Inflammation In Kidney Disease Research Articles

Edukasi Penggunaan Obat Saat Bulan Ramadhan Ditinjau dari Kesehatan dan Kaidah Islam di Lingkungan Warga Aisyiyah Kota Palangka Raya

Fasting is defined as worship holding back or abstaining from eating, drinking, and all things that cancel it, starting from dawn to sunset. Although obligatory, fasting has rukhsah (relief), which can be withdrawn, for example, in conditions that can endanger the safety of life or health if fasting is continued. Muslims who undergo fasting can have different medical conditions, for example, patients with hypertension, diabetes mellitus, peptic ulcer, gastroesophageal reflux disease, inflammatory bowel disease, lung disease, heart disease, kidney disease, and pregnancy. Therefore, knowledge of fasting and its effects on various medical conditions. Not many people understand very well about the rules of using drugs when fasting so that therapy does not go well, whereas illness that is not appropriately treated will disrupt our fasting. The solution offered is the existence of this service can provide an understanding to the citizens of Aisyiyah in the city of Palangka Raya about how to use drugs in the month of Ramadan in terms of health science and terms of Islamic principles.

Design and application of single-cell RNA sequencing to study kidney immune cells in lupus nephritis.

The immune mechanisms that cause tissue injury in lupus nephritis have been challenging to define. The advent of high-dimensional cellular analyses, such as single-cell RNA sequencing, has enabled detailed characterization of the cell populations present in small biopsy samples of kidney tissue. In parallel, the development of methods that cryopreserve kidney biopsyspecimens in a manner that preserves intact, viable cells, has enabled the uniform analysis of tissue samples collected at multiple sites and across many geographic areas and demographic cohorts with high-dimensional platforms. The application of these methods to kidney biopsy samples from patients with lupus nephritis has begun to define the phenotypes of both infiltrating and resident immune cells, as well as parenchymal cells, present in nephritic kidneys. The detection of similar immune cell populations in urine suggests that it might be possible to non-invasively monitor immune activation in kidneys. Once applied to large patient cohorts, these high-dimensional studies might enable patient stratification according to patterns of immune cell activation in the kidney or identify disease features that can be used as surrogate measures of efficacy in clinical trials. Applied broadly across multiple inflammatory kidney diseases, these studies promise to enormously expand our understanding of renal inflammation in the next decade.

Validity of urine neutrophile gelatinase-associated lipocalin in children with primary vesicoureteral reflux.

Vesicoureteral reflux (VUR) is the most common congenital urinary tract abnormality in children. The objective of this study was to evaluate the diagnostic value of urine neutrophil gelatinase-associated lipocalin (NGAL) in children with primary vesicoureteral reflux (VUR). A total of 69 patients were evaluated in 2 groups with (32) and without (37) VUR. Patients with secondary VUR, infectious or inflammatory disorders, obstructive uropathies, and acute or chronic kidney disease were excluded. Urine NGAL level was measured by ELISA kit. Mean age of children with VUR was 36.84 ± 28.16, compared to those without VUR 32.32 ± 29.08, with no significant difference (p = 0.51). Mean urine NGAL (p = 0.012) and urine NGAL/Cr (p = 0.003) were higher in patients with VUR. In addition, urine NGAL/Cr increased significantly in patients with decreased parenchymal function, compared to those with normal DMSA scan. Using the cutoff value of 0.888, urine NGAL had 84% sensitivity and 81% specificity for diagnosis of VUR. Based on AUC (0.86), urine NGAL had acceptable diagnostic accuracy in children with VUR. The results of this study support the evidence that urine NGAL/Cr is a sensitive, specific and accurate biomarker for diagnosis of children with primary VUR.

Цитратна терапія у дітей із запальними та незапальними захворюваннями нирок: показання та оцінка ефективності

Цитратна терапія у дітей із запальними та незапальними захворюваннями нирок: показання та оцінка ефективності

Urinary Activin A is a novel biomarker reflecting renal inflammation and tubular damage in ANCA-associated vasculitis.

