Microvascular inflammation in the absence of human leukocyte antigen-donor-specific antibody and C4d: An orphan category in Banff classification with cytotoxic T and natural killer cell infiltration.

Isolated microvascular inflammation (iMVI) without HLA donor-specific antibodies or C4d deposition in peritubular capillaries remains an enigmatic phenotype that cannot be categorized as antibody-mediated rejection (ABMR) in recent Banff classifications. We included 221 kidney transplant recipients with biopsies with ABMR (n = 73), iMVI (n = 32), and normal (n = 116) diagnoses. We compared peripheral blood leukocyte distribution by flow cytometry and inflammatory infiltrates in kidney transplant biopsies among groups. Flow cytometry showed fewer lymphocytes and total, CD4+, and CD8+ peripheral T cells in iMVI compared with ABMR and normal cases. ABMR and iMVI had fewer total natural Killer (NK) cells but more NKG2A+ NK cells. Immunohistochemistry indicated that ABMR and iMVI had greater CD3+ and CD68+ glomerular infiltration than normal biopsies, whereas CD8+ and TIA1+ cells showed only increased iMVI, suggesting they are cytotoxic T cells. Peritubular capillaries displayed more CD3+, CD56+, TIA1+, and CD68+ cells in both ABMR and iMVI. In contrast, iMVI had less plasma cell infiltration in peritubular capillaries and interstitial aggregates than ABMR. iMVI displayed decreased circulating T and NK cells mirrored by T cell and NK cell infiltration in the renal allograft, similar to ABMR. However, the lesser plasma cell infiltration in iMVI may suggest an antibody-independent underlying stimulus.

Redefining the Role of ADAM17 in Renal Proximal Tubular Cells and Its Implications in an Obese Mouse Model of Pre-Diabetes.

Acute and chronic kidney lesions induce an increase in A Disintegrin And Metalloproteinase domain 17 (ADAM17) that cleaves several transmembrane proteins related to inflammatory and fibrotic pathways. Our group has demonstrated that renal ADAM17 is upregulated in diabetic mice and its inhibition decreases renal inflammation and fibrosis. The purpose of the present study was to analyze how Adam17 deletion in proximal tubules affects different renal structures in an obese mice model. Tubular Adam17 knockout male mice and their controls were fed a high-fat diet (HFD) for 22 weeks. Glucose tolerance, urinary albumin-to-creatinine ratio, renal histology, and pro-inflammatory and pro-fibrotic markers were evaluated. Results showed that wild-type mice fed an HFD became obese with glucose intolerance and renal histological alterations mimicking a pre-diabetic condition; consequently, greater glomerular size and mesangial expansion were observed. Adam17 tubular deletion improved glucose tolerance and protected animals against glomerular injury and prevented podocyte loss in HFD mice. In addition, HFD mice showed more glomerular macrophages and collagen accumulation, which was prevented by Adam17 deletion. Galectin-3 expression increased in the proximal tubules and glomeruli of HFD mice and ameliorated with Adam17 deletion. In conclusion, Adam17 in proximal tubules influences glucose tolerance and participates in the kidney injury in an obese pre-diabetic murine model. The role of ADAM17 in the tubule impacts on glomerular inflammation and fibrosis.

Endothelial ADAM17 Expression in the Progression of Kidney Injury in an Obese Mouse Model of Pre-Diabetes.

