A case report of atypical anti-glomerular basement membrane disease.

BACKGROUND: Anti-glomerular basement membrane (anti-GBM) disease is characterized by crescentic necrotizing glomerulonephritis, with linear deposits of immunoglobulin G (IgG) in the GBM. Classic anti-GBM disease is clinically associated with rapidly progressive glomerulonephritis with or without pulmonary hemorrhage. Some patients have a better renal prognosis and milder symptoms than those with classic anti-GBM disease, which is termed atypical anti-GBM disease. CASE PRESENTATION: A 43-year-old Japanese woman was admitted to our hospital complaining of hematuria that had persisted for more than one month. Serological examination revealed negativity for anti-nuclear, anti-neutrophilic cytoplasmic, and anti-GBM antibodies. However, renal biopsy showed cellular crescents. Immunofluorescence revealed strong diffuse linear capillary loop staining for IgG. An indirect immunofluorescence antibody method was performed by applying the patient serum to normal kidney tissue to confirm the presence of autoantibodies binding to the GBM. Using this method, anti-GBM antibodies were detected. The patient was treated with high-dose steroids, cyclophosphamide, and plasma exchange. Aggressive treatment resolved proteinuria and hematuria and improved renal function. CONCLUSIONS: Renal biopsy is crucial in the diagnosis of anti-GBM disease, especially when serological tests are negative. Accurately identifying the presence of anti-GBM disease is important to initiate optimal treatment.

A case report of adult-onset COQ8B nephropathy presenting focal segmental glomerulosclerosis with granular swollen podocytes.

BACKGROUND: Primary coenzyme Q10 (CoQ10) deficiency of genetic origin is one of a few treatable focal segmental glomerulosclerosis (FSGS). Renal morphologic evidence for COQ8B mutation and CoQ10 deficiencies of other gene mutations is assessed using electron microscopy with marked increase of abnormal-shaped mitochondria in podocytes. However, light microscopic morphologic features of deficiencies other than FSGS have not been reported. CASE PRESENTATION: A 30-year-old woman was admitted to our hospital because proteinuria was found during four consecutive medical checkups. She had no medical history or family history of proteinuria and severe renal dysfunction. The swollen podocytes were stained to the same extent as mitochondria-rich proximal tubular cells under both Masson's trichrome and hematoxylin-eosin staining, whereas no mitochondrial abnormalities were detected under the first electron microscopic views. As proteinuria and estimated glomerular filtration rate (eGFR) deteriorated after pregnancy, we reevaluated the additional electron microscopic views and detected mitochondrial abnormalities. Genetic testing revealed COQ8B mutation (c.532C > T, p.R178W); therefore, we diagnosed COQ8B nephropathy. CoQ10 supplementation improved proteinuria and stopped eGFR reduction. CONCLUSIONS: This is the first report of granular swollen podocytes due to mitochondrial diseases detected under light microscopy. We propose that this finding can be the clue for the diagnosis of both COQ8B nephropathy and the other CoQ10 deficiencies.

Glomerular basement membrane injuries in IgA nephropathy evaluated by double immunostaining for α5(IV) and α2(IV) chains of type IV collagen and low-vacuum scanning electron microscopy.

BACKGROUND: The glomerulus contains well-developed capillaries, which are at risk of injury due to high hydrostatic pressure, hyperfiltration, hypertension and inflammation. However, the pathological alterations of the injured glomerular basement membrane (GBM), the main component of the glomerular filtration barrier, are still uncertain in cases of glomerulonephritis. METHODS: We examined the alterations of the GBM in 50 renal biopsy cases with IgA nephropathy (31.8 ± 17.6 years old) using double immunostaining for the α2(IV) and α5(IV) chains of type IV collagen, and examining the ultrastructural alterations by transmission electron microscopy (TEM) and low-vacuum scanning electron microscopy (LV-SEM). RESULTS: The GBM of IgA nephropathy cases showed various morphological and qualitative alterations. In the TEM findings, thinning, gaps, rupture, thickening with a lamellar and reticular structure and double contours were detected in the GBM. Double immunostaining for α5(IV) and α2(IV) showed thickening of the GBM with reduced α5(IV) and increased α2(IV), or mosaic images of α5(IV) and α2(IV), and holes, fractures, spiny projections and rupture of α5(IV) in the GBM. In addition, LV-SEM showed an etched image and multiple holes in a widening and wavy GBM. These findings might be associated with the development of a brittle GBM in IgA nephropathy. CONCLUSION: Glomerular basement membrane alterations were frequently noted in IgA nephropathy, and were easily evaluated by double immunostaining for α2(IV) and α5(IV) of type IV collagen and LV-SEM. The application of these analyses to human renal biopsy specimens may enhance our understanding of the alterations of the GBM that occur in human glomerular diseases.

