Proliferative Forms Of Glomerulonephritis Research Articles

Glomerular endothelial glycocalyx-derived heparan sulfate inhibits glomerular leukocyte influx and attenuates experimental glomerulonephritis.

Proliferative forms of glomerulonephritis are characterized by the influx of leukocytes, albuminuria, and loss of kidney function. The glomerular endothelial glycocalyx is a thick carbohydrate layer that covers the endothelium and is comprised of heparan sulfate (HS), which plays a pivotal role in glomerular inflammation by facilitating endothelial-leukocyte trafficking. We hypothesize that the exogenous glomerular glycocalyx may reduce the glomerular influx of inflammatory cells during glomerulonephritis. Indeed, administration of mouse glomerular endothelial cell (mGEnC)-derived glycocalyx constituents, or the low-molecular-weight heparin enoxaparin, reduced proteinuria in mice with experimental glomerulonephritis. Glomerular influx of granulocytes and macrophages, as well as glomerular fibrin deposition, was reduced by the administration of mGEnC-derived glycocalyx constituents, thereby explaining the improved clinical outcome. HSglx also inhibited granulocyte adhesion to human glomerular endothelial cells in vitro. Notably, a specific HSglx fraction inhibited both CD11b and L-selectin binding to activated mGEnCs. Mass spectrometry analysis of this specific fraction revealed six HS oligosaccharides, ranging from tetra- to hexasaccharides with 2-7 sulfates. In summary, we demonstrate that exogenous HSglx reduces albuminuria during glomerulonephritis, which is possibly mediated via multiple mechanisms. Our results justify the further development of structurally defined HS-based therapeutics for patients with (acute) inflammatory glomerular diseases, which may be applicable to non-renal inflammatory diseases as well.

Corticosteroid therapy alone for the treatment of C3 glomerulonephritis in association with monoclonal gammopathy .

C3 glomerulonephritis (C3GN) is a form of proliferative glomerulonephritis characterized by dominant glomerular C3 deposition. There is currently no consensus guideline on therapy for this disease. Experience with corticosteroids alone is scant in C3GN. We report the experience of treating patients with C3GN in association with monoclonal gammopathy with corticosteroid at a single center. Corticosteroid therapy alone was used to treat 6 patients with C3GN who were also found to have monoclonal gammopathy at the time of presentation. Median age of this cohort was 65 years. Median estimated glomerular filtration rate (eGFR) by MDRD equation was 31.6 mL/min/1.73m2 at presentation. After a median duration of follow-up of 23.5 months, all patients showed improvement in proteinuria: median proteinuria reduced from 2.3 to 0.5 g/d. Four of 6 patients showed improvement in kidney function. One patient who had required renal replacement therapy recovered renal function. Median eGFR at follow-up was 38.7 mL/min/1.73m2. In patients with C3GN in association with monoclonal gammopathy, corticosteroid therapy alone may be a viable treatment option. Work-up should be done to exclude a hematologic neoplasm and inherited complement abnormalities before proceeding to corticosteroid therapy. .

PECULIARITIES OF CYTOKINES AND THEIR PROGNOSTIC VALUE IN PATIENTS WITH CHRONIC GLOMERULONEPHRITIS

Introduction. Cytokines are important to take part in immunogenesis and progression of glomerulonephritis (GN), therefore the analysis of these indices in dependence of type of GN forms as prognosys results of treatment.
 Aim of the work is to determine the peculiarities of pro-inflammatory cytokines (TNFα, MCP-1, IL-17, -18, -23) and anti-inflammatory TGF- β1 and their association with form GN with nephritic syndrome (NS) and possibility use cytokines as prognostic markers.
 Materials and methods. Using IFA, the level of the above mentioned cytokines was studied in the blood serum of 117 patients with proliferative (33) and non-proliferative (84) CGN, NS forms. There was also analyzed the changes of these indices in the patients with subsequent clinical laboratory remission (59) and patients without one (58).
 Results. The GN, NS patients showed statistically higher level of the pro- inflammatory cytokines – TNFα, MCP-1, IL-17 (with more high indices last one in the proliferative forms of GN, and IL-17 in nonsensitive to immunotherapy patients). High level profibrogenic TGFβ, and the ratio TNFα /TGFβ reflect the prevalence of anti-inflammatory reactions and high activity of monocytes - macrophages and T-helpers17. The positive effect of the treatment associates with the statistically decreased TNFα, MCP-1 and TGFβ1 levels in the patients with proliferative forms GN; the TGFβ1 - for patients with non-proliferative GN forms.
 Conclusion. The changes cytokine profiles may be use as predictors of results the immunosuppressive therapy.

