Segmental Glomerular Necrosis Research Articles

Renal outcomes in primary IgA nephropathy patients with segmental glomerular necrosis: a case–control study

The renal prognosis and treatment of primary IgA nephropathy (IgAN) patients with segmental glomerular necrosis (SGN) remain controversial. Patients with primary IgAN confirmed by renal biopsy were enrolled. Patients with SGN on renal biopsy were selected as the necrosis group, and a propensity score matching method was used to match a control group according to age, gender, weight, height and follow-up time. A total of 825 IgAN patients were enrolled in the present study. Seventy-three (8.8%) patients with SGN were selected as the necrosis group, and 292 patients without SGN were matched as the control group. Compared to the control group, a significantly increased serum fibrinogen level (3.97 g/L vs 3.54 g/L, P=.002) and proportion of patients with macroscopic hematuria (35.6% vs 14.7%, P<.001) was observed in the necrosis group. According to the new IgA pathological classification system, crescent formation was more pronounced in the necrosis group (P=.001). The average estimated glomerular filtration rate was obviously higher in the necrosis group and decreased more slowly during follow-up. However, the time-averaged urine protein-to-creatinine ratio remained low in the necrotic group, whereas it gradually increased in the control group. SGN suggests an active renal inflammatory state, but it was not an independent risk factor for a poor renal outcome in patients treated with immunosuppressive therapy. Furthermore, patients with SGN had a more stable renal function and low urinary protein excretion during follow-up, which may be attributable to aggressive immunotherapy.

Outcomes of IgA Nephropathy with Segmental Glomerular Necrosis But without Crescent Formation

Background: The significance of segmental glomerular necrosis (SGN) was not evident in immunoglobulin A nephropathy (IgAN) patients. Especially, there were a number of patients who presented with slight histopathological damage except SGN. We, therefore, conducted a study to highlight the occurrence of these cases and to define their clinical characteristics and outcomes at our centre. Methods: The clinical, laboratory and pathological manifestations and outcomes of these IgAN patients were collected and compared with IgAN patients with simily histopathological background but without SGN. Survival curves were constructed according to the Kaplan-Meier method. Multivariate Cox regression analysis was used to identify independent factors for the development of endpoint. Results: Eighty-two patients with SGN but without crescents were found in Haas grades I-III. Macroscopic hematuria and prodromal infection were more popular and the mean daily proteinuria was significantly higher in patients with SGN. More patients had high serum IgA in the ecrotizing IgAN group. At last follow-up, there were no differences in hypertension, proteinuria, serum creatinine, estimated GFR and the incidence of end-point events between 2 groups. SGN was not an independent predictor for the prognosis of IgAN. Corticosteroid treatment could decrease proteinuria significantly. The outcomes of the 2 populations of necrotizing IgAN patients with or without corticosteroid treatment were not different. Conclusions: SGN can be found in mild pathological damage patients and is not always associated with crescent formation. Heavier proteinuria was found in these IgAN patients. SGN was not an independent predictor for the prognosis of IgAN.

Renal histopathology and clinical course in 94 patients with Wegener's granulomatosis.

The main purpose of this study was to examine histopathological changes seen in renal biopsies from patients with Wegener's granulomatosis (WG) with varying degrees of renal involvement and to study possible correlations between the morphological variables and the severity of the disease. Ninety-four patients with WG and active renal disease were included in this retrospective study. All patients had a percutaneous renal biopsy taken on their first admission to the hospital and 14 patients had a second biopsy. The patients were followed for a median of 42.5 months (range 0.5-184). Segmental necrotizing glomerulonephritis and extracapillary proliferation were present in 85.1 and 91.5% respectively. Of seven patients (7.4%) with normal serum creatinine and urinary protein excretion <0.5 g/day, all had crescents and six had segmental glomerular necrosis. Serum creatinine at biopsy correlated significantly with the percentage of glomeruli with crescents (rho=0.52, P=0.0004), with necrosis (rho=0.36, P=0.002) and with the percentage of normal glomeruli (rho=-0.55, P=0.0003). On a multivariate analysis, only the percentage of normal glomeruli was significantly associated with renal function and development of end-stage renal disease. In 14 second biopsies after a mean of 41.2 (+/-26) months, chronicity scores had increased significantly in 13 biopsies in spite of full immunosuppressive treatment. Although renal biopsy is of value in defining renal involvement in WG, it is of limited help in the early stage of the disease in predicting renal outcome for the individual patient. A follow-up biopsy can be useful in revealing the degree of activity and chronicity and hence be of importance for the choice of further therapy.