An ophthalmic solution of a peroxisome proliferator-activated receptor gamma agonist prevents corneal inflammation in a rat alkali burn model.

PURPOSE: We clarified the effects of an ophthalmic solution of a peroxisome proliferator-activated receptor gamma (PPARγ) agonist on corneal inflammation and wound healing after alkali burn injury in rats. METHODS: After alkali exposure, either an ophthalmic solution with 0.1% pioglitazone hydrochloride (the PPARγ group) or vehicle (the vehicle group) was topically applied to the cornea until day 14. Histological, immunohistochemical, and real-time reverse transcription polymerase chain reaction analysis were performed. RESULTS: After alkali injury, PPARγ expression increased, with the infiltration of many inflammatory cells. The infiltration of neutrophils and macrophages started from the corneal limbus within 6 h, and developed in the corneal center by day 7, with associated neovascularization. The accumulation of α-smooth muscle actin-positive myofibroblasts and the deposition of type III collagen were noted on day 14. The histological changes were suppressed significantly by treatment with the ophthalmic solution of the PPARγ agonist. In addition, the number of infiltrating M2 macrophages in the cornea was increased by PPARγ agonist treatment. In real-time reverse transcription polymerase chain reaction analysis, the messenger ribonucleic acid expression levels of interleukin-1ß (IL-1ß), IL-6, IL-8, monocyte chemoattractant protein-1, tumor necrosis factor-α, transforming growth factor beta 1, and vascular endothelial growth factor-A were decreased in the PPARγ group compared to the vehicle group in the early periods of corneal inflammation. CONCLUSIONS: The ophthalmic solution of the PPARγ agonist inhibited inflammation, decreased the fibrotic reaction, and prevented neovascularization in the cornea from the early phase after alkali burn injury. The ophthalmic solution of the PPARγ agonist may provide a new treatment strategy with useful clinical applications for corneal inflammation and wound healing.

Renal inflammatory changes in acute hepatic failure-associated acute kidney injury.

BACKGROUND/AIMS: Acute kidney injury (AKI) is a common complication in advanced liver dysfunction. Our aim is to clarify the mechanisms of acute hepatic failure (AHF)-associated AKI. METHODS: We examined the mechanisms of AHF-associated AKI, which is characterized by AKI in AHF and hyperbilirubinemia, following DA-to-Lewis rat liver transplantation. RESULTS: During the progression of AHF and hyperbilirubinemia in liver graft rejection, AHF-associated AKI gradually developed by day 11. Degeneration and apoptotic cells were apparent in tubular epithelial cells with bile pigment accumulation and mitochondrial degeneration. Injury of peritubular capillaries (PTCs) was also noted with apoptotic endothelial cells, decreased expression of endothelial nitric oxide synthase, accumulation of α-smooth muscle actin+ pericytes and/or myofibroblasts, and inflammation. Angiogenic factors including vascular endothelial growth factor, angiopoietin-1, and angiopoietin-2 in the cortex were decreased on day 11. In addition, a marked reduction in the velocity of red blood cells in PTCs was evident in vivo. CONCLUSIONS: AHF-associated AKI seems to be mediated by renal tubular epithelial cell injury with bile pigment accumulation, impaired microcirculation caused by PTC endothelial cell injury with depletion of endothelial nitric oxide synthase and angiogenic factors, and by a decrease in RBC velocity and renal inflammation. Multiple mechanisms including tubular and PTC injuries and renal inflammation may be involved in the development of AHF-associated AKI.

