- The role of the immune system in kidney disease. [Review]
- CEClin Exp Immunol 2018 Feb 17
- The immune system and the kidneys are closely linked. In health the kidneys contribute to immune homeostasis, while components of the immune system mediate many acute forms of renal disease and play ...
The immune system and the kidneys are closely linked. In health the kidneys contribute to immune homeostasis, while components of the immune system mediate many acute forms of renal disease and play a central role in progression of chronic kidney disease. A dysregulated immune system can have either direct or indirect renal effects. Direct immune-mediated kidney diseases are usually a consequence of autoantibodies directed against a constituent renal antigen, such as collagen IV in anti-glomerular basement membrane disease. Indirect immune-mediated renal disease often follows systemic autoimmunity with immune complex formation, but can also be due to uncontrolled activation of the complement pathways. Though the range of mechanisms of immune dysregulation leading to renal disease is broad, the pathways leading to injury are similar. Loss of immune homeostasis in renal disease results in perpetual immune cell recruitment and worsening damage to the kidney. Uncoordinated attempts at tissue repair, after immune-mediated disease or non-immune mediated injury, result in fibrosis of structures important for renal function, eventually leading to kidney failure. As renal disease often only manifests clinically when substantial damage has already occurred, new diagnostic methods and indeed treatments must be identified to inhibit further progression and promote appropriate tissue repair. Studying cases in which immune homeostasis is re-established may reveal new treatment possibilities. This article is protected by copyright. All rights reserved.
- The role of metabolic enzymes in mesenchymal tumors and tumor syndromes: genetics, pathology, and molecular mechanisms. [Review]
- LILab Invest 2018 Jan 16
- The discovery of mutations in genes encoding the metabolic enzymes isocitrate dehydrogenase (IDH), succinate dehydrogenase (SDH), and fumarate hydratase (FH) has expanded our understanding not only o...
The discovery of mutations in genes encoding the metabolic enzymes isocitrate dehydrogenase (IDH), succinate dehydrogenase (SDH), and fumarate hydratase (FH) has expanded our understanding not only of altered metabolic pathways but also epigenetic dysregulation in cancer. IDH1/2 mutations occur in enchondromas and chondrosarcomas in patients with the non-hereditary enchondromatosis syndromes Ollier disease and Maffucci syndrome and in sporadic tumors. IDH1/2 mutations result in excess production of the oncometabolite (D)-2-hydroxyglutarate. In contrast, SDH and FH act as tumor suppressors and genomic inactivation results in succinate and fumarate accumulation, respectively. SDH deficiency may result from germline SDHA, SDHB, SDHC, or SDHD mutations and is found in autosomal-dominant familial paraganglioma/pheochromocytoma and Carney-Stratakis syndrome, describing the combination of paraganglioma and gastrointestinal stromal tumor (GIST). In contrast, patients with the non-hereditary Carney triad, including paraganglioma, GIST, and pulmonary chondroma, usually lack germline SDH mutations and instead show epigenetic SDH complex inactivation through SDHC promoter methylation. Inactivating FH germline mutations are found in patients with hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome comprising benign cutaneous/uterine leiomyomas and renal cell carcinoma. Mutant IDH, SDH, and FH share common inhibition of α-ketoglutarate-dependent oxygenases such as the TET family of 5-methylcytosine hydroxylases preventing DNA demethylation, and Jumonji domain histone demethylases increasing histone methylation, which together inhibit cell differentiation. Ongoing studies aim to better characterize these complex alterations in cancer, the different clinical phenotypes, and variable penetrance of inherited and sporadic cancer predisposition syndromes. A better understanding of the roles of metabolic enzymes in cancer may foster the development of therapies that specifically target functional alterations in tumor cells in the future. Here, the physiologic functions of these metabolic enzymes, the mutational spectrum, and associated functional alterations will be discussed, with a focus on mesenchymal tumor predisposition syndromes.
- 18F-FDG PET/CT Imaging of Necrotizing Crescentic Glomerulonephritis With Anti-Glomerular Basement Membrane Disease. [Journal Article]
- CNClin Nucl Med 2018; 43(3):e96-e97
- A 30-year-old woman presented with lethargy, night sweats, and fever with raised inflammatory markers. Anti-neutrophil cytoplasmic antibody was negative. Abdominopelvic CT was unremarkable. Subsequen...
