Background: Seizures, neurological deficits, bradycardia, and, in the worst cases, cardiac arrest may occur following incidental durotomy during routine lumbar endoscopy. Therefore, we set out to measure the intraoperative epidural pressure during lumbar endoscopic decompression surgery. Methods: We conducted a retrospective observational cohort study to obtain intraoperative epidural measurements with an epidural catheter-pressure transducer assembly through the spinal endoscope on 15 patients who underwent lumbar endoscopic decompression of symptomatic lumbar herniated discs and spinal stenosis. The endoscopic interlaminar technique was employed. Results: There were six (40.0%) female and nine (60.0%) male patients aged 49.0667 ± 11.31034, ranging from 36 to 72 years, with an average follow-up of 35.15 ± 12.48 months. Three of the fifteen patients had seizures with durotomy and one of these three had intracranial air on their postoperative brain CT. Another patient developed spinal headaches and diplopia on postoperative day one when her deteriorating neurological function was investigated with a brain computed tomography (CT) scan, showing an intraventricular hemorrhage consistent with a Fisher Grade IV subarachnoid hemorrhage. A CT angiogram did not show any abnormalities. Pressure recordings in the epidural space in nine patients ranged from 20 to 29 mm Hg with a mean of 24.33 mm Hg. Conclusion: Most incidental durotomies encountered during lumbar interlaminar endoscopy can be managed without formal repair and supportive care measures. The intradural spread of irrigation fluid and intraoperatively used drugs and air entrapment through an unrecognized durotomy should be suspected if patients deteriorate in the recovery room. Ascending paralysis may cause nausea, vomiting, upper and lower motor neuron symptoms, cranial nerve palsies, hypotension, bradycardia, and respiratory and cardiac arrest. The recovery team should be prepared to manage these complications. Endoscopic spine surgery is much more widely practiced than just five years ago ,2,3. TheWith the surgical volume rising, publications on the incidence and management of complications of endoscopic lumbar decompression procedures have appeared in print, alerting spinal surgeons interested in implementing these innovative minimally invasive surgeries into their program to their potential pitfalls ,22,23,24A recent survey study among 97 spine surgeons suggested that durotomy rates are much higher among less experienced surgeons (1% to 10%) than the 0.1% rate previously reported by expert surgeons with thousands of cases of clinical experience. In that same study, some 70% of durotomies were reported by 20.4% of participating surgeons, and only 29% of surgeons had more than 10–15 years of clinical work experience . In contThis study aims to raise awareness of these durotomy-related complications, which likely occur at a higher rate than recognized by inexperienced endoscopic spine surgeons. The authors had three cases of postoperative seizures, transitory neurological deficits, and intracranial air entrapment, which motivated this study, in which the authors present their intraoperative epidural pressure measurements encountered during routine interlaminar endoscopies to make the case that these lesions should be suspected if an unexplained drop in blood pressure, seizures, or even cardiac arrest is encountered in the recovery room.Patients were enrolled into this retrospective observational sequential cohort study between March 2014 and April 2021 they had interlaminar decompression for herniated disc and spinal stenosis. There were 6 (40.0%) female and 9 (60.0%) male patients with an average age of 49.0667 ± 11.31034, ranging from 36 to 72 years. The average follow-up was 35.15 ± 12.48 months.Patients were included in the study if they presented with continuous cervical or lumbar radicular stemming from a herniated disc or spinal stenosis in the foramina or lateral spinal canal. Symptoms were required to be present for at least six months or more before the consultation, despite a recommended three-month physiotherapy regimen and medical and interventional pain management. Patients were further evaluated for clinical history and physical examination findings consistent with a disc herniation, including sensory deficits, motor weakness, and the presence of any upper and lower motor neuron signs. Necessary diagnostic imaging included standing lumbar X-rays, magnetic resonance imaging (MRI), or computed tomography (CT) scans. Patients were excluded if they had any underlying neurological condition or spinal-cord-compression-related upper motor neuron symptoms affecting their gait cycle and locomotion. Additional exclusion criteria for endoscopic decompression were severe bony central canal or excessive foraminal stenosis, excessive coronal and sagittal plane deformities above 40 degrees, conus medularis syndrome, systemic neuropathy or spinal tumors, blood dyscrasia, pregnancy, allergies, mental handicaps, or psychiatric conditions precluding adequate communication or language problems.The authors chose an interlaminar approach to cervical and lumbar disc herniation and any associated soft tissue and bony stenosis in the lateral recess . The patThe system’s design was optimized to allow the complete functionality of power instruments with exceptional visualization, allowing the authors to readily recognize even the smallest durotomies. The endoscopic instruments and power burrs used had a characteristic narrow profile that minimizes trauma to the soft tissues, ligamentum flavum, and neural structures. The surgery entails enlarging the interlaminar window with a power burr by performing a laminotomy at the trailing edge of the rostral lamina. In addition, partial resection of the inferior articular process (IAP) is typically required to access the ligamentum flavum. The latter must be opened with a blunt dissector and subsequently removed using endoscopic forceps and a Kerrison rongeur. The neural structures are retracted, and the disc herniation and any other bony or soft tissue stenoses are removed. A radiofrequency probe can be used for hemostasis and any frayed soft tissue shrinking. After completing the decompression, the cannula will be turned to visualize the neural structures and control the decompression by a palpation hook. All surgeries were performed by highly experienced endoscopic spine surgeons.For the intraoperative epidural hydrostatic pressure measurements at the endoscopic decompression site, a 1.8 mm diameter transparent catheter with three lateral orifices was guided down the endoscopic working channel and held right next to the surgical instrument used to decompress the herniated disc. This epidural/arterial catheter was attached to an Abbott Medex Disposable IBP Transducer (#IP-MX-300), plugged into a Dräger—the Perseus A500 anesthesia machine with a monitor. After the completion of decompression, the catheter was positioned close to the dural sac or right next to the incidental dural tear if one was encountered .Epidural hydrostatic pressures were taken at least three times in the same decompression area with and without concomitant use of the radiofrequency probe to see whether temperature variations caused by the probe would cause hydrostatic pressure changes in the epidural space. Pressure measurements were printed out and manually transferred into an excel database from which they were averaged and analyzed statistically as described below. Our epidural hydrostatic pressure measurements have their foundations are in prior work .Postoperatively, patients were followed during the first 6–12 weeks after their surgery to monitor their recovery and manage any postoperative problems. At the final follow-up, clinical outcomes were assessed using the visual analog pain score (VAS) for arm- or leg pain . DescripOur series included three patients with seizures who also had a recognized durotomy. One of these three patients had intracranial air on his postoperative brain CT after lumbar endoscopy . AnotherThe remaining patient of these three developed spinal headaches and diplopia on postoperative day one when her deteriorating neurological function was investigated with a brain computed tomography (CT) scan showing intraventricular hemorrhage consistent with a Fisher Grade IV subarachnoid hemorrhage  that didt-testing with a 95% confidence interval of a difference lower limit of 4.55789 and an upper limit of 5.97544 . The intraoperative pressure recordings in the epidural space were averaged for each patient and ranged from 20 to 29 mm Hg. The mean epidural pressure for the entire patient series was 24.33 ± 3.13 mm Hg. Sealing the endoscope’s working channel did not substantially raise the recorded epidural pressure. It never exceeded 30 mg Hg  and lateral recess stenosis. Interlaminar endoscopic decompressions were exclusively performed in all 14 of the 15 study patients at the L4/5 and L5/S1 levels. The remaining patient in our series underwent interlaminar C6/7 endoscopic discectomy surgery. All patients underwent single-level unilateral operations. The demographic and clinical outcome data are listed in 30 mg Hg .Endoscopic spine surgery is gaining popularity for structures beyond the lumbar spine. The worldwide publishing activity reflects an increasing surgical volume. While the preference for a particular surgical approach may vary from surgeon to surgeon, a recent survey indicated that transforaminal and interlaminar endoscopic approaches to the lumbar spine are among the most popular techniques . The traAs illustrated by our small cohort study, the actual rate of coincidental durotomies may be higher than reported in the literature. Therefore, the authors wanted to call attention to some of the graver clinical complications observed during their long-standing carrier as endoscopic spine surgeons. Many of this article’s authors have performed endoscopic spinal decompression surgery for more than 15 years and have encountered several durotomies. The literature suggests that the durotomy rate across the board is about 1% ,41,42,43In this article, the number one item on the authors’ agenda is to raise awareness for incidental durotomies during routine spinal endoscopy and alert the endoscopic spine surgeon to some of the more far-reaching consequences that could destabilize the patient’s neurological, respiratory, or cardiovascular system. Our series had three patients with severe reactions to the incidental durotomy: all had seizures one of which had free air in the brain, one suffered cardiac arrest, and another developed diplopia and had blood in the brain similar to a Fisher grade IV subarachnoid hemorrhage. The unintended consequences of overly aggressive endoscopic decompression surgery and the delayed institution of medical and supportive care measures could be far-reaching. Therefore, the authors were motivated to measure the typical epidural pressures during routine lumbar interlaminar endoscopic decompression surgery when instruments are introduced, removed, and reintroduced constantly. Since the intraoperatively measured irrigation pressure ranged between 20 to 29 mm Hg with an average of 24.33 mm Hg and is consequently higher than the intradural and intravenous pressure typically reported at 5 – 15 mg Hg; it seems reasonable to assume that irrigation fluid – in most cases 0.9% normal saline – and blood may enter the patient’s intradural space and travel via the neuroaxis into the brain’s subarachnoid space and ventricles. From the durotomy site, it can spread and flow rostrally where it can cause hydrocephalus. p = 0.24) with a 17.3 ± 8.62 mm Hg mean CEP when establishing the access portal and working