End-stage Renal Disease Kidney Research Articles

Mildly Elevated Basal Calcitonin Level in Patients With Thyroid Goiter: Using the Calcitonin Measurement in Fine-Needle Aspirate Washout Fluid of the Healthy Lobe to Define Medullary Thyroid Cancer and Reactive C-Cell Hyperplasia

Abstract Background: Mildly elevated basal calcitonin level (bCT), that suggests a bCT increase up to 100 pg/ml, may testify either medullary thyroid carcinoma (MTC) or reactive thyroid C-cell hyperplasia (CCH). The latter is observed under many conditions such as hypercalcemia, hypergastrinemia, thyroiditis, neuroendocrine tumors (NET), renal end-stage kidney disease, obesity, and smoking. The research is aimed at analyzing the clinical significance of the calcitonin measurement in the fine needle aspiration washout fluid sample (FNA-CT) for screening certain patients with nodular thyroidopathy and elevated bCT. Patients and Methods: 70 patients with mildly elevated bCT (for women 6-100 pg/ml, for men 19-100 pg/ml) underwent ultrasound-guided FNA-CT measurement of the thyroid nodules and healthy lobe tissue. After obtaining a FNA-CT specimen, the needle was washed with 0.5 ml of saline solution. The calcitonin (CT) was measured by ECLIA (LIAISON XL). Results: There were 51 females and 19 males, with a mean age of 46.8 ± 14.4 years (range 16-81). The mean value of bCT was 23.3 ± 19 pg/ml (range: 7-86.5). According to ultrasound, 66 patients (95%) presented with thyroid nodules, in 4 cases previously identified nodes were not confirmed. The mean lesion size was 10.8 ± 4.9 mm (range: 4-26). Thyroid nodules were evaluated by FNA biopsy which revealed according to the Bethesda system category I in 6 cases, II - 44, III - 2, IV - 4, V - 6, and VI - 1. Analyzing FNA-CT results we identified 13 cases (18%) with MTC with low CT level of healthy lobe tissue (1-89.6 pg/ml) and high CT level of the lesion (>2000 pg/ml), which was confirmed by final histological examination. Low CT level from both healthy lobe and the nodule (<20 pg/ml) was observed in 10 cases, we carried out the measurement of stimulated CT to exclude the extrathyroidal CT production, which was confirmed in 1 case. All 4 patients with no nodules possessed significantly higher T-rates (1650-2000 pg/ml). The remaining 43 cases (61%) had an increased CT-level of healthy tissue (>2000 pg/ml) with a lower level from the lesion. Among these patients, the probable predisposing CCH factors were obesity - 8 cases, thyroiditis - 12, NET - 3, hypercalcemia - 3, renal kidney disease - 1, and smoking - 3. These 54 patients were kept under dynamic control. The observation period for patients - 1 year. 4 patients underwent surgical treatment, subsequently, histological examination revealed papillary thyroid cancer, follicular adenoma, colloid goiter against CCH, and CT-producing NET. Conclusion: The measurement of FNA-CT of the healthy lobe tissue may be useful to differentiate MTC and CCH, but requires new data in a major cohort of patients. The disadvantage of this study is the impossibility of CCH histological verification in the follow-up group.

Acquired Cystic Kidney Disease-associated Renal Cell Carcinoma (ACKD-RCC) Harbor Recurrent Mutations in KMT2C and TSC2 Genes.

