Characteristic Glomerular Lesions Research Articles

CCR2 antagonism leads to marked reduction in proteinuria and glomerular injury in murine models of focal segmental glomerulosclerosis (FSGS).

Focal segmental glomerulosclerosis (FSGS) comprises a group of uncommon disorders that present with marked proteinuria, nephrotic syndrome, progressive renal failure and characteristic glomerular lesions on histopathology. The current standard of care for patients with FSGS include immunosuppressive drugs such as glucocorticoids followed by calcineurin inhibitors, if needed for intolerance or inadequate response to glucocorticoids. Renin-angiotensin-aldosterone (RAAS) blockers are also used to control proteinuria, an important signature of FSGS. Existing treatments, however, achieved only limited success. Despite best care, treatment failure is common and FSGS is causal in a significant proportion of end stage renal disease. Thus, an unmet need exists for novel disease modifying treatments for FSGS. We employed two widely-used murine models of FSGS to test the hypothesis that systemic inhibition of chemokine receptor CCR2 would have therapeutic benefit. Here we report that administration CCX872, a potent and selective small molecule antagonist of CCR2, achieved rapid and sustained attenuation of renal damage as determined by urine albumin excretion and improved histopathological outcome. Therapeutic benefit was present when CCX872 was used as a single therapy, and moreover, the combination of CCX872 and RAAS blockade was statistically more effective than RAAS blockade alone. In addition, the combination of CCR2 and RAAS blockade was equally as effective as endothelin receptor inhibition. We conclude that specific inhibition of CCR2 is effective in the Adriamycin-induced and 5/6 nephrectomy murine models of FSGS, and thus holds promise as a mechanistically distinct therapeutic addition to the treatment of human FSGS.

The effect of pentoxifylline on the glomerular function in patients with severe pre-eclampsia

Introduction Pentoxifylline (PTX) is a phosphodiesterase inhibitor that directly upregulates the expression of vascular endothelial growth factor mRNA. Pre-eclampsia (PE) is a pregnancy-specific vascular endothelial disorder with a characteristic glomerular lesion, glomerular endotheliosis, that is due to vascular endothelial growth factor deprivation. This study aimed to investigate the effect of PTX on the functional manifestations of the glomerular endothelial injury in patients with severe PE. Patients and methods Forty patients with severe PE admitted to the Ain Shams Obstetric ICU were assigned randomly in the immediate postpartum period to one of two groups (20 in each group): the PTX group received a continuous intravenous infusion of PTX 400 mg every 8 h daily for 3 days; the control group received normal saline solution as placebo every 8 h daily for 3 days. The primary endpoint was the improvement of renal assessment data in the form of the serum creatinine level, the urine protein/creatinine (P/C) ratio, and urine nephrin levels. Results PTX administration in patients with severe PE was associated with significant reduction of urinary nephrin compared with baseline values (day 1) as well as with the values on day 3 in the control group ( P = 0.007 and P Conclusion The current study demonstrates that PTX administration to patients with severe PE, as an additional treatment to standard therapy on admission to the ICU, exhibits a renoprotective effect.

Association of preeclampsia with podocyte turnover.

Preeclampsia is characterized by hypertension and proteinuria, and increased shedding of podocytes into the urine is a common finding. This finding raises the question of whether preeclamptic nephropathy involves podocyte damage. This study examined podocyte-related changes in a unique sample of renal tissues obtained from women who died of preeclampsia. All patients with preeclampsia who died in The Netherlands since 1990 and had available autopsy tissue were identified using a nationwide database of the Dutch Pathology Registry (PALGA). This resulted in a cohort of 11 women who died from preeclampsia. Three control groups were also identified during the same time period, and consisted of normotensive women who died during pregnancy (n=25), and nonpregnant controls either with (n=14) or without (n=13) chronic hypertension. Glomerular lesions, including podocyte numbers, podocyte proliferation, and parietal cell activation, were measured. Patients with preeclampsia had prominent characteristic glomerular lesions. The results showed that the number of podocytes per glomerulus did not differ significantly between the patients with preeclampsia and the control groups. However, preeclampsia was associated with a significant increase in intraglomerular cell proliferation (7.3% [SD 9.4] of the glomeruli of patients with preeclampsia had Ki-67-positive cells versus 1.6% [SD 3.3] of the glomeruli of hypertensive controls and 1.1% [SD 1.3] of nonpregnant controls; P=0.004) and activated parietal epithelial cells on a podocyte location (34% [SD 13.1] of the glomeruli of patients with preeclampsia versus 18.0% [SD 15.3] of pregnant controls, 11.9% [SD 13.2] of hypertensive controls, and 10.8% [SD 13.4] of nonpregnant controls; P=0.01). These findings suggest that the recently described mechanisms of podocyte replacement play a role in preeclampsia. These results provide key new insights into the pathogenesis of preeclamptic nephropathy, and they open new possibilities for developing therapeutic modalities.

