Activin inhibition limits early innate immune response in rat kidney allografts-a pilot study.

Activins are members of the transforming growth factor-beta (TGF-ß) superfamily of cytokines. They play critical roles in the onset of acute and chronic inflammatory responses. The aim of this study was to investigate how activin inhibition affects acute kidney injury and inflammation after transplantation. The study was carried out in kidney transplantation and renal ischemia-reperfusion models in the rat. Soluble activin type 2 receptor (sActRIIB-Fc) was used to inhibit activin signaling. Transplantation groups were as follows: (i) cyclosporine A (CsA) (ii) CsA + sActRIIB-Fc, (iii) CsA+ inactive protein control Fc-G1. IRI groups were as follows: (i) no treatment, (ii) sActRIIB-Fc. Serum activin B concentration was significantly elevated after transplantation and IRI, whereas activin A was produced locally in renal allografts. Activin inhibition efficiently limited neutrophil, macrophage, and dendritic cell infiltration to the allografts measured 72 h after transplantation. In addition, sActRIIB-Fc treatment modulated serum cytokine response after transplantation and reduced the early accumulation of fibroblasts in the graft interstitium. In conclusion activin inhibition reduces the innate immune response early after renal transplantation in the rat. It also limits the accumulation of fibroblasts in the graft suggesting that activins may be involved in the fibrogenic signaling already early after kidney transplantation.

Dual antiplatelet and anticoagulant APAC prevents experimental ischemia-reperfusion-induced acute kidney injury.

BACKGROUND: Renal ischemia-reperfusion predisposes to acute kidney injury (AKI) and mortality. APAC, mast cell heparin proteoglycan mimetic is a potent dual antiplatelet and anticoagulant inhibiting thrombosis in several vascular models. METHODS: Clinically relevant (0.06 and 0.13 mg/kg) and high (0.32 and 7.3 mg/kg) heparin doses of APAC and unfractionated heparin (UFH) were administered i.v. in pharmacological studies. Antithrombotic action of APAC and UFH was assessed with platelet aggregation to collagen, activated partial thromboplastin (APTT) and prothrombin (PT) times. Pharmacodynamics of [64Cu]-APAC or -UFH were monitored by PET/CT. Next, APAC and UFH doses (0.06 and 0.13 mg/kg) were i.v. administered 10 min prior to renal ischemia-reperfusion injury (IRI) in rats. RESULTS: APAC in contrast to UFH inhibited platelet aggregation. During 0.06 and 0.13 mg/kg dose regimens APTT and PT remained at baseline, but at the high APTT prolonged fourfold to sixfold. Overall bio-distribution and clearance of APAC and UFH were similar. After bilateral 30-min renal artery clamping, creatinine, urea nitrogen and neutrophil gelatinase-associated lipocalin concentrations and histopathology indicated faster renal recovery by APAC (0.13 mg/kg). APAC, unlike UFH, prevented expression of innate immune ligand hyaluronan and tubulointerstitial injury marker Kim-1. Moreover, in severe bilateral 1-h renal artery clamping, APAC (0.13 mg/kg) prevented AKI, as demonstrated both by biomarkers and survival. Compatible with kidney protection APAC reduced the circulating levels of vascular destabilizing and pro-inflammatory angiopoietin-2 and syndecan-1. No tissue bleeding ensued. CONCLUSION: APAC and UFH were similarly eliminated via kidneys and liver. In contrast to UFH, APAC (0.13 mg/kg) was reno-protective in moderate and even severe IRI by attenuating vascular injury and innate immune activation.

High NRBP1 expression in prostate cancer is linked with poor clinical outcomes and increased cancer cell growth.