Involvement of matrix metalloproteinase-2 in the development of renal interstitial fibrosis in mouse obstructive nephropathy.

Renal fibrosis is a common finding in progressive renal diseases. Matrix metalloproteinases (MMPs) are involved in epithelial-to-mesenchymal transition (EMT). We investigated the role of MMP-2 and the effect of inhibition of MMPs on the development of renal fibrosis. Renal fibrosis was induced in MMP-2 wild-type (MMP-2⁺/⁺) mice by unilateral ureteral obstruction (UUO). Renal histopathology, EMT-associated molecules, and activity of MMP-2 and MMP-9 were examined during the development of interstitial fibrosis. UUO-renal fibrosis was also induced in MMP-2 deficient (MMP-2⁻/⁻) and MMP-2⁺/⁺ mice treated with minocycline (inhibitor of MMPs). In MMP-2⁺/⁺ mice, MMP-2 and MMP-9 were expressed in damaged tubules, and their activities increased in a time-dependent manner after UUO. Interstitial fibrosis was noted at day 14, with deposition of types III and I collagens and expression of markers of mesenchymal cells (S100A4, vimentin, α-smooth muscle actin, and heat shock protein-47) in damaged tubular epithelial cells, together with F4/80+ macrophage infiltration. Fibrotic kidneys expressed EMT-associated molecules (ILK, TGF-ß1, Smad, Wnt, ß-catenin, and Snail). In contrast, the kidneys of MMP-2⁻/⁻ mice and minocycline-treated MMP-2⁺/⁺ mice showed amelioration of renal fibrosis with reduced expression of markers of mesenchymal cells in tubular epithelial cells, inhibition of upregulated EMT-associated molecules, and suppression of macrophage infiltration. The results suggested that MMP-2 have a pathogenic role in renal interstitial fibrosis, possibly through the induction of EMT and macrophage infiltration. Inhibition of MMPs may be beneficial therapeutically in renal fibrosis.

Caspase-3-independent internucleosomal DNA fragmentation in ischemic acute kidney injury.

BACKGROUND/AIMS: Renal tubular cell death in ischemia-reperfusion does not follow the classical apoptosis or necrosis phenotype. We characterized the morphological and biochemical features of injured tubular epithelial cells in ischemic acute kidney injury (AKI). METHODS: Ischemic AKI was induced in rats by 60 min of ischemia followed by 24 h of reperfusion. Light and electron microscopic TUNEL (LM-TUNEL and EM-TUNEL), gel electrophoresis of extracted DNA, and caspase-3 involvement were examined during the development of death. RESULTS: Damaged tubular epithelial cells with condensed and LM-TUNEL-positive (+) nuclei were prominent at 12 and 18 h after reperfusion with DNA 'ladder' pattern on gel electrophoresis. EM-TUNEL+ cells were characterized by nuclei with condensed and clumping chromatin, whereas the cytoplasm showed irreversible necrosis. The protein levels and activity of caspase-3 did not increase in kidneys after reperfusion. In addition, caspase inhibitor (ZVAD-fmk) failed to inhibit DNA fragmentation and prevent tubular epithelial cell death in ischemic AKI. CONCLUSION: Caspase-3-independent internucleosomal DNA fragmentation occurs in injured tubular epithelial cells undergoing irreversible necrosis in ischemic AKI. The manner of this cell death may be identical to the cell death termed apoptotic necrosis, aponecrosis, or necrapoptosis. Ischemia-reperfusion injury activates caspase-3-independent endonuclease, which in turn induces irreversible damage of tubular epithelial cells, and may contribute to the initiation and development of AKI.

Role of matrix metalloproteinase-2 in recovery after tubular damage in acute kidney injury in mice.

