Glomerular Mesangium Research Articles

Immune abnormalities in IgA nephropathy.

Immunoglobulin A (IgA) nephropathy (IgAN) is the most common primary glomerulonephritis worldwide and it is characterized by mesangial IgA deposition. Asymptomatic hematuria with various degrees of proteinuria is the most common clinical presentation and up to 20%-40% of patients develop end-stage kidney disease within 20 years after disease onset. The pathogenesis of IgAN involves four sequential processes known as the "four-hit hypothesis" which starts with the production of a galactose-deficient IgA1 (gd-IgA1), followed by the formation of anti-gd-IgA1 IgG or IgA1 autoantibodies and immune complexes that ultimately deposit in the glomerular mesangium, leading to inflammation and injury. Although several key questions about the production of gd-IgA1 and the formation of anti-gd-IgA1 antibodies remain unanswered, a growing body of evidence is shedding light on the innate and adaptive immune mechanisms involved in this complex pathogenic process. Herein, we will focus on these mechanisms that, along with genetic and environmental factors, are thought to play a key role in disease pathogenesis.

Noncoding RNAs associated with IgA nephropathy.

IgA nephropathy (IgAN) is one of themost commonglomerulonephritides. The disease is characterized by haematuria, proteinuria, deposition of galactose-deficient IgA1 in the glomerular mesangium and mesangial hypercellularity, further leading to extracellular matrix expansion. Kidney biopsy is the gold standard for IgANdiagnosis. Due to theinvasiveness of renal biopsy, there is an unmet need for noninvasive biomarkers to diagnose and estimate the severity of IgAN. Understanding the role of RNA molecules as genetic markers to target diseases may allow developing therapeutic and diagnostic markers. In this review we have focused on intrarenal, extrarenal and extracellular noncoding RNAs involved in the progression of IgAN. This narrative review summarizes the pathogenesis of IgAN along with the correlation of noncoding RNA molecules such as microRNAs, small interfering RNAs, circular RNAs and long non-coding RNAs that play an important role in regulating gene expression, and that represent another type of regulation affecting the expression of specific glycosyltranferases, a key element contributing to the development of IgAN.

A Case of ALECT2 Renal Amyloidosis Associated with IgG4 Related Kidney Disease, Membranous Nephropathy and Early Diabetic Kidney Injury

Abstract Introduction/Objective ALECT-2 amyloidosis is a rare type of amyloidosis that mostly involves kidneys with other organs rarely affected. It has a high prevalence among patients of Hispanic descent. Membranous nephropathy is one of the most common causes of proteinuria in adults. IgG4-related disease is a systemic disease, which commonly involves the pancreas, but occasionally affects the kidney and manifests as chronic renal insufficiency. Here we describe a very unusual case of concurrence of membranous nephropathy, IgG4 disease involving the kidney, ALECT2 amyloidosis, and early diabetic kidney injury. Methods/Case Report A 49-year-old Hispanic male patient with a history of diabetes and IgG4-related autoimmune pancreatitis and primary sclerosing cholangitis presented with abrupt onset of proteinuria and hypoalbuminemia. A kidney biopsy was performed and showed severe interstitial plasma cell-rich inflammatory infiltrates and interstitial fibrosis which had a storiform pattern. The glomerular basement membranes (GBM) showed focal pinpoint holes but no spikes by silver stain. Immunofluorescence microscopy (IF) showed diffuse and finely granular capillary loop staining for IgG, with Kappa and lambda light chains of equal intensity. IF for Anti-phospholipase A2 receptor (PLA2R) was negative. Immunohistochemical (IHC) stain showed IgG4 positivity in about 60% of IgG-positive plasma cells. Congo red was positive for birefringent deposits predominantly in the interstitium and arteriolar walls with focal deposits in the glomerular mesangium and capillary wall. IHC stain for Amyloid AA and DNAJB9 were negative. Electron microscopy showed scattered subepithelial immune complex-type electron dense deposits consistent with membranous nephropathy, randomly oriented fibrils in interstitium, mesangium and GBM, consistent with amyloidosis, and thickening of GBM (average 559 nm), consistent with early diabetic kidney change. The tissue was sent for mass spectrometry which showed a peptide profile consistent with ALECT-2 (Leukocyte chemotactic factor 2) type amyloidosis. Results (if a Case Study enter NA) NA Conclusion In up to a third of cases reported in the literature, a concomitant renal pathology was present. Diabetic nephropathy was the most common concurrent pathology, to be followed by IgA nephropathy and membranous nephropathy. However, the concurrence of membranous nephropathy, IgG4 disease involving the kidney, ALECT2 amyloidosis, and early diabetic kidney injury has never been described before.