Urine Macrophage Migration Inhibitory Factor Reflects the Severity of Renal Injury in Human Glomerulonephritis

ABSTRACT. Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine that plays a pathogenic role in experimental crescentic glomerulonephritis (GN). Renal expression of MIF is also upregulated in human GN and correlates with leukocytic infiltration, histologic damage, and renal dysfunction. The study presented here examined whether MIF can be measured in urine and if so, whether the urine MIF concentration reflects the degree of renal injury. Urine and serum MIF was measured by enzyme-linked immunosorbent assay in 10 normal healthy volunteers and in a cohort of 63 patients with GN (2 thin basement membrane disease [TBM], 15 membranous GN, 10 focal segmental glomerular sclerosis, 20 IgA glomerularnephritis, 11 crescentic GN, 10 systemic lupus erythematosis World Health Organization class IV). Renal MIF expression was assessed by immunostaining of biopsy tissue. MIF was detected in urine from normal volunteers (mean ± SD; 191 ± 132 pg MIF/μmol creatinine). The urine MIF concentration was unchanged in patients with nonproliferative nephropathies (343 ± 397 pg MIF/μmol Cr) but was increased 3.4-fold in proliferative nephropathies (645 ± 527 pg MIF/μmol Cr; P < 0.05 versus normal and nonproliferative). Stratified analysis showed the greatest increase in urine MIF in crescentic GN (4.5-fold). In contrast, serum MIF levels were not different between normal patients and any patient group. Immunostaining demonstrated a significant increase in renal MIF expression in proliferative glomerulonephritides that was associated with macrophage and T cell infiltration. There was a significant correlation between the urine MIF concentration and renal MIF expression, but not with serum MIF, indicating a renal origin for the excreted urine MIF. The urine MIF concentration also correlated with the degree of renal dysfunction, histologic damage, and leukocytic infiltration, but not with the amount of proteinuria. In conclusion, this study shows that the urine MIF concentration is significantly increased in proliferative forms of GN and correlates with the degree of renal injury. Urine MIF levels reflect MIF expression within the kidney and may be a useful noninvasive tool for monitoring patients with crescentic GN, particularly in disease exacerbation.

Local macrophage proliferation correlates with increased renal M‐CSF expression in human glomerulonephritis

Macrophage accumulation is a prominent feature in many forms of glomerulonephritis. Local proliferation of macrophages within the kidney has been described in human and experimental glomerulonephritis and may have an important role in augmenting the inflammatory response. The current study examined the relationship between local macrophage proliferation and renal expression of macrophage colony-stimulating factor (M-CSF). A total of 118 renal biopsies of patients with a wide range of glomerulonephridities were examined for M-CSF protein and macrophage proliferation (KP1+PCNA+cells) by single and double immunohistochemistry staining, respectively. Biopsies of thin membrane disease (TMD) with histologically normal kidney showed M-CSF protein expression by 33% of cortical tubules, while glomerular M-CSF expression was limited to resident macrophages and some podocytes. Glomerular M-CSF expression increased significantly in proliferative forms of glomerulonephritis, with M-CSF staining of infiltrating macrophages, podocytes and some mesangial cells. Segmental areas of strong M-CSF expression, particularly in crescents, co-localized with KP1+PCNA+ proliferating macrophages. There was also an increase in tubular M-CSF expression in most types of glomerulonephritis. Tubular M-CSF staining was strongest in areas of tubular damage and co-localized with KP1+ macrophages, including KP1+PCNA+ proliferating macrophages. Many interstitial macrophages and alpha-smooth muscle actin-positive myofibroblasts showed strong M-CSF staining. Statistical analysis showed a highly significant correlation between M-CSF expression and local macrophage proliferation in both the glomerulus and tubulointerstitium. Glomerular and tubular M-CSF expression gave a significant correlation with renal dysfunction. Glomerular and tubulointerstitial M-CSF expression is up-regulated in human glomerulonephritis, being most prominent in proliferative forms of disease. This correlated with local macrophage proliferation, suggesting that increased renal M-CSF production plays an important role in regulating local macrophage proliferation in human glomerulonephritis.