Activin A, a member of the transforming growth factor-beta superfamily, is a critical modulator of inflammation and plays a key role in controlling the cytokine cascade that drives the inflammatory response. However, the role of activin A in inflammatory kidney diseases remains unknown. To address this issue, we examined here whether activin A can be detected in the kidney and/or urine from patients with antineutrophil cytoplasmic antibody (ANCA) -associated vasculitis (AAV). Fifty-one patients who had been diagnosed with AAV and were treated in our department between November 2011 to March 2018 were included in this study. Forty-one patients had renal complications (renal AAV). Serum and urinary activin A levels were measured by enzyme-linked immunosorbent assay. Correlation of urinary activin A concentration with clinical parameters was analyzed. Urinary activin A was undetectable in healthy volunteers. In contrast, urinary activin A concentration was significantly increased in patients with renal AAV but not in those with non-renal AAV. Urinary activin A concentration decreased rapidly after immunosuppressive treatment. There was a significant correlation of urinary activin A level with urinary protein, L-FABP, and NAG. Histologic evaluation revealed that urinary activin A levels were significantly higher in patients with cellular crescentic glomeruli than in those lacking this damage. In situ hybridization demonstrated that the mRNA encoding the activin A βA subunit was undetectable in normal kidneys but accumulated in the proximal tubules and crescentic glomeruli of the kidneys of patients with renal AAV. Immunostaining showed that activin A protein also was present in the proximal tubules, crescentic glomeruli, and macrophages infiltrating into the interstitium in the kidneys of patients with renal AAV. These data suggested that urinary activin A concentration reflects renal inflammation and tubular damage in AAV and may be a useful biomarker for monitoring renal AAV.

Interleukin 17A Participates in Renal Inflammation Associated to Experimental and Human Hypertension.

Hypertension is now considered as an inflammatory disease, and the kidney is a key end-organ target. Experimental and clinical studies suggest that interleukin 17A (IL-17A) is a promising therapeutic target in immune and chronic inflammatory diseases, including hypertension and kidney disease. Elevated circulating IL-17A levels have been observed in hypertensive patients. Our aim was to investigate whether chronically elevated circulating IL-17A levels could contribute to kidney damage, using a murine model of systemic IL-17A administration. Blood pressure increased after 14 days of IL-17A infusion in mice when compared with that in control mice, and this was associated to kidney infiltration by inflammatory cells, including CD3+ and CD4+ lymphocytes and neutrophils. Moreover, proinflammatory factors and inflammatory-related intracellular mechanisms were upregulated in kidneys from IL-17A-infused mice. In line with these findings, in the model of angiotensin II infusion in mice, IL-17A blockade, using an anti-IL17A neutralizing antibody, reduced kidney inflammatory cell infiltrates and chemokine overexpression. In kidney biopsies from patients with hypertensive nephrosclerosis, IL-17A positive cells, mainly Th17 and γδ T lymphocytes, were found. Overall, the results support a pathogenic role of IL-17A in hypertensive kidney disease-associated inflammation. Therapeutic approaches targeting this cytokine should be explored to prevent hypertension-induced kidney injury.

Roles of Inflammasomes in Inflammatory Kidney Diseases

The immune system has a central role in eliminating detrimental factors, by frequently launching inflammatory responses towards pathogen infection and inner danger signal outbreak. Acute and chronic inflammatory responses are critical determinants for consequences of kidney diseases, in which inflammasomes were inevitably involved. Inflammasomes are closely linked to many kidney diseases such as acute kidney injury and chronic kidney diseases. Inflammasomes are macromolecules consisting of multiple proteins, and their formation initiates the cleavage of procaspase-1, resulting in the activation of gasdermin D as well as the maturation and release of interleukin-1β and IL-18, leading to pyroptosis. Here, we discuss the mechanism in which inflammasomes occur, as well as their roles in inflammatory kidney diseases, in order to shed light for discovering new therapeutical targets for the prevention and treatment of inflammatory kidney diseases and consequent end-stage renal disease.