BACKGROUND: We recently established the rationale that NRBP1 (nuclear receptor binding protein 1) has a potential growth-promoting role in cell biology. NRBP1 interacts directly with TSC-22, a potential tumor suppressor gene that is differently expressed in prostate cancer. Consequently, we analyzed the role of NRBP1 expression in prostate cancer cell lines and its expression on prostate cancer tissue microarrays (TMA). METHODS: The effect of NRBP1 expression on tumor cell growth was analyzed by using RNAi. NRBP1 protein expression was evaluated on two TMAs containing prostate samples from more than 1,000 patients. Associations with clinico-pathological features, the proliferation marker Ki67 and survival data were analyzed. RESULTS: RNAi mediated silencing of NRBP1 expression in prostate cancer cell lines resulted in reduced cell growth (P < 0.05). TMA analysis revealed NRBP1 protein expression in benign prostate hyperplasia in 6% as compared to 60% in both, high-grade intraepithelial neoplasia and prostate cancer samples. Strong NRBP1 protein expression was restricted to prostate cancer and correlated with higher expression of the proliferation marker Ki67 (P < 0.05). Further, patients with strong NRBP1 protein expression showed poor clinical outcomes (P < 0.05). Analysis of matched localized cancer tissues before and after castration revealed that post-therapy-related repression of NRBP1 expression was significantly associated with better overall survival. CONCLUSIONS: We demonstrate that expression of NRBP1 is up-regulated during the progression of prostate cancer and that high NRBP1 expression is linked with poor prognosis and enhanced tumor cell growth.

Locally advanced esophageal adenocarcinoma: response to neoadjuvant chemotherapy and survival predicted by ([18F])FDG-PET/CT.

BACKGROUND: ([18F])fluorodeoxyglycose-Positron Emission Tomography/Computer Tomography (([18F])FDG-PET/CT) is commonly used in staging of locally advanced esophageal cancer. Its predictive value for response to neoadjuvant therapy and survival after multimodality therapy is controversial. METHODS: Sixty-six consecutive patients with locally advanced adenocarcinoma of the esophagus or esophagogastric junction underwent surgery after neoadjuvant chemotherapy. Staging was done prospectively with ([18F])FDG-PET/CT, before and after completion of neoadjuvant therapy. Pre- and post-therapy maximal standardized uptake values for the primary tumor (SUV1 and SUV2) were determined, and their relative change (SUV∆%) calculated. Percentage change in SUV1 was compared with histopathologic response (HPR, complete or subtotal histologic remission), disease-free- (DFS) and overall survival (OS). RESULTS: Resection with negative margins was achieved in 60 patients. HPR rate was 14 of 66 (21.2%). Median follow-up was 16 months (range 4-72). For all patients, OS probability at three years was 59% and DFS 50%. In receiver operating characteristics (ROC) analysis, HPR was optimally predicted by a > 67% change in baseline maximal SUV (sensitivity 79% and specificity 75%). In univariate survival analysis (Cox regression proportional hazards), HPR associated with improved DFS (HR 0.208, p = 0.033) but not OS (HR 0.030, p = 0.101), SUV % > 67% associated with improved OS (HR 0.249, p = 0.027) and DFS (HR 0.383, p = 0.040). In a multivariate model (adjusted by age, sex, and ASA score), neither HPR nor SUV∆% > 67% was predictive of improved OS and DFS. However, SUV∆% as a continuous variable was an independent predictor of OS (HR 0.966, p < 0.0001) or DFS (HR 0.973, p < 0.0001). CONCLUSION: Our results support previous results showing that ([18F])FDG-PET/CT can distinguish a group of patients with worse prognosis after neoadjuvant chemotherapy in adenocarcinoma of the esophagus or esophagogastric junction. This information could offer a new independent preoperative marker of prognosis.

Amplification and overexpression of vinculin are associated with increased tumour cell proliferation and progression in advanced prostate cancer.

