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Glomerular deposition of monoclonal IgM, frequently in the form of intracapillary pseudothrombi, can be seen in Waldenström macroglobulinemia (WM) and type I cryoglobulinemia (CG). They are typically associated with plasma cell or B-lymphoid neoplasms, particularly lymphoplasmacytic lymphoma (LPL). While infection is a frequent trigger of mixed (type II and III) CG, its association with type I CG is uncommon. We report two cases in which striking lambda-chain-restricted IgM deposits and acute kidney injury (AKI) occurred in the setting of known or suspected systemic infections, with prompt resolution on treatment of the infection. [ABSTRACT FROM AUTHOR]

Context.--Graft-versus-host disease of the gastrointestinal tract is a common complication of hematopoietic stem cell transplant associated with significant morbidity and mortality. Accurate diagnosis can be difficult and is a truly clinicopathologic endeavor. Objectives.--To assess the diagnostic sensitivity of gastrointestinal graft-versus-host disease using the 2015 National Institutes of Health (NIH) histology consensus guidelines and to analyze histologic findings that support the guidelines. Design.--Patients with allogeneic hematopoietic stem cell transplants were identified via a retrospective search of our electronic medical records from January 1, 2005, to January 1, 2011. Endoscopies with available histology were reviewed by 2 pathologists using the 2015 NIH guidelines. The clinical diagnosis was used as the gold standard. A nontransplant set of endoscopic biopsies was used as a control. Results.--Of the 250 total endoscopies, 217 (87%) had a clinical diagnosis of gastrointestinal graft-versus-host disease. Use of the NIH consensus guidelines showed a sensitivity of 86% and a specificity of 65%. Thirty-seven of 58 (64%) cases with an initial false-negative histopathologic diagnosis were diagnosed as graft-versus-host disease on our review. Conclusions.--Use of the NIH histology consensus guidelines results in a high sensitivity and specificity, thereby decreasing false-negatives. Additionally, use of the NIH guidelines aids in creating uniformity and diagnostic clarity. Correlation with clinical and laboratory findings is critical in evaluating the differential diagnosis and to avoid false-positives. As expected, increased apoptosis with decreased inflammation was associated with a pathologic diagnosis of graft-versus-host disease and supports the NIH guidelines. doi: 10.5858/arpa.2017-0054-0A, Graft-versus-host disease (GVHD) of the gastrointestinal (GI) tract is a common complication of hematopoietic stem cell transplant (HSCT) and is associated with significant morbidity and mortality. (1-6) Graft-versus-host disease develops [...]

Infection-related glomerulonephritis is well recognized in patients with ongoing infections. It can be missed, however, if the infection is unusual or undetected. We present three cases where the renal biopsy findings prompted the identification or treatment of systemic infections. Case 1: A 84-year-old male presented with acute kidney injury (AKI) and IgA vasculitis on skin biopsy. A renal biopsy showed active glomerulonephritis with abundant neutrophils and predominantly mesangial immune complex deposits containing IgA. The findings prompted an infectious workup which was positive for COVID-19, suggesting exacerbation of IgA nephropathy by recent COVID-19 infection. Case 2: A 31-year-old female status post kidney transplant for granulomatosis with polyangiitis (GPA) had recent pregnancy with preterm delivery, disseminated herpes simplex virus (HSV) infection with HSV hepatitis, E. coli on urine culture, and AKI. A renal biopsy showed proliferative glomerulonephritis with subendothelial and mesangial immune complex deposits containing IgG and C3. The findings were most consistent with infection-related immune complex glomerulonephritis, most likely HSV-related. Case 3: A 78-year-old female presented with AKI, proteinuria, hematuria, and positive p-ANCA. Clinically, ANCA vasculitis was suspected, and renal biopsy did show focal, segmental, necrotizing glomerulonephritis. However, immunofluorescence and electron microscopy showed IgM-rich deposits in the mesangium. The unusual presentation prompted an infectious workup including a Bartonella antibody panel which showed very high titers, suggesting Bartonella endocarditis. Infection-related glomerulonephritis has a wide variety of presentations histologically and clinically. The three cases we present here emphasize the importance of recognizing these entities to help guide treatment and improve patient care. [ABSTRACT FROM AUTHOR]