NLRP3 Inflammasome Modulation by Melatonin Supplementation in Chronic Pristane-Induced Lupus Nephritis.

Lupus nephritis (LN) is a kidney inflammatory disease caused by systemic lupus erythematosus (SLE). NLRP3 inflammasome activation is implicated in LN pathogenesis, suggesting its potential targets for LN treatment. Melatonin, an endogenous indoleamine, is considered an important multitasking molecule that has been reported to have anti-inflammatory effects by inhibiting nuclear factor-kappa B (NF-κB)-mediated inflammatory responses in vivo. This molecule has also protective effects against the activation of the inflammasomes and, in particular, the NLRP3 inflammasome. Thus, this work evaluated the effect of melatonin on morphological alteration and NLRP3 inflammasome activation in LN pristane mouse models. To evaluate the melatonin effects in these mice, we studied the renal cytoarchitecture by means of morphological analyses and immunohistochemical expression of specific markers related to oxidative stress, inflammation and inflammasome activation. Our results showed that melatonin attenuates pristane-induced LN through restoring of morphology and attenuation of oxidative stress and inflammation through a pathway that inhibited activation of NLRP3 inflammasome signaling. Our data clearly demonstrate that melatonin has protective activity on lupus nephritis in these mice that is highly associated with its effect on enhancing the Nrf2 antioxidant signaling pathway and decreasing renal NLRP3 inflammasome activation.

Crosstalk between fibroblast growth factor 23, iron, erythropoietin, and inflammation in kidney disease.

Recent research has revealed that regulation of the bone-secreted hormone fibroblast growth factor 23 (FGF23) is not limited to classical mineral factors. Specifically, bidirectional relationships have been described between FGF23 production and anemia, iron status, and inflammation. Here, we will review the latest published articles on the crosstalk between FGF23 and the aforementioned nonclassical factors. It has been recently reported that erythropoietin, iron deficiency, and inflammation increase FGF23 production and metabolism. Moreover, FGF23 promotes anemia and regulates inflammatory responses. These findings are particularly important in the setting of chronic kidney disease which is characterized by elevated FGF23 levels and several associated comorbidities. Regulation of FGF23 is complex and involves many bone and renal factors. More recently, erythropoietin, iron deficiency, and inflammation have been also shown to affect FGF23 transcription and cleavage. Importantly, FGF23 has emerged as a regulator of erythropoiesis, iron metabolism, and inflammation. These findings provide novel and important insights into the pathophysiologic mechanisms of chronic kidney disease and may present new opportunities for therapeutic clinical interventions.

Етіологічна характеристика збудників мікробно-запальних захворювань нирок і сечових шляхів у дітей залежно від віку та статі

Етіологічна характеристика збудників мікробно-запальних захворювань нирок і сечових шляхів у дітей залежно від віку та статі

Novel 3D analysis using optical tissue clearing documents the evolution of murine rapidly progressive glomerulonephritis

Recent developments in optical tissue clearing have been difficult to apply for the morphometric analysis of organs with high cellular content and small functional structures, such as the kidney. Here, we establish combinations of genetic and immuno-labelling for single cell identification, tissue clearing and subsequent de-clarification for histoimmunopathology and transmission electron microscopy. Using advanced light microscopy and computational analyses, we investigated a murine model of crescentic nephritis, an inflammatory kidney disease typified by immune-mediated damage to glomeruli leading to the formation of hypercellular lesions and the rapid loss of kidney function induced by nephrotoxic serum. Results show a graded susceptibility of the glomeruli, significant podocyte loss and capillary injury. These effects are associated with activation of parietal epithelial cells and formation of glomerular lesions that may evolve and obstruct the kidney tubule, thereby explaining the loss of kidney function. Thus, our work provides new high-throughput endpoints for the analysis of complex tissues with single-cell resolution.

