Glomerular Capillary Lumen Research Articles

Endothelial cell apoptosis during glomerular capillary lumen formation in vivo.

Transforming growth factor-beta (TGF-beta) stimulates endothelial cell apoptosis in vitro, and inhibition of TGF-beta1 leads to retention of undifferentiated endothelial cells in developing glomerular capillaries and reduced lumen formation in vivo. This study explored the question whether glomerular capillary lumen formation in vivo may involve TGF-beta1-dependent endothelial cell apoptosis. Neutralizing anti-TGF-beta1 or non-immune IgY were infused into the renal arteries of 3-d-old rats, and the kidneys were examined 2 d later. By transmission electron microscopy, endocapillary apoptotic cells were observed at a frequency of 0.10/loop in immature glomeruli of 3-d-old rat pups. In 5-d-old rat pups given neutralizing TGF-beta1 antibody or control IgY, the frequency of endocapillary apoptotic cells was 0.03 and 0.09/loop, respectively (P < 0.001, chi(2)). Dual labeling with TUNEL and anti-von Willebrand factor (vWF) antibody showed that apoptotic cells in immature glomeruli of 5-d-old rat pups are endothelial cells. Quantitative analysis showed significantly fewer TUNEL/vWF-labeled cells in glomeruli after anti-TGF-beta1 antibody infusion than in controls. No endocapillary apoptotic cells were observed in any group in C-shaped or S-shaped bodies, and the TUNEL assay revealed no glomerular apoptotic cells in kidneys from mature rats. These findings suggest that superfluous endothelial cells are cleared from immature glomerular capillaries by apoptosis, a process regulated by TGF-beta1. Taken together with the previous finding, that TGF-beta1 blockade blunts glomerular capillary lumen formation in vivo, it is proposed that TGF-beta1-dependent apoptosis serves to open capillary lumens in this vascular bed during glomerular development.

Automatic Generation of Glomerular Capillary Topological Organization

Glomerular structural changes are conventionally investigated by optical or electron microscopy on two-dimensional (2D) sections. To understand the relationship between functional and structural changes of glomerular capillary networks in more detail, three-dimensional (3D) investigation of the capillary tufts is required. Since confocal microscopy and scanning electron microscopy cannot completely show the 3D topological organization of the capillary tuft, we have developed an automatic method to obtain a 3D model of the glomerular capillary lumen structure and to derive its topological organization. Serial semithin sections of a glomerular tuft, from rat kidney tissue, were digitized at high resolution. Capillary lumens were digitally outlined and segmented images were automatically aligned. A 3D model of the capillary tuft was automatically generated using the Visualization Toolkit library and the Marching Cubes algorithm. We then developed an original algorithm for automatic 3D skeletonization of capillary lumen volume to identify capillary segments and bifurcations and to obtain the topological organization of the network and geometric parameters of capillary segments (length, radius, and spatial configuration). Capillary segment connectivity was graphically presented in a 2D layout with an automatic procedure, revealing the lobular organization of the network. This technique, successfully applied to serial sections of a glomerular capillary, can be used to study a population of glomerular capillaries to disclose the structural effects of pathological conditions. The methodology can be extended to other vascular structures, such as the microcirculation of neoplastic tissues.

Therapeutic Apheresis for the Renal Complications of Multiple Myeloma and the Dysglobulinemias

Disordered immunoglobulin synthesis can result in a variety of different types of renal pathology. Multiple myeloma is often associated with the overproduction of light chains which may result in toxicity to the renal tubules and acute renal failure. Patients with mixed cryoglobulinemia will have renal involvement which is most often in the form of a membranoproliferative glomerulonephritis. Renal involvement in macroglobulinemia is relatively uncommon, but IgM thrombi can be so voluminous as to occlude the glomerular capillary lumen. In each of these examples, therapeutic plasma exchange has been found to be a useful adjunct to the eventual chemotherapy required for the definitive treatment of these disorders.

