelial neoplasms (16), all of müllerian origin, were subjected to PAX2 and PAX8 immunostaining. The staining frequency, extent, and intensity for these markers were compared. Virtually identical PAX2 and PAX8 expressions were noted in non-neoplastic tissue. They were constantly seen in most epithelial cells (but not in stromal cells) of the endocervix, endometrium, fallopian tube, paratubal cyst, endosalpingiosis, endometriosis, and endometrial polyp. Within the primary epithelial neoplasms, PAX2 and PAX8 expression was noted in 55% and 98% of serous tumors, 25% and 94% of endometrioid tumors, 19% and 100% of clear cell tumors, 11% and 67% of transitional/undifferentiated tumors, and 10% and 22% of mucinous tumors, respectively. Regardless of histologic subtypes, PAX2 staining was noted in fewer cells and with less staining intensity compared with PAX8. No tumor showed only PAX2 staining. Within the metastatic carcinomas, PAX2 and PAX8 expression was noted in 38% and 98% of cases, respectively, with a diffuse and strong staining for PAX8, contrasting with a patchy and weak PAX2 expression. PAX2 and PAX8 are constantly expressed in normal or non-neoplastic tissue of müllerian origin. For primary and metastatic müllerian epithelial tumors, PAX8 shows strong and diffuse staining in most cases of all histologic subtypes, except in mucinous tumors. In contrast, PAX2 expression is always less than PAX8, and exclusive staining for PAX2 is not seen. PAX8 supersedes PAX2 as probably the best epithelial marker hitherto for primary or metastatic müllerian epithelial tumors.

Crescentic glomerulonephritis (GN) in Wistar-Kyoto rats progresses to lethal kidney failure by macrophage (Mφ)-mediated mechanisms. Mφs in nephritic glomeruli express adenosine A(2A) receptors (A(2A)Rs), the activation of which suppresses inflammation. Here, we pharmacologically activated the A(2A)Rs with a selective agonist, CGS 21680, and inactivated them with a selective antagonist, ZM241385, to test the effects on established GN. When activation was delayed until antiglomerular basement membrane GN and extracellular matrix deposition were established, glomerular Mφ infiltration was reduced by 83%. There was also a marked improvement in glomerular lesion histology, as well as decreased proteinuria. A(2A)R activation significantly reduced type I, III, and IV collagen deposition, and E-cadherin expression was restored in association with a reduction of α-smooth muscle actin-positive myofibroblasts in the interstitium and glomeruli. In contrast, pharmacological inactivation of A(2A)Rs increased glomerular crescent formation, type I, III, and IV collagen expression, and enhanced E-cadherin loss. Activation of A(2A)Rs suppressed the expression of the Mφ-linked glomerular damage mediators, transforming growth factor-β, osteopontin-1, thrombospondin-1, and tissue inhibitor of metalloproteinase-1. Thus, A(2A)R activation can arrest GN and prevent progressive fibrosis in established pathological lesions.