The Challenge of Pneumatosis Intestinalis: A Contemporary Systematic Review.

PURPOSE: Pneumatosis intestinalis is a radiological finding with incompletely understood pathogenesis. To date, there are no protocols to guide surgical intervention. METHODS: A systematic review of literature, according to PRISMA criteria, was performed. Medline and PubMed were consulted to identify articles reporting on the items "emergency surgery, pneumatosis coli, and pneumatosis intestinalis" from January 2010 up to March 2022. This study has not been registered in relevant databases. RESULTS: A total of 1673 patients were included. The average age was 67.1 ± 17.6 years. The etiology was unknown in 802 (47.9%) patients. Hemodynamic instability (246/1673-14.7% of the patients) was associated with bowel ischemia, necrosis, or perforation (p = 0.019). Conservative management was performed in 824 (49.2%) patients. Surgery was performed 619 (36.9%) times, especially in unstable patients with bowel ischemia signs, lactate levels greater than 2 mmol/L, and PVG (p = 0.0026). In 155 cases, surgery was performed without pathological findings. CONCLUSIONS: Many variables should be considered in the approach to patients with pneumatosis intestinalis. The challenge facing the surgeons is in truly identifying those who really would benefit and need surgical intervention. The watch and wait policy as a first step seems reasonable, reserving surgery only for patients who are unstable or with high suspicion of bowel ischemia, necrosis, or perforation.

Malignancy risk in Bethesda class IV thyroid nodules in an iodine deficient region.

Background: According to the latest guidelines, in patients with high-risk nodules with indeterminate cytology, diagnostic lobectomy should be the preferable surgical approach in the absence of factors that suggest a total thyroidectomy. Methods: This retrospective observational study has as its main aim the evaluation of the cases that underwent surgery, for Bethesda class IV nodules in our iodocarent geographical area. Particular attention was paid to carcinoma incidence, preoperative nodule size, histological characteristics of the neoplasm, surgical approach and eventual need of radiometabolic treatment. A total of 320 patients were included that underwent surgery for Bethesda IV nodules, between January 2010 and December 2020, at the General Surgical Clinic of the University Hospital of Parma, Italy. Results: A total of 230 total thyroidectomies (71.9%) and 90 lobectomies (28.1%) were performed. Our data showed a strong impact of the 2015 ATA Guidelines on the surgical approach choice, with a progressive propensity towards a conservative approach and an increase of lobectomies from 7.2% to 41.5% after the new guidelines introduction. However, in our sample the percentage of lobectomies remains below 50%; this data is certainly influenced by the number of cases of multinodular pathology, often bilateral, in our geographical area. The nodules malignancy rate resulted 28.8%. Our data showed that increasing size correlated with an increasing malignancy rate (P<0.01), and follicular carcinomas were found to be larger than papillary carcinomas (P<0.001). A statistically significant correlation also emerged between nodule size increase and local/lymphovascular invasion (P<0.05). On the other hand, there was no statistically significant correlation between nodule size and multifocality, and between nodule size and presence of lymph node metastases. Out of the patients where it was possible to find this data, 66% underwent radioiodiometabolic treatment: 59% with papillary carcinoma, and 85% with follicular carcinoma. Conclusions: In patients with Bethesda IV thyroid nodules, diagnostic lobectomy should be the preferable surgical approach in absence of factors that suggest total thyroidectomy. In our opinion, total thyroidectomy remains the first choice in large nodules (≥4 cm) as these nodules have a high malignancy rate, greater local/lymphovascular invasion and a consequent frequent indication for post-operative radiometabolic treatment.

Fabric phase sorptive extraction-high performance liquid chromatography-photo diode array detection method for simultaneous monitoring of three inflammatory bowel disease treatment drugs in whole blood, plasma and urine.