space. However, the mean CEP increased to 35.1 ± 11.44 mm Hg when the epidural space was connected to the outer working space. The maximum recorded CEP was 45.2 ± 21.92 mm Hg seconds after opening the epidural space [A recent spinal endoscopy study investigated the cervical epidural pressure (CEP) in 20 patients undergoing single-level biportal endoscopic lumbar discectomy (BELD) . The autal space . The autIn the cervical durotomy patient, the intradural spread of blood and irrigation fluid caused the intensivist and neurosurgical team to initially think of an aneurysmal bleeding or an AV angioma since it resembled its classic appearance of a Fischer grade IV subarachnoid bleeding on computed tomography (CT) scanning of the brain ,45. TheyThe type of anesthesia employed during spinal endoscopy also deserves some discussion. Many surgeons operate on patients under local anesthesia and sedation. Others perform it on patients under general anesthesia and use local anesthesia of the surgical tract and foramen to reduce intraoperative stimulation. Others perform the endoscopic operation on patients under epidural anesthesia in the elderly with COPD and other medical comorbidities. The intradural spread of the commonly used local anesthetics bupivacaine and lidocaine effectively causes ascending paralysis from spinal anesthesia. Complications from ascending paralysis include but are not limited to nausea, vomiting, upper and lower motor neuron symptoms, cranial nerve palsies, hypotension, bradycardia, and respiratory and cardiac arrest. While a discussion of the most appropriate type of anesthesia to use for lumbar endoscopy may be beyond the scope of this article, surgeons should consider an unrecognized durotomy with an intradural spread of fluid, air, and intraoperatively applied drugs if their patient displays some of the above-described symptoms that seem out of proportion with the type of operation performed. A limited work-up with a head CT to rule out other intracranial pathologies may be indicated. Most patients will recover uneventfully with supportive care measures. Our study is limited by its observational nature and small patient number. However, the few patients with serious complications we treated prompted us to perform the epidural pressure measurements reported herein.The authors’ study illustrated that the pressure associated with interlaminar irrigated lumbar endoscopy measured at the epidural decompression site is relatively low, averaging 24.33 mm Hg. However, it is above the commonly found intradural pressure of 5 to 15 mm Hg . Inciden


The accuracy of TcCO2 has not been established in anesthetized apneic patients with obesity. In this secondary publication, we present a methods comparison analysis of TcCO2 with the gold standard arterial PCO2, in adult patients with body mass index (BMI) > 35kg/m2 who were randomized to receive high flow or low flow nasal oxygenation during post-induction apnea. Agreement between PaCO2 and TcCO2 at baseline, the start of apnea and the end of apnea were assessed using a non-parametric difference plot. Forty-two participants had a median (IQR) BMI of 52 (40–58.5) kg/m2. The mean (SD) PaCO2 was 33.9 (4.0) mmHg at baseline and 51.4 (7.5) mmHg at the end of apnea. The bias was the greatest at the end of apnea median  1.90 mmHg . Findings did not suggest significant systematic differences between the PaCO2 and TcCO2 measures. For a short period of apnea, TcCO2 showed inadequate agreement with PaCO2 in patients with BMI > 35 kg/m2. These techniques require comparison in a larger population, with more frequent sampling and over a longer timeframe, before TcCO2 can be confidently recommended in this setting.Transcutaneous carbon dioxide measurement (TcCO TcCO2 monitoring offers a potential benefit in this context but has not been studied in apneic obese patients.Transcutaneous COlunteers . The use2 with PaCO2 in patients with body mass index (BMI) > 35 kg/m2 in a perioperative setting have reported good accuracy and precision [2, comparing safe apnea time between those administered high flow nasal oxygen and those with standard nasal prongs [2 measurements obtained from arterial blood samples (PaCO2) and transcutaneous monitoring (TcCO2) at three time points in obese patients under apneic conditions.Studies comparing the accuracy and precision of TcCOl prongs . We aime2 was stated in the trial registration and included in the initial ethical approval. We tested the hypothesis that the use of Optiflow THRIVE™  at 70 L/min would increase the time to hypoxia and increase carbon dioxide elimination in apneic obese patients, when compared with 4 L/min oxygen administered via standard nasal prongs. The 42 participants were undergoing laparoscopic bariatric surgery, had BMI ranging from 38 to 68 kg/m2 and a mean (SD) PaCO2 at the end of apnea of 51.4 mmHg (7.5) (range 27.2–64.8 mmHg). The full inclusion and exclusion criteria and detailed methodology are available [This report comprises a secondary publication based on additional data that were collected during a single-center randomized controlled trial undertaken between September 2018 and May 2019 at the Royal Brisbane and Women’s Hospital . The tri2 1.0 at 10 L/min.All participants were monitored according to local standards, with the addition of invasive radial arterial catheters. Participants were randomized to Group T, in which they were administered high flow nasal oxygen using Optiflow THRIVE™ at 70 L/min, humidified using the Fisher & Paykel 950 humidifier, providing 70% relative humidity (oxygen concentration delivered at 100%); or to Group N, in which they were administered standard nasal prongs at 4 L/min . In both groups, pre-oxygenation occurred in the ramped position and with FiOInduction medications consisted of an opioid, propofol, and rocuronium with dosing at the discretion of the anesthetist. Anesthesia maintenance was achieved using propofol target controlled infusion. The patients were bag-mask ventilated to achieve an end-tidal oxygen fraction > 0.9. At this point, nasal oxygenation was applied according to group allocation and airway patency maintained using an oropharyngeal airway and two-handed airway maneuvers .2 was measured using the TCM5 FLEX transcutaneous monitor TC Sensor 92 and 32mm TOSCA fixation ring . The device sensor was calibrated for each patient, to reach the required temperature of 43.5 degrees Celsius. The participant’s skin was prepared with 70% isopropyl alcohol prior to placing the fixation ring over the clavicle and a small amount of contact gel applied before sensor attachment. Sensor membranes were replaced every three days. Arterial blood gas samples and TcCO2 measurements were obtained at baseline (prior to induction to anesthesia), at the start of apnea (T0), and the end of apnea (Tend). Tend was defined as the time at which peripheral arterial oxygen saturations (measured by pulse oximetry) dropped to ≤ 95% or a total of 360s of apnea, whichever occurred first. Participant characteristics were collected and these included age, sex, BMI, and co-morbidities including obstructive sleep apnea.Clinical observations and sampling occurred while the participants were anesthetized and apneic. TcCO2 post apnea or the rate of increase of PaCO2 during apnea. Therefore, for this methods comparison analysis, 42 participants were analyzed as one group. Agreement between PaCO2 and TcCO2 at the three time points was assessed using a non-parametric difference plot. Bias was reported as the median of the mean differences for each participant, with 95% confidence intervals (CI). The 95% limits of agreement (LOA) were estimated by the 2.5th and 97.5th percentiles with 90% CI, using quantile regression with cluster-robust bootstrap inference [The sample size was a convenience sample of 42, determined according to the primary outcome of the original study [2. Twenty-two (52.4%) were diagnosed with obstructive sleep apnea. Additional characteristics are reported elsewhere.4 In 14 (33.3%) participants, the apneic period lasted ≥ 360s. In the remaining 28, the mean (SD) time to desaturation to ≤ 95% (apneic period) was 190.3s (73.7). The mean (SD) PaCO2 was 33.9 (4.0) mmHg at baseline and 51.4 (7.5) mmHg at the end of apnea.42 participants had a mean (SD) age of 50.4 (11.1) years, 33 (78.6%) were female and they had a median (IQR) BMI of 52 (40–58.5) kg/m2, TcCO2 had a small upward bias (measurement greater than PaCO2) at baseline and small downward bias (measurement lower than PaCO2) at time points T0 and Tend  at baseline was −1.00 mmHg , at T0 was 1.10 mmHg , and at Tend was 1.90 mmHg . Figure 2 monitoring in apneic patients with obesity. Our results suggest that for a short period of apnea, TcCO2 monitoring may be inaccurate when used to estimate PaCO2 in patients with BMI > 35 kg/m2. The bias LOA were outside the recommended range of ± 7.5 mmHg, with wide 90% CIs at the start and end of apnea. The accuracy of TcCO2 in anesthetized apneic patients has been previously reported, but in populations with normal BMI [2 over longer apneic periods , these  highest . Their l highest .2 measurements offer a convenient and non-invasive method of detecting hypercapnia in non-obese, anesthetized, apneic patients. There remain limitations of the method that must be considered [2 measurements in patients with obesity have placed the sensor on the forearm to avoid increased subcutaneous tissue [2 measurement can be confidently recommended for patients with obesity under apneic conditions.TcCOnsidered . Correct


It is of increasing importance to understand and predict changes to the systemic and pulmonary circulations in pulmonary hypertension (PH). To do so, it is necessary to describe the circulation in complete quantitative terms. Characteristic impedance (Zc) expresses opposition of the circulation to pulsatile blood flow. Evaluation of systemic and pulmonary Zc relationships according to PH classification has not previously been described. Prospective study of 40 clinically indicated patients referred for CMR and RHC . CMR provided assessment of ascending aortic (Ao) and pulmonary arterial (PA) flow, and RHC, central Ao and PA pressure. Systemic and pulmonary Zc were expressed as the relationship of pressure to flow in the frequency domain. Baseline demographic characteristics were well‐matched across PH subclasses. In those with a mPAP ≤25mHg, systemic Zc and SVR were >2 times higher than pulmonary Zc and PVR. Only Pre‐cPH was associated with inverse pulsatile (systemic Zc 58 [45–69] vs pulmonary Zc 70 [58–85]), but not steady‐state (SVR 1101 [986–1752] vs. PVR 483 [409–557]) relationships. Patients with CpcPH and IpcPH had concordant pulsatile and steady‐state relationships . Measurement of, and the relationship between, systemic and pulmonary Zc in patients according to PH sub‐classification has not previously been described. Systemic Zc was routinely higher than pulmonary Zc, except in patients with newly diagnosed Pre‐cPH, where inverse pulsatile but not steady‐state relationships were observed. Systemic and pulmonary impedance relationships according to pulmonary hypertension classification. To do so, however, requires describing the arterial circulation in complete quantitative terms—including both steady‐state and pulsatile components. Whereas systemic vascular resistance (SVR) and pulmonary vascular resistance (PVR) are measures of steady‐state load, systemic and pulmonary impedance (Z) express the relationship between pulsatile pressure and flow  and pulmonary artery (PA) of humans meant that Z estimation was seldom performed outside of the research setting. With advances in noninvasive imaging techniques, the prognostic value of systemic characteristic impedance (Zc) as