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We report a 42-year-old woman who presents a few days after a spontaneous incomplete abortion at the ninth week of pregnancy with hypertension and nephrotic syndrome. Curettage findings and increased values for the β subunit of human chorionic gonadotrophin were suspicious for a trophoblastic disease. A uterine placental site trophoblastic tumor was diagnosed 2 months later after hysterectomy and treated successfully using chemotherapy. Kidney biopsy showed features consistent with an unusual form of thrombotic microangiopathy characterized by the presence of large thrombus-like structures occluding the capillary lumina and smaller aggregates in the mesangium and along glomerular basement membranes. These deposits were positive for immunoglobulin M, C4, C1q, κ and λ light chains, and fibrinogen. Electron microscopy showed fibrin deposits located primarily in the subendothelial space. The differential diagnosis of this presentation included pre-eclamptic nephropathy, Waldenström disease, lupus anticoagulant glomerulonephritis, systemic lupus erythematosus, and cryoglobulinemic glomerulonephritis. We review the pathogenic mechanisms involved in this case., (Copyright © 2011 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

The development of proteinuria has been observed in kidney-transplanted patients on m-TOR inhibitor (m-TORi) treatment. Recent studies suggest that m-TORi(s) may alter the behavior and integrity of glomerular podocytes. We analyzed renal biopsies from kidney-transplanted patients and evaluated the expression of nephrin, a critical component of the glomerular slit-diaphragm. In a group of patients on 'de novo' m-TORi-treatment, the expression of nephrin within glomeruli was significantly reduced in all cases compared to pretransplant donor biopsies. Biopsies from control transplant patients not treated with m-TORi(s) failed to present a loss of nephrin. In a group of patients subsequently converted to m-TORi-treatment, a protocol biopsy performed before introduction of m-TORi was also available. The expression of nephrin in the pre-m-TORi biopsies was similar to that observed in the pretransplant donor biopsies but was significantly reduced after introduction of m-TORi(s). Proteinuria increased after the m-TORi inititiation in this group. However, in some cases proteinuria remained normal despite reduction of nephrin. In vitro, sirolimus downregulated nephrin expression by human podocytes. Our results suggest that m-TORi(s) may affect nephrin expression in kidney-transplanted patients, consistently with the observation in vitro on cultured podocytes., (© 2010 The Authors Journal compilation © 2010 The American Society of Transplantation and the American Society of Transplant Surgeons.)

The most common immunological causes of delayed renal function failure in kidney grafts are recurrent glomerular disease, de novo glomerulonephritis, and chronic cellular or antibody-mediated rejection. Glomerulonephritis can recur any time in the natural history of renal allografts, with the same morphological features of the disease occurring in the native kidney. It has a frequency varying from 100% to 1% and a generally favorable prognosis with the exception of FSGS, SHU and diabetic glomerulosclerosis. The most frequent glomerular diseases to occur de novo in the kidney graft are membranous glomerulopathy, antiglomerular basement membrane disease in patients with Alport's syndrome, and nephrotic syndrome of the Finnish type with antinephrin antibodies in patients with NPHS1 gene mutations. Chronic rejection, including chronic transplant arteriopathy and chronic transplant glomerulopathy, is the cause of renal failure in up to 20% of kidney grafts and may occur as early as a few months after transplant.

Background: Although several studies have dealt with clinicopathological correlations in diabetic glomerulosclerosis (DGS), few have investigated the prognostic value of the renal biopsy., Methods: One hundred and thirty-five type2 diabetes mellitus (DM) patients with bioptically proven DGS and a mean follow-up of 56.1 months were subdivided in 5 groups according to the outcome: 1) living with preserved renal function; 2) living with renal failure, not requiring dialysis; 3) living in dialysis; 4) dead in dialysis; 5) dead with preserved renal function. Duration of DM, creatininemia and proteinuria values at the time of biopsy and a histologic scoring (from 0 to 3) of 10 morphologic features were considered for statistical analysis., Results: Statistically significant differences were observed in the distribution of the above mentioned parameters in the 5 groups with the exception of the duration of DM. The prognosis of DGS is poor: 79 patients needed dialysis and 60 died. Univariate analysis demonstrated the prognostic value of creatininemia (>or= 1.5 mg/dL), proteinuria (>or= 3 g/d) and histologic score (>or= 10) in assessing the relative risk of progression to dialysis (OR= 9.75, 4.12 and 11 respectively). The prognostic value of the histologic score (or= 2) was maintained when each morphologic parameter was separately evaluated (OR ranging from 2.8 to 8.5). Multivariate analysis was applied and only serum creatinine and histological score maintained their statistical significance (OR=4.45 and 2.46). The independence of these two variables means that the risk of progression to dialysis is multiplied in each single patient., Conclusions: Renal biopsy adds reliable information to that supplied by clinical and laboratory findings in DGS and therefore its extensive adoption should be recommended. Thanks to the prognostic value of the single morphologic parameters, also small tissue samples can give reliable results.

