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Clinical Medicine (London, England) Jul 2020We report a patient with chronic diabetes and was referred for recent onset proteinuria. Light microscopy of the renal biopsy specimen showed mildly expanded mesangium...
We report a patient with chronic diabetes and was referred for recent onset proteinuria. Light microscopy of the renal biopsy specimen showed mildly expanded mesangium with mesangial hypercellularity and segmental sclerosis, features compatible with diabetic glomerulosclerosis. However, crystalglobulin-induced nephropathy with crystal deposit was identified on electron microscopy. Renal biopsy is often performed for diabetic patients who present with proteinuria and light microscopy often shows features of diabetic glomerulosclerosis. Additional information may occasionally be revealed on electron microscopy, altering the subsequent plan of management.
Topics: Biopsy; Diabetic Nephropathies; Glomerular Mesangium; Humans; Proteinuria; Sclerosis
PubMed: 32675160
DOI: 10.7861/clinmed.2020-0116 -
The American Journal of Pathology Dec 2022The development of focal and segmental glomerulosclerosis (FSGS) as a consequence of glomerular hypertension resulting from arterial hypertension is widely considered a...
The development of focal and segmental glomerulosclerosis (FSGS) as a consequence of glomerular hypertension resulting from arterial hypertension is widely considered a podocyte disease. However, the primary damage is encountered in the mesangium. In acute settings, mesangial cells disconnect from their insertions to the glomerular basement membrane, causing a ballooning of capillaries and severe changes of the folding pattern of the glomerular basement membrane, of the arrangement of the capillaries, and thereby of the architecture of the tuft. The displacement of capillaries led to contact of podocytes and parietal epithelial cells, initiating the formation of tuft adhesions to Bowman's capsule, the committed lesion to progress to FSGS. In addition, the displacement of capillaries also caused an abnormal stretching of podocytes, resulting in podocyte damage. Thus, the podocyte damage that starts the sequence to FSGS is predicted to develop secondary to the mesangial damage. This sequence was found in two hypertensive rat models of FSGS and in human hypertensive nephrosclerosis.
Topics: Rats; Humans; Animals; Podocytes; Glomerulosclerosis, Focal Segmental; Nephrosclerosis; Capillaries; Glomerular Basement Membrane; Hypertension, Renal
PubMed: 36150506
DOI: 10.1016/j.ajpath.2022.08.007 -
IDCases 2020Granulicatella is a type of nutritionally variant Streptococcus (NVS) that requires special medium for growth. It has shown to cause infective endocarditis which is...
Granulicatella is a type of nutritionally variant Streptococcus (NVS) that requires special medium for growth. It has shown to cause infective endocarditis which is associated with higher mortality and complications. We present a case of Granulicatella causing endocarditis and glomerulonephritis. There has only been one such prior case report. An adult male with a remote history of gastric bypass presented with shortness of breath with exertion, lower extremity swelling of 1-month duration. Blood cultures 4/4 bottles grew Granulicatella albicans with infected tooth being the source. Transesophageal echocardiogram revealed a vegetation on the mitral valve. He received intravenous vancomycin. He was found to have acute kidney injury requiring hemodialysis. Kidney biopsy revealed immune complex deposits in the mesangium and along the capillary basement membrane suggestive of post infectious glomerulonephritis. It is crucial to recognize NVS as potential cause for endocarditis in cultures that are slow growing. NVS require a special medium. Though it is rare, NSV can also cause glomerulonephritis. Early recognition is important to help with determining treatment options which may include immunosuppressive therapy along with treatment of underlying infection.
PubMed: 32489865
DOI: 10.1016/j.idcr.2020.e00792 -
American Journal of Physiology. Renal... Oct 2020Acute kidney injury (AKI) frequently complicates major surgery and can be associated with hypertension and progress to chronic kidney disease, but reports on blood... (Comparative Study)
Comparative Study
Acute kidney injury (AKI) frequently complicates major surgery and can be associated with hypertension and progress to chronic kidney disease, but reports on blood pressure normalization in AKI are conflicting. In the present study, we investigated the effects of an angiotensin-converting enzyme inhibitor, enalapril, and a soluble epoxide hydrolase inhibitor, 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl)urea (TPPU), on renal inflammation, fibrosis, and glomerulosclerosis in a mouse model of ischemia-reperfusion injury (IRI)-induced AKI. Male CD1 mice underwent unilateral IRI for 35 min. Blood pressure was measured by tail cuff, and mesangial matrix expansion was quantified on methenamine silver-stained sections. Renal perfusion was assessed by functional MRI in vehicle- and TPPU-treated mice. Immunohistochemistry was performed to study the severity of AKI and inflammation. Leukocyte subsets were analyzed by flow cytometry, and proinflammatory cytokines were analyzed by quantitative PCR. Plasma and tissue levels of TPPU and lipid mediators were analyzed by liquid chromatography mass spectrometry. IRI resulted in a blood pressure increase of 20 mmHg in the vehicle-treated group. TPPU and enalapril normalized blood pressure and reduced mesangial matrix expansion. However, inflammation and progressive renal fibrosis were severe in all groups. TPPU further reduced renal perfusion on and . In conclusion, early antihypertensive treatment worsened renal outcome after AKI by further reducing renal perfusion despite reduced glomerulosclerosis.