Androgen withdrawal is the standard treatment for advanced prostate cancer. Although this therapy is initially effective, nearly all prostate cancers become refractory to it. Approximately 15% of these castration-resistant prostate cancers harbour a genomic amplification at 10q22. The aim of this study was to explore the structure of the 10q22 amplicon and to determine the major driving genes. Application of high-resolution array-CGH using the 244k Agilent microarrays to cell lines with 10q22 amplification allowed us to narrow down the common amplified region to a region of 5.8 megabases. We silenced each of the genes of this region by an RNAi screen in the prostate cancer cell lines PC-3 and 22Rv1. We selected genes with a significant growth reduction in the 10q22 amplified cell line PC-3, but not in the non-amplified 22Rv1 cells, as putative target genes of this amplicon. Immunohistochemical analysis of the protein expression of these candidate genes on a tissue microarray enriched for 10q22 amplified prostate cancers revealed vinculin as the most promising target of this amplicon. We found a strong association between vinculin gene amplification and overexpression (p < 0.001). Further analysis of 443 specimens from across all stages of prostate cancer progression showed that vinculin expression was highest in castration-resistant prostate cancers, but negative or very low in benign prostatic hyperplasia (p < 0.0001). Additionally, high tumour cell proliferation measured by Ki67 expression was significantly associated with high vinculin expression in prostate cancer (p < 0.0001). Our data suggest that vinculin is a major driving gene of the 10q22 amplification in prostate cancer and that vinculin overexpression might contribute to prostate cancer progression by enhancing tumour cell proliferation.

Changes in glomerular mesangium in kidneys with congenital nephrotic syndrome of the Finnish type.

Congenital nephrotic syndrome of the Finnish type (NPHS1, CNF) is an autosomal recessive disease caused by mutations in a major podocyte protein, nephrin. NPHS1 is associated with heavy proteinuria and the development of glomerular scarring. We studied the cellular and molecular changes affecting the glomerular mesangium in NPHS1 kidneys. Marked hyperplasia of mesangial cells (MC) was mainly responsible for the early mesangial expansion in NPHS1 glomeruli. The levels of the proliferation marker, mindbomb homolog 1 and the major MC mitogen, platelet-derived growth factor, and its receptors, however, were quite normal. Only a small number of cells were positive for CD68 (marker for phagocytic cells) and CD34 (marker for mesenchymal precursor cells) in the NPHS1 mesangium. MCs strongly expressed alpha-smooth muscle actin, indicating myofibloblast transformation. The expression levels of the profibrotic mediators osteopontin and transforming growth factor beta were up-regulated in NPHS1 glomeruli by 3.2 and 1.6-fold, respectively, compared to the controls. The synthesis by MCs of the typical fibroblast products collagen I, fibronectin, and tenascin, however, was low, and the extracellular matrix increase was caused by the accumulation of a normal MC product, collagen IV. The results indicate that severe glomerular sclerosis can develop without major qualitative cellular or molecular changes in the mesangium.

Peritubular capillaries are rarefied in congenital nephrotic syndrome of the Finnish type.

Congenital nephrotic syndrome of the Finnish type (NPHS1) is associated with the rapid development of glomerular and tubulointerstitial fibrosis. Here we measured morphologic and molecular changes in the peritubular capillaries of the kidney in patients with NPHS1. Immunohistochemical analysis for the endothelial cell marker CD31 showed marked narrowing and a moderate but significant reduction in peritubular capillary density, especially in areas of increased collagen I and alpha-smooth muscle actin content. No evidence of endothelial-mesenchymal transformation was found. There was increased expression (up to 43-fold) of hypoxia inducible factor-1alpha suggesting tubulointerstitial hypoxia. Double-labeling for CD31 and vimentin showed small foci of peritubular capillary loss and tubular cell damage. While the amount of intercellular adhesion molecule-1 was upregulated in endothelial cells, other adhesion molecules were only modestly expressed. Vascular endothelial growth factor expression was reduced by up to half and decreased endothelial progenitor cell marker CD34 expression indicated lack of vascular repair. Our results suggest that hypoxia in the tubulointerstitium caused by hypoperfusion of glomerular and tubulointerstitial capillaries and rarefaction of the latter may be important for the rapid progression of fibrosis in the kidneys of patients with NPHS1.

Androgen receptor amplification is associated with increased cell proliferation in prostate cancer.

