Tubular and interstitial expression of ICAM-1 as a marker of renal injury in IgA nephropathy

BACKGROUND: The upregulated renal expression of intercellular adhesion molecule 1 (ICAM-1) is associated with glomerular and interstitial infiltration of leukocytes. AIM: To test the hypothesis that renal expression of ICAM-1 may be predictive in the highly variable IgA nephropathy (IgAN). METHODS: ICAM-1 (CD54) in tubular epithelium and interstitial leukocytes, macrophages (CD14), and T cells (CD3) were assessed using avidin-biotin-peroxidase in renal biopsy specimens from 45 patients with IgAN and from 29 patients with no glomerulonephritis. RESULTS: In IgAN, tubular ICAM-1+ was seen in 25 of 45 (55%) biopsy specimens, associated with glomerular hypercellularity, glomerulosclerosis involving less than 50% of the glomerular area, interstitial cellular infiltration, tubular atrophy, and proteinuria (U = 44, p = 0.005). Interstitial ICAM-1+ leukocytes were correlated with glomerulosclerosis involving less and more than 50% of the glomerular area, tubular atrophy, interstitial fibrosis, and serum creatinine concentration (r = 0.6343, p < 0.001). In patients with an increase of 50% in the serum creatinine concentration, interstitial ICAM-1+ leukocytes and CD14+ and CD3+ cells were significantly more numerous than in patients with a stable creatinine concentration. In patients with no glomerulonephritis, tubular ICAM-1+ was seen in 7 of 29 (24%) biopsy specimens, inversely correlated with the number of normal glomeruli and associated with glomerulosclerosis covering more than 50% of the glomerular area, tubular atrophy, and creatinine. CONCLUSIONS: Tubular and interstitial expression of ICAM-1 can be a marker of tubulointerstitial disturbance in IgAN. Interstitial ICAM-1 may be an adverse predictor of disease progression.     

Primary focal sclerosing glomerulonephritis: A clinicopathological analysis

SUMMARY: The clinical and laboratory features, renal biopsy findings, and outcome of 68 patients with primary focal sclerosing glomerulonephritis were studied. the cumulative probability of not progressing to end-stage renal failure (ESRF) was 0.92 at 5 years and 0.73 at 10 years after presentation, and was significantly worse in patients with hypertension or severe renal impairment (serum creatinine >0.24 mmol/L) at presentation. Proteinuria of up to 1gm/day was associated with an excellent prognosis, whereas proteinuria of 1–3 gm/day and >3 gm/day had similar and poorer survivals. an adverse outcome was associated with, at presentation, age less than 30 years, hypertension, a family history of glomerulonephritis, cigarette smoking, impaired renal function, and heavy proteinuria. Renal biopsy findings which correlated with progressive renal failure included a higher percentage of glomeruli with global or segmental sclerosis, and the degrees of tubular atrophy, interstitial fibrosis, interstitial inflammation and arterial thickening. During follow-up the degrees of renal impairment and proteinuria, persistence or development of hypertension, transient decreases of renal function of >10%, and the total number of red cells and casts on centrifuged urine microscopy were all predictive of progressive renal disease. Multivariate analysis demonstrated that the indices with adverse effects on outcome induced all of the above except tubulointerstitial and vascular changes on renal biopsy. It is concluded that the prognosis may be better than has been suggested in the literature. It is possible to predict which patients are likely to have an adverse outcome, and this should assist with therapeutic decisions likely to retard progression of disease.     

Fibrillary and immunotactoid glomerulonephritis: Distinct entities with different clinical and pathologic features

