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CYP2C19 converts the tricyclic antidepressant imipramine to its active metabolite desipramine, which is subsequently inactivated by CYP2D6. The novel CYP2C19*17 allele causes ultrarapid metabolism of CYP2C19 substrates. We genotyped 178 depressed patients on imipramine for CYP2C19*17, and measured steady-state imipramine and desipramine plasma concentrations. Mean dose-corrected imipramine plasma concentration was significantly dependent on CYP2C19 genotype (Kruskal–Wallis test, P=0.01), with circa 30% lower levels in CYP2C19*17/*17 individuals compared with CYP2C19*1/*1 (wild-type) patients. The mean dose-corrected imipramine+desipramine plasma concentrations and imipramine/desipramine ratios were not significantly different between genotype subgroups (Kruskal–Wallis tests, P0.12). In a multivariate analysis, we found a significant, but limited effect (P=0.035, η2=0.031) of the CYP2C19*17 genotype on imipramine+desipramine concentrations. Although the CYP2C19*17 allele is associated with a significantly increased metabolism of imipramine, CYP2C19*17 genotyping will, in our view, not importantly contribute to dose management of patients on imipramine therapy guided by imipramine+desipramine plasma concentrations. [ABSTRACT FROM AUTHOR]

Islet transplantation is associated with a high rate of early graft failure caused by early immune attack and poor functionality of islets. Apoptosis of islet cells appears soon after islet isolation and primarily involves the beta-cell. The purpose of this study was to determine the effect of ligation to extracellular matrix (ECM) proteins on survival of the islets of Langerhans following islet isolation. Islets that had been cultured for 24 h on collagen type I showed an islet survival of 59.7 +/- 8.7%, while islets that had been cultured on collagen type IV and laminin showed an islet survival of 88.6 +/- 10.3 and 94.3 +/- 5.6%, respectively. Islets that had been pretreated with anti-beta1 antibodies and argenin-glycin-aspartic acid (RGD) peptides showed a decrease in the level of apoptosis by a factor of 2.5 and 3.1, respectively, and an increase of phospho-Akt Ser 473 activity by a factor of 3.1 and 2.9, respectively, compared with untreated islets. When detached from their natural ECM surrounding in the pancreas, islet cells undergo apoptosis, unless islets are cultured on collagen IV or laminin or treated with anti-beta1 integrin antibodies or RGD peptides to mimic ECM ligation. These results indicate that inhibition of anoikis may offer opportunities to improve function and viability of islet cells. [ABSTRACT FROM AUTHOR]

In global impact modeling, there is a need to address the heterogeneous characteristics of households and individuals that drive different behavioral responses to, for example, environmental risk, socio-economic policy changes and spread of diseases. In this research, we present GLOPOP-S, the first global synthetic population dataset with 1,999,227,130 households and 7,335,881,094 individuals for the year 2015, consistent with population statistics at an administrative unit 1 level. GLOPOS-S contains the following attributes: age, education, gender, income/wealth, settlement type (urban/rural), household size, household type, and for selected countries in the Global South, ownership of agricultural land and dwelling characteristics. To generate GLOPOP-S, we use microdata from the Luxembourg Income Study (LIS) and Demographic and Health Surveys (DHS) and apply synthetic reconstruction techniques to fit national survey data to regional statistics, thereby accounting for spatial differences within and across countries. Additionally, we have developed methods to generate data for countries without available microdata. The dataset can be downloaded per region or country. GLOPOP-S is open source and can be extended with other attributes., (© 2024. The Author(s).)

TGF-β is considered an important cytokine in the development of interstitial fibrosis in chronic kidney disease. The TGF-β co-receptor endoglin (ENG) tends to be upregulated in kidney fibrosis. ENG has two membrane bound isoforms generated via alternative splicing. Long-ENG was shown to enhance the extent of renal fibrosis in an unilateral ureteral obstruction mouse model, while short-ENG inhibited renal fibrosis. Here we aimed to achieve terminal intron retention of endoglin using antisense-oligo nucleotides (ASOs), thereby shifting the ratio towards short-ENG to inhibit the TGF-β1-mediated pro-fibrotic response. We isolated mRNA from kidney biopsies of patients with chronic allograft disease (CAD) (n = 12) and measured total ENG and short-ENG mRNA levels. ENG mRNA was upregulated 2.3 fold (p < 0.05) in kidneys of CAD patients compared to controls, while the percentage short-ENG of the total ENG mRNA was significantly lower (1.8 fold; p < 0.05). Transfection of ASOs that target splicing regulatory sites of ENG into TK173 fibroblasts led to higher levels of short-ENG (2 fold; p < 0.05). In addition, we stimulated these cells with TGF-β1 and measured a decrease in upregulation of ACTA2, COL1A1 and FN1 mRNA levels, and protein expression of αSMA, collagen type I, and fibronectin. These results show a potential for ENG ASOs as a therapy to reduce interstitial fibrosis in CKD., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Glomerular fibrillary deposits have occasionally been reported in diabetic nephropathy, but no large-scale, ultrastructural evaluation of these deposits has been reported so far. Here, we report our study of glomerular non-Congophilic, DnaJ homolog subfamily B member 9 negative fibrillary deposits in diabetic nephropathy as characterized by transmission electron microscopy. Clinical data from 55 patients with biopsy-confirmed diabetic nephropathy and 18 healthy living donors were reviewed, and their biopsies were evaluated by light microscopy, immunofluorescence, and electron microscopy. Small fibrillary structures with a diameter of 10 ± 1 nm were present in all cases with diabetic nephropathy, regardless of the histologic class. In addition, glomerular fibrillary structures with a diameter of 23 ± 5 nm or 30 ± 7 nm were present in 35 cases. Interestingly, especially the small- and medium-sized fibrils, usually without apparent organization, were comparable with fibrils in fibrillary glomerulopathy. We conclude that glomerular fibrillary deposits occur far more commonly in renal biopsies of patients with diabetic nephropathy than generally considered. This is an important finding because their similarity to fibrils in fibrillary glomerulonephritis may complicate the histologic diagnostic process, especially in cases of overlapping clinical manifestations. Therefore, when encountering fibrillary deposits on electron microscopy, it is important to consider diabetic nephropathy as an alternative diagnosis., (Copyright © 2024 United States & Canadian Academy of Pathology. Published by Elsevier Inc. All rights reserved.)

Background: Chronic exertional compartment syndrome involving the lower leg lateral compartment (lat-CECS) seldom occurs isolated but is usually combined with CECS of the anterior (ant-CECS) or deep posterior compartment (dp-CECS). Patient characteristics in lat-CECS and outcome after surgery are largely unknown. The aim of this prospective case series was to describe patient characteristics and symptoms and to report on outcome following a fasciotomy., Methods: All patients diagnosed with lat-CECS based on exertional lateral lower leg symptoms and elevated intracompartmental pressure (ICP) measurements according to the Pedowitz criteria (ICP ≥ 15 mm Hg at rest, and/or ≥30 mm Hg after 1 minute, and/or ≥20 mm Hg 5 minutes after exercise) were eligible for this study. A standard intake questionnaire scoring symptom patterns was completed by all patients. Patients who were operated for lat-CECS were asked to complete a 3-month and 12-month postoperative questionnaire scoring symptoms and surgical outcome. Patients with a history of CECS surgery, recent lower leg trauma, or peripheral neurovascular disease were excluded., Results: A total of 881 patients with possible lower leg CECS completed an intake questionnaire and 88 (10%) were diagnosed with lat-CECS according to the Pedowitz criteria (isolated lat-CECS n = 10; lat/ant CECS n = 54, lat/ant/dp CECS n = 19, lat/dp CECS n = 5). Severe pain during exercise and moderate tightness during rest were frequently reported. A group of 28 patients (49 legs; isolated lat-CECS n = 2; lat/ant CECS n = 22, lat/ant/dp CECS n = 3, lat/dp CECS n = 1) was analyzed after fasciotomy. Complications were minor (wound infection requiring antibiotics, n = 3; temporary complex regional pain syndrome with spontaneous recovery, n = 1). Superficial peroneal nerve damage was not observed. One year after surgery, 64% rated outcome as excellent or good, whereas 71% had resumed sports activities., Conclusion: One in 10 patients with anterolateral exertional lower leg pain evaluated in a tertiary referral center met diagnostic criteria for lat-CECS. Pain and tightness were present during exertion and were often reported occurring during rest and at night. In this series, we found fasciotomy-either an isolated (lateral) or a multiple (combined with anterior and/or deep posterior) compartment fasciotomy-is safe and beneficial in most patients., Level of Evidence: Level IV, case series., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. ICMJE forms for all authors are available online.