Mechanisms of prostate cancer progression during hormonal therapy and the pathobiologic consequences of androgen receptor (AR) gene amplification are inadequately known. To further investigate the hypothesis that AR gene amplification is associated with increased cell proliferation, we analyzed 123 paraffin-embedded prostate cancer specimens from men who experienced tumor relapse during androgen withdrawal therapy. We used fluorescence in situ hybridization to quantify AR gene copy number and Ki-67 immunohistochemistry to determine cell proliferation. One third of the tumors showed AR gene amplification. Among tumors with AR amplification, the mean cell proliferation rate was 19.8 (SD, 12.3; 95% confidence interval [CI], 15.4-24.1), whereas it was 13.0 (SD, 15.9; 95% CI, 9.1-16.8) in tumors without amplification (P = .032). In the best fitting logistic regression model, only proliferation remained significant (P = .040). When the median Ki-67 labeling index (6.7%) of all tumors was used as a cutoff point, the tumors with AR amplification were more frequently highly proliferating than tumors with no amplification (P = .010; odds ratio, 3.4; 95% CI, 1.4-8.3). Our results imply that progression of prostate cancer during androgen withdrawal therapy is associated with AR gene amplification and increased cell proliferation rate in one third of tumors. We suggest that AR gene amplification is an important molecular mechanism underlying the increase in proliferation rate of a substantial fraction of recurrent prostate carcinomas. However, efforts should be targeted to develop prostate cancer cell lines to study causal relationships between AR gene amplification and various biologic variables.

High serum C3 predicts poor outcome in IgM nephropathy.

BACKGROUND: IgM nephropathy (IgMN) is an idiopathic glomerulonephritis with mesangial IgM deposition. The etiology of the depositions and possible association of serum and mesangial immunoglobulins and complement findings with renal outcome in IgMN remain unknown. Here we brought out data supplementary to our previous findings by reporting associations of immunological parameters with the outcome of IgMN. METHODS: Serum IgA, IgG, IgM, C3 and C4 were measured in 110 IgMN patients by single radial immunodiffusion or nephelometry. Mesangial IgA, IgG, IgM, C1q and C3 assessed in immunofluorescent study were graded as +/-. Seven histopathological parameters were semiquantitatively graded into three classes. The relationship of serum and mesangial immunoglobulin and complement findings with the clinical outcome and prognosis of IgMN was examined. RESULTS: We found significantly lower serum IgG and higher serum C3 levels in patients with nephrotic syndrome. Serum C3 correlated with the severity of glomerular histopathological changes. Of immunological parameters evaluated a low serum IgG/C3 ratio correlated best with the progression of renal disease. However, serum C3 was associated independently with progression in the case of patients without nephrotic syndrome. CONCLUSIONS: In addition to previously reported factors, immunological parameters may also be helpful in determining the prognosis in IgMN. High serum C3 predicts poor outcome in IgMN, being associated with high-grade proteinuria, severe histopathological changes and progression.

Free digital image analysis software helps to resolve equivocal scores in HER2 immunohistochemistry.

Evaluation of human epidermal growth factor receptor 2 (HER2) immunohistochemistry (IHC) is subject to interobserver variation and lack of reproducibility. Digital image analysis (DIA) has been shown to improve the consistency and accuracy of the evaluation and its use is encouraged in current testing guidelines. We studied whether digital image analysis using a free software application (ImmunoMembrane) can assist in interpreting HER2 IHC in equivocal 2+ cases. We also compared digital photomicrographs with whole-slide images (WSI) as material for ImmunoMembrane DIA. We stained 750 surgical resection specimens of invasive breast cancers immunohistochemically for HER2 and analysed staining with ImmunoMembrane. The ImmunoMembrane DIA scores were compared with the originally responsible pathologists' visual scores, a researcher's visual scores and in situ hybridisation (ISH) results. The originally responsible pathologists reported 9.1 % positive 3+ IHC scores, for the researcher this was 8.4 % and for ImmunoMembrane 9.5 %. Equivocal 2+ scores were 34 % for the pathologists, 43.7 % for the researcher and 10.1 % for ImmunoMembrane. Negative 0/1+ scores were 57.6 % for the pathologists, 46.8 % for the researcher and 80.8 % for ImmunoMembrane. There were six false positive cases, which were classified as 3+ by ImmunoMembrane and negative by ISH. Six cases were false negative defined as 0/1+ by IHC and positive by ISH. ImmunoMembrane DIA using digital photomicrographs and WSI showed almost perfect agreement. In conclusion, digital image analysis by ImmunoMembrane can help to resolve a majority of equivocal 2+ cases in HER2 IHC, which reduces the need for ISH testing.