Extensive intraglomerular thrombi of monoclonal IgM-Κ in a patient with malignant lymphoma

We describe an 80-year-old man who developed malignant lymphoma (ML) complicated by extensive intraglomerular thrombi of immunoglobulin M (IgM)-Κ monoclonal immunoglobulin. The clinical picture was characterized by nephrotic syndrome and systemic lymphadenopathy. Laboratory examination showed mild anemia and a small amount of monoclonal IgM-Κ in the blood. The histopathologic findings and surface immunoglobulin analysis of the lymph node biopsy specimen were consistent with CD5-positive diffuse large B-cell (type, IgM-Κ) lymphoma. The subsequent renal biopsy showed a massive deposition of amorphous material in the glomerular capillary lumens, subendothelial areas, and mesangium. Nodular glomerulosclerosis was not found. An immunofluorescent study showed that the deposits consisted of IgM-Κ monoclonal immunoglobulin. Ultrastructurally, the deposits were composed of granular electron-dense material. Chemotherapy was effective for both the ML and nephrotic syndrome, and the patient's urine analysis results returned to normal. The histopathologic manifestations of this case are rare, and the pathogenesis of these glomerular lesions was obviously associated with ML.

Induction of Glomerular Lesions in the Kidneys of Mice Infected with Vero Toxin–ProducingEscherichia coliby Lipopolysaccharide Injection

Lipopolysaccharide was injected into germ-free mice after they had been infected with Vero toxin-producing Escherichia coli. Microscopic examination of the kidneys of these mice showed an increased number of mesangial cells and a vacancy in the glomerular capillary lumen. A significant elevation in the expression level of interferon (IFN)-gamma in the kidney may have played a key role in the induction of glomerular lesions, because the administration of neutralizing antibody to IFN-gamma markedly alleviated such lesions.

Endogenous asymmetrical dimethylarginine and hypertension associated with puromycin nephrosis in the rat.

1. The present experiments were designed to investigate the role of asymmetrical NG,NG-dimethyl-L-arginine (ADMA) in causing hypertension associated with the focal and segmental glomerulosclerosis (FSGS) produced by a single bolus of puromycin aminonucleoside (PAN) and successive injection of protamine for 7 days in rats which had undergone unilateral nephrectomy. 2. After the unilateral nephrectomy, and administering PAN and protamine, histological examinations of the kidney revealed a typical FSGS, that is, evident abnormalities including segmental mesangial proliferation, obliteration of glomerular capillary lumens and adhesions between the glomerulus and Bowman's capsule could be observed. Changes in the glomerular epithelial cells consisted of the swelling with bleb formation. 3. In the FSGS rats, urine volume and urinary protein were significantly (P<0.05 and P<0.005) increased throughout 4-week experimental period, while the creatinine clearance was significantly (P<0.005) and transiently decreased, and recovered 4 weeks later. These changes were associated with the sustained elevation of the systolic blood pressure. 4. ADMA levels in aortic endothelial cells, plasma and urine were significantly (P<0.05 and P<0.005) increased in the FSGS rats, but the level in the kidney remained unchanged. 5. The basal level and net production of cyclic GMP in the aortic vessel wall with endothelium when stimulated by norepinephrine and acetylcholine were significantly (P<0.05 and P<0.01) attenuated in the FSGS rats. 6. There were significant and positive correlations between systolic blood pressure (y) and ADMA levels (x) in endothelial cells (y=4.43x+122.2, r=0.979, P<0.0001), plasma (y=0.10x+71.9, r=0.921, P<0.001) and urine (y=0.48x+126.9, r =0.699, P<0.005), but not significant in the kidney (y=0.06x+102.7, r=0.252, NS). 7. These findings suggest that ADMA as an endogenous inhibitor of NO synthesis may play an important role for the pathogenesis in the hypertension associated with the experimental FSGS in the rat.