Disintegrin and metalloproteinase domain 17 (ADAM17) activates inflammatory and fibrotic processes through the shedding of various molecules such as Tumor Necrosis Factor-α (TNF-α) or Transforming Growht Factor-α (TGF-α). There is a well-recognised link between TNF-α, obesity, inflammation, and diabetes. In physiological situations, ADAM17 is expressed mainly in the distal tubular cell while, in renal damage, its expression increases throughout the kidney including the endothelium. The aim of this study was to characterize, for the first time, an experimental mouse model fed a high-fat diet (HFD) with a specific deletion of Adam17 in endothelial cells and to analyse the effects on different renal structures. Endothelial Adam17 knockout male mice and their controls were fed a high-fat diet, to induce obesity, or standard rodent chow, for 22 weeks. Glucose tolerance, urinary albumin-to-creatinine ratio, renal histology, macrophage infiltration, and galectin-3 levels were evaluated. Results showed that obese mice presented higher blood glucose levels, dysregulated glucose homeostasis, and higher body weight compared to control mice. In addition, obese wild-type mice presented an increased albumin-to-creatinine ratio; greater glomerular size and mesangial matrix expansion; and tubular fibrosis with increased galectin-3 expression. Adam17 deletion decreased the albumin-to-creatinine ratio, glomerular mesangial index, and tubular galectin-3 expression. Moreover, macrophage infiltration in the glomeruli of obese Adam17 knockout mice was reduced as compared to obese wild-type mice. In conclusion, the expression of ADAM17 in endothelial cells impacted renal inflammation, modulating the renal function and histology in an obese pre-diabetic mouse model.

Angiotensin-converting enzyme 2 influences pancreatic and renal function in diabetic mice.

Type 1 diabetes is a T-cell mediated autoimmune disease characterized by pancreatic beta cells destruction. Angiotensin-converting enzyme 2 (ACE2), a component of renin-angiotensin system (RAS) has been identified in pancreas from type 2 diabetic mice and its overexpression prevents beta cell dysfunction. We studied the effect of ACE2 deletion on pancreatic and renal function in the nonobese diabetic mice, a model that mimics type 1 diabetes. ACE2-deficient NOD mice and the respective controls were generated. Pancreas function and immunohistochemistry studies were performed. Renal function and RAS gene expression were also analyzed. Renal proximal tubular cells were obtained from these animals to dissect the effect of ACE2 deficiency in these cells. In NOD mice, ACE2 deletion significantly worsened glucose homeostasis, decreased islet insulin content, increased beta cell oxidative stress, and RIPK1-positive islets as compared with control mice. Angiotensin-converting enzyme and angiotensin II type 1 receptor (AT1R) were also increased in ACE2-deficient mice. In kidneys of 30-day diabetic mice, ACE2 deletion decreased podocyte number within the glomeruli, and altered renal RAS gene expression in tubules. ACE2 deletion influenced the expression of fibrosis-related genes in isolated primary renal proximal tubular cells before diabetes onset in NOD mice. Our findings suggest that ACE2 deletion may have a deleterious impact on beta cell and renal function, by promoting oxidative stress and increasing necroptosis mediators. In addition, this effect is accompanied by RAS alterations in both pancreas and renal proximal tubular cells, indicating that ACE2 may exert a renopancreatic protective effect on type 1 diabetes, which is activated before diabetes starts.

Risk Factors Associated with Major Complications after Ultrasound-Guided Percutaneous Renal Biopsy of Native Kidneys.

INTRODUCTION: Percutaneous renal biopsy (PRB) of native kidneys is an important tool for diagnosis and management of renal disease. In this study, we analyzed the success, safety, and risk complications of PRB in our center. METHODS: A retrospective review of ultrasound-guided PRB done at our institution from January 1998 to December 2017 was performed. Clinical and laboratory data were collected for 661 PRBs. Statistical analysis was performed using the Mann-Whitney U test for continuous variable and chi-square test for categorical variables. Multivariate analysis using logistic regression was performed to assess factors associated with increased risk of complications after PRB. RESULTS: The median age was 56 (42-68) years old, the majority were male (64%) and white (82%). Ten glomeruli were present in 63.5% of PRBs. Overall, the rate of complications was 16.6%, where 15.1% of them were minor complications and 1.5% were major complications. Perinephritic hematoma accounted for the minor complication that occurred most frequently, whereas the need of a blood transfusion was the prevalent for major complications. By multivariate analysis, increased activated partial thromboplastin time (aPTT; OR 1.11, 95% CI 1.035-1.180) and prebiopsy lower hemoglobin (Hgb; OR 1.61, 95% CI 1.086-2.304) were identified as independent risk factors for major complications. In addition, older patients (OR 1.057, 95% CI 1.001-1.117) were identified as an independent risk factor for blood transfusion requirement. CONCLUSION: The current risk of complications after native PRB is low. Major complications are most common in case of increased aPTT and decreased Hgb baseline level.