Expression of macrophage migration inhibitory factor in human glomerulonephritis

We have recently demonstrated that macrophage migration inhibitory factor (MIF) plays a pathogenic role in experimental glomerulonephritis (GN). The aim of the current study was to investigate MIF expression in human GN. MIF expression was examined by in situ hybridization and immunohistochemistry staining in 65 biopsies from a variety of glomerulonephridities. There is constitutive expression of MIF mRNA and protein in normal human kidney that is largely restricted to tubular epithelial cells and to some glomerular epithelial cells. There was little change in the pattern of MIF expression in nonproliferative forms of GN such as minimal change disease and membranous GN. However, there was a marked increase in both glomerular and tubular MIF expression in proliferative forms of GN, including focal segmental glomerulosclerosis (FGS), lupus nephritis, crescentic GN, and mesangiocapillary proliferative GN. The prominent macrophage and T-cell infiltrate in these diseases were largely restricted to areas with marked up-regulation of MIF expression, contributing to glomerular hypercellularity, glomerular focal segmental lesions, crescent formation, tubulitis, and granulomatous lesions. De novo MIF expression was evident in glomerular endothelial cells and mesangial cells in proliferative forms of GN. In addition, many infiltrating macrophages and T cells showed MIF mRNA and protein expression. Quantitative analysis found that increased glomerular and tubular MIF expression gave a highly significant correlation with macrophage and T-cell accumulation, the severity of histologic lesions, and the loss of creatinine clearance. Renal MIF expression is markedly up-regulated in proliferative forms of human GN, and this correlates with leukocyte infiltration, histologic damage, and renal function impairment. These results suggest that MIF may be an important mediator of renal injury in progressive forms of human GN. Based on these findings, together with the known pathogenic role of MIF in experimental GN, we propose that MIF is an attractive therapeutic target in the treatment of progressive forms of GN.

Expression of macrophage migration inhibitory factor in human glomerulonephritis

Expression of macrophage migration inhibitory factor in human glomerulonephritis.BacκoundWe have recently demonstrated that macrophage migration inhibitory factor (MIF) plays a pathogenic role in experimental glomerulonephritis (GN). The aim of the current study was to investigate MIF expression in human GN.MethodsMIF expression was examined by in situ hybridization and immunohistochemistry staining in 65 biopsies from a variety of glomerulonephridities.ResultsThere is constitutive expression of MIF mRNA and protein in normal human kidney that is largely restricted to tubular epithelial cells and to some glomerular epithelial cells. There was little change in the pattern of MIF expression in nonproliferative forms of GN such as minimal change disease and membranous GN. However, there was a marked increase in both glomerular and tubular MIF expression in proliferative forms of GN, including focal segmental glomerulosclerosis (FGS), lupus nephritis, crescentic GN, and mesangiocapillary proliferative GN. The prominent macrophage and T-cell infiltrate in these diseases were largely restricted to areas with marked up-regulation of MIF expression, contributing to glomerular hypercellularity, glomerular focal segmental lesions, crescent formation, tubulitis, and granulomatous lesions. De novo MIF expression was evident in glomerular endothelial cells and mesangial cells in proliferative forms of GN. In addition, many infiltrating macrophages and T cells showed MIF mRNA and protein expression. Quantitative analysis found that increased glomerular and tubular MIF expression gave a highly significant correlation with macrophage and T-cell accumulation, the severity of histologic lesions, and the loss of creatinine clearance.ConclusionsRenal MIF expression is markedly up-regulated in proliferative forms of human GN, and this correlates with leukocyte infiltration, histologic damage, and renal function impairment. These results suggest that MIF may be an important mediator of renal injury in progressive forms of human GN. Based on these findings, together with the known pathogenic role of MIF in experimental GN, we propose that MIF is an attractive therapeutic target in the treatment of progressive forms of GN. Expression of macrophage migration inhibitory factor in human glomerulonephritis. We have recently demonstrated that macrophage migration inhibitory factor (MIF) plays a pathogenic role in experimental glomerulonephritis (GN). The aim of the current study was to investigate MIF expression in human GN. MIF expression was examined by in situ hybridization and immunohistochemistry staining in 65 biopsies from a variety of glomerulonephridities. There is constitutive expression of MIF mRNA and protein in normal human kidney that is largely restricted to tubular epithelial cells and to some glomerular epithelial cells. There was little change in the pattern of MIF expression in nonproliferative forms of GN such as minimal change disease and membranous GN. However, there was a marked increase in both glomerular and tubular MIF expression in proliferative forms of GN, including focal segmental glomerulosclerosis (FGS), lupus nephritis, crescentic GN, and mesangiocapillary proliferative GN. The prominent macrophage and T-cell infiltrate in these diseases were largely restricted to areas with marked up-regulation of MIF expression, contributing to glomerular hypercellularity, glomerular focal segmental lesions, crescent formation, tubulitis, and granulomatous lesions. De novo MIF expression was evident in glomerular endothelial cells and mesangial cells in proliferative forms of GN. In addition, many infiltrating macrophages and T cells showed MIF mRNA and protein expression. Quantitative analysis found that increased glomerular and tubular MIF expression gave a highly significant correlation with macrophage and T-cell accumulation, the severity of histologic lesions, and the loss of creatinine clearance. Renal MIF expression is markedly up-regulated in proliferative forms of human GN, and this correlates with leukocyte infiltration, histologic damage, and renal function impairment. These results suggest that MIF may be an important mediator of renal injury in progressive forms of human GN. Based on these findings, together with the known pathogenic role of MIF in experimental GN, we propose that MIF is an attractive therapeutic target in the treatment of progressive forms of GN.

