Idiopathic Nephrotic Syndrome: Characteristics and Identification of Prognostic Factors.

There are various histopathological forms of idiopathic nephrotic syndrome, including minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS). Whereas some relapse predictor factors have been identified in renal transplantation, the clinical future of idiopathic nephrotic syndrome in the native kidney remains uncertain. We designed a multicentric retrospective descriptive cohort study including all patients aged 15 years and over whose renal biopsy confirmed MCD or FSGS between January 2007 and December 2014. We studied 165 patients with idiopathic nephrotic syndrome; 97 with MCD and 68 with FSGS. In the MCD cohort, 91.7% of patients were treated with corticosteroids for a median total duration of 13 months. During 45 months of follow-up, 92.8% of patients achieved remission and 45.5% experienced relapse. In this cohort, 5% of patients experienced terminal kidney disease. With respect to FSGS patients, 51.5% were treated with corticosteroids for a median total duration of 15 months. During 66 months of follow-up, 73.5% of patients achieved remission and 20% experienced relapse. In this cohort, 26.5% of patients experienced terminal kidney disease. No statistical association was observed between clinical and biological initial presentation and relapse occurrence. This study describes the characteristics of a cohort of patients with the nephrotic idiopathic syndromes of MCD and FSGS from the time of renal biopsy and throughout follow-up.

Combined late gadolinium-enhanced and double-echo chemical-shift MRI help to differentiate renal oncocytomas with high central T2 signal intensity from renal cell carcinomas.

OBJECTIVE: The purpose of our study was to evaluate the combination of dynamic contrast-enhanced T1-weighted and double-echo gradient-echo MR imaging to distinguish renal oncocytoma with high T2 signal intensity centrally from renal cell carcinoma (RCC). MATERIALS AND METHODS: Between 2006 and 2011, 63 renal tumors (59 patients) presenting with a high signal intensity (SI) central area on T2-weighted sequences were imaged with dynamic contrast-enhanced sequences, including phases later than 5 minutes after contrast injection, and double-echo chemical-shift sequences were selected from our institutional database. Two experienced radiologists visually assessed presence and distribution of signal enhancement of central areas after injection and measured SI changes on opposed-phase images for calculation of the SI index and tumor-to-spleen ratio. Cutoff values were derived from the receiver operating characteristic (ROC) curve. RESULTS: There were 19 oncocytomas (16 patients), 43 RCCs (42 patients), and one leiomyoma. Complete late enhancement of the central area was observed in 14 oncocytomas (74%) and in five RCCs (12%) (p = 0.05). The combination of complete enhancement and SI index lower than 2% (p = 0.02) or tumor-to-spleen ratio higher than -6% (p = 0.001) provided sensitivity of 36% and 55%, specificity of 95% and 97%, positive predictive value of 67% and 86%, and negative predictive value of 84% and 88%, respectively, for diagnosis of oncocytomas. CONCLUSION: Absence of central area SI inversion or presence of a signal drop on chemical-shift imaging may rule out the diagnosis of oncocytoma.

The experimental renal cell carcinoma model in the chick embryo.

The clear cell subtype of renal carcinoma (CCRCC) is highly vascularized and despite a slow progression rate, it is potentially a highly aggressive tumor. Although a doubling of median progression-free survival in CCRCC patients treated by targeted therapies has been observed, the fact that tumors escape after anti-VEGF treatment suggests alternative pathways. The chick chorioallantoic membrane (CAM) is a well-established model, which allows in vivo studies of tumor angiogenesis and the testing of anti-angiogenic molecules. However, only a few data exist on CCRCC grafted onto CAM. We aimed to validate herein the CAM as a suitable model for studying the development of CCRCC and the interactions with the surrounding stroma. Our study uses both CCRCC cell lines and fresh tumor samples after surgical resection. We demonstrate that in both cases CCRCC can be grafted onto the CAM, to survive and to induce an angiogenic process. We further provide insights into the transcriptional regulation of the model by performing a differential analysis of tumor-derived and stroma-derived transcripts.