Insufficient immune tolerance during pregnancy is associated with pathological conditions such as preeclampsia (PE). Soluble fms-like tyrosine kinase-1 (sFLT1), which exerts a role in the late stage of PE, has shown its beneficial anti-inflammatory effects in inflammation-associated diseases. Macrophage migration inhibitory factor (MIF) was reported to upregulate sFLT1 production in experimental congenital diaphragmatic hernia. However, the placental sFLT1 expression in early uncomplicated pregnancy and whether MIF can regulate sFLT1 expression in uncomplicated and preeclamptic pregnancy are unclear. We collected first-trimester placentas and term placentas from uncomplicated and preeclamptic pregnancies to investigate sFLT1 and MIF expression in vivo. Primary cytotrophoblasts (CTBs) and a human trophoblast cell line (Bewo) were used to study the regulation of MIF on sFLT1 expression in vitro. In placentas from first-trimester pregnancy, we observed a high expression of sFLT1, specifically in extravillous trophoblasts (EVTs) and syncytiotrophoblast (STB) cells. MIF mRNA levels strongly correlated with sFLT1 expression in term placentas from preeclamptic pregnancies. In in vitro experiments, sFLT1 and MIF levels increased significantly in CTBs during their differentiation to EVTs and STBs, and MIF inhibitor (ISO-1) significantly reduced sFLT1 expression in a dose-dependent manner during this process. sFLT1 showed significant upregulation with increasing doses of MIF in Bewo cells. Our results show that sFLT1 is highly expressed at the maternal-fetal interface during early pregnancy and that MIF can increase sFLT1 expression in early uncomplicated pregnancy and PE, which suggests that sFLT1 plays an essential role in the modulation of inflammation in pregnancy.

In this study, we couple an integrated flood damage and agent-based model (ABM) with a gravity model of internal migration and a flood risk module (DYNAMO-M) to project household adaptation and migration decisions under increasing coastal flood risk in France. We ground the agent decision rules in a framework of subjective expected utility theory. This method addresses agent's bounded rationality related to risk perception and risk aversion and simulates the impact of push, pull, and mooring factors on migration and adaptation decisions. The agents are parameterized using subnational statistics, and the model is calibrated using a household survey on adaptation uptake. Subsequently, the model simulates household adaptation and migration based on increasing coastal flood damage from 2015 until 2080. A medium population growth scenario is used to simulate future population development, and sea level rise (SLR) is assessed for different climate scenarios. The results indicate that SLR can drive migration exceeding 8000 and 10,000 coastal inhabitants for 2080 under the Representative Concentration Pathways 4.5 and 8.5, respectively. Although household adaptation to flood risk strongly impacts projected annual flood damage, its impact on migration decisions is small and falls within the 90% confidence interval of model runs. Projections of coastal migration under SLR are most sensitive to migration costs and coastal flood protection standards, highlighting the need for better characterization of both in modeling exercises. The modeling framework demonstrated in this study can be upscaled to the global scale and function as a platform for a more integrated assessment of SLR-induced migration., (© 2023. The Author(s).)

Purpose: To determine whether levels of pre-operative pain as recalled by a patient in the post-operative phase are possibly overestimated or underestimated compared to prospectively scored pain levels. If so, a subsequent misclassification may induce recall bias that may lead to an erroneous effect outcome., Methods: Data of seven retrospective cohort studies on surgery for chronic abdominal wall and groin pain using three different pain scores were systematically analyzed. First, it was assessed whether retrospectively acquired pre-operative pain levels, as scored by the patient in the post-operative phase, differed from prospectively obtained pre-operative pain scores. Second, it was determined if errors associated with retrospectively obtained pain scores potentially lead to a misclassification of treatment outcome. Third, a meta-analysis established whether recall misclassifications, if present, affected overall study conclusions., Results: Pain data of 313 patients undergoing remedial surgery were evaluated. The overall prevalence of misclassification due to a recall error was 13.7%. Patients not benefitting from surgery ('failures') judged their pre-operative pain level as more severe than it actually was. In contrast, patients who were pain free after remedial surgery ('successes') underestimated pre-operative pain scores. Recall misclassifications were significantly more present in failures than in successful patients (odds ratio 2.4 [95% CI 1.2-4.8])., Conclusion: One in seven patients undergoing remedial groin surgery is misclassified on the basis of retrospectively obtained pre-operative pain scores (success instead of failure, or vice versa). Misclassifications are relatively more present in failures after surgery. Therefore, the effect size of a therapy erroneously depends on its success rate., (© 2022. The Author(s), under exclusive licence to Springer-Verlag France SAS, part of Springer Nature.)

Chronic kidney disease (CKD) is a slow-developing, progressive deterioration of renal function. The final common pathway in the pathophysiology of CKD involves glomerular sclerosis, tubular atrophy and interstitial fibrosis. Transforming growth factor-beta (TGF-β) stimulates the differentiation of fibroblasts towards myofibroblasts and the production of extracellular matrix (ECM) molecules, and thereby interstitial fibrosis. It has been shown that endoglin (ENG, CD105), primarily expressed in endothelial cells and fibroblasts, can function as a co-receptor of TGF signaling. In several human organs, endoglin tends to be upregulated when chronic damage and fibrosis is present. We hypothesize that endoglin is upregulated in renal interstitial fibrosis and plays a role in the progression of CKD. We first measured renal endoglin expression in biopsy samples obtained from patients with different types of CKD, i.e., IgA nephropathy, focal segmental glomerulosclerosis (FSGS), diabetic nephropathy (DN) and patients with chronic allograft dysfunction (CAD). We showed that endoglin is upregulated in CAD patients (p < 0.001) and patients with DN (p < 0.05), compared to control kidneys. Furthermore, the amount of interstitial endoglin expression correlated with eGFR (p < 0.001) and the amount of interstitial fibrosis (p < 0.001), independent of the diagnosis of the biopsies. Finally, we investigated in vitro the effect of endoglin overexpression in TGF-β stimulated human kidney fibroblasts. Overexpression of endoglin resulted in an enhanced ACTA2, CCN2 and SERPINE1 mRNA response (p < 0.05). It also increased the mRNA and protein upregulation of the ECM components collagen type I (COL1A1) and fibronectin (FN1) (p < 0.05). Our results suggest that endoglin is an important mediator in the final common pathway of CKD and could be used as a possible new therapeutic target to counteract the progression towards end-stage renal disease (ESRD).