Electron microscopy defined classic patterns of hereditary glomerular disease long before genetics revealed an underlying specific mutation. Genetic analysis is now easier to perform in clinical practice but an earlier optimism that genetics would predict disease severity and phenotype is challenged. The classic paradigm is Alport nephritis in which only a subset of mutations may predict glomerular abnormalities and disease severity. Interpretation of ultrastructural pathology of monogenetic diseases like Alport nephritis is complicated when the proband is the first family member to be diagnosed or there is discrepancy between clinical presentation and ultrastructural changes. In this review the authors have selected a dozen cases representative of common monogenetic glomerular diseases as a platform to discuss the utility of diagnostic electron microscopy in the era of molecular genetics. The emphasis is on genotype/glomerular phenotype correlations.

Although there has been extensive research into the mechanisms involved in glomerular crescent formation, it is not yet fully understood how this change may cause renal function impairment. The aim of this study is to identify morphologic changes which may be responsible for this phenomenon. Thirty-eight renal biopsies showing glomerulonephritis with extracapillary proliferation (20 vasculitis-related, 6 idiopathic, 9 due to immune-complex deposition and 3 superimposed on diabetic nephropathy) were considered, and 146 glomeruli in which both crescents and the urinary pole were found at the same time, were studied. The involvement of the urinary pole by cellular crescents was observed in 93.1 and 100% of the glomeruli with segmental or circumferential crescents, respectively. A tridimensional study, for the evaluation of the glomeruli as a whole, was performed on 8 biopsies by means of the step-section technique and disclosed the involvement of the urinary space and a close contact between crescent and tubular cells in all 54 investigated glomeruli. The reported features do not seem to be related to the type of cells which formed the crescent. Indeed, as shown by immunohistochemical study on 10 cases with anti-cytokeratin and anti-CD68 antisera, the crescent localization at the urinary pole had no correlation with the prevalence of epithelial or macrophagic cells. These findings suggest that crescents, due to epithelial proliferation or macrophage clustering, tend to localize at the urinary pole and thus come into close contact with cells of the proximal convoluted tubule: the formation of a sort of plug or a 'glomerular stone' could well explain the block in the urine flow and the consequent impairment of renal function in the acute phase of the disease, even in those cases where crescents are segmental., (Copyright 2002 S. Karger AG, Basel)

Background: In Alport syndrome (AS) impaired production and/or assembly of col IV alpha-chain isoforms results in abnormal structure of glomerular basement membrane (GBM), haematuria and, frequently, progressive renal disease. We investigated the relationship between col IV alpha-chains expression and morphology of GBM, as a possible key to the better understanding of the pathogenesis of renal disease in AS., Methods: GBM distribution of col IV alpha1-, alpha3-, and alpha5-chain was investigated by immunohistochemistry in 32 patients (21 males and 11 females, mean age at biopsy of 11.5 years) with ultrastructural findings suggestive of AS. Ten patients had a proven COL4A5 mutation. Based on the severity of ultrastructural findings, the biopsies were grouped in three (I-III) electron microscopy (EM) classes. Significant EM changes of GBM (thinning, thickening, splitting, basket weaving of the lamina densa) were singularly evaluated using a semiquantitative scale (0-3)., Results: Col IV alpha1-chain was demonstrated in GBM of all patients. Three patterns of staining for col IValpha3- and alpha5-chains were observed: positive, negative, and alpha3(IV)-positive/alpha5(IV)-negative. By chi(2)-test, EM class III lesions and complete loss of alpha3(IV)- and alpha5(IV)-antigen were significantly more frequent (P<0.05 and P<0.01) in male patients, but no significant relation was observed between EM classes and immunohistochemical patterns. GBM alterations did not correlate with staining for alpha5(IV)-chain. Intensity of alpha3(IV)-chain staining, however, had a negative correlation (P<0.05) with the severity of GBM basket weaving., Conclusions: Our results suggest that the alpha3(IV)-chain-containing col IV-network plays a fundamental role in structural and, possibly, functional organization of GBM. Absence of alpha3(IV)-chain in GBM could indicate a more severe renal disease in AS.

