Reproducibility of the Oxford classification of immunoglobulin A nephropathy, impact of biopsy scoring on treatment allocation and clinical relevance of disagreements: evidence from the VALidation of IGA study cohort.

BACKGROUND: The VALidation of IGA (VALIGA) study investigated the utility of the Oxford Classification of immunoglobulin A nephropathy (IgAN) in 1147 patients from 13 European countries. Methods. Biopsies were scored by local pathologists followed by central review in Oxford. We had two distinct objectives: to assess how closely pathology findings were associated with the decision to give corticosteroid/immunosuppressive (CS/IS) treatments, and to determine the impact of differences in MEST-C scoring between central and local pathologists on the clinical value of the Oxford Classification. We tested for each lesion the associations between the type of agreement (local and central pathologists scoring absent, local present and central absent, local absent and central present, both scoring present) with the initial clinical assessment, as well as long-term outcomes in those patients who did not receive CS/IS. RESULTS: All glomerular lesions (M, E, C and S) assessed by local pathologists were independently associated with the decision to administer CS/IS therapy, while the severity of tubulointerstitial lesions was not. Reproducibility between local and central pathologists was moderate for S (segmental sclerosis) and T (tubular atrophy/interstitial fibrosis), and poor for M (mesangial hypercellularity), E (endocapillary hypercellularity) and C (crescents). Local pathologists found statistically more of each lesion, except for the S lesion, which was more frequent with central review. Disagreements were more likely to occur when the proportion of glomeruli affected was low. The M lesion, assessed by central pathologists, correlated better with the severity of the disease at presentation and discriminated better with outcomes. In contrast, the E lesion, evaluated by local pathologists, correlated better with the clinical presentation and outcomes when compared with central review. Both C and S lesions, when discordant between local and central pathologists, had a clinical phenotype intermediate to double absent lesions (milder disease) and double present (more severe). CONCLUSION: We conclude that differences in the scoring of MEST-C criteria between local pathologists and a central reviewer have a significant impact on the prognostic value of the Oxford Classification. Since the decision to offer immunosuppressive therapy in this cohort was intimately associated with the MEST-C score, this study indicates a need for a more detailed guidance for pathologists in the scoring of IgAN biopsies.

Impact of Τh1 and Τh2 cytokines in the progression of idiopathic nephrotic syndrome due to focal segmental glomerulosclerosis and minimal change disease.

BACKGROUND: Differential diagnosis between primary focal segmental glomerulosclerosis (FSGS) and minimal change disease (MCD) is sometimes difficult as nephrotic syndrome is the main clinical symptom in both diseases. OBJECTIVES: This study has attempted to evaluate the urinary excretion of Th1 and Th2 cytokines as potential biomarkers in distinguishing the two types of nephrotic syndrome, and predicting outcome of renal function. PATIENTS AND METHODS: Thirty-six patients with FSGS (M/F 22/14, Age; 41.9 ± 17 years, SCr=1.7 ± 0.8 mg/dL, UProt=4.7 ± 5.5 g/24 h), and 21 with MCD (M/F 5/16, Age; 41.4 ± 15 years, SCr = 1 ± 0.4 mg/dL, UProt = 7.9 ± 9.3 g/24 h) were included in the study. Τh1 (IL-2, IL-12, GM-CSF, INF-γ, TNF-α) and Th2 cytokines (IL-4, IL-5, IL-10, IL-13) were measured by multiple cytokine assay, Luminex technology, in first morning urinary samples collected at the day of renal biopsy. RESULTS: No significant differences in urinary excretion of all cytokines were found between FSGS and MCD patients. In FSGS however, IL-12 urinary levels were independent factor correlated with both global sclerosis (R = 0.5, P = 0.009) and interstitial fibrosis (R = 0.5, P = 0.02). Th1 cytokines (IL-2 and GM-CSF) were significantly increased in FSGS patients who did not respond to treatment (P = 0.03 and P = 0.007, respectively). Th2 cytokines (IL-4, IL-5, IL-10, IL-13) were significantly increased in MCD patients with frequent relapses (P = 0.05, P = 0.001, P = 0.01, P = 0.03). CONCLUSIONS: Urinary excretion of Th1 and Th2 cytokines cannot discriminate FSGS from MCD. Th1 cytokines, especially IL-12, IL-2 and GM-CSF, may be involved in pathology and progression of FSGS, while Th2 cytokines are implicated in frequent relapses of nephrotic syndrome in MCD.