Immunosuppressive effect of deoxyspergualin in proliferative glomerulonephritis.

A clinical trial of the immunosuppressive drug deoxyspergualin (DSG) was conducted in five patients with various forms of proliferative glomerulonephritis (immunoglobulin A nephropathy in two patients, purpura nephritis in one patient, membranoproliferative glomerulonephritis in one patient, and rapidly progressive glomerulonephritis in one patient). DSG was intravenously administered at 0.25 or 0.5 mg/kg/d for 4 weeks. A marked decrease in proteinuria (to <50% of baseline) was observed in four patients, and the other patient showed a 38% reduction in proteinuria, but the proteinuria was exacerbated again after discontinuation of DSG in three patients during a 4-week follow-up period. Proinflammatory CD16(+) (FcgammaRIII) monocytes disappeared from the peripheral blood during the administration of DSG but reappeared after DSG treatment was discontinued. A significant decrease in urinary macrophage counts that was far more marked than the decrease in peripheral blood monocyte counts was observed after administration of DSG. Interestingly, we also observed that the CD16 marker on the CD14(+) macrophage population in the urine disappeared in response to DSG treatment. These findings suggest that DSG may have a unique effect of suppression of FcgammaRIII expression on monocytes and/or macrophages that may result in amelioration of activated macrophage-mediated glomerulonephritis.

Neutrophils in IgA nephropathy

Summary: Neutrophil participation is prominent in proliferative forms of glomerulonephritis. They are recruited by antibody‐mediated chemoattractant complement fragments. Monocyte and endothelial derived cytokines or adhesion molecules may also recruit these cells. In most situations of inflammation, neutrophils induce injury by the release of reactive oxygen radicals and their production of lysosomal proteolytic enzymes. the clinical importance of neutrophils in mediating glomerular injury in IgA nephropathy (IgAN) has often been downplayed, although it has been recognized that IgA is involved in the initiation of intracellular oxidative metabolism in normal neutrophils. That disordered neutrophil activation could be relevant to the pathogenesis of IgAN seems likely from their prominent infiltration in glomerular capillaries in the acute phase of primary IgAN, increased expression of complement 3 receptors on neutrophils from patients with IgAN, and increased oxidative metabolism of neutrophils in these patients. Furthermore, recent data revealed heat‐aggregated forms of IgA prepared from patients with IgAN exert an up‐regulatory effect on calcium mobilization, inositol triphosphate production, and oxidative metabolism in human neutrophils. Interestingly, the plasma level of E‐selectin, mainly derived from activated vascular endothelial cells upon interaction with neutrophil, was elevated following synpharyngitic macrohaematuria in patients with IgAN. There was also a significant stepwise increase in circulating E‐selectin associated with increased histopathologic severity in these patients. These data tend to support the notion that neutrophils could be activated in IgAN despite lack of acute clinical exacerbation and may potentially be participating in the inflammatory process of glomerular and interstitial injury.