Renal biopsy specimens from 26 adult human immunodeficiency virus (HIV)-infected patients with glomerular involvement were reviewed from the files of three hospital pathology services in Northern Italy. All the patients were Italian and most (19 of 26 patients) were intravenous drug addicts. The types of glomerular lesions were as follows: minimal-change glomerulopathy (two cases), mesangial proliferative glomerulonephritis (GN) with scanty immunoglobulin deposits (four cases), and various patterns of immune complex-mediated glomerulonephritis, including postinfectious GN (six cases), membranoproliferative GN (one case), membranous GN (three cases), immunoglobulin (Ig) A nephropathy (four cases), a mixed membranous and proliferative (three cases) and diffuse proliferative lupus-like pattern with subendothelial deposits, and intraluminal thrombi (two cases) or subepithelial and subendothelial deposits (one case). None of the patients had evidence of HIV-associated nephropathy. Our study confirms previous observations on the low incidence of HIV-associated nephropathy among white HIV-infected patients in Europe, where immune complex-mediated GN seems to predominate. Apart from the frequent electron microscopic observation of endothelial tubuloreticular structures, none of the reported lesions could be distinguished on morphologic grounds from those occurring in uninfected patients. The high variability of the glomerular lesions upholds the need for accurate diagnosis for the clinician confronted with an HIV-positive patient with suspected glomerular involvement.

Immunotactoid glomerulopathy is characterized by the ultrastructural finding of fibrillary or microtubular deposits in patients without systemic diseases such as SLE, diabetes, paraproteinemias, cryoglobulinemia, or amyloidosis. These deposits correspond in most (but not all) cases to immunoglobulin and complement deposits as shown by immunohistochemical techniques. Different light microscopic patterns (mesangioproliferative, membranous, membranoproliferative, and crescentic) have been reported. Clinical presenting feature is characterized by proteinuria (often of nephrotic range), hematuria, and hypertension in most cases. Chronic renal failure requiring hemodialysis or transplantation is described in more than half the patients. Pathogenesis has not yet been elucidated and only some speculative hypotheses have so far been suggested. At present there is no clear evidence that we are dealing with a new pathologic entity, but larger series must be collected and studied in order to find a correct taxonomic collocation of this glomerulopathy.

A double glomerulopathy (IgA glomerulonephritis [IgAGN] associated with thin glomerular basement membrane disease [TGBMD]) is reported in a 39-year-old woman presenting with macroscopic-microscopic hematuria. Her 3-year-old daughter was also affected by microhematuria of probable glomerular origin. The diagnosis of IgAGN was made by means of immunofluorescence investigation, which showed generalized diffuse mesangial deposits. TGBMD was identified by electron microscopic investigations, which disclosed thinning (up to 160 nm) of basement membrane of several capillary loops and prominence of the lamina densa. Bearing in mind the known frequencies of the two glomerulopathies, their association may not be coincidental, and, therefore, is worthwhile researching in hematuric patients.

We report a case with IgG-kappa monoclonal gammopathy of unidentified significance (MGUS) and glomerulonephritis (GN) with organized microtubular deposits on electron microscopy (EM). Light microscopy (LM) examination showed exudative features and moderate extracapillary proliferation. An acute nephritic syndrome with a rapidly progressive renal failure was clinically manifest at the onset and during each relapse. The patient was treated with methylprednisolone pulses followed by oral prednisone, cyclophosphamide, plasmapheresis, and maintenance courses of chemotherapy. The response to treatment was good, with a temporary improvement of renal function and control of the downhill course over a 3-year follow-up.

The present report describes ultrastructural findings on twenty-three cases of CRYGN showing membranoproliferative pattern under light microscopy. Attention was paid to the presence of double contoured peripheral basement membranes and to the characteristics of the interposed cells. The latter, according to the well known characteristics of membranoproliferative GN, are thought to be mesangial in nature. In fact, mesangial cells were found in 8 cases only, always associated with monocytes. Only monocytes were recorded in 12 cases, whereas in other 3 cases double contours were not connected to cell interposition. Despite similarities under light microscopy, CRYGN is therefore rather different from idiopathic membranoproliferative GN because of the prevalence of exudative changes, mainly due to monocyte infiltration, over proliferative lesions.