This paper reports a novel fabric phase sorptive extraction-high performance liquid chromatography-photodiode array detection (FPSE-HPLC-PDA) method for the simultaneous extraction and analysis of three drug residues (ciprofloxacin, sulfasalazine, and cortisone) in human whole blood, plasma, and urine samples, generally administered in human patients to treat inflammatory bowel disease (IBD). The drugs of interest were well resolved using a Luna C18 column (250 mm × 4.6 mm; 5 µm particle size) in gradient elution mode within 20 min. The analytical method was optimized and validated in the range 0.05-10 µg/mL for whole blood, 0.25-10 µg/mL for human plasma, and 0.10-10 µg/mL for human urine. Blank human whole blood, plasma, and urine were used as the sample matrix for the method development and validation; while methyl-p-hydroxybenzoate was used as the internal standard (IS). Weighted-matrix matched standard calibration curves showed a good linearity up to a concentration of 10 µg/mL. The intra- and inter-day accuracy values (precision and trueness) were found in the range from -10.9% to 12.3%, and the performances of the validated FPSE-HPLC-PDA were further tested on real IBD patient samples. This is the first FPSE procedure applied simultaneously to whole blood, plasma, and urine samples for the determination of residual IBD drugs, which possess a wide range of polarity (logP values ranging from 2.30 for Ciprofloxacin, to 1.66 for Cortisone, and 2.92 for Sulfasalazine). The new approach exhibits high potential for immediate adoptation as a rapid, robust and green analytical tool for future clinical and pharmaceutical applications.

Apelin beyond kidney failure and hyponatremia: a useful biomarker for cancer disease progression evaluation.

Apelin regulates angiogenesis, stimulating endothelial cell proliferation and migration. It is upregulated during tumor angiogenesis, and its overexpression was reported to increase tumor growth. Furthermore, apelin controls vasopressin release and body fluid homeostasis. The aim of this study was to examine the correlations between apelin expression and clinical outcomes in oncologic patients, such as cancer disease progression and patient's survival. Apelin levels were evaluated in a cohort of 95 patients affected by different varieties of cancer. Partial remission and stable disease were assigned to the 'no progression' group, comparing it with the progressor group. Patients were followed up for 2 years. Receiver operating characteristics analysis was employed for identifying the progression of the oncologic disease and Kaplan-Meier curves assessed the survival. Adjusted risk estimates for progression endpoint were calculated using Cox proportional hazard regression analysis. Oncologic patients had higher apelin levels compared with healthy subjects, and apelin was closely related to the stages of the disease. In the hyponatremia group, apelin values were significantly higher than patients with eunatremia. After the follow-up of 24 months, 41 patients (43%) reached the endpoint. Progressor subjects presented significantly increased apelin values at baseline compared with non-progressor. Univariate followed by multivariate Cox proportional hazard regression analysis showed that apelin predicted cancer progression independently of other potential confounders. In patients with cancer, apelin closely reflects the stage of the disease and represents a strong and independent risk marker for cancer progression.

From water to aquaretics: a legendary route.

Man is water. When life appeared on earth, the primordial cell had a simple structure and could immediately ascertain from the surrounding aquatic environment the substances for nutrition and oxygen, without any need for structural complexity. As part of evolution, during the transition from aquatic to terrestrial life, vertebrates had to fight against dehydration as well as fish in the sea. In this complex mechanism of osmoregulation, the structure and function of some osmoregulatory hormones have been maintained during the evolution of species, from fish to man. Within the homeostatic mechanism, the renin-angiotensin-aldosterone system (RAAS) is crucial in the regulation of renal reasorption of water and sodium. It is also involved in the regulation of renal plasma flux, blood volume and blood pressure. Vasopressin plays a hormonal function in the mechanisms of water homeostasis acting through Aquaporins (AQP), channel-proteins that allow bi-directional water transport across cell membranes.

Proteinuric effect of transcranial magnetic stimulation in healthy subjects and diabetic patients with stage 3-4 CKD.