Mononuclear phagocytes orchestrate prolyl hydroxylase inhibition-mediated renoprotection in chronic tubulointerstitial nephritis

Prolyl hydroxylase domain enzyme inhibitors (PHDIs) stabilize hypoxia-inducible factors (HIFs), and are protective in models of acute ischemic and inflammatory kidney disease. Whether PHDIs also confer protection in chronic inflammatory kidney disease models remains unknown. Here we investigated long-term effects of PHDI treatment in adenine-induced nephropathy as a model for chronic tubulointerstitial nephritis. After three weeks, renal dysfunction and tubulointerstitial damage, including proximal and distal tubular injury, tubular dilation and renal crystal deposition were significantly attenuated in PHDI-treated (the isoquinoline derivative ICA and Roxadustat) compared to vehicle-treated mice with adenine-induced nephropathy. Crystal-induced renal fibrosis was only partially diminished by treatment with ICA. Renoprotective effects of ICA treatment could not be attributed to changes in adenine metabolism or urinary excretion of the metabolite 2,8-dihydroxyadenine. ICA treatment reduced inflammatory infiltrates of F4/80+ mononuclear phagocytes in the kidneys and supported a regulatory, anti-inflammatory immune response. Furthermore, interstitial deposition of complement C1q was decreased in ICA-treated mice fed an adenine-enriched diet. Tubular cell-specific HIF-1α and myeloid cell-specific HIF-1α and HIF-2α expression were not required for the renoprotective effects of ICA. In contrast, depletion of mononuclear phagocytes with clodronate largely abolished the nephroprotective effects of PHD inhibition. Thus, our findings indicate novel and potent systemic anti-inflammatory properties of PHDIs that confer preservation of kidney function and structure in chronic tubulointerstitial inflammation and might counteract kidney disease progression.

A Systematic Review of Case-Identification Algorithms Based on Italian Healthcare Administrative Databases for Three Relevant Diseases of the Digestive and Genitourinary System: Inflammatory Bowel Diseases, Celiac Disease, and Chronic Kidney Disease.

to identify and describe all Inflammatory Bowel Disease (IBD), Celiac Disease (CD), and Chronic Kidney Disease (CKD) case-identification algorithms by means of Italian Healthcare Administrative Databases (HADs), through a review of papers published in the past 10 years. this study is part of a project that systematically reviewed case-identification algorithms for 18 acute and chronic conditions by means of HADs in Italy. PubMed was searched for original articles, published between 2007 and 2017, in Italian or English. The search string consisted of a combination of free text and MeSH terms with a common part that focused on HADs and a disease-specific part. All identified papers were screened by two independent reviewers; exclusion criteria were the following: no details of algorithms reported, algorithm not developed in the Italian context, exclusive use of data from the death certificate register, or from general practitioner or pediatrician databases. Pertinent papers were classified according to the objective for which the algorithm had been used, and only articles that used algorithms for primary objectives (I disease occurrence, II population/cohort selection, III outcome identification) were considered for algorithm extraction. The HADs used (hospital discharge records, drug prescriptions, etc.), ICD-9 and ICD-10 codes, ATC classification of drugs, followback periods, and age ranges applied by the algorithms have been reported. Further information on specific objective(s), accuracy measures, sensitivity analyses and the contribution of each HAD, have also been recorded. the search string led to the identification of 98 articles for IBD, 42 articles for CD, and 390 for CKD. By screening the references, one paper for IBD was added. Finally, this led to 5, 9, and 8 pertinent papers respectively for IBD, CD, and CKD. Considering the papers on IBD and CD, specific age selections were applied to focus on children and young adult populations. When a selection on age was applied for CKD, instead, it mostly considered individuals aged more than 18 years. Three algorithms for IBD, 4 for CD, and 5 for CKD were extracted from papers and characterized. Drug prescription databases were used for both IBD and CKD algorithms, whereas the hospital discharge database and co-payment exemption database were used for IBD and CD. Pathology records and specialist visit databases were also used for CD and CKD, respectively. For each disease only one algorithm applied criteria for the exclusion of prevalent cases. External validation was performed only for Crohn's disease among IBDs, in one algorithm. the results of this review indicate that case identification for IBD and CD from routinely collected data can be considered feasible and can be used to perform different kinds of epidemiological studies. The same is not true for CKD, which requires further efforts, mainly to improve the detection of early stage patients.