Serum sCD30 in monitoring of alloresponse in well HLA-matched cadaveric kidney transplantations.

In kidney transplantation, pretransplant serum sCD30 testing has been proposed in immunological risk estimation together with anti-HLA antibodies. We evaluated the risks associated with high pretransplant serum sCD30 in well HLA-matched cadaveric kidney recipients recruited in a clinical study comparing different immunosuppressive regimens. Rejection rate was similar in 37 recipients with high pretransplant serum sCD30 compared to 117 recipients with low serum sCD30 (16% vs. 15%, P=NS). Compared to pretransplant levels, the posttransplant sCD30 levels generally decreased, also in patients with rejection, although on day 21 posttransplant, rejecting patients had significantly higher relative sCD30 than nonrejecting patients (P<0.01). However, steroid-resistant rejection was associated with increasing posttransplant sCD30 levels. High pretransplant sCD30 values were associated with tubulointerstitial rejection. There was no correlation of sCD30 with delayed graft function. Good HLA matching seems to be effective in neutralizing the negative effect of a high pretransplant serum sCD30.

Web-based virtual microscopy in teaching and standardizing Gleason grading.

Gleason grading forms the basis of prognostic and therapeutic assessment in prostatic carcinoma despite its subjective nature and substantial interobserver variation. The accuracy of Gleason grading can be improved by the use of educational tools such as reference images. However, conventional microscopy images are of limited educational value because it is neither possible to view the sample at different magnifications nor to navigate into different areas of the specimen. This limitation can be overcome by the use of virtual microscopy, which allows viewing entire digitized microscope slides. We created an interactive Web site ( www.webmicroscope.net/gleason ) featuring a comprehensive set of prostatic needle biopsies as virtual slides, which can be viewed with a standard Web browser (Internet Explorer or Netscape). To evaluate the validity of Web-based virtual microscopy for Gleason grading, an experienced uropathologist (TK) scored a series of 62 biopsies from the original glass slides and 6 weeks later from virtual slides on the Web site using an ordinary desktop computer. The intraobserver agreement was excellent, with identical Gleason scores found in 48 of the 62 cases ( kappa = 0.73). The 14 remaining scores differed only by 1 point on the Gleason scale (2-10). The virtual slides were viewed by 2 other uropathologists (PM and HH), with interobserver kappa coefficients ranging from 0.55 to 0.62, which is within the range of previously reported studies using glass slides. The 3 uropathologists' Gleason scores were included as reference scores on the Web site, which now serves as a publicly open platform for self-testing and learning of Gleason grading. We conclude that Web-based virtual microscopy is a promising new tool for teaching and standardizing Gleason grading.

IgM nephropathy: clinical picture and long-term prognosis.

BACKGROUND: Immunoglobulin M (IgM) nephropathy is an idiopathic glomerulonephritis with mesangial hypercellularity and diffuse IgM deposits. METHODS: We studied clinical presentation, morphological findings, and prognostic factors in 110 patients with IgM nephropathy without systemic diseases. The series included both pediatric and adult patients with nephrotic syndrome (NS) or minor urinary abnormalities. RESULTS: Mean postbiopsy follow-up was 8 years. During 15 years of follow-up, 36% of patients developed renal insufficiency and 23% reached end-stage renal failure. In multivariate analysis, hypertension at the time of renal biopsy was the only significant risk factor for renal insufficiency. Of histological parameters, interstitial fibrosis had the strongest prognostic value. Hypertension was diagnosed in 50% of patients with a postbiopsy follow-up of 15 years. Twenty-nine percent of nephrotic patients had disease resistant to corticosteroids, whereas 80% of patients with steroid-sensitive disease were steroid dependent. Eleven patients, 8 patients with NS and 3 patients with asymptomatic proteinuria, underwent repeated renal biopsy. In five samples, typical morphological characteristics of focal and segmental glomerulosclerosis were seen. CONCLUSION: We propose that IgM nephropathy can be divided into two subgroups with similar renal biopsy findings, but differences in sex distribution and initial presentation.