Topics: Acute Kidney Injury; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Blood Pressure; Disease Models, Animal; Disease Progression; Enalapril; Enzyme Inhibitors; Epoxide Hydrolases; Fibrosis; Glomerular Mesangium; Glomerulonephritis; Hypertension; Male; Mice; Phenylurea Compounds; Piperidines; Reperfusion Injury
PubMed: 32799675
DOI: 10.1152/ajprenal.00078.2020 -
JCI Insight Oct 2023Transglutaminase 2 (TGase2) has been shown to contribute to the mesangial IgA1 deposition in a humanized mouse model of IgA nephropathy (IgAN), but the mechanism is not...
Transglutaminase 2 (TGase2) has been shown to contribute to the mesangial IgA1 deposition in a humanized mouse model of IgA nephropathy (IgAN), but the mechanism is not fully understood. In this study, we found that inhibition of TGase2 activity could dramatically decrease the amount of polymeric IgA1 (pIgA1) isolated from patients with IgAN that interacts with human mesangial cells (HMC). TGase2 was expressed both in the cytosol and on the membrane of HMC. Upon treatment with pIgA1, there were more TGase2 recruited to the membrane. Using a cell model of mesangial deposition of pIgA1, we identified 253 potential TGase2-associated proteins in the cytosolic fraction and observed a higher concentration of cellular vesicles and increased expression of Ras homolog family member A (RhoA) in HMC after pIgA1 stimulation. Both the amount of pIgA1 deposited on HMC and membrane TGase2 level were decreased by inhibition of the vesicle trafficking pathway. Mechanistically, TGase2 was found to be coprecipitated with RhoA in the cellular vesicles. Membrane TGase2 expression was greatly increased by overexpression of RhoA, while it was reduced by knockdown of RhoA. Our in vitro approach demonstrated that TGase2 was transported from the cytosol to the membrane through a RhoA-mediated vesicle-trafficking pathway that can facilitate pIgA1 interaction with mesangium in IgAN.
Topics: Animals; Mice; Humans; Glomerulonephritis, IGA; Immunoglobulin A; Protein Glutamine gamma Glutamyltransferase 2; rhoA GTP-Binding Protein; Glomerular Mesangium; Polymers
PubMed: 37811653
DOI: 10.1172/jci.insight.160374 -
Clinical Journal of the American... Jul 2020IgA nephropathy is the most common primary glomerular disease in the world. Marked by mesangial inflammation and proliferation, it generally leads to progressive kidney...
BACKGROUND AND OBJECTIVES
IgA nephropathy is the most common primary glomerular disease in the world. Marked by mesangial inflammation and proliferation, it generally leads to progressive kidney fibrosis. As the Janus kinase signal transducer and activator of transcription pathway has been implicated as an important mediator of diabetic kidney disease and FSGS, detailed investigation of this pathway in IgA nephropathy was undertaken to establish the basis for targeting this pathway across glomerular diseases.
DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS
Well characterized patients with IgA nephropathy and controls were studied, allowing us to compare 77 patients with biopsy-proven IgA nephropathy with 45 healthy subjects. STAT phosphorylation was assessed in peripheral blood monocytes (PBMCs) by phosphoflow before and after cytokine stimulation. Kidney Janus kinase signal transducer and activator of transcription activity was studied by immunofluorescence and by transcriptomic studies. An STAT1 activity score was established using downstream transcriptional targets of pSTAT1 and associated with disease and clinical outcomes.
RESULTS
We found PBMCs to have upregulated pSTAT production at baseline in patients with IgA nephropathy with a limited reserve to respond to cytokine stimulation compared with controls. Increased staining in glomerular mesangium and endothelium was seen for Jak-2 and pSTAT1 and in the tubulointerstitial for JAK2, pSTAT1, and pSTAT3. Activation of the Janus kinase signal transducer and activator of transcription pathway was further supported by increased pSTAT1 and pSTAT3 scores in glomerular and tubulointerstitial sections of the kidney (glomerular activation scores: 7.1 and 4.5, respectively; values: <0.001 and <0.001, respectively). Clinically, phosphoflow results associated with proteinuria and kidney function, and STAT1 activation associated with proteinuria but was not associated with progression.