Idiopathic IgA nephropathy with segmental necrotizing lesions of the capillary wall

Segmental glomerular necrosis has been described in the biopsy material in a minority of patients with idiopathic IgA nephropathy in the oldest studies on this disease, but this marker of active capillaritis has received little attention in the subsequent literature, and its significance and relevance for the clinical outcome is still unknown. Thirty-five out of 340 patients (10.3%) biopsied in our division at the San Carlo Hospital since 1974 showed active segmental necrotizing lesions. The morphological features and the natural history of this group of patients were compared with those of a control group of 229 patients who had comparable serum creatinine and extent of glomerular sclerosis, but who lacked active segmental necrosis. Patients with the necrotic variant showed a significantly more marked extracapillary proliferation and interstitial accumulation of monocytes and T lymphocytes and, in the segmental areas of necrotizing and extracapillary lesions, infiltration of monocytes, deposition of fibrinogen, and expression of the adhesion molecule vascular cell adhesion molecule-1. No difference was found in the presenting clinical syndrome. The clinical course was frequently characterized by acute flare ups, and the progression to end-stage renal failure was more frequent, although actuarial renal survival was not significantly worse (P = 0.07). The aggressive treatment with steroids and cyclophosphamide, carried out in 20 of the 35 patients, has probably been beneficial, justifying the multicenter controlled trial that recently has been initiated. Vasculitic lesions of the glomerular capillaries, with histologic and immunohistological features similar to those of Henoch-Schönlein purpura and antineutrophil cytoplasmic antibody-positive renal vasculitis, were found in 10% of patients with idiopathic IgAN. Clinical features at presentation did not differ from those of the other patients with IgAN, and despite of the more frequent occurrences of recurrent acute flare ups, rapid progression to end-stage renal failure was a rare phenomenon, even in untreated patients.

Cellular crescents and segmental glomerular necrosis in IgA nephropathy are indicative of the beneficial effects of corticosteroid therapy.

Recent reports have revealed that corticosteroid (PSL) therapy has a long-term beneficial effect for stabilization of renal function in progressive IgA nephropathy. We analyzed serum creatinine (Cr), daily proteinuria and the results of other routine laboratory examinations during a short-term course of PSL therapy in 28 cases of progressive IgA nephropathy. The cases were divided into two groups according to changes in renal function during the PSL treatment period: group I (15 cases), improved renal function; group II (13 cases), no significant change in renal function. In group I, serum Cr and proteinuria were significantly decreased, with maximum effects observed at 3 months of PSL therapy, and remained low during the period of treatment. In contrast, group II showed no significant changes in serum Cr levels during the period of therapy, although proteinuria was transiently decreased after 3 months of therapy. Histologically, cellular/fibrocellular (C/F) crescents and/or segmental glomerular necrosis (SGN) occurred with a significantly higher incidence in group I (87%) than in group II (46%) (p < 0.05). These results suggested that the early response to PSL in reducing serum Cr and proteinuria by 3 months of treatment may be clinically useful to predict the prognosis of IgA nephropathy and that C/F crescents and/ or SGN may be histologically indicative of the beneficial effects of PSL therapy in IgA nephropathy.

Clinicopathological features of antineutrophil cytoplasmic antibodies-associated vasculitis in Japanese patients with IgA nephropathy

Antineutrophil cytoplasmic antibodies (ANCA) have been reported to be associated with systemic vasculitis. However, the roles of ANCA subtypes in patients with IgA nephropathy remain to be fully investigated. We describe three Japanese patients with IgA nephropathy complicated by ANCA-associated vasculitis. Two patients with IgG class ANCA developed rapidly progressive renal failure and demonstrated mesangial proliferation with extensive extracapillary proliferation and segmental glomerular necrosis. One patient with IgM class ANCA showed severe extrarenal symptoms, such as lung fibrosis and neuritis, in addition to glomerular crescent formation. All three patients received immunosuppressive therapies, including corticosteroids and cyclophosphamide. The two patients who received these treatments early showed improvement in urinary protein excretion and renal function, in accordance with a decrease in the serum titer of ANCA. However, one patient in whom serum creatinine was already elevated showed a poor response to the treatment. These results suggest that ANCA subtypes may participate in the pathogenesis of crescent formation in patients with IgA nephropathy, and that early treatment with a combination of methylprednisolone pulse therapy, oral prednisolone, and cyclophosphamide pulse therapy may be beneficial in these patients.

No Evidence of Epitope Spreading After Immunization with the Major Sm Epitope P-P-G-M-R-P-P Anchored to Sequential Oligopeptide Carriers (SOCs)

The sequence Pro-Pro-Gly-Meth-Arg-Pro-Pro (PPGMRPP) is the major B-cell epitope of the Sm autoantigen. The aim of the present study was to evaluate the immune response against the native forms of Sm and U1RNP and immune mediated tissue injury after immunization with the sequence PPGMRPP anchored in five copies to a new type helicoid sequential oligopeptide carrier (SOC) formed by the repetitive Lys-Aib-Gly moiety, [(PPGMRPP)5SOC5]. Rabbits (n=3) were immunized with 0.5mg of (PPGMRPP)5SOC5in complete Freud's adjuvant and boosted at days 26, 53, 99; control rabbits were immunized with the PPGMRPP alone (n=3), phosphate buffered saline (PBS) (n=1), SOC5alone (n=1), a peptide at aminoacid (aa) position 158–177 of myelin basic protein (MBP aa 158–147) (n=1) and three La/SSB autoantigen B-cell epitopes (n=3). Antibodies to (PPGMRPP)5SOC5were determined by enzyme linked immunosorbent assay (ELISA); precipitating anti-Sm and anti-U1RNP antibodies were detected by RNA precipitation and western blot on HeLa total cellular and nuclear extract and 12s sucrose gradient fraction of rat liver extracts. High titres of anti-(PPGMRPP)5SOC5antibodies not recognizing the native forms of Sm or U1RNP antigens were detected in the (PPGMRPP)5SOC5immunized but not in the control animals. The sera of two (PPGMRPP)5SOC5immunized but not of the control rabbits recognized a 67kDa protein in HeLa nuclear extract, distinct from the 70kDa U1RNP antigen. Diffuse and segmental increase of mesangeal matrix and cells, crescent formation, segmental glomerular necrosis, rarely massive subendothelial deposits occluding the lumen and C3 complement component in the mesangeal area were seen in the kidneys of one (PPGMRPP)5SOC5immunized, but not of the remaining animals. In conclusion, the immune response induced by (PPGMRPP)5SOC5was specific for the immunizing epitope but not for the native forms of Sm and U1RNP antigens, but it was associated with immune mediated kidney injury.

Treatment of systemic and renal-limited vasculitic disorders with pooled human intravenous immune globulin.

Idiopathic crescentic glomerulonephritis is characterized by an absence of immunohistological evidence of immune deposits, often with evidence of segmental glomerular necrosis. Such pauciimmune crescentic glomerulonephritis is the most common renal manifestation seen in patients with Wegener's granulomatosis, polyarteritis nodosa, and glomerulonephritis associated with other systemic vasculitic disorders (i.e., Churg-Strauss syndrome). Recently, the idiopathic crescentic glomerulonephritides, either in renal-limited form or in association with other systemic vasculitic disorders, were found to have in common a serologic marker, antineutrophil cytoplasmic autoantibodies. These cytoplasmic and perinuclear antineutrophil cytoplasmic autoantibodies are specific for constituents of neutrophil primary granules and monocyte lysosomes. As serologic markers for vasculitic disorders, they are also felt to be directly involved in the pathogenesis of necrotizing vascular injury. In vitro, both perinuclear and cytoplasmic antineutrophil cytoplasmic autoantibodies are capable of causing cytokine-primed neutrophils to undergo degranulation and respiratory burst, releasing toxic oxygen species and lytic enzymes. Anti-idiotype antibodies which inhibit antineutrophil cytoplasmic autoantibodies in vitro, in a V region-dependent manner, are found in pooled human gamma-globulin preparation. Intravenous immune globulin infusions in vivo have produced dramatic improvements in the necrotizing vascular injury produced by antineutrophil cytoplasmic autoantibodies, and a rapid reduction in these autoantibody levels is seen post-intravenous immune globulin infusion in most patients. The proposed mechanisms of action of intravenous immune globulin in vasculitic disorders include Fc-dependent mechanisms, and F(ab')2-dependent mechanisms are likely important. Intravenous immune globulin infusions appear to have an important place in the management of the necrotizing vascular injury. Blinded, randomized, placebo-controlled trials will be necessary to establish definitely intravenous immune globulin as a therapeutic option in vasculitic disorders.