A Case of Pulmonary-Renal Syndrome Leading to the Diagnosis of Legionnaires' Disease.

We report a case of a 51-year-old Caucasian man referred at our department due to acute renal failure (ARF) complicating respiratory failure during hospitalization in a regional hospital. The patient was previously started on steroids due to the suspicion of rapidly progressive glomerulonephritis (RPGN) in the context of Goodpasture syndrome. However, clinical and laboratory findings did not support this diagnosis; instead a careful evaluation limited differential diagnosis of the renal insult to acute tubular necrosis or acute interstitial nephritis (AIN) following respiratory infection. With lung function fully improved but renal function not recovering, a renal biopsy revealed AIN, a finding leading to further diagnostic testing and finally to the diagnosis of Legionnaires' disease as a cause of this patient's pulmonary-renal syndrome. The management consisted of progressive tapering of oral steroids associated with full recovery of the patient's renal function. This is a rare case of Legionnaires' disease causing immune-mediated AIN and highlights the possibility of Legionella infection as a cause of pulmonary-renal syndrome.

Up-regulation of urinary markers predict outcome in IgA nephropathy but their predictive value is influenced by treatment with steroids and azathioprine.

OBJECTIVE: Steroids and immunosuppressants can delay progression of renal function in IgAN, but their possible effect in local cytokines has not been studied. MATERIAL AND METHODS: Histology in 53 IgAN patients (M/F 35/18 age 40.5 years (17 - 65)) was evaluated using the Oxford classification system. IL-1ß, -2, -4, -5, -6, -10, -12 and -17, INF-γ and MCP-1 were measured subsequently by multiplex cytokine assay in first morning urine samples taken at the day of renal biopsy. After a 6-month course with RAASinhibitors + fish oils (FO), 35/53 patients, Group A, responded and continued on the same treatment, while in 18/53 who did not respond, Group B, steroids + azathiopine were added. RESULTS: The presence of endocapillary proliferation had significant correlation with the urinary excretion of pro-inflammatory and pro-fibrotic cytokines (IL-1ß, MCP-1, IL-17, INF-γ, IL-6 and IL-10). Serum creatinine at time of diagnosis had significant correlation with proteinuria (p = 0.02), urinary levels of IL-1ß (p = 0.03), IL-2 (p = 0.01) and MCP-1 (p = 0.03). GFR was reduced from 65 ± 29 to 57 ± 34 ml/min, p = 0.005 in Group A and remained stable in Group B patients (GFR from 63 ± 24 to 61 ± 30 ml/min, p = NS). Most of the measured cytokines in the urine predicted deterioration of renal function in Group A, but the urinary excretion of IL-6 seemed to predict renal function outcome in both groups of patients. CONCLUSION: Several cytokines are excreted in the urine of patients with IgAN, and their levels predict the outcome of the disease. Steroids + aza may exert their beneficial effect through suppression of the production or activation of most cytokines.

Detection of multiple cytokines in the urine of patients with focal necrotising glomerulonephritis may predict short and long term outcome of renal function.

BACKGROUND: Detection of urinary cytokines in pauci-immune focal segmental necrotizing glomerulonephritis (FSNGN) may provide valuable information about disease pathogenesis and prognosis. METHODS: Epidermal growth factor (EGF), transforming growth factor (TGF-ß1) and vascular endothelial growth factor (VEGF) were measured by ELISA, and Interleukins, monocyte chemotactic protein-1 (MCP-1), macrophage inflammatory protein (MIP1ß) by a multiplex cytokine assay, in 38 patients with FSNGN. Their levels were correlated with severity of histological findings and renal function outcome in short and long term. RESULTS: The percentage of crescents in renal biopsy had positive correlation with TGF-ß1 (p=0.004) and IL-15 urinary excretion (p=0.01), and negative correlation with EGF (p=0.01). Increased urinary excretion of IL-6, IL-15, VEGF and MIP-1ß was associated with poor renal function outcome, but increased levels of EGF, IL-2 and IL-9 predicted a favourable prognosis. In multiple regression analysis IL-6 and VEGF urinary levels were independent predictors of no-response at the acute phase (p=0.001 and p<0.0001, respectively), while, IL-6 was the only factor (p=0.03) predicted worse outcome at the end of follow-up (39.4±45 months). CONCLUSION: Increased urinary excretion of IL-6, IL-15, VEGF, TGF-ß1, MCP-1 and MIP-1ß and reduced EGF, IL-2, IL-9 may be associated with histological damage and influence response to treatment in pauci-immune FSNGN.

