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We performed next-generation sequencing in patients with familial steroid-sensitive nephrotic syndrome (SSNS) and identified a homozygous segregating variant (p.H310Y) in the gene encoding clavesin-1 (CLVS1) in a consanguineous family with 3 affected individuals. Knockdown of the clavesin gene in zebrafish (clvs2) produced edema phenotypes due to disruption of podocyte structure and loss of glomerular filtration barrier integrity that could be rescued by WT CLVS1 but not the p.H310Y variant. Analysis of cultured human podocytes with CRISPR/Cas9-mediated CLVS1 knockout or homozygous H310Y knockin revealed deficits in clathrin-mediated endocytosis and increased susceptibility to apoptosis that could be rescued with corticosteroid treatment, mimicking the steroid responsiveness observed in patients with SSNS. The p.H310Y variant also disrupted binding of clavesin-1 to α-tocopherol transfer protein, resulting in increased reactive oxygen species (ROS) accumulation in CLVS1-deficient podocytes. Treatment of CLVS1-knockout or homozygous H310Y-knockin podocytes with pharmacological ROS inhibitors restored viability to control levels. Taken together, these data identify CLVS1 as a candidate gene for SSNS, provide insight into therapeutic effects of corticosteroids on podocyte cellular dynamics, and add to the growing evidence of the importance of endocytosis and oxidative stress regulation to podocyte function.

We retrospectively examined the clinical characteristics, pathological features, and outcomes of BK viremia and nephropathy in a population of non-renal solid organ transplant patients (NRSOT) referred for outpatient nephrology consultation over a period of 5 years. In the entire cohort of liver, heart, and lung transplant recipients referred to this clinic, 14% percent were found to have BK viremia with a median peak serum BK viral load of 35 500 copies/ml (range 250 to 21 100 000 copies/ml). BK viremia resolved in six of the seventeen patients (35%). Four out of five patients biopsied showed BK virus (BKV) nephropathy. Eleven out of seventeen patients with BK viremia developed advanced (stage 4 or 5) chronic kidney disease. Four patients developed rejection of their solid organ transplant within the first year post detection of BK viremia after immunosuppression reduction. We conclude that a multi-center study is required to evaluate whether implementation of a systematic BK screening program would be effective in early detection and management of this problem in the NRSOT population., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The 2019 Association of Pathology Chairs Annual Meeting included a discussion group sponsored by the Senior Fellows Group (former chairs of academic departments of pathology who have remained active in Association of Pathology Chairs) that was focused on serving as temporary pathology chair. Such positions include "acting chair" (service while the permanent chair is on leave or temporarily indisposed), "interim chair" (service after departure of the prior chair and before a new chair is appointed), "term-limited chair" (usually one nonrenewable term of less than 5 years), and "terminal chair" (permanent chair being asked to stay until a successor is appointed). Discussion group panelists represented each of these positions and included the perspective of 3 former deans about the rationale for making such appointments. The potential benefits and risks of serving in these roles were discussed. Issues addressed included acting as "caretaker manager" or "change-agent leader"; whether such service and experience would enhance or harm one's chances to become a permanent chair of that or another department; the effect of such service on academic productivity; the influence of department and institutional factors on the position; the range of authority provided, particularly in addressing significant problems affecting the department's future; and the impact of time served in these various positions. The "lame-duck" effect of prolonged service as "terminal chair" was also discussed. The observations and advice provided by the panelists and audience discussion are reported and may be useful for those considering service as temporary chair in pathology as well as other academic leadership positions., Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2019.)

Microcrystalline cellulose (MCC) is an insoluble material commonly used as a binder and filler in oral medications. Identification of pulmonary intravascular deposition of MCC in transbronchial biopsies from lung transplant (LT) recipients following parenteral injection of oral medications has only been reported once. A search of our surgical pathology electronic database was performed from January 1, 2000 to November 1, 2017 using the text "transplant transbronchial." The diagnosis field for all cases retrieved was then searched for the text "cellulose." These cases were queried for patient demographics and outcomes. Between January 1, 2000 and November 1, 2017, 1558 lung transplants were performed in 1476 individual patients at our institution; 12 were identified to have MCC in their lung tissue. Patients with MCC identified on biopsies were more likely to be transplanted for cystic fibrosis versus other indications and younger versus older. MCC identified in 2 of our cases was favored to be donor derived. Of the 12 patients, 6 (50%) are deceased. MCC within the pulmonary vasculature may be an indicator of increased complications, mortality, or shortened survival in LT recipients. Detecting intravascular MCC and distinguishing it from aspirated foreign material can be challenging. Awareness of the differential diagnosis for pulmonary foreign material is of paramount importance for the pathologist., (© 2019 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Background: Tubulointerstitial nephritis (TIN) is typically seen in association with drug exposure and infection or in autoimmune diseases such as Sjogren's syndrome or systemic lupus erythematosis. The recently described IgG4-related systemic diseases can affect many organ systems including the kidney and typically respond to corticosteroid treatment., Case: We present a case of IgG4-related TIN in a patient with concomitant chronic lymphocytic leukemia. To our knowledge, IgG4-related TIN has not been associated with any hematological disorder such as chronic lymphocytic leukemia.
, Conclusion: We propose that all kidney biopsies with significant plasma cell infiltrate should be stained for IgG4 as response to treatment is common.