A Myxoid Fibrotic Reaction Pattern is Associated with Metastatic Risk in Cutaneous Squamous Cell Carcinoma.

Although desmoplasia has been associated with poor prognoses in cutaneous squamous cell carcinoma, little attention has been paid to the patterns of fibrosis. This study aimed to examine the different stromal fibrotic patterns as markers of metastatic risk. We performed a multicenter retrospective study that included 102 cutaneous squamous cell carcinomas (52 non-metastatic and 50 metastatic carcinomas). Clinical and histopathological data were registered. The fibrotic reaction pattern was classified as mature, intermediate or immature depending on the presence of keloid-like collagen and myxoid stroma. The immature pattern (areas characterized by myxoid changes with no inflammation) was observed in 18 samples and its presence was significantly associated with immunosuppression, budding, desmoplasia, perineural invasion, anatomic level, tumoural depth and metastatic risk in the multivariate analysis. Our findings suggest that the presence of an immature myxoid fibrotic pattern, which can be easily identified by routine hematoxylin-eosin staining, is strongly associated with metastatic risk.

The Polycomb proteins RING1B and EZH2 repress the tumoral pro-inflammatory function in metastasizing primary cutaneous squamous cell carcinoma.

Cutaneous squamous cell carcinoma (cSCC) is the second most common malignancy in humans and approximately 5% metastasize, usually to regional lymph nodes. Epigenetic regulation of gene expression may allow tumoral cells to acquire new functions in order to escape from the primary tumor. The aim of this study was to investigate the expression and function of proteins of the Polycomb family of epigenetic regulators in the metastatic process of cSCC. A higher expression of RING1B and EZH2 was detected by immunohistochemistry in a series of primary cSCC tumors that metastasized (MSCCs) when compared with non-metastasizing cSCCs (non-MSCCs). Stable downregulation of RING1B and EZH2 in cSCC cells results in enhanced expression of inflammatory cytokines and activation of the NF-κB signaling pathway. Accordingly, non-MSCCs display higher levels of membranous pS176-inhibitor of NF-kB kinase, and their stroma is enriched in neutrophils and eosinophils when compared with MSCCs. In vitro, hematopoietic cells exhibit a substantial migratory response to supernatants from Polycomb-depleted cSCC cells. Altogether, these data indicate that RING1B and EZH2 repress the innate inflammatory cSCC function and impair tumor immunosurveillance and suggest that patients with high-risk cSCCs could benefit from clinical therapies addressed to harness the immune response.

Sex dimorphism in ANGII-mediated crosstalk between ACE2 and ACE in diabetic nephropathy.