BACKGROUND/AIMS: Matrix metalloproteinases (MMPs) are zinc endopeptidases that degrade extracellular matrix and are involved in the pathogenesis of ischemic damage in acute kidney injury (AKI). In the present study, we analyzed the role of MMP-2 in the repair process in ischemic AKI. METHODS: AKI was induced in MMP-2 wild-type (MMP-2(+/+)) and MMP-2-deficient (MMP-2(-/-)) mice by 90-min renal artery clamping followed by reperfusion. Renal histology and the activity and distribution of MMP-2 were examined from day 1 to day 14. During the recovery from AKI, MMP-2(+/+) mice were also treated with MMP-2/MMP-9 inhibitor. RESULTS: In both MMP-2(+/+) and MMP-2(-/-) mice, AKI developed on day 1 after ischemia/reperfusion with widespread acute tubular injury, but subsequent epithelial cell proliferation was evident on days 3-7. During the repair process, active MMP-2 and MMP-9 increased in regenerating tubular epithelial cells in MMP-2(+/+) mice on days 7-14, and the tubular repair process was almost complete by day 14. On the other hand, in MMP-2(-/-) mice, less prominent proliferation of tubular epithelial cells was evident on days 3 and 7, and damaged tubules that were covered with elongated and immature regenerated epithelial cells were identified on days 7 and 14. Incomplete recovery of injured microvasculature was also noted with persistent macrophage infiltration. Similarly, treatment with MMP-2/MMP-9 inhibitor resulted in impaired recovery in MMP-2(+/+) mice. CONCLUSION: MMP-2 is involved in tubular repair after AKI. The use of the MMP-2/MMP-9 inhibitor was a disadvantage when it was administered during the repair stage of ischemic AKI. Treatment with MMP inhibitor for AKI needs to be modified to enhance recovery from AKI.

A case of monoclonal immunoglobulin G1-lambda deposition associated with membranous feature in a patient with hepatitis C viral infection.

A 63-year-old man with hepatitis C virus infection was admitted to our hospital for nephrotic syndrome. Light microscopic analysis of a percutaneous renal biopsy showed thickening of the glomerular capillary walls and spike formation. Immunofluorescence revealed granular deposition of monoclonal immunoglobulin G1-lambda and C3 complement along the glomerular basement membrane. Urinary protein excretion decreased slightly after combined treatment with steroid and an immunosuppressive agent. Monoclonal immunoglobulin deposition disease with membranous feature is rare. Additional reports of such cases are needed to elucidate the mechanisms and optimal therapy for this rare entity.

Development of lymphatic vasculature and morphological characterization in rat kidney.

BACKGROUND: The mechanisms and morphological characteristics of lymphatic vascular development in embryonic kidneys remain uncertain. METHODS: We examined the distribution and characteristics of lymphatic vessels in developing rat kidneys using immunostaining for podoplanin, prox-1, Ki-67, type IV collagen (basement membrane: BM), and α-smooth muscle actin (αSMA: pericytes or mural cells). We also examined the expression of VEGF-C. RESULTS: At embryonic day 17 (E17), podoplanin-positive lymphatic vessels were observed mainly in the kidney hilus. At E20, lymphatic vessels extended further into the developing kidneys along the interlobar vasculature. In 1-day-old pups (P1) to P20, lymphatic vessels appeared around the arcuate arteries and veins of the kidneys, with some reaching the developing cortex via interlobular vessels. In 8-week-old adult rats, lymphatic vessels were extensively distributed around the blood vasculature from the renal hilus to cortex. Only lymphatic capillaries lacking continuous BM and αSMA-positive cells were present within adult kidneys, with none observed in renal medulla. VEGF-C was upregulated in the developing kidneys and expressed mainly in tubules. Importantly, the developing lymphatic vessels were characterized by endothelial cells immunopositive for podoplanin, prox-1, and Ki-67, with no surrounding BM or αSMA-positive cells. CONCLUSION: During nephrogenesis, lymphatic vessels extend from the renal hilus into the renal cortex along the renal blood vasculature. Podoplanin, prox-1, Ki-67, type IV collagen, and αSMA immunostaining can detect lymphatic vessels during lymphangiogenesis.

Inhibition of matrix metalloproteinases reduces ischemia-reperfusion acute kidney injury.