Activation of the renin-angiotensin system contributes to the progression of chronic kidney disease. Based on the known cellular effects of ANG II to promote inflammation, we posited that stimulation of lymphocyte responses by ANG II might contribute to the pathogenesis of hypertensive kidney injury. We therefore examined the effects of the immunosuppressive agent mycophenolate mofetil (MMF) on the course of hypertension and kidney disease induced by chronic infusion of ANG II in 129/SvEv mice. Although it had no effect on the severity of hypertension or cardiac hypertrophy, treatment with MMF significantly reduced albuminuria and ameliorated kidney injury, decreasing glomerulosclerosis and reducing lymphocyte infiltration into the renal interstitium. Attenuation of renal pathology with MMF was associated with reduced expression of mRNAs for the proinflammatory cytokines interferon-[gamma] and tumor necrosis factor-[alpha] and the profibrotic cytokine transforming growth factor-[beta]. As infiltration of the kidney by T lymphocytes was a prominent feature of ANG II-dependent renal injury, we carried out experiments examining the effects of ANG II on lymphocytes in vitro. We find that exposure of splenic lymphocytes to ANG II causes prominent rearrangements of the actin cytoskeleton. These actions require the activity of Rho kinase. Thus, ANG II exaggerates hypertensive kidney injury by stimulating lymphocyte responses. These proinflammatory actions of ANG II seem to have a proclivity for inducing kidney injury while having negligible actions in the pathogenesis of cardiac hypertrophy. inflammation; kidney diseases; T lymphocytes

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. [ABSTRACT FROM AUTHOR]

Electron microscopy is a mainstay in the analysis of renal biopsies, where it is typically employed in a correlative fashion along with light and immunofluorescence microscopy. Despite the development of a growing armamentarium of molecular and biochemical analytic methods as well as new immunostains with a widening panel of immunoreactants, electron microscopy remains crucial to the diagnosis of a number of disorders involving the renal glomerulus, vasculature, and tubulointerstitial compartment. The number of renal biopsies continues to grow and the indications for these biopsies continue expanding together with our understanding of disease processes. Proper collection of biopsies and careful analysis of data emanating from diagnostic modalities, clinical information, imaging, gross and microscopic tissue analysis, including a wide range of ancillary studies, represent the essential paradigm for generating detailed diagnoses with clinical significance. This communication offers a guide to the pre-analytic and analytic process for renal biopsy examination, discusses diagnostic keys and pitfalls for an important category of renal diseases (immune complex disorders), and provides an introduction to a useful adjunct diagnostic method (ultrastructural immunolabeling). Renal pathologists should render expert diagnoses that guide patient management, provide prognostic information and lead to targeted new therapeutic interventions that are currently available. [ABSTRACT FROM AUTHOR]

Background. Donor-derived malignancy is a rare complication in patients who undergo organ transplant. Approaches to treatment have largely been individualized based on clinical circumstances given the lack of evidence-based guidelines, with therapeutic options ranging from discontinuation of immunosuppression and transplantectomy to the addition of chemotherapy or radiotherapy. Case Presentation. Herein, we describe a 60-year-old woman with metastatic donor-derived upper tract urothelial carcinoma (UTUC) discovered nine years postrenal transplant. Molecular diagnostic studies using polymerase chain reaction amplification of short tandem repeat alleles and HLA tissue typing proved that the urothelial carcinoma originated from donor tissue. She achieved sustained complete remission with transplant nephroureterectomy, retroperitoneal lymphadenectomy, immunosuppression withdrawal, and immunotherapy with pembrolizumab. Routine radiologic surveillance has demonstrated 15-month progression-free survival to date off pembrolizumab, and she is now under consideration for retransplantation. Conclusions. Immunotherapy using checkpoint inhibitors can serve as a novel treatment option for patients in the clinical predicament of having a solid organ transplant and simultaneous metastatic malignancy. In this report, we also discuss the oncogenic potential of BK virus, the use of checkpoint inhibitors in urothelial carcinoma, and the feasibility of retransplant for this patient population. [ABSTRACT FROM AUTHOR]

Kidney biopsy is a mainstay in the diagnosis and management of renal disease in patients with systemic lupus erythematosus. Though biopsies from patients with lupus typically show various forms of immune complex glomerulonephritis, other pathologies are occasionally encountered, including unusual lupus-related nephropathies, other forms of autoimmune disease, and occasional renal disorders without any direct connection with lupus or autoimmunity. Electron microscopy is a powerful tool for detecting and classifying these unusual conditions, which frequently have important therapeutic and prognostic implications. [ABSTRACT FROM AUTHOR]