Eleven cases of glomerulonephritis with dense deposits were selected on the basis of electron microscopic examination performed either on material treated according to conventional techniques (9 cases) or on previously paraffin-embedded material (2 cases). While uniform immunohistochemical patterns were observed, different features were shown by light microscopy: in only 3 cases were membranoproliferative or lobular patterns present, while in the others a varying degree of mesangial cell proliferation (moderate, mild or even very scanty with focal and segmental distribution) was detected. The generally accepted statement that glomerulonephritis with dense deposits represents a subgroup of membranoproliferative glomerulonephritis therefore seems questionable. In addition to several clinical and serological data, these morphological features give further support to the hypothesis that glomerulonephritis with dense deposits in all respects a peculiar and distinct form of glomerulonephritis.

Glomerular monocyte infiltration was searched for using staining for nonspecific esterase and/or electron microscopy in 28 patients with acute glomerulonephritis submitted to biopsy at different intervals from the beginning of the disease. Significant monocyte infiltration was detected in 12 cases displaying prominent intracapillary hypercellularity and granulocyte exudation. All cases but one were submitted to biopsy in the first 6 weeks of the disease. Negative cases, submitted to biopsy in the same period or in the later phases of the disease, displayed more or less evident mesangial hypercellularity as the prevailing feature. Most positive cases showed glomerular deposits of IgG. Phagocytosis of IgG by mononuclear cells was investigated in all cases positive for monocytes and in 10 negative ones, using an immunofluorescence technique on paraffin-embedded material. Only in the former group were a few or scanty IgG-phagocytosing monocytes detected in six cases. Our results only partially confirm the role of monocytes in causing glomerular hypercellularity in human acute glomerulonephritis. In fact, the relevance of this phenomenon appears much less important than in several well-known experimental models and in some cases of human chronic glomerulonephritis. Moreover, macrophage infiltration is present in cases with greater immunologic involvement and tends to decline with time. Therefore, it seems that, in human acute glomerulonephritis, glomerular hypercellularity results mainly from intrinsic cell proliferation.

Thirty-three renal biopsies of patients affected by cryoglobulinemic glomerulonephritis (CRYGN) were investigated by electron microscopy, paying particular attention to the nature of cells responsible of glomerular hypercellularity, the presence and site of electron-dense deposits and their ultrastructural characteristics. Personal as well as literature data suggest (a) diffuse glomerular hypercellularity found in most cases of CRYGN is mainly due to polymorphonuclear leukocytes and even more to monocyte exudation; (b) the interposition of the latter cell type in the glomerular capillary wall is the main responsible cause of the frequent occurrence of the membranoproliferative pattern in CRYGN, and (c) peculiar structures found in the electron dense deposits are characteristic of CRYGN and related to cryoglobulin composition. Electron microscopy therefore seems to be a valuable diagnostic procedure for this type of glomerulonephritis.

Synthetic polycations have been shown to bind and neutralize glomerular polyanions (GPA), thereby increasing the permeability of the glomerular capillary wall (GCW). In the present study it is demonstrated that human platelet-derived cationic proteins (HuPlt CP), which are able to increase cutaneous vascular permeability, bind in vitro to the GCW following incubation of normal human kidney sections with purified HuPlt CP or with washed human platelets stimulated with thrombin, immune complexes (IC) and platelet-activating factor (PAF), or stimulated with a suspension of washed human platelets and polymorphonuclear leukocytes in the presence of phagocytable substrate. The antiserum used in immunofluorescence test to detect the binding of HuPlt CP was specific for two different molecular types of HuPlt CP, both with an isoelectric point (pI) of 10.5. Glomerular deposits of HuPlt CP were also detectable by immunofluorescence microscopy in renal glomeruli present in tissue obtained by biopsy from patients with systemic lupus erythematosus (SLE), a disease in which platelets have been implicated as mediator of glomerular injury. These data indicate that when activated platelets release HuPlt CP in vivo, these proteins bind to glomerular structures. The binding of HuPlt CP to GCW appears to be ionic in nature since heparin, a polyanion, prevents this binding in vitro. In addition, heparin, as well as a high molarity buffer, removed deposits of HuPlt CP bound in vitro to normal GCW or bound in vivo to glomeruli of patients with SLE. The binding of HuPlt CP to GCW is associated with loss of colloidal iron staining, a qualitative technique that demonstrates primarily epithelial cell surface anionic sialoglycoproteins. In experiments of in vitro binding of purified HuPlt CP to section of normal kidney treatment with heparin completely restores the normal pattern of colloidal iron staining suggesting ionic neutralization of GPA. In contrast, heparin is only partially effective in restoring colloidal iron staining in normal kidney sections treated with platelets directly stimulated with IC or PAF or in kidney sections of patients with SLE. These observations indicate that under these conditions the ionic interaction of HuPlt CP with GCW is only partially responsible for the loss of colloidal iron staining. The results of the present study suggest that biologically active polycationic mediators released from stimulated platelets localize in GCW and participate in the induction of glomerular injury.

