Glomerular Capillary Injury Research Articles

Aberrant Blood Vessel Formation Connecting the Glomerular Capillary Tuft and the Interstitium Is a Characteristic Feature of Focal Segmental Glomerulosclerosis-like IgA Nephropathy.

Background:Segmental glomerulosclerosis without significant mesangial or endocapillary proliferation is rarely seen in IgA nephropathy (IgAN), which simulates idiopathic focal segmental glomerulosclerosis (FSGS). We recently recognized aberrant blood vessels running through the adhesion sites of sclerosed tufts and Bowman’s capsule in IgAN cases with mild glomerular histologic change. Methods:To characterize aberrant blood vessels in relation to segmental sclerosis, we retrospectively reviewed the clinical and histologic features of 51 cases of FSGS-like IgAN and compared them with 51 age and gender-matched idiopathic FSGS cases. Results:In FSGS-like IgAN, aberrant blood vessel formation was observed in 15.7% of cases, 1.0% of the total glomeruli, and 7.3% of the segmentally sclerosed glomeruli, significantly more frequently than in the idiopathic FSGS cases (p = .009). Aberrant blood vessels occasionally accompanied mild cellular proliferation surrounding penetrating neovessels. Clinically, all FSGS-like IgAN cases had hematuria; however, nephrotic range proteinuria was significantly less frequent than idiopathic FSGS. Conclusions:Aberrant blood vessels in IgAN are related to glomerular capillary injury and may indicate abnormal repair processes in IgAN.

The chloride intracellular channel 5A stimulates podocyte Rac1, protecting against hypertension-induced glomerular injury

Glomerular capillary hypertension elicits podocyte remodeling and is a risk factor for the progression of glomerular disease. Ezrin, which links podocalyxin to actin in podocytes, is activated through the chloride intracellular channel 5A (CLIC5A)-dependent phosphatidylinositol 4,5 bisphosphate (PI[4,5]P2) accumulation. Because Rac1 is involved in podocyte actin remodeling and can promote PI[4,5]P2 production we determined whether CLIC5A-dependent PI[4,5]P2 generation and ezrin activation are mediated by Rac1. In COS7 cells, CLIC5A expression stimulated Rac1 but not Cdc42 or Rho activity. CLIC5A alsostimulated phosphorylation of the Rac1 effector Pak1 in COS7 cells and in cultured mouse podocytes. CLIC5A-induced PI[4,5]P2 accumulation and Pak1 and ezrin phosphorylation were all Rac1 dependent. In DOCA/Salt hypertension, phosphorylated Pak increased in podocytes of wild-type, but not CLIC5-deficient mice. In DOCA/salt hypertensive mice lacking CLIC5, glomerular capillary microaneurysms were more frequent and albuminuria wasgreater than in wild-type mice. Thus, augmented hypertension-induced glomerular capillary injury in mice lacking CLIC5 results from abrogation of Rac1-dependent Pak and ezrin activation, perhaps reducing the tensile strength of the podocyte actin cytoskeleton.

Endothelial cell injury in acute and chronic glomerular lesions in patients with IgA nephropathy

Endothelial cell injury may contribute to the progression of various glomerular diseases. In the present study, we examined glomerular capillary injury in acute and chronic glomerular lesions in patients with Immunoglobulin A nephropathy (IgAN). We selected renal biopsy samples of IgAN (n = 200), and glomerular capillary injury in the acute and chronic glomerular lesions was assessed using immunohistochemistry for CD34 and electron microscopy. We examined the correlations between acute and chronic glomerular lesions and proteinuria, hematuria, and the renal function. The injured glomerular capillaries in the acute glomerular lesions were characterized morphologically by the separation of CD34+ endothelial cells from the glomerular basement membrane and the loss of glomerular endothelial cells and capillaries, together with inflammatory cell infiltration, fibrin exudation, rupture of the glomerular basement membrane, and/or crescent formation. In addition, the injured capillaries in the chronic glomerular lesions were characterized by the loss of CD34+ glomerular endothelial cells and capillaries exhibiting segmental and global glomerular sclerosis with or without fibrous crescents. In the acute glomerular lesions, the presence of endocapillary hypercellularity, fibrinoid necrosis, and cellular and fibrocellular crescents correlated significantly with hematuria, with or without proteinuria. In the chronic glomerular lesions, a significant relationship was evident between segmental or global sclerosis and proteinuria and/or the serum creatinine level. In conclusion, injuries of glomerular capillaries and the loss of endothelial cells occurred in the acute and chronic glomerular lesions in IgAN and may contribute to the development of hematuria, proteinuria, and renal dysfunction.