The renal draining lymph nodes in acute inflammatory kidney disease

Renal lymphatics are implicated in renal disease, but their function in inflammatory kidney diseases is relatively poorly defined. In the current issue, Kasinath etal. examine the role of the kidney draining lymph node in experimental glomerulonephritis, as well the role of fibroblastic reticular cells within lymph nodes. Removing the kidney-draining lymph nodes prior to the induction of glomerulonephritis attenuated disease, as did interventions that affected the function of lymph nodes in general.

Oxidant and antioxidant mechanisms in chronic kidney disease inflammation in CKD

Oxidant and antioxidant mechanisms in chronic kidney disease inflammation in CKD

Established and Emerging Concepts to Treat Imbalances of Iron Homeostasis in Inflammatory Diseases.

Inflammation, being a hallmark of many chronic diseases, including cancer, inflammatory bowel disease, rheumatoid arthritis, and chronic kidney disease, negatively affects iron homeostasis, leading to iron retention in macrophages of the mononuclear phagocyte system. Functional iron deficiency is the consequence, leading to anemia of inflammation (AI). Iron deficiency, regardless of anemia, has a detrimental impact on quality of life so that treatment is warranted. Therapeutic strategies include (1) resolution of the underlying disease, (2) iron supplementation, and (3) iron redistribution strategies. Deeper insights into the pathophysiology of AI has led to the development of new therapeutics targeting inflammatory cytokines and the introduction of new iron formulations. Moreover, the discovery that the hormone, hepcidin, plays a key regulatory role in AI has stimulated the development of several therapeutic approaches targeting the function of this peptide. Hence, inflammation-driven hepcidin elevation causes iron retention in cells and tissues. Besides pathophysiological concepts and diagnostic approaches for AI, this review discusses current guidelines for iron replacement therapies with special emphasis on benefits, limitations, and unresolved questions concerning oral versus parenteral iron supplementation in chronic inflammatory diseases. Furthermore, the review explores how therapies aiming at curing the disease underlying AI can also affect anemia and discusses emerging hepcidin antagonizing drugs, which are currently under preclinical or clinical investigation.

Emerging evidence of an effect of salt on innate and adaptive immunity.

Salt intake as part of a western diet currently exceeds recommended limits, and the small amount found in the natural diet enjoyed by our Paleolithic ancestors. Excess salt is associated with the development of hypertension and cardiovascular disease, but other adverse effects of excess salt intake are beginning to be recognized, including the development of autoimmune and inflammatory disease. Over the last decade there has been an increasing body of evidence demonstrating that salt affects multiple components of both the innate and adaptive immune systems. In this review we outline the recent laboratory, animal and human data, highlighting the effect of salt on immunity, with a particular focus on the relevance to inflammatory kidney disease.

Importance of Complete Parenteral Iron Replacement on Hemoglobin Normalization: A Retrospective Analysis

