IgG4-related kidney disease: Clinicopathologic features, differential diagnosis, and mimics.

IgG4-related kidney disease (IgG4-RKD) encompasses all forms of kidney disease that are part of IgG4-related disease (IgG4-RD). First recognized as IgG4-related tubulointerstitial nephritis (IgG4-TIN), and then IgG4-related membranous glomerulonephritis (IgG4-MGN), we now recognize additional patterns of interstitial nephritis, glomerular disease, and vascular disease that can be seen as part of IgG4-RKD. The clinical presentation is variable and can include acute or chronic kidney injury, proteinuria or nephrotic syndrome, mass lesion(s), and obstruction. While usually associated with other organ involvement by IgG4-RD, kidney-alone involvement is present in approximately 20 % of IgG4-RKD. Compared to IgG4-RD overall, patients with IgG4-RKD are more likely to show increased serum IgG4 or IgG, and more likely to have hypocomplementemia. In this review, we extensively cover other types of autoimmune and plasma cell-rich interstitial nephritis, mass forming inflammatory diseases of the kidney, and other mimics of IgG4-TIN, in particular ANCA-associated disease.

Identification of amyloidosis of the urinary tract and prostate: Opportunities for early diagnosis & intervention in systemic disease.

OBJECTIVES: To determine the prevalence of different amyloid types and frequency of associated systemic amyloidosis in the urinary tract/prostate. METHODS: We studied Congo red-positive prostate (n = 150) and urinary tract (n = 767) specimens typed by a proteomics-based method between 2008 and 2020. Clinical follow up was available for a subset (urinary tract, n = 111; prostate, n = 17). Amyloid types were correlated with various clinicopathologic features. For patients with clinical follow up, chart review was performed to establish localized versus systemic disease, frequency of initial diagnosis of amyloidosis on urinary tract/prostate specimens, presence of cardiac disease, and death from disease-related complications. RESULTS: The most common amyloid types were AL/AH in urinary tract (479/767, 62 %) and localized ASem1 in prostate (64/150, 43 %). Urinary tract AL/AH amyloid was usually localized, but systemic AL amyloidosis occurred in both sites (urinary tract: 5/71, 7 %; prostate: 2/2, 100 %). ATTR amyloidosis was seen in over a third of cases (urinary tract: 286/767, 37 %; prostate: 55/150, 37 %). Urinary tract/prostate was the site of the initial ATTR amyloidosis diagnosis in 44/48 patients (92 %), and 38/48 (79 %) were subsequently found to have cardiac involvement. Seminal vesicle/ejaculatory duct involvement was pathognomonic for ASem1-type amyloidosis (39/39, 100 %). CONCLUSIONS: Over 40 % of patients had systemic amyloidosis, with urinary tract/prostate often the first site in which amyloid was identified. Since early recognition of systemic amyloidosis is critical for optimal patient outcomes, there should be a low threshold to perform Congo red stain. Proteomics-based amyloid typing is recommended since treatment depends on correctly identifying the amyloid type.

Proteomic and Clinicopathologic Assessment of Penile Amyloidosis: A Single Institutional Review of 12 Cases.

OBJECTIVES: There is a paucity of data on penile amyloidosis. We aimed to assess the frequency of different amyloid types in surgical specimens from the penis involved by amyloidosis and correlate relevant clinicopathologic parameters with proteomic findings. METHODS: Since 2008, our reference laboratory has performed liquid chromatography/tandem mass spectrometry (LC-MS/MS) for amyloid typing. The institutional pathology archive and reference laboratory database were queried to retrospectively identify all penile surgical pathology specimens with LC-MS/MS results between January 1, 2008, and November 23, 2022. Archived H&E-stained and Congo red-stained sections were re-reviewed. RESULTS: Twelve cases of penile amyloidosis were identified, which represented 0.35% (n = 3,456) of penile surgical specimens. AL-type amyloid was most frequent (n = 7), followed by keratin-type amyloid (n = 3) and ATTR (transthyretin)-type amyloid (n = 2). AL-type amyloid cases often showed diffuse dermal/lamina propria deposition, whereas all keratin-type amyloid cases were localized to the superficial dermis. Two cases with keratin-type amyloid had concomitant cutaneous findings (penile intraepithelial neoplasia and condyloma). CONCLUSIONS: This series, the largest to date, demonstrates that penile amyloidosis has a heterogeneous proteomic landscape. To the best of our knowledge, this is the first study describing ATTR (transthyretin)-type penile amyloid.