Background: Mutations in podocin (NPHS2) are the most common cause of childhood onset autosomal recessive steroid-resistant nephrotic syndrome (SRNS). The disease is characterized by early-onset proteinuria, resistance to immunosuppressive therapy and rapid progression to end-stage renal disease. Compound heterozygous changes involving the podocin variant R229Q combined with another pathogenic mutation have been associated with a mild phenotype with disease onset often in adulthood. Methods: We screened 19 families with early-onset SRNS for mutations in NPHS2 and WT1 and identified four disease-causing mutations (three in NPHS2 and one in WT1) prior to planned whole-exome sequencing. Results: We describe two families with three individuals presenting in childhood who are compound heterozygous for R229Q and one other pathogenic NPHS2 mutation, either L327F or A297V. One child presented at age 4 years (A297V plus R229Q) and the other two at age 13 (L327F plus R229Q), one with steadily deteriorating renal function. Conclusions: These cases highlight the phenotypic variability associated with the NPHS2 R229Q variant plus pathogenic mutation. Individuals may present with early aggressive disease. [ABSTRACT FROM AUTHOR]

African Americans have a disproportionate risk for developing nephropathy. This disparity has been attributed to coding variants (G1 and G2) in apolipoprotein L1 (APOL1); however, there is little functional evidence supporting the role of this protein in renal function. Here, we combined genetics and in vivo modeling to examine the role of apol1 in glomerular development and pronephric filtration and to test the pathogenic potential of APOL1 G1 and G2. Translational suppression or CRISPR/Cas9 genome editing of apol1 in zebrafish embryos results in podocyte loss and glomerular filtration defects. Complementation of apol1 morphants with wild-type human APOL1 mRNA rescues these defects. However, the APOL1 G1 risk allele does not ameliorate defects caused by apol1 suppression and the pathogenicity is conferred by the cis effect of both individual variants of the G1 risk haplotype (I384M/S342G). In vivo complementation studies of the G2 risk allele also indicate that the variant is deleterious to protein function. Moreover, APOL1 G2, but not G1, expression alone promotes developmental kidney defects, suggesting a possible dominant-negative effect of the altered protein. In sickle cell disease (SCD) patients, we reported previously a genetic interaction between APOL1 and MYH9. Testing this interaction in vivo by co-suppressing both transcripts yielded no additive effects. However, upon genetic or chemical induction of anemia, we observed a significantly exacerbated nephropathy phenotype. Furthermore, concordant with the genetic interaction observed in SCD patients, APOL1 G2 reduces myh9 expression in vivo, suggesting a possible interaction between the altered APOL1 and myh9. Our data indicate a critical role for APOL1 in renal function that is compromised by nephropathy-risk encoding variants. Moreover, our interaction studies indicate that the MYH9 locus is also relevant to the phenotype in a stressed microenvironment and suggest that consideration of the context-dependent functions of both proteins will be required to develop therapeutic paradigms. [ABSTRACT FROM AUTHOR]

A study was conducted to determine the independent function and the additive effects of deficits for L-selectin and intercellular adhesion molecule-1 (ICAM-1) receptors in the reperfused ischemic liver. Results showed that L-selectin mediates microcirculatory disturbances and hepatocyte injury in the ischemic mouse liver. ICAM-1 mediates injury and microcirculatory disturbances in conjunction with L-selectin.

Ultrastructural examination remains a crucial diagnostic tool for analysis of renal biopsies, along with light and immunofluorescence microscopy. Several advantages of electron microscopy are the ability to detect most forms of glomerular disease/dysfunction; the ability to examine small, suboptimal, or unusual specimens; and superior resolution that allows the investigator to hunt without preconceived ideas of what he/she is looking for or will find. A few shortcomings must be noted for completeness, including inability to detect disorders without specific ultrastructural signature, biochemical heterogeneity of deposits with similar or identical ultrastructural appearances, and occasional false-negative results in diseases with focal manifestations. [ABSTRACT FROM AUTHOR]