Despite the recent development of many new immunosuppressive agents for use in transplantation, acute cellular and humoral rejection represent extremely prevalent and serious complications after lung transplantation. Acute cellular rejection, defined as perivascular or bronchiolar mononuclear inflammation, affects over 50% of lung transplant recipients within the first year. Furthermore, the frequency and severity of acute rejections are the most important risk factors for the subsequent development of bronchiolitis obliterans syndrome (BOS), a condition of progressive airflow obstruction that severely limits survival after lung transplantation. Treatment options for cellular rejection include high-dose methylprednisolone, antithymocyte globulin, or alemtuzumab. Emerging evidence also suggests that humoral rejection occurs in lung transplantation, characterized by local complement activation or the presence of antibody to donor human leukocyte antigens and is associated with an increased risk for BOS. Treatment options for humoral rejection include intravenous immunoglobulin, plasmapheresis, or rituximab. Herein, we review the clinical presentation, diagnosis, mechanisms, and treatment of cellular and humoral rejection after lung transplantation.

Background: A 57-year-old African American man presented to a tertiary care center with a 6-month history of fatigue and worsening abdominal pain. He had lost 9.1 kg in weight in the 3 months leading up to presentation, and described subjective fevers and night sweats for 1 month with a nonproductive cough and blurred vision for several weeks before presentation. He had chronic renal insufficiency, sleep apnea, hypertension, and peripheral vascular disease., Investigations: Physical examination, complete blood count, peripheral blood smear, leukocyte alkaline phosphatase score, bone marrow biopsy, CT of the chest, abdomen, and pelvis, MRI of the abdomen and pelvis, measurement of plasma and urine metanephrines, 24 h urine testing for cortisol and 17-ketosteroids, measurement of serum granulocyte colony-stimulating factor (G-CSF) level, histopathologic examination and immunohistochemical staining of resected tumor., Diagnosis: G-CSF-secreting adrenal carcinoma with rhabdoid-like differentiation., Management: En bloc surgical resection of kidney, suprarenal mass and spleen was performed, followed by initiation of mitotane chemotherapy 3 months later.

The immunity-related GTPases (IRG), also known as p47 GTPases, are a family of proteins that are tightly regulated by IFNs at the transcriptional level and serve as key mediators of IFN-regulated resistance to intracellular bacteria and protozoa. Among the IRG proteins, loss of Irgm1 has the most profound impact on IFN-gamma-induced host resistance at the physiological level. Surprisingly, the losses of host resistance seen in the absence of Irgm1 are sometimes more striking than those seen in the absence of IFN-gamma. In the current work, we address the underlying mechanism. We find that in several contexts, another protein in the IRG family, Irgm3, functions to counter the effects of Irgm1. By creating mice that lack Irgm1 and Irgm3, we show that several phenotypes important to host resistance that are caused by Irgm1 deficiency are reversed by coincident Irgm3 deficiency; these include resistance to Salmonella typhimurium in vivo, the ability to affect IFN-gamma-induced Salmonella killing in isolated macrophages, and the ability to regulate macrophage adhesion and motility in vitro. Other phenotypes that are caused by Irgm1 deficiency, including susceptibility to Toxoplasma gondii and the regulation of GKS IRG protein expression and localization, are not reversed but exacerbated when Irgm3 is also absent. These data suggest that members of the Irgm subfamily within the larger IRG family possess activities that can be opposing or cooperative depending on the context, and it is the balance of these activities that is pivotal in mediating IFN-gamma-regulated host resistance.

Acute interstitial nephritis (AIN) is a known cause of acute renal failure in children. In most instances, drug therapy is the offending agent. Although granuloma formation has been observed in drug-induced interstitial nephritis, it is not a commonly associated manifestation. This is a case of a 15-year-old white female with Tetralogy of Fallot and pulmonary atresia who developed acute renal failure secondary to drug-induced interstitial nephritis and renal granulomas. In addition to interstitial edema with eosinophils and lymphocytes, her renal biopsy showed interstitial granulomas, immune complexes within tubular basement membranes, and the unusual feature of multinucleated giant cells engulfing tubules. Her acute renal failure resolved after the withdrawal of antibiotics and the initiation of intravenous steroid therapy.

Glomerular lesions that complicate patients with human immunodeficiency virus (HIV) infection include HIV-associated nephropathy, membranous glomerulopathy, and immune-complex glomerulonephritides. This case series presents 3 patients with clinically significant renal disease and positive test results for anti-glomerular basement membrane (anti-GBM) antigen. Characteristic histological findings that would suggest anti-GBM antibodies have a significant role in the pathological state of each patient's kidney disease were absent. In addition, each patient recovered without specific treatment for anti-GBM disease. This case series suggests that anti-GBM antibodies likely are related to the B-cell expansion previously described in patients with HIV infection. We propose that clinicians interpret results of anti-GBM antibody tests carefully for patients with HIV infection, considering biopsy before empiric therapy, particularly in a clinical presentation that is atypical for Goodpasture disease.