IntroductionIron deficiency anemia (IDA) is the most common cause of anemia in the United States (US) and occurs most often in patients with chronic diseases and inflammation.Although oral iron therapy is often prescribed for iron deficiency anemia, parenteral iron therapy is necessary for patients who cannot tolerate or are nonresponsive to oral iron. Parenteral iron therapy is also used in patients with chronic diseases such as inflammatory bowel disease, cancer or chronic kidney disease when rapid iron replacement is desirable. Currently, several parenteral iron therapies are available in the US and they vary in dose strengths and administration schedules. There are limited data on the dosing patterns of parenteral iron therapy and its effectiveness in the real world setting. The objective of this analysis was to assess the importance of parenteral iron dosing on serum hemoglobin (Hgb) level normalization in real world clinical practice.MethodsData was obtained from the Decision Resources Group (DRG) Real World Evidence Data Repository US database, which includes medical and pharmacy claims, and electronic health record data representing more than 300 million patient lives. Adult patients (≥18 years of age) who were treated with parenteral iron between 3/1/2015 and 2/28/2017 were included in the analysis. Eligible patients were required to have their most recent baseline Hgb level below normal (Hgb <12 g/dL for females and <13.5 g/dL for males) and recorded <30 days prior to or on the date of their index (first) parenteral iron therapy claim. Patients were excluded from the study if they received parenteral iron 6 weeks prior to the index date, received dialysis, or had insufficient data to identify comorbidities one year prior to index date.Parenteral iron dose required to correct for iron deficit was calculated using the Ganzoni formula. Patients were categorized based on whether or not they received the full amount of parenteral iron required to correct for iron deficit during the 3 weeks after the index date. Patients were assessed to determine the proportions of patients achieving normalized Hgb levels (≥12 g/dL for females and 13.5 g/dL for males) within 8 weeks after index date and until the end of data availability. Logistic regression was used to estimate the effect of receiving the full amount of required parenteral iron dose within 3 weeks of treatment initiation on the likelihood of Hgb level normalization while controlling for gender, age, comorbid conditions, and use of prescription oral iron therapy.ResultsA total of 2,966 patients were included in the analysis (68.2% female, 58.4% ≥65 years; 60.1% chronic kidney disease, 50.1% congestive heart failure, 64.4% inflammatory bowel disease, and 59.5% cancer). Most (95%) patients did not receive prescription oral iron therapy within 3 months before or after index date. Mean (SD) number of injections during the 3-week period after index date was 2.5 (1.4).Parenteral iron dose required to correct for iron deficit ranged from 343.7mg to 1915.0mg. Parenteral iron dose received during the first three weeks ranged from 600mg to 2000mg. About a third of patients (33.9%, n=1,006) received the full amount of required parenteral iron dose within the 3-week treatment course. A total of 582 (19.6%) patients had normalized Hgb levels within 8 weeks of treatment initiation and 53.9% (n=1,599) had normalized Hgb levels at any time during the entire study period (median study follow-up=108 weeks).Patients who received the full amount of required dose to correct for iron deficit within 3 weeks of treatment initiation were significantly more likely to have normalized Hgb levels within 8 weeks of treatment initiation than those patients who did not receive the full amount of required dose over the same time period [adjusted odds ratio (95% CI) =2.67 (2.20, 3.24)]. Similarly, when normalized Hgb levels were analyzed using data available for the entire study period, patients who received the full amount of required dose within 3 weeks of treatment initiation were significantly more likely to have normalized Hgb levels than those patients who did not receive the full amount of required dose within 3 weeks of treatment initiation [adjusted odds ratio (95% CI) =2.32 (1.96, 2.75)].ConclusionThe results of this analysis underscore the importance of initial complete iron replacement on rapidly improving clinical outcomes for IDA patients receiving parenteral iron therapy. DisclosuresLaVallee:Daiichi Sankyo, Inc.: Research Funding. Cronin:Daiichi Sankyo, Inc.: Research Funding. Bansal:Daiichi Sankyo, Inc.: Research Funding. Kwong:Daiichi Sankyo, Inc.: Employment.

Novel Hermanksky-Pudlak Syndrome Type 6 Missense Variant Associated with Subclinical Oculocutaneous Albinism and Mild Bleeding

▪Qualitative disorders of platelets are often missed at clinical evaluation. Hermansky-Pudlak (HPS) syndrome is a rare genetic metabolic disorder with subtype specific clinical associations most prevalent in Puerto Rico with strong link to consanguinity. HPS is usually associated with albinism, visual impairment and a qualitative platelet dysfunction due to absence of dense granules. Ceroid accumulation can be associated with inflammatory bowel disease, pulmonary fibrosis and kidney disease. Ten variants have been described with types 1, 2 and 4 associated with severe disease whilst type 3, 5 and 6 is associated with mild disease. Little is known about types 7, 8, 9 and 10. A Caucasian adult female presented with a history of intermittent episodes of severe bleeding. She carried the diagnosis of probable von Willebrand's disease at presentation. This particular patient did not respond to cryoprecipitate infusion but bleeding stopped secondary to infusion of normal platelets, a clue to a platelet storage disorder. Hence she was re-investigated for a bleeding disorder and initial coagulation testing identified abnormal platelet aggregation and amplitude pattern to epinephrine. She was subsequently evaluated with platelet transmission electron microscopy and platelet flow cytometry at the Mayo Clinic Hematopathology. Platelet TEM showed complete absence of dense granules and a normal flow cytometry. HPS was suspected and initial genetic studies identified a variant genetic abnormality. Further studies were done at the NIH. Classical clinical features of HPS like nystagmus, and ocular albinism was not identified at initial neurological and ophthalmologic examination. But more detailed evaluation revealed subclinical oculocutaneous albinism. Genome wide SNP analysis showed regions of homozygosity including HPS 1 and HPS 6; deletions were not identified in these genes. Full length HPS1 transcript was amplified by PCR of genomic DNA. Targeted next-generation sequencing identified a novel homozygous missense variant [c.383T>C (p.V128A)] in HPS6. Reduced HPS6 mRNA levels were found in the patient's skin fibroblasts compared to cells from patients with HPS-1 and normal control cells. HPS6 protein expression in the patient's cells was also low and approximately 60% lower than that of normal cells. HPS is a rare platelet storage disorder that can often be missed. Platelet aggregation tests need to be followed up by platelet TEM and genetic testing to definitively diagnose this condition. Further work up has defined a new missense variant by SNP analysis, next generation sequencing and fibroblast culture. It is important to identify the subtype of HPS, because certain subtypes of HPS (HPS 1, 2 and 4) have clinical manifestations like progressive pulmonary fibrosis. Identification of the platelet storage disorder also helps in management of the bleeding diathesis. DisclosuresNo relevant conflicts of interest to declare.

Exclusive expression of transmembrane TNF aggravates acute glomerulonephritis despite reduced leukocyte infiltration and inflammation

Tumor necrosis factor-α (TNF) is a cytokine mediating inflammatory kidney diseases such as immune complex glomerulonephritis. Its two receptors, TNFR1 and TNFR2, play distinct roles in this process, with TNFR2 strongly required for induction of disease. In contrast to soluble TNF (sTNF), transmembrane TNF robustly activates TNFR2. Thus, we examined the functional role of transmembrane TNF by inducing heterologous nephrotoxic serum nephritis in wild-type and transgenic TNFΔ1-9,K11E knock-in mice expressing transmembrane TNF but no sTNF (memTNF mice). Compared to wild-type, nephritis was exacerbated in memTNF mice on day 5, indicated by increased albuminuria, higher serum urea levels, and more pronounced glomerular deposits, together with higher numbers of dying and proliferating glomerular cells. This was associated with greater loss of glomerular endothelial cells, increased podocyte stress, and signs of augmented necroptosis in memTNF kidneys. Aggravation of nephritis was dependent on transmembrane TNF expression in parenchymal cells, but not leukocytes. Surprisingly, increased kidney injury was associated with reduced renal leukocyte infiltration in memTNF mice, which correlated with decreased renal mRNA expression of pro-inflammatory mediators. This effect was also present in isolated memTNF glomeruli stimulated with interleukin-1β invitro. Thus, uncleaved transmembrane TNF is an important mediator of renal tissue damage characterized by increased renal cell death and loss of glomerular endothelial cells in murine glomerulonephritis. In contrast, sTNF predominantly mediates renal leukocyte recruitment and inflammation. These findings highlight the importance of transmembrane TNF in inflammatory kidney disease as a possible therapeutic target.