Identification and characterization of circulating immune complexes in IgA nephropathy.

The underlying pathology of immunoglobulin A (IgA) nephropathy (IgAN), the most common glomerulonephritis worldwide, is driven by the deposition of immune complexes containing galactose-deficient IgA1 [Tn(+)IgA1] in the glomerular mesangium. Here, we report that novel anti-Tn circulating immune complexes (anti-Tn CICs) contain predominantly IgM, representing large macromolecular complexes of ~1.2 megadaltons to several megadalton sizes together with Tn(+)IgA1 and some IgG. These complexes are significantly elevated in sera of patients with IgAN, which contains higher levels of complement C3, compared to healthy individuals. Anti-Tn CICs are bioactive and induce specific proliferation of human renal mesangial cells. We found that these anti-Tn CICs can be dissociated with small glycomimetic compounds, which mimic the Tn antigen of Tn(+)IgA1, releasing IgA1 from anti-Tn CICs. This glycomimetic compound can also significantly inhibit the proliferative activity of anti-Tn CICs of patients with IgAN. These findings could enhance both the diagnosis of IgAN and its treatment, as specific drug treatments are now unavailable.

Particulate matter of air pollution may increase risk of kidney failure in IgA nephropathy

IgA nephropathy (IgAN) is characterized by deposition of galactose-deficient IgA1 (Gd-IgA1) in glomerular mesangium associated with mucosal immune disorders. Since environmental pollution has been associated with the progression of chronic kidney disease in the general population, we specifically investigated the influence of exposure to fine particulate matter less than 2.5 μm in diameter (PM2.5) on IgAN progression. Patients with biopsy-proven primary IgAN were recruited from seven Chinese kidney centers. PM2.5 exposure from 1998 to 2016 was derived from satellite aerosol optical depth data and a total of 1,979 patients with IgAN, including 994 males were enrolled. The PM2.5 exposure levels for patients from different provinces varied but, in general, the PM2.5 exposure levels among patients from the north were higher than those among patients from the south. The severity of PM2.5 exposure in different regions was correlated with regional kidney failure burden. In addition, each 10 μg/m3 increase in annual average concentration of PM2.5 exposure before study entry (Hazard Ratio, 1.14; 95% confidence interval, 1.06-1.22) or time-varying PM2.5 exposure after study entry (1.10; 1.01-1.18) were associated with increased kidney failure risk after adjustment for age, gender, estimated glomerular filtration rate, urine protein, uric acid, hemoglobin, mean arterial pressure, Oxford classification, glucocorticoid and renin-angiotensin system blocker therapy. The associations were robust when the time period, risk factors of cardiovascular diseases or city size were further adjusted on the basis of the above model. Thus, our results suggest that PM2.5 is an independent risk factor for kidney failure in patients with IgAN, but these findings will require validation in more diverse populations and other geographic regions.

Emerging Insights into Glomerular Vascular Pole and Microcirculation.

The glomerular vascular pole is the gate for the afferent and efferent arterioles and mesangial cells and a frequent location of peripolar cells with an unclear function. It has been studied in definitive detail for >30 years, and functionally interrogated in the context of signal transduction from the macula densa to the mesangial cells and afferent arteriolar smooth muscle cells from 10 to 20 years ago. Two recent discoveries shed additional light on the vascular pole, with possibly far-reaching implications. One, which uses novel serial section electron microscopy, reveals a shorter capillary pathway between the basins of the afferent and efferent arterioles. Such a pathway, when patent, may short-circuit the multitude of capillaries in the glomerular tuft. Notably, this shorter capillary route is enclosed within the glomerular mesangium. The second study used anti-Thy1.1-induced mesangiolysis and intravital microscopy to unequivocally establish in vivo the long-suspected contractile function of mesangial cells, which have the ability to change the geometry and curvature of glomerular capillaries. These studies led me to hypothesize the existence of a glomerular perfusion rheostat, in which the shorter path periodically fluctuates between being more and less patent. This action reduces or increases blood flow through the entire glomerular capillary tuft. A corollary is that the GFR is a net product of balance between the states of capillary perfusion, and that deviations from the balanced state would increase or decrease GFR. Taken together, these studies may pave the way to a more profound understanding of glomerular microcirculation under basal conditions and in progression of glomerulopathies.