A case of systemic lupus erythematosus associated with hemolytic uremic syndrome

We report a case of systemic lupus erythematosus (SLE) associated with hemolytic uremic syndrome (HUS). The patient was a 13-year-old boy who had complained of nausea and diarrhea. Abnormal urinalysis, pancytopenia and renal dysfunction were revealed. The immunological studies showed an elevation of antinuclear antibody and anti-double-stranded DNA antibody titers with a low complement level. Renal biopsy specimens showed diffuse membranous glomerulonephritis with microthrombi in the glomerular capillary lumen. He was diagnosed as having SLE with HUS. Methylprednisolone pulse therapy was performed. Renal function, proteinuria and hematuria were gradually improved. Prednisolone and an immunosuppressive agent (mizoribine) were prescribedper os. In our case, diarrheal prodrome was present, so gastro-enteritis was suggested as the trigger of HUS, but the causal agent was not detected. HUS was considered to be an accelerator in the renal lesions of SLE. There have been few reported cases in children of SLE associated with HUS.

Ultrastructural localization of vascular cell adhesion molecule-1 in proliferative and crescentic glomerulonephritis.

Recent studies have demonstrated an important role of vascular cell adhesion molecule-1 (VCAM-1) in the pathogenesis of nephritis. In the present study, renal biopsy specimens from patients with proliferative and crescentic glomerulonephritis were subjected to immunoelectron microscopy using an anti-VCAM-1 monoclonal antibody. In control normal kidney tissue, VCAM-1 expression was restricted to the free surface of parietal epithelial cells. In diseased glomeruli, VCAM-1 was expressed on the free surface of parietal and visceral epithelial cells, on the luminal surface of capillary endothelial cells, on infiltrating monocyte/macrophage-like cells, on mesangial cells, and in the matrix of the expanded mesangium. There was also VCAM-1 expression on almost all cell types in the crescents, including macrophage-like cells, fibroblast-like cells, and epithelial cells. Some cells also showed VCAM-1 positivity in the rough endoplasmic reticulum and the perinuclear space. Both the glomerular capillary lumen and urinary spaces of Bowman's capsule contained positive reaction products, which were often associated with exocytosis by the surrounding cells. VCAM-1 was predominantly expressed on the basal and lateral surfaces of a few proximal tubules, but it could not be localized ultrastructurally. These findings suggest that production and secretion of VCAM-1 by both infiltrating monocyte/macrophages and resident glomerular cells may be related to the pathogenesis of proliferative and crescentic glomerulonephritis.

Alterations in glomerular permeability in streptozotocin-induced diabetic rats

The alteration in glomerular basement membrane permeability associated with microangiopathy in streptozotocin-induced diabetic rats was studied by determining the movement across the glomerular basement membrane of anionic ferritin probes injected into rats at different points in the development of the disease. Visualization of the concentration gradient of anionic ferritin and changes in ultrastructure was accomplished by electron microscopic examination of renal tissue prepared from both control and diabetic rats. In all control rats, the anionic ferritin did not leave the glomerular capillary lumen, nor were there any changes in the normal morphology of the glomerular capillary wall. In the diabetic animals, the concentration of anionic ferritin shifted from the capillary lumen in the abluminal direction. Distinct morphologic changes, such as widening of endothelial intercellular junctions, focal detachment of podocyte foot processes, and extensive thickening of the glomerular basement membrane, were noted in the diabetic rat, and these changes appear to correlate with the observed increase in permselectivity of anionic ferritin across the glomerular capillary wall.

Renal denervation prevents intraglomerular platelet aggregation and glomerular injury induced by chronic inhibition of nitric oxide synthesis.

Nitric oxide (NO) inhibits platelet adhesion and aggregation in vitro. In vivo, chronic inhibition of NO synthesis induces nephrosclerosis and hypertension. Although the pathophysiological mechanism of this glomerular injury has not been clarified, sympathetic nerve activation, a potent procoagulant stimulus elicited by NO inhibition, may play a role. To investigate the role of renal sympathetic nerves in the development of renal injury induced by NG-nitro-L-arginine methyl ester (L-NAME), a specific NO synthesis inhibitor, we examined renal histological changes in four groups of Sprague-Dawley rats: (1) sham operated, vehicle treated; (2) sham operated, L-NAME treated; (3) denervated, vehicle treated, and (4) denervated, L-NAME treated. Following renal denervation or sham operation, L-NAME was administered orally for 4 weeks. Chronic NO inhibition induced platelet aggregation and erythrocyte stasis in the glomerular capillary lumen accompanied by electron-microscopic glomerular injury. Renal denervation abrogated platelet aggregation and glomerular injury in L-NAME-treated animals. Thus, chronic NO synthesis inhibition induced intraglomerular platelet aggregation and glomerular injury, which was attenuated by renal nerve denervation. These results suggest that intrinsic NO may have an antithrombotic effect in the glomeruli and may play a protective role in the progression of glomerular injury possibly mediated by renal sympathetic nerves.