IQGAP1 interacts with components of the slit diaphragm complex in podocytes and is involved in podocyte migration and permeability in vitro.

IQGAP1 is a scaffold protein that interacts with proteins of the cytoskeleton and the intercellular adhesion complex. In podocytes, IQGAP1 is associated with nephrin in the glomerular slit diaphragm (SD) complex, but its role remains ill-defined. In this work, we investigated the interaction of IQGAP1 with the cytoskeleton and SD proteins in podocytes in culture, and its role in podocyte migration and permeability. Expression, localization, and interactions between IQGAP1 and SD or cytoskeletal proteins were determined in cultured human podocytes by Western blot (WB), immunocytolocalization (IC), immunoprecipitation (IP), and In situ Proximity Ligation assay (IsPL). Involvement of IQGAP1 in migration and permeability was also assessed. IQGAP1 expression in normal kidney biopsies was studied by immunohistochemistry. IQGAP1 expression by podocytes increased during their in vitro differentiation. IC, IP, and IsPL experiments showed colocalizations and/or interactions between IQGAP1 and SD proteins (nephrin, MAGI-1, CD2AP, NCK 1/2, podocin), podocalyxin, and cytoskeletal proteins (α-actinin-4). IQGAP1 silencing decreased podocyte migration and increased the permeability of a podocyte layer. Immunohistochemistry on normal human kidney confirmed IQGAP1 expression in podocytes and distal tubular epithelial cells and also showed an expression in glomerular parietal epithelial cells. In summary, our results suggest that IQGAP1, through its interaction with components of SD and cytoskeletal proteins, is involved in podocyte barrier properties.

Detection of intrarenal microstructural changes with supersonic shear wave elastography in rats.

OBJECTIVES: To evaluate, in a rat model of glomerulosclerosis, whether ultrasonic shear wave elastography detects kidney cortex stiffness changes and predicts histopathological development of fibrosis. MATERIALS AND METHODS: Three groups were studied transversally: a control group (n = 8), a group after 4 weeks of L-NAME administration (H4, n = 8), and a group after 6 weeks (H6, n = 15). A fourth group was studied longitudinally (n = 8) before, after 4 weeks and after 7 weeks of L-NAME administration. Shear modulus of renal cortex was quantified using supersonic shear imaging technique. Urine was analysed for dosage of protein/creatinine ratio. Kidneys were removed for histological quantification of fibrosis. RESULTS: Diseased rats showed an increased urinary protein/creatinine ratio. Cortical stiffness expressed as median (interquartile range) was 4.0 kPa (3.3-4.5) in control kidneys. It increased in all but one pathological groups: H4: 7.7 kPa (5.5-8.6) (p < 0.01); H6: 4.8 kPa (3.9-5.9) (not significant); in the longitudinal cohort, from 4.5 kPa (3.1-5.9) to 7.7 kPa (5.9-8.3) at week 4 (p < 0.05) and to 6.9 kPa (6.1-7.8) at week 7 (p < 0.05). Stiffness values were correlated with the proteinuria/creatininuria ratio (r = 0.639, p < 0.001). CONCLUSIONS: Increased cortical stiffness is correlated with the degree of renal dysfunction. More experience in other models is necessary to understand its relationship with microstructural changes.

Identification of a complex 17q rearrangement in a metanephric stromal tumor.

Metanephric stromal tumor is a rare benign entity belonging to the group of metanephric renal tumors in children. Although metanephric stromal tumors can be cured by simple nephrectomy, differential diagnosis based on histopathologic criteria with other pediatric renal tumors requiring aggressive chemotherapy can be difficult. To our knowledge, cytogenetic characterization of metanephric stromal tumor has never been reported. We describe conventional ("R-bands" karyotyping) and molecular [fluorescence in situ hybridization (FISH), multicolor FISH, oligo array-comparative genomic hybridization] cytogenetic examinations of a metanephric stromal tumor in a 3-year-old boy. Cytogenetic analysis revealed a complex homogeneous gain between bands 17q22 and 17q25.3, resulting in partial triplication of the segment between bands 17q22 and 17q24.3, and duplication of the segment between bands 17q24.3 and 17q25.3. Cytogenetic confirmatory studies in metanephric stromal tumors are currently needed to assess 17q22q25.3 gain as a recurring cytogenetic abnormality of metanephric stromal tumors.