BACKGROUND: Many authors have investigated the numerous connections between the nervous system and kidneys, and recent literature has indicated that these similar systems are interconnected. Recent scientific works have shown that there is similarity between the cerebral cortex 'viscera representation' and the 'motor omunculus'. We studied the connection between the brain and kidney in vivo using repetitive transcranial magnetic stimulation (rTMS). Proteinuria and albuminuria were used as markers of renal response in patients with diabetes (DP) and in a group of healthy subjects (HSs) who received rTMS for 5 consecutive days. METHODS: The study population consists of the following four groups: Group A (HS stimulated), Group B (HS sham), Group C (DP stimulated) and Group D (DP sham). All subjects in Groups A and C underwent rTMS delivered at a frequency corresponding to 90% of the threshold at rest for 5 consecutive days. All subjects in Groups B and D underwent rTMS delivered with the coil placed on the scalp without delivering electromagnetic stimuli, while another coil at a distance of ∼2 m emitted stimuli at a very low intensity. This strategy ensured that brain stimulation would not occur, so that the subjects felt the vibrations produced by the click of the TMS coil. The proteinuria and albuminuria of 24 h and creatinine clearance were measured at time 0 (T0), after the first session (T1), at the end of the treatment (T5) and 24 h after the last stimulation (Post 24 h). RESULTS: In Group A, there was a statistically significant increase in albuminuria (5.65 ± 0.52 versus 12 ± 0.55 mg/24 h, P = 0.0001) and proteinuria (6.05 ± 0.48 versus 13.1 ± 0.60 mg/24 h, P = 0.0001) at the end of the treatment (T5) compared with the baseline values (T0). In Group C, the albuminuria was statistically higher at T5 than the baseline T0 (416.22 ± 181 versus 677.25 ± 280 mg/24 h, P = 0.04), as was proteinuria (561.37 ± 86 versus 865.125 ± 104 mg/24 h, P = 0.0001); in Group C, the increase in albuminuria (T0 versus post 24 h, P = 0.02) and proteinuria (T0 versus 24 h post, P = 0.0002) persisted at 24 h post. In Groups B and D, statistically significant changes were not found in proteinuria (Group B T0 versus T5, P = 0.61; Group D: T0 versus T5, P = 0.66) and albuminuria (Group B T0 versus T5, P = 0.15; Group D T0 versus T5, P = 0.44) measured at the same times. CONCLUSIONS: Consecutive rTMS is able to induce a statistically significant increase in albuminuria and proteinuria in HS and DP. A functional link between the brain and kidney is possible. For the first time, the results have indicated an increase of proteinuria in subjects undergoing transcranial stimulation.

"Normoalbuminuric" diabetic nephropathy: tubular damage and NGAL.

The aim of this study was to demonstrate that neutrophil gelatinase-associated lipocalin (NGAL) increased before the onset of microalbuminuria in patients with type 1 diabetes mellitus (T1DM), representing an important biochemical parameter with high sensitivity and specificity to make a precocious diagnosis of "normoalbuminuric" diabetic nephropathy (DN). Serum NGAL (sNGAL) and urinary NGAL (uNGAL) levels were evaluated in a cohort of fifty patients affected by T1DM. They had no signs of clinical nephropathy. Thirty-five healthy subjects (HS) were recruited. sNGAL levels were significantly higher compared with those measured in HS [193.7 (103.2-405.4) vs. 46.4 (39.8-56.2) ng/ml; p < 0.0001], as were uNGAL levels [25.5 (14.2-40.2) vs. 6.5 (2.9-8.5) ng/ml; p < 0.0001]. sNGAL was found to be directly correlated with glycated hemoglobin. uNGAL also positively correlated with albuminuria, whereas an inverse correlation was found with uric acid. After multivariate analysis, significance was maintained for the correlation between uNGAL and microalbuminuria. In ROC analysis, sNGAL showed a good diagnostic profile such as uNGAL. NGAL increases in patients with T1DM, even before diagnosis of microalbuminuria representing an early biomarker of "normoalbuminuric" DN with a good sensitivity and specificity. NGAL measurement could be useful for the evaluation of early renal involvement in the course of diabetes.