BACKGROUND: Controversy surrounds the relatedness of fibrillary glomerulonephritis (FGN) and immunotactoid glomerulonephritis (IT). METHODS: To better define their clinicopathologic features and outcome, we report the largest single center series of 67 cases biopsied from 1980 to 2001, including 61 FGN and 6 IT. FGN was defined by glomerular immune deposition of Congo red-negative randomly oriented fibrils of < 30 nm (mean, 20.1 +/- 0.4 nm). IT was defined by glomerular deposition of hollow, stacked microtubules of > or = 30 nm (mean, 38.2 +/- 5.7 nm). RESULTS: FGN comprised 0.6% of total native kidney biopsies and IT was tenfold more rare (0.06%). Deposits in FGN were immunoglobulin G (IgG) dominant and polyclonal in 96%. IgG subtype analysis in 19 FGN cases showed monotypic deposits in four (two IgG1 and two IgG4) and oligotypic deposits in 15 (all combined IgG1 and IgG4). In IT, deposits were IgG dominant in 83% and monoclonal in 67% (three IgG1 kappa and one IgG1 lambda). FGN patients were a mean age of 57 years, 92% were Caucasian, and 39% were male. At biopsy, FGN patients had the following clinical characteristics (mean, range): creatinine 3.1 mg/dL (0.5 to 14), proteinuria 6.5 g/day (0.8 to 25), 60% microhematuria, and 59% hypertension. Histologic patterns of FGN were diverse, including diffuse proliferative glomerulonephritis (DPGN) (nine cases), membranoproliferative glomerulonephritis (MPGN) (27 cases), mesangial proliferative/sclerosing (MES) (13), membranous glomerulonephritis (MGN) (four), and diffuse sclerosing (DS) (eight). The more proliferative (MPGN and DPGN) and sclerosing (DS) forms presented with a higher creatinine and greater proteinuria compared to MES and MGN. Median time to end-stage renal disease (ESRD) was 24.4 months for FGN and mean time to ESRD varied by histologic subtype: DS 7 months, DPGN 20 months, MPGN 44 months, compared to MES 80 months and MGN 87 months. There was no statistically significant effect of immunosuppressive therapy (given to 36% of FGN patients). By Cox regression (hazard ratio, confidence interval, P value), independent predictors of progression to ESRD were creatinine at biopsy [2.05 (1.55 to 2.72) P < 0.001] and severity of interstitial fibrosis [2.01 (1.05 to 3.85) P = 0.034]. Although IT had similar presentation, histologic patterns, and outcome compared to FGN, it had a greater association with monoclonal gammopathy (P = 0.014), underlying lymphoproliferative disease (P = 0.020), and hypocomplementemia (P = 0.032). CONCLUSION: FGN is an idiopathic condition characterized by polyclonal immune deposits with restricted gamma isotypes. Most patients present with significant renal insufficiency and have a poor outcome despite immunosuppressive therapy, and outcome correlates with histologic subtype. By contrast, IT often contains monoclonal IgG deposits and has a significant association with underlying dysproteinemia and hypocomplementemia. Differentiation of FGN from the much more rare entity IT appears justified on immunopathologic, ultrastructural, and clinical grounds.     

Primary focal sclerosing glomerulonephritis: A clinicopathological analysis

The clinical and laboratory features, renal biopsy findings, and outcome of 68 patients with primary focal sclerosing glomerulonephritis were studied. The cumulative probability of not progressing to end-stage renal failure (ESRF) was 0.92 at 5 years and 0.73 at 10 years after presentation, and was significantly worse in patients with hypertension or severe renal impairment (serum creatinine >0.24 mmol/L) at presentation. Proteinuria of up to 1gm/day was associated with an excellent prognosis, whereas proteinuria of 1–3 gm/day and >3 gm/day had similar and poorer survivals. An adverse outcome was associated with, at presentation, age less than 30 years, hypertension, a family history of glomerulonephritis, cigarette smoking, impaired renal function, and heavy proteinuria. Renal biopsy findings which correlated with progressive renal failure included a higher percentage of glomeruli with global or segmental sclerosis, and the degrees of tubular atrophy, interstitial fibrosis, interstitial inflammation and arterial thickening. During follow-up the degrees of renal impairment and proteinuria, persistence or development of hypertension, transient decreases of renal function of >10%, and the total number of red cells and casts on centrifuged urine microscopy were all predictive of progressive renal disease. Multivariate analysis demonstrated that the indices with adverse effects on outcome included all of the above except tubulointerstitial and vascular changes on renal biopsy. It is concluded that the prognosis may be better than has been suggested in the literature. It is possible to predict which patients are likely to have an adverse outcome, and this should assist with therapeutic decisions likely to retard progression of disease.     

