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Abstract Background Small vessel childhood primary angiitis of the central nervous system (SV-cPACNS) is a rare disease characterized by inflammation within small vessels such as arterioles or capillaries. Case presentation We report a case of SV-cPACNS in an 8-year-old boy confirmed by brain biopsy. This patient was also incidentally found to have anti-glial fibrillary acidic protein (GFAP) antibodies in the cerebrospinal fluid (CSF) but had no evidence of antibody-mediated disease on brain biopsy. A literature review highlighted the rarity of SV-cPACNS and found no prior reports of CSF GFAP-associated SV-cPACNS in the pediatric age group. Conclusion We present the first case of biopsy proven SV-cPACNS vasculitis associated with an incidental finding of CSF GFAP antibodies. The GFAP antibodies are likely a clinically insignificant bystander in this case and possibly in other diseases with CNS inflammation. Further research is needed to determine the clinical significance of newer CSF autoantibodies such as anti-GFAP before they are used for medical decision-making in pediatrics.

Disseminated toxoplasmosis is an uncommon but highly lethal cause of hyperferritinemic sepsis after hematopoietic cell transplantation (HCT). We report two cases of disseminated toxoplasmosis from two centers in critically ill adolescents after HCT: a 19-year-old who developed fever and altered mental status on day +19 after HCT and a 20-year-old who developed fever and diarrhea on day +52 after HCT. Both patients developed hyperferritinemia with multiple organ dysfunction syndrome and profound immune dysregulation, which progressed to death despite maximal medical therapies. Because disseminated toxoplasmosis is both treatable and challenging to diagnose, it is imperative that intensivists maintain a high index of suspicion for Toxoplasma gondii infection when managing immunocompromised children, particularly in those with known positive T. gondii serologies.

Background Patients with restless legs syndrome (RLS) have increased silent microvascular disease by magnetic resonance imaging. However, there has been no previous autopsy confirmation of these magnetic resonance imaging findings. RLS is also frequently associated with inflammatory and immunologically mediated medical disorders. The postmortem cortex in patients with RLS was therefore evaluated for evidence of microvascular and immunological changes. Methods and Results Ten microvascular injury samples of precentral gyrus in 5 patients with RLS (3 men, 2 women; mean age, 81 years) and 9 controls (2 men, 7 women; mean age, 90 years) were studied by hematoxylin and eosin stains in a blinded fashion. None of the subjects had a history of stroke or neurologic insults. In a similar manner, the following immunohistochemistry stains were performed: (1) glial fibrillary acidic protein (representing gliosis, reactive change of glial cells in response to damage); (2) CD3 (a T‐cell marker); (3) CD19 (a B‐cell marker); (4) CD68 (a macrophage marker); and (5) CD117 (a mast cell marker). Patients with RLS had significantly greater silent microvascular disease (P=0.015) and gliosis (P=0.003). T cells were increased in RLS compared with controls (P=0.009) and tended to colocalize with microvascular disease (P=0.003). Other markers did not differ. There was no correlation between microvascular lesion load and RLS severity or duration. Conclusions Patients with RLS had statistically significantly more silent cerebral microvascular disease and gliosis than controls compatible with previous magnetic resonance imaging studies and with studies showing a link between RLS and hypertension, clinical stroke, and cardiovascular disease. T‐cell invasion may be a secondary phenomenon.

This case of infective endocarditis masquerading as mixed cryoglobulinemia in a man with a history of intravenous drug use (IVDU) and hepatitis C virus (HCV) highlights the importance of maintaining a broad differential and continually re-evaluating the working diagnosis as new information presents itself. The patient presented to an outside hospital and was treated for presumptive mixed cryoglobulinemia with corticosteroid therapy. When the patient did not improve, he was transferred to a tertiary care center for possible Rituximab and/or plasmapheresis. Further investigation revealed Enterococcus bacteremia with subsequent workup consistent with infective endocarditis (IE). This case highlights a diagnostic dilemma and demonstrates the importance of a thorough evaluation as it pertains to overlapping features of IE and mixed cryoglobulinemia.