Glomerular endothelial cell injury and focal segmental glomerulosclerosis lesion in idiopathic membranous nephropathy.

BackgroundFocal segmental glomerulosclerosis (FSGS) lesions have often been discussed as a negative predictor in idopathic membranous nephropathy (MN). The mechanism of the development of FSGS lesion in MN is still uncertain.MethodsFrom 250 cases of MN, 26 cases contained FSGS lesion. We compared the clinicopathological characteristics between MN cases with FSGS lesion [MN-FSGS(+)] and MN without FSGS lesion [MN-FSGS(−)], matched for gender, age, stage of MN.ResultsThe glomerular filtration rate (eGFR) was significantly lower in MN-FSGS(+) cases compared to MN-FSGS(−), although nephrotic syndrome, hematuria, and systolic blood pressure levels were not significantly different between the two groups. Pathologically, glomeruli in MN-FSGS(+) cases showed narrowing and loss of glomerular capillaries with separating from GBM or disappearance of CD34+ endothelial cells, and accumulation of extracellular matrix (ECM) in capillary walls, indicating the development of glomerular capillary injury. These findings of endothelial injury were seen even in MN-FSGS(−) cases, but they were more prominent in MN-FSGS(+) than MN-FSGS(−) by computer assessed morphometric analysis. In MN-FSGS(+) cases, 44 out of 534 glomeruli (8.2%) contained FSGS lesions (n = 31, NOS lesion; n = 13, perihilar lesion). Significant thickness of GBM with ECM accumulation was evident in MN-FSGS(+) cases. Podocyte injury with effacement of foot processes was also noted, but the expression of VEGF on podocytes was not different between the two groups, which suggests that the significant thickness of capillary walls may influence the function of VEGF from podocyte resulting in the glomerular capillary injury that contribute to the development of FSGS lesion in MN.ConclusionGlomerular capillary injury was seen in all MN cases. Furthermore, the prominent injuries of glomerular capillaries may be associated with the deterioration of eGFR and the formation of FSGS lesions in MN.

The role of MPO-positive cells and MPO deposition in glomerular capillary injury in patients with various glomerulonephritis

The role of MPO-positive cells and MPO deposition in glomerular capillary injury in patients with various glomerulonephritis

The role of myeloperoxidase and myeloperoxidase–antineutrophil cytoplasmic antibodies (MPO-ANCAs) in the pathogenesis of human MPO-ANCA-associated glomerulonephritis

It is well known that antineutrophil cytoplasmic antibodies (ANCAs) are pathogenic and have a diagnostic value for ANCA-associated vasculitis. We demonstrated that a rise in myeloperoxidase (MPO)-ANCA titers during remission is often predictive of a future relapse in MPO-ANCA-associated vasculitis. Pathological examination of renal biopsies indicated that not only MPO-ANCAs, but also extracellular MPO, an in situ immune complex composed of MPO and MPO antibodies, may play important roles in the pathogenesis of glomerular capillary injury in MPO-ANCA-associated vasculitis.

Early Humoral-Mediated Graft Injuries in ABO-Incompatible Kidney Transplantation in Human Beings

IntroductionAcute humoral rejection is the most important risk factor for early graft loss in ABO-incompatible (ABO-i) renal transplantation (RTx) and is present from the early period after RTx. However, the characteristics of early humoral-mediated graft injury are pathologically uncertain. ObjectiveTo analyze tissue from 10 protocol graft biopsies performed in 10 patients within 30 days post-RTx to clarify the pathologic features of early humoral-mediated graft injuries in ABO-i RTx. MethodsPathologic findings were examined using light and electron microscopy and immunofluorescence studies for C4d. Protocol biopsies were performed within 30 days after RTx in the absence of an episode of dysfunction (creatinine concentration 1.21–1.81 mg/dL). ResultsThe immunofluorescence study demonstrated C4d deposition in peritubular and glomerular capillaries. Acute glomerulitis with infiltration of mononuclear cells and neutrophils was observed in 3 patients. Furthermore, glomerulitis was accompanied by endothelial cell injuries, widening of subendothelial spaces with a double-contoured glomerular basement membrane, and mesangiolysis. ConclusionIn ABO-i RTx, early humoral-mediated graft injuries were observed in approximately 30% of patients despite normal graft function. They were characterized by C4d deposition and glomerular capillary injury. These findings suggest that renal glomeruli are the first site of graft injury by anti-A or anti-B blood type antibody with complement activation in ABO-i RTx.