Chorioamnionitis Causes Kidney Inflammation, Podocyte Damage, and Pro-fibrotic Changes in Fetal Lambs.

BackgroundPerinatal 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.MethodsIn 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 (TNFA), Interleukin 10 (IL10), desmin (DES), Platelet derived growth factor beta (PDGFB), Platelet derived growth factor receptor beta (PDGFRB), synaptopodin (SYNPO), and transforming growth factor beta (TGFB) was measured using quantitative PCR.ResultsAnimals with extended (but not acute) LPS exposure had an inflammatory response in the kidney. MPO staining was significantly increased after 8 and 15 days (p = 0.003 and p = 0.008, respectively). Expression of TNFA (p = 0.016) and IL10 (p = 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.ConclusionWe 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.

Sickle Cell Disease and Kidney

Sickle cell disease causes several kidney manifestations. They include defects in urine concentration, impaired handling of potassium and hydrogen ion, albuminuria, acute kidney injury, and chronic kidney disease to name a few. Glomerular hyperfiltration, tubular hyperfunctioning, endothelial damage from repeated sickling and vaso-occlusive episodes, and iron-induced proinflammatory changes in the glomerular mesangium and tubulointerstitium are some of the mechanisms of kidney damage. Albuminuria is one of the most and common clinical features of kidney disease and progresses with age. Kidney disease in patients with sickle cell is associated with increased mortality. Annual screening for proteinuria starting at age 10 years and limiting the use of nonsteroidal anti-inflammatory agents and the use of angiotensin-converting enzyme inhibitors may help in early detection and delaying the progression of kidney disease. Adequate hydration, angiotensin-converting enzyme inhibitors, and adequate control of sickle cell are the main stay of treatment for albuminuria. The hemoglobin goal for patients with sickle cell nephropathy is lesser (10 g/dL) than that for patients with chronic kidney disease due to other causes given that a higher hemoglobin level increases viscosity and the risk of precipitating vaso-occlusive episodes. A multidisciplinary approach is recommended for managing patients with sickle cell and kidney diseases.

Chronic intermittent hypoxia induces the pyroptosis of renal tubular epithelial cells by activating the NLRP3 inflammasome

ABSTRACT Obstructive sleep apnea syndrome (OSAS) is a respiratory disorder and chronic intermittent hypoxia (CIH) is an important pathological characteristic of OSAS. Injuries on renal tubular epithelial cells were observed under the condition of CIH. Pyroptosis is a programmed mode of cell death following cell apoptosis and cell necrosis, which is mediated by NLRP3 signaling. The present study aims to investigate the effects of CIH on the pyroptosis of renal tubular epithelial cells and the underlying mechanism. Firstly, CIH was induced in two renal tubular epithelial cell lines, HK-2 cells and TCMK-1 cells. As the aggravation of hypoxia, an increasing trend of elevated apoptotic rate was observed in HK-2 cells and TCMK-1 cells, accompanied by the excessive release of ROS and LDH, and upregulation of NLRP3. Subsequently, the CIH model was established on rats. The pathological analysis results indicated that in CIH rats, the glomerular bottom membrane and mesangium were slightly thickened and edema was observed in the renal tubule epithelium. More serious injury was observed in the moderate intermittent hypoxia group. The expression level of IL-1β and IL-18 was promoted as the aggravation of hypoxia, accompanied by the elevated production of LDH and ROS. The expression level of cleaved Caspase-1, Caspase-1, GSDMD, TLR4, MyD88, NF-κB, p-NF-κB, and NLRP3 was found significantly upregulated as the aggravation of hypoxia. Lastly, the pathological changes in rats induced by CIH were dramatically abolished by MCC950, a specific inhibitor of NLRP3. Collectively, CIH triggered the pyroptosis of renal tubular epithelial cells by activating the NLRP3 inflammasome.