pulsatile pressure–flow estimation has now been described in healthy human subjects and a variety of cardiovascular disease states using simultaneous applanation tonometry (AT), echocardiographic and/or cardiac magnetic resonance (CMR) techniques  and steady‐state  relationships in a cohort of clinically indicated patients undergoing routine right heart catheterization (RHC) and CMR assessment. We hypothesized that the PA impedance spectrum would be qualitatively similar to that of the systemic circulation, albeit with a smaller ratio of peripheral resistance and characteristic impedance, except in those patients with precapillary pulmonary hypertension (Pre‐cPH).22.1All new patients with dyspnea and suspected PH referred for RHC over a 12‐month period, with a concurrent clinical indication for CMR, were screened for participation in this study. Forty patients were subsequently enrolled. Indications for CMR in addition to RHC included RV assessment in known or suspected PH, pretransplantation assessment, evaluation of cardiac anatomy and physiology in patients with underlying structural heart disease, and/or advanced heart failure assessment. The most common reasons for exclusion included: unable to complete both RHC and CMR protocol, concurrent pulmonary vasodilator or inotrope therapy (included patients were therefore newly diagnosed and/or treatment naive), evening administration of any medication with a 24‐h systemic vasodilatory effect, significant intracardiac shunt (Qp:Qs > 1.5), or significant (>2+) valvular pathology including tricuspid regurgitation. Morning prescription of any medication with a systemic vasodilatory effect was withheld while the patient was fasted until completion of the RHC/CMR protocol. Each patient underwent same day RHC, followed directly thereafter by CMR.−5 and mean postcapillary wedge pressure (mPAWP) ≤ 15 mmHg. Isolated postcapillary PH (Ipc‐PH) of left‐sided heart disease was defined as a mPAP > 20 mmHg with a PVR < 240 dynes s cm−5 and mPAWP of >15 mmHg. Combined pre‐ and postcapillary PH (Cpc‐PH) was defined as a mPAP > 20 mmHg and PVR > 240 dynes s cm−5 and mPAWP > 15 mmHg . Local hospital Human Research Ethics committee approved the study. Research was performed in accordance with local hospital guidelines and the Declaration of Helsinki. Informed consent was obtained from all participants prior to enrolment.Precapillary PH (Pre‐cPH) was defined as a mean PA pressure (mPAP) > 20 mmHg with a PVR > 240 dynes s cm2.2CMR studies were performed in a 3T magnet with dedicated phased‐array cardiac coil during successive end‐expiratory breath‐holds . Steady‐state free precession (SSFP) images covering the entire LV and RV volumes were first acquired using a standard protocol. In addition, SSFP images were acquired during breath‐hold perpendicular to the ascending aorta and PA. Average scan parameters were repetition time (TR)/echo time (TE) of 3.8/1.6 ms, flip angle 45°, views per segment 8, slice thickness 8 mm, pixel spacing 0.76 mm, acquisition matrix 224 × 192, and temporal resolution 10 ms. Ascending aorta and PA flow velocity data were obtained during breath‐hold at the level of, or prior to, the bifurcation of the main pulmonary artery (MPA) using through plane phase‐contrast quantitative flow (PC Qflow) imaging. Average scan parameters were TR/TE of 4.3–4.6/2.1–2.7 ms, flip angle 15°, slice thickness 8 mm, pixel size 1.25–2.05 mm, acquisition matrix of 256 × 208, views per segment 2, and effective temporal resolution 17 ms. Encoding velocity was adjusted according to known aortic valve gradient or pulmonary artery systolic pressure (sPAP) to minimize aliasing artifact. All CMR analyses were performed using CVI 42 .2.3Blood pressure was measured with brachial cuff sphygmomanometer just prior to arterial tonometry (AT) pressure data acquisition. Arterial tonometry was performed using a Millar SPT‐301 high fidelity arterial tonometer  in the radial artery directly prior to or after CMR scan. Using the SphygmoCor 8.1 system , radial AT was calibrated to brachial sphygmomanometer cuff systolic pressures (SP) and diastolic pressures (DP), averaged over 10 cardiac cycles, and then converted to aortic pressure waveforms using a validated transfer function described previously  (expressed as dynes s cm−5) was calculated as: PVR = (mPAP [mmHg] − PAWP [mmHg]) − CO (L/min) × 80, where mPAP represents mean pulmonary arterial pressure, PAWP represents pulmonary artery wedge pressure, and CO represents cardiac output obtained by the thermodilution method. The PA pressure waveform was routinely obtained in the main PA 0.5–1 cm distal to the pulmonic valve as confirmed by echocardiography and fluoroscopic assessment. These waveforms were acquired using S5 Collect software with a sampling frequency of 50 Hz. Consecutive signals of PA pressure during 15–20 s without large variation were selected. Pressure signals were divided into each beat according to the R wave of ECG, if available, or the maximum value of the first derivative of PA or RV pressure, followed by ensemble average by 10–15 pressure beats as described previously  via the right internal jugular vein. The fluid‐filled catheters and manometer system were routinely calibrated pre‐measurement to ensure reliability. RHC was performed by a single procedural operating team (KK/EK) with more than 15 years of experience. RHC‐derived measurements included right atrial pressure (RAP), sPAP, diastolic PAP (dPAP), mean PAP (mPAP), cardiac output (CO), and pulmonary artery wedge pressure (PAWP). CO measurement was performed using the thermodilution method, expressed as the average of 3–5 consecutive measurements . PAWP measurement was performed at end‐expiration, expressed as the average of 3–5 consecutive measurements (mPAWP) . Systemic vascular resistance was calculated as: SVR = (mAP [mmHg] − RAP [mmHg]) − CO (L/min) × 80, where 2.5−5) were then estimated by deconstructing aortic and PA pressure and flow waveforms into their component harmonics for frequencies up to 8–10 Hz, and its modulus averaged between 2 and 10 Hz . Normally distributed variables are presented as means ± SD; nonnormally distributed variables are presented as median (interquartile range [IQR]), unless otherwise specified. Normality was tested by assessing the mean, median, and standard deviation, and a quantile–quantile plot. Student's 3−5, and mPAWP < 5 mmHg and were assigned to a separate group. Of those with PH, 16 (40%) patients had Pre‐cPH, eight (20%) Ipc‐PH, and eight (20%) had Cpc‐PH. One patient assigned to the Ipc‐PH group had a past history of CTEPH treated successfully with pulmonary endarterectomy, with a more proximate diagnosis of heart failure with preserved ejection fraction (HFpEF). Baseline demographic data are reported in Table The mean age of the study population was 56 ± 18 years, 28 (70%) females. Twenty‐four (60%) patients had evidence of Pre‐cPH or Cpc‐PH on RHC, while eight (20%) had left‐sided heart disease and the remaining eight (20%) patients with a mPAP < 25 mmHg, PVR < 240 dynes s cm3.1p = 0.79). There was no significant difference in SVR according to PH subclassification (p = 0.96). SVR was highest in patients with Cpc‐PH (1640 [1213–1942] dynes s cm−5) and lowest in in patients with Ipc‐PH  . PVR was higher in all patients with PH except for those with Ipc‐PH   and Pre‐cPH (42 [39–50] mmHg) and lowest in patients with left‐sided heart disease from Ipc‐PH , the mean PA pressure can increase fourfold in patients with PH and this is accompanied by arterial dilatation and disturbed flow–velocity profile (Chemla et al., In general terms, Z is calculated from the ratio of the pressure difference across the system under study and the flow through the system (Murgo et al., 4.2Murgo et al. over half a century ago, PVR was demonstrated to be approximately 8% lower than SVR, and pulmonary Zc approximately 43% lower than systemic Zc (Murgo & Westerhof, Relative to the systemic circulation, the normal pulmonary vascular bed is a low‐pressure, low‐resistance, and high‐compliance system capable of accommodating large increases in blood flow with minimal elevations of PA pressure (Verhoeff & Mitchell, 4.3Impedance estimation is highly sensitive to any changes to the human circulation, either within a given subject under certain physiological conditions, as a result of pharmacological interventions, or between groups of subjects under different physiological or pathological states (Laskey et al., As PH develops, the vascular bed becomes a high‐pressure, high‐resistance, and low‐compliance system (Chemla et al., −5 is comparable with a prior invasive study by Laskey et al. (Laskey et al., In this study, unique pressure–flow relationships were observed in patients with PH. For patients with Pre‐cPH, a pulmonary Zc value of 70 [58–85] dynes s cmAside from study of pulmonary Zc patterns in healthy individuals and Pre‐cPH, limited work has been done to evaluate pulmonary Zc in patients with PH secondary to mitral stenosis or left ventricular failure. Patterns of pulmonary Zc in patients with mitral stenosis and/or left ventricular failure have previously demonstrated an increase in the resistive component of modulus, an increase in frequency of the first minimum of the modulus and of phase cross over, as well as an increase in pulmonary Zc (Chen et al., 4.4p > 0.05; Table We have developed a hybrid method by which systemic and pulmonary Zc may be measured during routine CMR and RHC evaluation. Our method combines “gold standard” invasive and noninvasive tools to measure pressure, volume, and flow, which are then combined to provide high‐quality impedance assessment. Nonetheless, some limitations do exist. Six patients in the mPAP ≤ 25 mmHg had a mPAP between 20 and 25 mmHg, meaning we were not able to assign this group as a “healthy” control population. As per inclusion criteria, patients were not on any concurrent pulmonary vasodilator, inotrope therapy, or systemic vasodilatory therapy at time of study and were therefore, in most part, newly diagnosed and/or treatment naive. We were not able to perform RHC simultaneously with CMR due to technical constraints. It is possible that an alteration in hemodynamic loading conditions occurred between RHC and CMR study that may have affected results to an extent, however, every care was taken to ensure stable supine resting conditions for both measurements and no significant difference in HR or BP between RHC and CMR was observed (both 5This study has demonstrated for the first time, inverse pulsatile, but not steady‐state, relationships in patients with newly diagnosed Pre‐cPH. The value of routine Zc measurement in better defining patient prognosis, and of predicting clinical outcomes of medical and interventional therapies remains to be determined. What is clear, is that the newfound ease of noninvasive Zc estimation by CMR, is expected to yield further information about systemic/pulmonary relationships, above and beyond conventional resistance indices alone.Sara Hungerford, Katherine Kearney, and Ning Song: All aspects of study writing and design. Eugene Kotlyar, Nicole K. Bart, Edmund Lau, Andrew Jabbour, Christopher Simon Hayward, David William Marshall Muller: Study design, supervisor support, and review of article. Audrey Adji: All aspects of study writing and design.The study was approved by the local hospital Human Research and Ethics Committee.Dr Katherine Kearney and Dr Ning Song are supported by an Australian Government research training program grant. All other authors have reported that they have no funding disclosures relevant to the contents of this article to disclose.All authors have reported that they have no relationships relevant to the contents of this paper to disclose.


