Data on first-trimester screening test results, perinatal outcomes, and graft function (assessed using serum creatinine concentrations) were analyzed. The analysis of first-trimester screening parameters revealed no difference in nuchal translucency (NT) measurements and uterine artery flow. However, free beta-hCG MoM and PAPP-A values were higher in posttransplant pregnancies than in controls: 3.47 ± 2.08 vs. 1.38 ± 0.85 (p = 0.035) and 1.46 ± 0.81 vs. 0.98 ± 0.57 (p = 0.007), respectively. The false positive rate of trisomy 21 (T21) screening in graft recipients was 25.9% vs. 3% in the controls. The free β-hCG MoM values positively correlated with serum creatinine levels before , during , and after pregnancy . There was a statistically significant negative correlation for PAPP-A MoM values for postpartum serum creatinine concentration . Our results show significantly higher serum concentrations of free beta-hCG and PAPP-A in posttransplant pregnancies than in healthy controls, confirmed when exhibited as MoM values and their association with graft function was assessed by serum creatinine concentration. Taking those changes into account would reduce the high number of false positive test results in this group. The validated first-trimester screening algorithm that considers altered kidney function in pregnant kidney graft recipients remains to be developed.Data on serum biochemistry markers as a component of the first-trimester screening test in pregnant kidney graft recipients are limited. In the absence of a separate validated algorithm, biochemical testing is commonly used in the first-trimester screening in kidney transplant recipients. Therefore, the study aimed to analyze first-trimester serum biochemical markers and the first trimester combined screening results in pregnant kidney graft recipients. A retrospective study was carried out in pregnant women who underwent the first-trimester combined screening test performed per the Fetal Medicine Foundation (FMF) protocol in 2009–2020. The study group included 27 pregnancies in kidney graft transplant recipients, and the control group was 110 patients with normal kidney function, matched according to age, body mass index (BMI), and gestational age. The biochemical serum markers (free beta-human chorionic gonadotropin [beta-hCG] and pregnancy-associated plasma protein A [PAPP-A]) were evaluated using the FMF-approved Roche Elecsys The first report of pregnancy after kidney transplantation was published in 1963, and since then, thousands of posttransplant pregnancies have been reported worldwide . In manyThe primary aim of non-invasive prenatal screening is to find a high-risk group for the most frequent chromosomal abnormalities . The combined first-trimester screening is based on maternal age and history, ultrasound measurement of the thickness of fetal nuchal translucency (NT) performed between 11 + 0 and 13 + 6 weeks of gestation, and the maternal serum concentrations of free β-human chorionic gonadotrophin (free β-hCG) and pregnancy-associated plasma protein-A (PAPP-A). Ultrasound NT assessment allows the detection of approximately 75–80% of fetuses with an abnormal karyotype, with a false positive rate (FPR) of 5% [Data on the serum biochemistry results in pregnant kidney graft recipients are limited. However, other serum markers widely used in clinical practice, such as serum tumor markers, increase in posttransplant patients, supposedly in relation to renal function impairment . It is wCurrently, there is still no consensus on the performance of first-trimester combined screening in posttransplant pregnancies. The individual risk of chromosomal aberrations is calculated according to the Fetal Medicine Foundation (FMF) algorithm for the general population without taking kidney function into account. In the absence of a separate validated algorithm, biochemical testing is commonly used in the first-trimester screening in kidney transplant recipients. Therefore, the study aimed to analyze first-trimester serum biochemical markers and the first-trimester combined screening results in pregnant kidney graft recipients.® assay  approved by the FMF. All ultrasound scans were performed transabdominally with a Voluson E6 ultrasound machine  operated by an experienced sonographer, holder of the Certificate of Competence, in the 11 + 0 to 13 + 6-weeks scan and Doppler scan issued by the Fetal Medicine Foundation . Ultrasound markers such as NT and the uterine artery pulsatility index (UtA PI) were assessed per the FMF protocol. Patients were given their adjusted individual risk for trisomy 21, 18, and 13, and those with a high risk (>1:300 according to Polish Society of Obstetricians and Gynecologists guidelines) were given the option of invasive testing for fetal karyotype. Data on pregnancy outcomes were collected from the hospital maternity records or directly from patients. Graft function was assessed using serum creatinine concentrations for background prepregnancy (up to six months before conception), first trimester, and the first week postpartum.A retrospective study was carried out in a group of pregnant women who underwent routine ultrasound scans at 11–13 + 6 weeks in the Ist Department of Obstetrics and Gynaecology of the Medical University of Warsaw and continued care in our department until delivery. From 2009 until 2020, we identified 27 pregnancies in kidney graft transplant recipients who underwent a combined first-trimester screening test. The control group included 110 healthy patients  matched according to age, BMI, and gestational age. All patients had the first-trimester combined screening test performed per the FMF protocol, beginning with a questionnaire on maternal age, racial origin, method of conception, smoking, parity, and medical history. Maternal weight and height were taken on the day of the scan. A blood sample for free beta-hCG and PAPP-A was taken. These biochemical markers were evaluated using a Roche Elecsysp < 0.05 was considered statistically significant. All statistical analyses were performed with IBM SPSS statistics software .Statistical analysis: Statistical comparison of variables between study and control groups was carried out. Data were presented as mean values. Pearson’s correlation was used to investigate the correlation of variable factors, and The characteristics of the study and control groups are presented in Both groups were similar in baseline maternal characteristics . The study group patients had a higher incidence of chronic hypertension, pregnancy complications, cesarean section, and preterm delivery. The average time from transplant surgery to delivery was 8.9 ± 4.5 years, and for three women, it was a repeated surgery. The immunosuppressive regimens were primarily tacrolimus-based (70.4%), with the remainder administered cyclosporin A and one patient azathioprine only. Kidney function assessed using serum creatinine concentration remained satisfactory throughout the pregnancy, with no acute graft rejection episodes. The median baseline and pregnancy laboratory parameters of the study group are presented in The analysis of the first-trimester screening parameters  revealedThe subgroup analysis, taking into account tacrolimus or cyclosporine-A-based regimens, revealed no statistically significant difference in first-trimester serum biochemical markers, as well as in perinatal outcomes or graft function .p = 0.038) and postpartum , which was not the case in the CsA-treated subgroup   were compared to those during pregnancy  .p < 0.001), during , and after pregnancy . For PAPP-A MoM values, we found a statistically significant negative correlation only for postpartum serum creatinine concentration . In the study group, PAPP-A MoM values were also significantly higher in patients that did not develop pregnancy-induced hypertension later on .We also analyzed serum association between serum creatinine concentration and biochemical serum markers expressed as MoM values in kidney graft recipients. The free β-hCG MoM values positively correlated with serum creatinine levels before  in 7 out of 27 posttransplant pregnancies (with the highest risk > 1:4 in one patient), with no cases of abnormal fetal karyotype. This accounts for 25.9% of false positive test results versus 3% in the controls.Our study aimed to evaluate first-trimester biochemical serum markers in pregnant kidney graft recipients and the performance of first-trimester combined screening in this unique group of patients. Our results show significantly higher serum concentrations of free β-hCG and PAPP-A in posttransplant pregnancies than in healthy controls, confirmed when exhibited as MoM values. What is more, the false positive high-risk test results were found in 25.9% of pregnancies, whereas the population FPR threshold is set at 3–5%, depending on the screening protocol and how many ultrasound markers are considered .p < 0.001; r = 0.619, p = 0.001; r = 0.697, p < 0.001, respectively).The increase in β-hCG concentration has been described in the posttransplant population. Our results indicate that the median free β-hCG value in the study group was 3.47 ± 2.08 MoM, which is 2.5 times more than in healthy controls. In a series of eleven women with renal transplant, published in 2013, the median value for free β-hCG was 2.15 MoM . The abnIn trisomy 21, the average levels of free β-hCG between 11 and 13 + 6 weeks of gestation are close to 2.0 MoM, in contrast to 1.0 MoM in the case of normal fetal karyotype . Anotherp = NS), in accordance with the results by Valentin et al. in a population of patients with renal disease [Interestingly, the paper by Grande et al. investigates three models for adjusting the false positives rates . It was  disease . Therefo disease . It woulp= 0.007). Similar results were published by Grande et al. in the earlier mentioned series of 11 kidney transplant pregnancies (1.41 vs. 1.07 MoM) [p = 0.035). The lower first-trimester PAPP-A values in our posttransplant cohort were associated with a higher postpartum serum creatinine concentration and more frequent pregnancy-induced hypertension development. Inadequate placentation, reflected by low first-trimester maternal serum PAPP-A, is a causal factor of hypertension development in pregnancy [p = NS).In our cohort, PAPP-A MoM values were also significantly increased compared to healthy controls  . In contregnancy . As the regnancy . High leregnancy . It is rWhether these phenomena influence the reliability of the combined test or early prediction of preeclampsia in kidney graft recipients similarly to elevated free beta-hCG levels remains to be established.The perinatal outcomes in our posttransplant population confirm those by Transplant Pregnancy Registry International, with a trend towards more preterm deliveries and more babies delivered via cesarean section . As confThe main limitation to our study is a retrospective analysis of posttransplant pregnancies that ended in delivery, with no data on early pregnancy loss. On the other hand, to our knowledge, this is the largest published cohort of kidney posttransplant pregnancies concentrating on the clinical utility of the first-trimester combined test that is routinely used in the general population.To sum up the characteristics of serum biochemical markers after kidney transplantation, beta-hCG increases in the presence of impaired kidney function. At the same time, an increase in PAPP-A can be associated with both kidney graft dysfunction and inflammation/vascular damage and a decrease with impaired placentation, presumably more often appearing in kidney transplant pregnancies. Taking those changes into account would reduce the high number of false positive test results in this group. It is essential as other methods of non-invasive prenatal testing, such as cell-free fetal DNA tests, are also problematic in pregnant women with a kidney transplant. They demonstrate three types of circulating cell-free DNA: maternal, deriving from the trophoblast tissue, and kidney graft, which might influence fetal aneuploidy assessment ,20. The