Angiotensin-converting enzyme (ACE) and ACE2 play a critical role in the renin-angiotensin system (RAS) by altering angiotensin II (ANGII) levels, thus governing its deleterious effects. Both enzymes are altered by sex and diabetes, and play an important role in the development of diabetic nephropathy (DN). Importantly, previous evidence in diabetic and ACE2-deficient (ACE2KO) males suggest a sex-dependent crosstalk between renal ACE and ACE2. In the present work, we aimed to study the sex-specific susceptibility to diabetes and direct infusion of ANGII in kidney disease progression, with a special focus on its link to ACE2 and ACE. In our mouse model, ANGII promoted hypertension, albuminuria, reduced glomerular filtration, and glomerular histological alterations. ANGII adverse effects were accentuated by diabetes and ACE2 deficiency, in a sex-dependent fashion: ACE2 deficiency accentuated ANGII-induced hypertension, albuminuria, and glomerular hypertrophy in diabetic females, whereas in diabetic males exacerbated ANGII-mediated glomerular hypertrophy, mesangial expansion, and podocyte loss. At the molecular level, ANGII downregulated renal ACE gene and enzymatic activity levels, as well as renin gene expression in ACE2KO mice. Interestingly, male sex and diabetes accentuated this effect. Here we show sex dimorphism in the severity of diabetes- and ANGII-related renal lesions, and demonstrate that ACE2- and ACE-related compensatory mechanisms are sex-specific. Supporting our previous findings, the modulation and ANGII-mediated crosstalk between ACE2 and ACE in DN progression was more evident in males. This work increases the understanding of the sex-specific role of ACE2 and ACE in DN, reinforcing the necessity of more personalized treatments targeting RAS.

CD274 (PDL1) and JAK2 genomic amplifications in pulmonary squamous-cell and adenocarcinoma patients.

AIMS: CD274 (PDL1) and JAK2 (9p24.1) gene amplifications have been recently described in pulmonary carcinomas in association with programmed death-ligand 1 (PD-L1) expression. Furthermore, PTEN loss has been explored preclinically in relation to PD-L1 expression. Our aim was to determine whether these genomic alterations affect PD-L1 expression levels in non-small-cell lung cancer. METHODS AND RESULTS: PD-L1 and PTEN expression determined by immunohistochemistry (IHC), and CD274, JAK2 and PTEN copy number alterations (CNAs) determined by fluorescence in-situ hybridisation, were studied in 171 pulmonary carcinoma specimens. PD-L1 expression was positive in 40 cases (23.3%), and CD274 amplification was present in 14 tumours (8.8%). Concordance between both events was found in 12 of 14 amplified cases (P = 0.0001). We found nine JAK2-amplified cases (5.7%), seven with PD-L1 expression (P = 0.0006). Moreover, six of the seven cases had JAK2 and CD274 coamplification (9p24.1 genomic amplification). Remarkably, the average PD-L1 IHC score was higher in these amplified cases (230 versus 80; P = 0.001). Non-statistical associations were observed between PD-L1 expression and PTEN loss and PTEN deletions. CONCLUSIONS: We describe a subset of patients (8.2%) who had 9p24.1 amplifications resulting in high expression of PD-L1. Our results provide evidence for genomic up-regulation of PD-L1 expression in non-small-cell lung cancer.

Membrane Attack Complex and Factor H in Humans with Acute Kidney Injury.

BACKGROUND AND AIMS: Complement system seems to play an important role in the pathogenesis of Acute Kidney Injury (AKI). The aim of this study was to investigate the role of complement system in the pathogenesis of human AKI. For this purpose, we studied Membrane Attack Complex (MAC) and factor H in plasma and kidney tissue in AKI. METHODS: Plasmatic concentrations of MAC and Factor H were studied in patients with hospital-acquired AKI and their respective controls. MAC and Factor H expression and localization within the kidney were studied by immunohistochemistry in kidney tissue samples from autopsies. Demographical, past medical, and laboratory data in patients on admission and 3 years after discharge were recorded. RESULTS: Plasmatic MAC concentrations were significantly higher in AKI-patients (5848±3604 vs 3703±1483 mAU/mL, p< 0.01), mainly in the severe cases, as measured by the need of renal replacement therapy, non-recovery of renal function, RIFLE classification and CKD development. MAC deposition was observed in tubular epithelial cell basal membranes, showing a larger number of tubules with MAC deposition, larger perimeter of affected tubules and greater intensity of MAC immunostaining in AKI patients. Factor H concentrations were higher in AKI patients (0.86±0.05 vs 0.60±0.04 mg/mL, p=0.007), showing a strong positive association with plasmatic MAC (r=0.7, p< 0.01)). Factor H immunostaining showed a tubular cytoplasmic pattern, with significant variations in the staining intensity, associated with the severity of histologic damage. CONCLUSION: Our data confirm that complement system is involved in human AKI, through the lytic action of MAC in tubular epithelial cells. These results suggest that complement system activation in AKI could be related with CKD development.