Idiopathic IgA nephropathy with diffuse crescent formation

OBJECTIVE: To investigate the clinicopathological features and outcome of idiopathic IgA nephropathy with diffuse crescent formation in Chinese patients. METHODS: Twenty-five patients with diffuse crescentic IgA nephropathy (DCIgAN), 15 males and 10 females with median age of 28.5, and median disease duration of 5.1 months, were studied. Their clinical, laboratory and pathological features and outcome were investigated. Twenty-one were administered pulse immunosuppressive therapy, and 15 were followed up for more than 6 months. RESULTS: 1.14% had total IgA nephropathy, and 16.4% total diffuse crescentic glomerulonephritis. Clinically, most of patients (88%) showed rapidly progressive glomerulonephritis associated with a high level of serum creatinine (418 +/- 264 micromol/l). Gross hematuria was noted in 72%, hypertension in 64%, and nephrotic syndrome in 48%. Pathologically, except for diffuse crescent formation (a median 65% and range 50-95%), we observed segmental necrosis of glomerular capillaries in 60%, glomerular infiltrating cells in 48%, endothelial cells proliferation in 32%, and rupture of Bowmans' capsule in 24%. Severe tubular interstitial damage was also found, tubular atrophy in 64%, interstitial fibrosis in 60%, diffuse interstitial infiltrating cells in 74%, and interstitial vasculitis in 40%. Immunopathologically, four phenotypes were observed; however, IgA associated with IgM deposition was higher than that in patients with general IgA nephropathy (IgAN). In addition, the infiltrating CD4+, CD8+, CD68+ and PCNA+ cells in renal tissue were significantly high compared with that in controls. In a follow-up study, 66.7% of patients had life-sustaining renal function, 4 of them had normal range of serum creatinine (<124 micromol/l), and only 5 were dialysis-dependent. CONCLUSIONS: The patients with crescentic IgA nephropathy mostly show rapidly progressive nephritis associated with more severe pathological changes including glomerular, tubular interstitial and vascular lesions than in patients with general IgAN. The infiltrates in glomeruli may contribute to the crescentic formation, and the intensive immune suppressing treatment is useful to improve renal damage in patients with DCIgAN.     

The product of duration and amount of proteinuria (proteinuria index) is a possible marker for glomerular and tubulointerstitial damage in IgA nephropathy

BACKGROUND/AIMS: IgA nephropathy (IgAN) is one of the major causes for chronic renal failure (CRF). Presence of massive proteinuria, hypertension, increased serum creatinine level and sclerotic histopathological changes of the glomerulus are known to be determinants for the progression of CRF. However, the relationships between duration of proteinuria/hematuria and histopathological changes, which may be correlated with the renal prognosis, have not been clarified. METHODS: A cross-sectional, univariate analysis of clinical parameters on the four glomerular and three tubulointerstitial histopathological grades in 57 untreated biopsy-proven IgAN patients (M/F = 32/25) was performed. RESULTS: The age at the time of renal biopsy (35.2 +/- 13.0 years; mean +/- SD), average duration of proteinuria (5.3 +/- 5.8 years), mean urinary protein excretion (0.99 +/- 1.22 g/day), serum creatinine (Cr 0.97 +/- 0.28 mg/dl), Cr clearance (Ccr 75.5 +/- 29.4 ml/min), and blood urea nitrogen (BUN 15.4 +/- 3.9 mg/dl) were well correlated with both histopathological grades. The product of duration (years) and urinary protein excretion (g/day) at the time of renal biopsy was more significantly correlated with glomerular and tubulointerstitial histopathological grades and serum Cr. CONCLUSION: The natural course of IgAN is steadily progressive depending on the duration and amount of proteinuria. The product of these two factors (proteinuria index) may be a useful predictor for glomerular and interstitial histopathological changes and the fate of renal function in IgAN.     