The Glomerular Injury of Preeclampsia

Preeclampsia is a pregnancy-specific disorder that complicates approximately 5% of all pregnancies, making it perhaps the most common glomerular disease in the world. It is characterized by new-onset hypertension and proteinuria, in association with a characteristic glomerular lesion, endotheliosis. "Glomerular endotheliosis" represents a specific variant of thrombotic microangiopathy that is characterized by glomerular endothelial swelling with loss of endothelial fenestrae and occlusion of the capillary lumens. Associated thrombosis is unusual. Recent evidence suggests that this unusual glomerular lesion is mediated by a soluble vascular endothelial growth factor receptor that deprives glomerular endothelial cells of the vascular endothelial growth factor that they require, leading to cellular injury and disruption of the filtration apparatus with subsequent proteinuria. This review summarizes the histologic changes and the pathogenesis of the glomerular lesions of preeclampsia.

Mesangiolytic Glomerulopathy after Radiotherapy and Chemotherapy of Gastric Lymphoma

Mesangiolytic glomerulopathy is an uncommon complication of irradiation and chemotherapy of THP-COP [pirarubicin, cyclophosphamide (CPA), vincristin (VCR), predonisolone (PSL)] and CHOP (CPA, Doxorubicin, VCR, PSL). We report a case of 63-year-old man 7 months status post radiation, and 10 months post chemotherapy for gastric lymphoma. The patient showed proteinuria and mild renal insufficiency. Renal biopsy revealed marked mesangiolysis in the glomeruli without any immune depositions. After the administration of angiotensin II receptor blocker, the patient's renal function remained stable for over two years. Mesangiolysis was thought to be a characteristic glomerular lesion in this patient treated with both chemoagents and radiation.

Zonal distribution of glomerular collapse in renal allografts: Possible role of vascular changes

Collapsing glomerulopathy (CG), an aggressive variant of focal segmental glomerular sclerosis, is a renal disease with severe proteinuria and rapidly progressive renal failure. The pathogenesis of CG is unknown. It strongly resembles human immunodeficiency virus (HIV)-associated nephropathy, but the patients are HIV negative. The characteristic glomerular lesion is capillary loop collapse with prominent podocytes filling Bowman's space. Interestingly, these glomerular changes are usually associated with severe tubulointerstitial injury, including tubular epithelial degenerative changes, microcystic dilation of several tubules, and interstitial inflammatory cell infiltrate. Recently, it became evident that the morphologic pattern of CG may appear not only in native kidneys, but also de novo in renal allografts, and that the pattern of CG in renal transplants is not always associated with severe proteinuria. Studies describing CG in renal allografts are all based on biopsies. We report 3 allograft nephrectomy specimens that showed a zonal distribution of the characteristic collapsing glomerular changes with associated tubulointerstitial injury. All 3 kidneys had obliterative vascular changes. One nephrectomy specimen had chronic obliterative transplant arteriopathy, 1 had acute vascular rejection, and 1 had thrombotic microangiopathy. None of the patients had severe proteinuria. Our cases suggest that the morphologic pattern of CG in renal allografts may not represent the same disease process as CG in native kidneys and provide further evidence that collapsing glomerular changes do not define the disease entity of CG, but rather represent a pattern of renal injury. Among other factors, hemodynamic disturbance may play a role in the development of the pattern of CG in renal allografts. HUM PATHOL 33:437-441. Copyright 2002, Elsevier Science (USA). All rights reserved.

Alterations in extracellular matrix components and integrins in patients with preeclamptic nephropathy.