Assessment of biphasic calcium phosphate to repair nasal septum defects in sheep.

BACKGROUND: Saddle nose and septal perforations are among the most surgically challenging situations in nasal reconstruction. They require a significant volume of autologous graft and a complex surgical procedure. The aim of this study was to evaluate the biocompatibility of the biphasic calcium phosphate implant in the nasal septum and its ability to replace septal skeleton with unilateral or bilateral exposure. METHODS: Thirty sheep underwent anterior nasal septum perforation. Only 20 septa were repaired with the implant exposed to nasal content on bilateral (group 2) and unilateral (group 3) sides. After 45 days of spontaneous cicatrization, the surface of new airway mucosa covering implants and the amount of closure were evaluated macroscopically. Light microscopy, histomorphometry, immunohistochemistry, and transmission electron microscopy were performed to assess soft-tissue growth and differentiation. Statistical analysis was performed by means of the Mann-Whitney test. RESULTS: The mean rate of mucoperichondrial flap recovery of the implant was 66 percent in group 2 and 82 percent in group 3, and was significantly different from that of the control group (p < 10(-4)). The mean amount of closure was 32 and 64 percent, respectively (p < 10(-3)). The thickness of the perichondrium was greater than the control on both sides (p < 10(-4)). Vascularized soft tissues and bone formation invaded pores of implants. No pathologic inflammation was observed in submucosa. Moderately differentiated and well differentiated newly formed epithelium were the most frequent types observed, with good correlation between immunostaining and morphologic features. CONCLUSION: These data suggest a good biocompatibility of biphasic calcium phosphate and its ability to repair the nasal septum in sheep.

Combination of cell delivery and thermoinducible transcription for in vivo spatiotemporal control of gene expression: a feasibility study.

PURPOSE: To demonstrate the feasibility of combining in situ delivery of genetically modified cells into the rat kidney, to induce expression of a reporter gene under transcriptional control of a heat-inducible promoter activated with magnetic resonance (MR)-guided focused ultrasonography (US), and to demonstrate in vivo the local expression of the synthesized protein. MATERIALS AND METHODS: Experiments were conducted in agreement with the European Commission guidelines and directives of the French Research Ministry. C6 cells were genetically modified by incorporating the firefly luciferase (LucF) gene under transcriptional control of a heat-sensitive promoter (human heat shock protein 70B). Engineered cells were injected in the renal artery of a superficialized left kidney (15 rats). Two days later, intrarenal LucF expression was induced noninvasively by local hyperthermia in 15 renal locations in nine rats with focused US and was controlled with MR temperature imaging. Six hours after heating, LucF activity was detected in vivo with bioluminescence imaging. RESULTS: The genetically engineered C6 cell line was characterized in vitro for LucF expression related to the heating parameters. Changes in renal morphology and hemodynamic parameters as a result of rat kidney superficialization were not significant. Intrarenal temperature measurement at the focal point followed the scheduled temperature in 13 of 15 cases. On bioluminescence images, LucF activity was present only in heated regions. The level of LucF expression was also dependent on heating parameters. Substantial tissue damage was noted at histologic analysis in only the two cases in which temperature control was inadequate. CONCLUSION: A strategy combining cell delivery of a transgene and a thermosensitive promoter that can be locally activated with MR-guided focused US is able to induce in vivo gene expression controlled in space and time. SUPPLEMENTAL MATERIAL: http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.10100767/-/DC1.

Ectopic Cushing's syndrome due to an adrenal ganglioneuroma.