In this review, we provide an update on the pathogenesis, diagnosis, and management of adults with idiopathic intracranial hypertension (IIH) and implications of the cerebral venous system, highlighting the progress made during the past decade with regard to mechanisms of the venous outflow pathway and its connection with the cerebral glymphatic and lymphatic network in genesis of IIH. Early diagnosis and treatment are crucial for favorable visual outcomes and to avoid vision loss, but there is also a risk of overdiagnosis and misdiagnosis in many patients with IIH. We also present details about treatment of intracranial hypertension, which is possible in most cases with a combination of weight loss and drug treatments, but also in selected cases with surgical interventions such as optic nerve sheath fenestration, cerebral spinal fluid (CSF) diversion, or dural venous sinus stenting for some patients with cerebral venous sinus stenosis, after careful analysis of mechanisms of intracranial hypertension, patient clinical profile, and method risks. Idiopathic intracranial hypertension (IIH) is considered a relatively rare disorder characterized by elevated intracranial pressure (ICP) without a clear cause, remaining a diagnosis of exclusion, after other known situations associated with raised ICP have been evaluated. Several approaches have proposed different names of this entity according to the knowledge and understanding at that point in time. In 1904, ‘pseudotumor cerebri’ was proposed by Nonne, and in 1937 Walter Dandy  and duraAlthough early diagnosis and treatment are crucial for favorable visual outcomes in IIH patients, there is also a risk of overdiagnosis and misdiagnosis in as many as 40% of patients initially diagnosed with IIH , the preThe process of collection and selection of published papers for this review started with a search of the PubMed and Cochrane Libraries for all peer-reviewed articles from 2002 to date with a combination of key words, including “idiopathic intracranial hypertension,” “pseudotumor cerebri”, and “benign intracranial hypertension”, and after that a second search was started for more narrow and detailed information about “cerebral glymphatic ”, ”cerebral lymphatic”, ”cerebral venous sinus stenosis”, ”cerebral venous sinus stenosis stenting”, “lumboperitoneal shunts and intracranial hypertension”, and “optical nerve sheath fenestration”. Other references from the articles that were identified in the initial search and important data for clinical studies of IIH treatment were also selected and reviewed for extraction of additional information or points of view.In this synthetic review of the literature, we provide the latest information and points of view with respect to the pathogenesis, diagnosis, and management of adult idiopathic intracranial hypertension, and we highlight the progress made during the past decade regarding the mechanisms of venous outflow pathway obstruction, emphasizing the role of cerebral venous sinus stenosis, but also of its connection with the cerebral glymphatic and lymphatic network in genesis of IIH. We present details about treatment of intracranial hypertension related to venous sinus stenosis and IIH, which is possible in most cases using a combination of weight loss and drug treatments, but also surgical interventions such as optic nerve sheath fenestration, cerebral spinal fluid (CSF) diversion, and dural venous sinus stenting in selected cases of cerebral sinus stenosis, after careful analysis of mechanisms of intracranial hypertension, patient clinical profile, and risks.Starting with the historical hypothesis of Monro and Kelly, later completed by Magendie and Burrows, the skull was described as a rigid structure containing incompressible brain, and it was stated that the sum of the volume of brain, blood, and cerebrospinal fluid (CSF) is constant: an increase in one causes a decrease in one or both of the remaining two, but once the period of compliance due to the displacement of CSF or blood runs out, there is an exponential curve of a rise in intracranial pressure. An increased volume of the brain parenchyma is classically associated with cerebral edema , or intraparenchymal expanding lesions such as hematomas or tumors, but this is not the main objective of this review ,7.The epithelial cells of the choroid plexus are the main source of CSF secretion, with a rate of 0.3–0.4 mL/min, while a secondary source is the interstitial fluid of the brain resulting from filtration through the blood–brain barrier, which is estimated to be of a much lower importance, but the overall volume of CSF is about 150–160 mL .Both osmotic and hydrostatic pressure gradients contribute to CSF formation. As alterations to osmolarity modify water flux across the choroid plexus, the transport of ions across the blood–CSF barrier is important in the secretion process. In this process, ions are transported from circulating blood into the CSF via their respective transporters in the choroid cells’ walls, while water is likely transported by a combination of a transcellular process against an osmotic gradient by cotransporters and via tight junctions .Although osmotic and hydrostatic pressure gradients between choroid plexus cells and ventricles could play a role for CSF secretion in some instances, this role is minor, and some cotransporter proteins may have a significant role. While aquaporin-1 (AQP1)-dependent water channels have an important role at the apical membrane of choroid cells, the water permeability at the basolateral membrane is dependent on other proteins, such as the glucose carrier GLUT1. At the same time, paracellular water transport through the tight junctions toward lateral spaces between epithelial cells is determined by proteins from the claudin family  ,8.Water enters from interstitial space and the capillary pole into the choroid cells through the basolateral membrane and participates in CSF formation at the apical membrane of choroid plexus, with both processes mediated by aquaporin-1, and it can be upregulated by retinoids and glucocorticoids, which explains the implication of some medications in IIH ,8.+ gradient driving HCO3− and Cl− into the epithelial cells. The Na+–K+-ATPase pump and Na+–K+–2Cl− cotransporter (NKCC1) are very important to these processes, but also the Na+–HCO3 cotransporter, with accumulation of HCO3− and H+ from carbonic anhydrase activity. This derives the role of acetazolamide inhibition of carbonic anhydrase and the further reduction of CSF production by almost 50%, as well as the same effect of the NKCC1 inhibitor bumetanide [The cotransporter proteins act at the basolateral membrane of epithelial cells  and the apical membrane , facilitating the movement of some ions with importance in CSF production, the Nametanide ,8,9,10.The secretion and resorption of CSF must be balanced to maintain a constant volume of CSF of around 150–160 mL, whereby an excess amount will produce a rise in intracranial pressure through an increase of the total fluid content of the brain. There are several possibilities for CSF’s contribution to raised intracranial pressure. First, it could be an increased production with insufficient outflow, such as in tumors of the choroid plexus, where sometimes hydrocephalus can occur, whereas in idiopathic intracranial hypertension the ventricles remain a normal size. Another mechanism is the case of obstructive hydrocephalus that could result secondary to an obstruction along the CSF pathway, in contrast with non-obstructive hydrocephalus, where a decreased resorption is the cause of accumulation of CSF. Classically, the arachnoid granulations have the main role in CSF clearance. Absorption of CSF depends on the pressure gradient between the venous sinus and the subarachnoid space, so a rise in venous pressure needs a concomitant increase in CSF pressure to maintain absorption rates. There are instances such as subarachnoid hemorrhage or meningitis where a blockage of the arachnoid granulation and lymphatics by blood cells or fibrosis is produced, where reduced absorption of CSF could result in intracranial hypertension and communicating hydrocephalus, but in IIH such development is not visible ,11.Through a similar mechanism, both CSF hypercellularity, as seen in malignant meningitis, and high CSF protein in Guillian–Barré syndrome, can elevate ICP. Vitamin A deficiency can also lead to elevated ICP, with evidence of thickening of the extracellular matrix in the arachnoid villi ,11.Interstitial fluid of the brain is produced by fluid secretion and filtration at the blood–brain barrier level, being distributed between neurons, glial cells, and capillary cells within the parenchyma, while CSF fills the ventricles and subarachnoid space. There is an interaction between interstitial fluid and cerebrospinal fluid that takes place in the perivascular spaces surrounding the small penetrating vessels in the brain parenchyma, where a slow convective flow takes place through the glymphatic system ,11.From the subarachnoid spaces, the CSF enters the periarterial spaces, traveling from the cortex toward the deep white matter along the courses of the pial and the perforator arteries in a centripetal distribution . This prThis slow flow of CSF into the brain parenchyma induces a convective flow of interstitial fluid toward the perivenous spaces surrounding the large-caliber draining veins . The draThe lymphatic system of the brain was described as