Individuals with acquired cystic kidney disease (ACKD) in the setting of end-stage renal disease (ESRD) have a high risk of developing renal cell carcinoma (RCC). ACKD-RCC is considered a distinct renal neoplasm in the International Society of Urologic Pathologists (ISUP)-World Health Organization (WHO) classification of kidney tumors which may behave aggressively. Since its original description, there have been multiple case reports and series published; however, the pathogenesis of this neoplasm is uncertain and there is limited data on the genetic aberrations of this tumor. Herein, we present our experience with ESRD kidneys, with emphasis on ACKD-RCC, associated cysts, and the somatic mutation analysis of a subset of ACKD-RCCs using next-generation sequencing. Our data on 59 cases with ESRD that underwent nephrectomy, shows that ACKD-RCC represents more than half of the tumors (25/46; 54%) developing in ESRD, followed by papillary RCC (13; 28%). History of dialysis, male sex, and African American race were potential risk factors for developing ACKD-RCCs. Further, ACKD-RCC-like cysts are possible precursors of RCCs in the ACKD setting noted in 40 of 46 (87%) cases with tumors. Next-generation sequencing analysis revealed recurrent mutations in the KMT2C gene in 4 of 5 ACKD-RCCs (80%), exclusively exhibiting cribriform "sieve-like" morphology; whereas the case negative for KMT2C mutations exhibited "type 2" papillary RCC morphology and lacked "sieve-like" growth pattern. Pathogenic mutations in TSC2 were the second common abnormality (3/5; 60%), often coexisting with KMT2C mutations. Deleterious mutations in additional genes such as CBL, PDGFRA, and SYNE1, etc. were noted but were nonrecurrent and always coexisted with mutations in KMT2C or TSC2. To conclude, our study highlights that mutations in a chromatin-modifying gene KMT2C may potentially be oncogenic drivers for the development of ACKD-RCC with classic sieve-like morphology. In addition, pathogenic mutations in TSC2 possibly play a role in the development of cysts/tumors in a subset of ACKD patients. If corroborated in larger cohorts, these findings would be useful in planning surveillance and early intervention in ESRD patients developing ACKD.

MON-457 Reactive Thyroid C-Cell Hyperplasia or Medullary Thyroid Cancer in a Patient with Nodular Thyroidopathy. May the Calcitonin Measurement in Fine-Needle Aspirate Washout Fluid of the Healthy Lobe Help to Define These Conditions?

Background: Serum basal calcitonin (bCT) is used as a biomarker of medullary thyroid carcinoma (MTC) but bCT can also be elevated in patients with hypercalcemias, hypergastrinemias, thyroiditis, neuroendocrine tumors, renal end-stage kidney disease, obesity and cigarette smoking. The application of bCT and calcitonin measured in the FNA washout fluid sample (FNA-CT) for screening certain patients with nodular thyroidopathy can be controversial. Case: A 44 yo patient presented with elevated bCT level - 24pg/ml (N for male <18). He had a morbid obesity (BMI-45kg/m2) and thereby received GLP-1 receptor agonists Liraglutide 18 mg in total throughout one month. The ultrasound thyroid examination showed 2 nodules in the right lobe: 11mm and 9 mm (EU-TIRADS 2 and 4). Thyroid nodules were evaluated by fine needle aspiration biopsy (FNAB) which revealed benign colloid nodules (Bethesda II). Following the most updated ATA guidelines, to accurately diagnose MTC we performed FNA-CT measurement. The concentration from both nodules exceeded the upper reporting range of 2000 pg/ml. The patient stopped his therapy with Liraglutide and after one month of following, his bCT dropped at 18 pg/ml. He underwent a second workup with same results. We examined FNA-CT of contralateral healthy lobe and obtained 913 pg/ml. After this case, 17 patients with high-normal rate of bCT: 14 of them had a nodule (Bethesda II) and elevated FNA-CT of healthy tissue of the contralateral lobe (>2000 pg/ml) were determined in follow-up group. The remaining 3 patients with nodules (Bethesda IV-VI) and FNA-CT of healthy lobe which did not exceed bCT rate, were operated. MTC was confirmed. Discussion: Our patient had not only many factors which can occur his bCT level (obesity, smoking), but also unfavourable FNA washout results. Additionally, since in clinical studies GLP-1 receptor activation has been associated with C-cell hyperplasia (CCH), we cannot completely exclude the possible effect of this treatment on patient’s bCT level. We confronted a situation when, on the one hand, FNA-CT data indicate the MTC nature of hypercalcitoninemia, but on the other hand, decreasing bCT-level in dynamic observation is not common for MTC. FNAB of the healthy lobe and obtaining high rates of CT in the washout fluid sample allowed us to confirm the diffuse CCH process, thus to follow up these patients. CT stimulation test cannot distinguish between minimal MTC and CCH and has no reference range. The weak point of the proposed study is the lack of morphological data in the follow-up group of patients. Conclusion: It is possible to use rate of FNA-CT of the healthy lobe to differentiate between various C-cell diseases, but requires new data.