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.

A case of immune-complex glomerulonephritis with membrano-proliferative patterns in a patient with mixed IgG-IgM cryoglobulinemia has been investigated; particular attention has been payed to histological immunofluorescence, histochemical and electron microscopical findings in order to elucidate the nature of the intraluminal thrombi. The so called thrombi, strongly positive for IgG and IgM with the immunofluorescence, appeared to be clusters of mononuclear cells which, for their ultrastructural and histochemical (non-specific esterase activity) patterns have been considered as monocytes. They showed cytoplasmic vacuoles containing microtubular structures; the latter have been detected free in the capillary lumina and in the basement membranes as well. These structures have been considered as the ultrastructural counterpart of the IgG-IgM immune-complexes responsible of the nephropathy. Monocytes have been hypothesized to play a pathogenetical role, acting as cleaners of the cryoprecipitate from the capillary lumina.

A focal discontinuity of glomerular basement membrane (GBM) with extravasation of a monocyte is described in a case of acute postinfectious glomerulonephritis in a 2-year-old girl. It is proposed that also monocytes could play a role in causing disruption of glomerular capillary wall. Moreover, this finding gives morphologic support to the hypothesis that monocyte-forming crescents reach the urinary space through GBM gaps.

Glomerular monocyte infiltration was evaluated by histochemical means (nonspecific esterase) and/or electron microscopy in 305 renal biopsies belonging to a wide variety of human renal diseases. Significant monocyte infiltration was never observed in a first group of nepropathies (minimal change disease, nephrotic syndrome with IgM deposits, focal segmental glomerulosclerosis, membranous GN, Berger's GN, healed GN, dense deposit disease, chronic non specific GN, benign familial haematuria, Alport's disease, renal amyloidosis, arteriosclerotic kidney, light chain GN). Conversely, it was present at varying frequency in a second group of nephropathies including: acute GN (58.3%), persistent GN (10%), membranoproliferative GN (25.2%), eryoglobulinaemic GN (82.6%), lupus GN (36%), extracapillary proliferative GN (50%) and Schoenlein-Henoch GN (40%). The results indicate: 1) there is an evident association between monocyte infiltration and the subendothelial site of deposits; 2) the presence of monocytes is not affected by the size and extension of subendothelial deposits; 3) monocytes were more frequently observed when IgG, IgM and fibrinogen were present in the subendothelial deposits, Conversely, complement fractions do not seem to affect monocytic activity; 4) polymorphonuclear leukocyte exudation is less frequently found and mostly associated with monocyte infiltration; 5) in some GNs (persistent GN, cryoglobulinaemic GN and membranoproliferative GN), proteinuria was significantly higher in patients with than in those without monocyte infiltration, giving support to the hypothesis that in human beings as in experimental animals monocytes play a role in the pathogenesis of proteinuria.

The potentialities of electron microscopy in detecting monocytes in human glomeruli are discussed and its reliability is compared with that of other techniques (such as enzyme histochemistry and immunohistochemistry) having the same purposes. The major advantages of electron microscopy are: the same material can be used for both monocyte detection and conventional diagnostic purposes; its high resolution power allows for information on the site of monocyte infiltration and clarification of some functions of the latter (such as the phagocytic activity on immune complexes or their participation to the basement membrane damage). Nevertheless, the suggested technique also has some disadvantages, in particular it permits to investigate only a small number of glomeruli and it creates difficulties in the identification of nonstimulated monocytes.