A combination of livedo racemosa, occlusion of cerebral blood vessels, and nephropathy: Kidney involvement in sneddon's syndrome

A 59-year-old woman with retinal vein thrombosis and livedo racemosa had hematuria (4+) and proteinuria (1.7 g/day). Skin biopsy showed swollen blood vessel walls with infiltration of mononuclear cells, which were compatible with livedo racemosa (vasculitis). Magnetic resonance imaging (MRI) of the brain demonstrated multiple lacunar infarctions in the basal ganglia and white matter. Renal biopsy showed that small round cells had infiltrated into the interstitium, and a reticular structure was observed in the glomerular hilus. An amorphous substance composed of a single cell was present in the glomerular capillary lumen. Immunofluorescent study demonstrated the deposition of only IgA, in a segmental pattern differing from the diffuse global mesangial pattern seen in IgA nephropathy. After combined therapy including 40 mg/day prednisolone, 50 mg/day cyclophosphamide, antiplatelet drug, and anticoagulant was started, proteinuria and hematuria improved to 0.5 g/day and 2+, respectively, at the time of discharge. Sneddon's syndrome is a rare entity characterized by livedo racemosa and cerebrovascular lesions. In our patient with livedo racemosa, occlusion of cerebral blood vessels, and nephropathy with segmental immunoglobulin A (IgA) deposition, no antiphospholipid antibodies were detected on routine examination. Dermatologists, neurologists, psychiatrists, and nephrologists should be aware of the existence of Sneddon's syndrome with nephropathy (LI-O-N).

Transcellular biosynthesis of lipoxin A4 during adhesion of platelets and neutrophils in experimental immune complex glomerulonephritis

Polymorphonuclear neutrophils are important effectors of injury in host defense and inflammation. Many inflammatory diseases are self-limiting, raising the possibility that compounds are generated in vivo during the course of inflammation that inhibit neutrophil recruitment and tissue destruction. Lipoxins, a more recent addition to the families of bioactive eicosanoids, are potential candidates in this regard. Lipoxins are generated via pathways that initially involve the dual lipoxygenation of arachidonic acid and are potent inhibitors of several neutrophil trafficking events in vitro. Here, we present evidence that lipoxin A4 is generated in rat kidneys during experimental immune complex-mediated glomerulonephritis in vivo. Renal lipoxin A4 levels were markedly reduced by prior depletion of animals of either neutrophils or platelets, suggesting that most lipoxin A4 generated in vivo was derived from transcellular biosynthetic pathways during platelet-neutrophil interactions. Electron microscopic examination of glomerulonephritic kidneys revealed areas of intimate contact between neutrophils and platelets within the lumen of glomerular capillaries. P-selectin on platelets is an important mediator of platelet-neutrophil adhesion in vitro and in vivo. Prior treatment of animals with a blocking monoclonal antibody (mAb) against P-selectin (mAb CY1747), but not an isotype-matched non-blocking control mAb (mAb PNB1.6), caused striking inhibition of lipoxin A4 generation without attenuating neutrophil recruitment. Anti-P-selectin mAb also blunted transcellular lipoxin A4 generation during coincubations of activated neutrophils and platelets in vitro.(ABSTRACT TRUNCATED AT 250 WORDS)

The role of antiphospholipid antibodies in lupus nephropathy.