Rationale: The main hindrance to long-term success of lung transplantation is bronchiolitis obliterans syndrome (BOS), generally thought to be a manifestation of chronic allograft rejection. BOS is associated histologically with epithelial injury, bronchocentric mononuclear inflammation, and fibrosis of small airways known as bronchiolitis obliterans (BO). Few studies have directly compared clinical, radiographic, and histologic findings of BOS and BO, particularly in the era of improved immunosuppression and infection prophylaxis. Patients undergoing pulmonary retransplantation for BOS provide a unique opportunity to investigate these relationships., Methods: All patients who underwent pulmonary retransplantation for BOS from 1992 to 2004 at Duke University Medical Center were reviewed. Pathology findings in explanted lung allografts were compared with clinical, radiographic, and transbronchial biopsy data., Results: Over the 12-year study period, 12 patients underwent pulmonary retransplantation for BOS. The median time to BOS was 517 days (intraquartile range, 396 to 819.8 days). BOS scores prior to retransplantation were 2 in 2 patients and 3 in 10 patients. We developed a semiquantitative scoring system for epithelial, inflammatory, and fibrotic changes in affected airways to permit better comparison between BO and BOS. Somewhat surprisingly, only 50% (6 of 12 patients) had severe fibrotic changes, although all had some degree of epithelial injury, fibrosis, or inflammation centered around the bronchi and bronchioles. Furthermore, pathology findings other than BO were present in most explanted allografts and included cholesterol clefts (n = 4), focal invasive aspergillosis (n = 1), interstitial fibrosis (n = 2), and chronic vascular rejection (n = 1)., Conclusions: In this series of patients with advanced BOS undergoing retransplantation, at least some degree of BO was present in all explanted allografts. However, the degree of epithelial changes, fibrosis, and inflammation present among affected bronchi varied considerably. Furthermore, a wide range of pathologic processes of potential clinical significance were evident in half of the patients. We conclude that significant histologic heterogeneity exists among patients undergoing retransplantation for BOS, potentially contributing to the variability of patient responses to treatment.

The glomerular podocyte plays a key role in maintaining the integrity of the glomerular filtration barrier. This function may be regulated by activation of cell surface G protein-coupled receptors (GPCR). Studies suggest that podocytes express GPCR that are implicated in the pathogenesis of glomerular diseases. Common to these GPCR systems is activation of phospholipase C through the Gq alpha-subunit (Galpha q). For investigating the role of Galpha q-coupled signaling pathways in promoting renal injury in podocytes, a constitutively active Galpha q subunit (Galpha qQ > L) was expressed in glomerular podocytes using the mouse nephrin promoter. Transgenic (TG) mice demonstrated albuminuria as well as a decrease in both kidney mass and nephron number. By light microscopy, a portion of the TG mice had glomerular abnormalities, including focal to diffuse hypercellularity and segmental sclerosis. Consistent with injury-promoting effects of Galpha qQ > L, there was a significant reduction in podocalyxin mRNA as well as nephrin mRNA and protein levels in glomeruli from TG mice compared with non-TG controls. Expression of the transgene also seemed to increase susceptibility to glomerular injury, because treatment with puromycin aminonucleoside enhanced proteinuria in TG mice compared with non-TG littermate controls (4.2 +/- 1.0 [TG] versus 1.6 +/- 0.3 [non-TG] mg/24 h; P = 0.0161). Thus, activation of Galpha q in glomerular podocytes caused alterations in glomerular histomorphology, albuminuria, decreased nephron mass, and reduced glomerular expression of both nephrin and podocalyxin as well as enhanced susceptibility to glomerular damage induced by puromycin aminonucleoside. It is speculated that Galpha q-coupled signaling cascades may be important effector pathways mediating renal injury.

Although innate immunity is crucial to pulmonary host defense and can initiate immune and inflammatory responses independent of adaptive immunity, it remains unstudied in the context of transplant rejection. To investigate the role of innate immunity in the development of allograft rejection, we assessed the impact of two functional polymorphisms in the toll-like receptor 4 (TLR4) associated with endotoxin hyporesponsiveness on the development of acute rejection after human lung transplantation. Patients and donors were screened for the TLR4 Asp299Gly and Thr399Ile polymorphisms by polymerase chain reaction using sequence-specific primers. The rate of acute rejection at 6 months was significantly reduced in recipients, but not in donors, with the Asp299Gly or Thr399Ile alleles as compared with wild type (29 vs. 56%, respectively, p = 0.05). This association was confirmed in Cox proportional hazards and multivariate logistic regression models. Our results suggest activation of innate immunity in lung transplant recipients through TLR4 contributes to the development acute rejection after lung transplantation. Therapies directed at inhibition of innate immune responses mediated by TLR4 may represent a novel and effective means to prevent acute rejection after lung transplantation.