Comparison of Renal Anastomosing Hemangiomas in End-Stage and Non–End-Stage Kidneys: A Meta-Analysis With a Report of 2 Cases

Renal anastomosing hemangioma (RAH) is a very rare distinct entity composed of anastomosing sinusoidal (spleen-like) capillary-sized vessels lined by flat or hobnail endothelial cells. Most of the published cases of RAH occurred in the setting of end-stage renal disease (ESRD). We present 2 cases of RAH in ESRD along with a literature review. We compared clinicopathologic features of RAHs in end-stage and non-end-stage kidneys. A meta-analysis was conducted with PubMed and a manual search through references of relevant publications. Individual patient data gathered from the literature were used in the analysis. Our systematic review revealed 49 RAHs, including our 2 cases. Thirty-two (65.3%) cases were in ESRD, only 17 (34.7%) were in patients with non-ESRD. RAHs in ESRD were in younger patients, smaller in size, multifocal, and seen more with renal epithelial neoplasms when compared with RAHs in non-ESRD ( P < .05). Extramedullary hematopoiesis was seen mostly in RAHs in ESRD kidneys (85% vs 41.7%) ( P = .018). Follow-up data were available for 25 cases with a mean follow-up of 24.58 ± 38.54 months. Recurrence, metastasis, or death have never been described related to RAH in any patients. In conclusion, RAHs are rare and mostly arise in kidneys with end-stage damage. RAHs in ESRD and non-ESRD differ in terms of clinicopathologic features.

Transplantation rénale pédiatrique

To describe indications, surgical aspects, results and outcomes of kidney transplantation in children. An exhaustive systematic review of the scientific literature was performed in the Medline database (http://www.ncbi.nlm.nih.gov) and Embase (http://www.embase.com) using different associations of the following keywords (MESH): "kidney transplantation", "pediatric", "children", "outcomes". Publications obtained were selected based on methodology, language, date of publication (last 10 years) and relevance. Prospective and retrospective studies, in English or French, review articles; meta-analysis and guidelines were selected and analyzed. This search found 2608 articles. After reading titles and abstracts, 18 were included in the text based on their relevance. Kidney transplantation is the gold-standard treatment for end stage renal kidney disease in children. The surgical procedure is well standardized with a retroperitoneal approach when child and kidney size allow it or a transperitoneal approach in child less than 15kg and big size kidney graft. Anastomosis sites include iliac vessels in the retroperitoneal approach, and inferior vena cava and aorta in case of transperitoneal procedure. Ureteral reimplantation used most of the time a Campos Freire technique. Sometimes, particular conditions in the recipient (such as vena cava thrombosis) required procedure adaptation. Graft survival dramatically increased over the past few years and is now superior to those observed in adult kidney transplantation, particularly in experienced team with microsurgery skills. Immunosuppressive treatments are similar to adults. Viral infections and post-transplant lymphoproliferative disorder are the main complications of renal transplantation in children and may lead to lethal outcomes. An increase graft loss is observed during boyhood due to immunosuppressive drugs uncompliance.

MP59-02 RENAL FUNCTION IMPAIRMENT AFTER NEPHRON SPARING SURGERY OR RADICAL NEPHRECTOMY IN PATIENTS WITH CLINICAL T1A-T1B RENAL MASS AND NORMAL PREOPERATIVE GLOMERULAR FILTRATION RATES: RESULTS FROM A LARGE MULTI-INSTITUTIONAL STUDY