Blood Pressure and Diabetic Nephropathy

This is the fourth of a series of articles based on presentations at the American Diabetes Association Scientific Sessions held 5–9 June 2009 in New Orleans, Louisiana, pertaining to blood pressure and renal disease in diabetes. ### Diabetic nephropathy and obesity At the Clinical Update in Diabetic Nephropathy at the American Diabetes Association Scientific Sessions, Karen A. Griffin (Maywood, IL) discussed interrelationships between obesity and the kidney, noting that obesity appears to be related to the increase in end-stage renal disease (ESRD), in part because of its relationship to diabetes and hypertension, but with a 1.2-to 1.6-fold increase in chronic kidney disease (CKD) risk even correcting for these associations. Reviewing CKD staging, in stages 3, 4, and 5, the glomerular filtration rate (GFR) is 30–59, 15–29, and <15 ml/min per 1.73 m2 BSA, respectively, and Griffin pointed out that the adjustment for body surface is quite important when considering the effect of body size. In a Kaiser Permanente analysis of 1,471 subjects developing ESRD in a 8,347,955 person-year follow-up, adjusted for age, sex, race, education, cigarette use, diabetes, blood pressure, lipids, and other variables, obesity increased the likelihood of ESRD with BMI ≥35 associated with a 5-fold increase, BMI 30–34.9 associated with a 3-fold increase, and BMI 25–29.9 associated with a 1.5-fold increase in risk (1). There are a number of different forms of obesity-related CKD, with the majority of cases associated with microalbuminuria, endothelial dysfunction, and mild-to-moderate decrease in GFR, mainly associated with cardiovascular risk. Coexistent obesity and CKD lead, however, to accelerated progression of the latter (2,3). A form of glomerulopathy occurs with obesity characterized by glomerular enlargement (which is more common in obesity) and focal segmental glomerulosclerosis (4). The pathogenesis may involve hyperfiltration, leading to glomerular capillary injury and sclerosis, in a fashion similar to occurring experimentally with 5/6 …

Glomerular Capillary Tenascin Staining in Renal Allografts and Its Correlation with Capillary Loop ‘Double Contours’, Proteinuria and Graft Outcome

Background: Glomerular capillary injuries result in proteinuria, previously reported to be a risk factor for renal allograft dysfunction. According to the Banff 97 Working Classification of Renal Allograft Pathology, ‘double contours’ in glomerular capillary loops (GC-DC) were suggested to be most specific for chronic transplant glomerulopathy. Tenascin-C (TN), a component of extracellular matrix, is known to be overexpressed in various conditions. Methods: TN immunostaining was performed by the labeled streptavidin biotin method. The correlations between glomerular capillary TN (GC-TN) and proteinuria, and between GC-DC and GC-TN, were studied in 27 biopsies showing chronic allograft nephropathy (CAN) lesions. In 14 patients (serum creatinine <2.0 mg/dl at biopsy), graft outcome was studied. Graft function 3 years after biopsy was classified as stable or deteriorated; the term ‘deteriorated’ was used if serum creatinine had increased 20% over baseline, or if the patient required dialysis. Results: In CAN, GC-TN correlated with GC-DC. Proteinuria in patients with intense GC-TN tended to increase during 1 year after biopsy. In graft outcome analysis, GC-TN was significantly lower in stable grafts than in deteriorated ones. Furthermore, all 3 patients demonstrating weak GC-TN without GC-DC returned to dialysis. Conclusion: TN immunostaining is a sensitive method to detect glomerular capillary injury with a predictive value for renal allograft dysfunction.