Steroids and azathioprine in the treatment of IgA nephropathy.

AIM: IgA nephropathy (IgAN) is a very common glomerulonephritis among young adults, but the best therapeutic approach has not been fully elucidated. This study evaluated the effect of two different treatment regimes in IgAN, steroids alone or in combination with azathioprine. METHODS: Among 122 patients with primary IgA nephropathy diagnosed in the 2000-2007 period, 22 fulfilled the inclusion criteria for the study: estimated glomerular filtration rate (eGRF) ≥30 ml/min/1.73 m(2), urine protein (Upr) ≥1 g/24 h, blood pressure (BP) <130/80 mmHg, and previous treatment with renin-angiotensin system inhibitors (RAASi) and polyunsaturated fatty acids (PFA) for at least 6 months. Patients were randomized to receive either methylprednisolone alone (MP group) or MP in combination with azathioprine (MP + Aza group) for 12 months, while treatment with RAASi + PFA continued unchanged in both groups. RESULTS: At the completion of the trial, renal function in the MP group remained stable, eGFR from 52 ± 26.7 to 53.6 ± 27.3 ml/min/1.73 m(2), p = NS, and Upr decreased from 2.4 ± 0.9 to 0.8 ± 0.5 g/24 h, p < 0.001. In the MP + Aza group, eGFR slightly increased from 57.4 ± 28.7 to 66 ± 31 ml/min/1.73 m(2), p = NS, and Upr decreased from 2.4 ± 1 to 0.7 ± 0.7 g/24 h, p < 0.001. Four patients from the MP group with partial remission at the end of the trial had a complete response when converted to Aza. Eleven patients (5 from the MP and 6 from the MP + Aza group) relapsed after stopping treatment and were restarted on lower doses. CONCLUSIONS: Both, steroid treatment alone and steroids in combination with azathioprine seem to be effective in reducing the severity of proteinuria and stabilizing renal function in IgAN. Patients who do not respond to steroids may have a better response with the combination of steroids and azathioprine.

Osmotic nephrosis due to the use of anti-adhesive membrane intraperitoneally.

BACKGROUND: A common strategy for the prevention of intra-abdominal adhesions post-operatively has been the application of adhesion barriers into the peritoneal cavity. Side effects of these barriers are infection, abscesses and inadequate wound healing. There is no information about such a side effect of these materials on renal function. The aim of this study was to evaluate the effect of two different, commercially available polysaccharide-based anti-adhesive materials on renal function. METHODS: In 24 adult Wistar rats, an abdominal midline incision was performed, and an anti-adhesion membrane was placed in the peritoneal cavity so as to cover its whole surface. Four rats were used as the control group. In 12 rats, a membrane of macromolecular polysaccharides, weighing 40 mg/cm2, was placed intra-abdominally and in 8 rats, a hyaluronic acid-hydroacidmethylcellulose membrane weighing 0.4 mg/cm2 was placed. At 24 or 70 h, the rats were sacrificed, and we evaluated changes in serum creatinine, urea, uric acid, K and Na, and histologic examination of the kidney was performed. RESULTS: The use of the thicker macromolecular membrane was associated with a rise in serum creatinine and urea levels, vacuolization of all the tubular epithelial cells and mild interstitial infiltration. Rats in which the hyaluronic acid-hydroacidmethylcellulose membrane was used did not show any creatinine elevation, and they presented milder histologic lesions. CONCLUSION: Polysaccharide and cellulose anti-adhesive membrane cause renal damage with tubular cell vacuolization. The severity of kidney damage is relative to the quantity of the membrane material used.

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.

AIM: Urinary cytokine excretion may reflect histological changes in immunoglobulin A nephropathy (IgAN), and their measurement can give information about disease outcome. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

C5b-9 glomerular deposition and tubular alpha3beta1-integrin expression are implicated in the development of chronic lesions and predict renal function outcome in immunoglobulin A nephropathy.