Role of C4d in the Diagnosis and Prognosis of Native Renal Diseases.

Introduction:C4d is a biomarker of the complement cascade and has a primary role in the diagnosis of antibody-mediated rejection in solid organ transplantation. The present study was undertaken to investigate the role of C4d in the diagnosis and prognosis of native renal diseases.Methods:An observational cross-sectional study was conducted in the Department of Pathology from September 2017 to September 2019. In this study, we applied C4d staining by immunohistochemistry in 51 native renal biopsies. Semiquantitative scoring was done on the basis of intensity of C4d staining along the glomerular capillary wall (0–3) and mesangium (0–3), tubules (0–3), and arteries (0–3). These individual scores were added to get the total C4d score (0–12) which was correlated with chronicity index, serum urea and creatinine levels. Glomerular C4d score was correlated with 24 h urinary protein as well as with immunofluorescence deposition of immunoglobulins and complements.Results:We found a linear positive correlation (P < 0.05) between the total C4d score and serum creatinine; tubular C4d score and serum creatinine; and glomerular C4d score along capillary wall and 24 h urinary protein. A positive correlation (P < 0.05) was found between glomerular C4d score along the capillary wall with immunofluorescence deposits of immunoglobulins and complements, suggesting the efficacy of C4d as a surrogate marker in the diagnosis of native renal diseases.Conclusions:C4d deposition is associated with a poor prognosis in renal diseases and an accelerated deterioration of renal function. It also plays a role as a surrogate marker in diagnosis of native renal diseases.

The importance of immunoglobulin A nephropathy early diagnosis and management – case report

Immunoglobulin A (IgA) nephropathy is one of the most common glomerulonephritis. Its clinical manifestations vary from asymptomatic forms to cases with nephritic syndrome or nephrotic-range proteinuria. The prognosis depends on the level of proteinuria, decline of glomerular filtration rate and control of blood pressure. The pathognomonic histological changes are represented by the granular IgA deposits in the mesangium. The treatment consists of comprehensive support care and immunosuppressive therapy. We discuss the case of a 50-year-old man who presented microscopic hematuria, nephrotic-range proteinuria and decreased renal function, exacerbated in the last 6 months prior the admission. We performed a renal biopsy and granular deposits were present in the glomerular mesangium that were highly suggestive for IgA nephropathy. Immunosuppressive therapy was instituted immediately, but the decline of the renal function continued and renal replacement therapy was needed. Patients with poor prognosis have an unsatisfactory response to the immunosuppressants, especially those with a delayed diagnosis.

Collectin11 and Complement Activation in IgA Nephropathy.

IgA nephropathy is the most common primary GN worldwide. Previous research demonstrated that collectin11, an initiator of the complement lectin pathway, was involved in both AKI and chronic tubulointerstitial fibrosis. Here, we investigated the potential role of collectin11 in the pathogenesis of IgA nephropathy. The deposition of collectin11 and other complement proteins was detected in glomeruli of 60 participants with IgA nephropathy by immunofluorescence. In vitro, human mesangial cells were treated with IgA1-containing immune complexes derived from participants with IgA nephropathy. Then, the expression of collectin11 in mesangial cells was examined by quantitative RT-PCR and immunofluorescence. The codeposition of collectin11 with IgA1 or C3 on mesangial cells was detected by immunofluorescence and proximity ligation assays. In total, 37% of participants with IgA nephropathy (22 of 60) showed codeposition of collectin11 with IgA in the glomerular mesangium. Using an injury model of mesangial cells, we demonstrated that IgA1-immune complexes derived from participants with IgA nephropathy increased the secretion of collectin11 in mesangial cells with the subsequent deposition of collectin11 on the cell surface via the interaction with deposited IgA1-immune complexes. In vitro, we found that collectin11 bound to IgA1-immune complexes in a dose-dependent but calcium-independent manner. Furthermore, deposited collectin11 initiated the activation of complement and accelerated the deposition of C3 on mesangial cells. In situ-produced collectin11 by mesangial cells might play an essential role in kidney injury in a subset of patients with IgA nephropathy through the induction of complement activation.