PD-L1 Expression is Increased in Metastasizing Squamous Cell Carcinomas and Their Metastases.

Programmed cell death ligand 1 (PD-L1) expression by tumor cells plays an important role in the inhibition of T cell-mediated immune response in cancer. PD-L1 expression by tumor cells has been linked to poor prognosis in a wide variety of cancers. However, PD-L1 expression in cutaneous squamous cell carcinoma (cSCC) has been scarcely studied, and its role as a prognosis biomarker remains controversial. The association of PD-L1 expression and the metastatic risk in a series of cSCC was assessed. PD-L1 and CD8 immunostainings of full excision sections of 99 primary tumors and 24 lymphatic metastases were semiquantitatively evaluated. Primary cSCCs were grouped according to the development of lymphatic metastatic spread [metastasizing squamous cell carcinoma (MSCC)] (n = 48) or the absence of progression [nonmetastasizing squamous cell carcinoma (NMSCC)] (n = 51). PD-L1-positive expression (cut off ≥1%) was found in 26% NMSCCs and in 50% MSCCs (P = 0.02). PD-L1 association with an increased metastatic risk was confirmed in the multivariate analysis (P < 0.05), along with the following features: recurrence, poor differentiation, and perineural invasion. Ninety percent of the metastases of PD-L1-positive tumors were also positive for PD-L1, displaying a trend toward a higher PD-L1 expression when compared with their primary tumors (P = 0.058). No significant differences in the peritumoral inflammatory infiltrate or in the expression of CD8 were found between metastasizing and nonmetastasizing primary tumors. Our results suggest that PD-L1 may play a relevant role in metastatic spread and may be a candidate prognostic biomarker in cSCC.

Impact of anthropometric features on the applicability and accuracy of FibroScan® (M and XL) in overweight/obese patients.

BACKGROUND AND AIM: Transient elastography is the reference method for liver stiffness measurement (LSM) in the general population, having lower applicability in obese patients. We evaluated the applicability and diagnostic accuracy of the M and XL probes in overweight/obese patients to establish the most appropriate approach. METHODS: From May 2013 to March 2015, we evaluated patients with a body mass index (BMI) ≥ 28 kg/m2 . We constructed an algorithm with variables independently related to unreliable LSM with the M probe. RESULTS: A total of 1084 patients were evaluated. M and XL probe applicability was 88.8% and 98%, respectively. Waist circumference (WC) (OR; 95% CI; P) (0.97; 0.94-0.99; P < 0.001) and skin-capsule distance (SCD) (0.83; 0.79-0.87; P < 0.001) were independently related to unreliable LSM (M probe). The SCD was > 25 mm in 5.5% of individuals with a BMI ≤ 35 kg/m2 and a WC ≤ 117 cm, with LSM (M probe) applicability rising to 94.3%. In contrast, 36.9% of patients with a BMI > 35 kg/m2 and/or a WC > 117 cm presented an SCD > 25 mm, with M probe applicability being 73.1%. The diagnostic accuracy (area under the receiver operator characteristic) using the M probe to identify significant steatosis (0.76), fibrosis (0.89), and cirrhosis (0.96) was very high in patients with a BMI ≤ 35 kg/m2 and a WC ≤ 117 cm. CONCLUSIONS: The applicability and accuracy of the FibroScan® M probe to identify fibrosis and steatosis was excellent in overweight and obesity grade I (BMI ≤ 35 kg/m2 ) with a WC ≤ 117 cm. The XL probe increased the applicability of transient elastography in obesity grade II-III (BMI > 35 kg/m2 ).