Apelin, plasmatic osmolality and hypotension in dialyzed patients.

BACKGROUND/AIMS: To evaluate the balance between arginine-vasopressin (AVP) and apelin during hemodialysis and its role in hypotension onset and in the inflammation status. METHODS: We enrolled 50 patients chronically treated with hemodialysis. We assessed plasmatic osmolality, AVP, apelin, mean blood pressure (BP), high-sensitivity C-reactive protein (hsCRP) and ß(2)-microglobulin. RESULTS: Apelin rises during dialytic treatment (from 0.68 ± 0.34 to 1.89 ± 0.56 pg/ml, p < 0.0001), while plasmatic osmolality (from 325 ± 4.54 to 311 ± 1.20 mosm/kg H(2)O, p < 0.0001), AVP (from 4.28 ± 1.12 to 2.48 ± 0.50 pg/ml, p < 0.0001) and mean BP (from 124 ± 6 to 110 ± 7 mm Hg, p < 0.0001) decrease. At multivariate regression with respect to apelin, only mean BP remains (r = -0.95, p < 0.0001). We also correlated the AVP/apelin ratio with BP. Moreover, apelin is inversely related to hsCRP (r = -0.79, p < 0.0001). CONCLUSIONS: The AVP/apelin balance changes with plasmatic osmolality variations induced by hemodialytic sessions and could represent a physiopathological marker of arterial hypo- and hypertension. Finally, apelin appears inversely related to inflammation markers.

A biotechnological T-shirt monitors the patient's heart during hemodialysis.

Uremic patients are characterized by a "pro-arrhythmic substrate." Arrhythmia appearance during hemodialysis (HD) is an unexpected event with a high incidence of mortality and morbidity and difficult to record in patients repeatedly checked using electrocardiogram (ECG). Furthermore the carrying out of this important examination by classical devices during HD is uncomfortable and sometimes stressful for the patient. It may be very useful to monitor the patient's cardiac activity during the whole HD session. We tried to overcome these difficulties using Whealthy(®) (Wearable Health Care System), a wearable system in a T-shirt composed of conductors and piezoresistive materials, integrated to form fibers and threads connected to tissular sensors, electrodes, and connectors. ECG and pneumographic impedance signals are acquired by the electrodes in the tissue, and the data are registered by a small computer and transmitted via GPRS or Bluetooth.

NGAL as an early biomarker of kidney disease in Joubert syndrome: three brothers compared.

Joubert syndrome (JBTS) is a rare autosomal recessive disorder with an underestimated prevalence due to lack of recognition of clinical signs or failure to diagnose this pathology. JBTS is clinically heterogeneous, and it is characterized by a multiple organ involvement predominantly due to the requirement for Joubert gene function in several tissues. Renal disease affects approximately 30% of patients with JBTS, presenting itself in most cases as nephronophthisis (NPHP), a structural tubulo-interstitial disorder characterized by thickened basal membrane of the tubular epithelium and progressive interstitial fibrosis, associated with cysts at the cortico-medullary junction. We propose three cases concerning three patients with JBTS having different years of illness and degrees of renal impairment, evaluating the parameters of renal function at the time of genetic diagnosis and seen after a follow-up of 7 years. We measured neutrophil gelatinase-associated lipocalin (NGAL), considered as an excellent predictor of kidney injury, to evaluate whether this biomarker might be an early biomarker for JBTS-related kidney disease. NGAL was high in all three cases, but with different levels, indicating a tubular suffering typical of this syndrome, with dissimilar severity in the analyzed subjects. NGAL could represent an early indicator of renal damage useful to start an intensive nephrologic follow-up.

Fibrosis, regeneration and cancer: what is the link?