The Great Italian Masquerade.

Tuberculosis and sarcoidosis are both granulomatous diseases centered on the lung but capable of myriad extrapulmonary manifestations. Because of substantial similarity in their presentations, these two entities can be notoriously challenging to differentiate. This can be particularly true of countries in which tuberculosis is rarely encountered because of a reflexive tendency to ascribe granulomatous inflammation in the lung to sarcoidosis, especially if the granulomas are non-necrotizing. However, as our case from a non-endemic country reminds, sarcoidosis can be comfortably diagnosed only after convincing exclusion of infectious causes of granulomas. Distinguishing these two diseases is of utmost importance as, despite their overlapping presentations, they have completely non-overlapping treatments which can lead to harm if erroneously applied. At the end of our discussion, we summarize the clinical features favoring one diagnosis over the other.

Malignant pleural effusion from squamous cell carcinoma of the vulva: extremely rare metastatic pattern of a rarely metastasizing cancer.

The discovery of a malignant pleural effusion indicates metastatic disease and thus invariably results in the highest possible cancer stage. Although the female reproductive tract overall is a common primary tumor site giving rise to malignant pleural effusion, vulvar carcinoma stands out for its propensity for locoregional spread rather than distant metastasis. Our case contributes to the extremely limited number of published descriptions of thoracic involvement by vulvar carcinoma, with malignant pleural effusion being a particularly unusual pattern.

Three's company: A woman with rash, uterine mass and cystic lungs.

Cystic lung disease encompasses a wide variety of clinical entities, the diagnosis of which is sometimes straightforward and other times obscure.  To narrow the list of possibilities, it behooves the physician to consider the context in which the cystic lung disease is uncovered. Clues to the diagnosis might be provided by findings that are not initially obvious and are not located in the thorax. We describe an instructive case of a woman with cystic lungs detected during a search for malignancy prompted by a diagnosis of dermatomyositis. Malignancy was indeed uncovered in the form of endometrial carcinoma, the management of which eventually also established the etiology of cystic lung disease. In the discussion we attempt to connect the patient's autoimmune disease, uterine cancer, and lung cysts. The potential interplay among these three components of her presentation makes for intriguing mechanistic speculation.

Urinary Extracellular Vesicles of Podocyte Origin and Renal Injury in Preeclampsia.

Renal histologic expression of the podocyte-specific protein, nephrin, but not podocin, is reduced in preeclamptic compared with normotensive pregnancies. We hypothesized that renal expression of podocyte-specific proteins would be reflected in urinary extracellular vesicles (EVs) of podocyte origin and accompanied by increased urinary soluble nephrin levels (nephrinuria) in preeclampsia. We further postulated that podocyte injury and attendant formation of EVs are related mechanistically to cellfree fetal hemoglobin (HbF) in maternal plasma. Our study population included preeclamptic (n=49) and normotensive (n=42) pregnant women recruited at delivery. Plasma measurements included HbF concentrations and concentrations of the endogenous chelators haptoglobin, hemopexin, and α1- microglobulin. We assessed concentrations of urinary EVs containing immunologically detectable podocyte-specific proteins by digital flow cytometry and measured nephrinuria by ELISA. The mechanistic role of HbF in podocyte injury was studied in pregnant rabbits. Compared with urine from women with normotensive pregnancies, urine from women with preeclamptic pregnancies contained a high ratio of podocin-positive to nephrin-positive urinary EVs (podocin+ EVs-to-nephrin+ EVs ratio) and increased nephrinuria, both of which correlated with proteinuria. Plasma levels of hemopexin, which were decreased in women with preeclampsia, negatively correlated with proteinuria, urinary podocin+ EVs-to-nephrin+ EVs ratio, and nephrinuria. Administration of HbF to pregnant rabbits increased the number of urinary EVs of podocyte origin. These findings provide evidence that urinary EVs are reflective of preeclampsia-related altered podocyte protein expression. Furthermore, renal injury in preeclampsia associated with an elevated urinary podocin+ EVs-to-nephrin+ EVs ratio and may be mediated by prolonged exposure to cellfree HbF.