Distribution of the granulocyte serine proteinases proteinase 3 and elastase in human glomerulonephritis

The serine proteinases proteinase 3 (PR3) and elastase are target antigens of antineutrophil cytoplasmic autoantibodies (ANCAs), which are found in various systemic vasculitides with rapidly progressive glomerulonephritis (RPGN). The expression of both proteinases was studied immunohistologically (avidin-biotin complex method) with murine monoclonal antibodies against PR3 (WGM2) and elastase (NP 57) in 122 human renal biopsy specimens to investigate their role in mediating renal damage. Expression of PR3 predominated in ANCA-associated RPGN and was independent of the serologic ANCA pattern (c-/p-ANCA). The PR3 staining pattern was patchy and not always related to distinct granulocytes due to antigen spreading by disintegrating cells. It was found in crescentic glomeruli and the interstitium of ANCA-positive RPGN. In contrast, glomerular and interstitial elastase staining pattern was much more granulocyte related and was even found in noncrescentic glomeruli in c-ANCA- and p-ANCA-positive pauci-immune RPGN. Endothelial cell and glomerular basement membrane-bound PR3 or elastase expression were not observed. A faint glomerular PR3/elastase expression was seen in Goodpasture's syndrome and within the interstitium in crescentic mesangioproliferative glomerulonephritis (granulocyte related). Both serine proteinases were found in the glomeruli in ANCA-negative acute postinfectious glomerulonephritis. In conclusion, this study provides evidence, for the first time, for the implication of the granulocyte serine proteinases PR3 and elastase in mediating pauci-immune ANCA-positive RPGN and different forms of proliferative glomerulonephritis. The expression of ANCA antigens in ANCA-negative glomerulonephritis suggests that this finding is a marker of neutrophil activation. The role of circulating antibodies (ANCA) in mediating the development of the characteristic pauci-immune RPGN and systemic vasculitis remains to be elucidated.

The Immunohistology of IgA Nephropathy

The glomerular immunohistologic characteristics of 180 patients with IgA nephropathy (IgAN), defined by 2+ or greater (out of 0 to 4+) mesangial IgA-dominant or codominant immunostaining and no evidence for systemic lupus erythematosus, were compared with those of 84 patients with proliferative lupus glomerulonephritis and 254 patients with other forms of proliferative glomerulonephritis. The IgAN population increased in number by only 5% if the IgA immunostaining criterion was lowered to 1+, and it decreased by only 2% if IgA codominant staining was disallowed. A distinctive immunohistologic feature of IgAN in comparison with other immune complex-mediated glomerulopathies, in addition to the predominance of IgA immunostaining, was a high frequency (67%) of patients with greater lambda- than kappa-immunoglobulin light chain immunostaining. There was no correlation between the absolute or relative intensities or frequencies of IgA, IgG, or IgM immunostaining and the severity of glomerular disease; however, the presence of capillary wall immune deposits correlated with more severe disease. Terminal complement components were consistently present and were more conspicuous in more severely injured glomeruli. Immunostaining for the early classical complement activation pathway component C1q was absent or scanty in IgAN. This finding was particularly useful in the immunohistologic differentiation of IgAN from proliferative lupus glomerulonephritis, which was the form of glomerulonephritis with the greatest overlap with IgAN with respect to IgA immunostaining. When the diagnostic criteria for IgAN were 2+ or greater, dominant or codominant mesangial IgA immunostaining and less than 2+ C1q immunostaining, an immunohistologic diagnosis of IgAN was made with 98% accuracy.