Tubulo-interstitial fibrosis constitutes the final common pathway for all pathological conditions that evolve towards chronic kidney disease, and transforming growth factor-ß1 plays a key role in this process. Furthermore, neutrophil gelatinase-associated lipocalin appears not only to be a simple marker of renal injury but also an active player in disease progression. We are not yet able to control and modulate this phenomenon. Therefore, a better understanding of fibrogenic molecular mechanisms is necessary to detect possible therapeutic strategies that interfere with fibrosis and then stop the progression of renal disease. The line of research called 'regenerative medicine' works toward this. According to many authors, the formation of a fibrotic extracellular matrix disrupts the cells' polarity and stimulates their proliferation, creating conditions for cancer development. However, there is another plausible hypothesis: is it possible that fibrosis provides a sort of 'protection' from the development of a cancer as a consequence of the intense proliferation that characterizes any inflammatory process? In superior organisms, and also in humans, regeneration may have been selected negatively and replaced by fibrosis in the course of evolution, to warrant species survival: in fact, unchecked pluripotent cell production and proliferation can lead to tumour development and the potential death of a single individual. Hence, tumours might be the outcome of the failure of fibrotic processes, most likely due to some mediators predominating over others. So, valid experimental models are necessary to understand the interactions that exist between fibrosis and tumours and to evaluate the real advantage of therapies that aim to inhibit the fibrotic process at the renal level or that of other organs. The ideal approach would be to limit fibrosis and then organ function loss but without exposing the patient to risks of developing a tumour, starting from as early as the drugs prescribed.

Obestatin: an interesting but controversial gut hormone.

Obestatin is a 23-amino acid peptide hormone released from the stomach and is present not only in the gastrointestinal tract, but also in the spleen, mammary gland, breast milk and plasma. Obestatin appears to function as part of a complex gut-brain network whereby hormones and substances from the stomach and intestines signal the brain about satiety or hunger. In contrast to ghrelin, which causes hyperphagia and obesity, obestatin appears to act as an anorectic hormone, decreasing food intake and reducing body weight gain. Further studies have shown that obestatin is also involved in improving memory, regulating sleep, affecting cell proliferation, increasing the secretion of pancreatic juice enzymes and inhibiting glucose-induced insulin secretion. This hormone has not only been studied in the field of physiology but also in the fields of obesity and diabetes mellitus, and in patients with psychogenic eating disorders. Obestatin has a role in regulating the cell cycle by exerting proliferative effects that may be seen in cell physiology and oncology. Given the current controversy regarding the effects of obestatin and its cognate ligand, this article provides the latest review of the physiological and pathological characteristics of this hormone.

Levels of neutrophil gelatinase-associated lipocalin in 2 patients with crush syndrome after a mudslide.

Neutrophil gelatinase-associated lipocalin is one of the most promising biomarkers for the diagnosis of acute kidney injury. An increase in the level of neutrophil gelatinase-associated lipocalin is a good predictor of acute kidney injury and is associated with an increase in the serum level of creatinine. Two victims of a mudslide in Messina, Italy, initially had crush syndrome followed by development of acute kidney injury. The development of acute kidney injury is the second most common cause of death after large earthquakes and other natural disasters, but at the same time, crush-related acute kidney injury is one of the few life-threatening complications of crush injuries that can be reversed if diagnosed early and treated. In this case, measuring the level of neutrophil gelatinase-associated lipocalin enabled early diagnosis of acute kidney injury and anticipation of the changes in levels of conventional markers such as creatinine.

From chronic kidney disease to transplantation: the roles of obestatin.