A 30-year-old woman presented with lethargy, night sweats, and fever with raised inflammatory markers. Anti-neutrophil cytoplasmic antibody was negative. Abdominopelvic CT was unremarkable. Subsequently, she underwent FDG PET/CT showing globally enlarged kidneys with diffuse hypermetabolic activity within the renal parenchyma bilaterally. Renal biopsies showed morphologic features of an active necrotizing crescentic glomerulonephritis, which was confirmed clinically and treated. This case demonstrates the role that FDG PET/CT can play in inflammatory conditions, such as glomerulonephritis, where it may be clinically useful when the presentation is atypical.
- Diffuse alveolar haemorrhage complicated by pulmonary embolism - problems with treatment. [Journal Article]
- ARAdv Respir Med 2017; 85(6):328-332
- Diffuse alveolar haemorrhage (DAH) refers to a clinical syndrome resulting from injury of the alveolar capillaries, arterioles and venules leading to red blood cel accumulation in the distal air spac...
Diffuse alveolar haemorrhage (DAH) refers to a clinical syndrome resulting from injury of the alveolar capillaries, arterioles and venules leading to red blood cel accumulation in the distal air spaces. The conditions associated with DAH and underlying disease determine the prognosis and the treatment regimen. The coexistence of DAH with venous thromboembolism (VTE) is a seroius problem for clinicians and poses a challenge in the therapeutic management. We describe a young patient who developed massive DAH in the course of anti-glomerular basement membrane (anti-GBM) disease (formerly called Goodpasture's syndrome) complicated by pulmonary embolism (PE).
- Plasticity and heterogeneity of Th17 in immune-mediated kidney diseases. [Review]
- JAJ Autoimmun 2018; 87:61-68
- Anti-neutrophil cytoplasmatic antibody (ANCA)-associated glomerulonephritis, anti-glomerular basement membrane (GBM) glomerulonephritis and lupus nephritis are the most common causes of rapid progres...
Anti-neutrophil cytoplasmatic antibody (ANCA)-associated glomerulonephritis, anti-glomerular basement membrane (GBM) glomerulonephritis and lupus nephritis are the most common causes of rapid progressive glomerulonephritis (RPGN) in the Western world. These aggressive forms of autoimmune kidney diseases significantly contribute to end-stage renal disease and are associated with high morbidity and mortality. Moreover, patients show significant heterogeneity with respect to clinical outcome and response to therapy. T cell infiltration is a morphological hallmark of RPGN and it is a critical driver of kidney injury. Different CD4+T cell subsets that are endowed with distinct regulatory and effector functions are involved in this detrimental inflammatory process. In particular, the identification and functional characterization of IL-17-expressing CD4+Th17 cells have substantially advanced our understanding of organ-specific autoimmunity. In experimental models of crescentic and proliferative GN, including ANCA-associated GN, anti-GBM-GN and lupus nephritis, the Th17/IL-17 axis significantly contributes to renal tissue damage. In patients with ANCA-associated GN or lupus nephritis, IL-17 serum levels correlated with disease activity. Moreover, Th17 cells are present in the kidneys of these patients and represents a topic of intense ongoing clinical and basic research. Importantly, recent studies have challenged the view of CD4+T cells subsets as terminally differentiated homogenous cells, showing that T cells, in particular Th17 cells, are much more flexible and heterogeneous than previously thought. However, analysis of Th17 cell fate in mouse models of autoimmune kidney disease revealed a high degree of stability within these cells, an observation that is in contrast to Th17 cells in other models of autoimmune diseases including experimental autoimmune encephalomyelitis. Interestingly, anti-CD3 treatment interferes with stable Th17 cells and induces a potential regulatory phenotype in Th17 cells, highlighting the therapeutic potential of targeting pathogenic Th17 cells in autoimmunity. In this review, we discuss the current knowledge of Th17 cell plasticity and heterogeneity in autoimmune kidney diseases with a special focus on the underlying mechanisms of this process and debate if Th17 cell plasticity is beneficial or harmful to renal inflammation.
- Rapidly progressive glomerulonephritis due to anti-glomerular basement membrane disease accompanied by IgA nephropathy: An unusual association. [Case Reports]
- SJSaudi J Kidney Dis Transpl 2017 Nov-Dec; 28(6):1404-1407
- Anti-glomerular basement membrane (anti-GBM) disease is a systemic autoimmune disorder characterized by circulating IgG antibodies (rarely IgA and IgM) to the carboxyterminal, noncollagenous 1 (NC1) ...
Anti-glomerular basement membrane (anti-GBM) disease is a systemic autoimmune disorder characterized by circulating IgG antibodies (rarely IgA and IgM) to the carboxyterminal, noncollagenous 1 (NC1) domain of type IV collagen of GBM also known as Goodpasture antigen. Patients typically present with rapidly progressive glomerulonephritis (RPGN) and pulmonary hemorrhage in the presence of which it is referred to as Goodpasture's disease. Anti-GBM disease has been reported to coexist with pauci-immune antineutrophil cytoplasmic autoantibody-positive glomerulonephritis and membranous glomerulopathy. The sequential or concurrent presentation of anti-GBM disease with IgA nephropathy has been rarely described. We herein report a case of a 22-year-old female who presented with RPGN, and renal biopsy revealed crescentic glomerulonephritis with strong linear IgG (+2) staining of GBM and extensive mesangial IgA (+3) deposits. The patient was treated with three pulses of IV methylprednisolone followed by oral steroids. Plasmapheresis and cytotoxic agents were not included in the therapeutic armamentarium as the patient had no pulmonary hemorrhage and biopsy revealed established chronic changes. The association of anti-GBM disease with IgA nephropathy could open up new vistas on the implication of these IgA mesangial deposits in the pathogenesis and prognosis of anti-GBM disease.
- Cystic Lung Disease in Genetic Syndromes with Deficient Tumor Suppressor Gene Function. [Journal Article]
- RRespiration 2017; 94(6):467-485
- Cystic lung diseases constitute a distinct group of rare lung disorders, among which two result from monogenic defects affecting tumor suppressor genes: lymphangioleiomyomatosis, either sporadic or a...
Cystic lung diseases constitute a distinct group of rare lung disorders, among which two result from monogenic defects affecting tumor suppressor genes: lymphangioleiomyomatosis, either sporadic or associated with tuberous sclerosis complex, and Birt-Hogg-Dubé syndrome. These disorders have similarities in their clinical expression, including occurrence in young adults, multiple pulmonary cysts, recurrent pneumothorax, skin hamartomas, and renal tumors. However, they markedly differ in their gender distribution, pathogenesis, disease course, and prognosis. Our knowledge on these two rare conditions is rapidly expanding. Management of lymphangioleiomyomatosis has substantially improved in the past decade with the understanding of its pathogenic mechanisms, the discovery of an effective therapy, and development of large cohorts and international guidelines. Birt-Hogg-Dubé syndrome has been described more recently and still awaits deeper understanding of its pathophysiology.
- Predicting Outcome in Patients with Anti-GBM Glomerulonephritis. [Journal Article]
- CJClin J Am Soc Nephrol 2018 Jan 06; 13(1):63-72
- 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.
- Genetic variants and acute kidney injury: A review of the literature. [Review]
- JCJ Crit Care 2017 Nov 13; 44:203-211
- CONCLUSIONS: Most studies of AKI genetics involve hypothesis-driven (rather than hypothesis-generating) candidate gene investigations that have failed to identify contributory variants consistently. A limited number of unbiased, larger-scale studies have been carried out, but there remains a pressing need for additional GWA studies.
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- Renal Amyloidosis Associated With 5 Novel Variants in the Fibrinogen A Alpha Chain Protein. [Journal Article]
- KIKidney Int Rep 2017; 2(3):461-469
- Fibrinogen A alpha chain amyloidosis is an autosomal dominant disease associated with mutations in the fibrinogen A alpha chain (FGA) gene, and it is the most common cause of hereditary renal amyloid...
Fibrinogen A alpha chain amyloidosis is an autosomal dominant disease associated with mutations in the fibrinogen A alpha chain (FGA) gene, and it is the most common cause of hereditary renal amyloidosis in the UK. Patients typically present with kidney impairment and progress to end-stage renal disease over a median time of 4.6 years.