OBJECTIVE: Tubular atrophy is one of the factors predicting poor outcome of renal function in primary immunoglobulin A nephropathy (IgAN). However, the development of tubular atrophy is a late phenomenon during the disease progression. It would be useful to identify early factors that potentially result in renal damage and could be used as early predictors of renal outcome. MATERIAL AND METHODS: Forty-eight patients with IgAN were examined retrospectively. All patients had a renal biopsy at the beginning of the study. Histological parameters were reviewed and immunohistochemistry was performed on cryostat sections. Monoclonal antibodies used were against C5b-9, alpha3beta1-integrin, transforming growth factor-beta1 (TGF-beta1) and alpha-smooth muscle actin (alpha-SMA), and the results were correlated with histological data and long-term outcome of renal function. RESULTS: In the glomeruli the extent of C5b-9 deposition had significant positive correlations with the degree of focal glomerulosclerosis (p=0.005), tubular atrophy (p=0.003), interstitial inflammation (p=0.005) and tubular expression of alpha3beta1 (p=0.0001). alpha3beta1 tubular expression correlated positively with the severity of proteinuria (p=0.01), number of glomerular and tubulointerstitial myofibroblasts, and the degree of tubular atrophy (p=0.0001) and interstitial monocyte infiltration (p =0.005). Tubular alpha3beta1 expression and the degree of tubular atrophy had significant implications in the development of renal failure at the beginning and at the end of follow-up, respectively. CONCLUSIONS: Glomerular deposition of C5b-9 may participate in the development of glomerulosclerosis in IgAN. Furthermore, its positive correlation with the intensity of tubular alpha3beta1-integrin suggests a possible implication in the development of tubulointerstitial fibrosis.

Mixed exocrine-endocrine tumor of the pancreas.

CONTEXT: Neoplasms of the pancreas usually show ductal, acinar or endocrine differentiation. Tumors with mixed exocrine and endocrine components are unusual. We herein describe a case of a mixed ductal-endocrine tumor. CASE REPORT: A 65-year-old woman was referred to our department with a diagnosis of carcinoma of the tail of the pancreas. The patient had a short history of upper abdominal pain, nausea and melena. Upper gastrointestinal endoscopy revealed gastric fundus varices and CT scan demonstrated an inhomogeneous tumor located in the tail of the pancreas infiltrating the spleen and the splenic vein. The patient underwent distal pancreatectomy and splenectomy, and had an uneventful recovery. Pathological examination revealed a mixed ductal-endocrine tumor. The endocrine component was immunoreactive for glucagon, gastrin and somatostatin, and non-reactive for insulin. CONCLUSIONS: Because of the rarity and unpredictable biologic behavior of these tumors, the need for adjuvant therapy has not yet been well-defined. The patient has had a follow-up CT scan every six months, and one and a half years later remains disease free.

Rare manifestations of sirenomelia syndrome: a report of five cases.

Five cases of sirenomelia presented with rare manifestations are discussed. Three neonates were born alive and died within 2 to 12 hours after birth. One case was the offspring of a triple in vitro fertilization pregnancy with history of early intrauterine death of one of the triplets. The main features included fusion of lower extremities (five of five), renal agenesis (three of five), polycystic renal dysplasia (two of five), anal atresia with large bowel hypoplasia (three of five), pulmonary hypoplasia (four of five), and single umbilical artery (five of five). Other features that have only rarely been associated with sirenomelia included concurrence of congenital heart disease and neuroblastoma, gallbladder agenesis, and upper extremity defects.

A rare case of solitary fibrous tumor of the nasal cavity.

Solitary fibrous tumor (SFT) arises in the pleura and less commonly in extrapleural sites. SFT can be found in various head and neck sites. SFTs of the nasal cavity and paranasal sinuses are extremely rare with only ten previously reported cases in the world literature. This case report presents an additional case of SFT of the nasal cavity underlining the benign pattern and the bleeding tendency of nasal SFT, that surgeons managing these tumors should be aware of. Diagnostic procedure, clinical and histopathological findings as well as immunoreactivity of this tumor are discussed, with a review of the current literature.