CONCLUSIONS
Janus kinase signal transducer and activator of transcription signaling was activated in patients with IgA nephropathy compared with controls. There were altered responses in peripheral immune cells and increased message and activated proteins in the kidney. These changes variably related to proteinuria and kidney function.
Topics: Adult; CD4-Positive T-Lymphocytes; Case-Control Studies; Endothelium; Female; Gene Expression Profiling; Glomerular Mesangium; Glomerulonephritis, IGA; Humans; Interferon-gamma; Janus Kinase 1; Janus Kinase 2; Kidney Tubules; Male; Middle Aged; Monocytes; Phosphorylation; STAT1 Transcription Factor; STAT3 Transcription Factor; Signal Transduction; Young Adult
PubMed: 32354727
DOI: 10.2215/CJN.11010919 -
Medicine Apr 2023Polycythemia vera (PV) is a myeloproliferative neoplasm which is characterized by excessive production of erythrocytes as well as myeloid and megakaryocytic...
BACKGROUND
Polycythemia vera (PV) is a myeloproliferative neoplasm which is characterized by excessive production of erythrocytes as well as myeloid and megakaryocytic proliferation. PV associated with IgA nephropathy (IgAN) has rarely been reported in the literature. The long-term renal prognosis of these patients is unknown.
METHODS
Clinical and pathological characteristics of 7 patients with renal biopsy-proven IgAN associated with PV were retrospectively analyzed.
RESULTS
The 7 patients were all males, with a mean age of 49.1 ± 18.8 years when admitted to our hospital. Systemic symptoms include: hypertension in case 2, 3, 5, and 6, splenomegaly in case 2, 4, and 5, and multiple lacunar infarction in case 6. Bone marrow biopsy test revealed relative erythroid hyperplasia and atypical megakaryocyte proliferation which consistent with a chronic myeloproliferative neoplasm. All patients had JAK2V617F and BCR-ABL tested, and JAK2V617F positive in 2 patients. Mild mesangial proliferation was observed in 5 patients and moderate/severe mesangial proliferation in 2patients. Immunofluorescence mainly showed diffuse granular deposition of dominant IgA in mesangium. After follow-up of 56.7 ± 44.0 months, hemoglobin level was 144 ± 29 g/L and hematocrit lever was 0.470 ± 0.03, compared with 187 ± 29 g/L and 0.563 ± 0.087 respectively when admitted to our hospital. The urine protein was 0.85 ± 0.64 g/24 h compared with 3.97 ± 4.68 g/24 h. Case 3 progressed to end stage renal disease and had received hemodialysis for 5 years before renal transplantation.
CONCLUSIONS
The results of this study showed that PV associated with IgAN mainly occurs in males and is often accompanied by hematuria and mild-to-moderate renal insufficiency. The long-term prognosis was good for most patients, and few progressed relatively quickly to end stage renal disease.
Topics: Male; Humans; Adult; Middle Aged; Aged; Glomerulonephritis, IGA; Polycythemia Vera; Retrospective Studies; East Asian People; Kidney Failure, Chronic; Myeloproliferative Disorders
PubMed: 37026962
DOI: 10.1097/MD.0000000000033493 -
Frontiers in Pediatrics 2022Perinatal complications, such as prematurity and intrauterine growth restriction, are associated with increased risk of chronic kidney disease. Although often associated...
BACKGROUND
Perinatal complications, such as prematurity and intrauterine growth restriction, are associated with increased risk of chronic kidney disease. Although often associated with reduced nephron endowment, there is also evidence of increased susceptibility for sclerotic changes and podocyte alterations. Preterm birth is frequently associated with chorioamnionitis, though studies regarding the effect of chorioamnionitis on the kidney are scarce. In this study, we aim to unravel the consequences of premature birth and/or perinatal inflammation on kidney development using an ovine model.
METHODS
In a preterm sheep model, chorioamnionitis was induced by intra-amniotic injection of lipopolysaccharide (LPS) at either 2, 8, or 15 days prior to delivery. Control animals received intra-amniotic injections of sterile saline. All lambs were surgically delivered at 125 days' gestation (full term is 150 days) and immediately euthanized for necropsy. Kidneys were harvested and processed for staining with myeloperoxidase (MPO), Wilms tumor-1 (WT1) and alpha-smooth muscle actine (aSMA). mRNA expression of tumor necrosis factor alpha (), Interleukin 10 (), desmin (), Platelet derived growth factor beta (), Platelet derived growth factor receptor beta (PDGFRB), synaptopodin (SYNPO), and transforming growth factor beta () was measured using quantitative PCR.