Night shift work has been found to be associated with a higher risk of cardiovascular and cerebrovascular disease. One of the underlying mechanisms seems to be that shift work promotes hypertension, but results have been variable. This cross-sectional study was carried out in a group of internists with the aim of performing a paired analysis of 24 h blood pressure in the same physicians working a day shift and then a night shift, and a paired analysis of clock gene expression after a night of rest and a night of work. Each participant wore an ambulatory blood pressure monitor (ABPM) twice. The first time was for a 24 h period that included a 12 h day shift (08.00–20.00) and a night of rest. The second time was for a 30 h period that included a day of rest, a night shift (20.00–08.00), and a subsequent period of rest (08.00–14.00). Subjects underwent fasting blood sampling twice: after the night of rest and after the night shift. Night shift work significantly increased night systolic blood pressure (SBP), night diastolic blood pressure (DBP), and heart rate (HR) and decreased their respective nocturnal decline. Clock gene expression increased after the night shift. There was a direct association between night blood pressure and clock gene expression. Night shifts lead to an increase in blood pressure, non-dipping status, and circadian rhythm misalignment. Blood pressure is associated with clock genes and circadian rhythm misalignement. Shift work has been found to be associated with a higher risk of cardiovascular and cerebrovascular disease ,2. The mThe negative effects of night shifts on health seem to be due to the disruption of the normal 24 h circadian rhythm. This rhythm is based on a master clock that resides in the suprachiasmatic nucleus of the hypothalamus, which is entrained by light, and on peripheral clocks that integrate signals coming from the master clock as well as the periphery, such as light and food . The cloA person working at night and sleeping during the day suffers from a state of desynchrony, being unable to undergo complete adaptation because of the many external stimuli promoting a day-oriented schedule, as evidenced by the lack of complete adaptation of the core body temperature, melatonin levels, and cortisol rhythm . DesynchThis observational study was carried out in a group of internists with the aim of performing a paired analysis of 24 h blood pressure in the same physicians working a day shift and then a night shift, and a paired analysis of clock gene expression after a night of rest or a night of work.The general characteristics of the 25 internists on shift work are reported in The paired analysis of ABPM results showed that day diastolic blood pressure (DBP) and day heart rate (HR) were higher when physicians were at work b,c. NighBMAL, CLOCK, PER1, PER2, and PER3 , interleukin (IL)-1β, IL-6, and tumor-necrosis factor (TNF)-α after a night of rest as compared to a night of work . On the and PER3 a–e, whert change f–i.PER3 gene expression on the morning after. On the night shift day, there was a direct correlation between night SBP and night DBP and PER2 gene expression on the morning after. In addition, PER2 gene expression on the morning after the night shift was related to the dipping during the recovery period. Otherwise, dippings were not related to age, sex, BMI, or workload.Focusing on night blood pressure, night SBP and night DBP were related to sex  and BMI PER3 gene expression on the cnt day and the associations between night SBP and DBP and PER2 gene expression on the night shift day  as a technique to identify predictors of blood pressure, as shown in the variance importance plots . The maiPER3, and sex , such that participants had a blood pressure and heart rate non-dipping profile during their night shift. Blood pressure has a circadian rhythm, and, at night, it generally decreases by 10–20%, which is known as dipping. The loss of this blood pressure nocturnal decline is known as non-dipping and it is associated with metabolic and cardiovascular disease ,12,13,14Our data show that during the night shift, SBP increased by an average of 10.3 mmHg and DBP increased by an average of 12.1 mmHg, which is consistent with previous work demonstrating an association between shift work and blood pressure. In general, shift workers seem to be more likely to have hypertension  . In addiBMAL, CLOCK, PER1, PER2, and PER3, which is consistent with circadian rhythm misalignment. The human 24 h circadian rhythm is controlled by a master clock in the suprachiasmatic nucleus (SNC) and by peripheral clocks that integrate signals coming from the master clock as well as the periphery, such as light and food [PER1, PER2, and PER3) and Cryptochrome (Cry homologs CRY1 and CRY2). Once they are translated, PER and CRY form a heterodimer that stops the transcription of BMAL1 and CLOCK. Once PER and CRY are degraded, BMAL1 and CLOCK transcription begins again. In normal conditions, PER1, PER2, and PER3 transcripts peak during the biological night, while BMAL1 transcripts peak during the biological day [PER2 upregulation in a different time period [Bmal1 and Per1 between 0 and 6 am, while overall rhythmicity was preserved [Our study also showed that after a night shift, there was a significant increase in the expression of most clock genes, namely and food . These iical day . It has e period . Additioreserved .PER3 expression both on the cnt and night shift day. By contrast, night workload as assessed by steps, the number of calls, and admissions was not related to the blood pressure level, possibly because light exposure (which is experienced during night shifts) may be a sufficient suppressor of circadian rhythm [Per1 in hypertensive male mice resulted in lower blood pressure as compared to wild-type mice, suggesting that loss of Per1 was protective in the setting of hypertension [Per1 is a positive regulator of sodium reabsorption genes [PER1 was upregulated in the kidneys of hypertensive subjects [CLOCK, PER1, PER3, and CRY1 [CRY1 and CRY2 polymorphisms and blood pressure in patients with metabolic syndrome [PER2 and BMAL1 polymorphisms and the non-dipper phenotype in 372 young hypertensive patients [BMAL1 in 1304 individuals showed that two BMAL1 haplotypes were associated with type 2 diabetes and hypertension [It has been argued that circadian misalignment has an impact on some physiological parameters, such as blood pressure, which is one of the mechanisms whereby shift work can have negative health consequences . In our n rhythm ,24, whicn rhythm . Deletiortension . Cell cuon genes ,28. Addisubjects . In addisubjects , and sigand CRY1 . Other ssyndrome , or assopatients . A genetrtension .Going back to our study, and its strengths and limitations, its strengths include recruitment of physicians working night shifts in the same setting/hospital and the possibility to perform paired analyses (as the same physicians were tested twice). On the other hand, limitations include the age of physicians (median age was 33), as it is possible that results would differ in older cohorts; the lack of blood sampling and biochemical measurements at night; and the small sample size. The number of physicians recruited did not allow us to assess the impact of other variables on blood pressure in the model for repeated measures, so larger studies are needed to confirm and extend our findings. In particular, we believe that, in future studies, it would be useful to add gene expression and biochemistries at midnight to gain more information on circadian rhythm misalignment and possible hormonal changes during night shifts.PER2-3 expression. Our data provide further evidence on the negative impact of night work on cardiovascular health as well as on the association between circadian clock misalignment and blood pressure control. These data support interventions aiming to improve sleep and recovery and reduce fatigue, contributing to the sustainable employability of healthcare workers [In conclusion, in line with previous work, our study shows that night shift increased blood pressure leading to a non-dipping blood pressure status, which is a cardiovascular disease risk factor. Night shifts increased clock gene expression on the morning after, consistent with circadian misalignment, and there was an independent association between blood pressure during the night shift and  workers .This is an observational cross-sectional study, whose aims were (i) to perform a paired analysis of 24 h blood pressure in the same physicians working a day shift and then a night shift; (ii) to perform a paired analysis of clock gene expression after a night of rest or a night of work.Participants were consecutively recruited among physicians working in the Department of Internal Medicine . Inclusion criteria were aged between 25 and 60 years; working night shifts in the same Department of Internal Medicine; consent to take part in the study. Exclusion criteria were history of cardiovascular or endocrine disorders; children with age <2 years; return to work after holidays in the 3 weeks before enrollment; shifts in COVID-19 wards.After providing the informed consent, each participant wore an ambulatory BP monitor (ABPM) twice. The first time  was for a 24 h period (from 09.00 to 09.00) that included a 12 h day shift (08.00–20.00) and a night of rest. The second time  was for a 30 h period (from 09.00 to 13.00) that included a day off, a night shift (20.00–08.00), and a period of rest (08.00–13.00) the following day. The ABPM was a SpaceLabs Oscillometric Model 90207 . The ABPM was applied by a resident physician, who evaluated and calibrated the readings at time of placement and at removal. Before its placement, we measured anthropometric parameters and collected the history of each participant. Participants were also asked to keep a diary of their activities, write down when they slept on the CNT day, and to provide details of their activity during the night shift. In particular, participants were asked to write down the number of steps, the number of calls they received, and admissions they had to take care of during the night shift. In addition, they were asked to fast from 24.00 to 09.00 on both the cnt and ns days. When the ABPM was removed, participants underwent blood sampling after fasting to measure glucose, cortisol, melatonin, CRP, IL-1β, IL-6, and TNF-α and to evaluate clock gene expression.Dipping was calculated as follows: (mean wake hours BP − mean sleep BP divided by mean wake hours BP) × 100. Non-dipping status was defined as sleep hours BP or HR dipping of less than 10% .This study was conducted in accordance with the Declaration of Helsinki, and the protocol was approved by the Institutional Review Board and Ethics Committee (CEUR 107_2020H).Glucose, CRP, and cortisol were measured using an autoanalyzer. Melatonin , IL-1β , IL-6 , and TNF-α  were measured using ELISA, according to the manufacturer’s instructions. The intra-assay coefficients of variations were 5.28% for melatonin, 3.51% for IL-1β, 5.37% for IL-6, and 3.72% for TNF-α. The inter-assay coefficients of variations were 5.02% for melatonin, 9.91% for IL-1β, 11.40% for IL-6, and 8.74% for TNF-α, as already described ,37.TM Plus  solution, and then centrifuged at 2400 rpm for 30 min at room temperature. The mononuclear cell layer that was obtained was used to extract RNA, as already described [To isolate peripheral blood mononuclear cells (PBMCs), blood samples were collected in EDTA tubes, layered