Platelet endothelial cell adhesion molecule-1 and angiogenic factor expression in idiopathic membranous nephropathy

Background: Idiopathic membranous nephropathy (IMN), a principal disease of glomerular capillaries, was investigated for some aspects of glomerular capillary injury and repair (angiogenesis). Methods: Fifteen cases of IMN were studied immunohistochemically for expression of the endothelial cell antigen platelet endothelial cell adhesion molecule-1 (PECAM-1[CD31]) and the angiogenesis-stimulating factors vascular endothelial growth factor (VEGF) and thymidine phosphorylase (TP). An equal number of normal control kidneys of fetal and mature origin were tested for the same antigens. Results: Normal tissues expressed PECAM-1 in both glomerular and interstitial endothelial cells, whereas VEGF and TP were expressed in the tubular epithelium. IMN was characterized by complete or partial loss of PECAM-1 expression from glomerular capillaries and a parallel gain/expression of this antigen by the tubular epithelium. In addition, VEGF and TP expression was lost or considerably reduced from tubular cells of IMN. Conclusion: We hypothesize that PECAM-1 expression by tubular epithelial cells represents uptake of CD31+ cell-surface fragments released by glomerular endothelial cells after glomerular damage. The damage is confounded by the failure of angiogenic mechanisms to promote glomerular angiogenesis (repair) because both VEGF and TP stimulation by the tubular epithelium is eliminated. It is suggested that immunohistochemical detection of VEGF or TP in the tubular epithelium may be useful in understanding the pathogenesis of IMN. Am J Kidney Dis 41:360-365.

Low Density Lipoprotein Receptors Mediate Intracellular Calcium Signals in Microalbuminuric Hypertensives

Hyperlipidemia is an established risk factor for progressive renal damage and proteinuria. Platelets and vascular smooth muscle cells (VSMC) are known to possess low density lipoprotein (LDL) cholesterol receptors. We used platelet LDL receptors to investigate the hypothesis that elevated lipids could activate intracellular calcium [Ca 2+] i signals, leading to altered vascular tone and permeability. We divided essential hypertensives into microalbuminuric positive (MA+) and negative (MA−) groups and measured baseline and LDL stimulated levels of [Ca 2+] i. The MA+ group demonstrated a significantly higher mean baseline [Ca 2+] i level (119.0 ± 24.5 v 86.2 ± 25.4 μmol/mL, P = .001). The MA+ group also displayed greater elevations in [Ca 2+] i levels after stimulation with LDL in concentrations of 10 and 25 μg/mL (100.9 ± 54.8 v 40.9 ± 20.2, P = .04 and 111.6 ± 51.0 v 52.9 ± 39.9 μmol/mL, P = .03, respectively). Our data indicate that hypertensive patients with early glomerular capillary injury display exaggerated influx of [Ca 2+] i after LDL receptor stimulation. Heightened LDL receptor sensitivity may facilitate LDL mediated [Ca 2+] i signals, leading to increased VSMC tone and proliferation and progressive renal disease.

Nature of the glomerular capillary injury in human membranous glomerulopathy.

A differential solute clearance technique was used to evaluate glomerular capillary wall function in 20 patients with membranous glomerulopathy and massive proteinuria. The clearance of inulin, the filtration fraction, and the fractional clearance of uncharged dextrans of a radius of 28-48 A were depressed significantly below control values in 20 healthy volunteers (P less than 0.01). In contrast, the fractional clearance of dextrans of radius greater than 50 A was elevated markedly. A theoretical model of solute transport that depicts the major portion of the glomerular capillary wall as an isoporous membrane and the minor portion as a nondiscriminatory shunt pathway revealed the calculated glomerular ultrafiltration coefficient to be five times lower and mean pore radius of the major membrane component to be 4 A smaller than control values. However, the fraction of filtrate volume permeating the shunt pathway was three- to fourfold above control values and correlated strongly in individual patients with the fractional clearance of albumin (r = 0.76) and of IgG (r = 0.80). Lowering renal plasma flow by 24% during indomethacin therapy in seven patients resulted in a 74% reduction in proteinuria accompanied by a corresponding diminution of filtrate formed through the shunt pathway. Morphometric analysis of glomerular ultrastructure revealed the magnitude of depression of the glomerular filtration rate and of urinary protein leakage to be related strongly to changes in the epithelial layer of the glomerular capillary wall, but not to the density of subepithelial immune deposits. We conclude that glomerular capillaries in membranous glomerulopathy are characterized by a loss of ultrafiltration capacity and of barrier size-selectivity, and that subepithelial immune deposits do not provide a structural basis for these functional alterations.