a dural network extending from the dural sinuses to both eyes, the cribriform plate via the olfactory bulbs and following the dural arteries and veins into the dura mater, penetrating the skull base with the adjacent vessels through the anatomical foramina, and the transported CSF is discharged into the sheaths of the cranial nerves, finally joining the deep cervical lymph nodes . TherefoTraditionally, it was considered that the arachnoid villi (invaginations of the arachnoid across the dura mater into the lumen of the venous sinus) represent the main pathway of resorption of the CSF from the subarachnoid spaces. Some authors  considerThere are medical hypotheses linking the CSF and interstitial fluid with the glymphatic, lymphatic, and venous pathways of drainage and idiopathic intracranial hypertension. First, it was observed (with 3D volumetric MRI measurements) that IIH patients have an excess of cerebral interstitial fluid and CSF in subarachnoid spaces, suggesting a congestion of the glymphatic system . A seconIn more than half of the population, the cerebral venous drainage is asymmetric, with predominance of the right side in most cases. An obstruction of the dominant transverse sinus will have a more deleterious effect than of the non-dominant one.There is a debate as to whether a collapsed wall of the intracranial venous sinus is the cause of intracranial hypertension, or the result of it, but at some point, a cycle of venous hypertension, cerebral swelling, further venous compression, and therefore augmented intracranial hypertension occurs, and this could be a mechanism of worsening. There is a close connection between intracranial pressure and cortical venous pressure, with cortical venous pressure being ~2–5 mmHg higher than intracranial pressure, so there will be a venous flow as long as the ICP does not exceed the inflow venous pressure .The lack of valves in the cranio-vertebral venous system leads the vena cava pressure to be reflected in the CSF pressure, revealing the fact that the venous side of cerebral circulation has much more impact for ICP than the arterial resistance side, but also explaining why an obstacle in venous outflow could be located not only in the intracranial region but also in cervical, thoracal, or abdominal regions.In case of intracranial obstruction of venous outflow generating an increase of intracranial pressure, the cause of the obstacle could be a focal external venous compression , an internal obstruction , or a local venous sinus stenosis with idiopathic anatomical local changes; however, sometimes the sinus stenosis could be functional, due to a large volume of arterial blood flowing into the sinus, such as in arteriovenous malformations (AVM) and dural arteriovenous fistulas (DAF) . In thesExcept for the direct connection between dural venous sinuses of the posterior cranial fossa and sigmoid–jugular venous system, the lateral, posterior, and anterior condylar veins and the mastoid and occipital emissary veins were found to represent another venous connection between the posterior cranial fossa venous sinuses and the vertebral venous systems. All these structures were shown by MR venography. In upright positions, venous drainage preferentially occurs via the spinal venous system, while it is the anterior jugular system in the lying position .An obstruction or difficulty of the venous outflow at the cervical level is possible in particular positions of the neck, such as persistent flexion with lateral rotation, in tight cervical collars, local tumors, and very rarely in jugular compression due to a long styloid process, especially when the opposite venous sigmoid sinus is hypoplastic .Intrathoracic and abdominal causes of venous mechanisms of increased intracranial pressure were associated with positive pressure ventilation in the treatment of chest infection and adult respiratory distress syndrome (ARDS), that can severely raise intrathoracic pressure, severe obesity, and abdominal compartment syndrome with raised intra-abdominal pressure .Severe obesity is indeed frequently encountered in IIH patients, and the hypothesis that it produces a retrograde increase of venous pressure, and further intracranial transmitted, only partly explained the IIH since most of the obese persons with IIH were women, but men with an even higher body mass index (BMI) did not have intracranial hypertension. In some trials, a decrease in BMI was clearly associated with a reduction of headache, papilledema, and CSF opening pressure. The mechanism by which weight loss improves idiopathic intracranial hypertension is not known. The effect of weight in terms of mass alone is not a complete explanation, because BMI and lumbar puncture opening pressure have a non-significant correlation . Obesity2) women of fertile age, developing some classical signs of intracranial hypertension dominated by headache and visual disturbances (including papilledema).The vast majority of patients with IIH are obese , color vision with Ishihara’s plates, pupil examination, and visual fields . The visual field evaluation is considered more sensitive than the decrease of visual acuity in patients with IIH, so it should be carefully assessed at each visit. Dilated fundus examination for optic nerve head and retina is the first very important step to rule out or to confirm a papilledema, which if present should be graded by severity and exclude other ocular causes for disc swelling.Transient visual obscurations (TVOs) refer to sudden loss or shadowy, fogginess, black, white, or grey vision in one or both eyes, lasting for a minute or less than 30 s, sometimes related to a change of position of the body. Increased pressure in liquid from surrounding optic nerve sheaths could compress the thin vascular small arteries and veins at this level, producing a transient ischemia of the optic nerve head [rve head . While nDiplopia in patients with IIH is due in most cases to a sixth nerve palsy, with this nerve being particularly vulnerable to increased intracranial pressure. Diplopia is horizontal, binocular, and if associated with significant abducens nerve palsy, there is a limited abduction of the eye and strabismus. Third and fourth cranial nerve palsies have been described in patients with IIH but are much less frequently encountered.Papilledema is encountered in a vast majority (~95%) of patients with IIH, and because of that it is one of the most important elements of the diagnosis criteria and should be assessed in all patients suspected of having this condition. Sometimes, papilledema may be asymmetrical, with 7% of patients having a difference of 2 Frisen grades or more between the two eyes [2O presenting spontaneous venous pulsation, so this situation does not rule out raised intracranial pressure [two eyes . In chrotwo eyes  proved tpressure .Sometimes, distinguishing pseudo-papilledema from papilledema requires clinical experience. Pseudo-papilledema may be due to congenitally anomalous discs, optic nerve head drusen, titled myopic discs, inflammation associated with a juxtapapillary optical neuritis, or malignant arterial hypertension. Ophthalmic ultrasound scanning is a useful method to more precisely detect the drusen of the optic nerve head. Optic nerve head drusen was responsible for 6% of misdiagnoses of IIH. B-scan ultrasound is considered diagnostic if there is an area of hyperreflectivity present at the nerve head or if acoustic shadowing of posterior structures of the optic nerve head is detected .Optical coherence tomography (OCT) generates non-invasive, high-resolution cross-sectional images of the retina using a near-infrared light source through undilated pupils. OCT is a useful tool to identify and quantify papilledema, along with some details such as an increase of peripapillary retinal nerve fiber layer thickness and peripapillary choroidal and/or retinal folds, proving a true papilledema . The optVisual loss in IIH could associate a loss in the visual field with a loss of visual acuity. An enlarged blind spot is well-recognized as a common early visual field defect in raised ICP. In the baseline patient group from the Idiopathic Intracranial Hypertension Treatment Clinical Trial, the co-existence of visual field defects with a loss of visual acuity manifesting as an enlarged blind spot and inferior partial arcuate defects were described as the most frequent pathological changes, even in patients with mild disease [ disease . Loss of disease .Pulsatile tinnitus [tinnitus ,31 is antinnitus ,31. It iThe primary role of brain imaging in idiopathic intracranial hypertension (IIH) is to exclude other pathologies causing intracranial hypertension, but also to sustain the diagnosis with evidence of subtle radiologic findings suggestive of IIH.Some visible modifications derive from bony erosion from IIH, such as empty sella, meningocele, and foramen ovale widening, while others are due to mechanical deformation from IIH , or a limitation of normal flow of fluids in the optic nerve sheath with optic nerve head protrusion and distention of the optic nerve sheath ,36 Figu.2 being the most sensitive modification (95.5%). Posterior globe flattening had a sensitivity of 56.3% and specificity of 95.3%, optic nerve head protrusion had a sensitivity of 29.1% and specificity of 97.0%, and optic nerve sheath distension had a pooled sensitivity and specificity of 68.6% and 86.1%, respectively, with individual sensitivity of 78.8% and specificity of 94.2% for a maximum optic nerve sheath diameter > 5.60 mm.In a meta-analysis  of MRI mEmpty sella is the most commonly reported imaging finding in patients with IIH, with a sensibility up to 80%, but it is also encountered in the general population. When using the definition based on the cross-sectional area of the sella, the pooled specificity is estimated as 83% (95% CI: 76–90) . When thOptic nerve protrusion is defined by a focal hyperintensity at the optic nerve head, protruding in the eye, visible on MRI with contrast, and is a representation of papilledema due to increased CSF pressure in the optic nerve sheath and correlates with optic nerve edema seen on OCT as well as the papilledema grade. The detection of contrast enhancement has a smaller sensitivity due to the small dimension of the nerve head and could also be produced in some inflammatory lesions of the optic nerve [ic nerve . In a coic nerve .Posterior ocular globe flattening can be seen on axial MRI at the bulbar insertion of the optic nerve, and is probably produced by increased pressure in posterior juxtabulbar perioptic CSF, compared with the pressure inside the ocular globe. However, this pressure gradient could also be encountered in situations with decreased intraocular pressure and normal ICP, such as ocular