DNA fragmentation in acute and chronic rejection after renal transplantation

Acute and chronic rejections are important denominators for the long-term function of renal grafts. One important indicator of cell damage is enzymatic DNA fragmentation. To investigate possible mechanisms, the rate of DNA fragmentation (TUNEL staining), the expression of tissue transglutaminase II (a marker of advanced DNA damage), and 8-hydroxy-2'-deoxyguanosine (8-OhdG), an indicator of oxidative injury of nucleic acids, were studied by immunohistochemistry. Semithin sections of renal biopsies revealed 23 patients to show acute interstitial rejections (Banff 97 IA, IB); eight patients, acute vascular rejection (Banff 97 IIA, IIB); and 20 patients, chronic allograft nephropathy (Banff 97 I to III). Correlations were calculated between apoptotic cells and serum creatinine at the time of biopsy and after 6 months. In acute rejection, the proximal tubular cells were apoptotic, particularly in regions with mononuclear infiltrates. In consecutive sections, these apoptotic tubular cells also showed damage by reactive oxygen species (positive 8-OhdG staining). Patients with acute interstitial rejection revealed the highest number of tubular DNA fragmentation (14.9 +/- 10.3) versus chronic allograft nephropathy (9.2 +/- 5.6) as TUNEL-positive cells per 80,000 micro m(2) (P < .05). Patients with acute vascular rejection showed a low degree of tubular apoptosis (6.8 +/- 5.1). There was no significant difference in glomerular DNA fragmentation between acute interstitial and chronic rejections: acute interstitial rejection = 7.1 +/- 5.9 versus chronic allograft nephropathy=6.1 +/- 3.9 TUNEL-positive cells per 80,000 micro m(2). There was a significant negative correlation between the degree of tubular (P < .01) and glomerular (P < .05) apoptosis and the serum creatinine at the time of biopsy as well as after 6 months in all patients irrespective of the Banff class. However, there was heterogeneity in the correlation between renal function and the degree of apoptosis in the glomerular and tubular compartments in the various Banff classes. A positive correlation (P < .01) was observed between the degree of tubular apoptosis and serum creatinine at 6 months after biopsy among patients with acute vascular rejection (Banff 97 IIA, IIB). The present data revealed a high degree of tubular DNA fragmentation associated with oxidative stress in acute interstitial rejection. Nevertheless, apoptosis did not generally negatively influence future renal function and may be important to clear proliferating cells. Apoptosis may also play a different pathophysiological role depending on the type of rejection.     

Diffuse proliferative lupus nephritis: identification of specific pathologic features affecting renal outcome

Prerandomization renal biopsy specimens were examined in 102 patients upon entry into prospective therapeutic trials of lupus nephritis in an attempt to identify early predictors of renal failure outcome. All 11 renal failures occurred among the 72 individuals with diffuse proliferative or membranoproliferative glomerulonephritis (DPGN/MPGN); thus, these patients were at modestly, but significantly, increased risk of endstage renal disease compared to those with focal proliferative, membranous, or mesangial glomerulonephritis. Considering the low incidence of endstage renal disease among patients with DPGN/MPGN, we sought to refine the prognostic information obtained from renal morphology by semiquantitative scoring of individual histologic features and by derivation of composite histologic scores specified by Activity (AI) and Chronicity (CI) Indices. Among the 72 patients with DPGN/MPGN, the composite AI was more strongly predictive of renal failure than were the individual active histologic features; cellular crescents and extensive fibrinoid necrosis yielded positive associations, while endocapillary proliferation, leucocytic exudation, and hyaline thrombi in glomeruli and interstitial inflammation by themselves did not emerge as useful prognostic indicators. However, chronicity items (glomerular sclerosis, fibrous crescents, tubular atrophy, and interstitial fibrosis) considered individually, as well as in the composite CI, were highly predictive of renal failure outcome. Particularly striking was the prognostic value of tubular atrophy; all 11 renal failures were among the 43 patients with tubular atrophy on prerandomization renal biopsy. While no single pathologic variable improved outcome predictions among those with tubular atrophy, examination for interactions among variables revealed that glomerular sclerosis and cellular crescents had a synergistic effect which augmented the prognostic information derived from analysis of tubular atrophy alone.(ABSTRACT TRUNCATED AT 250 WORDS)     

Long-term prognosis of chronic idiopathic membranous glomerulonephritis. An analysis of 334 cases with particular regard to tubulo-interstitial changes