BACKGROUND: Cushing's syndrome (CS), rare in children, is due to pituitary or, less frequently, to adrenocortical tumors. Ectopic adrenocorticotropin (ACTH) secretion is exceptional. METHOD: A case of apparently ACTH-independent CS in a child is reported. RESULTS: CS was due to an adrenal ganglioneuroma where neuroendocrine cells were immunopositive for ACTH responsible for the syndrome through a paracrine effect. Cortical cell hyperplasia was observed. CONCLUSION: Benign and differentiated tumors of the neural crest such as ganglioneuromas may be responsible for CS.

Case study of the month. Complete histologic remission after sunitinib neoadjuvant therapy in T3b renal cell carcinoma.

The authors present the first case report of complete histologic remission after neoadjuvant sunitinib treatment on primary renal tumour and vena cava thrombus. A 78-yr-old woman with an Eastern Cooperative Oncology Group (ECOG) score of 0 presented with a T3b renal tumour. She refused surgical treatment but agreed to percutaneous biopsy and medical treatment. A Fuhrman III renal cell carcinoma was histologically confirmed on percutaneous biopsy, and sunitinib treatment was administered over 6 mo. A significant objective response was observed for tumour size and thrombus. The patient finally accepted surgical treatment. Pathologic examination concluded with a complete response of primary tumour and thrombus.

Predominance of CD8+ T lymphocytes among periglomerular infiltrating cells and link to the prognosis of class III and class IV lupus nephritis.

OBJECTIVE: Recent studies have revealed a potential implication of CD8+ T lymphocytes in the pathogenesis of systemic lupus erythematosus (SLE) through their ability to induce tissue damage. The aim of the present study was to analyze the localization of CD8+ cells in the kidneys of patients with class III and class IV lupus nephritis and to establish correlations with histologic, biologic, and clinical features of SLE. METHODS: Twenty-five consecutive SLE patients with class III or class IV lupus nephritis were enrolled. Phenotype analyses of blood lymphocytes and renal immunohistochemistry studies were performed. RESULTS: CD8+ T cells were the predominant kidney-infiltrating subset of cells. The mean +/- SD numbers of CD8+ T cells and CD4+ T cells were 66.2 +/- 65.2/mm(2) and 19.3 +/- 29.4/mm(2), respectively. There was a significant correlation between the percentage of blood CD3+,CD8+,DR+ cells and the total number of renal CD8+ T cells (r = 0.42, P = 0.039). Renal CD8+ T cell infiltration correlated well with the renal activity index (r = 0.63, P = 0.0007) and with high serum creatinine levels (r = 0.75, P = 0.0001). This CD8+ T cell infiltrate, which was predominantly in the periglomerular area, was correlated with cellular crescents and Bowman's capsule rupture and was associated with a poor response after conventional induction therapy. CONCLUSION: CD8+ T lymphocytes infiltrate the periglomerular area in patients with severe (class III and class IV) lupus nephritis and are linked to a poor outcome after induction therapy. These results reveal a new potential effector pathway operant in lupus nephritis.

Azoospermia as a new feature of Fabry disease.

OBJECTIVE: To describe two cases of azoospermia in men with Fabry disease. DESIGN: Case report. SETTING: Centre hospitalier universitaire, maternité Pellegrin, Bordeaux, France. PATIENT(S): Two infertile men with azoospermia and with Fabry disease. INTERVENTION: Testicular biopsies. MAIN OUTCOME MEASURE: Histological and electron microscopy analysis of testicular biopsies. RESULT(S): Testicular biopsies revealed characteristic aspects of trihexosid ceramid deposits in Leydig cells by optical and electronic microscopic analysis. Using testicular sperm extraction and intracytoplasmic sperm injection, sperm retrieval led to pregnancies and deliveries of healthy children. CONCLUSION(S): Azoospermia should be considered as a possible complication of Fabry disease. We recommend a routine sperm analysis in the follow-up of young patients with Fabry disease. Azoospermia was still present after 4 years of agalsidase-beta therapy. Because we do not know the efficacy of agalsidase therapy on the genital involvement in Fabry disease, sperm cryopreservation is recommended.