Preeclampsia and Extracellular Vesicles.

Preeclampsia is a hypertensive pregnancy disorder characterized by development of hypertension and proteinuria after 20 weeks of gestation that remains a leading cause of maternal and neonatal morbidity and mortality. While preeclampsia is believed to result from complex interactions between maternal and placental factors, the proximate pathophysiology of this syndrome remains elusive. Cell-to-cell communication is a critical signaling mechanism for feto-placental development in normal pregnancies. One mechanism of cellular communication relates to activated cell-derived sealed membrane vesicles called extracellular vesicles (EVs). The concentrations and contents of EVs in biological fluids depend upon their cells of origin and the stimuli which trigger their production. Research on EVs in preeclampsia has focused on EVs derived from the maternal vasculature (endothelium, vascular smooth muscle) and blood (erythrocytes, leukocytes, and platelets), as well as placental syncytiotrophoblasts. Changes in the concentrations and contents of these EVs may contribute to the pathophysiology of preeclampsia by accentuating the pro-inflammatory and pro-coagulatory states of pregnancy. This review focuses on possible interactions among placental- and maternal-derived EVs and their contents in the initiation and progression of the pathogenesis of preeclampsia. Understanding the contributions of EVs in the pathogenesis of preeclampsia may facilitate their use as diagnostic and prognostic biomarkers.

CT Evolution of Hematoma and Surrounding Hypodensity in a Cadaveric Model of Intracerebral Hemorrhage.

BACKGROUND: The evolution of intracerebral hematoma and perihematoma edema in the ultra-early period on computed tomographic (CT) scans in patients with intracerebral hemorrhage (ICH) is not well understood. We aimed to investigate hematoma and perihematoma changes in "neutral brain" models of ICH. METHODS: One human and five goat cadaveric heads were used as "neutral brains" to provide physical properties of brain without any biological activity or new bleeding. ICH was induced by slow injection of 4 ml of fresh human blood into the right basal ganglia of the goat brains. Similarly, 20 ml of fresh blood was injected deep into the white matter of the human cadaver head in each hemisphere. Serial CT scans of the heads were obtained immediately after hematoma induction and then 1, 3, and 5 hours afterward. Analyze software (AnalyzeDirect, Overland Park, KS, USA) was used to measure hematoma and perihematoma hypodensity volumes in the baseline and follow-up CT scans. RESULTS: The initial hematoma volumes of 11.6 ml and 10.5 ml in the right and left hemispheres of the cadaver brains gradually decreased to 6.6 ml and 5.4 ml at 5 hours, showing 43% and 48% retraction of hematoma, respectively. The volume of the perihematoma hypodensity in the right and left hemisphere increased from 2.6 ml and 2.2 ml in the 1-hour follow-up CT scans to 4.9 ml and 4.4 ml in the 5-hour CT scan, respectively. Hematoma retraction was also observed in all five goat brains ICH models with the mean ICH volume decreasing from 1.49 ml at baseline scan to 1.01 ml at the 5-hour follow-up CT scan (29.6% hematoma retraction). Perihematoma hypodensity was visualized in 70% of ICH in goat brains, with an increasing mean hypodensity volume of 0.4 ml in the baseline CT scan to 0.8 ml in the 5-hour follow-up CT scan. CONCLUSION: Our study demonstrated that substantial hematoma retraction and perihematoma hypodensity occurs in ICH in the absence of any new bleeding or biological activity of surrounding brain. Such observations suggest that active bleeding is underestimated in patients with no or small hematoma expansion and our understanding of perihematoma hypodensity needs to be reconsidered.