hypotony, with similar posterior globe flattening on MRI appearance, an aspect that explains why this sign is not of absolute specificity in IIH. The sensitivity of MRI-detected posterior globe flattening in IIH ranges from 43% to 85% but is still important to be recognized because in some cases, it may precede the installation of papilledema [illedema .Distension of the optical nerve sheaths is possibly correlated with high CSF pressure in the optic nerve sheath and can be seen on MRI imaging  as a widened ring of CSF surrounding an optic nerve. Definitions for distention of the optical nerve sheaths vary, but a diameter of the CSF ring of more than 2 mm is commonly used [nly used .Tortuosity of the optic nerve occurs due the fixation of the nerve at proximal and distal points and increased CSF pressure in the optic nerve sheath enlarging the nerve and forcing it to be “kinked”. Detection of tortuosity depends on the MRI slice thickness and orientation, with horizontal tortuosity being less common but more specific for increased ICP than vertical tortuosity [rtuosity .In a dedicated comparison of before and after treatment of patients with IIH with papilledema, in the group with resolution of papilledema, all patients showed improvement in two or more of the MRI characteristics of IIH . Sella configuration, ocular globe configuration, and horizontal orbital optic nerve tortuosity were different between the IIH pretreatment group and controls, but not between controls and the IIH post-treatment group .Narrowing or collapse of the walls of the lateral ventricles, referred to as slit-like ventricles, are very rarely described in association with IIH compared to other causes of intracranial hypertension with associated cerebral edema.Multiple studies have found that severe bilateral transverse sinus stenosis is present on magnetic resonance venography (MRV) in almost 100% of people with IIH, depending on the definition of transverse sinus stenosis, but as was detailed in pathogenesis, whether transverse sinus stenosis is a primary cause or a consequence of IIH is still under debate. A pathological cycle of stenosis of the sinus contributing to intracranial hypertension with further collapsing of the sinus is possible. This could explain both the reversibility of stenosis with treatment of the increased ICP and the success of the stenting procedure of transverse sinus stenosis in people with IIH. Bilateral transverse sinus stenosis greater than 50% has been found to be a very sensitive imaging marker of IIH .Transverse sinus diameter has been demonstrated to correlate with invasive measured venous pressure gradients in patients with IIH. The degree of stenosis of 30–35%, predictive of a clinically significant pressure gradient in the venous sinuses, was considerably lower than the arterial stenosis at which pathologic hemodynamic alterations occur with a significant pressure gradient. For every 10% increase in the degree of venous stenosis, an approximate increase in the pressure gradient of 3.5 mmHg was seen .In another published study , a signiAccurate assessment of transverse sinus diameter is important to diagnose IIH, but also for treatment decisions and follow-up. MR venography (MRV) can be performed by gadolinium-enhanced or by non-enhanced (including time-of-flight and phase-contrast) techniques. Non-enhanced MRV may be susceptible to effects related to slow or turbulent flow with a risk of underestimating the degree of stenosis, while Gadolinium-enhanced MRV may overestimate the lumen of the transverse sinus, because the dural lining also enhances. In a prospective evaluation, the dural venous sinus diameters were measured in an IIH patient population on two-dimensional time-of-flight MRV and three-dimensional contrast-enhanced (3D-CE), and thereafter MRV were compared with real-time endoluminal measurements with intravascular ultrasound (IVUS) as the reference. The CE-MRV significantly overestimated the cerebral venous sinuses compared to TOF-MRV, while the TOF-MRV sinus measurements were in good agreement with the IVUS measurements .Finally, it is better to use MRV (or CT venography) as a screening tool in case of indication of endoluminal stenting, and if the degree of venous stenosis is significant, the catheter venography will be used for further analysis and measurement of the pressure inside the transverse sinus, before and after the stenosis area, so one can make sure of whether there is a significant pressure gradient or not.In some, but not all, of these patients, the diameter of optic nerve sheaths decreased after lumbar puncture, and maybe this could be a useful sign for selection of patients for methods of treatment such as CSF diversion, while a close follow-up of visual acuity and visual field for the non-responders and selection of other methods of treatment could be helpful. Mean values of optic nerve diameters were around 2.4–2.7 mm, while mean optic disc elevation in IIH patients was 1.2 ± 0.3 mm in both eyes, and neither were influenced by lumbar puncture CSF removal .p < 0.001) in IIH patients. Bilateral transverse sinus stenosis was also more common in IIH patients than in the control group and the migraine group (p = 0.02) [In a retrospective study, MRI findings of patients with migraine and IIH (including patients with migraine-like headache) were significantly different, where decreased pituitary gland height, optic nerve sheath distention, and flattened posterior globe were found to be statistically significant ( = 0.02) .Overall, in a meta-analysis, the bilateral > 50% transverse sinus stenosis with MRI diagnosis had a sensibility of 93.0% and a specificity of 96.4% .The ultrasound assessment of the orbital region could provide important information for IIH patients in an accessible manner, especially about the mean optic disk elevation as a result of papilledema, the diameter of the optic nerve, and the optic nerve sheaths measured 3 mm behind the papilla. In a published study , the meaLP is mandatory for the diagnosis of IIH but checking for a normal CSF composition should also exclude meningitis or meningeal carcinomatosis. Reference values of ICP and lumbar pressure of CSF were evaluated in a recent meta-analysis  which inAll patients with papilledema and MRI examination without an expanding intracerebral lesion should have a lumbar puncture to measure the CSF pressure .2O in adults and 28 cm H2O in children. However, it is important to note that these cut-offs are not of absolute value, with 2.5% of normal adults having ICP above 25 cm H2O in some populational studies and 10% of patients with acute pseudotumor cerebri having ICP less than 25 cm H2O [The diagnostic criteria of pseudotumor cerebri  require 5 cm H2O ,47.Since increased values of ICP may occur intermittently, especially in IIH patients without papilledema, in the presence of suspected intracranial hypertension syndrome with classical clinical presentation and suggestive MRI findings for intracranial hypertension, a second lumbar puncture should be performed if the first lumbar puncture revealed an opening pressure of CSF within the normal range .The main principles of management of IIH are targeting the underlying disease if diagnosed, the protection of vision, and to reduce the headache morbidity. During the last decades, a combination of lifestyle measures, drug treatments, and in selected cases different surgical and endovascular interventional therapies were developed. Before deciding the treatment strategy of an IIH patient, the first step is to check if other known factors associated with increased intracranial hypertension are present, and if identified, they should be addressed. According to Friedman , the mos2O), headache, and papilledema, although a correlation between the amount of obesity and CSF pressure was not always found [A large majority of patients with pseudotumor cerebri are overweight, but especially obese (90–95%), with 90% of them being women of fertile age. In the year preceding a diagnosis of IIH, many patients had a weight gain of about 5–15%, but in a cohort study, a weight loss of 15% was associated with a significant reduction of ICP , and induces appetite suppression, leading to potential weight loss.An open-label study of 40 patients with idiopathic intracranial hypertension compared topiramate (100–150 mg per day) and acetazolamide (1000–1500 mg per day) . The maiFor patient with previous migraine overlapping with an increased intracranial pressure syndrome, some classical drugs used for migraine attack treatment are still useful (triptan acute therapy used in combination with NSAID or paracetamol and antiemetics), avoiding long-term abuse of analgesics. Topiramate could be used for the prevention of migraine attacks, but in some cases for patients with associated depression, venlafaxine could also play a positive role, avoiding the risk of weight gain seen with betablockers, tricyclic antidepressants, or sodium valproate.CSF divergence can be the logical step to reduce the disturbed balance between secretion and drainage of CSF, with an increase in total intracranial fluid content, to compensate for other possible links such as intracerebral venous and glymphatic system compression secondary to intracranial hypertension, but also large venous sinus compression with extrinsic stenosis. This secondary venous sinus stenosis can lead to a further increase in ICP, which creates a vicious cycle where the increase in ICP produces a worsened secondary sinus stenosis and higher venous pressure ,54. TherIn patients with a high risk for visual loss, CSF divergence can be sight-saving. If the surgical procedure is likely to be delayed for 24–48 h, it is possible to insert a lumbar drain at the time of the lumbar puncture. Other methods are a lumbo-peritoneal shunt, where a catheter is inserted into the subarachnoid space at the lumbar spine and the distal part enters the peritoneum, but this method is not appropriate in the case of patients with low-lying cerebellar tonsils, as there is an increased risk of tonsillar herniation following the shunt. A ventriculoperitoneal shunt diverts CSF from the lateral ventricle to the peritoneum, and a ventriculoatrial shunt diverts CSF from the lateral ventricle to the atrium of the heart, while a ventriculopleural shunt diverts it to the pleural cavity, but the last two techniques are less used. The surgical risks include shunt malfunction, infection, and over-drainage. Due to the lower reported rate of shunt revisions per patient, the ventriculoperitoneal route should be the preferred CSF diversion procedure for visual deterioration in IIH .The results of CSF drainage methods were evaluated through some retrospective case series and a meta-analysis of them. In a retrospective study  