You have accessJournal of UrologyKidney Cancer: Localized IV1 Apr 2014MP59-02 RENAL FUNCTION IMPAIRMENT AFTER NEPHRON SPARING SURGERY OR RADICAL NEPHRECTOMY IN PATIENTS WITH CLINICAL T1A-T1B RENAL MASS AND NORMAL PREOPERATIVE GLOMERULAR FILTRATION RATES: RESULTS FROM A LARGE MULTI-INSTITUTIONAL STUDY Umberto Capitanio, Carlo Terrone, Alessandro Antonelli, Andrea Minervini, Alessandro Volpe, Fabio Castiglione, Maria Furlan, Rayan Matloob, Federica Regis, Luisa Zegna, Gianni Vittori, Ettore Di Trapani, Marco Carini, Claudio Simeone, Francesco Montorsi, and Roberto Bertini Umberto CapitanioUmberto Capitanio More articles by this author , Carlo TerroneCarlo Terrone More articles by this author , Alessandro AntonelliAlessandro Antonelli More articles by this author , Andrea MinerviniAndrea Minervini More articles by this author , Alessandro VolpeAlessandro Volpe More articles by this author , Fabio CastiglioneFabio Castiglione More articles by this author , Maria FurlanMaria Furlan More articles by this author , Rayan MatloobRayan Matloob More articles by this author , Federica RegisFederica Regis More articles by this author , Luisa ZegnaLuisa Zegna More articles by this author , Gianni VittoriGianni Vittori More articles by this author , Ettore Di TrapaniEttore Di Trapani More articles by this author , Marco CariniMarco Carini More articles by this author , Claudio SimeoneClaudio Simeone More articles by this author , Francesco MontorsiFrancesco Montorsi More articles by this author , and Roberto BertiniRoberto Bertini More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2014.02.1798AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail Introduction and Objectives Some reports suggested that nephron sparing surgery (NSS) may protect against renal function impairment (RFI) when compared with radical nephrectomy (RN) in patients with small renal masses. In the current study, we aimed to test the effect of treatment type (NSS vs. RN) on prevalence of RFI and renal end-stage kidney disease (ESRD) after accounting for clinical characteristics, comorbidities and individual cardiovascular risk. Methods A multi-institutional collaboration among four European Tertiary Care Centers allowed collecting 2024 patients with a clinical T1a-T1b N0 M0 renal mass and complete functional follow-up data. Patients underwent RN (n=765, 37.8%) or NSS (n=1259, 62.2%) and showed normal estimated glomerular filtration rates (eGFR) before surgery (defined as a pre-operative eGFR≥60 ml/min/1.73 m2). Univariable and multivariable Cox regression analyses predicting RFI were performed. To adjust for inherent baseline differences among patients, we included as covariates: preoperative creatinine, age, clinical tumor size, gender, presence of hypertension or diabetes at diagnosis, baseline Charlson comorbidity index (CCI), body mass index and smoker status. Results At a mean follow up period of 68.2 months, 81.1% vs. 55.8% patients showed normal renal function after NSS vs. RN, respectively (p<0.001). The prevalence of mild RFI, severe RFI and ESRD resulted 25.3, 1.0% and 2.1%. However, after stratifying for treatment type, the prevalence of mild RFI, severe RFI and ESRD resulted higher in the group of patients treated with RN relative to NSS (39.7 vs. 16.6%, 1.4 vs. 0.8% and 3.0 vs. 1.5%, respectively, p<0.001). At multivariable analyses, patients who underwent PN showed significantly lower risk to harbour RFI compared with their RN-treated counterparts (hazard ratio [HR]: 0.63; 95% confidence interval, 0.44-0.89; p=0.008). Increasing age (HR: 1.06, p<0.001), larger tumors (HR: 1.04, p<0.001), presence of hypertension (HR: 5.39, p=0.006) and presence of diabetes (HR: 1.56, p=0.05) resulted independent predictors of RFI. Conclusions Although the risk of severe renal function impairment and ESRD is negligible, up to 30% of the patients with clinical T1a-T1b renal masses and a normal preoperative kidney function harbour mild RFI after surgery. Also after accounting for clinical characteristics, comorbidities and cardiovascular risk at diagnosis, NSS significantly decrease the risk of RFI relative to RN. © 2014FiguresReferencesRelatedDetails Volume 191Issue 4SApril 2014Page: e650 Advertisement Copyright & Permissions© 2014MetricsAuthor Information Umberto Capitanio More articles by this author Carlo Terrone More articles by this author Alessandro Antonelli More articles by this author Andrea Minervini More articles by this author Alessandro Volpe More articles by this author Fabio Castiglione More articles by this author Maria Furlan More articles by this author Rayan Matloob More articles by this author Federica Regis More articles by this author Luisa Zegna More articles by this author Gianni Vittori More articles by this author Ettore Di Trapani More articles by this author Marco Carini More articles by this author Claudio Simeone More articles by this author Francesco Montorsi More articles by this author Roberto Bertini More articles by this author Expand All Advertisement Advertisement PDF DownloadLoading ...