The glomerular features of patients with preeclampsia consist of swelling of endothelial cells, subendothelial deposits of incompletely defined material, and thickening of the capillary walls. These abnormalities are thought to resolve in the postpartum period. The distribution of extracellular matrix (ECM) components and integrins was investigated in 10 such patients. Frozen sections and paraffin-embedded sections were stained with antibodies to type IV collagen, laminin (LN), fibronectin (FN), vitronectin (VN), tenascin (TN), fibronectin receptor (FNR), and vitronectin receptor (VNR). In preeclamptic nephropathy, the accumulation of type IV collagen, LN, FN, TN, and FNR was observed in the thickened capillary walls, particularly in the subendothelial layer and, to some extent, in the mesangium. However, deposits of VN were sparse and the distribution of VNR was similar to that in normal kidney. In segmental sclerotic lesions, the amounts of type IV collagen, LN, FN, VN, and TN were increased, whereas those of FNR and VNR were markedly decreased. These results suggest that the materials deposited in the subendothelial space consist of ECM components as well as of plasma-derived proteins, and that the deposition of ECM components and of FNR may be involved in the development and the reparative process of the characteristic glomerular lesions. The formation of sclerotic lesions was linked to the accumulation of ECM components, but not to an interaction with integrins.

Probucol Reduces Renal Injury in the ExHC Rat

To investigate the potential roles of oxidized lipoproteins and glomerular macrophages in the pathogenesis of lipid-induced glomerular injury, we examined the effects of administration of probucol on the development of renal injury in ExHC rats. ExHC rats are derived from the Sprague-Dawley strain and are highly susceptible to dietary hypercholesterolemic stimuli. We reported previously that ExHC rats fed a cholesterol-supplemented diet (HCD) develop proteinuria and characteristic glomerular lesions. These lesions include marked accumulation of numerous lipid-filled foam cells, which have a surface marker that identifies them as macrophages, within mesangial regions, as well as segmental clusters of foam cells that are associated with capsular adhesions, the destruction of glomerular tufts and glomerular sclerosis. ExHC rats were maintained on an HCD or on an HCD supplemented with 5% (wt/wt) probucol for 8 weeks. Probucol reduced the extent of renal injury, as evidenced by proteinuria and segmental glomerular lesions, in ExHC rats fed an HCD, in the absence of any significant reduction in plasma cholesterol levels. Both low-density lipoprotein and beta-very-low density lipoprotein isolated from the plasma of probucol-treated rats were found to be resistant to oxidative modification by cupric ions. Both the size and the number of foam cells within glomeruli in the probucol-treated rats were significantly reduced as compared to those of foam cells in the untreated rats. Probucol might reduce renal injury in ExHC rats by limiting the oxidative modification of lipoproteins and, subsequently, by restricting the foam cell transformation of macrophages within glomeruli and by inhibiting the recruitment of macrophages into glomeruli. The results of the present study may be interpreted to indicate that local glomerular oxidative modification of lipoproteins might occur in vivo, and both oxidized lipoproteins and glomerular macrophages may play important roles in the pathogenesis of lipid-induced glomerular injury.

Characteristic glomerular lesions in the ExHC rat: a unique model for lipid-induced glomerular injury.

ExHC rats were bred from the Sprague-Dawley strain and are highly susceptible to dietary hypercholesterolemic stimuli. Although chemical and histological examination of the aorta from ExHC rats fed a diet containing 3% cholesterol, 0.6% sodium cholate and 15% olive oil (high-cholesterol diet, HCD) has been reported, renal injury in this model has not been investigated to date. Therefore, we examined the renal pathological changes and proteinuria in this model. ExHC rats fed an HCD developed proteinuria and characteristic glomerular lesions within 4-8 weeks after initiation of the diet. The most striking glomerular change observed in this model was the marked accumulation of numerous lipid-filled foam cells, with a surface marker that identified them as macrophages, within the mesangial regions which could have been involved in focal and segmental glomerular sclerosis. Our study demonstrates that ExHC rats fed a cholesterol-supplemented diet develop glomerular injury that may be mediated by infiltrating macrophages. These results imply that ExHC rats may be well-suited for the use in investigations of the role of macrophages in the pathogenesis of lipid-induced glomerular injury.

Insulin receptors of isolated glomeruli

1. 1. To investigate a possible action of insulin on the glomerulus, the binding of [ 125I]insulin to isolated glomeruli prepared from rat kidney was examined. When incubated at 22°C, [ 125I]insulin binding proceeded with time and reached a steady state at 45 min at which time non-specific binding was less than 25% of total binding. 2. 2. This binding was specific to insulin in that other hormonal agents known to act on the glomerulus were without effects on the binding. Increasing concentrations of non-labelled insulin displaced [ 125Ijinsulin binding in a dose-dependent fashion. Scatchard plot of data was curvilinear. 3. 3. The addition of excess non-labeled insulin to the glomeruli preincubated with [ 125I]insulin resulted in a rapid dissociation ofapprox 70% of bound [ 125I]insulin. 4. 4. Insulin decreased the increments in glomerular cyclic AMP levels by epinephrine and by prostaglandin E 2, but not those by histamine. 5. 5. The autoradiographic studies demonstrated the presence of insulin binding primarily on the surface of the endothelium and epithelium. 6. 6. These data showed the presence of specific insulin receptors in the glomeruli, probably in the endothelium and epithelium, and that insulin action may be, at least in part, through modulation of glomerular cyclic AMP concentrations. 7. 7. Such action of insulin may underlie the alteration in glomerular ultrafiltration and the development of characteristic glomerular lesions in diabetes mellitus, a disease in which insulin deficiency or tissue resistance to insulin exists.