onto the Ficoll-Paqueescribed ,39.BMAL, CLOCK, PER1, PER2, PER3, CRY1, CRY2) and inflammation (IL-6 and TNF-α) was analyzed via RT-qPCR using the SYBR Green system (Thermo Fisher Scientific). Primer sequences used with the SYBR Green system are reported in GAPDH and reported as a ratio compared with the level of expression in controls, which were given an arbitrary value of 1.RNA extraction was performed with the AllPrep DNA/RNA Mini Kit , according to the manufacturer’s instructions. A total of 700 ng of RNA was subsequently used to synthesize cDNA with the Superscript First-Strand Synthesis System for RT-PCR . The expression of genes related to circadian rhythm . To detect a mean difference in blood pressure of 4.6 mmHg [t-test would require 19 subjects. Based on this estimate, we decided to include all the internists working in the department who consented to participate in this study. All statistical analyses were carried out in R system for statistical computing . Statistical significance was set at p < 0.05. A Shapiro–Wilk test was applied to continuous variables to check for distribution normality. Quantitative variables were reported as median with range (1st Qu–3rd Qu) or mean ± standard deviation, depending on distribution. Categorical variables were reported as absolute frequencies and/or percentages. Continuous variables were compared using a Mann–Whitney test  or Student’s t-test (and ANOVA), depending on data distribution and number of groups. A repeated-measures ANOVA model was performed to compare the effect of time on SBP, DBP, SBP dipping, and DBP dipping during the night of rest (t1), the night shift (t2), and the recovery time after the night shift (t3). For every ANOVA model, normality checks were carried out on the dependent variables by group (three different time points), which were approximately normally distributed. If Mauchly’s test of sphericity was not met (only for the dipping DBP model) Greenhouse–Geisser sphericity correction was applied. Post hoc analyses were performed with a Bonferroni adjustment. Correlation coefficients were calculated based on data distribution. Associations with a p-value below 0.10 were considered for multivariate linear regression to evaluate factors influencing blood pressure. In addition, in order to identify covariates related to blood pressure, we used random forest regression (RF), which is used when there are several covariates and small sample sizes to select a smaller number of relevant predictors. We retained the top 3 predictors based on mean square error (MSE) decrease in accuracy for each feature removal (%IncMSE), and we applied a linear multivariate regression model to estimate the β-regression coefficient of each predictor. Statistical analyses were performed with the randomForest package in R.Sample size was calculated with openepi.com (4.6 mmHg , with a


In clinical trials enrolling patients with type 2 diabetes (T2D) at high cardiovascular risk, many glucagon-like peptide-1 receptor agonists (GLP-1 RAs) improved albuminuria status and possibly mitigated kidney function loss. However, limited data are available regarding the effects of GLP-1 RAs on albuminuria status and kidney function in real-world settings, including populations with a lower baseline cardiovascular and kidney risk. We assessed the association of GLP-1 RAs initiation with long-term kidney outcomes in the Maccabi Healthcare Services database, Israel.Adults with T2D treated with  ≥ 2 glucose-lowering agents who initiated GLP-1 RAs or basal insulin from 2010 to 2019 were propensity-score matched (1:1) and followed until October 2021 (intention-to-treat [ITT]). In an as-treated (AT) analysis, follow-up was also censored at study-drug discontinuation or comparator-initiation. We assessed the risk of a composite kidney outcome, including confirmed  ≥ 40% eGFR loss or end-stage kidney disease, and the risk of new macroalbuminuria. Treatment-effect on eGFR slopes was assessed by fitting a linear regression model per patient, followed by a t-test to compare the slopes between the groups.2 (SD 19.3) and median UACR was 14.6 mg/g [IQR 0.0–54.7]. Medians follow-up were 81.1 months (ITT) and 22.3 months (AT). The hazard-ratios [95% CI] of the composite kidney outcome with GLP-1 RAs versus basal insulin were 0.96 [0.82–1.11] (p = 0.566) and 0.71 [0.54–0.95] (p = 0.020) in the ITT and AT analyses, respectively. The respective HRs for first new macroalbuminuria were 0.87 [0.75–0.997] and 0.80 [0.64–0.995]. The use of GLP-1 RA was associated with a less steep eGFR slope compared with basal insulin in the AT analysis .Each propensity-score matched group constituted 3424 patients, 45% women, 21% had a history of cardiovascular disease, and 13.9% were treated with sodium-glucose cotransporter-2 inhibitors at baseline. Mean eGFR was 90.6 mL/min/1.73 mInitiation of GLP-1 RAs in a real-world setting is associated with a reduced risk of albuminuria progression and possible mitigation of kidney function loss in patients with T2D and mostly preserved kidney function.The online version contains supplementary material available at 10.1186/s12933-023-01829-0. Around 20–40% of patients with type 2 diabetes have chronic kidney disease (CKD), defined by either reduced kidney function, the presence of albuminuria, or other evidence of kidney damage –4. CKD iMany glucagon-like peptide-1 receptor agonists (GLP-1 RAs) improve cardiovascular outcomes  and albuIn this observational cohort study, we used the Maccabi Healthcare Services (MHS) database, Israel's second-largest healthcare maintenance organization (HMO), to compare kidney outcomes in patients with type 2 diabetes initiating GLP-1 RAs versus basal insulin. We also assessed the risk for albuminuria progression and change in eGFR over time between treatment groups.2, an indication of kidney transplantation or dialysis treatment, or those treated with the comparator drug within the year prior index date. Patients with an indication of pregnancy within 9 months before the index date were also excluded. To reduce bias associated with physicians' preference to treat severely ill patients with familiar and less costly drugs, we excluded patients with a diagnosis of dementia; history of organ transplantation; in MHS’ cancer (within the past 5 years) or heart failure registers; or those hospitalized for  ≥ 5 consecutive days within the past 180 days  or basal insulin between February 2010 to December 2019. The day of drug initiation was defined as the index date, and the year preceding the index date was defined as the baseline period. We selected basal insulin as a comparator to ensure comparability between the groups, because during these years in Israel both drugs were mainly used as injectable drugs for glycemic control in advanced stages of diabetes. Accordingly, we included patients treated with at least two other glucose-lowering agents (GLAs) at the baseline period, reflecting the common use at Israel at the time. Only those with at least one eGFR measurement at the baseline period were included. We excluded patients with type 1 diabetes, eGFR < 15 mL/min/1.73 mIn the protocol, we defined two follow-up periods. In the intention to treat (ITT) analysis, follow-up continued until the end of data availability, death, or October 2021. In the as-treated (AT) analysis, follow-up was censored also at exposure discontinuation (added by 180 days of grace period) or the initiation of the comparator. In addition, we performed a sensitivity analysis censoring the ITT follow-up for all patients after 4 years of follow-up (ITT-48mo). The rationale behind this analysis was to terminate follow-up when a large portion of the participants was still exposed to the study drugs. Four years cut-off was also selected to emulate the follow-up duration of the LEADER trial .The study was approved by the institutional review board (IRB) at MHS. Due to the de-identified nature of the data, the IRB did not require obtaining informed consent from the participants.International Classification of Diseases-9 diagnosis codes, Anatomical Therapeutic Chemical medications codes, and MHS registries are presented in Additional file Points Location Intelligence Ltd, combining geographic and socioeconomic information for each neighborhood . This score is highly correlated with the SES measured by the Israeli Central Bureau of Statistics. This parameter was categorized into 4 groups  ) .The main kidney outcome was a composite of confirmed  ≥ 40% eGFR reduction from baseline or new ESKD. Additional outcomes were confirmed or single-measurement eGFR reductions of  ≥ 30, ≥ 40, ≥ 50, or  ≥ 57% (corresponding to a doubling of serum creatinine) or new ESKD alone. We also assessed albuminuria outcomes: (1) a categorical increase of urine albumin-to-creatinine ratio (UACR) for the following categories:  < 30, 30- < 300 or  ≥ 300 mg/g; (2) or new-onset macroalbuminuria (UACR ≥ 300) among those with UACR ≤ 230 mg/g at baseline (resembling a ≥ 30% increase in UACR). The albuminuria-based outcomes were assessed either as a single- or as confirmed -measurement. In addition, we compared the eGFR slopes between the groups.2), HbA1c , UACR , treatment with ACEi/ARBs, and treatment with SGLT2i. Patients were also divided into subgroups by their baseline eGFR (≥ 90 and < 90 mL/min/1.73 m2); this threshold was selected owing to the relatively preserved kidney function of the study population. As a sensitivity analysis, we also divided patients into three eGFR subgroups .In addition to the entire study population, analyses were performed in subgroups defined by sex, age (< 60 or ≥ 60 years), presence of CVD, years in diabetes registry (≤ 10 or > 10 years), body mass index (< 30 or ≥ 30 kg/m2).Participants were propensity-score (PS) matched in 1:1 ratio using greedy matching, as previously described . The modBaseline values were described using mean and standard deviation , median and IQR (continuous variables with skewed distribution), or proportions . Standardized difference (STD) was used to assess differences between the GLP-1 RAs and basal insulin group, with values of  < 10% considered negligible.Cumulative incidence functions were used to describe the incidence of the outcomes in each group. Cox proportional hazard regression models were applied to estimate hazard ratios, confidence intervals, and p-value. The models were adjusted for the competing risk of mortality using cause-specific hazard models for the cumulative incidence functions and by using sub-distribution hazard functions for the Cox model .The eGFR change from baseline at different time points was estimated using mixed models for repeated measures. We defined time windows of 6 months during the first 3 years and each year thereafter. At each time window, we included for each patient the eGFR measurement closest to the end of the period. Differences between groups at different time points were estimated using mixed-effect models with repeated measures. In randomized controlled trials (RCTs), eGFR slopes are also estimated using mixed-effect models with repeated measures; however, this approach may not fit the irregular sampling in real-world settings, where the times of measurements vary between patients. Therefore, to assess eGFR slopes, we fitted a linear regression model per patient , enabling us to use all available eGFR measurements. The between-group difference in the linear slope estimates were compared using a t-test. We included in this analysis only patients with  ≥ 2 eGFR measurements with  ≥ 180 days between the first and last evaluations.This study did not include formal hypothesis testing, and the p-values are presented for descriptive purposes only. No correction for multiple testing was performed. We consider a p < 0.05 as statistically significant. Analyses were performed using SAS version 9.4.The study was funded by Novo Nordisk. The funder was involved in the study design, data analysis, data interpretation, writing of the report, and the decision to submit the paper for publication. This report was written according to a predefined protocol, including main and additional outcomes.2, and HbA1c of 9.0% (1.4). Cardiovascular disease was prevalent in 21.0%, mean eGFR was 90.6 mL/min/1.73 m2 (19.3), and median [IQR] UACR was 14.6 mg/g [0.0–54.7]. At baseline, 74.9% were treated with ACEi/ARBs and 13.9% were treated with SGLT2 inhibitors. Baseline characteristics were well balanced between the groups following PS-matching. . This association was not significant when those with eGFR < 90 were further divided into eGFR < 60 or 60- < 90 mL/min/1.73 m2, although the direction was similar (p-interaction = 0.083 [ITT] and 0.129 [AT]) , but not in the ITT (HR 0.96 [0.82–1.12]) or ITT-48mo (0.83 [0.63–1.10) analyses. Similar trends were observed for other categorical eGFR thresholds, whether defined as single- or confirmed-measurement . No significant differences were observed in the whole study population in the ITT  or ITT-48mo analyses  . eGFR loss mitigation was observed in the ITT analysis only at time points 12, 24, and 30 months (p ≤ 0.036), but not in others .  