A retrospective long-term study (average follow-up time 5.2 years) of 334 patients with idiopathic membranous glomerulonephritis (MGN) was carried out with the following results: 1) MGN was found to have a relatively good prognosis when all cases were considered together: 5-year kidney survival rate (KSR) -88%, and 10-year KSR -77%. 2) Univariate survivorship analysis showed the following morphological and clinical parameters to be associated with an increased risk of terminal renal insufficiency or death from renal disease: a) tubulo-interstitial changes; b) glomerular stage III as opposed to stages I and II; c) elevation of serum creatinine concentration at the time of the biopsy; d) arterial hypertension at the time of the biopsy. 3) Multivariate analysis showed that only tubulo-interstitial changes (interstitial fibrosis and/or acute renal failure) found at the time of the biopsy and their clinical correlate, serum creatinine concentration, were significant and therefore of definite prognostic importance. 4) Unsystematic therapy with steroids and/or cytostatic agents does not improve the long-term prognosis of MGN. 5) The cause of disease in the tubulo-interstitial system in MGN is discussed. Interstitial fibrosis is considered to develop possibly as a consequence of unresorbed interstitial edema which can develop during an episode of acute renal failure. Coexisting T-cell-mediated disease in the region of the intertubular capillaries is also considered as a possible factor in the development of interstitial fibrosis.     

Significance of CD25 positive cells and macrophages in noncrescentic IgA nephropathy

The aim of this study was to determine whether infiltration by CD25 positive cells, macrophages, and activated macrophages in the kidney is predictive of chronic histological injury and renal prognosis in adults with noncrescentic IgA nephropathy. Renal biopsies of 36 patients with noncrescentic IgA nephropathy were examined by immunohistochemistry for glomerular and interstitial CD4, CD8, and CD25 positive cells, monocytes/macrophage (Mac387), and activated macrophages (27E10). Renal injury (glomerulosclerosis, mesangial cell hypercellularity, tubular atrophy, and interstitial fibrosis) at the time of biopsy and renal prognosis (follow-up creatinine and creatinine clearance) were assessed. The mean follow-up period was 22.5 +/- 16.5 months. The number of interstitial CD8 positive cells was the best predictor of renal injury at the time of biopsy, and was positively correlated with glomerulosclerosis (p = 0.04), tubular atrophy (p = 0.04), and interstitial fibrosis (p = 0.01) but not with mesangial cell hypercellularity. The number of interstitial Mac387 and 27E10 positive cells were the best predictors of renal prognosis (r2 = 0.33 and 0.34 respectively, both p < 0.01). These data suggest the presence of CD8 cells and macrophages in the kidney at the time of biopsy could potentially serve as pathological markers to identify patients with IgA nephropathy, which may warrant more aggressive medical therapy.     

Clinicopathologic correlations in a series of 143 patients with IgA glomerulonephritis

In an unselected series of patients with IgA glomerulonephritis, old age, high blood pressure, and high urinary protein excretion at the time of renal biopsy were found to correlate with impaired renal function, whereas sex, estimated duration of the disease, or high serum IgA levels did not. The following clinical features were favorable prognostic signs: asymptomatic proteinuria, macroscopic hematuria, and isolated microscopic hematuria. The degree of diffuse mesangial alteration and the presence of segmental glomerular lesions correlated clearly with the subsequent clinical outcome. Vascular lesions, i.e. arteriosclerosis and renal vascular deposition of C3, were most often present in patients with severe glomerulopathy. The presence of electron-dense deposits in glomerular capillary walls was also an unfavorable prognostic finding. Renal biopsy findings of interstitial infiltrates of inflammatory cells and IgA distributed along glomerular capillary walls were usually associated with extrarenal manifestations of the disease.     

Predictors of renal outcome in diffuse proliferative lupus nephropathy: data from repeat renal biopsy.