Mucormycosis: an unusual cause of gastric perforation and severe bleeding in immunocompetent patients.

Mucormycosis is a rare and often fatal opportunistic infection that especially occurs in immunocompromised patients. Primary gastrointestinal infection is uncommon and accounts for only approximately 7% of all cases of mucormycosis but it is associated with an 85% mortality rate due to perforation and massive bleeding. Very few cases of gastrointestinal mucormycosis in an immunocompetent host have been reported. We describe a case of gastric necrosis and massive bleeding due to fulminant invasive mucormycosis.

Impact of the Banff 2013 classification on the diagnosis of suspicious versus conclusive late antibody-mediated rejection in allografts without acute dysfunction.

BACKGROUND: The Banff classification is used worldwide to characterize pathological findings in renal allograft biopsies. During the 11th Banff meeting, relevant changes were introduced in the diagnostic criteria for Category 2 antibody-mediated rejection (ABMR). Here, we assess the effect of these changes on the diagnosis of late chronic ABMR. METHODS: Seventy-three indication renal graft biopsies (chronic dysfunction, proteinuria and/or the presence of de novo donor-specific antibodies) from 68 kidney transplant recipients initially classified following the Banff 2009 criteria were reviewed and reclassified as per the new Banff 2013 criteria. RESULTS: The diagnostic category changed in 18% of the study biopsies with Banff 2013. The reclassification mainly involved Category 2 cases, from which 23.5% of the biopsies from older patients with worse graft function were overlooked by Banff 2009. ABMR was ruled out in 13% of cases under the Banff 2009 criteria. A significant number of the study samples were conclusively diagnosed as ABMR (40% as per Banff 2009 and 74% as per Banff 2013; P = 0.006), because of the inclusion of microvascular inflammation and the acceptance of some ultrastructural diagnostic criteria. However, when following the criteria of the new classification, samples with histological signs of chronic ABMR, in which human leucocyte antigen donor-specific antibodies are not detected or ultrastructural studies are not performed, may be inadequately characterized. CONCLUSIONS: The Banff 2013 classification helps in making a diagnosis of late ABMR, identifying cases, decreasing the percentage of suspected ABMR and making more conclusive diagnoses.

Study of Epithelial to Mesenchymal Transition in Atypical Fibroxanthoma and Undifferentiated Pleomorphic Sarcoma to Discern an Epithelial Origin.

Atypical fibroxanthoma (AFX) is considered a fibroblastic or myofibroblastic neoplasm probably corresponding to a superficial variant of undifferentiated pleomorphic sarcoma (UPS). However, an epithelial origin has also been postulated. An immunohistochemical study of the epithelial to mesenchymal transition (EMT) phenomenon was performed in a series of 19 AFX and 4 UPS to discern an epithelial origin. A panel of epithelial (cytokeratins AE1-AE3 panel, podoplanin D2-40, and E-cadherin) and EMT (vimentin, Twist, Zeb1, and Snail1) markers were evaluated in both tumoral cells and the adjacent epidermis. Podoplanin and Snail1 were negative in all the samples. Nuclear E-cadherin, Twist, and Zeb1 were detected in most lesions, as previously reported in other sarcomas. In the epidermis, E-cadherin showed a normal membranous pattern and only isolated cells were positive for vimentin. Twist and Zeb1 were mainly negative in the epidermis. None of the immunohistochemical markers mentioned above elicited a conspicuous bridging between the epidermis and the dermis. Our findings suggest that EMT does not play a role in the development of AFX or UPS.

Scarlet fever: A not so typical exanthematous pharyngotonsillitis (based on 171 cases).