RESULTS
Animals with extended (but not acute) LPS exposure had an inflammatory response in the kidney. MPO staining was significantly increased after 8 and 15 days ( = 0.003 and = 0.008, respectively). Expression of ( = 0.016) and ( = 0.026) transcripts was increased, peaking on day 8 after LPS exposure. Glomerular aSMA and expression of TGFB was increased on day 8, suggesting pro-fibrotic mesangial activation, however, this was not confirmed with PDFGB or PDGFRB. The number of WT1 positive nuclei in the glomerulus, as well as expression of synaptopodin, decreased, indicating podocyte injury.
CONCLUSION
We report that, in an ovine model of prematurity, LPS-induced chorioamnionitis leads to inflammation of the immature kidney. In addition, this process was associated with podocyte injury and there are markers to support pro-fibrotic changes to the glomerular mesangium. These data suggest a potential important role for antenatal inflammation in the development of preterm-associated kidney disease, which is frequent.
PubMed: 35444963
DOI: 10.3389/fped.2022.796702 -
Journal of Biological Engineering Aug 2022Diabetic nephropathy, a kidney complication arising from diabetes, is the leading cause of death in diabetic patients. Unabated, the growing epidemic of diabetes is... (Review)
Review
Diabetic nephropathy, a kidney complication arising from diabetes, is the leading cause of death in diabetic patients. Unabated, the growing epidemic of diabetes is increasing instances of diabetic nephropathy. Although the main causes of diabetic nephropathy have been determined, the mechanisms of their combined effects on cellular and tissue function are not fully established. One of many damages of diabetic nephropathy is the development of fibrosis within the kidneys, termed mesangial expansion. Mesangial expansion is an important structural lesion that is characterized by the aberrant proliferation of mesangial cells and excess production of matrix proteins. Mesangial expansion is involved in the progression of kidney failure in diabetic nephropathy, yet its causes and mechanism of impact on kidney function are not well defined. Here, we review the literature on the causes of mesangial expansion and its impacts on cell and tissue function. We highlight the gaps that still remain and the potential areas where bioengineering studies can bring insight to mesangial expansion in diabetic nephropathy.
PubMed: 35918708
DOI: 10.1186/s13036-022-00299-4 -
Molecular and Cellular Biochemistry Mar 2020Progressive alteration of the extracellular matrix (ECM) is the characteristic of hypertensive nephropathy (HN). Both mesangial and endothelial cells have the ability to...
Progressive alteration of the extracellular matrix (ECM) is the characteristic of hypertensive nephropathy (HN). Both mesangial and endothelial cells have the ability to synthesize and degrade ECM components, including collagens through the activation of matrix metalloproteinases (MMPs) in stress conditions, such as in hypertension. On the other hand, hydrogen sulfide (HS) has been shown to mitigate hypertensive renal matrix remodeling. Surprisingly, whether HS ameliorates receptor-mediated (urokinase plasminogen activator receptor-associated protein, uPARAP/Endo180) collagen dysregulation in Ang-II hypertension is not clear. The purpose of this study was to determine whether Ang-II alters the expression of Endo180, tissue plasminogen activator (tPA), MMPs, and their tissue inhibitors (TIMPs) leading to the dysregulation of cellular collagen homeostasis and whether HS mitigates the collagen turnover. Mouse mesangial cells (MCs) and glomerular endothelial cells (MGECs) were treated without or with Ang-II and HS donor GYY (GYY4137) for 48 h. Cell lysates were analyzed by Western blot and RT-PCR, and cells were analyzed by immunocytochemistry. The results indicated that, while Ang-II differentially expressed MMP-13 and TIMP-1 in MCs and in MGECs, it predominantly decreased tPA, Endo 180, and increased plasminogen activator inhibitor-1 (PAI-1), MMP-14, and collagen IIIA and IV in both the cell types. Interestingly, HS donor GYY treatment normalized the above changes in both the cell types. We conclude that Ang-II treatment causes ECM remodeling in MCs and MGECs through PAI-1/tPA/Endo180 and MMP/TIMP-dependent collagen remodeling, and HS treatment mitigates remodeling, in part, by modulating these pathways.
Topics: Animals; Endothelial Cells; Glomerular Mesangium; Hypertension, Renal; Matrix Metalloproteinase 13; Matrix Metalloproteinase 14; Mice; Receptors, Collagen; Stress, Physiological
PubMed: 31912277
DOI: 10.1007/s11010-019-03680-y