Although several clinical and morphological changes observed in overt systemic lupus erythematosus have been associated with the presence of antiphospholipid antibodies (aPL), the relation between these antibodies and lupus nephropathy (LN) is not clear. Twenty-three patients with biopsyproved LN were retrospectively studied (average age 28.5 +/- 12.3 years, all women) in order to investigate the relationship between the presence of aPL and clinical and immunobiological data. The average follow-up period was 55 +/- 42 months. The presence of aPL (IgG and IgM) was detected at least once in all patients by ELISA and/or lupus anticoagulant (kaolin time). Seven patients (30.4%) were aPL+, and the remainder aPL-. We did not find differences related to age, period of follow-up, blood pressure and livedo reticularis. However the prevalence of thrombosis, strokes and hemolysis was slightly higher in the aPL+ patients. The levels of antinuclear antibodies or anti-DNA antibodies, immunoglobulins and complement serum levels (C3, C4) were also similar in both groups. In the aPL+ group, proteinuria was significantly higher than in aPL- cases (2.21 +/- 1.5 and 0.91 +/- 1.07 g/24 h, respectively; p = 0.029). The renal histological pattern in both series was similar. However, microthrombosis in the glomerular capillary lumens was more frequent in the aPL+ group. The evolution of renal function was less favorable in aPL+ patients when compared with aPL- patients. We conclude that the presence of aPL in patients with LN is associated with several characteristics of renal impairment which may contribute to its evolution.

Glomerular perm-selective function

The glomerular capillary wall functions as an efficient barrier that restricts the passage of plasma proteins and allows a high flow rate of filtration for plasma water and small solutes. Experimental studies have confirmed the theoretical predictions that circulating macromolecules are retained within the lumen of glomerular capillaries because of their size, shape and electrical charge [1–6]. The selective function of the glomerular capillary wall allows an almost complete restriction of large proteins and albumin while low molecular weight proteins are almost freely filtered and reabsorbed at tubular level [7, 8]. Glomerular permeability to circulating macromolecules has been extensively studied in the last few years, both by experimental studies and clinical investigations, with the aim of elucidating the mechanisms by which the glomerular membrane loses its selective function during development of most glomerular diseases. More recently additional interest in this area has been generated by the observation that the use of angiotensin converting enzyme (ACE) inhibitors in experimental models of glomerular dysfunction and in patients, beside reducing blood pressure, prevents or lessens urinary protein excretion. Experimental research in this field has focused on the mechanisms by which such pharmacological treatment can restore, at least partially, the selective function of the glomerular barrier [9–12]. The objective of this communication is to review some recent developments in experimental and clinical research on glomerular selectivity that illustrate new aspects of the glomerular charge- and size-selective function. In particular, recent studies are reviewed that indicate the distribution of restrictive sites on the glomerular basement membrane (GBM) to the filtration of albumin. Since recent evidence indicates that epithelial cells, in addition to GBM, exert a major role in determining the selective function of the glomerular capillary wall, other studies are discussed which aimed to clarify whether there was a correlation between changes in permselective function and quantification of structural changes of glomerular cells as assessed using morphometrical techniques. Observations on the filtration of test macromolecules with different configuration are also presented since they provide new insights on the efiFects of molecular configuration on the filtration of test macromolecules. Theoretical analysis of experimental results obtained with these test macromolecules has been carried out to determine membrane permeability parameters in both the normal state and in a model of glomerular injury in the rat. Both theoretical analyses are reviewed because they indicate that glomerular size-selective function is more restrictive than that estimated previously by experimental and human studies.

Dysfunction of glomerular fibrinolysis in experimental antiglomerular basement membrane antibody glomerulonephritis.