MR evaluation of the glomerular homing of magnetically labeled mesenchymal stem cells in a rat model of nephropathy.

PURPOSE: To assess renal glomerular homing of intravenously injected superparamagnetic iron oxide (SPIO)-labeled mesenchymal stem cells (MSCs) at in vivo and ex vivo magnetic resonance (MR) imaging in an experimental rat model of mesangiolysis. MATERIALS AND METHODS: Animal procedures were performed in accordance with protocols approved by Institutional Animal Care and Use Committee. Fourteen rats were divided into two groups: one pathologic (n = 10), with persistent mesangiolysis following simultaneous injection of OX-7 monoclonal antibody and puromycin aminonucleoside in which 10(7) SPIO- and DiI-labeled MSCs were injected, and one control (n = 4). In vivo and ex vivo MR imaging examinations were performed with 4.7- and 9.4-T spectrometers, respectively, and T2*-weighted sequences. In vivo signal intensity variations were measured in the liver and kidney before and 6 days after MSC injection. Intrarenal signal intensity variations were correlated with histopathologic data by means of colocalization of DiI fluorescence, alpha-actin, and Prussian blue stain-positive cells. Histologic differences between the glomerular homing of MSCs in different kidney portions were correlated to the areas of MR signal intensity decrease with nonparametric statistical tests. RESULTS: On in vivo images, signal intensity measurements of pathologic kidneys following MSC injection did not show any signal intensity decrease (P = .7), whereas a 34% +/- 14 (mean +/- standard deviation) signal intensity decrease was observed in the liver (P < .01), where a substantial number of labeled cells were trapped. On ex vivo images, pathologic kidneys showed focal cortical (glomerular) areas of signal intensity loss, which was absent in controls. The areas of low signal intensity correlated well with alpha-actin and Prussian blue stain- and DiI-positive areas (P < .01), which indicates that MSCs specifically home to injured tissue. No MSCs were detected in the kidneys of control animals. CONCLUSION: Intravenously injected MSCs specifically home to focal areas of glomerular damage and can be detected at ex vivo MR imaging.

Rhabdomyosarcoma: value of myogenin expression analysis and molecular testing in diagnosing the alveolar subtype: an analysis of 109 paraffin-embedded specimens.

BACKGROUND: Identification of the alveolar subtype of rhabdomyosarcoma (ARMS) is important, because the poor prognosis associated with this subtype necessitates a modified therapeutic regimen. At present, ARMS diagnoses are made on the basis of histologic findings and the extent of myogenin immunopositivity. Nonetheless, the absence of an alveolar pattern in the solid variant, the low degree of differentiation in certain embryonal rhabdomyosarcomas (ERMS), and the increasing use of microbiopsy samples make the diagnosis of ARMS somewhat difficult. Two specific translocations have been found in ARMS, and fusion transcripts can be detected by reverse transcriptase-polymerase chain reaction (RT-PCR) analysis of paraffin-embedded tissue (PET). METHODS: To assess the value of myogenin staining and molecular testing in the diagnosis of rhabdomyosarcoma, the authors examined 109 rhabdomyosarcoma samples (45 ARMS samples and 64 ERMS samples). Real-time RT-PCR analysis of PET was performed in all 109 rhabdomyosarcomas, and RT-PCR analysis of frozen material was performed in 24 cases. RESULTS: PAX fusion transcripts were present in 44 cases (39 ARMS and 5 ERMS) and absent in 52 cases (2 ARMS and 50 ERMS). In 13 cases (4 ARMS and 9 ERMS), the results were not interpretable. Results were concordant between paired frozen and fixed tumor samples. All 35 interpretable ERMS samples that contained < 50% myogenin-positive cells failed to yield detectable PAX fusion transcripts. Of the 61 interpretable tumor samples (41 ARMS and 20 ERMS) that contained > 50% myogenin-positive cells, 44 (39 ARMS and 5 ERMS) yielded detectable PAX fusion transcripts. CONCLUSIONS: The current study demonstrates that molecular detection of PAX fusion transcripts via real-time RT-PCR analysis of PET is a sensitive and specific method for the diagnosis of ARMS and that immunohistochemical analysis of myogenin expression can be used to select cases for such molecular testing. Although RT-PCR analysis appears not to possess diagnostic value in tumors with < 50% tumor cell immunopositivity, it is strongly recommended for the diagnosis of tumors containing > 50% myogenin-positive cells.