BACKGROUND: Kidney transplantation is the therapy of choice in most cases of end stage renal disease. The purpose of the present study was to evaluate serum obestatin levels in kidney transplant recipients (Tx), compare levels in patients with renal failure (CKD) with those in healthy subjects (HS), and to assess the role of this hormone in energetic metabolism. PATIENTS AND METHODS: A total of 95 subjects were studied: 40 were Tx; 35 had CKD and 20 were HS. Inclusion criteria were age>18years and good allograft function. Patients with an inflammatory disease or a diagnosis of cancer were excluded from the study. RESULTS: Obestatin levels in Tx patients were significantly lower than in HS (3.5 [3-4.8] versus 11 [8.56-28.60] ng/mL; p<0.0001) and patients with CKD (3.5 [3-4.8] versus 4.7 [3, 5-6, 1] ng/mL; p=0.008). At univariate analysis, a direct correlation was found between obestatin and calcemia (p: 0.0001; r: 0.51), phosphoremia (p: 0.0005; r: 0, 46), calcium-phosphate product (p<0.0001; r:0.53), and parathormone (p: 0.01; r: 0.32), whereas significant inverse correlations were evidenced for BMI (p<0.0001; r: -0.52). At multivariate analysis, significance was maintained for the correlation between obestatin and phosphoremia (ß=0.47; p=0.008), for the calcium-phosphate product (ß=0.55; p=0.0005) and for BMI (ß=-0.53; p=0.01). CONCLUSION: Obestatin, present in lower levels in Tx patients than in CKD patients and HS, plays a role in energy metabolism, affecting BMI and the metabolism of calcium-phosphorus.

NGAL is a precocious marker of therapeutic response.

NGAL (Neutrophil Gelatinase-Associated Lipocalin) is a small 25-kD peptide belonging to the lipocalin superfamily. Several studies highlight its role as an organ injury and disease activity biomarker. In the present review, instead, we wanted to study NGAL as a precocious marker of therapeutic response in renal and non-renal diseases (glomerulonephritis, vasculitis, LES, Crohn's disease and other chronic inflammatory pathologies). The obtained outcomes support the hypothesis that NGAL could be employed as a biomarker of response to different therapeutic schemes, because its levels sensibly and precociously change compared to other haematologic and biochemical parameters.

Obestatin: a new element for mineral metabolism and inflammation in patients on hemodialysis.

BACKGROUND: Obestatin plays a key role in the process of energy balance maintenance with an anorectic effect. The main aim of the study was to evaluate obestatin in uremic patients to determine whether it is correlated with nutritional and inflammatory status. METHODS: We studied plasma obestatin in uremic patients (n = 50) undergoing hemodialysis therapy and in healthy subjects. Plasma obestatin was measured using an ELISA kit. RESULTS: Obestatin levels in uremic patients were lower than in healthy subjects (p < 0.0001). Patients with a body mass index (BMI) >23 had lower obestatin levels than those with a BMI <23 (p = 0.001). After multivariate analysis, direct correlations were maintained between obestatin and high-sensitivity C-reactive protein (ß = 0.68, p < 0.0001) and total alkaline phosphatases (ß = 0.30, p = 0.03), while inverse correlations were found with iron (ß = -0.32, p = 0.002) and calcium-phosphorous product (ß = -0.40, p = 0.001). CONCLUSIONS: Based on the present observational data, obestatin might be implicated in the inflammatory state and the disturbances of calcium/phosphate metabolism of hemodialysis patients. However, further studies are warranted to determine whether this hormone plays a key role in contributing to malnutrition and to the chronic inflammatory process.

Erythropoietin and the truths of science.

In recent years, the use of recombinant human erythropoietin (rHuEpo) has exploded all over the world, and thanks to this, the anemia of patients with chronic renal failure has practically been resolved with its administration. Administration of rHuEpo certainly plays a role in regenerative medicine in vitro and in vivo, because it intervenes in angiogenesis, the persistent natural regenerative activity of humans. Unfortunately, in recent randomized studies, the beneficial effects of rHuEpo have been accompanied by an unanticipated increase in mortality. Its effects are negative in presence of cancer development, but positive in other conditions, as it can protect heart tissue, brain and kidney. Now that its adverse effects have caused the US Food and Drug Administration to issue a black-box warning, it may be time to review what we know about the history and physiology of this plasma factor that appears to be more than just an erythrocyte production factor. Directions for future research hold promise, but only after we have fully understood the physiology of this potent growth factor.