Glomerular plasminogen activator inhibitor-1 (PAI-1) steady-state mRNA and bioactivity were increased after the induction of an augmented form of antiglomerular basement membrane (GBM) antibody glomerulonephritis. PAI-1 mRNA expression was noted at 6 h, peaking at 1 day, and although falling thereafter, remained higher than that of the control group through Day 17. PAI-1 mRNA expression correlated with glomerular PAI-1 bioactivity as determined by a functional tissue type plasminogen activator (t-PA) binding assay. Glomerular PAI-1 bioactivity, not detected in controls, increased to 1.4 +/- 0.3 ng/mg of glomerular lysate at 6 h and then decreased to 0.7 +/- 0.1 ng/mg of glomerular lysate by Day 6. The mRNA of the plasminogen activators (urokinase plasminogen activator), t-PA) either remained unchanged or declined through Day 1, with a slight increase in t-PA mRNA at Day 6. Interleukin-1 beta mRNA expression was maximal at 6 h, declining by Day 3. Transforming growth factor beta 1 (TGF-beta 1) mRNA began to increase at Day 1, was maximal at Day 6, and fell only slightly by Day 17. Epidermal growth factor mRNA decreased. The increase in PAI-1 mRNA and bioactivity, possibly induced early by the interleukin-1 beta response and perhaps later by the TGF-beta 1 response, was associated with striking glomerular capillary lumen fibrin accumulations on Day 1, which decreased and appeared to recanalize as the PAI-1 mRNA and bioactivity fell. The glomerular lesion continued to have some fibrin deposits even on Day 17 and, in addition, had changes of thickened GBM, suggestive of the early stages of diffuse glomerulosclerosis. The latter had a temporal relationship with the persisting increase in TGF-beta 1 and PAI-1 mRNA levels. These observations suggest the possibility that inhibition of enzymes capable of remodeling excessive extracellular matrix production may have contributed to the thickened GBM.

Tissue-type plasminogen activator and its inhibitor in human glomerulonephritis.

We carried out an immunohistochemical study of tissue-type plasminogen activator (PA) and urokinase-type PA, and their inhibitors, PA inhibitor-1 and PA inhibitor-2, using renal biopsy specimens obtained from 86 patients with various forms of glomerulonephritis. The controls were four normal renal tissue specimens. On immunofluorescent observation, granular staining for tissue-type PA was found to be distributed along the glomerular capillary walls. The fluorescence was weak in the normal renal tissue and occasionally intense in the tissues of patients with IgA nephritis, minimal change nephrotic syndrome, and lupus nephritis. PA inhibitor-1 was abundant in the glomerular epithelial cells and scarce in the mesangial area and glomerular capillary lumens of the normal renal tissues. This was confirmed by immunoelectron microscopy using gold staining. The fluorescence of PA inhibitor-1 was weaker in some specimens of nephritic tissues than in the normal renal tissues. Urokinase-type PA and PA inhibitor-2 were negative within the glomeruli in all the specimens. In the glomerulonephritic tissues which were fibrin deposition-positive, tissue-type PA expression in the glomeruli tended to be strong. An association between fibrin deposition and PA inhibitor-1 staining was not clear. These data suggest that expression of tissue-type PA in the glomeruli increases in association with fibrin deposition.

Correlation between reduction of polymorphonuclear leucocytes in glomeruli injected with a newly developed monoclonal antineutrophil antibody and proteinuria in Masugi nephritis.

The effects of the reduction of neutrophils in glomeruli on the improvement of proteinuria and glomerular injuries were determined in the first (heterologous) phase of Masugi (nephrotoxic) nephritis. Male (6-week-old) WKA/Hkm rats were initially injected with 2.0 ml of a newly developed monoclonal antineutrophil antibody and then injected with 1.0 ml of nephrotoxins. This monoclonal anti-neutrophil antibody was found to have selectively reduced the number of neutrophils in the glomerular capillary lumen in cases of Masugi nephritis by light microscopy. Malondialdehyde (MDA) levels or superoxide dismutase (SOD) activities in renal tissues of such rats were also examined. However, there were no significant differences in the levels of proteinuria and the number of glomerular cells containing resident cells and infiltrated mononuclear cells in the first phase of Masugi nephritis with or without pretreatment with antineutrophil antibody. No significant differences were observed in the levels of MDA or SOD activities in renal tissues of Masugi nephritis with or without pretreatment with such an antibody either. It appeared that infiltration of neutrophils in the glomeruli might not be related to proteinuria and glomerular injuries in the first phase of Masugi nephritis. It was postulated that the massive proteinuria in the first phase of Masugi nephritis might be correlated with the activities of reactive oxygen species induced by the glomerular cells, i.e. glomerular resident cells and infiltrated mononuclear cells.