Matrix metalloproteinases (MMPs) are endopeptidases that degrade extracellular matrix and involved in ischemic organ injuries. The present study was designed to determine the role of MMP-2 in the development of ischemic acute kidney injury (AKI). AKI was induced in MMP-2 wild-type (MMP-2(+/+)) mice by 30, 60, 90, and 120 min renal ischemia and reperfusion. Renal histology, expression and activity of MMP-2 and MMP-9, and renal function were examined during the development of AKI. AKI was also induced in MMP-2-deficient (MMP-2(-/-)) mice and MMP-2(+/+) mice treated with inhibitor of MMPs (minocycline and synthetic peptide MMP inhibitor). In MMP-2(+/+) mice, MMP-2 and MMP-9 activities increased significantly at 2 to 24 h, peaked at 6 h, after reperfusion. Immunohistochemical analysis identified MMP-2 in the interstitium around tubules and peritubular capillaries in the outer medulla. Acute tubular injury (ATI), including apoptosis and necrosis, was evident in the outer medulla at 24 h, along with renal dysfunction. As ischemia period increases, MMP-2 and MMP-9 activities at 6 h and severity of AKI at 24 h increased depending on the duration of ischemia between 30 and 120 min. However, the kidneys of MMP-2(-/-) mice showed minimal ATI; serum creatinine 24 h after reperfusion was significantly low in these mice. Inhibitors of MMPs reduced ATI and improved renal dysfunction at 24 h. We conclude that MMPs, especially MMP-2 have a pathogenic role in ischemia-reperfusion AKI, and that inhibitors of MMPs can protect against ischemic AKI.

Statin attenuates experimental anti-glomerular basement membrane glomerulonephritis together with the augmentation of alternatively activated macrophages.

Macrophages are heterogeneous and include classically activated M1 and alternatively activated M2 macrophages, characterized by pro- and anti-inflammatory functions, respectively. Macrophages that express heme oxygenase-1 also exhibit anti-inflammatory effects. We assessed the anti-inflammatory effects of statin in experimental anti-glomerular basement membrane glomerulonephritis and in vitro, focusing on the macrophage heterogeneity. Rats were induced anti-glomerular basement membrane glomerulonephritis and treated with atorvastatin (20 mg/kg/day) or vehicle (control). Control rats showed infiltration of macrophages in the glomeruli at day 3 and developed crescentic glomerulonephritis by day 7, together with increased mRNA levels of the M1 macrophage-associated cytokines, interferon-gamma, tumor necrosis factor-alpha, and interleukin-12. In contrast, statin reduced the level of proteinuria, reduced infiltration of macrophages in glomeruli with suppression of monocyte chemotactic protein-1 expression, and inhibited the formation of necrotizing and crescentic lesions. The number of glomerular ED3-positive macrophages decreased with down-regulation of M1 macrophage-associated cytokines. Furthermore, statin augmented ED2-positive M2 macrophages with up-regulation of the M2 macrophage-associated chemokines and cytokines, chemokine (C-C motif) Iigand-17 and interleukin-10. Statin also increased the glomerular interleukin-10-expressing heme oxygenase-1-positive macrophages. Statin inhibited macrophage development, and suppressed ED3-positive macrophages, but augmented ED2-positive macrophages in M2-associated cytokine environment in vitro. We conclude that the anti-inflammatory effects of statin in glomerulonephritis are mediated through inhibition of macrophage infiltration as well as augmentation of anti-inflammatory macrophages.

Renal thrombotic microangiopathy associated with chronic humoral graft versus host disease after hematopoietic stem cell transplantation.

