Chronic Histological Lesions Research Articles

Characterization of Amyloid in Equine Recurrent Uveitis as AA Amyloid

Two horses with chronic uveitis and histological lesions consistent with equine recurrent uveitis (ERU) were examined. Microscopical findings in the ciliary body included deposits of amyloid lining the non-pigmented epithelium, intracytoplasmic, rod-shaped, eosinophilic inclusions and intraepithelial infiltration of T lymphocytes. Ultrastructural examination of the ciliary body of one horse confirmed the presence of abundant extracellular deposits of non-branching fibrils (9-11 nm in diameter) consistent with amyloid. Immunohistochemistry revealed strong positive labelling for AA amyloid and mass spectrometry showed the amyloid to consist primarily of serum amyloid A1 in both cases. The findings suggest that localized, intraocular AA amyloidosis may occur in horses with ERU.

Hypoxic Patterns of Placental Injury: A Review

In utero hypoxia is an important cause of perinatal morbidity and mortality and can be evaluated retrospectively to explain perinatal outcomes, to assess recurrence risk in subsequent pregnancies, and to investigate for medicolegal purposes by identification of many hypoxic placental lesions. Definitions of some placental hypoxic lesions have been applied relatively liberally, and many of them are frequently underreported. Objectives To present a comprehensive assessment of the criteria for diagnosing acute and chronic histologic features, patterns, and lesions of placental and fetal hypoxia and to discuss clinicopathologic associations and limitations of the use thereof. The significance of lesions that have been described relatively recently and are not yet widely used, such as laminar necrosis; excessive, extravillous trophoblasts; decidual multinucleate extravillous trophoblasts; and, most important, the patterns of diffuse chronic hypoxic preuterine, uterine, and postuterine placental injury and placental maturation defect, will be discussed. Literature review. The placenta does not respond in a single way to hypoxia, and various placental hypoxic features should be explained within a clinical context. Because the placenta has a large reserve capacity, hypoxic lesions may not result in poor fetal condition or outcome. On the other hand, very acute, in utero, hypoxic events, followed by prompt delivery, may not be associated with placental pathology, and many poor perinatal outcomes can be explained by an etiology other than hypoxia. Nevertheless, assessment of placental hypoxic lesions is helpful for retrospective explanations of complications in pregnancy and in medicolegal investigation.

Myocardial fibrosis associated with previous ingestion of yew (Taxus sp.) in a Holstein heifer

Twenty-six 5-month-old Holstein calves were accidentally exposed to discarded branches of yew bushes (Taxus sp.). Several calves were found dead approximately 24 hr after exposure; however, a few calves died several days after exposure. One calf died 18 days after the initial exposure to Taxus sp. and was examined on the farm via necropsy. Gross lesions included ascites, and dilated and flaccid myocardial ventricles. Sections of formalin-fixed heart were submitted to the Indiana Animal Disease Diagnostic Laboratory for histopathologic examination; fresh rumen contents were submitted for toxicologic testing. Histologically, large areas of myocardium were replaced by fibrous connective tissue, suggesting previous myocardial necrosis. Taxus alkaloids were identified in the rumen contents using gas chromatography-mass spectrometry. Based on the clinical history, the gross and histologic lesions, the identification of Taxus alkaloids in the rumen contents, and lack of exposure to other known cardiotoxic agents, yew toxicity was considered the cause of death in this calf. Ingestion of taxines is known to cause acute and subacute toxicity in human beings and animals; however, a chronic clinical course and severe histologic lesions have not been previously associated with yew toxicity. Although only 1 calf was examined, this case suggests that yew toxicity can result in a prolonged clinical course in cattle and can cause histologic myocardial lesions.