Diabetic nephropathy (DN) is a major life-threatening complication of diabetes. Renal lesions affect glomeruli and tubules, but the pathogenesis is not completely understood. Phospholipids and glycolipids are molecules that carry out multiple cell functions in health and disease, and their role in DN pathogenesis is unknown. We employed high spatial resolution MALDI imaging MS to determine lipid changes in kidneys of eNOS−/−db/db mice, a robust model of DN. Phospholipid and glycolipid structures, localization patterns, and relative tissue levels were determined in individual renal glomeruli and tubules without disturbing tissue morphology. A significant increase in the levels of specific glomerular and tubular lipid species from four different classes, i.e., gangliosides, sulfoglycosphingolipids, lysophospholipids, and phosphatidylethanolamines, was detected in diabetic kidneys compared with nondiabetic controls. Inhibition of nonenzymatic oxidative and glycoxidative pathways attenuated the increase in lipid levels and ameliorated renal pathology, even though blood glucose levels remained unchanged. Our data demonstrate that the levels of specific phospho- and glycolipids in glomeruli and/or tubules are associated with diabetic renal pathology. We suggest that hyperglycemia-induced DN pathogenic mechanisms require intermediate oxidative steps that involve specific phospholipid and glycolipid species.

Background: Acute tubular necrosis and pigment induced kidney injury are well described consequences of cocaine abuse. However, acute interstitial nephritis associated with cocaine use has been previously reported in only three patients. Case presentation: We present the case of a 49-year-old man who developed acute kidney injury from biopsy-proven interstitial nephritis after nasal insufflation of cocaine. Unlike prior reports, our patient remained non-oliguric and did not require renal replacement therapy. Conclusions: Interstitial nephritis should be considered as a potential cause of acute kidney injury associated with cocaine use. The approach to management of cocaine associated acute kidney injury (AKI) may be different in patients with interstitial nephritis than for those with tubular necrosis or pigment induced renal injury.

Summary: Theories for restless legs syndrome (RLS) pathogenesis include iron deficiency, dopamine dysregulation and peripheral neuropathy. Increased prevalence of small intestinal bacterial overgrowth (SIBO) in controlled studies in RLS and case reports of post-infectious RLS suggest potential roles for inflammation and immunological alterations. A literature search for all conditions associated with RLS was performed. These included secondary RLS disorders and factors that may exacerbate RLS. All of these conditions were reviewed with respect to potential pathogenesis including reports of iron deficiency, neuropathy, SIBO, inflammation and immune changes. A condition was defined as highly-associated if there was a prevalence study that utilized an appropriate control group. Small case reports were recorded but not included as definite RLS-associated conditions. Fifty four diseases, syndromes and conditions have been reported to cause and/or exacerbate RLS. Of these, 38 have been reported to have a higher prevalence than age-matched controls, 9 have adequate sized reports and have general acceptance as RLS-associated conditions and 7 have been reported in case report form. Overall, 42 of the 47 RLS-associated conditions (89%) have also been associated with inflammatory and/or immune changes. In addition, 43% have been associated with peripheral iron deficiency, 40% with peripheral neuropathy and 32% with SIBO. Most of the remaining conditions have yet to be studied for these factors. The fact that 95% of the 38 highly-associated RLS conditions are also associated with inflammatory/immune changes suggests the possibility that RLS may be mediated or affected through these mechanisms. Inflammation can be responsible for iron deficiency and hypothetically could cause central nervous system iron deficiency-induced RLS. Alternatively, an immune reaction to gastrointestinal bacteria or other antigens may hypothetically cause RLS by a direct immunological attack on the central or peripheral nervous system. [Copyright &y& Elsevier]

Presents several studies on hypertension and systemic disease. Alternatives to measuring ambulatory pressure; Analysis of the extent of microvascular injury characterized by fragmented red blood cells in the mesangium of glomeruli in diabetic nephropathy; Effectiveness of percutaneous transluminal angioplasty in renal artery stenosis; Effects of stent placement for renal artery stenosis on the function of treated and contra-lateral kidneys.