Leukocyte analysis using monoclonal antibodies in human glomerulonephritis

The leukocyte subpopulations were analyzed within both the glomeruli and the interstitium in renal biopsies from 145 patients with various forms of glomerulonephritis. Cells were identified by monoclonal antibodies to leukocyte cell-surface antigens and immunoperoxidase labelling. Leukocytes, as defined by a monoclonal antibody to the leukocyte common antigen (PHM1), were present in normal, human renal tissue in both glomeruli (2.8 +/- 0.6 cells/glom. cross section) and interstitium (102 +/- 18 cells/mm2). Monocytes constituted the predominant infiltrating cell type in normal glomeruli (1.3 +/- 0.2) and T cells were rarely found (0.3: range 0 to 0.8), whereas both monocytes (34 +/- 10/mm2) and T lymphocytes (33 +/- 14/mm2) were found in the normal interstitium. In the non-proliferative forms of glomerulonephritis there was no significant increase in the number of glomerular inflammatory cells when compared with normal glomeruli. However, significantly increased numbers of T lymphocytes were seen in the interstitium of biopsies with minor non-specific changes (67 +/- 15/mm2), membranous nephropathy (134 +/- 30/mm2), focal glomerulosclerosis (207 +/- 53/mm2), and diabetic nephropathy (198 +/- 81/mm2). In the proliferative forms of glomerulonephritis only crescentic GN and post-infectious GN demonstrated significantly-increased glomerular monocytes and granulocytes. There was no significant increase in the number of glomerular T cells when compared with normal glomeruli. However, there was a significant increase in the number of interstitial T lymphocytes in all forms of proliferative glomerulonephritis when compared with the normal interstitial cell population.(ABSTRACT TRUNCATED AT 250 WORDS)

Are Anticoagulants of Value in the Treatment of Renal Disease? An Introduction to the Controversy

THE DEBATE over the putative benefits of interrupting the coagulation cascade or preventing aggregation of platelets in the treatment of a variety of renal diseases has been ongoing for 15 to 20 years. In this issue of The American Journal of Kidney Diseases, this controversy is expertly discussed by two recognized authorities who have contributed to the general field, namely, Professors Kincaid-Smith of the Royal Melbourne Hospital and Wayne Border of the University of Utah Medical Center. Professor Kincaid-Smith has long been recognized as an advocate of an important role for coagulation and/or platelet thrombi in the pathogenesis of renal disease originally stemming from her pioneering efforts in the treatment of various forms of proliferative glomerulonephritis, thrombotic microangiopathies, and allograft rejection. Her positive approach towards this form of therapy has arisen, at least in part, because of a strong morphologic bias in which fibrin deposition and platelet thrombi are viewed as common and pathogenetically important accompaniments of progressive renal disease. The view espoused by Professor Border is that morphologic evidence of coagulation is merely indicative of a secondary event having trivial significance in the pathogenesis of progressive lesions. Admittedly, morphologic studies and in vitro investigations provide only indirect evidence for a primary or supportive role of coagulation in progressive renal disease as opposed to a secondary epiphenomena of trivial significance. However, improvement of morphologic and functional aspects of a disease entity following effective anticoagulation or inhibition of platelet aggregation would provide a more convincing argument for an important role of these events rather than merely for their participation as bystanders in various renal diseases. It is regarding this issue that Professors Kincaid-Smith and Border depart significantly from each other. Both positive and negative results with anticoagulants and inhibitors of platelet aggregation have been reported in experimental renal disease , thus making it possible for both discussants to find support for their points of view in the literature. While a positive result of a therapeutic intervention, if properly controlled, carries more weight in an argument of this nature than a negative result , there seems to be little doubt that under certain circumstances severe experimental renal injury is not greatly benefitted by vigorous and potentially lethal anticoagulation. On the other hand, it appears likely that crescent formation in glomeruli is highly dependent upon fibrinogen prolimerization in Bowman space . Of great importance, as Kincaid-Smith has pointed out, is a possibly important role of coagulation or platelet aggregation in the induction and progression of segmental glomerulosclerosis and hyalinosis , which should not be overlooked. Segmental glomerulosclerosis and hyalinosis appears to be a common final pathway emanating in end-stage glomerular capillary obliteration in a variety of disease states. Unfortunately, despite the cogent arguments of both the debaters , little of the definitive nature can be gleaned from the trials of anticoagulants and antithrombotics in clinical situations . Also, there is a paucity of prospective randomized trials. This has arisen in part because of the difficulty of carrying out such studies in relatively uncommon diseases; in part because of the hidden heterogeneity of renal disease, which frustrates the efforts of clinicians and pathologists to properly design a satisfactorily controlled, properly stratified, and randomized study; and in part because of the very justifiable urge to do something when renal disease is rapidly progressive and does not respond to conventional management. The more widespread use of plasma exchange therapy in the treatment of rapidly progressive renal disease has contributed to a lessening of interest in studying the role of anticoagulants or antithrombotic agents per se in the course of renal

Rapidly Progressive Glomerulonephritis with Extensive Glomerular Crescent Formation