enrolling patients with type 2 diabetes at high cardiovascular risk , 15 withIn most CVOTs involving GLP-1 RA, the drugs reduced the risk of new macroalbuminuria compared to placebo , 15, how2, or with UACR ≥ 30 mg/g. In the PIONEER 5 study enrolling patients with T2D and CKD, oral semaglutide use for one year versus placebo did not exert statistically significant changes in eGFR levels [When meta-analyzing data of CVOTs, the effects of GLP-1 RAs on worsening kidney function  reached only marginal statistical significance with high heterogeneity among trials . A recenR levels . HoweverR levels , especiaR levels . ConsistR levels ). FindinStudies from the past decade show that GLP-1 RA and SGLT2i are disease-modifying drugs with kidney and cardiovascular benefits that exceed their glucose-lowering effects . BecauseThis is an observational study, and while we used different approaches to emulate an RCT setting, no causation can be concluded. Real-world analyses pose several challenges requiring careful expertise. In this study, we followed recent recommendations . Namely,2.Compared with basal insulin, initiation of GLP-1 RAs in a real-world setting is associated with a reduced risk of albuminuria progression and possible mitigation of kidney function loss in patients with T2D and mostly preserved kidney function. The association between GLP-1 RAs use and the kidney outcome seemed to be observed primarily among those with baseline eGFR < 90 mL/min/1.73 mAdditional file 1: Table S1. Variable definitions, including ICD-9 and ATC codes, and MHS registries used for this study. Table S2. Baseline parameters in initiators of GLP-1 RAs or basal insulin before propensity-score matching. Table S3. Year of treatment initiation by study group, before and after matching. Table S4. Medianfollow-up duration per each follow-up analyses overall and by treatment arms. Table S5. Median number of eGFR measurements during follow-up per each follow-up analysis overall and by treatment arms. Table S6. Risk of the primary composite kidney outcomeor mean eGFR lossin patients with baseline eGFR > 90, 60- < 90, and < 60 mL/min/1.73 m2. Figure S1. CONSORT diagram describing the formation of the study population. Figure S2. The association between initiation of GLP-1 RA versus basal insulin and the risk of categorical eGFR decline or albuminuria progression in the ITT-48mo analyses.


Chronic Kidney Disease (CKD) constitutes a global health crisis, silently affecting millions worldwide. This condition, characterized by a gradual decline in kidney function, places a significant burden on healthcare systems and profoundly affects an individual’s quality of life. In this editorial from the Special Issue “Chronic Kidney Disease: Early Detection, Mechanisms, and Therapeutic Implications”, we emphasize the importance of early detection, the role of innovative diagnostic tools, and the ongoing research efforts in the battle against CKD. CKD progresses slowly, often remaining asymptomatic until its advanced stages. Despite its widespread implications, our ability to promptly identify and manage this clinical condition has been hindered by a lack of early, predictive, and non-invasive biomarkers. Currently, kidney function is assessed using diverse equations to analyze the levels of serum creatinine, cystatin C, and albuminuria, and the estimated glomerular filtration rate (eGFR). In the paper titled “Emerging Biomarkers for Early Detection of Chronic Kidney Disease”, we delve into the ongoing efforts to unearth novel biomarkers that could enhance early detection and monitoring, with the aim of improving patient outcomes . HoweverInnovative technologies, such as Raman spectroscopy, have emerged as promising assets for the diagnosis of kidney diseases. Delrue et al. highlight the potential of this non-invasive technique in early CKD detection and monitoring . Its abiWhile no non-invasive CKD biomarkers currently exist, recent works have been focused on small RNAs within urinary exosomes for the assessment of kidney function. Huang et al. demonstrated significant progress by isolating human urinary exosomes using a combination of ultracentrifugation and SEC column purification, addressing contamination concerns . The choButyricicoccus genus with worsening kidney function underscores the importance of delving deeper into the functional aspects of the gut microbiome in patients with CKD. Further investigations accounting for the functional capacity of the gut microbiome are imperative to identify potential therapeutic targets for alleviating chronic inflammation and mitigating the impact of uremic toxins in CKD.CKD, marked by uremic toxin accumulation impacting multiple organs, involves complex factors influencing protein-bound uremic toxin (PBUT) levels, notably, free plasma concentrations. In a 5.5-year prospective study of 523 non-dialysis CKD patients across G1 to G5 stages . HoweverN-acetyl-beta-D-glucosaminidase, Transferrin, and Ganglioside-activating protein GM2. Crucially, this research has also underscored that subclinical damage persists in individuals who continue to smoke, but can be reversed upon smoking cessation. By identifying subclinical kidney damage and providing a panel of biomarkers for early detection, this study marks a pioneering step in the prevention of smoking-related CKD and the avoidance of acute events stemming from potentially nephrotoxic treatments in smokers.Lifestyle choices and habits have a substantial influence on the development of CKD. The paper “Early Diagnosis of Kidney Damage Associated with Tobacco Use: Preventive Application” accentuates a direct relationship between smoking and early subclinical kidney damage . Signifi2S) plays a role in both CVD and CKD. Thiosulfate, a H2S derivative, has also been studied. Researchers found that H2S, Thiosulfate, and their ratio correlated differently with CVD risk markers in 56 children and adolescents with CKD stages G1–G4. Some children with CKD exhibit higher blood pressure, even in early stages. Patients with abnormal blood pressure had distinct H2S-to-Thiosulfate ratios. These findings suggest potential strategies for combating CVD in young patients with CKD by targeting the H2S signaling pathway. Further research is necessary, especially for early stage CKD. Understanding these biomarkers can refine risk assessments and personalized CKD care. Exploring H2S may open the door for novel CVD therapies for pediatric CKD.Finally, children with CKD face unique challenges. The paper “Hydrogen Sulfide-to-Thiosulfate Ratio Associated with Blood Pressure Abnormalities in Pediatric CKD” explores the connection between biomarkers and blood pressure issues in these young patients . Identif2S-to-Thiosulfate ratio, offers pathways to reduce cardiovascular risks. Our unwavering commitment to understanding CKD, innovative diagnostics, and personalized care increases global healthcare quality.This editorial underscores the importance of early detection, innovative diagnostics, and dedicated research in the battle against CKD. While the search for an ideal non-invasive biomarker continues, progress is ongoing. Risk assessments and rigorous preclinical evaluations are capable of guiding us toward early CKD detection. Key highlights in CKD research include nomogram-based predictive models, such as those for patients with type 1 diabetes mellitus, potentially enabling the early detection of CKD using routine data, leading to improved patient care. Innovative technologies, such as Raman spectroscopy, have potential as non-invasive tools, pending rigorous validation. Urinary exosome research promises specific CKD risk biomarkers, thereby advancing early detection. The direct link between smoking and subclinical kidney damage emphasizes the importance of early detection and biomarkers. Investigating the role of the gut microbiome in CKD progression has uncovered therapeutic targets. Pediatric CKD research, including that on the H


The primary outcome was cardiovascular death. Secondary outcomes included hospitalization for heart failure, major adverse cardiovascular events, CKD progression, all-cause mortality, treatment discontinuation, and acute kidney injury (AKI). The relative risk (RR) was estimated using a random-effects model. Twelve RCTs were included in this meta-analysis . Use of an SGLT-2 inhibitor in patients with CKD was associated with a lower incidence of cardiovascular death  and of heart failure , compared with placebo. Heart failure risk reduction with SGLT-2 inhibitors was larger among patients with CKD compared with patients without CKD . SGLT-2 inhibitors were associated with a lower incidence of CKD progression among patients with pre-existing CKD: RR 0.77 (95% CI 0.68–0.88), compared with placebo. Among patients with CKD, a lower risk of AKI  and treatment discontinuation was seen with SGLT-2 inhibitors compared with placebo. SGLT-2 inhibitors offer substantial protection against cardiovascular and renal outcomes in patients with CKD. These results strongly advocate in favor of using them in patients with CKD and keeping them as kidney function declines.The effect of sodium-glucose co-transporter-2 (SGLT-2) inhibitors on cardiovascular and renal outcomes has not been systematically reviewed across baseline kidney function groups. We conducted a systematic review and meta-analysis of randomized control trials (RCTs) with SGLT-2 inhibitors in patients with and without CKD. We performed a PubMed/Medline search of randomized, placebo-controlled, event-driven outcome trials of SGLT-2 inhibitors versus active or placebo control in patients with and without diabetes from inception to November 2022. CKD was defined as an estimated glomerular filtration rate (eGFR) < 60 ml/min/1.73m The cardiovascular and renal benefits of SGLT-2 inhibitors have been demonstrated in several large randomized clinical trials (RCT) in patients with type 2 diabetes