Objective: The International Society of Nephrology/Renal Pathology Society classification is the gold standard for the characterisation of lupus nephritis (LN) on renal biopsy, with therapeutic repercussions. Its recent revision simplified the current class subdivisions, eliminating the S/G forms of class IV, although data on a possible pathogenetic/clinical value of this subdivision are still contradictory., Methods: 353 renal biopsies from Belimumab International Study in LN were assessed through central pathology review. Univariate logistic models and a decision tree were performed on 314 adequate biopsies to evaluate the impact of histological features on focal/diffuse classes. Removing class I/II (n=6) and 'pure' class V (n=34), principal component analysis (PCA) and heatmap were used to explore similarities among III, IVS and IVG biopsies either incorporating or not the mixed classes (+V, n=274). Finally, a method aimed at partitioning the cases into k clusters based on their similarity (KMeans), was used to study features from the cohort of 'pure' class III/IVS/IVG cases (n=214) to determine alternative subdivisions based on phenotypic data., Results: Segmental endocapillary hypercellularity (EH) was prevalent in class III, global EH, wire loops, hyaline thrombi and double contours were hallmarks of class IVG, with IVS cases showing intermediate characteristics. Heatmap and PCA confirmed the segregation of these features among classes, showing better segregation for focal/diffuse LN as compared with the mixed classes (+V). KMeans revealed the presence of two main clusters, membranoproliferative-like (n=83) or vasculitis-like (n=131)., Conclusions: This study reveals new phenotypic forms of LN surpassing the traditional classes as determined by the current classification. Future validation and confirmation are required to confirm these findings., Competing Interests: Competing interests: IB, JAB, HTC, FF, L-HN received honoraria from GlaxoSmithKline (London, Great Britain) for their participation in the BLISS-LN trial as central review board., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: We aimed to determine the presence, amount and origin of microchimerism in peripheral blood of pregnant and non-pregnant parous women with systemic lupus erythematosus (SLE) as compared to control subjects., Methods: We performed a comparative study in which peripheral blood was drawn from eleven female non-pregnant SLE-patients and 22 control subjects, and from six pregnant SLE-patients and eleven control subjects during gestation and up to six months postpartum. Quantitative PCR for insertion-deletion polymorphisms and null alleles was used to detect microchimerism in peripheral blood mononuclear cells and granulocytes., Results: Microchimerism was detected more often in non-pregnant SLE-patients than control subjects (54.4% vs. 13.6%, respectively; p=0.03). When present, the median total number of foetal chimeric cells was 5 gEq/106 in patients and 2.5gEq/106 in control subjects (p=0.048). Microchimerism was mostly foetal in origin; maternal microchimerism was detected in one patient and one control subject. In control subjects, microchimerism was always derived from only one source whereas in 50% of patients it originated from multiple sources. The pregnant patients had a significantly higher median number of foetal chimeric cells in the granulocyte fraction just after delivery than control subjects (7.5 gEq/106 vs. 0 gEq/106, respectively; p=0.02)., Conclusions: Just after delivery, SLE-patients had more microchimerism than control subjects. Three months post-partum, microchimerism was no longer detectable, only to reappear many years after the last pregnancy, more often and at higher levels in SLE-patients than in control subjects. This suggests that these chimeric cells may originate from non-circulating foetal chimeric stem cells.

(1) Background: Soluble Fms-like tyrosine kinase 1 (sFLT1) is an endogenous VEGF inhibitor. sFLT1 has been described as an anti-inflammatory treatment for diabetic nephropathy and heart fibrosis. However, sFLT1 has also been related to peritubular capillary (PTC) loss, which promotes fibrogenesis. Here, we studied whether transfection with sFlt1 aggravates experimental AKI-to-CKD transition and whether sFLT1 is increased in human kidney fibrosis. (2) Methods: Mice were transfected via electroporation with sFlt1 . After confirming transfection efficacy, mice underwent unilateral ischemia/reperfusion injury (IRI) and were sacrificed 28 days later. Kidney histology and RNA were analyzed to study renal fibrosis, PTC damage and inflammation. Renal sFLT1 mRNA expression was measured in CKD biopsies and control kidney tissue. (3) Results: sFlt1 transfection did not aggravate renal fibrosis, PTC loss or macrophage recruitment in IRI mice. In contrast, higher transfection efficiency was correlated with reduced expression of pro-fibrotic and pro-inflammatory markers. In the human samples, sFLT1 mRNA levels were similar in CKD and control kidneys and were not correlated with interstitial fibrosis or PTC loss. (4) Conclusion: As we previously found that sFLT1 has therapeutic potential in diabetic nephropathy, our findings indicate that sFLT1 can be administered at a dose that is therapeutically effective in reducing inflammation, without promoting maladaptive kidney damage.

In this study, the effect of heterozygous germline mutations in the heparan sulfate (HS) glycosaminoglycan chain co-polymerases EXT1 and EXT2 on glomerular barrier function and the endothelial glycocalyx in humans is investigated. Heparan sulfate (HS) glycosaminoglycans are deemed essential to the glomerular filtration barrier, including the glomerular endothelial glycocalyx. Animal studies have shown that loss of HS results in a thinner glycocalyx. Also, decreased glomerular HS expression is observed in various proteinuric renal diseases in humans. A case report of a patient with an EXT1 mutation indicated that this could result in a specific renal phenotype. This patient suffered from multiple osteochondromas, an autosomal dominant disease caused by mono-allelic germline mutations in the EXT1 or EXT2 gene. These studies imply that HS is indeed essential to the glomerular filtration barrier. However, loss of HS did not lead to proteinuria in various animal models. We demonstrate that multiple osteochondroma patients do not have more microalbuminuria or altered glycocalyx properties compared to age-matched controls (n = 19). A search for all Dutch patients registered with both osteochondroma and kidney biopsy (n = 39) showed that an EXT1 or EXT2 mutation does not necessarily lead to specific glomerular morphological phenotypic changes. In conclusion, this study shows that a heterozygous mutation in the HS backbone elongating enzymes EXT1 and EXT2 in humans does not result in (micro)albuminuria, a specific renal phenotype or changes to the endothelial glycocalyx, adding to the growing knowledge on the role of EXT1 and EXT2 genes in pathophysiology., (© 2022. The Author(s).)

Introduction: Lupus nephritis (LN) class III or IV is strongly related to patient mortality and morbidity. The interobserver agreement of endocapillary hypercellularity by routine light microscopy, one of the most important lesions determining whether class III or IV is present, is moderate. In IgA nephropathy (IgAN), the presence of glomerular CD68+ cells was found to be a good surrogate marker for endocapillary hypercellularity. We investigated whether the presence of glomerular CD68+ cells could serve as a surrogate marker for endocapillary hypercellularity as well in LN., Methods: A total of 92 LN biopsies were scored for the number of glomerular CD68+ cells using CD68 staining, including endocapillary hypercellularity and the activity index (AI). A new AI was calculated in which CD68+ cells replaced endocapillary hypercellularity. Clinical parameters were obtained from time of biopsy, 1 year after, and 2 years after., Results: The number of glomerular CD68+ cells significantly correlated with endocapillary hypercellularity. A cutoff value of 7 for the maximum number of CD68+ cells within 1 glomerulus in a biopsy yielded a sensitivity of 88% and a specificity of 67% for the presence of endocapillary hypercellularity. Both endocapillary hypercellularity and CD68+ cells correlated with renal function during follow-up. The current and the new AI correlated equally well with the clinical outcome., Conclusion: In LN, CD68+ cells can be used as a surrogate marker for endocapillary hypercellularity., (© 2022 International Society of Nephrology. Published by Elsevier Inc.)

Background: Chronic exertional compartment syndrome (CECS) of the anterior leg compartment (ant-CECS) is frequently treated with a minimally invasive fasciotomy. Several operative techniques and operative devices exist, but none have been compared in a systematic and randomized manner., Purpose: To compare efficacy, safety, and postoperative pain of a novel operative device (FascioMax fasciotome) with a widely accepted device created by Due and Nordstrand (Due fasciotome) during a minimally invasive fasciotomy for ant-CECS., Study Design: Randomized controlled trial; Level of evidence, 2., Methods: Patients with bilateral isolated ant-CECS between October 2013 and April 2018 underwent a minimally invasive fasciotomy using the FascioMax fasciotome in 1 leg and the Due fasciotome in the contralateral leg in a single operative session. Symptom reduction at 3 to 6 months and >1 year, postoperative pain within the first 2 weeks, peri- and postoperative complications, and ability to regain sports were assessed using diaries, physical examination, and timed questionnaires., Results: Included in the study were 50 patients (66% female; median age, 22 years [range, 18-65 years]). No differences between the devices were found in terms of perioperative complications (both had none), minor postoperative complications including hematoma and superficial wound infection (overall complication rate: FascioMax, 8% vs Due, 6%), or reduction of CECS-associated symptoms at rest and during exercise. At long-term follow-up (>1 year), 82% of the patients were able to regain their desired type of sport, and 67% (33/49) were able to exercise at a level that was comparable with or higher than before their CECS-associated symptoms started., Conclusion: Both the FascioMax and the Due performed similarly in terms of efficacy, safety, and levels of pain within the first 2 weeks postoperatively., Registration: NL4274; Netherlands Trial Register., Competing Interests: The authors declared that there are no conflicts of interest in the authorship and publication of this contribution. AOSSM checks author disclosures against the Open Payments Database (OPD). AOSSM has not conducted an independent investigation on the OPD and disclaims any liability or responsibility relating thereto., (© The Author(s) 2021.)

Objective: Peripheral artery disease (PAD) and chronic exertional compartment syndrome (CECS) both cause exercise-induced lower limb pain. CECS is mostly described in young individuals and may therefore not be considered in older patients with intermittent claudication. The aim of our study was to identify differences in characteristics and symptomatology between patients with CECS and PAD that may help in recognizing CECS in patients ≥50 years with exercise-induced lower limb pain., Methods: In this case-control study, patients with CECS ≥50 years were selected from a prospectively followed cohort and compared with a sample of newly diagnosed patients with PAD ≥50 years. A questionnaire assessed frequency and severity of lower limb pain, tightness, cramps, muscle weakness, and altered skin sensation at rest and during exercise., Results: At rest, patients with CECS (n = 43, 42% female, 57 years; range, 50-76 years) reported significantly more pain, tightness, muscle weakness and altered skin sensation (all P < .01) than patients with PAD (n = 41, 39% female, 72 years; range, 51-93 years). Having CECS was associated with a significantly higher combined symptom score at rest (P = .02). During exercise, patients with CECS experienced more tightness, muscle weakness and altered sensation (P < .01), but not pain and cramps (P = .36; P = .70). Exercise-induced complaints occurred much later in patients with CECS than in patients with PAD (15 minutes vs 4 minutes; P < .01). Persistence of pain over 4.5 minutes proved most discriminative for the presence of CECS (sensitivity, 95%; specificity, 54%; positive predictive value, 65%). Exercise cessation completely alleviated complaints in all patients with PAD (n = 41) but not in 73% (n = 29) of the patients with CECS. Ongoing discomfort strongly predicted the presence of CECS (sensitivity, 73%; specificity, 100%; positive predictive value, 100%)., Conclusions: Patients with CECS ≥50 years report a symptom pattern that is different from patients with PAD. These differences may aid vascular surgeons in identifying older patients with CECS., (Copyright © 2020 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

The endothelial glycoprotein thrombomodulin regulates coagulation, inflammation, and apoptosis. In diabetic mice, reduced thrombomodulin function results in diabetic nephropathy (DN). Furthermore, thrombomodulin treatment reduces renal inflammation and fibrosis. Herein, thrombomodulin expression was examined in human kidney samples to investigate the possibility of targeting thrombomodulin in patients with DN. Glomerular thrombomodulin was analyzed together with the number of glomerular macrophages in 90 autopsied diabetic cases with DN, 55 autopsied diabetic cases without DN, and 37 autopsied cases without diabetes or kidney disease. Thrombomodulin mRNA was measured in glomeruli microdissected from renal biopsies from patients with DN and nondiabetic controls. Finally, glomerular thrombomodulin was measured in diabetic mice following treatment with the selective endothelin A receptor (ET A R) blocker, atrasentan. In diabetic patients, glomerular thrombomodulin expression was increased at the mRNA level, but decreased at the protein level, compared with nondiabetic controls. Reduced glomerular thrombomodulin was associated with an increased glomerular influx of macrophages. Blocking the ET A R with atrasentan restored glomerular thrombomodulin protein levels in diabetic mice to normal levels. The reduction in glomerular thrombomodulin in diabetes likely serves as an early proinflammatory step in the pathogenesis of DN. Thrombomodulin protein may be cleaved under diabetic conditions, leading to a compensatory increase in transcription. The nephroprotective effects of ET A R antagonists in diabetic patients may be attributed to the restoration of glomerular thrombomodulin., (Copyright © 2021 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Introduction: The podocyte is thought to be the mainly affected cell type in focal segmental glomerulosclerosis (FSGS). However, recent studies have also indicated a role for glomerular endothelial cells and podocyte-endothelial crosstalk in FSGS development. An experimental model for podocyte injury showed that increased endothelin-1 (ET-1) signaling between podocytes and endothelial cells induces endothelial oxidative stress and subsequent podocyte loss. In the current study, we investigated endothelial endothelin receptor A (ET A R) expression in patients with FSGS and its association with podocyte injury and glomerular oxidative stress., Methods: We selected 39 biopsy samples of patients with FSGS and 8 healthy control subjects, and stained them for ET A R, nephrin and 8-oxo-guanine, a DNA lesion caused by oxidative damage. Glomeruli with ET A R-positive endothelium and with nephrin loss were scored, and the 8-oxo-guanine-positive glomerular area was measured., Results: The mean percentage of glomeruli with ET A R-positive endothelial cells in patients with FSGS was higher compared to that in healthy control subjects (52% vs. 7%; P  < 0.001). The presence of glomerular ET A R-positive endothelium was strongly associated with nephrin loss both on the biopsy level (rho = 0.47; P  < 0.01), as on the level of individual glomeruli (odds ratio = 2.0; P  < 0.001). Moreover, glomeruli with ET A R-positive endothelium showed more 8-oxo-guanine-positive staining (1.9% vs. 2.4%; P  = 0.037). Finally, 8-oxo-guanine positivity in glomeruli was associated with increased levels of proteinuria., Conclusion: Taking together our findings, we show that ET A R is increased in glomerular endothelial cells of patients with FSGS and associated with podocyte damage and glomerular oxidative stress. These findings support the hypothesis that ET-1 signaling in glomerular endothelial cells contributes to disease development in patients with FSGS., (© 2021 International Society of Nephrology. Published by Elsevier Inc.)

The endothelial glycoprotein thrombomodulin regulates coagulation, vascular inflammation and apoptosis. In the kidney, thrombomodulin protects the glomerular filtration barrier by eliciting crosstalk between the glomerular endothelium and podocytes. Several glomerular pathologies are characterized by a loss of glomerular thrombomodulin. In women with pre-eclampsia, serum levels of soluble thrombomodulin are increased, possibly reflecting a loss from the glomerular endothelium. We set out to investigate whether thrombomodulin expression is decreased in the kidneys of women with pre-eclampsia and rats exposed to an angiogenesis inhibitor. Thrombomodulin expression was examined using immunohistochemistry and qPCR in renal autopsy tissues collected from 11 pre-eclamptic women, 22 pregnant controls and 11 hypertensive non-pregnant women. Further, kidneys from rats treated with increasing doses of sunitinib or sunitinib in combination with endothelin receptor antagonists were studied. Glomerular thrombomodulin protein levels were increased in the kidneys of women with pre-eclampsia. In parallel, in rats exposed to sunitinib, glomerular thrombomodulin was upregulated in a dose-dependent manner, and the upregulation of glomerular thrombomodulin preceded the onset of histopathological changes. Selective ET A R blockade, but not dual ET A/B R blockade, normalised the sunitinib-induced increase in thrombomodulin expression and albuminuria. We propose that glomerular thrombomodulin expression increases at an early stage of renal damage induced by antiangiogenic conditions. The upregulation of this nephroprotective protein in glomerular endothelial cells might serve as a mechanism to protect the glomerular filtration barrier in pre-eclampsia.

Diabetic nephropathy (DN) is a complication of diabetes mellitus that can lead to proteinuria and a progressive decline in renal function. Endoglin, a co-receptor of TGF-β, is known primarily for regulating endothelial cell function; however, endoglin is also associated with hepatic, cardiac, and intestinal fibrosis. This study investigates whether endoglin contributes to the development of interstitial fibrosis in DN. Kidney autopsy material from 80 diabetic patients was stained for endoglin and Sirius Red and scored semi-quantitatively. Interstitial endoglin expression was increased in samples with DN and was correlated with Sirius Red staining ( p < 0.001). Endoglin expression was also correlated with reduced eGFR ( p = 0.001), increased creatinine ( p < 0.01), increased systolic blood pressure ( p < 0.05), hypertension ( p < 0.05), and higher IFTA scores ( p < 0.001). Biopsy samples from DN patients were also co-immunostained for endoglin together with CD31, CD68, vimentin, or α-SMA Endoglin co-localized with both the endothelial marker CD31 and the myofibroblast marker α-SMA. Finally, we used shRNA to knockdown endoglin expression in a human kidney fibroblast cell line. We found that TGF-β1 stimulation upregulated SERPINE1 , CTGF , and ACTA2 mRNA and α-SMA protein, and that these effects were significantly reduced in fibroblasts after endoglin knockdown. Taken together, these data suggest that endoglin plays a role in the pathogenesis of interstitial fibrosis in DN., Competing Interests: The authors declare no conflict of interest.

Clusterin, a glycoprotein encoded by the CLU gene, is expressed in many tissues, including the kidney, and clusterin expression is upregulated in the glomeruli of patients with various forms of kidney disease. Here, we investigated the role of clusterin in diabetic nephropathy (DN). In this study, we found that glomerular clusterin expression was increased in both patients with DN and streptozotocin-induced diabetic mice and that it co-localised with the podocyte marker WT1, indicating clusterin is expressed in podocytes. In our in vitro analysis, we found no significant change in CLU mRNA expression in podocytes following stimulation with high glucose and angiotensin II; in contrast, CLU mRNA expression was significantly upregulated following methylglyoxal stimulation. Methylglyoxal treatment also significantly decreased the mRNA expression of the slit diaphragm markers ZO-1 and NEPH1 and significantly increased the mRNA expression of the oxidative stress marker HO-1. Lastly, we showed that pre-incubating podocytes with recombinant human clusterin protein increased podocyte survival, prevented slit diaphragm damage, and reduced oxidative stress‒induced apoptosis following methylglyoxal stimulation. Taken together, our results indicate that glomerular clusterin is upregulated in DN, and this increase in clusterin expression may protect against oxidative stress-induced apoptosis in podocytes, providing a possible new therapeutic target for DN and other kidney diseases.

Background and Objectives: The histopathologic classification for ANCA-associated GN distinguishes four classes on the basis of patterns of injury. In the original validation study, these classes were ordered by severity of kidney function loss as follows: focal, crescentic, mixed, and sclerotic. Subsequent validation studies disagreed on outcomes in the crescentic and mixed classes. This study, driven by the original investigators, provides several analyses in order to determine the current position of the histopathologic classification of ANCA-associated GN., Design, Setting, Participants, & Measurements: A validation study was performed with newly collected data from 145 patients from ten centers worldwide, including an analysis of interobserver agreement on the histopathologic evaluation of the kidney biopsies. This study also included a meta-analysis on previous validation studies and a validation of the recently proposed ANCA kidney risk score., Results: The validation study showed that kidney failure at 10-year follow-up was significantly different between the histopathologic classes ( P <0.001). Kidney failure at 10-year follow-up was 14% in the crescentic class versus 20% in the mixed class ( P =0.98). In the meta-analysis, no significant difference in kidney failure was also observed when crescentic class was compared with mixed class (relative risk, 1.15; 95% confidence interval, 0.94 to 1.41). When we applied the ANCA kidney risk score to our cohort, kidney survival at 3 years was 100%, 96%, and 77% in the low-, medium-, and high-risk groups, respectively ( P <0.001). These survival percentages are higher compared with the percentages in the original study., Conclusions: The crescentic and mixed classes seem to have a similar prognosis, also after adjusting for differences in patient populations, treatment, and interobserver agreement. However, at this stage, we are not inclined to merge the crescentic and mixed classes because the reported confidence intervals do not exclude important differences in prognosis and because an important histopathologic distinction would be lost., (Copyright © 2020 by the American Society of Nephrology.)

Background: Chronic exertional compartment syndrome (CECS) mostly occurs in the anterior or deep posterior compartments (ant-CECS and dp-CECS, respectively) of the leg. It is generally accepted that CECS of the third or lateral compartment (lat-CECS) always occurs together with ant-CECS. However, whether exertional leg pain (ELP) can be caused by an isolated form of lat-CECS is unknown., Purpose: To determine the existence of isolated lat-CECS and study whether history taking and a physical examination aid in discriminating between different subtypes of CECS., Study Design: Case series; Level of evidence, 4., Methods: Patients were eligible for this single-center study, conducted between January 2013 and February 2018, if they reported anterolateral ELP and completed a questionnaire scoring the frequency and intensity of pain, tightness, cramps, muscle weakness, and paresthesia during rest and exercise. They were asked to mark areas of altered foot skin sensation, if present, on a drawing. All patients underwent a dynamic intracompartmental pressure (ICP) measurement of the anterior and lateral compartments simultaneously. The diagnosis of CECS was confirmed by elevated ICP (Pedowitz criteria). There were 3 patient groups: (1) isolated ant-CECS with elevated ICP in the anterior compartment and normal ICP in the lateral compartment, (2) isolated lat-CECS with elevated ICP in the lateral compartment but normal ICP in the anterior compartment, and (3) ant-/lat-CECS with elevated ICP in both the anterior and lateral compartments., Results: A total of 73 patients with anterolateral ELP fulfilled study criteria (isolated ant-CECS: n = 26; isolated lat-CECS: n = 5; ant-/lat-CECS: n = 42). Group differences were not observed regarding age (isolated ant-CECS: median, 26 years [range, 13-68 years]; isolated lat-CECS: median, 20 years [range, 17-63 years]; ant-/lat-CECS: median, 28 years [range, 17-57 years]; χ 2 (2) = 0.466; P = .79), sex (isolated ant-CECS: 50% male; isolated lat-CECS: 40% male; ant-/lat-CECS: 62% male; P = .49), or bilateral symptoms (isolated ant-CECS: 54%; isolated lat-CECS: 80%; ant-/lat-CECS: 69%; P = .40). However, cramps at rest were present in a portion of the patients with isolated ant-CECS (38%) and ant-/lat-CECS (57%) but not in those with isolated lat-CECS ( P = .032). Patient drawings of altered foot skin sensation did not contribute to the diagnosis ( P = .92). ICP values after provocation were all lower in patients with isolated ant-CECS and isolated lat-CECS compared with those with ant-/lat-CECS ( P < .05)., Conclusion: Seven percent of patients with CECS and anterolateral ELP who had symptoms due to isolated lat-CECS in the presence of normal muscle pressure in the anterior compartment., Competing Interests: The authors declared that there are no conflicts of interest in the authorship and publication of this contribution. AOSSM checks author disclosures against the Open Payments Database (OPD). AOSSM has not conducted an independent investigation on the OPD and disclaims any liability or responsibility relating thereto., (© The Author(s) 2019.)

Early event detection and response can significantly reduce the societal impact of floods. Currently, early warning systems rely on gauges, radar data, models and informal local sources. However, the scope and reliability of these systems are limited. Recently, the use of social media for detecting disasters has shown promising results, especially for earthquakes. Here, we present a new database for detecting floods in real-time on a global scale using Twitter. The method was developed using 88 million tweets, from which we derived over 10,000 flood events (i.e., flooding occurring in a country or first order administrative subdivision) across 176 countries in 11 languages in just over four years. Using strict parameters, validation shows that approximately 90% of the events were correctly detected. In countries where the first official language is included, our algorithm detected 63% of events in NatCatSERVICE disaster database at admin 1 level. Moreover, a large number of flood events not included in NatCatSERVICE were detected. All results are publicly available on www.globalfloodmonitor.org.

Proteinuria develops when specific components in the glomerular filtration barrier have impaired function. Although the precise components involved in maintaining this barrier have not been fully identified, heparan sulfate proteoglycans are believed to play an essential role in maintaining glomerular filtration. Although in situ studies have shown that a loss of heparan sulfate glycosaminoglycans increases the permeability of the glomerular filtration barrier, recent studies using experimental models have shown that podocyte-specific deletion of heparan sulfate glycosaminoglycan assembly does not lead to proteinuria. However, tubular reabsorption of leaked proteins might have masked an increase in glomerular permeability in these models. Furthermore, not only podocytes but also glomerular endothelial cells are involved in heparan sulfate synthesis in the glomerular filtration barrier. Therefore, we investigated the effect of a global heparan sulfate glycosaminoglycan deficiency on glomerular permeability. We used a zebrafish embryo model carrying a homozygous germline mutation in the ext2 gene. Glomerular permeability was assessed with a quantitative dextran tracer injection method. In this model, we accounted for tubular reabsorption. Loss of anionic sites in the glomerular basement membrane was measured using polyethyleneimine staining. Although mutant animals had significantly fewer negatively charged areas in the glomerular basement membrane, glomerular permeability was unaffected. Moreover, heparan sulfate glycosaminoglycan-deficient embryos had morphologically intact podocyte foot processes. Glomerular filtration remains fully functional despite a global reduction of heparan sulfate.

Background: The VALidation of IGA (VALIGA) study investigated the utility of the Oxford Classification of immunoglobulin A nephropathy (IgAN) in 1147 patients from 13 European countries. Methods. Biopsies were scored by local pathologists followed by central review in Oxford. We had two distinct objectives: to assess how closely pathology findings were associated with the decision to give corticosteroid/immunosuppressive (CS/IS) treatments, and to determine the impact of differences in MEST-C scoring between central and local pathologists on the clinical value of the Oxford Classification. We tested for each lesion the associations between the type of agreement (local and central pathologists scoring absent, local present and central absent, local absent and central present, both scoring present) with the initial clinical assessment, as well as long-term outcomes in those patients who did not receive CS/IS., Results: All glomerular lesions (M, E, C and S) assessed by local pathologists were independently associated with the decision to administer CS/IS therapy, while the severity of tubulointerstitial lesions was not. Reproducibility between local and central pathologists was moderate for S (segmental sclerosis) and T (tubular atrophy/interstitial fibrosis), and poor for M (mesangial hypercellularity), E (endocapillary hypercellularity) and C (crescents). Local pathologists found statistically more of each lesion, except for the S lesion, which was more frequent with central review. Disagreements were more likely to occur when the proportion of glomeruli affected was low. The M lesion, assessed by central pathologists, correlated better with the severity of the disease at presentation and discriminated better with outcomes. In contrast, the E lesion, evaluated by local pathologists, correlated better with the clinical presentation and outcomes when compared with central review. Both C and S lesions, when discordant between local and central pathologists, had a clinical phenotype intermediate to double absent lesions (milder disease) and double present (more severe)., Conclusion: We conclude that differences in the scoring of MEST-C criteria between local pathologists and a central reviewer have a significant impact on the prognostic value of the Oxford Classification. Since the decision to offer immunosuppressive therapy in this cohort was intimately associated with the MEST-C score, this study indicates a need for a more detailed guidance for pathologists in the scoring of IgAN biopsies., (© The Author(s) 2018. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

Recent studies suggest that complement plays a role in the pathogenesis of focal segmental glomerulosclerosis (FSGS). Moreover, co-localization of IgM and C3 deposits with FSGS lesions has frequently been reported. Here, we investigated whether glomerular complement deposition precedes the development of FSGS and whether it represents local complement activation. Renal biopsies from 40 patients with primary FSGS, 84 patients with minimal change disease, and 10 healthy individuals were stained for C4d, C1q, and mannose-binding lectin. C4d deposits were also measured in renal allograft biopsies from 34 patients with native primary FSGS, 18 of whom subsequently developed recurrent FSGS. Lastly, we measured C4d deposits in the Munich Wistar Frömter rat model of FSGS. The prevalence of C4d-positive glomeruli was significantly higher among patients with FSGS (73%) compared to patients with minimal change disease (21%) and healthy individuals (10%). Moreover, segmental sclerosis was absent in 42% of C4d-positive glomeruli. Glomerular C1q was significantly more prevalent in FSGS compared to minimal change disease or healthy individuals, while mannose-binding lectin was infrequently observed. C4d deposition was significantly more prevalent in recurrent FSGS (72%) before the development of sclerotic lesions compared to control transplant samples (27%). Finally, at the onset of albuminuria but before the development of FSGS lesions, Munich Wistar Frömter rats had a significantly higher percentage of C4d-positive glomeruli (31%) compared to control rats (4%). Thus, glomerular C4d deposition can precede the development of FSGS, suggesting that complement activation may play a pathogenic role in the development of FSGS., (Copyright © 2019 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Complement factor C4d was recently observed in renal biopsies from patients who had IgA nephropathy and a poor prognosis. We previously reported that C4d is a common denominator in microangiopathies. In this retrospective cohort study, we investigated whether C4d is a marker of microangiopathy in both IgA nephropathy and IgA vasculitis with nephritis, and whether patients with C4d and microangiopathy have poor renal outcome. We examined 128 renal biopsies from adult and pediatric patients, including normotensive and hypertensive patients, who presented with IgA nephropathy or IgA vasculitis with nephritis. Biopsies were re-evaluated in accordance with the Oxford classification, scored for additional lesions, and stained for complement proteins using immunohistochemistry, including C4d and C5b-9. Clinical data were collected with a mean (±SD) follow-up period of 51 ± 39 months. Changes in estimated glomerular filtration rate over time were compared using linear mixed-effects models. Renal survival was analyzed using multivariable Cox regression. Microangiopathic lesions were present in 20% of all biopsies (23% and 9% of patients with IgA nephropathy and IgA vasculitis with nephritis, respectively). Microangiopathy was associated with C4d and C5b-9 deposits, a higher number of chronic lesions, and hypertension (all p < 0.05). Patients with C4d and microangiopathic lesions had significantly poorer renal survival than patients without these findings, corrected for hypertension (p < 0.01). In conclusion, patients with IgA nephropathy or IgA vasculitis with nephritis with a combination of C4d positivity and microangiopathy comprise a clinical subgroup with an increased number of chronic lesions, lower estimated glomerular filtration rate, and poorer renal survival, even when corrected for hypertension. These data suggest that complement activation is involved in the development of microangiopathy in patients with IgA nephropathy and IgA vasculitis with nephritis, and that complement-mediated microangiopathy contributes to disease progression.

Proteinuria has been identified as prognosticator of renal outcome in patients with ANCA-associated glomerulonephritis, but whether proteinuria is related to podocyte abnormalities in these patients is largely unknown. We here investigate podocyte foot process width and number of podocytes positive for the podocyte marker WT-1 in diagnostic renal biopsies of 25 Caucasian patients with ANCA-associated glomerulonephritis in relation to proteinuria. Control tissue was used from pre-transplantation donor kidney biopsies. Proteinuria at 10 weeks follow-up correlated significantly with foot process width ( P = 0.04). Biopsies with foot process width ≥600 nm belonged more often to the crescentic or mixed class, whereas biopsies with a foot process width <600 nm were most often categorized as focal class ( P = 0.03). The mean number of podocytes based upon expression of WT-1 was significantly lower in patients compared to controls (15 vs. 34 podocytes per glomerulus; P < 0.0001). The significant decrease in expression of the podocyte WT-1 marker in ANCA-associated glomerulonephritis is considered indicative of actual podocyte loss or at least, of a loss of functionality. Furthermore, our study indicates that podocyte foot process width at baseline could be indicative for proteinuria at short term follow up. For prognostic purposes, we therefore suggest to include a description of the foot process width in the diagnostic report of a biopsy with ANCA-associated glomerulonephritis.

Background:: Up to 8% of patients who underwent a fasciotomy for leg anterior chronic exertional compartment syndrome (ant-CECS) report sensory deficits suggestive of iatrogenic superficial peroneal nerve (SPN) injury. In the current study we aimed to thoroughly assess the risk of SPN injury during a semiblind fasciotomy of the anterior compartment using 2 separate approaches., Methods:: A modified semiblind fasciotomy of the anterior compartment was performed via a longitudinal 2-cm skin incision 2 cm lateral of the anterior tibial crest halfway along the line fibular head-lateral malleolus both in cadaver legs and in patients with ant-CECS. In the cadaver legs, the skin was removed after the procedure and possible SPN injuries and spatial relationships between the SPN and the opened fascia were studied. Between January 2013 and December 2016, 64 ant-CECS patients who underwent a fasciotomy of the anterior compartment were prospectively followed. Iatrogenic SPN injuries were assessed using questionnaires and physical examinations., Results:: Macroscopic SPN nerve injury was not observed in any of the 9 cadaver legs. In 8 specimens, the SPN was located at least 5 mm posterolateral to the opened fascia. In 1 specimen, an undamaged SPN branch crossed the operative field in a ventral plane. De novo sensory deficits suggestive for iatrogenic SPN injury were not observed in any of the 64 patients (120 legs; 36 females; median age, 22 years) who underwent a fasciotomy of the anterior compartment., Conclusion:: The proposed semiblind fasciotomy for treatment of ant-CECS was not associated with SPN injury in either the cadaveric study or our clinical series., Level of Evidence:: Level IV, case series.

Dynamin plays an essential role in maintaining the structure and function of the glomerular filtration barrier. Specifically, dynamin regulates the actin cytoskeleton and the turnover of nephrin in podocytes, and knocking down dynamin expression causes proteinuria. Moreover, promoting dynamin oligomerization with Bis-T-23 restores podocyte function and reduces proteinuria in several animal models of chronic kidney disease. Thus, dynamin is a promising therapeutic target for treating chronic kidney disease. Here, we investigated the pathophysiological role of dynamin under proteinuric circumstances in a rat model and in humans. We found that glomerular Dnm2 and Dnm1 mRNA levels are increased prior to the onset of proteinuria in a rat model of spontaneous proteinuria. Also, in zebrafish embryos, we confirm that knocking down dynamin translation results in proteinuria. Finally, we show that the glomerular expression of dynamin and cathepsin L protein is increased in several human proteinuric kidney diseases. We propose that the increased expression of glomerular dynamin reflects an exhausted attempt to maintain and/or restore integrity of the glomerular filtration barrier. These results confirm that dynamin plays an important role in maintaining the glomerular filtration barrier, and they support the notion that dynamin is a promising therapeutic target in proteinuric kidney disease. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland., (© 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.)

Objectives: To determine predictors of renal relapse and end-stage renal failure (ESRF) in patients with ANCA-associated vasculitis., Methods: Data from four European Vasculitis Society randomized controlled trials, conducted roughly simultaneously between 15 March 1995 and 30 September 2002, was pooled to determine predictors of long-term renal outcome. The respective trial inclusion criteria covered the entire spectrum of disease severity. Baseline predictors of time to first renal relapse and time to ESRF were assessed by competing events analysis and Cox proportional hazards regression. The effect of renal relapse on time to ESRF was assessed by adding renal relapses to the competing events analysis as a time-varying covariate., Results: The number of patients participating was 535; mean serum creatinine (±s.d.) at entry was 341 ± 321 µmol/l and 19.7% developed ESRF. One or more renal relapse(s) was experienced by 101 patients. Multivariable regression analysis demonstrated that, in addition to impaired baseline renal function, developing ⩾1 renal relapse was an independent risk factor for ESRF (subhazard ratio 9; 95% CI 4, 19; P < 0.001). No predictive factors for renal relapse were found., Conclusion: In addition to baseline renal function, the occurrence of renal relapses is an important determinant of ESRF in patients with ANCA-associated vasculitis. We did not find any clinical predictors for renal relapse itself, including disease activity elsewhere. In light of the silent nature of renal relapse in ANCA-associated vasculitis, we stress the need for long-term vigilant monitoring for early signs of renal relapse and propose performing 3-monthly urinalysis. This will enable timely treatment and help further improve renal outcome.

Exercise-induced lower leg pain may be caused by chronic exertional compartment syndrome (CECS). Anterior or deep posterior compartments are usually affected. Knowledge about CECS of the lateral compartment (lat-CECS) is limited and outcome after fasciotomy is unknown. The purpose of this study is to report on success rates of fasciotomy in patients with lat-CECS. Surgical success rates in patients with lat-CECS diagnosed with a dynamic intracompartmental pressure (ICP) measurement were studied using a questionnaire (success: excellent or good as judged by the patient; unsuccessful: moderate, fair or poor). We conducted ICP measurements in 247 patients for suspected lat-CECS, of whom 78 were positively diagnosed. Following exclusion (n=11), 30 of the eligible 67 patients completed the questionnaire. Bilateral (70%, n=21/30) exertional pain (97%, n=29) and a feeling of tightness (93%, n=28) were the most frequently reported symptoms. Four years after fasciotomy, severity and frequency of symptoms had dropped significantly. Long-term surgical success was reported by 33% (n=10; excellent n=4, good n=6). Seventy-three percent (n=22) had resumed sports activities (9 same level, 13 lower level). In conclusion, a fasciotomy for lat-CECS was successful in the long term in just one of three operated patients in this retrospective study., Competing Interests: The authors declare no conflict of interest., (© Georg Thieme Verlag KG Stuttgart · New York.)

In diabetic nephropathy, differential expression of growth factors leads to vascular changes, including endothelial cell activation, monocyte infiltration, and inflammation. Endoglin plays an important role in endothelial function and is also associated with inflammation. In the kidney, vascular endoglin expression is increased in animal models of renal injury, where it contributes to disease severity, possibly by promoting endothelial cell activation and inflammation. Herein, we investigated whether endoglin expression is associated with diabetic nephropathy. In addition, we examined whether reducing endothelial endoglin expression in vitro affects endothelial cell activation and monocyte adhesion and, if so, which intracellular pathways are involved. Finally, we analyzed whether glomerular endoglin expression is correlated with endothelial cell activation in patients with diabetic nephropathy. Endoglin levels were significantly increased in mice with type 1 diabetes compared with control mice. Reducing endoglin expression in cultured endothelial cells significantly impaired the vascular endothelial growth factor-A-induced up-regulation of activation markers and monocyte adhesion. This was mediated by increased phosphorylation of Akt, thereby inhibiting activating transcription factor 2 phosphorylation, which regulates vascular cell adhesion molecule-1 (VCAM1) gene transcription in these cells. Last, endoglin colocalized with VCAM-1 in the glomeruli of diabetic patients, glomerular VCAM-1 expression was significantly increased in these patients, and this increase in VCAM-1 expression was correlated with increased glomerular endoglin expression. Thus, targeting endoglin function may have therapeutic value in patients at risk for diabetic nephropathy., (Copyright © 2018 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Anti-plasminogen antibodies (α-PLG) were previously detected in a subpopulation of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) patients, showing a relation to renal lesions and outcome. Several studies showed different proportions of α-PLG positive AAV patients, possibly due to differences in the assays used. We here present a new, optimized α-PLG Enzyme-Linked Immuno Sorbent Assay (ELISA) and validate the presence of α-PLG in AAV. Different ELISA set-ups were tested regarding plasminogen (PLG) antigen, concentrations, coating buffers, blocking agents, and environmental conditions. Purified lysine-PLG (lys-PLG) showed better differentiation between positive samples and negative samples than glutamic acid-PLG (glu-PLG). Therefore, lys-PLG was used as coating antigen. With the optimized α-PLG ELISA we found α-PLG in 14.3% of the myeloperoxidase (MPO)-ANCA patients, whereas all our proteinase-3 (PR3)-ANCA patients tested in our new assay were negative. Concluding, in this study we have combined important technical findings and methods from previous studies to optimize the α-PLG assay, which can be used for future research purposes and will aid in uniform reporting of α-PLG status of patients., Competing Interests: EG, YS, JW are employees of Euro Diagnostica and their salaries are paid by Euro Diagnostica. Euro Diagnostica did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. This commercial affiliation does not alter our adherence to PLOS ONE policies on sharing data and materials.

We present a consensus report pertaining to the improved clarity of definitions and classification of glomerular lesions in lupus nephritis that derived from a meeting of 18 members of an international nephropathology working group in Leiden, Netherlands, in 2016. Here we report detailed recommendations on issues for which we can propose adjustments based on existing evidence and current consensus opinion (phase 1). New definitions are provided for mesangial hypercellularity and for cellular, fibrocellular, and fibrous crescents. The term "endocapillary proliferation" is eliminated and the definition of endocapillary hypercellularity considered in some detail. We also eliminate the class IV-S and IV-G subdivisions of class IV lupus nephritis. The active and chronic designations for class III/IV lesions are replaced by a proposal for activity and chronicity indices that should be applied to all classes. In the activity index, we include fibrinoid necrosis as a specific descriptor. We also make recommendations on issues for which there are limited data at present and that can best be addressed in future studies (phase 2). We propose to proceed to these investigations, with clinicopathologic studies and tests of interobserver reproducibility to evaluate the applications of the proposed definitions and to classify lupus nephritis lesions., (Copyright © 2018 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Background: Lower leg chronic exertional compartment syndrome (CECS) is usually diagnosed in young and athletic individuals. The presence of CECS in older patients has received little attention in the literature, and patient characteristics are unknown., Purpose: To determine the prevalence of CECS in older patients (≥50 years) and to assess whether older patients with CECS differ clinically from younger patients with CECS., Study Design: Cohort study; Level of evidence, 3., Methods: All individuals with exercise-induced lower leg pain who visited a referral center for CECS between January 2001 and December 2013 were eligible for analysis. Patients were included if history, physical examination, and dynamic intracompartmental pressure measurement indicated CECS. Characteristics of patients 50 years of age or older were compared with characteristics of patients younger than 50., Results: A total of 698 patients with CECS were included: 98 patients were aged 50 years or older and 600 patients were younger than 50 years. Older individuals more often reported a history of lower leg events or comorbidities (≥50 years, 45% vs <50 years, 25%; P < .01) and unilateral symptoms (≥50 years, 45% vs <50 years, 22%; P < .01). Most older patients (62%) did not participate in sport or only walked or hiked, whereas the same was true of only 7% of the younger population. Pain (≥50 years, 94%; <50 years, 96%) and tightness (≥50 years, 57%; <50 years, 62%) were the predominant symptoms of CECS in both groups. Type of CECS differed significantly ( P < .01); the anterior muscle compartment was involved more frequently in older patients (≥50 years, 82% vs <50 years, 59%) and deep flexor muscle CECS was more often diagnosed in younger patients (≥50 years, 26% vs <50 years, 53%)., Conclusion: In the present population, 1 in 7 patients diagnosed with lower leg CECS was 50 years of age or older. These individuals were less active and had more comorbidities than patients younger than 50 years. Older individuals predominantly have anterior CECS. Clinicians should consider CECS in older individuals with exercise-induced lower leg pain, particularly if it is unilateral., Competing Interests: The authors declared that they have no conflicts of interest in the authorship and publication of this contribution.

Background and Objectives: Large studies on long-term kidney outcome in patients with anti-glomerular basement membrane (anti-GBM) GN are lacking. This study aimed to identify clinical and histopathologic parameters that predict kidney outcome in these patients., Design, Setting, Participants, & Measurements: This retrospective analysis included a total of 123 patients with anti-GBM GN between 1986 and 2015 from six centers worldwide. Their kidney biopsy samples were classified according to the histopathologic classification for ANCA-associated GN. Clinical data such as details of treatment were retrieved from clinical records. The primary outcome parameter was the occurrence of ESRD. Kidney survival was analyzed using the log-rank test and Cox regression analyses., Results: The 5-year kidney survival rate was 34%, with an improved rate observed among patients diagnosed after 2007 ( P =0.01). In patients with anti-GBM GN, histopathologic class and kidney survival were associated ( P <0.001). Only one of 15 patients with a focal class biopsy sample (≥50% normal glomeruli) developed ESRD. Patients with a sclerotic class biopsy sample (≥50% globally sclerotic glomeruli) and patients with 100% cellular crescents did not recover from dialysis dependency at presentation. In multivariable analysis, dialysis dependency at presentation (hazard ratio [HR], 3.17; 95% confidence interval [95% CI], 1.59 to 6.32), percentage of normal glomeruli (HR, 0.97; 95% CI, 0.95 to 0.99), and extent of interstitial infiltrate (HR, 2.02; 95% CI, 1.17 to 3.50) were predictors of ESRD during follow-up., Conclusions: Dialysis dependency, low percentage of normal glomeruli, and large extent of interstitial infiltrate are associated with poor kidney outcome in anti-GBM GN. Kidney outcome has improved during recent years; the success rate doubled after 2007., Podcast: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2017&#95;11&#95;21&#95;CJASNPodcast&#95;18&#95;1&#95;v.mp3., (Copyright © 2018 by the American Society of Nephrology.)

In 2012, the Systemic Lupus International Collaborating Clinics (SLICC) presented a new classification for systemic lupus erythematosus (SLE). In this classification, biopsy-confirmed lupus nephritis with positive antinuclear or anti-double-stranded DNA antibodies became a stand-alone criterion. Because of the unknown diagnostic performance among patients from nephrology clinics, we aimed to test the validity of the SLICC classification, compared with the American College of Rheumatology classification, in a cohort of patients whose renal biopsies would raise the clinicopathologic suspicion of lupus nephritis. All patients with a renal biopsy showing full house glomerular deposits and clinical follow-up in our center were included and reevaluated, after which clinicians and a pathologist reached a consensus on the reference-standard clinical diagnosis of SLE. The diagnostic performance and net reclassification improvement were assessed in 149 patients, 117 of whom had clinical SLE. Compared with the American College of Rheumatology classification, the SLICC classification had better sensitivity (100 vs. 94%); although, this was at the expense of specificity (91 vs. 100%; net reclassification improvement -0.03). Excluding the stand-alone renal criterion, the specificity of the SLICC classification reached 100%, with a significant net reclassification improvement of 0.06 compared with the American College of Rheumatology classification. The SLICC classification performed well in terms of diagnostic sensitivity among patients with full house glomerular deposits; whereas, the stand-alone renal criterion had no additional value and compromised the specificity. Thus, presumed patients with lupus nephritis in nephrology clinics reflect a distinct SLE disease spectrum warranting caution when applying SLE classification criteria., (Copyright © 2017 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Knowledge about lower leg chronic exertional compartment syndrome (CECS) is largely obtained from highly selected populations. Patient characteristics may therefore not be appropriate for the general population. Our purpose was to describe a heterogeneous population of individuals suspected of lower leg CECS and to identify predictors of CECS. Charts of individuals who were analyzed for exercise-induced lower leg pain in a referral center between 2001 and 2013 were retrospectively studied. Patients were included if history and physical examination were suggestive of CECS and if they had undergone a dynamic intracompartmental pressure measurement. Six hundred ninety-eight of 1411 individuals were diagnosed with CECS in one or more of three lower leg muscle compartments (anterior tibial, deep flexor, lateral). Prevalence of CECS peaked around the age of 20-25 years and decreased thereafter, although a plateau around 50 years was found. Age, gender, bilateral symptoms, previous lower leg pathology, sports (running and skating) and tender muscle compartments were identified as independent predictors of lower leg CECS. The proposed predictive model has moderate discriminative ability (AUC 0.66) and good calibration over the complete range of predicted probabilities. The predictive model, displayed as a nomogram, may aid in selecting individuals requiring an invasive dynamic intracompartmental muscle pressure measurement., Competing Interests: Conflict of Interest: The authors have no conflict of interest to declare., (© Georg Thieme Verlag KG Stuttgart · New York.)

Chronic intervillositis of unknown etiology (CIUE) is a poorly understood, relatively rare condition characterized histologically by the intervillous infiltration of mononuclear cells in the placenta. Clinically, CIUE is associated with poor pregnancy outcome (e.g., impaired fetal growth, preterm birth, fetal death) and high risk of recurrence in subsequent pregnancies. Because CIUE is not defined consistently, it is essential to clearly define this condition. We therefore review the published definitions of CIUE. In addition, we provide an overview of the reviewed histopathological and maternal characteristics, obstetric features, and pregnancy outcomes. Medical publication databases were searched for articles published through February 2017. Eighteen studies were included in our systematic review. The sole inclusion criterion used in all studies was the presence of intervillous infiltrates. Overall, CIUE was characterized by adverse pregnancy outcome. Miscarriage occurred in 24% of cases, with approximately half of these miscarriages defined as late. Impaired growth was commonly observed, 32.4% of pregnancies reached term, and the live birth rate was 54.9%. The high recurrence rate (25.1%) of the intervillous infiltrates in subsequent pregnancies underscores the clinical relevance of CIUE, the need for increased awareness among pathologists and clinicians, and the need for further research. Criteria for the diagnosis of CIUE are proposed and a Delphi study could be used to resolve any controversy regarding these criteria. Future studies should be designed to characterize the full clinical spectrum of CIUE., (Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Complement activation plays a role in various organs in patients with diabetes. However, in diabetic nephropathy (DN), the role of complement activation is poorly understood. We examined the prevalence and clinical significance of complement deposits in the renal tissue of cases with type 1 and type 2 diabetes with and without DN., Methods: We measured the prevalence of glomerular C4d, C1q, mannose-binding lectin (MBL), and C5b-9 deposits in 101 autopsied diabetic cases with DN, 59 autopsied diabetic cases without DN, and 41 autopsied cases without diabetes or kidney disease. The presence of complement deposits was scored by researchers who were blinded with respect to the clinical and histological data., Results: C4d deposits were more prevalent in cases with DN than in cases without DN in both the glomeruli (46% vs. 26%) and the arterioles (28% vs. 12%). C1q deposits were also increased in the glomerular hili (77% vs. 55%) and arterioles (33% vs.14%), and were correlated with DN ( P  < 0.01). MBL deposits were only rarely observed. C5b-9 deposits were more prevalent in the cases with diabetes mellitus (DM) than in the cases without DM (69% vs. 32%; P  < 0.001). Finally, glomerular C4d and C5b-9 deposits were correlated with the severity of DN (ρ = 0.341 and 0.259, respectively; P  < 0.001)., Conclusion: Complement activation is correlated with both the presence and severity of DN, suggesting that the complement system is involved in the development of renal pathology in patients with diabetes and is a promising target for inhibiting and/or preventing DN in these patients.