Cephalometric Features of Moyamoya Disease: A case control study.

CONTRIBUTION OF AUTHORS: Adnan I Qureshi, Waqas I Gilani MD, Sarwat I. Gilani MD, Malik M. Adil MD . Equally assisted in the synthesis and discussion of ideas, and share equal responsibility for the information written in the manuscript above. CONFLICT OF INTEREST: No conflict of interests. RUNNING TITLE: Cephalometric Features of Moyamoya Disease. BACKGROUND: Moyamoya disease is highly prevalent among patients with syndromes that have unique cephalometric characteristics such as Down syndrome. We performed a case control study to investigate the relationship between cephalometric parameters and Moyamoya disease. METHODS: Patients [aged 16-82 years] with angiographically confirmed Moyamoya disease who underwent cranial CT scan were analyzed. We identified three controls for each patient who were matched for age (±1 year), gender, and race (white or African American). The fronto-occipital diameter, bi-parietal diameter, and distance between bregma and occiput were measured from the head CT scans of cases and controls. The cephalic index was calculated by determining the ratio between bi-parietal diameter and fronto-occipital diameter and multiplying the value by 100. RESULTS: A total of 13 cases of Moyamoya disease and 39 controls were analyzed. The stage of Moyamoya disease in cases was as follows: stage 1 (n=0), stage 2 (n=1), stage 3 (n=4), stage 4 (n=2), stage 5 (n=5) and stage 6 (n=1). There was a significantly greater bi-parietal diameter in Moyamoya disease patients compared with controls (141.5±3.7 mm versus 136.9±5.4 mm, p=0.007). There was a significantly greater fronto-occipital diameter in Moyamoya disease patients compared with controls (186.5±6.5 mm versus 180.2±8.7mm, p=0.02). The distance between bregma and occiput was shorter among cases compared with controls (81.1±6.2 versus 87.5±7.0, p=0.01). CONCLUSIONS: We observed an association between cephalometric parameters and Moyamoya disease. Further study of the unique cephalometric characteristics among Moyamoya disease patients may provide additional insight into disease occurrence in white and African American populations.

Walk score and risk of stroke and stroke subtypes among town residents.

BACKGROUND: Regular physical activity, including light-to-moderate activity, such as walking, has well-established benefits for reducing the risk of ischemic stroke. It remains unknown, however, whether the characteristics of cities themselves can influence the risk of stroke by promoting such activity. OBJECTIVES: We tested the hypothesis that how walkable a city will be associated with the risk of ischemic stroke in persons residing in that city. METHODS: We calculated the age-adjusted annual incidence rates of ischemic stroke among residents in each of the 63 cities in Minnesota for which Walk Scores were available using 2011 Minnesota Hospital Association (MHA) data. Walk Score®, an online service, uses an exclusive algorithm to compute a walkability score between 0 and 100 for any location within the United States. The score is calculated based on the distance to amenities in nine categories (grocery, restaurants, shopping, coffee, banks, parks, schools, books, and entertainment) weighed according to their importance. RESULTS: There are 2,910,435 persons residing in the 63 Minnesota cities in our data (average population per town is 46,197). The average Walk Score of the 63 towns in Minnesota was 34, ranging from 14 to 69. The average median age of residents was similar in tertiles of towns based on Walk Score as follows: ≤25 (n=9) 36 years; 26-50 (n=46) 37 years; and 51-100 (n=8) 35 years. The age-adjusted incidence of ischemic stroke was similar in tertiles of towns based on Walk Score as follows: ≤25 (n=9) 341 per 100,000; 26-50 (n=46) 308 per 100,000; and 51-100 (n=8) 330 per 100,000 residents. The correlation between age-adjusted ischemic stroke incidence and Walk Score was low (R (2)=0.09) within Minnesota. CONCLUSIONS: The ready availability of indices such as Walk Score make them attractive options for ischemic stroke risk correlation. Despite the lack of relationship in our study, further studies are required to measure the magnitude and health benefits of light-to-moderate activities performed within a town.