Pathomorphological study of focal and segmental sclerosing glomerulopathy (-nephritis)

From 44 patients with f.s.s.g. 75% suffered from a nephrotic syndrome, 25% from proteinuria, and 48% from erythrocyturia. The characteristic glomerular lesion is a progressive increase in mesangial matrix (sclerosis) which in early stages concerns only few glomeruli and within these only a portion of the capillary tuft. Histologically the remaining glomeruli show minimal changes, only. Electron microscopy, however, reveals these glomeruli as pathologically altered, too. PAS-positive hyaline deposits are identified with the light microscope in about 80% of all patients. Electron dense deposits, identical with immune deposits are regularly found within sclerosing areas, but rarely occur in minimally changed glomeruli, too. Immunofluorescence microscopy reveals a corresponding segmental deposition of IgM and C3. The findings suggest that the underlying mechanism is a diffuse one, but associated with focal accentuation which might depend on or be promoted by deposited immune aggregates.

Focal and segmental sclerosing glomerulopathy (-nephritis).

10 out of 44 renal biopsy specimens obtained from patients with focal and segmental sclerosing glomerulopathy (-nephritis) (focal sclerosing lesion, sclerose s. hyalinose segmentaire et focale) were examined with the electron microscope and 11 by immunofluorescence microscopy. Particularly ultrastructural alterations are described in detail. A nephrotic syndrome was observed in 33 (75%), proteinuria in 11 (25%), and erythrocyturia in 21 (48%) patients. As the characteristic glomerular lesion a progressive increase in mesangial matrix material (sclerosis) is found which in the beginning concerns only few glomeruli and within these only a portion of the capillary tuft. The remaining glomeruli histologically show minimal changes. Electron microscopy, however, reveals these glomeruli as pathologically altered, too, indicating that the underlying mechanism is a diffuse one. Progression of sclerosing processes finally results in complete sclerosis of more and more capillary loops and glomeruli, respectively. Lightmicroscopically identifiable PAS-positive hyaline deposits were present in about 80%, thus representing an important diagnostic tool. Electron dense deposits, identical with typical immune deposits, are a regular finding in sclerosing areas and very rarely occur in minimally changed glomeruli, too. Immunofluorescence microscopy reveals a corresponding segmental deposition pattern of mostly IgM and C3 globulins. These findings are discussed with regard to an immune pathogenesis of the focal and segmental lesion.

Glomerulonephritis induced in mice by ECHO 9 virus.

Two hundred and twenty-two suckling HaM/ICR mice were inoculated with ECHO 9 virus intraperitoneally. The renal lesions were studied by light microscopy, electron microscopy and immunofluorescent technics. Characteristic glomerular lesions resembling acute glomerulonephritis were seen six days after inoculation. The frequency and severity of glomerular lesions increased with time and reached a maximum two to three weeks after inoculation. Later, the lesions decreased in frequency and severity and almost disappeared at six weeks after inoculation, although viral antigen was present up to 54 days. Viral antigen deposits were observed in the glomeruli, indicating that the glomerulonephritis was viral in origin and the result of either direct infection or an antigen-antibody reaction.

Blood Pressure Elevation and Renal Pathology in Rats Fed Simulated Japanese Diets

Albino rats fed diets composed of Japanese foods for 6 to 12 months had significantly higher systolic blood pressures than control rats fed a standard laboratory ration. Addition of NaCl or soy sauce to the standard ration in amounts calculated to match the Na intake afforded by the Japanese diets did not have a hypertensive effect. Reduction of the molar Na/K ratio of the Japanese diets by addition of KCl or by removal of sources of Na decreased but did not abolish the elevations of blood pressure. Hypertensive rats fed the Japanese diets consistently showed elevations of serum total cholesterol concentration, cardiac and renal hypertrophy, and renal pathology involving a characteristic glomerular lesion, tubular damage, and “renal failure” casts.