Lower incidence of chronic allograft nephropathy at 1 year post-transplantation in patients treated with mycophenolate mofetil.

Chronic allograft nephropathy (CAN) is the main cause of graft failure after the first year of transplantation. This prospective, centrally randomized, open-label study was conducted to examine the possibility that mycophenolate mofetil (MMF) can prevent the emergence of CAN. The incidence of biopsy-proven CAN at 1 year was compared between two cyclosporine-based regimens comprising either mycophenolate mofetil (MMF) or azathioprine (AZA). The AZA group (n = 34) and the MMF group (n = 37) were balanced for all baseline characteristics of donors and recipients, the pre-existence of renal lesions on donor biopsy, the incidence of delayed graft function and acute rejection. Based on an intent-to-treat analysis, the number of patients with CAN at 1 year post-transplantation was significantly reduced in the MMF group (17/37-46%) compared with the AZA group (24/34-71%) (p = 0.03). When observed data were considered, 56/71 (78.8%) patients had a 1-year biopsy, and the number of patients with CAN was significantly lowered in the MMF group (9/29-31%) compared with the AZA group (17/27-63%) (p = 0.01). These results suggest a beneficial effect of MMF on the incidence of CAN at 1 year post-transplantation.

[Nasal and auricular inverted papillomas]. / Papillomes inversés nasal et auriculaire.

We report a rare case of an inverted papilloma with an unusual clinical course: development in the middle ear, multiples recurrences, and invasion of the temporal bone.

Renal diffusion and BOLD MRI in experimental diabetic nephropathy. Blood oxygen level-dependent.

PURPOSE: To investigate the possibility of using combined blood oxygen level-dependent (BOLD) imaging and diffusion-weighted imaging (DWI) to detect pathological and physiological changes in renal tissue damage of the kidney induced by chronic renal hyperfiltration. MATERIALS AND METHODS: The apparent diffusion coefficient (ADC) and the T(2)* value within the inner compartments of the kidneys of 17 rats with diabetes mellitus were compared with the results obtained from a control group (N = 16). The influence of dynamic changes of the renal function on the blood-oxygen saturation was evaluated by comparing the T(2)* values before and after the active reduction of tubular transport by furosemide injection. RESULTS: All compartments of the diabetic kidney showed significantly (P < 0.05) lower T(2)*-values compared to the control group. In particular, the very low values in the outer stripe (OS) of the outer medulla (OM) (T(2)*-normal: 69.4 +/- 10.9 msec; T(2)*-diabetic: 51.4 +/- 13.9 msec) indicated either hypoxia due to hyperfiltration, or renal blood volume changes. Diffusion imaging of the same area showed significantly lower ADC values (ADC-normal: 1.45 +/- 0.26; ADC-edema: 1.19 +/- 0.25 [10(-9)m(2)/s]) that correlated with pathological findings on histopathology. The injection of furosemide significantly (P < 0.05) increased T(2)* in all compartments of both populations while the ADC remained unchanged. CONCLUSION: BOLD-contrast imaging appears to be able to depict tissue at risk from ischemia by revealing information about the balance between tubular workload and delivery of oxygen, and thus may reflect a measure of the reserve capacity. The diffusion measurements apparently reveal complementary information. Although ADC imaging is not sensitive to the current energy metabolism, it appears toreflect the pathological changes within the issue. Therefore, ADC measurements may be a sensitive indicator of the severity of ischemic lesions.