Docosahexaenoic acid reverts resistance to UV-induced apoptosis in human keratinocytes: involvement of COX-2 and HuR.

The dramatic increase in the incidence of nonmelanoma skin cancer over the last decades has been related to the augmented exposure to ultraviolet (UV) radiation (UVR). It is known that apoptosis is induced as a protective mechanism after the acute irradiation of keratinocytes, whereas apoptotic resistance and carcinogenesis may follow the chronic exposure to UVR. We found that not all the human keratinocytes lines studied underwent apoptosis following acute exposure to UVR (10-60 mJ/cm(2)). Whereas UVR induced apoptosis in the HaCaT cells, NCTC 2544 and nr-HaCaT cells showed apoptosis resistance. The cytokeratin pattern of the apoptosis-resistant cells indicated that they possessed a degree of differentiation lower than that of HaCaT cells. They also showed an enhanced expression of cyclooxygenase-2 (COX-2), an early marker of carcinogenesis in various tissues, including skin. n-3 polyunsaturated fatty acids have drawn increasing interest as nutritional factors with the potential to reduce UVR carcinogenesis, and since they are apoptosis inducers and COX-2 inhibitors in cancer cells, we investigated the ability of n-3 polyunsaturated fatty acids to influence the resistance to UVR-induced apoptosis in keratinocytes. We observed that docosahexaenoic acid (DHA) reverted the resistance of nr-HaCaT cells to UVR-induced apoptosis, increasing the Bax/Bcl-2 ratio and caspase-3 activity, and reduced COX-2 levels by inhibiting the expression of the human antigen R (HuR), a known COX-2 mRNA stabilizer in keratinocytes. The transfection of nr-HaCaT cells with HuR siRNA mimicked the proapoptotic effect of DHA. Overall, our findings further support the role of DHA as a suitable anticarcinogenic factor against nonmelanoma skin cancers.

[From oxygen to erythropoietin, as a protagonist of the skin-brain-kidney axis]. / Dall'ossigeno all'EPO, protagonista dell'asse cute-cervello-rene.

Erythropoietin synthesis is one of the essential adaptive responses to a hypoxic environment. In mammals, a renal oxygen sensor capable of stimulating erythropoietic hormone synthesis through a transcriptional factor called HIF (hypoxia-inducible factor) has long been identified. Recent research has demonstrated that cerebral astrocytes and skin keratocytes can also produce erythropoietin as a response to different oxygen concentrations. Therefore, it is possible to hypothesize a skin-brain-kidney link which, through erythropoietin production, modulates the oxygen contribution to tissues. Moreover, the results are not so unambiguous and further research on the pleiotropic effects of erythropoetin would be opportune.

[Erythropoietin: pleiotropic actions]. / Aspetti pleiotropici dell'eritropoietina.

The erythropoietin is produced by the kidney and other organs. EPO does not only affect erythroid cells, but also other blood cell lines, such as myeloid cells, lymphocytes and megakaryocytes. This hormone can also enhance phagocytes function of the polymorph nuclear cells and reduces the activation of macrophages, thus modulating the inflammatory process. Hematopoietic and endothelial cells probably have the same cellular origin, and the discovery of erythropoietin receptors also on mesangial and myocardial cells and smooth muscle fibro-cells has prompted the study of the pleiotropic actions of this hormone. Through its receptors, spread out over the body, it carries out many actions which range from the erythrogenesis after hypoxic stimuli to the tissue protection of the heart and the brain after ischemia. Erythropoietin also acts in the endothelial proliferation of new vessels involving the tumor genesis, but it opens new frontiers to the employment of rHuEPO in the Regenerative Medicine.