with 53 In a meta-analysis of 17 studies with a CSF diversion including 435 patients , the heaOverall, different methods of CSF shunting have benefits in reducing CSF pressure, in improving visual deficits, and in preventing visual loss, but this is not the procedure of choice for intracranial hypertension headache prevention or treatment.Stenosis, as previously defined by Marmarou et al. , is an aThe DSA estimated pattern of venous drainage in a cohort of patients showed that a right-side dominance is the most prevalent pattern of drainage (49%), while codominance occurs in 43% and left-side dominance in 8%. A complete unilateral drainage is seen in 19% (right) and 1% (left) of patients .Dural sinus stenosis is generally described as intrinsic or extrinsic, although some patients may have both. An intrinsic obstruction pattern is a focal filling defect secondary to arachnoid granulation , whereas an extrinsic stenosis may be related to local hypertrophic scarring or related to elevated intracranial hypertension, which itself compresses the wall of the sinus  .The arachnoid granulations were present in the superior sagittal sinus in 50% of patients, with a 7% incidence of sinus stenosis. Most of the stenosis in the sinuses was due to the arachnoid granulations (77% on LTS and 71% on RTS) . OverallThe hypothesis linking the dural venous sinus stenosis and IIH leads to the conclusion that solving the stenosis using angioplasty and placement of a stent could serve as another method for treatment of the disease, especially in patients who are unresponsive to medical therapy. Research evaluating this therapy began with Higgins and colleagues, in 2003, who demonstrated a clinical improvement in 7 of 12 medically refractory IIH patients treated with venous sinus stenting, 5 of whom experienced complete resolution of symptoms .2O and elevated superior sagittal sinus pressures (>18 mmHg) in the absence of an intracranial mass lesion. Based on central venous pressure and the presence of significant venous sinus stenosis, four subtypes of CIVHS were proposed: (1) Central-type patients have elevated central venous pressure without concomitant venous sinus stenosis, whereby morbid obesity or cardiorespiratory disease result in significant central venous pressure elevations with subsequent elevations in intracranial venous pressures. These patients account for about 25% of patients with IIH, are not candidates for venous sinus stents, and tend to respond to weight loss or furosemide to reduce central venous volume and therefore central venous pressure. (2) Craniocervical-type patients demonstrate pathologic venous sinus stenosis with low–moderate CVP, wherein the venous outflow obstruction at the venous stenosis manifests as the primary driver of elevated intracranial venous pressure. These patients are often excellent candidates for venous sinus stents. (3) Mixed-type patients are the largest subset of patients and demonstrate both pathologic venous sinus stenosis as well as moderate to high venous sinus stents, wherein both are independent and additive drivers of high intracranial venous pressure. (4) Post-thrombotic patients demonstrate impaired intracranial venous outflow due to chronic venous sinus thrombosis, and are the rarest [Recently, a new proposal emerged  for chane rarest ,64.Evaluation of venous cerebral circulation should especially detail the location, extension, and degree of stenosis of dural venous sinuses, if possible, with noninvasive imaging such as CT venography, or contrast-enhanced magnetic resonance venography, which can also demonstrate intrinsic/extrinsic stenoses. A direct retrograde catheter venography with venous manometry is required to determine whether a venous pressure gradient exists across the stenotic segment. Pressures are measured from the segments of the superior sagittal sinus, bilateral transverse sinuses, sigmoid sinus, jugular bulb, and cervical internal jugular. A stenosis is considered clinically significant if a trans-stenotic gradient above a certain level is found between the proximal and distal segments of the evaluated venous stenosis. Normal gradients between the superior sagittal sinus and the jugular bulb range between 0 and 3 mmHg in healthy patients. A universally recognized cut-off value for the trans-stenotic gradient to determine which patients are appropriate candidates for stenting has not been established, although most practitioners prefer 8 mmHg for the selection of patients for stenting, and the maximum values are frequently more than 10 mmHg .The likelihood for a cerebral venous pressure gradient is almost 5 times higher  in patients diagnosed with IIH, but very low in patients with a preexisting shunt  and absent in those with normal ICP .There are opinions that the trans-stenotic venous gradient should be measured before and after lumbar puncture, and confirmation of indication for stenting of the venous stenosis remains in patients without significant post-puncture improvement of the gradient. Secondary venous sinus stenosis due to external compression within an intracranial hypertension syndrome may respond to a decrease of ICP after lumbar puncture, while gradient pressure due to intrinsic stenosis is thought to be less responsive to a post-lumbar puncture decrease of ICP . Howeverp = 0.033) and higher changes in pressure gradients after stent placement  compared with those with unfavorable outcomes. In a multivariate stepwise logistic regression controlling for multiple factors, the change in pressure gradient with stent placement was found to be an independent predictor of favorable outcome (p = 0.028). Using a pressure gradient of 21 mmHg as a cut-off, 94.2% of patients with a gradient > 21 mmHg achieved favorable outcomes, compared with 82.0% of patients with a gradient ≤ 21 mmHg (p = 0.022), but the high percentage (82%) of patients with favorable outcome with pressure gradient ≤ 21 mmHg made it difficult to choose this value as a definitive indication for intervention [In a meta-analysis of 32 eligible studies, a total of 186 patients were included for predicting outcome values of pressure gradients . Patientrvention .Ultimately, venous manometry is the most important parameter to select a venous stent indication as a treatment after diagnosis of significant intracranial hypertension with progressive symptoms/vision loss and an obstructive venous outflow pattern , without a response to weight loss and maximal medical therapy, after careful comparison of other alternative surgical methods and patient particularities.Prior to stent placement, patients are provided with seven days of aspirin 75 mg and clopidogrel 75 mg daily or loading doses of aspirin 325 mg and clopidogrel 600 mg. Trans-stenotic maximal venous pressures and pressure gradients are reconfirmed prior to placement of the venous stent. For venous sinus stenosis, the stents need to be self-expanding with adequate radial force to overcome any external stenosis from elevated ICP and long constructs to ensure they extend >10 mm pre- and post-stenosis .Post-stenting venograms are performed to look at the drainage patterns. A CT scan is performed to rule out an intracranial hemorrhage. Patients will be on dual-antiplatelet therapy for one month and single-antiplatelet therapy for at least 3–6 months ,69. An aThere are no studies specifically reporting on synchronous bilateral transverse sinus stenting for patients with IIH. The vast majority of published studies performed unilateral stenting of the most stenotic transverse sinus, with good procedural outcomes .The clinical outcomes of dural sinus stenting are related to headache, but especially improvement of visual parameters , and as a secondary achievement, the improvement or disappearance of the tinnitus. In the published meta-analysis and retrospective reviews of case series , there wIn a dedicated meta-analysis of 395 patients  with avaThe rate of major complication of the procedure  varied from 0% to 1.5–2.9% ,61,74. SCompared with the other interventional/surgical procedures for IIH, the rate of improvement of the associated tinnitus is higher with stenting of venous sinus stenosis. Pulsatile tinnitus in the majority of patients with IIH is described as a whooshing sound synchronous with their pulse. This has been attributed to turbulent venous flow through a stenotic segment, and compression of the ipsilateral jugular vein may result in its cessation. A 3 T/four-dimensional (4D) flow magnetic resonance imaging with fast-field echo study  proved tThere are very few dedicated studies on ONSF in IIH patients, and in general, they are retrospective case series. The mechanisms through which ONSF reduces the optic nerve consequences of high ICP are not clear. The MRI-proven increase of optic sheath thickness and increased tortuosity of the optical nerve could lead to the idea that the ONSF exerts its action by local fistula formation between the nerve sheath and dura, with slow drainage and resorption of the excess of fluid in the orbital tissue, or a local hypertrophic scarring in the first segment of the optic nerve with a further limitation of transmission of increased pressure in the distal optic nerve and papilla .ONSF was more often considered in patients with asymmetrical papilledema and mainly in patients where headache is not significant, because of the more modest improvement rate compared to the other treatment methods, or in a situation when CSF diversion surgery is considered to carry a high risk or is contraindicated.The meta-analysis of Satti et al. of optic nerve sheath fenestration included 712 patients. Post-procedure, there was an improvement of vision in 59%, headache in 44%, and papilledema in 80%, and 14.8% of patients required a repeated procedure with major and minor complication rates of 1.5% and 16.4%, respectively . The majUnilateral ONSF in a case series of 62 patients  significThe accurate diagnosis of idiopathic intracranial hypertension is essential as visual deterioration due to papilledema may be irreversible. An increase in incidence is expected in the future because of the rising levels of obesity. Although the mechanisms of this heterogeneous syndrome are complex and not all of them are fully elucidated, there are advances in the understanding of idiopathic intracranial hypertension and improvements in diagnosis, based on current available criteria, including specific CSF pressure levels. The therapeutic options include reducing weight strategies , medication , and in selected severe cases, some interventional therapies such as ventriculoperitoneal shunts, optical nerve sheath fenestration, and intracranial venous sinus stenosis stenting, with a possibility to adapt them to the patient’s clinical profile for the best results.


Recent advances have improved our understanding of the epidemiology and pathophysiology of acute kidney injury (AKI). So far, the Kidney Disease: Improving Global Outcome guidelines define and stratify kidney injury based on increases in serum creatinine level and/or decreases in urine output. Although the term AKI acknowledges the existence of cellular injury, its diagnosis is still only defined by the reduced excretory function of the kidney. New biomarkers that aid a better understanding of the relationship between acute tubular injury and kidney dysfunction have been identified, reflecting the advances in molecular biology. The expression of some of these novel biomarkers precedes changes in conventional biomarkers or can increase their predictive power. Therefore, they might enhance the clinical accuracy of the definition of AKI. This review summarizes the limitations of the current AKI classification and a panel of candidate biomarkers for augmenting AKI classification and recognition of AKI subphenotypes. We expect that the integration of appropriately selected biomarkers in routine clinical practice can improve AKI care. FH-S, TR, and KK prepared all manuscript drafts and were involved in reviewing and editing. CR was involved in the writing and editing of the manuscript, including the figures. In addition, CR conceived the concept underlying the manuscript, was involved in reviewing and editing, and is the paper's senior author.1Over the last decade, there has been considerable progress in understanding acute kidney injury (AKI) epidemiology and pathophysiology and its diagnostic testing. AKI is now recognized as a collection of entities , includi2AKI epidemiology and etiology differ between high-vs. vs. middle-to low-income countries  and are Independent of its etiology, AKI is associated with increased short- and long-term mortality ,17 and l3AKI diagnosis and classification is based on the 2012 Kidney Disease: Improving Global Outcomes (KDIGO) consensus criteria   easi5.12/1000 having 92% sensitivity and 46% specificity while a score >2.0 (ng/ml)2/1000 has 37% sensitivity and 95% specificity for the occurrence of AKI stage 2–3 [2/1000. The urine concentration of [TIMP-2]•[IGFBP7] is not increased in stable CKD [The two urinary biomarkers TIMP-2  and IGFBP7  are secreted in the early phase of tubular damage 2/1000] tests, the occurrence of AKI stage 2–3 during the first seven days was 13% [2/1000], respectively [Two trials evaluated serial measurements of urinary [TIMP-2]•[IGFBP7]. The ProCESS (Protocolized Care for Early Septic Shock) trial randomly assigned 1351 patients from 31 hospitals presenting with septic shock at the emergency department to receive one of three different resuscitation strategies . Of thos was 13% . In contectively .. These biomarkers were assessed when patients were admitted to a multidisciplinary ICU. Among septic patients, the positivity of both tests implied a higher risk of AKI and death. Furthermore, in patients without sepsis, the double positivity correlated only with higher AKI risk but not mortality •[IGFBP7] > 2.0 (ng/ml)2/1000 progressed to AKI requiring KRT (stage 3D).A retrospective single-center study evaluated the association of urinary [TIMP-2]•[IGFBP7] with serum procalcitonin and the development of AKI or deathortality . The relortality . Howeverortality . None of5.2NGAL is one of the most extensively investigated kidney biomarkers. It is a molecule that binds small iron-carrying molecules called siderophores that act as chelators/transporters in several diseases . NGAL isNGAL can be measured in urine or plasma and proposed as a distal tubule damage biomarker  for diagThe BICARBONATE trial, a multicenter, parallel randomized controlled trial comparing perioperative bicarbonate infusion for preventing AKI to usual patient care, explored whether urinary NGAL and the urinary NGAL/hepcidin-25 ratio could predict AKI stage 3D in patients undergoing cardiac surgery with cardiopulmonary bypass . The samConsidering the newly proposed framework of AKI that considers kidney damage biomarkers in addition to the traditional parameters of kidney function , the autSerial assessments of urinary NGAL were carried out in a specific pediatric cohort of 66 patients with diabetic ketoacidosis . AKI wasAnother specific scenario where NGAL has been deployed was in patients with COVID-19. A retrospective cohort study showed that AKI occurred in 1835 (46%) of 3993 hospitalized adults . Patient5.3Urinary kidney injury molecule 1 (KIM-1) is a 38.7-kDa type 1 transmembrane glycoprotein produced by proximal tubular cells. It is released into the urine in response to tubular damage and functions in clearing apoptotic cells, and has anti-inflammatory properties ,80,81. I5.4Liver-type fatty acid-binding protein (L-FABP) is a 14-kDa intracellular lipid chaperone that mobilizes lipid peroxides from the cytoplasm of tubular epithelial cells to the tubular lumen. L-FABP gene expression is increased by peroxisome proliferator-activated receptor α  and hypo5.5The RUBY study, an international prospective observational study designed for detecting biomarkers associated with persistent (≥72 h) AKI stage 3, identified urinary C–C motif chemokine ligand 14 (CCL14) as a reliable predictor of persistent AKI . The coh5.6Urinary dickkopf-3 is a 38-kDa stress-induced, renal tubular epithelia-derived secreted glycoprotein that induces tubulointerstitial fibrosis through its action on the canonical Wnt–β-catenin signal pathway  by promo5.72 to confirm CKD diagnosis, provided no other renal structural abnormalities are present [Cystatin C, an established surrogate marker of GFR, is a cysteine protease inhibitor formed at a relatively constant rate by all nucleated cells . Due to  present . Cystati present . Cystati present .5.82 = 0.91; p < 0.001) [131I-hippuran and 125I-iothalamate  [Proenkephalin A is a stable fragment derived from the precursor enkephalin, a small endogenous opioid peptide produced throughout the human body, including the kidneys . The glo< 0.001) . In pati< 0.001) .Endogenous opioid peptides also exert cardiodepressant effects  and kidn6A panel of biomarkers can enrich AKI diagnosis, yielding insights from the pathophysiological mechanisms of different AKI subtypes and highlighting the most affected segments of the renal tubules. Simultaneous analysis of a group of biomarkers can yield clues to the predominant etiology of coexisting kidney insults  . An obseN-acetyl-β-glucosaminidase), McWilliams and co-workers confirmed the proximal tubule as the expected anatomical site of injury in the nephrons of premature neonates exposed to aminoglycosides [Using a panel of urinary biomarkers  presented normal urinary NGAL, KIM-1, and sed eGFR . These rsed eGFR . It is wsed eGFR , incremesed eGFR . Moreovesed eGFR . These fsed eGFR .The DAMAGE  study was a prospective observational trial investigating the utility of urinary AKI biomarkers on ICU admission at two academic medical centers. The study recruited 717 patients. The primary outcome was developing any stage of AKI during the first seven days following ICU admission. Only the KDIGO serum creatinine criteria but not the urine output criteria were used in the AKI staging. The urinary panel consisted of NGAL, albumin, KIM-1, L-FABP, and cystatin C. Thirty-eight percent of the patients developed AKI, 215 (84%) during the first 48 h and 42 (16%) after 48 h but before seven days . A secon7Data indicate that AKI is associated with 13%–18% of hospital admissions  and affe8Although several markers have been shown to detect AKI earlier and are more sensitive than the current markers of AKI , there are still substantial knowledge gaps that need to be covered in future studies. A recent consensus paper on AKI biomarkers made recommendations for clinical practice and future research . In partFinally, laboratory implementation of AKI biomarkers requires the determination of reference intervals, their widespread availability, and concordance between assays. For example, a recent position paper of the American Association for Clinical Chemistry highlighted that the cystatin C assay cannot be universally recommended due to poor standardization, the lack of availability from most vendors and high cost (in comparison with serum creatinine) worldwide . We anti9The recent gain of knowledge in the field of AKI reflects the advances in molecular biology. The role of several molecules involved in complex AKI mechanisms has been partially unraveled, propelling the investigation of the clinical utility of these molecules as biomarkers. In the roadmap for an update in AKI classification the incorporation of biomarkers is of utmost relevance. The judicious use of the new clinical available biomarkers allows the early laboratory detection of AKI and the recognition of AKI subphenotypes. This is especially pertinent in high-risk patients in whom the additional information brought by laboratory results enriches and makes risk assessment tools more reliable. Preventive actions and early interventions can be tailored to the patients that might benefit them most, ultimately mitigating the burden and adverse outcomes associated with AKI.A wake-up call is needed to alert healthcare policymakers and clinical practitioners to integrate the new biomarkers in protocols for AKI management. In parallel, researchers are encouraged to assess biomarkers as outcomes in trials evaluating their cost-effectiveness and the safety profile of pharmacological and non-pharmacological interventions concerning the kidneys. Undoubtedly, these actions will be major drivers in the progress of nephrology.This work did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.TR has received funding for lectures, been consultant or advisory board member for AstraZeneca, B. Braun, Baxter, bioMérieux, Contatti Medical (CytoSorbents), Eurofarma, Jafron. CR has received funding for lectures, been consultant or advisory board member for Asahi, Astute, B. Braun, Baxter, bioMérieux, Bioporto, CytoSorbents, Estor, Fresenius Medical Care, General Electric (GE), Jafron, Medtronic, Toray. None of the other authors declare any competing interests. The authors shared manuscript design, literature collection, literature analysis and interpretation, preparation, review, and approval of the manuscript. The corresponding author had full access to all of the work and had final responsibility for the decision to submit for publication.


Despite good quality of fit and comparable regions of interest in baseline and follow-up CEUS examinations, quantification of perfusion imaging showed a slightly improved cortical perfusion without reaching statistical significance after CNI cessation. This is the first study that systematically investigates the suitability of CEUS to detect changes of microvascular perfusion in kidney transplant recipients in vivo. No significant differences could be detected in perfusion measurements before and after CNI cessation.Calcineurin inhibitors (CNIs) have improved short-term kidney allograft survival but are nephrotoxic and vasoconstrictive. Vasoconstriction is potentially reversible after switching from CNIs to belatacept. The kidney allograft shows optimal requirements for dynamic perfusion imaging using contrast-enhanced ultrasound (CEUS). We performed standardized CEUS in patients after switching from CNIs to belatacept for clinical indication to study the suitability of CEUS, in order to assess the effects of CNI cessation on kidney allograft perfusion. Eleven kidney transplant patients were enrolled from February 2020 until November 2020. Demographic, clinical, and laboratory parameters, as well as perfusion imaging, were assessed at baseline and 6 months after switching immunosuppression. Quantification of perfusion imaging on CEUS was performed using a post-processing software tool on uncompressed DICOM cine loops. After CNI cessation, estimated glomerular filtration rate increased by 4.8 mL/min/1.73 m Calcineurin inhibitors (CNIs) have substantially improved short-term graft survival in kidney transplantation. However, CNIs have unfavorable effects on long-term outcomes of kidney transplant recipients (KTRs) due to potential nephrotoxicity and cardiovascular adverse effects ,2,3,4,5.CNI nephrotoxicity is a result of both reversible changes and irreversible damage to all compartments of the kidneys, including glomeruli, arterioles, and tubulo-interstitium. Acute CNI toxicity is caused by a variety of pathophysiological changes and consequentially leads to several histopathological findings: vasoconstriction of the afferent arterioles displayed by reduced vessel diameter, toxic effects on tubuli resulting in isometric vacuolization of the tubular cytoplasm, and thrombotic microangiopathy .While acute CNI toxicity can cause dramatic impairment of kidney function, especially in the early post-transplant period, this has little impact on the long-term outcome due to its reversibility. On the contrary, chronic CNI toxicity plays an important role in chronic allograft injury and graft failure . The comAgainst the background of those shortcomings of CNIs, alternatives have been widely studied to improve long-term outcomes of KTR. Most recently, belatacept, a fusion protein linking the human IgG1 Fc fragment to the modified extracellular domain of cytotoxic T-lymphocyte-associated antigen 4, has shown promising results . BelatacB-Mode ultrasound (US) and color-coded duplex ultrasound (CCDS) including measurement of resistance indices (RI) remain the primary imaging modalities in follow-up (FU) of renal grafts. In general, CCDS depicts the macrovascularization with limitations on assessment of cortical vascularity due to their small vessels and low arterial flow. Ultrasound contrast agents (UCA) and dynamic depiction of the renal microvascularity overcome the physical limitation of CCDS by visualization of both the macro- and the microvasculature. After intravenous injection, the main branches enhance first, rapidly followed by the segmental to arcuate and interlobular arteries, and finally complete cortical enhancement within seconds. Due to its dynamic contrast imaging, contrast-enhanced ultrasound (CEUS) is additionally used for identification of early vascular complications and whole-organ perfusion , or inflammatory complications (such as abscess) with a higher sensitivity by depiction of microvascularization ,11.Due to its superficial localization and small movement during breathing, the renal graft shows optimal requirements for dynamic perfusion imaging in standardized longitudinal planes using a post-processing tool. In order to study the suitability of CEUS to assess the effects of CNI cessation on kidney allograft perfusion, we performed standardized CEUS in patients who underwent the switch from CNIs to belatacept for clinical indication. Additionally, we compared the suitability of convex and linear probes when performing standardized CEUS in renal allografts.We enrolled eleven patients who underwent the switch of immunosuppressive regimen from CNIs to belatacept for clinical indication. Belatacept was administered 5 mg/kg every 14 days for 8 weeks, and then every 4 weeks thereafter. CNI treatment was tapered as follows: 100% on day 1, 40–60% on day 15, 20–30% on day 23, and none on day 29 and beyond.Donor characteristics evaluated included age, sex, and living versus deceased donation. Recipient characteristics evaluated included age, sex, cause of chronic kidney failure, type of dialysis, duration of dialysis, induction immunosuppressive regimen, early graft function, time since transplantation, cause of switch of immunosuppression, arteriolar hyalinosis (ah) grade according to Banff 2017 classification in the latest kidney allograft biopsy, and baseline immunosuppression. Delayed graft function was defined as the need of dialysis within seven days after transplantation. Recipient serum creatinine, microalbuminuria, and kidney biopsy results were examined at baseline (day of first measurement) and m6 (day of last measurement).®, Bracco Imaging, Milan, Italy) was injected and a cine loop of 60 s was stored to assess inflow and washout. After a time delay of 10 min, the examination was repeated with a linear array transducer using a penetration depth of up to 5 cm focused on the superficial renal cortex. A cine loop of 60 s after a second injection of 1.6 mL SonoVue® was repeated after full washout of the ultrasound contrast agent of the first scan. B-mode ultrasound of all renal transplants was performed using a convex array transducer to assess organ position and standardized longitudinal planes. All convex transducers employed in study patients were required to be for abdominal use with a frequency range of 1–6 MHz. CEUS examinations were performed using high-end ultrasound systems  with state-of-the-art CEUS-specific protocols. A low mechanical index (<0.1) was used to avoid early microbubble destruction, especially in the near field. A bolus of 1.6 mL of a second-generation ultrasound contrast agent  by using uncompressed DICOM cine loops. After initial software calibration , regions of interest (ROI) were manually placed in the renal cortex by an experienced radiologist specialized in CEUS. The ROI was placed in the renal cortex excluding the medullar pyramids  and “R” version 4.1.1. Eleven patients were enrolled with the mean age at inclusion being 47 ± 13 years. The immunosuppressive regimen was switched 7.8 years after transplantation on average, with 8/11 patients receiving tacrolimus and 3/11 patients receiving cyclosporine before CNI cessation. All patients except for one, who was on dual antiplatelet therapy, underwent kidney allograft biopsy before switching to belatacept. Severe arteriolar hyalinosis (ah3) as a sign of chronic CNI toxicity was found in 8/11 patients. Additionally, one patient showed moderate arteriolar hyalinosis (ah2), one patient showed acute tubular CNI toxicity (isometric tubular cell vacuolization) but no chronic vessel changes (ah0), and one patient—for whom no biopsy could be obtained—received rescue switch due to marginal kidney function. Additional patient characteristics are shown in 2 at baseline to 29.2 ± 10.3 mL/min/1.73 m2 at the end of the study period (p = 0.045) as shown in p = 0.14), which is due to increased glomerular perfusion pressure after the reversal of afferent vasoconstriction. No acute rejection episodes were observed during the observation period.All patients had a functioning graft at the end of the study period. eGFR increased significantly from 24.4 ± 10 mL/min/1.73 m2 (baseline) vs. 9.2 cm2 (FU) for CEUS with a convex transducer and 3.5 vs. 2.6 cm2 for CEUS using a linear transducer. As represented in The quality of fit on the perfusion imaging was high in the convex (baseline 95.6% and FU 96.6%) and linear transducer (baseline 97.7% and FU 96.6%). Mean ROI size in perfusion assessment was 9.4 cm2 (16%) after CNI cessation, which is comparable to other studies [In this pilot study including eleven kidney transplant patients, standardized CEUS perfusions analysis did not show a statistically significant change of renal perfusion after switching immunosuppression from CNIs to belatacept for clinical indication. This is the first study that systematically investigates the suitability of CEUS to assess microvascular perfusion changes in KTR in vivo. After CNI cessation, an increased microvascular perfusion is expected due to the reversal of CNI-induced vasoconstriction of the afferent arterioles. This increase in perfusion is displayed by the average eGFR increase of 4.8 mL/min/1.73 m studies .Over the last decade, the clinical use of CEUS has consistently increased by implementation in guidelines. While liver imaging represents the major clinical application, which is denoted by a separate guideline of hepatic imaging, all extrahepatic indications are implemented within one guideline ,12. In rUsing newer software tools or post-processing applications, perfusion imaging shows the possibility of parametric imaging with the assessment of renal perfusion in real time. Thus, quantitative time-related or intensity-related parameters are presented by time–intensity curve analysis. CEUS is an established tool in the assessment of focal lesions, but newer studies have focused on the evaluation of whole-organ perfusion. In a recently published study, El-Bandar and colleagues demonstrated only a minor correlation of CEUS parameter and split renal function assessed on preoperative scintigraph evaluation in living kidney donors . The stup = 0.01), while time-related parameters such as time-to-peak did not  [Quantification of whole-organ perfusion was also analyzed by Chen and colleagues to assess the renal function in children with ureteropelvic junction obstruction. The study group investigated CEUS perfusion imaging in 102 kidneys of 51 children with unilateral disease. Similar to our study findings, no significant difference in perfusion parameter and their AUC was detected between the diseased and healthy kidneys . HarroisIn pre-clinical studies, both RI measurements and CEUS perfusion parameters showed only partially promising results in perfusion changes during hypoxia . In a grData on the evaluation of perfusion imaging using a high-frequency linear transducer and low-frequency convex transducer are rare. Agreement among three readers regarding the evaluation of the degree of enhancement, internal homogeneity, and the perfusion defects in breast lesions varied between fair and substantially better for the evaluation with linear transducers . The intDue to an immense wide range of perfusion parameters  using the convex probe, the linear probe showed better suitability with smaller range and more robust data. Although a smaller field of view, wash-in/-out characteristics may demonstrate improved visualization on the cortical level. In conclusion, for dynamic assessment of cortical perfusion, the linear probe may be more adequate and should be used in detailed follow-up studies. While further investigations with larger sample sizes may detect significant changes for certain CEUS parameters in a comparable experimental setup, this pilot study indicates that routine CEUS is not able to detect slight changes in microvascular perfusion with sufficient accuracy to be transferred to clinical practice in the near future. Since most patients received late conversion to belatacept in the present study, arteriolar hyalinosis may be more pronounced and less reversible in comparison to patients who receive early conversion to belatacept in the first post-transplant year. It would be interesting to study CEUS in patients with early conversion to belatacept, where improvement in microvasculature is suspected to be more pronounced.The major technical limitation of perfusion analysis was the missing standardization. Although all ROIs are placed equally, the parametric intensity values are not comparable between patients. Likewise, the wide spread of values regarding intensity parameters is difficult to compare in one patient. This may be due to different US parameters, although gain was not changed and calibrated on perfusion analyses. Thus, in the discussion we focused on the more robust parametric values assessed by the linear transducer. The smaller scan field and superficial approach were associated with a smaller range of values. Moreover, the use of different US machines may influence all values, although post-processing analysis should allow comparison of different US machines and probes.A methodological limitation which could be improved in following studies is the missing assessment of renal microvascular changes by follow-up biopsy. Such follow-up biopsies could add further evidence that CNI cessation improved microvascular perfusion besides eGFR improvement. On the other hand, histopathological changes in kidney allograft biopsies are patchy, and the effect of CNI withdrawal on microvascular diameter can be expected to be mostly functional and small. Therefore, changes of microvasculature can be undetectable by routine biopsy, and functional parameters such as eGFR may be better suited. Lastly, CEUS is not well established in kidney allograft, which limits its applicability to detect small changes in microvascular perfusion.