AIM: To describe the age, signs and clinical symptoms of children with scarlet fever at the present time, and to check whether they are equivalent to those with traditional streptococcal pharyngotonsillitis. STUDY DESIGN: An observational, retrospective study was conducted on the clinical records of 5500 children aged from 0 to 15 years attending a primary health care center. A record was made of the percentage of the cases in which signs and symptoms appear and the Centor score was calculated. Microbiological diagnosis of the disease was made using the rapid antigen-detection test or traditional culture. RESULTS: A total of 171 out of 252 scarlet fever diagnoses were microbiologically verified in 158 patients. The median age was 3.8 years (interquartile range: 2.91-4.78), with the majority (57%) under the age of 4 years. There was fever in 89% of the processes (95% CI: 84-94%), with a temperature of >38°C in 73% (95% CI: 65-80%), enlarged lymph nodes in 70% (95% CI: 58-82%), absence of cough in 73% (95% CI: 65-80%), and tonsillar exudate in only 24% (95% CI: 17-31%). The Centor score (n=105) was ≤2 points in 86% (95% CI: 79-92%). The only difference regarding age is that episodes in patients under the age of 4 years old have significantly higher fever (>38°C) than the older ones (80% versus 63%. OR 3.13; 95% CI: 1.46-6.71). CONCLUSION: Scarlet fever pharyngotonsillitis differs from the traditional streptococcal pharyngotonsillitis, and its evaluation using clinical prediction rules such as Centor or McIsaac is questionable. The main diagnostic key must certainly be rash, regardless of patient age.

A Case of Peritoneal Carcinomatosis After Hyperprogression in Human Papillomavirus-Positive (HPV+) Oropharyngeal Squamous Cell Carcinoma.

Immunotherapy has been shown to provide clinical benefit in selected patients with head and neck squamous cell carcinoma (HNSCC), regardless of human papillomavirus (HPV) infection, and including recurrent/metastatic (R/M) platinum refractory tumors. Hyperprogression is an uncommon negative outcome of treatment with immunotherapy. We present the case of a patient with HPV+ HNSCC who presented hyperprogression after immunotherapy and a rare metastasis location with peritoneal carcinomatosis and subcutaneous nodules. HPV+ HNSCC is related to distant recurrence after a longer interval of time and more diverse metastasis sites compared with HPV- disease. However, the literature on peritoneal metastasis in HNSCC remains limited, with few documented cases. To the best of our knowledge, this is the first case reporting peritoneal carcinomatosis after hyperprogression in HNSCC.

Sociological genealogy of a non-teleological concept of evolution.

The aim of this article is to carry out a sociological-conceptual genealogy of the evolutionist perspective (non-teleological) of approaching social reality. While during the first phases of modernity, a teleological and progressive conception of evolution was imposed, clearly manifested in the proposals of Auguste Comte or Herbert Spencer, in the last decades important bifurcations, processes, and developments have emerged that question the linearity and the finalist character of these positions. We consider that these approaches are closer to the nature of change and social phenomena, so it seems important to us to analyze some of the most outstanding contributions-in the form of sociological genealogy, as we have already mentioned-that have developed this perspective. In order to carry out our task, we have organized four sections: In the first, we make a critique of the sociological evolutionism represented by Comte, Spencer, and Parsons, focusing on the limits of their proposals and the blind spots associated with them. Second, we will analyze the anti-teleological cognitive approaches of Donald and the importance they attach to cultural transmission as a key element for understanding the evolution of both cognition and human societies. In a third moment, we will analyze the coexistence in Weber's work between the dynamics of 'disenchantment' and 're-enchantment' of the world in modern societies, understood as the two sides of the same coin that are in constant dynamic tension and that break with the evolutionary vision that goes from magic through religion to science, or from belief to knowledge. In a fourth moment, we analyze the relevance of approaches focused on what we have called 'multiple evolutions' (plural) that collide with each other-the conflicting simultaneity of the non-simultaneous-of their rhythms and directions, inspired by the works of Knöbl, Koselleck, Luhmann, Rosa, Eisenstadt, Abbott, and Zerubavel, which pave the way for the construction of a non-teleological approach to evolution.