Pattern of informed consent acquisition in patients undergoing emergent endovascular treatment for acute ischemic stroke.

BACKGROUND: Telephone consent and two physician consents based on medical necessity are alternate strategies for time sensitive medical decisions but are not uniformly accepted for clinical practice or recruitment into clinical trials. We determined the rate of and associated outcomes with alternate consenting strategies in consecutive acute ischemic stroke patients receiving emergent endovascular treatment. METHODS: We divided patients into those treated based on in-person consent and those based on alternate strategies. We identified clinical and procedural differences and differences in hospital outcomes: symptomatic ICH and favorable outcome (defined by modified Rankin Scale of 0-2 at discharge) based on consenting methodology. RESULTS: Of a total of 159 patients treated, 119 were treated based on in-person consent (by the patient in 27 and legally authorized representative in 92 procedures). Another 40 patients were treated using alternate strategies (20 telephone consents and 20 two physician consents based on medical necessity). There was no difference in the mean ages and proportion of men among the two groups based on consenting methodology. There was a significantly greater time interval incurred between CT scan and initiation of endovascular procedure in those in whom in-person consent was obtained (117 ± 65 min versus 101 ± 45 min, p = 0.01). There was no significant difference in rates of ICH (9% versus 8%, p = 0.9), or favorable outcome at discharge (28% versus 30%, p = 0.8). CONCLUSIONS: Consent through alternate strategies does not adversely affect procedural characteristics or outcome of patients and may be more time efficient than in-person consenting process.

Vitamin D deficiency and osteoporosis in stroke survivors: an analysis of National Health and Nutritional Examination Survey (NHANES).

BACKGROUND AND PURPOSE: An inverse association between 25-hydroxyvitamin D (25[OH]D) levels and stroke was emphasized in recent studies. Our objective was to determine the rate of Vitamin D deficiency and risk of associated osteoporosis among stroke survivors in a nationally representative population. METHODS: Participants from the National Health and Nutritional Examination Survey (NHANES) from 2001 to 2006 were included. Stroke survivors were then divided into two groups depending on serum 25(OH)D levels: <30 ng/dl as Vitamin D deficiency and ≥30 ng/dl as normal. Comparisons of demographics and risk factors between two groups were performed using SAS software. Multivariate analysis was performed to determine the association between Vitamin D deficiency and osteopororis in stroke survivors after adjusting for potential confounding factors. RESULTS: There were 415 (4.0%) stroke survivors among 10,255 participants in NHANES. The mean age (±SD) of stroke survivors was 67.6 (±17.3) years and 211 (50.8%) were men. Mean 25(OH)D concentrations were not significantly different in patients with stroke (20.3 versus 21.8 ng/ml, p = 0.65) although the rate of osteoporosis was significantly higher among stroke survivors (17.9% versus 6.9%, p < 0.0001). Out of 415 stroke patients, Vitamin D deficiency was seen in 71.0% of patients. The rates of osteoporosis were similar between patients with or without Vitamin D deficiency. After adjusting for potential confounders, there was no association between Vitamin D deficiency and osteoporosis. CONCLUSIONS: Vitamin D deficiency and osteoporosis are highly prevalent among stroke survivors; however, there does not appear to be a relationship between the two entities.