Abnormal Lipoprotein and Apolipoprotein Pattern in Lipoprotein Glomerulopathy

Recently, two cases of renal disease were observed in which there was an abnormal accumulation of lipids, "lipoprotein thrombi," in the glomerular capillary lumen. This disease has been designated as lipoprotein glomerulopathy. Four other cases have been diagnosed independently by renal histology in other clinical laboratories. All six patients showed proteinuria (1.6 to 10 g/d), normal lecithin-cholesterol acyltransferase (LCAT) activity, type III hyperlipoproteinemia-like lipoprotein profiles, and significantly (P less than 0.01) higher levels of plasma apolipoprotein (apo) E (greater than 10 mg/dL) compared with the control patients with hyperlipidemic nephrotic syndrome without lipoprotein thrombi and type IIb hyperlipoproteinemia without renal disease. Lipoprotein glomerulopathy is not familial type III hyperlipoproteinemia (dysbetalipoproteinemia), because apolipoprotein E3 is present. Apo E isoforms were all rare: five cases of E2/3 and one case of E4/4. These results suggest that excessive apo E is associated with apo E isoform and lipoprotein metabolic derangement in such a renal disease. Further studies are needed on the relationship between the apo E hyperlipoproteinemia and the formation of lipoprotein thrombi.

Evidence for a Pathogenic Linkage Between Glomerular Hypertrophy and Sclerosis

Primary renal disease of immunologic or nonimmunologic mechanisms induces loss of substantial nephron population. It is presumed that the initial loss of functioning nephrons causes alterations of function and metabolism in remnant nephrons, which per se are self-inflictive, leading to further loss of nephrons. The ultimate outcome of this vicious cycle is the end-stage kidney. The potential role of various pathophysiologic mechanisms has been explored. These studies have shown a tight link between glomerular hypertrophy and sclerosis. Analysis of individual glomeruli show a biphasic pattern of these two parameters. Early development of glomerular sclerosis takes place along with the hypertrophy of the glomerulus, and further advancement of sclerosis occurs with shrinkage in glomerular size. Thus, we propose that, after initial nephron loss, the remnant glomeruli are exposed to increased growth-promoting factors, which are self-inflictive in nature due to their capacity to produce excessive amounts of extracellular matrix in the mesangial area. When the excessive matrix obliterates the glomerular capillary lumen, a typical sclerotic lesion appears. This is a vicious and accelerating process, since sclerosis induces further reduction in the nephron population, thereby imposing greater influence of growth-promoting factors even on glomeruli that are initially resistant.

Interdigitating reticulum cells in human renal grafts

Seventeen human renal graft biopsies taken 1 h to 50 days after transplantation and 3 human renal non-graft biopsies (2 minimal change and 1 non-tumour portion of angiomyolipoma) were investigated with immunoelectron microscopy in order to identify interdigitating reticulum cells (IDC) or dendritic cells (DC) in renal tissues. The antibodies used consisted of a rabbit polyclonal antibody of antihuman S100 beta protein, mouse monoclonal antibodies of antihuman HLA-DR, anti-CD3, and anti-CD1a. IDC or DC were identified in 11 renal grafts. They were found both in the glomerular and interstitial (peritubular) capillary lumens but not in the interstitium of 1 case: both were present in the interstitial capillary lumens and interstitium of another case, and in the interstitium only of 9 cases. In the remaining 6 grafts and 3 non-grafts they were not detected. These 6 grafts and 3 non-grafts did not show any pathological change except for foot process fusion of the glomerular epithelia in 2 cases of minimal change. These findings suggest that IDC or DC are not normally present in human renal tissues. The presence of the cell in the glomerular and peritubular capillary lumens of a biopsy taken after 1 h and their presence in the interstitial capillary lumens of another graft biopsy, suggest that the IDC or DC in human renal grafts are derived from recipients, not donors, and that they migrate from the circulating blood toward the interstitium.