Animal models that mimic human diabetic nephropathy are useful to identify key factors in pathogenesis of this disease, as well as the development of new therapies. Several mouse models of diabetes have features of human diabetic nephropathy, yet none of these completely fulfill the Animal Models of Diabetes Complications Consortium criteria and completely reproduce pathological and functional features of the human disease. The Akita mouse carries a mutation in the insulin-2 gene and, to date, only survives as heterozygotes that develop spontaneous type 1 diabetes. Here we show that Akita mice with mutation of both insulin-2 alleles (Akita knockout (KO)) survive if crossed onto the Balb/c background. These mice develop hyperglycemia, more severe albuminuria, and mesangial sclerosis compared with heterozygous mice on the same genetic background. Interestingly, crossing these AkitaKO mice with integrin α1KO mice, a model of exacerbated glomerulosclerosis after injury and also on the Balb/c background, resulted in a 16-fold increase in albuminuria, significant mesangial matrix expansion, nodular and diffuse glomerulosclerosis, and a 2-fold increase in glomerular basement membrane thickening when compared with nondiabetic mice. Moreover, a significant decline in glomerular filtration was evident in the α1KOAkitaKO mice at 6 months of age. Thus, the integrin α1KOAkitaKO Balb/c mouse represents a promising model presenting with most features of human diabetic nephropathy. [ABSTRACT FROM AUTHOR]

Objectives: Amyloid light chain (AL)-κ and AL-λ share common histopathologic changes; however, the potential difference in clinical manifestations, histologic findings, and clinical significance between the 2 subtypes remain unclear., Methods: In a retrospective study, 94 kidney biopsies for AL amyloidosis were evaluated using the composite scarring injury score (CSIS) and amyloid score (AS). Results were then compared between AL-κ and AL-λ., Results: Comparing AS and CSIS between AL-κ and AL-λ, the AS was significantly higher in AL-κ than in AL-λ, with 2 components of AS (capillary wall and vascular amyloid) scoring higher in AL-κ than in AL-λ, while mesangial and interstitial ASs were similar in the 2 cohorts. In addition, the proportion of periodic acid-Schiff strong-staining amyloid in AL-κ was markedly higher than in AL-λ. There was no significant difference in CSIS and its components between the 2 subtypes of AL amyloidosis., Conclusions: Overall, AL-κ presents with higher serum creatinine and a higher AS score than AL-λ at biopsy, which may indicate a worse prognosis and be an important reference for clinical management., (© The Author(s) 2023. Published by Oxford University Press on behalf of American Society for Clinical Pathology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Competing Interests: A.B. Fogo reports consultancy for Novartis; research funding from Bayer, Gilead, and Novartis; honoraria from Amgen, GSK, and Novartis; being on the advisory committee for Bayer; being on the editorial board for American Journal of Physiology-Renal Physiology, American Journal of Pathology, Human Pathology, and JASN; being an associate editor for Kidney International and Laboratory Investigation; being a subject editor for Nephrology Dialysis Transplantation; being the guest editor for the yearly pathology focus in Current Opinion in Nephrology and Hypertension; being a speaker at various national nephrology meetings, Associate Editor Kidney International; and being President Elect of the ISN (president as of April 19, 2021). The remaining author has nothing to disclose.