BACKGROUND: Diffuse proliferative lupus nephropathy (DPLN) is the most frequent and severe form of renal disease in patients with systemic lupus erythaematosus. Histological parameters at the initial biopsy of patients with DPLN that would predict the progression of renal pathology or function at the second biopsy are not clearly defined. METHODS: The prognostic significance of renal histological indices, such as glomerular activity index and volume density of cortical interstitium [Vv(int/cortex)], was evaluated from successive renal biopsies in 21 patients with DPLN. RESULTS: At the time of the second biopsies, performed an average of 43 months after the first biopsies, seven patients (33%) showed progressive renal insufficiency. Only three cases (14%) transformed to World Health Organization class I or III. The seven patients with clinical progression exhibited a higher frequency of hypertension, higher percent glomerulosclerosis, and larger Vv(int/cortex) at the time of second biopsy as compared with the 14 patients without renal insufficiency. At the first biopsy, patients with clinical progression showed a higher glomerular activity index (2.9+/-1.2 vs 1.3+/-0.8, P<0.05) and larger Vv(int/cortex) (0.13+/-0.07 microm(3)/microm(3) vs 0.05+/-0.03 microm(3)/microm(3), P<0.05) than the patients without progression. The glomerular activity index at the first biopsy correlated directly with per cent glomerulosclerosis, Vv(int/cortex), and serum creatinine level at the second biopsy. Vv(int/cortex) in the first biopsy also showed a significant relation with per cent glomerulosclerosis and serum creatinine level at the second biopsy. CONCLUSIONS: These results suggest that higher glomerular activity and larger interstitial volume density at the initial biopsy can predict future progression of renal pathology or function in DPLN.     

Long-term prognosis of membranoproliferative glomerulonephritis type I. Significance of clinical and morphological parameters: an investigation of 220 cases

We carried out a retrospective investigation in 220 patients to assess the influence of various parameters on the long-term course of membranoproliferative glomerulonephritis (MPGN) type I. 50 patients (23%) died during the follow-up period of 59 months on average, in another 57 (26%) end-stage renal failure developed. 54 patients (24%) suffered from chronic renal failure, stable renal function (creatinine below 1.3 mg/dl) was preserved in 59 patients (27%). 5 years after biopsy 49% of the patients had already died or needed regular dialysis treatment; after 10 years this proportion increased to 64%. Morphological findings: The outcome was--with the exception of focal crescent formations--not determined by the severity of glomerular changes; the survival rate, however, decreased significantly, if tubulointerstitial lesions were present as defined by acute renal failure, interstitial fibrosis or a combination of both. Clinical parameters: A progressive deterioration of renal function and an increasing number of renal deaths was noticed, when elevated serum creatinine levels at the time of biopsy and high blood pressure values during the follow-up period were observed. 26 patients died from hypertension, 18 of whom before reaching end-stage renal failure. Nephrotic syndrome and the degree of proteinuria as well as antiphlogistic and immunosuppressive treatment did not influence the prognosis of MPGN type I.     

Long-term prognosis of focal sclerosing glomerulonephritis. An analysis of 250 cases with particular regard to tubulointerstitial changes

The following results were obtained in a long-term retrospective study including 250 patients with focal sclerosing glomerulonephritis: 1. The renal survival rate (RSR) was 90% at 5 years and 67% at 10 years, the average period of observation being 4.7 years. 2. Univariate analysis revealed that the following morphologic and clinical parameters are associated with an increased risk of terminal renal failure or death due to renal causes: a) Tubulointerstitial changes in the form of interstitial fibrosis, with or without acute renal failure; b) Advanced glomerular lesions; c) Advanced vascular alterations; d) Nephrotic syndrome present at the time of the biopsy; e) Elevated serum creatinine concentration at the time of the biopsy; f) Arterial hypertension at the time of the biopsy; g) Greater age at diagnosis; h) Male sex. 3. Multivariate survivorship analysis showed that tubulointerstitial changes and the presence of nephrotic syndrome at the time of biopsy are the only variables with significant independent predictive value for the outcome. Assessment of these factors thus allows the pathologist to make a relevant statement concerning the probable course and prognosis of the disease at the time of the diagnostic biopsy.     

Number of interstitial capillary cross-sections assessed by monoclonal antibodies: relation to interstitial damage

Using thin Plexiglass sections stained with silver, the peritubular capillary area and number of capillary cross-sections can predict both interstitial damage and plasma creatinine concentrations. This technique is both difficult to perform and time-consuming. We have restudied this topic using conventional cryostat sections from 46 biopsies with chronic glomerulonephritis and tubulointerstitial nephritis and two monoclonal antibodies (MoAb) recognising capillary endothelium. Seven pretransplant biopsies acted as controls. The number of capillary cross-sections/mm2 was counted, and the degree of tubular atrophy, interstitial fibrosis and cell infiltration of the interstitium independently assessed on a semiquantitative scale using paraffin sections. These results were correlated with the plasma creatinine or 51Cr-EDTA glomerular filtration rate. Mean number of capillary cross-sections in normal interstitium was 373 +/- 50/mm2, and in the 46 biopsies studied 242 +/- 57/mm2. The number of capillary cross-sections reflected the plasma creatinine (r = 0.82, P less than or equal to 0.0001) and the glomerular filtration rate (r = 0.64, P less than or equal to 0.0001) at the time of biopsy with greater accuracy than any of the conventional gradings of interstitial damage on paraffin sections. We conclude that the use of anti-endothelial cell monoclonal antibodies makes counting capillary cross-sections easy and reliable, and that this technique can be employed to assess the extent of interstitial damage in conventional cryostat sections.     

Kidney biopsy as a predictor for renal outcome in ANCA-associated necrotizing glomerulonephritis

BACKGROUND: In kidney biopsies of patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated systemic vasculitis, a variety of histopathological lesions occur, and their relationship to renal outcome is virtually unknown. This multicenter European study reports a clinicopathological analysis of biopsies from 157 patients with systemic vasculitis. METHODS: The biopsies were evaluated according to a previously standardized scoring protocol. Serum creatinine values were measured at the time of biopsy and one year later. In addition, the lowest creatinine level during follow-up was taken into account as the optimum level of renal function recovery. The clinical prognostic value of the histopathological parameters was analyzed with the Kruskal-Wallis one-way analysis of variance and the Mann-Whitney U-test. RESULTS: The percentage of normal glomeruli correlated most significantly with renal outcome at all points of measurement (all P < 0.001). Other lesions predicting for renal function were glomerular sclerosis (P < 0.0005 at one year after the biopsy), diffuse interstitial infiltrates (P < 0.0001 at entry, P < 0.0003 at one year), tubular necrosis (P < 0.0025 at entry), and tubular atrophy (P < 0.002 at entry, P < 0.0002 at one year). CONCLUSION: Traditionally, attention is focused on the extent of active lesions in the renal biopsy in order to determine the severity of renal disease and its implication for renal outcome. Because of their significant impact on renal function, combined with their easy recognition, we recommend the use of the percentage of normal glomeruli in an adequate biopsy in predicting renal function of patients with systemic vasculitis.     

Wegener's granulomatosis: inflammatory cells and markers of repair and fibrosis in renal biopsies--a clinicopathological study.

OBJECTIVE: This study aimed to quantitate inflammatory cells in renal biopsies from patients with Wegener's granulomatosis (WG) and to identify cells participating in early fibrogenesis. The goal was to determine whether these cells correlated with the severity of renal disease and whether their presence had a bearing on renal prognosis. MATERIAL AND METHODS: Sixty-one patients with WG who had a renal biopsy taken at the time of diagnosis were included in the study. Immunostaining with monoclonal antibodies towards macrophages (CD68), T- and B-lymphocytes, alpha-smooth muscle actin (alpha-SMA) and vimentin was done. RESULTS: The dominating intraglomerular leucocytes were macrophages (29.9 +/- 15 cells/glomerular cross-section) and to a lesser extent T-cells (2.57 +/- 1.8 cells/glomerular cross-section). No B-lymphocytes were detected in the glomeruli. More than two-thirds of the T-cells were CD8+ (cytotoxic) cells. Macrophages and T-lymphocytes were distributed equally in the renal interstitium and were numerous around crescentic glomeruli. Glomerular and interstitial macrophages and interstitial T-cells correlated significantly with serum (S-) creatinine at the time of biopsy but not after 1 year. S-creatinine at the time of biopsy and after 1 year differed significantly among the three levels of interstitial alpha-SMA staining. S-creatinine at biopsy was highest when tubular vimentin staining was strongest, and tubular vimentin staining was strongest in patients with acute tubular damage. CONCLUSIONS: Evidence was found for a cellular type IV immune response in WG, with CD8+ T-lymphocytes and macrophages dominating the cellular infiltrate. The detection of interstitial alpha-SMA, probably staining myofibroblasts implicated in renal fibrogenesis, indicated a low glomerular filtration rate 1 year after renal biopsy.     