and more recently in patients without type 2 diabetes3. Assessing the magnitude of the protective effect of SGLT-2 inhibitors on these outcomes based on the presence or absence of chronic kidney disease (CKD) at baseline remains an important question in order to confirm whether their therapeutic effect is independent of kidney function4.Sodium-glucose co-transporter-2 (SGLT-2) inhibitors are glucose-lowering drugs that act by reducing renal reabsorption of glucose at the S1 segment of the proximal tubule in the kidney. They induce glycosuria and natriuresis and are associated with reduction in glycated hemoglobin (Hb1Ac), blood pressure, albuminuria, and body weightThe aim of this study is to perform a systematic review and meta-analysis of RCTs assessing the effect of SGLT-2 inhibitors on cardiovascular and renal outcomes according to baseline CKD status in individuals with or without type 2 diabetes. This is the most recent meta-analysis on this important question, including the most recent clinical trials with SGLT-2 inhibitors.5. The protocol for this review was prospectively registered in the International Prospective Register of Systematic Reviews (PROSPERO registration number CRD42019131774) and can be accessed at: http://www.crd.york.ac.uk/PROSPERO/display_record.php?ID=CRD42019131774.This systematic review and meta-analysis was conducted and reported using the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statementWe searched MEDLINE from inception to November 2022 to identify potentially eligible studies. The following search terms were used:  OR (stroke or cerebrovascular accident)) OR (heart failure or cardiac failure)) OR ) OR (“Cardiovascular Diseases”Mesh])) OR (kidney failure)) AND ((empagliflozin or canagliflozin or dapagliflozin or sotagliflozin or ertugliflozin or ipragliflozin or tofogliflozin or sergliflozin or remogliflozin or luseogliflozin) OR (“Sodium-Glucose Transporter 2 Inhibitors”[Mesh])). Search was limited to clinical trials or RCTs.2. RCTs had to be peer reviewed manuscripts with a minimum follow-up of 6 months. At least one of the following cardiovascular or renal outcomes had to be reported: cardiovascular death, hospitalization for heart failure, major adverse cardiovascular events, renal death, or CKD progression.We included all randomized, placebo-controlled, event-driven outcome trials of SGLT-2 inhibitors versus active or placebo control. Trials including participants with type 1 diabetes or individuals < 18 years of age were excluded. Inclusion of patients with CKD was required. CKD was defined as an eGFR < 60 ml/min/1.73mTwo authors (K.G. and M.T.) independently screened the titles and abstracts of all identified articles and, when required, reviewed full-text manuscripts to identify potentially relevant studies. The reference lists of all selected studies and available meta-analyses were also reviewed to search for any additional qualifying studies. Any disagreement related to the identification or eligibility of studies was resolved through discussion with a third author (T.M.).Two authors (T.M. and K.G.) independently extracted all relevant baseline characteristics and study outcomes using a standardized digital extraction form, including treatment effects in patient subgroups defined by the presence or absence CKD. Any discrepancies in data extraction or risk-of-bias assessment were resolved by consensus.Efficacy outcomes of interest included: major adverse cardiovascular events (MACE), including cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke; the composite of cardiovascular death or hospitalization for heart failure or their individual components, CKD progression , and all-cause mortality. The primary outcome was cardiovascular mortality. We also extracted information on treatment discontinuation and acute kidney injury. A detailed definition of clinical outcomes in each trial included in this meta-analysis is depicted in Table 2 in most studies. In the DAPA-CKD trial, patients with a urine albumin to creatinine ratio (UACR) of 200–5000 mg/g and an eGFR as high as 75 ml/min/1.73m2 were included3. Similarly, in the EMPEROR-Reduced and EMPEROR-Preserved studies, CKD was defined as eGFR < 60 ml/min/1.73m2 or a UACR > 300 mg/g for the outcomes of cardiovascular death, all-cause mortality, or for the composite renal outcome7. In EMPA-KIDNEY, CKD was defined as eGFR < 45 ml/min/1.73m2 regardless of the level of albuminuria or a UACR > 200 mg/g and an eGFR of 45–89 ml/min/1.73m28.CKD was defined as an eGFR < 60 ml/min/1.73m9.The relative risk (RR) with associated 95% confidence intervals was the principal summary measure. When the number of events per group was not reported, RR were calculated from the incidence rates, the hazard ratio, and the total number of events and participants10. Results were presented in a Forest plot. Prediction intervals were also reported. Prediction intervals reflect the effect to be expected in future patients and their use in meta-analyses has been strongly advocated by prominent scholars in the field11.The pooled RR for each outcome was estimated using a random-effects model with the standard DerSimonian & Laird approachInteraction effects were estimated to test for treatment effect modification by CKD status. Only studies reporting outcomes in patients with and without CKD were included for interaction terms calculation. The natural logarithm of the relative risk ratio and the standard error of the natural logarithm of the relative risk were pooled using the inverse variance method and a random effects model.12.For study quality assessment (performed by K.G. and M.T.), the second version of the Cochrane Risk-of-bias tool for RCTs (RoB2) was used2 index was used to quantify heterogeneity and assess inconsistency. A funnel plot was drawn to assess publication bias. Heterogeneity was considered to be low, moderate, or high if I2 was less than 25%, 26% to 75%, or greater than 75%, respectively13.The I14. The initial rating for RCTs was high and decreased in presence of serious inconsistency, indirectness, imprecision, risk of bias, or when publication bias was likely.The GRADE approach was used to rate confidence in effect estimatesWe used the risk in the placebo group, along with the pooled relative risk for overall patients at long-term follow-up from the systematic review, to calculate the absolute effect estimates in our evidence summaries.robvis tool15.Statistical analyses were performed in Stata . Risk of bias plots were created using the 32. These studies enrolled a total of 89,191 patients, including 38,949 with an eGFR < 60 ml/min/1.73m2. Study characteristics for the included trials are shown in Table A total of 405 articles were identified. After title and abstract screening, 41 articles were selected for full-text review. Twelve RCTs (19 publications) were identified and included in this meta-analysis  for all RCTs included in this meta-analysis  but not in the CKD group (I2 = 0%). There was no interaction between CKD status and the effect of SGLT-2 inhibitors on cardiovascular death .Use of an SGLT-2 inhibitor was associated with a lower incidence of cardiovascular death in patients with CKD, compared with placebo: RR 0.87  . A significant interaction was detected between CKD status and the effect of SGLT-2 inhibitors on heart failure : risk reduction with SGLT-2 inhibitors was more important among patients with CKD  Fig. . MoreoveKD Table .Figure 22 of 14% and 0%). There was no interaction between CKD status and the effect of SGLT-2 inhibitors on cardiovascular death or heart failure .SGLT-2 inhibitors were associated with a lower incidence of cardiovascular death or hospitalization for heart failure among patients with CKD, compared with placebo: RR 0.79  . There was no interaction between CKD status and the effect of SGLT-2 inhibitors on MACE .We only included studies using the 3-point MACE definition . SGLT-2 inhibitors were associated with a lower incidence of MACE in patients with CKD, compared with placebo: RR 0.84  , respectively. There was no interaction between CKD status and the effect of SGLT-2 inhibitors on the composite renal outcome .Definition of the composite renal outcome was highly variable across different studies. In addition to variable percentages of eGFR decline and incidence of kidney failure, some of the trials grouped together cardiovascular death with death from renal cause and with CKD progression Table . SGLT-2 2 of 12% and 71%, respectively). There was no interaction between CKD status and the effect of SGLT-2 inhibitors on all-cause mortality .SGLT-2 inhibitors were associated with a lower incidence of death from any cause among patients with CKD, compared with placebo: RR 0.87   .Four studies examined treatment discontinuation by CKD status at baseline25. Among patients with CKD, AKI was less commonly observed in the SGLT-2 inhibitor arm compared with the placebo arm: RR 0.82  .Five studies examined acute kidney injury (AKI) by CKD status at baselineEpisodes of euglycemic ketoacidosis were rare and not reported by CKD status in the included trials.2.This meta-analysis of RCTs examines cardiovascular and renal outcomes in patients with and without CKD and includes results from the most recently published clinical trials with SGLT-2 inhibitors in patients with and without diabetes. We show that the protective effect of SGLT-2 inhibitors is maintained as kidney function declines and that, due to the high baseline risk in patients with CKD, the absolute risk reduction with this treatment is greater in these patients. In addition, we show that the efficacy of these agents in reducing heart failure events is greater in patients with CKD, compared with patients with preserved renal function. These findings strongly support use of SGLT-2 inhibitors in patients with an eGFR < 60 ml/min/1.73m2. Could these agents be used in patients with lower eGFRs? Five of the trials included in this analysis had formal discontinuation criteria. Three of them used these agents in patients with an eGFR as low as 15 ml/min/1.73m2, while in one trial (CREDENCE) canagliflozin was continued until dialysis initiation21. Dapagliflozin was initiated with an eGFR as low as 25 ml/min/1.73m2 and empagliflozin with an eGFR of 20 ml/min/1.73m226. We did not observe any safety signals and the benefit of SGLT-2i on CKD progression was maintained in these studies. In addition, rates of treatment discontinuation were lower in the SGLT-2 inhibitor arm compared with the placebo arm among patients with CKD. However, the exact reason for discontinuation was unfortunately not reported. Finally, dapagliflozin was found to be associated with lower incidence of abrupt renal function decline, defined as doubling of serum creatinine from most recent value, suggesting a protective effect against AKI30. Future studies should examine if these benefits are maintained when CKD progresses to kidney failure.When SGLT-2 inhibitors were introduced in clinical practice, they were not recommended in patients with CKD because of concerns of reduced efficacy in this setting. In this report, we present evidence that the cardiovascular and kidney benefits of these agents are maintained, if not reinforced, in patients with an eGFR at least as low as 30 ml/min/1.73m15. This study only enrolled patients with established cardiovascular disease that may not get the same benefit from SGLT-2 inhibitors as patients at risk for cardiovascular disease. In addition, this study was performed in an era when