Thrombotic microangiopathy (TMA) is a known complication of hematopoietic stem cell transplantation (HSCT). The pathogenesis of TMA is controversial but considered to involve various factors such as total body irradiation, use of calcineurin inhibitors for prophylaxis against graft versus host disease (GVHD), viral infection, and GVHD. Herein we describe a case with renal TMA after HSCT, which was probably associated with antibody-mediated endothelial cell injury from chronic GVHD (termed here 'chronic humoral GVHD'). A 49-year-old man presented two years after HSCT with renal dysfunction and proteinuria but without the clinical features of TMA. Histopathological examination of renal biopsy showed chronic glomerular endothelial cell injury with double contour of the glomerular basement membrane, microthrombi and the deposition of complement split product C4d along the glomerular capillaries. Renal tubulitis and peritubular capillaritis were also noted with a multilayered basement membrane and patchy C4d deposition on peritubular capillaries. These findings resemble those of chronic antibody-mediated rejection after kidney transplantation. Furthermore, C4d deposition suggests complement activation. Although circulating anti-blood type and anti-human leukocyte antigen antibodies were not detected, the renal TMA in this case was probably associated with chronic humoral GVHD.

Low-Vacuum Scanning Electron Microscopy to Assess Histopathological Resolution of Class V Lupus Nephritis: A Case Report.

Lupus nephritis (LN) is most frequently associated with poor outcomes in patients with systemic lupus erythematosus (SLE). LN manifests as histopathological changes in the kidney caused by immune complex formation and deposition. In particular, immunoglobulin G (IgG) deposits are frequently observed by immunofluorescence staining, which helps to establish the diagnosis of LN. In this case report, we describe a 57-year-old woman with SLE who had been undergoing treatment on an outpatient basis for 11 years. Her first and second renal biopsies revealed class V LN with a coarsely granular pattern of IgG deposition in the peripheral capillary walls. However, her third renal biopsy showed no IgG deposition, which indicated histopathological resolution of her class V LN. We used low-vacuum scanning electron microscopy (LV-SEM) to examine the three-dimensional structural alterations in her glomerular basement membranes. In this report, we describe findings that indicated resorption of epithelial deposits, that is, resolution of LN. The results of repeated kidney biopsies confirmed by LV-SEM suggested the possibility of a state unrelated to LN.

ANG II receptor blockade enhances anti-inflammatory macrophages in anti-glomerular basement membrane glomerulonephritis.

Macrophages are heterogeneous immune cell populations that include classically activated and alternatively activated (M2) macrophages. We examined the anti-inflammatory effect of ANG II type 1 receptor (AT(1)R) blocker (ARB) on glomerular inflammation in a rat model of anti-glomerular basement membrane (GBM) glomerulonephritis (GN). The study focused on infiltrating CD8(+) and CD4(+) cells and macrophages, as well as the heterogeneity of intraglomerular macrophages. Wistar-Kyoto rats were treated with high-dose olmesartan (3 mg.kg(-1).day(-1)), low-dose olmesartan (0.3 mg.kg(-1).day(-1)), or vehicle (control) 7 days before induction of anti-GBM GN. Control rats showed mainly CD8(+) cells and ED1(+) macrophages, with a few CD4(+) cells infiltrating the glomeruli. Necrotizing and crescentic glomerular lesions developed by day 7 with the increase of proteinuria. AT(1)R was expressed on CD8(+) and CD4(+) cells and on ED1(+) macrophages. Low-dose ARB had no anti-inflammatory effects in anti-GBM GN. However, high-dose ARB reduced glomerular infiltration of CD8(+) cells and ED1(+) macrophages and suppressed necrotizing and crescentic lesions by days 5 to 7 (P < 0.05). In addition, high-dose ARB reduced the numbers of ED3(+)-activated macrophages, suppressed glomerular TNF-alpha and IFN-gamma production, and downregulated M1-related chemokine and cytokines (monocyte chemoattractant protein type 1, IL-6, and IL-12). High-dose ARB also enhanced ED2(+) M2 macrophages by day 7 with upregulation of glomerular IL-4 and IL-13 and augmented CCL17, IL-1 receptor antagonist, and IL-10. We concluded that high-dose ARB inhibits glomerular inflammation by increasing the numbers of M2 macrophages and upregulation of anti-inflammatory cytokines and by suppressing M1 macrophage development with downregulation of M1-related proinflammatory cytokines.

Inhibition of capillary repair in proliferative glomerulonephritis results in persistent glomerular inflammation with glomerular sclerosis.

The pathological process of glomerulonephritis (GN) includes glomerular capillary damage, and vascular endothelial growth factor (VEGF) has an important role in glomerular capillary repair in GN. We examined the effect of inhibition of glomerular capillary repair after capillary injury in GN. Experimental Thy-1 GN was induced in rats that were divided into two groups: rats that received anti-VEGF neutralizing antibody (50 µg per 100 g body weight per day) and those treated with the vehicle from day 2 to day 9. We assessed the renal function and histopathology serially until week 6. Rats of the Thy-1 GN group showed diffuse glomerular mesangiolysis with ballooning destruction of the capillary network by day 3. VEGF(164) protein levels increased in the damaged glomeruli during days 5 to 10, and endothelial-cell proliferation increased with capillary repair in the vehicle-injected group. Proliferative GN resolved subsequently with decreased mesangial hypercellularity, and recovery of most of the glomeruli to the normal structure was evident by week 6. In contrast, administration of anti-VEGF antibody significantly decreased endothelial-cell proliferation and capillary repair in glomeruli by week 2. Thereafter, glomerular mesangial-cell proliferation and activation continued with persistent infiltration of macrophages. At week 6, segmental glomerular sclerosis developed with mesangial matrix accumulation and proteinuria. Deposition of type I collagen was also noted in sclerotic lesions. We conclude that impaired capillary repair was the underlying mechanism in the prolongation of glomerular inflammation in proliferative GN and in the development of glomerular sclerosis. Capillary repair has an important role in the recovery of glomerular damage and in the resolution of proliferative GN.

Angiotensin II receptor blockade inhibits acute glomerular injuries with the alteration of receptor expression.

Angiotensin II receptor blockade (ARB) suppresses the progression of chronic kidney disease. However, the renoprotective effect of ARB in the active phase of glomerulonephritis (GN) has not been evaluated in detail. We examined the alteration of angiotensin II receptors' expression and the action of ARB on acute glomerular injuries in GN. Thy-1 GN was induced in rats that were divided into three groups (n=7, in each group); high dose (3 mg/kg/day) or low dose (0.3 mg/kg/day) olmesartan (Thy-1 GN+HD- or LD-ARB group), and vehicle (Thy-1 GN group). Renal function and histopathology were assessed by week 2. In the Thy-1 GN group, diffuse mesangiolysis and focal aneurysmal ballooning developed by day 3. Marked mesangial proliferation and activation progressed with glomerular epithelial injury. We confirmed that both angiotensin II type 1 receptor (AT1R) and type 2 receptor (AT2R) were expressed on glomerular endothelial, mesangial, epithelial cells, and macrophages, and increased 7 days after disease induction. However, ARB treatment caused a decrease in AT1R and a further increase in AT2R expression in glomeruli. ARB prevented capillary destruction and preserved eNOS expression after diffuse mesangiolysis. Mesangial proliferation and activation was suppressed markedly with low levels of PDGF-B expression. Glomerular desmin expression, which is a marker for injured glomerular epithelial cells, was diminished significantly with retained expression of nephrin and podoplanin. Glomerular macrophage infiltration was also inhibited. Proteinuria was suppressed significantly. Furthermore, these effects of ARB showed dose dependency. These results provide insights that ARB affects individual glomerular cells and macrophages through angiotensin II receptors, with the alteration of both AT1R and AT2R expressions, and leads to inhibition of the acute destructive and proliferative glomerular lesions in GN.

Current status and issues of C1q nephropathy.