Deletions in VANGL1 are a risk factor for antibody-mediated kidney disease

SummaryWe identify an intronic deletion in VANGL1 that predisposes to renal injury in high risk populations through a kidney-intrinsic process. Half of all SLE patients develop nephritis, yet the predisposing mechanisms to kidney damage remain poorly understood. There is limited evidence of genetic contribution to specific organ involvement in SLE.1,2 We identify a large deletion in intron 7 of Van Gogh Like 1 (VANGL1), which associates with nephritis in SLE patients. The same deletion occurs at increased frequency in an indigenous population (Tiwi Islanders) with 10-fold higher rates of kidney disease compared with non-indigenous populations. Vangl1 hemizygosity in mice results in spontaneous IgA and IgG deposition within the glomerular mesangium in the absence of autoimmune nephritis. Serum transfer into B cell-deficient Vangl1+/− mice results in mesangial IgG deposition indicating that Ig deposits occur in a kidney-intrinsic fashion in the absence of Vangl1. These results suggest that Vangl1 acts in the kidney to prevent Ig deposits and its deficiency may trigger nephritis in individuals with SLE.

TRIM40 inhibits IgA1-induced proliferation of glomerular mesangial cells by inactivating NLRP3 inflammasome through ubiquitination

IgA nephropathy, as the most common type of glomerulonephritis, causes chronic renal disease and progresses into kidney failure. Aberrant IgA deposition in the glomerular mesangium induces NLRP3 inflammasome activation for massive local inflammation, and is recognized as the primary pathogenesis in IgA nephropathy. Tripartite motif (TRIM)-containing proteins are E3 ubiquitin ligases that possess crucial regulatory functions in innate immunity, but their functional roles in IgA nephropathy are still unclear. Here, we aimed to identify TRIM-containing proteins that regulate IgA nephropathy and their underlying mechanisms. An in vitro IgA1-induction model was established in glomerular mesangial cells (GMCs) and showed that IgA1 could promote GMC proliferation by activating NLRP3 inflammasome. TRIM40, which was downregulated by IgA1 and interacted with NLRP3, was recognized as a promising candidate. In addition, TRIM40 could suppress IgA1-induced GMC proliferation by inhibiting the activation of NLRP3 inflammasome. Based on coimmunoprecipitation and ubiquitination assays, we confirmed that TRIM40 could mediate the ubiquitination of NLRP3, which explained its regulatory effects on NLRP3 inflammasome and GMC proliferation. More importantly, a dominant-negative mutant of TRIM40 lacking the RING domain (ΔRING) did not affect NLRP3 ubiquitination, and had no effects on IgA1-induced GMC proliferation or NLRP3 inflammasome activation. This study revealed the biological functions of TRIM40 in IgA nephropathy, facilitating its application as therapeutic target for IgA nephropathy and other NLRP3 inflammasome-relevant diseases.

The relationship between glomerular IgG staining and poor prognostic findings in patients with IgA nephropathy: the data from TSN-GOLD working group

BackgroundGalactose-deficient IgA1 (Gd-IgA1) has an increased tendency to form immunocomplexes with IgG in the serum, contributing to IgAN pathogenesis by accumulating in the glomerular mesangium. Several studies showed that glomerular IgG deposition in IgAN is an important cause of mesangial proliferation and glomerular damage. This study aims to determine the association of the positivity of IgG and the intensity of IgG staining with a poor renal prognosis.MethodsA total of 943 IgAN patients were included in the study. Glomerular IgG staining negative and positive patients were compared using Oxford classification scores, histopathological evaluations, proteinuria, eGFR, albumin, blood pressures. IgG positive patients were classified as (+), (++), (+++) based on their staining intensity, and the association with the prognostic criteria was also evaluated.Results81% (n = 764) of the patients were detected as IgG negative, while 19% (n = 179) were positive. Age, gender, body mass index, blood pressure, proteinuria, eGFR, uric acid values were similar in IgG positive and negative patients who underwent biopsy (p > 0.05). Intensity of glomerular IgG positivity was not found to be associated with diastolic and systolic blood pressure, urea, uric acid, age, eGFR, albumin, proteinuria (p > 0.05 for all, r = − 0.084, r = − 0.102, r = − 0.006, r = 0.062, r = 0.014, r = − 0.044, r = − 0.061, r = − 0.066, r = 0.150, respectively). There was no difference for histopathological findings between IgG (+), IgG (++), IgG (+++) groups (for all, p > 0.05).ConclusionGlomerular IgG negativity and positivity detected by routine IFM in IgAN patients is not associated with poor renal prognostic risk factors.