the hemodynamic and renal effects of SGLT-2 inhibitors were not widely known and this might have influenced discontinuation rates with this agent in patients without CKD who were thought to develop acute kidney injury when exposed to empagliflozin.Heterogeneity was low for most outcomes, with the notable exception of cardiovascular death, death from any cause, or treatment discontinuation in the non-CKD subgroup. For these analyses, heterogeneity was driven by the point estimates from the EMPA-REG OUTCOME trial33. Furthermore, the effect of patient compliance and understanding of these rules on real-world clinical outcomes has not been adequately studied. However, reasonable concerns about rare side-effects should not preclude using these agents in patients with CKD. It is very important for the nephrology community to advocate for higher uptake of SGLT-2 inhibitors in our patients who will probably benefit the most from their use. Low rates of use of renin–angiotensin–aldosterone blockers among patients with CKD, more than 20 years after establishing their benefit in this population, warns against therapeutic inertia that disproportionally affects patients with CKD34.Based on these findings, we suggest using SGLT-2 inhibitors for cardiovascular and renal protection in patients with CKD and maintaining this treatment as kidney function declines until initiation of renal replacement therapy. Use in patients with severely reduced eGFR (stage V CKD) or on dialysis is not recommended at this time and requires further study. Careful monitoring of kidney function in patients experiencing acute events, such as infection or dehydration, is of utmost importance and use of a sick day rule is critical for patient educationOur study has several limitations. It is treating eGFR using a dichotomous value because we did not have access to patient level data that would allow using individual creatinine or eGFR values. In addition, all outcomes were not reported in all studies by CKD status and definition of cardiovascular and renal outcomes was not uniform across the studies. However, inclusion of 38,949 patients with CKD from 12 trials with different inclusion criteria, representing a diverse population, absence of significant heterogeneity for most outcomes, and similar results in various analyses constitute unique strengths of our meta-analysis. A future meta-analysis using patient-level data will allow for a more granular representation of the effect of renal function on the safety and efficacy of SGLT-2 inhibitors. In such a study, a standardized definition for the renal outcome, such as the composite outcome of 40% GFR decline, ESKD, or renal death as primary renal endpoint, could be used to improve comparability. A patient-level meta-analysis will also allow to report rare side effects, such as euglycemic ketoacidosis, by CKD status at baseline. Another important consideration is inclusion of ethnically diverse populations and people from underserved areas that needs to be addressed in future studies. Finally, although there seems to be a class effect from SGLT-2 inhibitors with respect to their cardiovascular and renal benefits, future studies should proceed with head-to-head comparisons of different SGLT-2 inhibitors.In conclusion, SGLT-2 inhibitors offer strong protection against cardiovascular and renal outcomes in patients with CKD, with and without diabetes. These results strongly advocate in favor of using these agents in patients with CKD and keeping them until dialysis initiation. The challenge for the nephrology community to widely use this therapeutic option is now ahead.Supplementary Figures.


Children with type 1 diabetes mellitus (T1DM) have an increased risk of developing kidney involvement. Part of the risk establishes at the beginning of T1DM. In fact, up to 65% of children during T1DM onset may experience an acute kidney injury (AKI) which predisposes to the development of a later chronic kidney disease (CKD). The other part of the risk establishes during the following course of T1DM and could be related to a poor glycemic control and the subsequent development of diabetic kidney disease. In this review, we discuss the acute and chronic effects of T1DM on the kidneys, and the implications of these events on the long-term prognosis of kidney function. Children with type 1 diabetes mellitus (T1DM) can present with kidney involvement both in the acute setting presenting with acute kidney injury (AKI), as well as tubular damage and in the chronic setting presenting with diabetic kidney disease (DKD) .It has been shown that during the onset of T1DM, an AKI—associated or not with tubular damage biomarkers—can occur in 43.8% of patients . A furthFurthermore, patients with T1DM may eventually develop DKD in 15–20% of cases, which in susceptible patients begins soon after the disease onset and may accelerate during adolescence .For these reasons, kidney health for children with T1DM must not be neglected at each step of illness in order to avoid the development of CKD and a possible future progression towards kidney failure.In this review, we discuss the acute and chronic effects of T1DM on the kidneys, and the implications of these events on the long-term prognosis of kidney function.According to the Kidney Disease/Improving Global Outcome (KDIGO), AKI can be defined by an increase of the serum creatinine or a reduction of the urine output .Since diabetic patients usually present polyuria and polydipsia during the onset of the disease, the urine output criterion seems to be less reliable for the diagnosis of AKI. In fact, only 15% of patients with AKI at T1DM onset met the urinary output KDIGO criteria ., 44.4, 4The level of albuminuria instead has been shown to predict the progression to CKD stage 5 , 46, andTranslating the evidence about the relationship between AKI and CKD, in our opinion AKI itself could be considered a risk factor for DKD. The results of the study by Huang et al.  reinforcIn addition to the AKI-related CKD risk, it has been proven that an AKI is independently associated with a 22% increase of the odds of developing hypertension which is in turn related to DKD . DKD, inScreening for DKD should begin at 11 years with 2–5 years diabetes duration [Furthermore, longitudinal follow-up of albumin excretion is also important to identify patients with progressive small increases of the urinary albumin excretion within the normal range, which might be a prelude to the development of microalbuminuria.Patients with DKD eventually develop hypertension, in fact 10 years after the onset of the disease an increase of BP can occur . The relth percentile), two additional oscillometric or auscultatory BP measurements should be performed at the same visit and averaged [Various pediatric diabetes clinical practice guidelines suggest measuring BP at least annually or twice-yearly for children with T1DM . As indiaveraged . To confaveraged .Considering that even a mild episode of AKI stage 1 can double the risk of CKD , an anti2 had a low risk of accelerated loss of kidney function [Urine albumin–creatinine ratio (Ua:CR) measured after AKI is a strong and potentially modifiable risk factor for more rapid loss of kidney function . Stoumpofunction . Howeverfunction . This, iBP and Ua:CR, (on the first urine of the morning taken on rising) 12 months after AKI.Annual BP and Ua:CR for life.Serum creatinine if previous measurement elevated or if proteinuria or raised BP develops .It has been recommended that patients with AKI should be monitored through the evaluation of:The clinical management of DKD is fully described in the ISPAD 2018 guidelines . In summMoreover, antiproteinuric drugs represent a pivotal treatment in cases of microalbuminuria, and renin–angiotensin–aldosterone system (RAAS) inhibitors are considered the mainstay of treatment for DKD. In fact, pharmacological renoprotective treatment with angiotensin-converting enzyme inhibitors (ACE-I) is indicated for all patients with persistent microalbuminuria regardless of BP measurements –58.The principal mechanism of kidney protection by RAAS inhibitors is to reduce intraglomerular pressure and glomerular hyperfiltration , 60, andACE-I are recommended for use in children and adolescents with hypertension and microalbuminuria . TherapyIf this drug is not tolerated , an angiotensin receptor blocker (ARB) can be used; indeed, this latter class is considered to have similar effects on lowering BP and decreasing albuminuria .Many studies completed in hypertensive children showed that ACE-I To detect microalbuminuria early on and achieve regression of microalbuminuria.Lastly, we can summarize the three main targets of management in the chronic setting:Part of the future risk of developing CKD in T1DM is established at the onset of diabetes. Indeed, up to 65% of the patients at T1DM onset can develop AKI, which in turn is associated with an increased risk of CKD. The more severe the AKI episode, the higher the associated risk of developing CKD and kidney failure .As a preventive measure, a higher parental awareness to the red flags of T1DM should be provided by Pediatricians in order to facilitate an early diagnosis of T1DM reducing the risk of AKI at T1DM onset and then of later CKD [In addition to the “first hit” to kidneys at T1DM onset, during the years of the illness additional hits can further deteriorate the kidney function such as recurrent DKA with recurrent concomitant AKI. AKI, however, can also develop in non-diabetes-related conditions such as acute gastroenteritis or community acquired pneumonia , 81. TheMoreover, poor glycemic control predisposes to DKD development with subsequent risk of CKD, indicating the importance of an adequate compliance to T1DM treatment.Finally, in patients with T1DM regular follow-up visits are important to identify the possible onset of microalbuminuria or hypertension to start a timely and adequate treatment. These conditions, in fact, can facilitate both onset and progression of CKD.At T1DM onset, AKI occurs in 1/5 of patients without DKA and 2/3 of patients with DKA.With more severe onset of T1DM, there is higher risk of AKI and subsequent increased risk of CKD.DKD is a microvascular chronic complication of T1DM. It can occur in almost 1/5 of patients.Poor glycemic control and previous AKI episodes increase the risk of developing DKD.Regular T1DM follow-up visits are important to identify the possible onset of microalbuminuria or hypertension. Timely and adequate treatment with renin–angiotensin–aldosterone system inhibitors should be considered.… could manifest in about 2/3 of children with DKA… is extremely rare… is usually not reversible… could manifest in about of 2/3 of children without DKAAcute kidney injury in children at T1DM onset…osmotic polyuriadelayed T1DM diagnosisacidosisolder age at T1DM onsetIn AKI pathophysiology for patients at the onset of T1DM, all of the following factors are involved with the exception ofurine albumin to creatinine ratio > 30 mg/g creatinine2eGFR < 60 mL/min/1.73 m.urine albumin to creatinine ratio > 300 mg/g creatinineglycosuriaThe presence of diabetic kidney disease may be indicated by all the following parameters with the exception of:angiotensin-converting enzyme inhibitorscalcium channel blockersdiureticsbeta-blockersThe first-choice pharmacological treatment for hypertension in children with T1DM ispoor glycemic controlprevious AKI episodeuntreated hypertensionall of the aboveThe risk of developing DKD increases in case of: