Glomerular Mesangiolysis Research Articles

Clinical value of the renal pathologic scoring system in complement-mediated thrombotic microangiopathy

Objectives This study was initiated to establish a renal thrombotic microangiopathy (TMA) scoring system based on clinical needs and investigate its predictive value for patients’ long-term outcomes. Methods Kidney biopsy-proven Complement-mediated TMA (C-TMA) patients from January 2000 to December 2017 in Peking University First Hospital were retrospectively studied. Both acute and chronic TMA-related lesions, including 15 pathologic indices, were semiquantitatively scored. The interobserver and intraobserver reproducibility and correlation between the pathologic indices and clinical parameters were analyzed. Furthermore, the patients were divided into 2 groups by dialysis use at baseline, and the association of these pathologic indices with their prognostic outcomes was assessed between the two groups. Results Ninety-two patients with renal biopsy-proven C-TMA were enrolled. All fifteen included pathology indices showed good or moderate interobserver and intraobserver reproducibility and correlated well with several clinical parameters. Several clinicopathological indices were worse in the dialysis group than in the nondialysis group, such as serum creatinine, hemoglobin, platelet count, and estimated glomerular filtration rate. Moreover, morphologic features in the dialysis group presented with more severe vascular lesions. Interstitial fibrosis and chronic tubulointerstitial lesions were related to a trend of high risk of continuous dialysis in the dialysis group. Based on univariate and multivariable Cox regression analysis, more severe glomerular lesions, including glomerular mesangiolysis, glomerular basement membrane double contours and glomerular mesangial proliferation, were identified as risk factors predicting worse prognosis. Conclusions Our renal C-TMA semiquantitative scoring system is reliable with good reproducibility and prognostic value in clinical practice, which needs further validation.

Dose-Dependent Effects of Paraquat on C-reactive protein, Some Lipid Profile Parameters and Histology of Tissues in Male Albino Rats

Paraquat is a highly toxic and widely used herbicide with no antidote. Its toxicity in man and animals has been reported to cause severe acute and long term health problems which eventually could lead to death. Measurement of blood C-Reactive Protein level (CRP) serves as a useful screen for infections and inflammatory diseases. Since it is known that paraquat exerts its toxic effects through generation of reactive oxygen species which causes injury to the cells thereby causing inflammation, this study was designed to determine the dose-dependent effects of paraquat on C-reactive protein, cholesterol, triglycerides and histology of liver and kidney in rats. Thirty albino rats weighing between 150 g and 200 g grouped into five groups of six rats in each were used. Rats in group A serves as control and were given feed and water only freely. Rats in group B, C, D and E were treated orally with 15 mg/kg (below sublethal dose), 25 mg/kg (sub-lethal dose), 35 mg/kg (below lethal dose) and 45 mg/kg (below lethal dose) of paraquat dichloride respectively for a period of fourteen days. The blood plasma collected was analyzed for CRP (using an immune-turbidimetric assay method), cholesterol and triglycerides while liver and kidney excised from sacrificed rats were used for histopathological studies. The result obtained showed that the concentration of CRP (12.38 ± 0.09 mg/L), cholesterol (8.61 ± 0.49 mg/L) and triglycerides (189.47 ± 2.59 mg/L) in control group was significantly lower (p<0.05) than the other groups. The higher the concentration of paraquat administered, the higher its toxicity and the higher the levels of CRP, cholesterol and triglycerides. Histopathological findings revealed some pathologic conditions ranging from diffuse vacuolar degeneration of hepatocyte and glomerular mesangiolysis in the liver and kidney of paraquattreated group respectively. This present study therefore suggests that the induction of inflammation and oxidative damage by paraquat could be accompanied by elevated C-reactive protein, cholesterol and triglycerides in albino rats.

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. VEGF164 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.

Deficiency of Endothelial Nitric-Oxide Synthase Confers Susceptibility to Diabetic Nephropathy in Nephropathy-Resistant Inbred Mice

Recent studies have implicated dysfunctional endothelial nitric-oxide synthase (eNOS) as a common pathogenic pathway in diabetic vascular complications. However, functional consequences are still incompletely understood. To determine the role of eNOS-derived nitric oxide (NO) in diabetic nephropathy, we induced diabetes in eNOS knockout (KO) and wild-type (WT) mice on the C57BL6 background, using low-dose streptozotocin injection, and we investigated their glomerular phenotype at up to 20 weeks of diabetes. Although the severity of hyperglycemia in diabetic eNOS KO mice was similar to diabetic WT mice, diabetic eNOS KO mice developed overt albuminuria, hypertension, and glomerular mesangiolysis, whereas diabetic WT and nondiabetic control mice did not. Glomerular hyperfiltration was also significantly reduced in diabetic eNOS KO mice. Electron micrographs from diabetic eNOS KO mice revealed an injured endothelial morphology, thickened glomerular basement membrane, and focal foot process effacement. Furthermore, the anionic sites at glomerular endothelial barrier estimated by cationic ferritin binding were reduced in diabetic eNOS KO mice. In aggregate, these results demonstrate that deficiency of eNOS-derived NO causes glomerular endothelial injury in the setting of diabetes and results in overt albuminuria and glomerular mesangiolysis in nephropathy-resistant inbred mice. The findings indicate a vital role for eNOS-derived NO in the pathogenesis of diabetic nephropathy.

Effects of leukocytosis and macrophage activation on anti-Thy 1.1 glomerulonephritis in the rat.