Evolution of renal injury in a chronic model of IgA immune-complex-associated nephropathy

IgA nephropathy (IgAN) is characterized by intense and diffuse IgA mesangial deposits, a variety of histopathological changes and unpredictable clinical course. To elucidate the cause of the discrepancy between the unvariable IgA deposition and the histological picture, we examined the short- and long-term influence of glomerular IgA immune complexes (IgA-IC) on the progression of renal lesions in experimental IgAN. IgA-IC renal deposits were induced by sequential administration of IgA antiphosphorylcholine and pneumococcal C polysaccharide. Mice treated every other day by three injections (groups A) or nine injections (groups B) were sacrificed 24 h and 1, 4, or 8 weeks (groups 1-4) after cessation of treatment. Group A1 showed segmental glomerular necrosis and thrombosis. Lesions then converted to segmental mesangial proliferation (A2), more pronounced in A3 and minimal in A4. Group B1 showed severe proliferative glomerulonephritis and segmental necrosis. The pattern altered to mesangial expansion with glomerular/interstitial infiltration in B2, milder features in B3 and residual mesangial proliferation in B4. Proteinuria increased progressively during treatment reaching its maximum in group B1, but it returned to near normal levels in group B4. The development of proteinuria paralleled glomerular/interstitial T cell infiltration. These findings demonstrate that renal histopathological alterations observed in experimental IgA nephropathy are sustainable only by continuous deposition of nephritogenic IgA-IC.

Segmental glomerular necrosis as an active index of IgA nephropathy: a study with 100 serial sections of 128 cases.

One hundred serial sections from each of 128 cases with immunoglobulin A (IgA) nephropathy were examined by light microscopy to clarify the relationship between segmental glomerular necrosis (SGN) and progression of glomerular injury. The cases were divided into five groups according to the percentage of glomeruli with cellular/fibrocellular (C/F) crescents, fibrous adhesion and/or sclerosis: grade I, 0%; grade II, < 20%; grade III, 20-50%; grade IV, 50-80%; and grade V, 80% or more. The serial sections revealed unequivocally focal occurrence of SGN in 39 cases (30%). Segmental glomerular necrosis was never found in the cases of grade I (0%, 0/28), while it appeared in those of grade II (33%, 12/36), grade III (46%, 13/28), grade IV (48%, 13/27) and grade V (11%, 1/9). The incidence of the cases with C/F crescents showed a similar tendency among the groups. In addition, focal C/F crescents were more frequent in cases with SGN (82%) than in those without SGN (24%). In particular, cellular crescents in 26 cases were formed in close proximity to SGN. These results suggested that SGN in IgA nephropathy was a more common finding than formerly evaluated and that it potentially participated in the progression of glomerular injuries closely associated with crescent formation. Unequivocally, focal occurrence of SGN corresponded well with the slowly progressive course of the glomerular disease.

Severe proteinuria in IgA nephropathy. Clinicopathological study of 8 cases with 100 serial sections

Using 100 serial sections for light microscopy, we studied the clinicopathologic characteristics of IgA nephropathy with severe proteinuria. Eight out of 128 cases with IgA nephropathy exhibited severe proteinuria of 3.0g/day or more. These cases consisted of 5 males and 3 females with an age range from 15 to 73 years. Daily proteinuria ranged from 3.3 to 7.1 g. At the time of biopsy, the serum creatinine level was 1.2 mg/dl or more in 6 cases; two of these developed end-stage renal failure during the follow-up period. In most of the cases, routine sections for light microscopy revealed moderate to severe mesangial proliferation and tubulointerstitial damage. In 7 cases, variable percentages of glomeruli, ranging from 20% to 95%, were involved by chronic lesion represented by sclerosis and fibrous crescents/adhesion, while only 2 cases exhibited active lesion characterized by segmental glomerular necrosis and/or cellular/fibrocellular crescents. In contrast, thorough observation of 100 additional serial sections disclosed the focal presence of active lesion in all except one case with features of endstage kidney. In addition, the highest percentage of glomeruli with active lesion in the serial sections correlated well with the severity of proteinuria. The results suggested that severe proteinuria in IgA nephropathy depends on, at least in part, focal outbreak of active lesion characterized by segmental glomerular necrosis and cellular/fibrocellular crescents.