We evaluated the clinical significance of the new non-invasive vascular indices to explore their potential utility using repeated cuff-oscillometric inflation. In 250 consecutive outpatients, we performed a cross-sectional, retrospective, single-center, observational study to investigate sequential differences in arterial stiffness using blood pressure, arterial velocity pulse index (AVI), and arterial pressure volume index (API) with repeated measurements. Males accounted for 62.7% of the patients, and the mean age was 68.1 ± 12.1 years. The mean systolic blood pressure (SBP) and diastolic blood pressure (DBP) of the first reading in repeated measurements were 133.07 ± 21.20 mmHg and 73.94 ± 13.56 mmHg, respectively. The mean AVI and API were 23.83 ± 8.30 and 31.12 ± 7.86, respectively. In each measurement of these parameters, although DBP and AVI did not show significant changes throughout repeated measurements, SBP and API decreased significantly according to the measurement orders. Furthermore, changes in SBP and API were significantly correlated in several of the models. In this study, it was concluded that upper-arm SBP decline associated with repeated cuff-oscillometric inflation was significantly correlated with the arterial stiffness index. The findings of this study will allow clinicians to easily recognize the progression of atherosclerosis through regular, routine practice. In conclusion, this study suggests that changes in repeated SBP measurements may be predictive of arterial stiffness and atherosclerosis. Atherosclerosis is the common result of the advanced progression of diseases based on diet and exercise in daily life, such as hypertension (HT), diabetes, dyslipidemia (DL), or lifestyle-related diseases. Consequently, atherosclerosis can lead to fatal cardiovascular events, and it is necessary to salvage and counteract life-threatening diseases such as acute myocardial infarction and acute cerebral infarction. Even if fatality can be avoided, it is a strong limiting factor for healthy life expectancy as it can cause serious sequelae with disability and result in the need for permanent nursing care ,2,3.To date, the mainstream countermeasures against atherosclerotic events have been the establishment of a life-saving emergency system that concentrates medical resources on the disease and its symptoms that develop in an acute catastrophe and the control of population risk through public and personal hygiene by controlling blood pressure (BP), blood sugar, and lipids, which are risk factors for the disease. The former requires not only enormous social costs, including human and medical resources and costs, for unpredictable lethal events but also poses other challenges, such as regional disparities among nationwide healthcare services that can and cannot supply them and inappropriate work overload for healthcare personnel ,5. The lRecent technological innovations have made it possible for us to use the AVE-1500 , which can easily measure indices reflecting arterial stiffness and central arterial pressure with little physical burden using the cuff-oscillometric method. The AVE-1500 can measure the arterial pressure volume index (API), an index reflecting arterial stiffness, and the arterial velocity pulse index (AVI), an index reflecting central arterial pressure. Several studies have clarified the relationship between these indices and arterial stiffness ,9.HT is one of the most important lifestyle-related diseases that causes atherosclerosis. Guidelines for the management of HT have been established by various academic societies worldwide. It is frequently observed that repeated measurement of BP changes its value; therefore, the guidelines recommend using an average of two or three measurements on a single occasion ,11,12. RIt is unknown how repeated cuff-oscillometric inflations with BP measurement are related to arterial stiffness and central arterial pressure and how changes to the API and AVI will be brought about by repeated cuff-oscillometric inflations. Therefore, in the present study, we evaluated the clinical significance of the new non-invasive vascular indices, AVI and API, in outpatients with various clinical backgrounds to explore the potential utility of these two indices by using repeated cuff-oscillometric inflation in actual clinical settings.We performed a cross-sectional, retrospective, observational study at the Yokohama City University Hospital in Japan. The study protocol was registered and approved by the ethics committee of Yokohama City University Hospital in 2015 (B150701005) with notifications for guaranteed withdrawal of participants on the website providing means of ‘‘opt-out,” and due to the non-invasive observational study design, we did not request additional informed consent from the participants.We used a multifunctional BP monitoring device, AVE-1500 , to evaluate the AVI and API in 250 consecutive outpatients in the Department of Medical Science and Cardiorenal Medicine between May 2013 and March 2015. Patients who had atrial fibrillation were excluded from the study. Medical records were reviewed to collect data for each patient’s profile, general status, medical history, laboratory data, and concomitant medications. HT was defined as systolic BP (SBP) of ≥140 mmHg, diastolic BP (DBP) of ≥90 mmHg, or ongoing medical treatment for HT. DL was defined as a low-density lipoprotein (LDL) cholesterol level of ≥140 mg/dl, triglyceride level of ≥150 mg/dl, high-density lipoprotein (HDL) cholesterol level of ≤40 mg/dl, or ongoing medical treatment for DL. Chronic heart failure was defined as a B-type natriuretic peptide level of ≥40 pg/mL caused by cardiovascular disease. Valvular heart disease was defined as valve regurgitation/stenosis of at least a moderate degree. Plasma glucose and triglyceride levels were measured using casual blood sampling without overnight fasting.Both AVI and API are novel arterial indices measurable by a multifunctional BP monitoring device, AVE-1500 , with cuff-oscillometric-based technologies. The AVI is an index of the characteristics of the pulse waveform at high cuff pressures above the maximum BP. Recent findings have revealed that central arterial stiffness and characteristics are strongly reflected in the pulse wave in this pressure region ,9. This The API is an index of arterial pressure–volume characteristics derived from the arterial volume change resulting from cuff pressure relative to the internal and external pressure difference (BP–cuff pressure) applied to the arterial wall. Previous studies have shown that softer vessels show more rapid changes in arterial volume with changes in cuff pressure and that the degree of the slope of this curve varies primarily with the stiffness of the vessel’s media and adventitia. API has developed and indexed a method to stably evaluate the differences in this characteristic .The AVE-1500  is a newly developed device that can non-invasively evaluate arterial stiffness and endothelial dysfunction of the central arteries (AVI) and peripheral arteries (API) using a cuff-oscillometric method in a single BP measurement. AVI and API were measured using an AVE-1500 with the participants in the supine position. Finally, the AVE-1500 can evaluate the conventional SBP, DBP, API, AVI, and pulse rate in a single measurement.Measurements were taken at least thrice for each participant in a quiet temperature-controlled room (24.0–26.8 °C). The average measurements for API and AVI at the time of participant enrollment were used for subsequent analyses.p < 0.05. The relationships between AVI and API and all other variables were analyzed using a linear regression model and Pearson’s correlation coefficient. Statistical analysis was performed using R version 4.1.2 .Data are shown as the mean ± standard deviation for continuous variables and as frequencies and percentages for categorical variables. Analysis for time-series measurements was compared using repeated measures analysis of variance and Friedman rank sum test, with additional analysis using the Holm method. Statistical significance was set at 2, respectively. In Of the 250 enrolled participants, 236 who met the inclusion criteria and did not have missing key data were analyzed. The baseline patient characteristics are shown in The results of the repeated measurements of BP (SBP/DBP), AVI, and API are shown in Univariate and multivariate analyses of SBP change, defined as “∆SBP = (SBP01 − SBP03)/SBP01, were conducted to determine the association between each clinical parameter and measure . In the The AVE-1500 is a newly developed medical device that can simultaneously measure BP and evaluate peripheral arterial stiffness and central arterial pressure ,15. In tSeveral studies have reported changes with repeated BP measurements on a single occasion. Some reports have suggested that the second measurement is lower than the first, and the third measurement is lower than the second ,17. OtheIn previous studies that investigated the relationship between BP and API/AVI on single measurements, almost all the studies we examined showed significant correlations between SBP and API ,22,23,24The results of the analyses of the relationship between the changes in API and SBP with repeat measurements and some variables in the four models showed that SBP and API were related to variables known to be associated with arterial stiffness and atherosclerosis. Although previous studies have examined SBP and API using single measurements (not repeated measurements), significant correlations were noted for age, the prevalence of diabetes, smoking, and sex, and the results were consistent with those of the present study ,21,22,23Although there have been several previous reports on the comparison of BP and API/AVI with risk factors for atherosclerosis in single measurements, to the best of our knowledge, this is the first report of a study investigating the relationship between BP and API/AVI with changes in repeated measurements. Prior to the development of the AVE-1500, BP and vascular stiffness indices such as API/AVI were evaluated separately with different devices to measure them; therefore, the relationship between them was undetermined. However, with the new development of the AVE-1500 BP and pulse wave meter, both can now be compared simultaneously, making it possible to better determine the relationship between BP and central artery index and arterial stiffness. Although the relationship between SBP and API in a single measurement has already been reported in previous studies because of the availability of simultaneous measurements, we confirmed that the relationship was stronger by adding evaluation with repeated measurements in the present study. The reason for the strong relationship between SBP and API may be that API is an index of arterial stiffness, as mentioned above, as well as an index of arterial volume change from the viewpoint of the measurement principle; therefore, it is appropriate from the measurement principle that the changes in API show a strong relation to the changes in SBP. In other words, this study suggests that changes in repeated SBP measurements may be predictive of arterial stiffness and atherosclerosis. However, we cannot conclude whether “SBP decline with repeated cuff-oscillometric pressure” can be used as a substitute for arterial stiffness in this study alone, and we can only propose a hypothesis. It is necessary to examine it from a different perspective, for example, by comparing it with other stiffness modalities.The present study has some limitations. The study was cross-sectional and retrospective, and the sample size was relatively small. In addition, the participants of this study were outpatients of a cardiorenal division. Therefore, future research is required, and we believe that this study only proves the concept of a voluminous subject. However, we have concluded that we might be able to take arterial stiffness and stiffness one step further in the present study by using the new device AVE-1500. The authors should discuss the results and how they can be interpreted from the perspective of previous studies and the working hypotheses. These findings and their implications should be discussed in the broadest possible context. Future research directions may also be highlighted.In conclusion, this study suggests that changes in repeated SBP measurements may be predictive of arterial stiffness and atherosclerosis.