In anti-Thy 1.1 proliferative glomerulonephritis (GN), glomerular infiltration of polymorphonuclear leukocytes (PMNs) reaches a peak level after 1 h and that of macrophages does so 24 h after induction. However, the roles of PMNs and macrophages in the pathogenesis of anti-Thy 1.1 GN remain unclear. We examined the effects on this model of leukocytosis induced by granulocyte colony-stimulating factor (G-CSF) and of macrophages stimulated by macrophage colony-stimulating factor (M-CSF). Anti-Thy 1.1 GN was induced in male Wistar rats by intravenous injection of OX-7, a monoclonal antibody to the Thy 1 antigen. G-CSF (10 microg/kg/day), M-CSF (20 microg/kg/day) or vehicle was administered intraperitoneally for 7 days starting 24 h before the injection of OX-7. Histological examination of renal biopsy specimens was performed on Days 1, 5 and 14 after induction. Circulating and glomerular-infiltrating PMNs (RP-3-positive cells) were increased at Day 5 in G-CSF-treated rats compared with controls receiving vehicle, and glomerular mesangiolysis continued at Day 5. The number of proliferating cells positive for proliferating cell nuclear antigen at Day 5 and matrix scores at Day 14 were smaller in G-CSF-treated rats than in control rats. The mesangiolysis score was significantly higher in the G-CSF group than in the control group at Days 5 and 14, but not at Day 1. ED-1-positive cells were increased in number at Day 5 and matrix accumulation decreased at Day 14 in M-CSF-treated rats compared with controls. Serum creatinine level at Day 14 was lower in the M-CSF group, but not in the G-CSF group, compared with the control group. Activated macrophages may inhibit excess matrix accumulation and ameliorate the recovery of renal function, whereas leukocytosis inhibits the repair of mesangial cell injury in this model.

Human parvovirus B19 infection associated with hemolytic uremic syndrome

A 59-year-old woman developed hemolytic uremic syndrome (HUS) associated with acute human parvovirus B19 (HPVB19) infection. A renal biopsy revealed glomerular mesangiolysis with segmental hypercellularity; mild fibrinogen/fibrin deposits were noted by immunofluorescence study and severe endothelial injury was noted electron microscopically. The histological findings were compatible with HUS. We discuss the relation of HPVB19 to HUS, with special reference to the tropism of the virus for endothelial cells.

Intravascular malignant lymphomatosis involving the kidney: three case reports

We report three autopsy cases of patients with renal symptoms related to intravascular malignant lymphomatosis (IML) exclusively involving both kidneys. The patients were one woman and two men, aged 64, 65, and 82 years, respectively. Their presenting symptoms included fever, anemia, thrombocytopenia, icterus, dyspnea, weight loss, and enlarged adrenal glands. All patients presented with acute renal dysfunction, with creatinine ranging from 2.0 to 6.5 mg/dl, or with modest proteinuria. One patient had an underlying bilateral disease, chronic pyelonephritis. Another patient also had an autoimmune disease. None of the three patients were aggressively treated. All died of progressive disease 2 weeks to 2 months after the onset of their renal symptoms. The diagnosis of the lymphomas was confirmed by morphological and immunohistochemical studies of the postmortem material. The lymphomas were subclassified as large-cell, characterized by angiotropism. Immunophenotyping revealed that all were B-lineage neoplasms. Renal involvement by IML was characterized histologically by a unique pattern of multifocal neoplastic disseminations within the glomerular and peritubular capillaries, with relative sparing of the interstitum. In one patient, glomerular mesangiolysis in association with embolic proliferations of lymphoma cells was a striking feature. All patients had bilateral renal involvement by IML which occurred in a setting of widespread disease. Our studies indicate that IML is an unusual subset of secondary renal lymphomas with bilateral diseases, and, rarely, may produce renal symptomatology early in the course.

Antihypertensive drug treatment in chronic renal allograft rejection in the rat. Effect on structure and function.

To gain insight into the contribution of immunologic and hemodynamic factors in the progressive demise of structure and function in chronic renal allograft dysfunction, we studied the histological changes, the immunostainable glomerular anionic sites, and glomerular capillary hydrostatic pressures of rat renal allografts with chronic rejection. Recipient animals were left untreated, received 8 weeks of treatment with the immunosuppressive drug cyclosporine, or received antihypertensive drugs consisting of the combination of reserpine, hydralazine and hydrochlorothiazide, the angiotensin-converting enzyme inhibitor cilazapril, or the angiotensin II receptor blocker L-158,809. Grafts in untreated recipients developed chronic interstitial inflammation, as well as vascular and glomerular lesions consistent with chronic rejection. These lesions were associated with immunohistochemical loss of the negatively charged heparan sulfate proteoglycan side chain. All treatment regimens decreased the systemic and glomerular capillary pressures and were associated with no loss of function, decreased proteinuria, and a tendency to improved graft function. Cyclosporine prevented all histological manifestations of rejection, and antihypertensive drugs decreased the extent of glomerular mesangiolysis and glomerulosclerosis; L-158,809 and cilazapril also inhibited graft atherosclerosis and tubular atrophy. We conclude that chronic rejection is primarily an immune-mediated process, but hemodynamic and angiotensin II-mediated effects may play a pivotal role in the expression of immune-mediated lesions.

Severe glomerular mesangiolysis in a patient with rectal adenocarcinoma treated with cytotoxic drugs

A 72 year old man with rectal adenocarcinoma developed chronic renal failure when treated by surgery and subsequent chemotherapy (5-fluorouracil, Mitomycin C and Cytosine arabinoside) and immunotherapy. Light microscopy provided evidence of severe glomerular changes with extensive mesangiolysis and vascular damage. Electron microscopy confirmed the mesangiolysis and showed nuclear changes in mesangial cells with nuclear pockets, chromatin loss and margination. There was further indirect evidence of endothelial cell damage. It is suggested that the glomerular changes should be attributed to a direct cytotoxic effect on the mesangial cells.