Goose nephritic astrovirus infection increases autophagy, destroys intercellular junctions in renal tubular epithelial cells, and damages podocytes in the kidneys of infected goslings

Goose nephritic astrovirus (GNAstV) has recently been identified, which causes kidney swelling and visceral gout in goslings. However, the pathological changes in kidney tissue due to GNAstV infection have not yet been described. In the study, fifty goslings were orally infected with GNAstV, and fifty goslings received PBS as a control. Kidney tissue was collected at different days following infection (dpi) to assess the injury. GNAstV infection reduced body weight, increased the relative weight of the kidney, and increased serum uric acid and creatinine levels. GNAstV was found within renal epithelial cells, and the viral load in the kidney peaked at 7 dpi. Pale and swollen kidney tissue was observed in infected goslings, especially at 5 and 7 dpi. GNAstV infection caused degeneration and necrosis of renal epithelial cells, structural destruction of the brush border, glycogen deposition in the glomerular mesangium, increased fibrosis, and infiltration of inflammatory cells into the renal interstitium. Moreover, swollen mitochondria, broken mitochondrial ridges, autophagosomes, and autophagolysosomes were observed under ultrahistopathological examination. GNAstV infection increased levels of LC3B, ATG5, and Beclin 1, and decreased p62, and downregulated WT1 mRNA and upregulated desmin mRNA. At early stages, GNAstV infection decreased expression of intercellular junction-related genes, including ZO-1, occludin, claudin-10, and catenin-α2. In conclusion, GNAstV infection causes renal epithelial cell autophagy, destruction of brush border and intercellular junctions, podocyte damage, and increased fibrosis, ultimately resulting in damage to the kidney.

Renal Outcome of IgM Nephropathy: A Comparative Prospective Cohort Study.

Immunoglobulin M nephropathy (IgMN) is an idiopathic glomerulonephritis characterized by diffuse deposits of IgM in the glomerular mesangium. However, its renal prognosis remains unknown. We compared renal outcomes of IgMN patients with those of patients with minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS), or mesangial proliferative glomerulonephritis (MsPGN) from a prospective observational cohort, with 1791 patients undergoing native kidney biopsy in eight hospitals affiliated with The Catholic University of Korea between December 2014 and October 2020. IgMN had more mesangial proliferation and matrix expansion than MsPGN and more tubular atrophy and interstitial fibrosis than MCD. IgMN patients had decreased eGFR than MCD patients in the earlier follow-up. However, there was no significant difference in urine protein or eGFR among all patients at the last follow-up. When IgMN was divided into three subtypes, patients with FSGS-like IgMN tended to have lower eGFR than those with MCD-like or MsPGN-like IgMN but higher proteinuria than MsPGN-like IgMN without showing a significant difference. The presence of hypertension at the time of kidney biopsy predicted ≥20% decline of eGFR over two years in IgMN patients. Our data indicate that IgMN would have a clinical course and renal prognosis similar to MCD, FSGS, and MsPGN.

Primary Anetoderma and Acquired Cutis Laxa Associated with Glomerulonephritis in a 37-year-old Filipino Male: A Case Report

A 37-year-old Filipino man presented with a 9-month history of sagging skin progressing cephalocaudally from the chin and neck to the axillae, side of the trunk, and pelvic area. This was followed by a 2-month history of increasing serum creatinine levels associated with periorbital and bipedal edema, generalized weakness, decreased appetite, vomiting, and headache. Subsequently, skin-colored, non-tender sac-like plaques appeared on the abdomen, inguinal, and intergluteal areas. Histopathology of the latter lesions showed increased spaces between collagen bundles in the dermis. Staining with Verhoeff-van Gieson revealed focal sparse elastic fibers in the papillary dermis compared to that of the reticular dermis consistent with anetoderma. Further work-up revealed normal ANA titer and low serum C3. Kidney biopsy showed IgG deposition in the tubular basement membrane and trace C3 deposition in the glomerular mesangium, giving a diagnosis of rapid progressive glomerulonephritis. On subsequent follow-up, the sac-like plaques became lax and presented as generalized wrinkling of the skin, raising the question whether cutis laxa and anetoderma are occurring in a spectrum instead as distinct entities. Based on the current review of literature, this is the first reported case of primary anetoderma co-occurring with cutis laxa in a patient with glomerulonephritis. Deposition of immunoglobulins along the elastic fibers could have activated the complement system, mediating the destruction of the elastic fibers, resulting to cutis laxa and anetoderma. This case also considers the possibility of anetoderma and type I acquired cutis laxa occurring either in a spectrum or as distinct diseases in a single patient. Further investigations may identify an ultrastructural pattern that can help differentiate the two entities.