Thirty-nine patients with severe crescentic glomerulonephritis and rapidly progressive renal failure were reviewed. Nineteen patients had a focal necrotizing glomerulonephritis, they usually presented with signs of multi-system disease, and eight had histologically-proven microscopic polyarteritis. A second group of 20 patients presented with an acute nephritic syndrome, often with nephrotic features, and had only minor prodromal symptoms. Renal biopsy material showed various forms of proliferative glomerulonephritis in addition to crescents. The most important prognostic feature at admission was renal function: only four of 21 patients who required dialysis recovered any renal function. The prognosis was worse for those with necrotizing glomerulonephritis, of whom two-thirds had oliguria on admission. All patients who were not oliguric, and some with oliguria, were treated with high doses of corticosteroids, usually accompanied by azathioprine and anticoagulants. Seventeen of 18 patients who were not oliguric initially retained or regained renal function, although three subsequently went into renal failure, and three others died of non-renal causes. At the most recent review, 25 of the 39 patients were either dead (16 patients) on dialysis or transplanted (nine patients). Ten were alive with diminished renal function, one had normal renal function but persisting proteinuria, and three were well. Prompt treatment may have contributed to these favourable results in a very severe disease.

On Treating Glomerulonephritis

A patient seeks treatment for hematuria and proteinuria and undergoes diagnostic examination that excludes urologic lesions and does not reveal characteristic findings of specific renal diseases, such as acute poststreptococcal glomerulonephritis. To clarify further the nature of the disease, a renal biopsy is performed. It is naive to anticipate that renal histopathology will regularly provide a diagnosis. Of course, recognition of amyloid or diabetic nephropathy identifies lesions, the natural histories of which are well known. More often a combination of immunofluorescent staining for inimunoglobulins or fibrin or both, coupled with assessment of proliferation of the distinct types of intraglomerular cells, allows a descriptive pathologic diagnosis, such as membranous glomerulopathy, IgA mesangial glomerulonephritis, or the crescentic form of proliferative glomerulonephritis, which is also called rapidly progressive glomerulonephritis. These lesions have multiple causes. For example, IgA nephritis may be the renal lesion of Henoch-Schonlein purpura, of systemic lupus erythematosus, or of Berger's

IMMUNOLOGIC INJURY OF RENAL HOMOGRAFTS

Rejection of renal allografts in man and animals is most frequently induced by cell-mediated immunity, the morphologic hallmark of which is the infiltration of the graft by mononuclear cells. In some presensitized recipients rejection may be mediated by humoral transplantation antibodies, and this is characterized clinically by a rapid tempo of rejection and morphologically by accumulation of polymorphonuclear neutrophils and renal cortical necrosis. In recipients treated with immunosuppressive drugs, most renal allografts function well for over 1 yr. However, late deterioration is observed in many grafts. This may take the form of proliferative glomerulonephritis with accumulation of immunoglobulin and complement along glomerular basement membranes. This glomerular lesion of the graft may be of immunologic nature without being rejection. In many instances the glomerular lesion may be due to recurrence of the original disease of the recipient. In other instances it may represent a de novo immunologic process induced by the response to antigens shared by the graft and recipient as evidenced by animal experiments. The glomerular lesion in the graft may also be caused by humoral transplantation antibodies. Therefore, the final outcome of the renal transplantation may to a great extent depend on the strength of transplantation antibody response, being more favorable for low than high responders.

Immunosuppressive therapy of proliferative glomerulonephritis in children.

THE VARIOUS forms of proliferative glomerulonephritis, with or without the nephrotic syndrome, are difficult therapeutic challenges and with few exceptions lead inexorably to renal failure. Excluded from consideration are patients with acute poststreptococcal glomerulonephritis in whom complete recovery usually occurs without specific therapy2and a high percentage of patients with the nephrotic syndrome of childhood who respond to adrenocortical steroid management.3Some patients with severe lupus glomerulonephritis may recover normal renal function and nearlynormal morphology after intensive treatment with corticosteroids,4,5although the incidence of serious complications remains high. Involvement of immune processes in the pathogenesis of glomerulonephritis is supported by a large body of information collected during the past 50 years.6The more recent availability of serial renal biopsy specimens and improved morphologic techniques, particularly immunofluorescence and electron microscopy, together with the measurement of serum immunoglobulins, have further emphasized the probable pathogenic role of immune mechanisms