Activation of type 1 angiotensin (AT(1)) receptors causes hypertension, leading to progressive kidney injury. AT(1) receptors are expressed on immune cells, and previous studies have identified a role for immune cells in angiotensin II-dependent hypertension. We, therefore, examined the role of AT(1) receptors on immune cells in the pathogenesis of hypertension by generating bone marrow chimeras with wild-type donors or donors lacking AT(1A) receptors (BMKO). The 2 groups had virtually identical blood pressures at baseline, suggesting that AT(1) receptors on immune cells do not make a unique contribution to the determination of baseline blood pressure. By contrast, in response to chronic angiotensin II infusion, the BMKOs had an augmented hypertensive response, suggesting a protective effect of AT(1) receptors on immune cells with respect to blood pressure elevation. The BMKOs had 50% more albuminuria after 4 weeks of angiotensin II-dependent hypertension. Angiotensin II-induced pathological injury to the kidney was similar in the experimental groups. However, there was exaggerated renal expression of the macrophage chemokine monocyte chemoattractant protein 1 in the BMKO group, leading to persistent accumulation of macrophages in the kidney. This enhanced mononuclear cell infiltration into the BMKO kidneys was associated with exaggerated renal expression of the vasoactive mediators interleukin-1beta and interleukin-6. Thus, in angiotensin II-induced hypertension, bone marrow-derived AT(1) receptors limited mononuclear cell accumulation in the kidney and mitigated the chronic hypertensive response, possibly through the regulation of vasoactive cytokines. [ABSTRACT FROM AUTHOR]

With improving survival following solid organ transplantation, clinicians must be aware of post-transplant complications. One increasingly frequent complication is the development of malignancy after transplantation. The most common malignancies encountered in the post--solid organ transplant setting are nonmelanoma skin cancers, post-transplant lymphoproliferative disorders, and Kaposi's sarcoma (KS). The pathogenesis of these tumors is likely related to the immunosuppressive drugs used post-transplantation and subsequent viral infection. Treatment involves modification of the immunosuppressive drug regimen, resection of localized disease, and chemotherapy. We present the second reported case of a patient with lung transplantation who developed KS in the lung graft. [ABSTRACT FROM AUTHOR]

Background and Aims: Rho kinase (ROCK) inhibition reduces systemic blood pressure (BP) and decreases renal damage in animal models of kidney disease. The aim of this study was to determine if ROCK inhibition might have beneficial effects in glomerular disease processes that are independent of systemic BP. Methods: We investigated the effects of the ROCK inhibitor Y27632 and hydralazine in murine puromycin aminonucleoside (PAN) nephrosis. Results: Treatment with either Y27632 or hydralazine similarly reduced systolic BP compared to vehicle-treated controls. Seven days after treatment with PAN, albuminuria, proteinuria and effacement of podocyte foot processes were significantly reduced in Y27632- and hydralazine-treated mice compared to vehicle-treated animals. Treatment with PAN significantly reduced expression of the podocyte proteins nephrin and Neph1, and the loss of glomerular nephrin was attenuated by treatment with Y27632 but not by treatment with hydralazine. In cultured podocytes, PAN potently activated both Rho and ROCK, and PAN-induced ROCK activation was prevented by Y27632. Conclusions: The ROCK inhibitor Y27632 attenuated glomerular nephrin loss in murine PAN nephrosis independent of its effects on systemic BP. Copyright © 2008 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Introduction: Posttransplant lymphoproliferative disorder (PTLD) is a relatively infrequent but devastating complication that occurs after solid-organ transplantation. Although the optimal treatment for this condition is unknown, rituximab, a murine/human chimeric monoclonal antibody, has shown promise in the treatment of PTLD. In this report, we define the incidence, clinical features at presentation, and response to treatment of all cases of PTLD observed at our institution over a 10-year period, including four patients who received treatment with rituximab. Methods: A review of all patients who underwent lung or heart-lung transplant at Duke University from 1992 to 2002 was performed (n = 400), and demographic and clinical outcome data were extracted. Results: PTLD was observed in 10 of 400 patients (2.5%). Patients who acquired PTLD were predominately > 55 years old (8 of 10 patients) and with a native disease of COPD (7 of 10 patients). Diagnosis of PTLD was made a median of 343 days after transplant. The type of transplant and Epstein-Barr virus (EBV) status prior to transplant did not appear to influence the risk for PTLD. Patients presented with thoracic organ involvement (7 of 10 patients), extrapulmonary disease (2 of 10 patients), or both (1 of 10 patients). Histologic subtypes included polymorphic B cell (n = 4), monomorphic B cell (n = 3), B cell without further classification (n = 2), and anaplastic T cell (n = 1). Only one patient responded to reduced immunosuppression alone. Patients treated with surgery or radiation (n = 2) or rituximab (n = 4) had favorable responses to therapy. Both patients treated with chemotherapy died related to complications of treatment and PTLD. Conclusions: Presentation and histologic appearance of PTLD varies considerably among lung transplant recipients. PTLD was more frequent among older patients with COPD, regardless of pretransplant EBV serology. Rituximab appears effective as a first-line therapy for PTLD, but additional studies are needed in order to define its efficacy and side effect profile in this population of patients. [ABSTRACT FROM AUTHOR]