C1q nephropathy, first proposed by Jennette and Hipp [Am J Clin Pathol 83:415-420, 1985; Am J Kidney Dis 6:103-110, 1985], was described as a distinct glomerular disease entity characterized by extensive mesangial deposition of C1q, with associated mesangial immune complexes, and the absence of any clinical and laboratory evidence of systemic lupus erythematosus. Now, 20 years since the first report, the disease entity is gradually attaining recognition, particularly in the field of pediatrics. C1q is the subcomponent of C1 in the classical pathway of complement activation. Generally, C1q deposition is caused by the activation of C1 by immunoglobulin G (IgG) and IgM; therefore, C1q nephropathy is considered as an immune complex glomerulonephritis. However, in C1q nephropathy, it remains unclear whether the deposition of C1q in the glomeruli is in response to the deposition of immunoglobulin or immune complex, or whether deposition is non-specific trapping that accompanies increased glomerular protein trafficking associated with proteinuria. Since not only the pathogenesis of C1q deposition in glomeruli but also its significance are still uncertain, it has not yet been established as an independent disease. From recent publications of the clinical and pathological characterizations, C1q nephropathy has been thought to be a subgroup of primary focal segmental glomerular sclerosis. However, many reports describe different symptoms, histopathologies, therapeutic responses and prognoses, suggesting that C1q nephropathy is not a single disease entity, but that it may be a combination of several disease groups. There are many uncertain areas requiring further investigation, though it is hoped that a detailed examination of future cases will clarify the subgroups making up C1q nephropathy and their clinicopathological characteristics, and will lead to the establishment of C1q nephropathy as an independent disease entity.

Ultrastructural and immunohistochemical analysis of fibrous long-spacing collagen fibrils in malignant mesothelioma.

Three cases of biphasic mesothelioma and 2 cases of sarcomatoid mesothelioma were investigated using light and electron microscopy. In 2 of the 3 cases of biphasic mesotheliomas, fibrous long-spacing (FLS) collagen fibrils were discovered with a symmetrical cross-striation of 130 nm in periodicity. However, no connection between the FLS fibrils and usual collagen fibrils were observed. Periodic acid silver methenamine stain revealed unstained bands with periods of 130 nm in FLS fibrils, whereas the usual collagen fibrils showed continuous positive staining. All 3 cases of biphasic mesotheliomas showed deposits of hyaluronic acid, whereas both cases of sarcomatoid mesotheliomas showed little hyaluronic acid. As a high concentration of hyaluronic acid induces the formation of FLS collagen fibrils in vitro, the authors propose that FLS fibrils from mesothelioma may be special structures that occur as the tropocollagens are assembled into new collagen fibrils in the presence of hyaluronic acid.

Comparative study of calcified changes in aortic valvular diseases.

Calcification of the aortic valve leads to stenosis or regurgitation or both. To clarify the mechanism of heart valve calcification, comparative studies using histological and ultrastructural examinations were performed of calcified aortic valves. These valves were obtained at valve replacement surgery from 11 patients with rheumatic aortic valvular disease (RAVD), 10 patients with degenerative aortic valve disease (DAVD), and 10 patients with congenitally bicuspid aortic valves (CBAV). For electron microscopic study, 5 cases were selected from each group. In RAVD, histological examination revealed calcification in a degenerated amorphous area at the center of fibrous thickened regions and in laminar fibrous thickened areas near the valve surface. In DAVD, calcification was observed mainly in the fibrosa near the valve ring. In CBAV, basic pathological changes were similar to those in DAVD; however, additional severe calcification of the raphe was observed, if the raphe was present. Ultrastructural examinations showed deposition of electron-dense materials in two patterns in all three groups; one pattern was observed in the interfibrillar spaces of collagen fibrils, and the other pattern was widespread macular deposition unrelated to the preexisting structure. In RAVD, microfibril-like fibrillar structures were found in the areas of deposition of electron-dense materials. These findings suggest that newly formed connective tissue degraded and became necrotic because of nutritional deprivation, especially in the thickened central area, causing calcium deposition. In DAVD and CBAV, numerous lipid vacuoles were found in the electron-dense deposition areas similar to lipid deposition in aortic atherosclerosis. Localized calcium deposition in the fibrosa suggests that the stress of valvular motion and pressure load induces sclerotic changes with the degeneration of collagen fibers, providing a core for calcification. In CBAV, the raphe was the main location of calcification, wherein spiraled collagen fibrils were observed. Increasing the hemodynamic load with abnormal structure might influence calcification. The ultrastructural pattern of calcification of the valve is common; however, additional findings suggest that the cause and mechanism are different in each type of heart valve disease.