Effects of T Lymphocytes, Interleukin-1, and Interleukin-6 on Renal Fibrosis in Canine End-Stage Renal Disease

Canine end-stage renal disease (ESRD) is defined as the almost complete failure of renal function or irreversible destruction and is characterized by extensive glomerular sclerosis, tubular atrophy, interstitial inflammation, and fibrosis. Renal fibrosis is a common pathway leading to kidney failure. Infiltrating immunocytes in the end-stage kidney and several related factors are involved in renal fibrogenesis. A total of 18 renal tissue samples were obtained from canine patients with ESRD using biopsy and necropsy procedures. The extent of renal fibrosis was histopathologically examined by Masson trichrome staining. T-cell and B-cell localization and macrophage lineages were determined by immunohistochemical staining. Additionally, interleukin-1 (IL-1), IL-2, and IL-6 levels in the canine ESRD kidney were immunohistochemically evaluated and compared with expression patterns in the normal kidney. Significant fibrosis and infiltrating immunocytes consistent with lymphocytes were observed. Although the B-cell count was increased in the end-stage kidney, immunostaining patterns disclosed a marked increase in the number of CD3(+) cells. Furthermore, the remarkable increase in IL-1 and IL-6 levels suggests that T cells in the kidneys of dogs with ESRD spontaneously express these cytokines. In this study, the correlation between the degree of renal fibrosis and cytokines in canine ESRD was examined. The present study shows that T lymphocytes and IL-6 play important roles in renal fibrosis.

Spectrum of Epithelial Neoplasms in End-Stage Renal Disease

Most (up to 71%) of renal cell neoplasms occurring in patients with end-stage renal disease (ESRD), particularly with acquired cystic disease of the kidney (ACDK), have been reported to be papillary renal cell carcinoma (RCC). Our initial experience with tumors in such a setting indicated that many tumors were histologically difficult to classify into the known subtypes of RCC or had features that were different from those in sporadically occurring RCCs. In this study on 66 ESRD kidneys (52 of which showed features of ACDK) removed because tumors were detected in them, we found two major groups of RCC. Overall, there were 261 grossly identified tumors in these kidneys, and many additional tumors were observed on microscopic evaluation in some. Of the two major groups of RCCs, one consisted of tumors similar to those seen in sporadic settings (ie, clear-cell, papillary, and chromophobe RCC), and these formed the dominant mass in 12 (18%), 10 (15%), and 5 (8%) of the 66 kidneys, respectively. The other group consisted of two subtypes of RCC that appear quite unique to ESRD. The more common tumor that we have designated as "acquired cystic disease-associated RCC" was seen as the dominant mass in 24 (36%) of 66 of the kidneys, and it formed the most common tumor type among the smaller nondominant masses, as well. It was characterized by a typical microcystic architecture, eosinophilic cytoplasm with Fuhrman's grade 3 nuclei, and frequent association with intratumoral oxalate crystals. Additionally, these tumors frequently, but usually focally, exhibited papillary architecture, and clear cytoplasm. These tumors occurred only in kidneys with ACDK, and not in noncystic ESRD. The other category was "clear-cell papillary RCC of the end-stage kidneys," present as the dominant mass in 15 (23%) of the 66 kidneys and occurring in both the ACDK and noncystic ESRD. These predominantly cystic tumors showed prominent papillary architecture with purely clear-cell cytology. Immunohistochemical studies in tumors with histology similar to the known subtypes of sporadic RCC showed immunoprofiles similar to that reported in sporadically occurring tumors. The two subtypes of RCC unique to ESRD had distinctive immunoprofiles supporting their separate morphologic subcategorization. Only the acquired cystic disease-associated RCC showed lymph node metastases in 2 cases and sarcomatoid features in 2 more cases. One of the latter 2 died with widespread metastatic disease within 34 months of nephrectomy. Thus, a broad spectrum of renal cell tumors exist in ESRD, only some of which resemble the sporadic RCCs. Acquired cystic disease-associated RCC is the commonest tumor subtype in ESRD, and biologically it appears to be more aggressive than the other tumor subtypes in ESRD.

T cell lines and clones preferentially recognizing kidney-associated antigens in end-stage renal disease.