Organized or structured deposits are encountered during electron microscopic examination of kidney tissue in a wide variety of primary renal and multisystemic disorders. They are most commonly seen in the renal glomerulus, though extraglomerular sites are occasionally involved. In some cases, organized deposits herald the presence of a specific disease process. Included in this category are organized substances containing immunoglobin molecules or parts thereof as well as non-immunoglobin-containing materials that accumulate in several rare heritable disorders. A second broad category of structured deposits include substances that accumulate in response to non-specific tissue injuries. In many instances, such "look-alikes" can be difficult o distinguish from disease-specific structured deposits. Ultrastructural pathology is central to the detection and characterization of organized deposits in the kidney and is the primary focus of this paper. Correlative light microscopic studies are often useful, however, and will be described as well.. [ABSTRACT FROM AUTHOR]

Influenza infection is increasingly recognized to cause significant morbidity and mortality in the community, especially in pediatric patients and elderly persons. Influenza infection, however, has not been well described among thoracic organ transplant recipients. We provide the first detailed clinical, radiographic, and histologic description of influenza pneumonia among three lung transplant recipients. The presentation varied considerably among the three patients and, in some cases, was atypical, for influenza. Despite treatment, a persistent decline in pulmonary function occurred in all three patients after the acute illness. Interestingly, on follow-up biopsy specimens, each patient had histologic evidence of acute rejection and/or obliterative bronchiolitis. Additional research, therefore, is needed to clarify the relationship between influenza infection, acute rejection, and obliterative bronchiolitis. [ABSTRACT FROM AUTHOR]

Gastroesophageal reflux (GER) is increasingly recognized as contributing to a number of pulmonary disorders. The relationship of GER to pulmonary allograft dysfunction after lung transplantation is unknown. In this report, we describe a lung transplant recipient who developed an acute decline in pulmonary function several months after a retransplantation for chronic rejection. A pulmonary workup at that time, including bronchoscopy with biopsy, revealed bronchial inflammation with no allograft rejection or infection. Because of increasing GI symptoms after retransplantation, the patient also underwent additional testing, which revealed severe acid reflux. The treatment of this patient's acid reflux with Nissen fundoplication surgery resuited in a prompt and sustained improvement in his pulmonary function. We suggest that GER should be considered among the potential causes of allograft dysfunction after lung transplantation. [ABSTRACT FROM AUTHOR]

Renal diseases involving glomerular deposits of fibrillary material are an important diagnostic challenge for the ultrastructural pathologist. Two primary disorders of this type, termed ``fibrillary glomerulonephritis'' (characterized by fibrils measuring approximately 20nm in diameter) and ``immunotactoid glomerulopathy'' (characterized by larger, microtubular deposits), have been described. The possible relatedness of these two disorders and their potential association with other systemic illnesses are subjects of current debate. Other multisystemic diseases, including amyloidosis and various forms of cryoglobulinemia, can also present with fibrillary or microtubular deposits in the kidney. Five cases are presented in which fibrillar or microtubular structures were identified in renal biopsies by ultrastructural examination. The distinction between fibrillary glomerulonephritis,immunotactoid glomerulopathy, and other processes that have similar ultrastructural features are discussed. [ABSTRACT FROM AUTHOR]

Examines the independent role and additive effects of deficits for leukocyte-selectin and intercellular adhesion molecule-1 (ICAM-1) receptors in the reperfused ischemic liver. Susceptibility of liver to the ischemia-reperfusion (I/R) injury; Effects of hepatic ischemia on animal survival; Details on I/R injury.