Arm-specific multicolor fluorescence in situ hybridization reveals widespread chromosomal instability in glioma cell lines.

An investigation of numerical and structural chromosome aberrations using chromosome arm-specific multicolor fluorescence in situ hybridization (armFISH) revealed considerable genetic heterogeneity among and within 11 glioma cell lines. Despite the substantial variation in numerical chromosome alterations among the cell lines, several distinct and glioma growth-associated losses or gains were frequently observed, that is, losses of chromosomes 10, 13, and 22 and gain of chromosome 7 in particular. Structural aberrations frequently affected chromosomes 1, 4, 7, 16, and 19; however, no single structural chromosome aberration common to all or even several glioma cell lines could be found. Structural alterations were often multiform, and a large variety of unstable chromosome structures were detected. Two of the cell lines also harbored small marker chromosomes containing mainly heterochromatin and chromosomal insertions within hetero-chromatic regions. Altogether, the armFISH provides a versatile tool for the identification of chromosomal aberrations as well as their formation patterns in tumors with a complex genome at the level of chromosome arms.

Comparison of computed tomography and systematic lymph node dissection in determining TNM and stage in non-small cell lung cancer.

OBJECTIVE: To compare computed tomography (CT)-based clinical TNM and staging to surgical-pathological staging with systematic lymph node dissection in primary non-small cell lung cancer. METHODS: The study included 49 non-small cell lung cancer patients that underwent lung resection and systematic lymph node dissection between 1997 and 2001. Preoperative clinical and CT findings were compared with surgical-pathological findings. Lymph nodes with a shortest diameter of over 1 cm on CT were considered abnormal, but did not contraindicate surgery. Patients with CT indicating an invasive T4 tumor, pleural carcinosis, or bulky N2 disease were excluded. RESULTS: Sixty-five percent (32/49) had epidermoid carcinoma, and 25% (12/49) had adenocarcinoma. N2 metastases were found in 12% (6/49). The clinical T category was correct in 71% (35/49), and the N category in 55% (27/49). The sensitivity for detecting N2 disease was 67% (4/6), and the specificity was 81% (35/43). The positive predictive value for N2 disease was 33% (4/12), and the negative predictive value was 95% (35/37). Node-by-node agreement on N2 metastatic location was 17% (1/6). Skip N2 metastases without any N1 involvement were found in 4% (2/49), or 33% (2/6) of all N2 cases. The clinical stage was correct in 45% (22/49), and complete TNM agreement was 37% (18/49). CONCLUSIONS: The clinical TNM and staging based on CT are inaccurate. The sensitivity for detecting N2 disease is poor, especially on node-by node basis. Preoperative exclusion of N2 metastases is quite reliable, but a positive finding should always be verified. Systematic mediastinal lymph node dissection is necessary to detect N2 metastases inaccessible to cervical mediastinoscopy, and skip N2 metastases without N1 involvement.

The immunohistochemical characterisation of an SV40-immortalised human corneal epithelial cell line.

Alternatives to the Draize rabbit eye irritation test are currently being investigated. Because of morphological and biochemical differences between the rabbit and the human eye, continuous human cell lines have been proposed for use in ocular toxicology studies. Single cell-type monolayer cultures in culture medium have been used extensively in ocular toxicology. In the present study, an SV40-immortalised human corneal epithelial (HCE) cell line was characterised immunohistochemically, by using 13 different monoclonal antibodies to cytokeratins (CKs), ranging from CK3 to CK20. The results from the monolayer HCE cell cultures were compared with those from the corneal epithelium of human corneal cryostat sections. Previous studies have shown that the morphology of the HCE cell is similar to that of primary cultured human corneal epithelial cells, and that the cells express the cornea-specific CK3. In the study reported here, we show that the cell line also expresses CKs 7, 8, 18 and 19. These CKs are typically expressed by simple epithelial cells, and are not found in the human cornea in vivo. Therefore, the monolayer HCE cell line grown in culture medium does not express the CK pattern that is typical of human corneal epithelium. This should be taken into consideration when using HCE cell cultures in similar single cell-type experiments for ocular toxicology.