The specificity in the mixed lymphocyte kidney culture (MLKC) of T cell lines and clones derived from human end-stage renal disease (ESRD) kidneys was studied using collagenase dispersed kidney cells compared with lymphocytes as stimulating cells. These experiments were performed because of previous studies in which infiltrating lymphocytes freshly isolated from ESRD kidney tissue at nephrectomy (as well as autologous splenic T cells) were seen to directly generate this lymphoproliferative MLKC response when stimulated with autologous renal cortical cells. In the current studies, histopathologic staining of tissues and suspensions of infiltrating kidney lymphocytes showed predominance of OKT4 labeled phenotypes, and the stimulation indices in MLKC in general showed a direct relationship with the percentage of helper cells seen in the infiltrates. When T cell lines and clones derived from lymphocytes infiltrating the ESRD kidneys were tested in MLKC, there was evidence of kidney-associated, as opposed to lymphocyte-associated (MLC) reactivity using (3H) thymidine uptake as a reflection of a lymphoproliferative response. Several cell lines and clones derived from these T lymphocytes exhibited a dual reactivity. They served as responding cells in the MLKC reaction and completely suppressed a non-specific allogeneic MLC when added as third-party cells. Quantitatively, some clones suppressed when third-party x-irradiated cells were only 5% of the responding cell number in coculture. In addition to the dual reactivity, phenotypic analysis of these same cell lines and clones employing monoclonal antibodies revealed that individual cells expressed both OKT4 and OKT8 determinants. However, approximately 90% of the cells in the MLC enhancing line were labeled with OKT4. These results indicate that there is a complexity in the autologous MLKC response in that cells with both helper/inducer and suppressor/cytotoxic function take part in the reaction. Although delayed-type hypersensitivity to kidney-associated antigens is inferred as a result of these in vitro assays, nonspecific suppression of other Ia-dependent reactions can simultaneously occur.

THE BIOLOGIC SIGNIFICANCE OF THE MIXED LYMPHOCYTE KIDNEY CULTURE IN HUMANS

The mixed lymphocyte kidney culture (MLKC) in humans has been studied in normal and abnormal clinical conditions. Human renal cortical cells were extracted by collagenase treatment from the kidneys of "normal" heart-beating cadaver organ donors (n = 13), patients with end-stage renal disease (ESRD) at pretransplant bilateral nephrectomy and splenectomy (n = 13), and from irreversibly rejected renal allografts at the time of graft nephrectomy (n = 5). Proliferation of peripheral blood T lymphocytes of 2-DR-mismatched volunteers occurred in response to kidney cortical cells extracted from each of the 3 donor categories in a reaction termed the allogeneic mixed lymphocyte kidney culture. Additionally, splenic T cells from cadavers and patients with ESRD were seen to react to their autologous kidney cells. The renal cortical cells extracted from ESRD kidneys were more stimulatory in the allogeneic and autologous MLKC responses than those extracted from "normal" cadaver kidneys even when the ESRD kidneys were 99% depleted of passenger T and B lymphocytes by treatment with monoclonal antibodies T11 and B1. In order to help define the antigens operative in the MLKC, we pretreated stimulating lymphocytes and renal cortical cells with anti-class II monoclonal antibodies. The allogeneic mixed lymphocyte reaction and MLKC were inhibited ca. 80% and 30%, respectively. The autologous MLKC was unaffected by this treatment. To further support that tissue-specific immune mechanisms were operative in the reaction, experiments were performed with infiltrating lymphocytes isolated from the ESRD kidneys, which were seen to generate a proliferative response when stimulated with autologous cortical cells. However, the response of these same infiltrating lymphocytes when stimulated with allogeneic lymphocytes (MLR), was markedly weaker than the response of the patients' autologous spleen cells. In addition, two kidneys were obtained at rejection from recipients that had received grafts from HLA-MLR-identical sibling donors. A lymphoproliferative reaction of recipient peripheral blood T lymphocytes occurred in response to (donor) renal cortical cells, but not to donor peripheral blood lymphocytes. In contrast, infiltrating (recipient) kidney lymphocytes responded to the kidney cortical cells and to donor peripheral blood lymphocytes. Moreover, peripheral blood T lymphocytes of the HLA-identical donor responded to his own kidney cortical cells, which were isolated from the rejected recipient kidney, and did not respond to recipient peripheral blood lymphocytes. Finally, a "normal" cadaveric kidney was fortuitously available at the same time that a rejected transplant (cadaver)