The Phenotypic Difference of IgA Nephropathy and its Race/Gender-dependent Molecular Mechanisms.

IgA nephropathy (IgAn), defined by the pre dominant de position of IgA in the glomerular mesangium, is the most common form of GN throughout the world. However, its incidence, sex distribution, clinical presentation, and progression and pathogenic initiating factors are largely variable and do not fit such a simple definition. To assess the heterogeneity of this disease, we recently conducted a clinical survey on the presentation and clinical management of patients with IgAn in Europe and Japan. This clinical survey highlights similarities and differences in patients from different cont inents. The survey revealed obvious differences between nations in the frequency of gastrointestinal complications, including inflammatory bowel diseases (IBD) and celiac disease, which were more frequent in European patients. Such findings are compatible with susceptibility loci related to intestinal immunity and IBD in recent genome wide association studies (GWAS) on IgAn. However, most of the molecules in these mucosal-related loci fulfill the immunologic function not only of gut-associated lymphoid tissue (GALT), but also nasopharyngeal/bronchial-associated lymphoid tissues (NALT/BALT). Indeed, a similar frequency of macrohematuria coinciding with upper respiratory infection, a hallmark manifestation of this disease, was found in the survey, emphasizing the pathogenic roles of these molecules in the NALT/BALT of patients with IgAn. Recent experimental and clinical studies including GWAS on multiple common infections and IBD indicate immune crosstalk between GALT and NALT/BALT, and some related mediators, such as TNF superfamily ligands (APRIL/BAFF). This review explains the epidemiologic heterogeneity of this disease with the clinical survey, and discusses race and sex-dependent molecular mechanisms.

Stromal Cell-Derived Factor (SDF)-1-Pretreated Bone Marrow Mesenchymal Stem Cells (BMSCs) Ameliorates Acute Kidney Injury in Mice

To explore the effects of stromal cell-derived factor (SDF-1) pretreatment of bone marrow mesenchymal stem cells (BMSCs) on acute kidney injury (AKI) in mice. BMSCs were cultured and treated with SDF-1 to detect osteogenic and adipogenic ability. Cisplatin (20 mg/kg) was used to establish AKI model and then divided into blank group, control group 2 (BMSCs injection), and experimental group (intraperitoneal injection of BMSCs treated with SDF-1 (80 ng/ml)) followed by analysis of serum cytokines (Toll like receptor 4 (TLR4), tumor necrosis factor-α (TNF-α), and interleukine-6 (IL-6)) by enzyme linked immunosorbent assay (ELISA). In cultured BMSCs, positive rates of CD29, CD44, CD45, and CD11b were 98.2%, 97.6%, 2.5% and 2.1%, respectively. When the concentration of SDF-1 was within 80 ng/mL, the chemotaxis and proliferation ability was dose-dependent (p &lt; 0.05). SDF-1 pretreatment did not affect BMSCs adipogenic and osteogenic abilities. The creatinine and serum cytokines (TLR4, TNF-α, and IL-6) level in experimental group showed statistical significance (p &lt; 0.05). At 24 h, thrombosis and tubular dilatation in the mesangial region of control group 2 and experimental group under light microscope were similar without difference of inflammatory cell infiltration and fibrosis. At 72 h, the glomerular mesangium widened in control group 2 with focal segmental sclerosis, renal tubules dilated, and protein casts and inflammatory cell infiltration and fibrosis. Experimental group showed a small amount of cell proliferation in the glomerular mesangium with few inflammatory cell infiltration and fibrosis. SDF-1 can enhance the migration and proliferation activity of BMSCs, reduce extracellular matrix precipitation, improve renal fibrosis, and alleviate AKI.