Background Patients with restless legs syndrome (RLS) have increased silent microvascular disease by magnetic resonance imaging. However, there has been no previous autopsy confirmation of these magnetic resonance imaging findings. RLS is also frequently associated with inflammatory and immunologically mediated medical disorders. The postmortem cortex in patients with RLS was therefore evaluated for evidence of microvascular and immunological changes. Methods and Results Ten microvascular injury samples of precentral gyrus in 5 patients with RLS (3 men, 2 women; mean age, 81 years) and 9 controls (2 men, 7 women; mean age, 90 years) were studied by hematoxylin and eosin stains in a blinded fashion. None of the subjects had a history of stroke or neurologic insults. In a similar manner, the following immunohistochemistry stains were performed: (1) glial fibrillary acidic protein (representing gliosis, reactive change of glial cells in response to damage); (2) CD3 (a T-cell marker); (3) CD19 (a B-cell marker); (4) CD68 (a macrophage marker); and (5) CD117 (a mast cell marker). Patients with RLS had significantly greater silent microvascular disease ( P =0.015) and gliosis ( P =0.003). T cells were increased in RLS compared with controls ( P =0.009) and tended to colocalize with microvascular disease ( P =0.003). Other markers did not differ. There was no correlation between microvascular lesion load and RLS severity or duration. Conclusions Patients with RLS had statistically significantly more silent cerebral microvascular disease and gliosis than controls compatible with previous magnetic resonance imaging studies and with studies showing a link between RLS and hypertension, clinical stroke, and cardiovascular disease. T-cell invasion may be a secondary phenomenon.

This case of infective endocarditis masquerading as mixed cryoglobulinemia in a man with a history of intravenous drug use (IVDU) and hepatitis C virus (HCV) highlights the importance of maintaining a broad differential and continually re-evaluating the working diagnosis as new information presents itself. The patient presented to an outside hospital and was treated for presumptive mixed cryoglobulinemia with corticosteroid therapy. When the patient did not improve, he was transferred to a tertiary care center for possible Rituximab and/or plasmapheresis. Further investigation revealed Enterococcus bacteremia with subsequent workup consistent with infective endocarditis (IE). This case highlights a diagnostic dilemma and demonstrates the importance of a thorough evaluation as it pertains to overlapping features of IE and mixed cryoglobulinemia.

Drugs are associated frequently with the development of various types of acute and chronic kidney diseases. Nephrotoxicity is associated most commonly with injury in the tubulointerstitial compartment manifested as either acute tubular injury or acute interstitial nephritis. A growing number of reports has also highlighted the potential for drug-induced glomerular disease, including direct cellular injury and immune-mediated injury. Recognition of drug-induced nephropathies and rapid discontinuation of the offending agents are critical to maximizing the likelihood of renal function recovery. This review will focus on the pathology and pathogenesis of drug-induced acute interstitial nephritis and drug-induced glomerular diseases., (© 2016 John Wiley & Sons Ltd.)

Retinoic acid (RA) has been used therapeutically to reduce injury and fibrosis in models of AKI, but little is known about the regulation of this pathway and what role it has in regulating injury and repair after AKI. In these studies, we show that RA signaling is activated in mouse and zebrafish models of AKI, and that these responses limit the extent of injury and promote normal repair. These effects were mediated through a novel mechanism by which RA signaling coordinated the dynamic equilibrium of inflammatory M1 spectrum versus alternatively activated M2 spectrum macrophages. Our data suggest that locally synthesized RA represses proinflammatory macrophages, thereby reducing macrophage-dependent injury post-AKI, and activates RA signaling in injured tubular epithelium, which in turn promotes alternatively activated M2 spectrum macrophages. Because RA signaling has an essential role in kidney development but is repressed in the adult, these findings provide evidence of an embryonic signaling pathway that is reactivated after AKI and involved in reducing injury and enhancing repair., (Copyright © 2016 by the American Society of Nephrology.)

Tolosa-Hunt syndrome is an idiopathic inflammatory process of the cavernous sinus or orbit manifesting as painful ophthalmoplegia. In this report, we detail the case of a 6-year-old boy who presented with several weeks of unilateral headache and diplopia. He was found to have an infiltrative process involving the bilateral cavernous sinuses and pituitary gland on MRI. Given a progressing infiltrative central nervous system process on repeat MRI and the development of cerebral salt wasting, a biopsy was performed revealing actinomycosis. To our knowledge, this is the first reported case of actinomycosis masquerading as Tolosa-Hunt syndrome in a child., (© 2016 S. Karger AG, Basel.)