Cluster Analysis Shows that Chronic Damage in Early Indication Biopsies Predicts Long-Term Graft Survival, While Early Active Inflammation Does Not

Background: Recently, it has become clear that specific disease like antibody-mediated rejection and glomerular pathologies are very often the final reason for graft loss. It remains to be determined how early chronic histological damage, without specific pathophysiologic explanation, affects long-term graft survival. Methods: All (N=1197) recipients of a renal allograft or a combined kidney-pancreas graft, transplanted at a single center between January 1, 1991 and December 31, 2001 were included in this study. The data were collected prospectively. All indication biopsies (N=917 in 563 patients) performed within the first year after transplantation were rescored according to the current Banff classification. Principal component analysis, k means clustering and unsupervised hierarchical clustering was applied to reveal the relationships between the different histological lesions. Survival analysis was performed using Cox proportional hazards analysis and log-rank testing. Mean follow-up time is 15.3±2.97 years. Results: Adjusted for baseline demographic covariates, arteriolar hyalinosis (p=0.003) and transplant glomerulopathy (p< 0.0001) independently predict long-term graft survival. Inflammatory lesions, including tubulitis, interstitial inflammation, microcirculation inflammation and C4d deposition in the first year after transplantation associate with early graft loss, but do not affect long-term graft survival. Unsupervised hierarchical clustering analysis of the histological lesions confirms this clear distinction between the chronic histological lesions and lesions associated with inflammatory activity (Figure A). K-means clustering analysis identifies 2 clearly distinct patient groups, which differ from each other with respect to these same chronic histological lesions (interstitial fibrosis, tubular atrophy, arteriolar hyalinosis, mesangial matrix increase, transplant glomerulopathy, vascular intimal thickening and glomerulosclerosis). This clustering of the patients according to the chronic lesions offers a better predictor of long-term graft survival than each of the chronic lesions separately (HR 2.1 [CI 1.5-3.1]; p=0.0001) (Figure B).[Figure 1]Conclusion: Individual chronic lesions like arteriolar hyalinosis, tubular atrophy, interstitial fibrosis, glomerulosclerosis, mesangial matrix increase and vascular intimal thickening closely associate with each other. These lesions cannot be seen as individual entities and likely share common pathophysiology. It is not possible to tell apart the individual contribution of these different lesions to the clinical outcome of these patients. The global burden of early chronic histological damage within the first year after transplantation importantly affects the fate of the allografts, while active inflammation in early indication biopsies is not associated with long-term graft survival.

Severity of nephrotic IgA nephropathy according to the Oxford classification

IgA nephropathy with nephrotic syndrome (nephrotic IgAN) is a rare form of IgAN. Its prognosis and response to steroid therapy are still controversial because the differential diagnosis between nephrotic IgAN and minimal change nephrotic syndrome with IgA depositions is sometimes confused. In this retrospective cohort analysis, we accurately diagnosed 42 cases of nephrotic IgAN (4.4%) from 954 IgAN patients, according to the Oxford classification. We analyzed the clinical and histological data, prognosis, and response to steroid therapy. In nephrotic IgAN, mean estimated glomerular filtration rate (eGFR) was 51.1 ± 24.6 ml/min, proteinuria was 5.71 ± 2.56 g/day, and urinary red blood cells were 51.0 ± 37.8 high power field. Both active and chronic histological lesions were observed. Cumulative renal survival rate was significantly lower in nephrotic IgAN than in non-nephrotic IgAN (the control group consisted of 47 non-nephrotic IgAN patients diagnosed between 1995 and 1996) (log-rank test: P < 0.0001). The cases with steroid therapy significantly improved their prognosis, though their male-to-female ratio and blood pressure level measured at renal biopsy were significantly lower than in the cases without steroid therapy. Steroid therapy was particularly effective in cases with low-grade tubular atrophy and interstitial fibrosis (T-grade in Oxford classification). Without steroid therapy, lower eGFR and higher T-grade were independent risk factors for severe outcome by multivariate Cox regression. Nephrotic IgAN is a very severe form of IgAN, with renal dysfunction, massive hematuria, and active and chronic histopathological lesions. Renal outcome is severe; however, steroid therapy can improve prognosis in cases with higher eGFR and lower T-grade, according to the Oxford classification.

Corticosteroids in Patients with IgA Nephropathy and Severe Chronic Renal Damage

Little is known about the utility of treating patients with advanced IgA nephropathy (IgAN). From 2001 to 2005, four patients came to our observation because of serum creatinine higher than 3 mg/dL, proteinuria ranging from 1.8 to 5.1 g/day, and a histological picture of diffuse sclerotic lesions. A corticosteroid course of 12 months was given. Patients were observed for a mean follow up of 84 months. At the end of the steroid course, proteinuria lowered quickly below 1 g/day in two patients, whereas the other two experienced a slower and less persistent decrease of proteinuria. Despite similar lesion severity at renal biopsy, renal function stabilized only in these two ones. In conclusion, these preliminary observations suggest a possible efficacy of corticosteroids in slowing down the progression of renal disease and in postponing the need of dialysis in IgAN patients with stage IV CKD and severe chronic histological lesions.

Specificity of Histological Markers of Long-Term CNI Nephrotoxicity in Kidney-Transplant Recipients Under Low-Dose Cyclosporine Therapy

The specificity of chronic histological lesions induced by calcineurin inhibitors (CNI) is often questioned, but few studies have directly compared long-term lesions in renal-transplant patients who received this treatment and those who did not. We therefore conducted a retrospective study of 141 kidney-transplant recipients treated with (n = 48) or without (n = 93) cyclosporine (CsA) to compare the histological lesions observed at 3-month, 24-month and 10-year protocol biopsies. All of the chronic elementary lesions (glomerulosclerosis, interstitial fibrosis, tubular atrophy, arteriolar hyalinosis, fibrointimal thickening) progressed in frequency and severity in both groups, although significantly more in the CsA group. Ten-year biopsy results showed that 92% of patients in the CsA-treated group and 65% in the control group had arteriolar hyalinosis lesions. When we focused on muscular arteriolar hyaline deposits more specific to CsA arteriolopathy, we observed these lesions in 68% of CsA patients and 28% of patients who had never received CsA. CsA was not the sole factor involved in the development of arteriolar hyalinosis and was independently associated with an increased risk of graft loss. In summary, we observed that histological lesions commonly attributed to CsA nephrotoxicity were not sufficiently specific to definitively diagnose CNI nephrotoxicity.

Diagnosis of Placental Abruption: Relationship Between Clinical and Histopathological Findings

Despite intensive investigation, it is unclear whether the diagnosis of placental abruption should be based on established clinical criteria or histopathological findings. Although the vast majority of placental abruption cases appear to have a chronic etiology, it also remains speculative as to whether abruption is an acute or chronic process. The aim of the present multicenter, case-control study was to assess the concordance between clinical and histopathological diagnostic indicators of placental abruption. A secondary aim was to investigate acute and chronic histological lesions associated with clinical abruption. The clinical and histologic criteria for abruption were compared using data obtained from the New Jersey-Placental Abruption Study. The study subjects, 162 women with a confirmed clinical diagnosis of placental abruption, were matched with 173 controls without placental abruption. Criteria for the clinical diagnosis of placental abruption included painful vaginal bleeding accompanied by nonreassuring fetal status, uterine hypertonicity, evidence of clinically significant retroplacental bleeding, or clot(s) or placental abruption diagnosed on prenatal ultrasound. The pathological criteria for a diagnosis of abruption included hematoma with or without recent or old infarctions, foci of villous compression, fibrin deposition, and hemosiderin-laden histiocytes in cases with older hematomas. Histologic lesions were grouped as acute or chronic histologic lesions. Acute lesions included chorioamnionitis, funisitis, acute deciduitis, meconium-stained membranes associated with amnion necrosis and pigmented macrophages, villous stromal hemorrhage, and villous edema. Chronic lesions included chronic deciduitis, maternal floor decidual necrosis, decidual vasculopathy, placental infarction, villous mal-development with delayed or accelerated maturation, hemosiderin deposition, intervillous thrombosis, and villitis. Of the 162 clinically diagnosed cases, only 30.2% (n = 49) were confirmed as placental abruption based on gross or histological findings, whereas the specificity for a histologic confirmation of abruption was 100%. Among clinically diagnosed cases, the most common indication for a clinical diagnosis of abruption was evidence of retroplacental clot(s) or bleeding (77.1%). Two chronic lesions, placental infarction and decidual vasculopathy, were significantly associated with abruption, but no acute lesions were significantly associated with abruption. The investigators conclude from these finding that there is poor concordance between the clinical and pathological diagnosis of placental abruption. The diagnosis of abruption should be based on clinical criteria such as evidence of retroplacental bleeding or clot(s), ultrasound visualization of abruption, or painful vaginal bleeding accompanied by either nonreassuring fetal status or uterine hypertonocity.

Conservative Management, Immunosuppressive Treatment or both for Patients with Primary Immunoglobulin a Nephropathy?

Immunoglobulin A nephropathy (IgAN) is the most commonly encountered primary glomerulonephritis and it usually follows an indolent clinical course. However, hypertensive patients with proteinuria and renal insuf-ficiency at presentation and patients with severe histological involvement are at high risk to develop end-stage renal failure. Patients with normal renal function, mild proteinuria (&lt;1 g/24h) and mild histopathological involvement need only observation, whereas patients with heavy proteinuria, impaired renal function and moderate to severe histopathological involvement are usually treated with immunosuppressive drugs. Angiotensin converting enzyme (ACE) inhibitors are used in patients with arterial hypertension and/or proteinuria 1–2 g/24h. Corticosteroids are indicated in patients with heavy proteinuria (&gt;3 g/24h) and in progressive disease despite treatment with ACE inhibitors. Combinations of corticosteroids and cytotoxic drugs are saved for patients with IgA nephropathy and a rapidly progressive course. Fish oil might be an alternative to cor-ticosteroids in cases with renal insufficiency and chronic histological lesions.

Diagnosis of placental abruption: relationship between clinical and histopathological findings

Objective We evaluated the extent to which histologic lesions bearing a diagnosis of abruption conform to a diagnosis based on established clinical criteria. We further examined the profile of chronic and acute histologic lesions associated with clinical abruption. Methods Data from the New Jersey-Placental Abruption Study – a multi-center, case-control study – were utilized to compare the clinical and histologic criteria for abruption. The study was based on 162 women with clinically diagnosed abruption and 173 controls. We examined the concordance between clinical indicators for abruption with those of a histopathological diagnosis. The clinical criteria for a diagnosis of abruption included (i) evidence of retroplacental clot(s); (ii) abruption diagnosed on prenatal ultrasound; or (iii) vaginal bleeding accompanied by nonreassuring fetal status or uterine hypertonicity. The pathological criteria for abruption diagnosis included hematoma, fibrin deposition, compressed villi, and hemosiderin-laden histiocytes in cases with older hematomas. Acute lesions included chorioamnionitis, funisitis, acute deciduitis, meconium stained membranes, villous stromal hemorrhage, and villous edema. Chronic lesions included chronic deciduitis, decidual necrosis, decidual vasculopathy, placental infarctions, villous mal-development (delayed or accelerated maturation), hemosiderin deposition, intervillous thrombus, and chronic villitis. Results Of clinically diagnosed cases, the sensitivity and specificity for a histologic confirmation of abruption were 30.2% and 100%, respectively. Presence of retroplacental clots remained the single most common finding (77.1%) among clinically diagnosed cases. Among the acute lesions, chorioamnionitis and funisitis were associated with abruption. The only chronic histologic lesion associated with abruption was placental infarctions. Conclusions The concordance between clinical and pathologic criteria for abruption diagnosis is poor. The criteria for diagnosing a clinical abruption should include sonographic visualization of abruption, evidence of retroplacental clots, or vaginal bleeding accompanied by nonreassuring fetal status or uterine hypertonicity.

Urinary levels of epidermal growth factor, interleukin‐6 and monocyte chemoattractant protein‐1 may act as predictor markers of renal function outcome in immunoglobulin A nephropathy

Urinary cytokine excretion may reflect histological changes in immunoglobulin A nephropathy (IgAN), and their measurement can give information about disease outcome. Thirty-three IgAN patients were prospectively followed for 5.6 +/- 3.1 years. Urinary levels of monocyte chemoattractant protein-1 (MCP-1), interleukin (IL)-6 and epidermal growth factor (EGF) were measured at diagnosis and repeated 1 year later for IL-6 and EGF. Urinary MCP-1 and IL-6 levels were increased significantly, while EGF excretion reduced in IgAN patients, compared to controls. IL-6 urinary levels showed significant positive correlation with chronic histological lesions. Patients were classified into five groups, according to the Haas classification system. MCP-1 and IL-6 urinary levels were increased, whereas EGF levels were reduced in the progression of staging. EGF urinary excretion was a strong predictor factor of disease outcome, significantly correlated with creatinine clearance at time of diagnosis (r = 0.5, P = 0.005), and at the end of follow up (r = 0.6, P = 0.001). Urinary EGF levels measured a year later could predict long-term outcome better, and a cut of 0.05 pg/mg urine creatinine levels could distinguish between progressors and non-progressors. Urinary MCP-1, IL-6 and EGF levels may represent histology in IgAN. EGF excretion can be a predictive marker and its serial measurements may give information about disease outcome and the effect of treatment.

Les biopsies de dépistage en transplantation rénale : du rejet aigu infra-clinique aux lésions chroniques de l’allogreffe

Kidney biopsies for screening purposes have the advantage of revealing the early appearance of lesions having a poor prognosis before kidney function is altered. Early screening of subclinical rejections allows preventive treatment of kidney transplantation in patients taking cyclosporine or azathioprine, thus improving their renal function and reducing the incidence of chronic histological lesions. However, this benefit has yet to be demonstrated in patients taking tacrolimus or mycophenolic acid. As for interstitial fibrosis lesions and tubular atrophy, biopsies can screen subclinical immunological lesions or those related to nephrotoxicity of anticalcineurins, which have a negative prognostic value in terms of graft survival. In addition, detection of these lesions could be a very useful criterion of efficacy in clinical studies. Moreover, they could help decide on modifying immunosuppressor treatment and evaluate the therapeutic strategies in patients at risk for humoral rejection. Finally, given the cost of biopsies and the inconvenience for the patient, the question of the timing and the number of screening biopsies is crucial. However, interventional studies evaluating notably immunosuppressor treatment modifications based on histological data are necessary to justify the daily use of screening biopsies.

What have we learned from the use of ciclosporin A in the treatment of nephrotic patients with idiopathic membranous nephropathy?

Background: Ciclosporin A (CsA) has been widely used in the treatment of patients with nephrotic syndrome over the last 10 years. Objective: Review of the accumulated knowledge from the use of CsA in patients with nephrotic syndrome due to idiopathic membranous nephropathy (IMN). Methods: The most important articles concerning the use of CsA in IMN patients have been reviewed. Results/conclusion: CsA, a potentially nephrotoxic drug, induces remission of nephrotic syndrome in > 80% of IMN patients. Relapses occur after its withdrawal and long-term treatment is necessary. Repeat renal biopsies show no signs of CsA nephrotoxicity, but show deterioration of chronic histological lesions with time, even in cases with remission. Thus, CsA is effective in IMN patients, but its long-term use should be examined with caution.

Cyclosporin exposure correlates with 1 year graft function and histological damage in renal transplanted patients.

Cyclosporin (CsA) level obtained 2 h after the morning dose (C(2)) has been shown to accurately predict total CsA exposure and acute rejection (AR) risk, whereas conventional trough levels (C(0)) do not. The impact of C(2) monitoring on long-term kidney graft function, independent from AR risk, is still unclear, however, and it was assessed in the present study. We enrolled 39 CsA-treated renal transplant recipients and used 1 year graft function and histological structure as surrogate markers of graft outcome. CsA dose was adjusted according to C(2) levels. In the first 7 days after grafting, 40-51% of patients failed to reach target C(2) levels; nevertheless, at 1 year the incidence of AR was only 2.5% and graft and patient survival was 100%. The decrease of serum creatinine (12-6 months) was associated with significantly higher C(2) levels over time (P = 0.0003) and lower intrapatient variability of CsA relative absorption (CV) (P = 0.0006). One year graft biopsy showed chronic tubulointerstitial lesions in 54.5% of patients. Both C(2) mean levels and the percentage CV independently predicted the severity of chronic histological lesions (R = 0.69, P<0.0001). Higher C(2) levels, within the proposed target range values, seem to be associated with better renal function and structure.

Therapeutic Approach of Patients with IgA Nephropathy

Immunoglobulin A nephropathy (IgAN) is the most commonly encountered primary glomerulonephritis and it usually follows an indolent clinical course. However, hypertensive patients with proteinuria and renal insufficiency at presentation and patients with severe histological involvement are at high risk to develop end stage renal failure. There is no consensus for the treatment of patients with IgA nephropathy. In general, patients with normal renal function, mild proteinuria (< 1 g/24 h) and mild histopathological involvement need only observation, whereas patients with heavy proteinuria, impaired renal function and moderate to severe histopathological involvement are candidates for specific treatment. Angiotensin converting enzyme (ACE) inhibitors are used in patients with arterial hypertension and/or proteinuria 1–2 g/24 h. Corticosteroids are indicated in patients with heavy proteinuria (> 3 g/24 h) and in progressive disease despite treatment with ACE inhibitors. Fish oil might be an alternative to corticosteroids in cases with renal insufficiency and chronic histological lesions. Combinations of corticosteroids and cytotoxic drugs are saved for patients with IgA nephropathy and a rapidly progressive course.

Early elimination of cyclosporine in kidney transplant recipients receiving sirolimus prevents progression of chronic pathologic allograft lesions

Cyclosporine elimination in a regimen including sirolimus has been shown to be a safe and effective approach to improve graft function. Nevertheless, it is still unknown whether the functional benefit of CyA withdrawal coincides with a subsequent reduction in histologic lesions of chronic damage or development of chronic allograft nephropathy. This consideration would forcast a reduction in the rate of long-term graft loss. We analyzed 114 graft biopsies from a subgroup of 57 patients that had been included in a randomized study to eliminate CyA at 3 months posttransplant from a regimen including sirolimus either in group A CyA + SRL vs group B of SRL with CyA elimination at 3 months. Every patient had two biopsies, one at transplantation and another at 1 year. The biopsy reading was performed in a blinded manner by a central pathologist using the Banff 1997 and the CADI classifications. A significantly lower rate of progression of tubular and interstitial chronic lesions between basal and 1-year biopsies was observed for group B patients. In addition, the incidence of new cases of chronic allograft nephropathy during the first year was significantly lower in the group in which CyA had been eliminated at 3 months posttransplant. We conclude that early elimination of CyA in the first months posttransplant, when SRL is used as the main immunosuppressant, reduces the appearance or worsening of chronic histologic lesions, probably as a consequence of long-term CyA toxicity prevention.

Prednisolone and Azathioprine in IgA Nephropathy

Background: Immunoglobulin A nephropathy (IgAN) is one of the most common primary glomerular diseases. Although its clinical course is usually benign, some patients develop end-stage renal failure (ESRF). The role of immunosuppressive drugs in the treatment of IgAN remains controversial. The effect of treatment with prednisolone and azathioprine and the clinical and histological parameters related to a poor outcome are examined retrospectively in this analysis. Methods: Seventy-four patients with IgAN and a follow-up period of 10 years were included in this study. Forty-one were treated with prednisolone (initially 60 mg/day) and azathioprine (initially 2 mg/kg BW/day) in gradually reduced doses for 24 ± 9 months, whereas 33 patients received no immunosuppressive drugs. The clinical course was estimated using the end-points of doubling of baseline serum creatinine and/or ESRF. The contribution of clinical and histological parameters in the clinical outcome was estimated by univariate and multivariate analyses. Results: The overall clinical courses of both groups of patients showed a rather similar pattern. Doubling of serum baseline creatinine was observed in 9 of 41 treated (22%) and in 10 of 33 untreated (30%), whereas ESRF developed in 6 treated (15%) and 6 untreated patients (18%) (p = NS). However, treated patients with heavy proteinuria (>3 g/24 h) had a significantly better outcome compared to untreated (doubling of serum creatinine in 29 vs. 78% and ESRF in 17 vs. 55%, p < 0.05). Proteinuria (p < 0.01), mean blood pressure (p < 0.02), baseline serum creatinine (p = 0.02) and severity of interstitial myofibroblast expression (p = 0.02) were identified as independent risk factors related to a poor outcome by multivariate analysis. Side effects of treatment were not uncommomn and observed in 10 (24%) patients. Conclusion: Treatment with prednisolone and azathioprine is beneficial in ameliorating the clinical course of a subset of IgAN patients with heavy proteinuria or impaired renal function. Patients with advanced renal failure and severe chronic histological lesions should not be treated by this regimen as no benefit is expected and there is a risk of side effects.

Outcome of IgA nephropathy in adults graded by chronic histological lesions

This prognostic study of primary immunoglobulin A (IgA) nephropathy focused on chronic irreversible glomerular sclerosis and interstitial fibrosis, based on the premise that this disease is characterized by a protracted and, for many, progressive course. We used a chronicity-based histological grading system to assess the biopsy specimens of 126 adults with IgA nephropathy over a median follow-up of 10 years. Our grading system included a glomerular grading (GG) of 1 to 3 based on the extent of glomerular sclerosis, a tubulointerstitial grading (TIG) of 1 to 3 based on the degree of tubular loss or interstitial fibrosis, and the evaluation of hyaline arteriolosclerosis (HA). These three histological parameters were correlated with each other and with serum creatinine level, degree of proteinuria, and blood pressure at the time of renal biopsy. Univariate analysis showed that these three histological and three clinical parameters were significantly correlated with renal survival. By multivariate analysis using the Cox regression model, GG, serum creatinine level, and degree of proteinuria represented independent prognostic factors of renal survival. For a subset of patients at a relatively early stage of disease with a serum creatinine level less than 130 μmol/L at the time of biopsy, all three histological features and degree of proteinuria were significantly correlated with renal survival, and GG was the only independent prognostic factor for renal outcome. This study shows that glomerular sclerosis represents the most important prognostic factor in adult patients with primary IgA nephropathy and has a strong predictive value. Our chronicity-based histological grading system not only correlates well with the natural history of IgA nephropathy but is also reproducible and relatively simple to apply.

Evaluation of the Kidney as a Potential Site of Avian Influenza Virus Persistence in Chickens

One-day-old chickens were inoculated intravenously with one of three low-pathogenicity avian-origin influenza isolates. On day 5 postinoculation (PI), the frequency of influenza virus isolation from cloacal swabs following challenge with each isolate ranged from 83% to 100% for clinically normal euthanatized chickens. Influenza virus was also frequently isolated from kidneys of these chickens (47%) and from chickens that died (100%). Kidneys positive for virus isolation had lesions of nephrosis and/or acute nephritis, and influenza viral nucleoprotein was demonstrated in nuclei and cytoplasm of necrotic renal tubule epithelium. On sampling days 28 and 45/60 PI, influenza virus was neither isolated from nor immunohistochemically demonstrated in kidneys (0/125); however, the kidneys (47%) did have chronic histologic lesions that suggested previous influenza virus infection of the kidneys. Influenza virus was isolated from cloacal swabs of two of 44 chickens on day 28 PI, but all cloacal swabs were negative for virus recovery on sampling day 45/60 PI (0/81). These results indicate that replication of influenza virus in renal tubule epithelial cells did not result in persistence of type A influenza virus in this immunologically privileged site.