Histologic and clinical findings in living donor allografts with long-term stable function

BACKGROUND/AIMS: Protocol biopsy is an important strategy which assesses the histological changes that can occur in the renal allograft and adversely affect its outcome. We aimed to evaluate histological changes in long-term living donor transplants. METHODS: Elective biopsies were done for 120 live donor renal transplant recipients with well-functioning grafts and no rejection history at least 1 year or more after transplant. All patients had serum creatinine levels <2 mg/dl. The histopathological findings using the chronic allograft damage index score were correlated with different clinical and immunological parameters. RESULTS: Chronic tubulointerstitial fibrosis was the most prevalent finding (85% of cases), mostly of mild degree. Normal biopsies were reported in only 7.5% of cases, whereas chronic cyclosporine nephrotoxicity was detected in 5.8% of biopsies. Posttransplant hypertension was significantly correlated with glomerulosclerosis, and posttransplant diabetes with glomerulosclerosis, mesangial matrix increase, tubular atrophy and interstitial fibrosis. The main risk factors associated with a high chronic allograft damage index score were DR mismatching, posttransplant diabetes and time of biopsy. All histopathological changes increased with advancing donor age and declining graft function. CONCLUSION: Elective biopsies showed that histopathological findings do exist even with stable renal function that may pave the way for predicting long-term graft outcome.     

Systemic hypertension in patients with glomerulonephritis

Although systemic hypertension is very common in patients with glomerulonephritis there is a dispute if this alteration is consequence of the glomerulonephritis "per se" or is a consequence of the renal failure secondary to the glomerular lesion. With the aim to analyze the factors associated with systemic hypertension, 196 patients with different forms of nephritis were studied. The systemic arterial pressure was measured by standard sphygmomanometer, renal function was evaluated by the determination of the serum creatinine concentration or creatinine clearance. The diagnosis of the type of glomerulonephritis was made on the basis of an examination of kidney biopsy specimens. The prevalence of arterial hypertension among patients with glomerulonephritis was 62.7%. The hypertensive patients were older (hypertensive = 30.6 +/- 12.8; normotensive = 25.4 +/- 1.6 years; P = 0.03). The prevalence of arterial hypertension was lower in patients with minimal glomerular lesion (12.5%), though their ages were also lower (18.1 +/- 3.6 and 29.1 +/- 1.03 years; P = 0.03). Arterial hypertension did not correlate with the serum levels of creatinine and albumin; creatinine clearance and 24-h proteinuria. IN CONCLUSION: In the patients with glomerulonephritis, the presence of arterial hypertension was associated with a higher mean age whereas the intensity of proteinuria, the level of renal function or the type of glomerulonephritis was not different between the two groups.     

The spectrum of acute renal failure in IgA nephropathy

Background: Acute renal failure rarely complicates the course of IgA nephropathy. In this study, we have tried to define the mode of presentation, the spectrum of morphology, and the prognostic factors for renal outcome. Methods: Twenty patients with biopsy-proven IgA nephropathy who developed acute renal failure were identified from 2000 to 2009 at a medical center in Taiwan. The patients' records were retrospectively reviewed with respect to clinical presentation, morphology of renal biopsy, and outcomes. Results: On histology, glomerular crescents were present in 11 patients (55%), acute tubular necrosis was identified in 11 patients (55%), acute interstitial nephritis was seen in 4 patients (20%), and extensive tubular red blood cell casts were present in 4 patients (20%). At the end of follow-up, 2 patients (10%) had died, 11 patients (55%) were in remission, and 7 patients (35%) developed end-stage renal disease. The prognostic factors for renal outcome were peak serum creatinine, dialysis support requirement, morphology (prominent glomerular/tubular injury), percentage of glomeruli affected by crescents, and interstitial infiltration (p = 0.04, <0.001, 0.013, 0.05, 0.02, respectively). Conclusions: Our findings suggested that there were four pathogenic mechanisms involved in IgA nephropathy with acute renal failure including (1) crescentic IgA nephropathy; (2) acute tubular necrosis associated with microhematuria and red blood cell casts occluding tubules; (3) acute tubular necrosis not related to microhematuria; and (4) acute interstitial nephritis, apparently induced by drugs. In general, patients with prominent tubular injury had a much higher remission rate than patients with prominent glomerular injury.