The establishment of a network of European human research tissue banks.

This is a report of a workshop held on the establishment of human research tissue banking which was held in Levi, Finland 21-24 March 2002. There were 21 participants from 7 European countries. This meeting was attended by representatives from academia, research tissue banks and from the Biotech and Pharmaceutical Industries. The principal aim of the workshop was to find a way to progress the recommendations from ECVAM workshop 44 (ATLA 29, 125-134, 2001) and ECVAM workshop 32 (ATLA 26, 763-777, 1998). The workshop represented the first unofficial meeting of the European Network of Research Tissue Banks (ENRTB) steering group. It is expected that in the period preceding the next workshop the ENRTB steering group will co-ordinate the ethical, legislative and organisational aspects of research tissue banking. Key issues dealt with by the Levi workshop included the practical aspects of sharing expertise and experiences across the different European members. Such collaboration between research tissue banks and end users of such material seeks to ultimately enable shared access to human tissue for medical and pharmaco-toxicological research while maintaining strict adherence to differences in legal and ethical aspects related to the use of human tissue in individual countries.

Histopathology and biomarkers in prediction of renal function in children after kidney transplantation.

BACKGROUND: Early detection of chronic allograft injury is a major challenge after kidney transplantation (RTx) in adults and children. We correlated the expression of four immunohistochemical biomarkers, P-selectin glycoprotein ligand-1 (PSGL-1), vimentin, α-smooth muscle actin (α-SMA) and collagen IV, to the kidney graft histology and function in pediatric RTx patients. METHODS: We analyzed the histopathology and immunohistochemical stainings of 165 biopsies from 56 patients. Histopathology was scored according to Banff '05 classification and biomarker expression semiquantitatively. Glomerular filtration rate (GFR) was measured annually by (51)Cr-EDTA clearance. RESULTS: In protocol biopsies, the expression of all four biomarkers correlated with the interstitial fibrosis and tubular atrophy (IF/TA) changes, which increased during the first 36months after RTx. At the time of 18month biopsy, we observed the deterioration of GFR in patients with high (≥2) IF/TA score (50 vs. 68ml/min/1.73m(2), p=0.004) or collagen IV expression (45 vs. 65ml/min/1.73m(2), p=0.016). Intense stainings of IF/TA, collagen IV and vimentin are also associated with poor GFR at 36 and 48months, however, the biomarker scores revealed no additional predictive value for concomitant or late GFR compared to IF/TA score. Patients with high and low biomarker expressions showed no significant differences in annual deterioration of GFR, which declined on average 2.2ml/min/1.73m(2)/year over the 7years follow-up. CONCLUSIONS: Overall, the results suggest that traditional histopathology is a sufficient predictor for graft function, and the routine use of these histochemical markers as surrogates for graft function deterioration is questioned.

Membranoproliferative glomerulonephritis complicating Propionibacterium acnes infection.

BACKGROUND: Propionibacterium acnes (P. acnes) is a common microbe of the skin and mucosal surfaces rarely considered a true pathogen. However, it has been reported to cause serious infections. Subsequent ongoing low-grade antigenaemia may, in turn, lead to an immune-mediated glomerulonephritis with various renal histologies including that of membranoproliferative glomerulonephritis (MPGN). METHODS: Here, we describe two cases of P. acnes infection-induced MPGN and their treatment. RESULTS: Both patients were successfully treated by the eradication of the infection. One patient also received immunosuppressive medication prior to the correct diagnosis. CONCLUSIONS: A vigorous exclusion of infection is warranted in MPGN type I or immune-complex-mediated MPGN and may sometimes yield a diagnosis of secondary MPGN.