Vicugna pacos) have physiologic adaptations to live at high altitude. These adaptations may result in unexpected responses to changes in cardiac performance and blood pressure during general anesthesia. There are few studies evaluating cardiovascular variables in anesthetized alpacas. The purpose of this study was to report cardiovascular performance in anesthetized mature alpacas during normotension, hypotension, and hypertension using ultrasound dilution and echocardiography. Six adult alpacas, 3 females and 3 castrated males, weighing 62.6 to 88.7 kg were anesthetized and maintained with isoflurane and placed in right lateral recumbency. Each alpaca underwent ultrasound dilution and echocardiography measurements during three cardiovascular phases, normotension, hypotension via increased isoflurane concentration, and hypertension via phenylephrine infusion. Variables were analyzed with a Friedman test and a post hoc Dunn’s test when significant. A p < 0.05 was used for significance. Cardiac output, cardiac index, systemic vascular resistance, stroke volume, total ejection fraction, left ventricular internal diameter during diastole, and total stroke volume indexed to body weight were greater for hypertension compared to hypotension. Total ejection fraction, stroke volume, and left ventricular ejection time were greater for hypertions compared to normotension. There was no difference between ultrasound dilution and echocardiography determined cardiac output measurements within each cardiovascular phase. Phenylephrine appeared to have increased ventricular performance and/or increased preload in anesthetized, mature alpacas. For detecting change in cardiovascular status in anesthetized alpacas, ultrasound dilution and echocardiography may be useful.Alpacas ( Vicugna paco) are commonly domesticated pack and fiber animals and, more recently have gained popularity as companion animals [Alpacas , the volume of blood pumped by the heart per unit of time, is a cardiac performance variable used in research studies evaluating anesthetized animals. The practical gold standard method to measure CO uses pulmonary arterial catheters (PAC) introduced into the heart and has been associated with complications such as pneumothorax, arrhythmias, pulmonary artery rupture, valve injury, and embolism in humans ,6. Thus,Ultrasound velocity dilution (UDCO) is a relatively new technique for determining CO and other cardiovascular variables that eliminates many of the disadvantages of PAC use. It utilizes peripherally placed catheters, does not involve blood loss, and uses a physiologic non-cumulative signal (isotonic fluid) ,8. The tTransthoracic echocardiography (ECHO) can also be used to assess cardiac anatomy and function in a non-invasive manner. Multiple approaches have been proposed to calculate CO using ECHO in humans . FollowiPhenylephrine is a selective α1-adrenergic receptor agonist that has been used to induce vasoconstriction and increased blood pressure for evaluation of blood pressure and other cardiac performance measurement devices ,19.The purpose of this study was to report cardiovascular performance in anesthetized mature alpacas during normotension (NORMO), hypotension (HYPO) induced with isoflurane, and hypertension (HYPER) induced with phenylephrine using UDCO and ECHO. The hypotheses were: 1) when compared to the normotensive state (baseline), CO would decrease during treatment HYPO induced with inhalant anesthetic; 2) CO would decrease during treatment HYPER induced with phenylephrine; 3) CO measurement via UDCO for each treatment would not be different from CO measurement via M-mode ECHO.Six adult alpacas, 3 females and 3 castrated males were used in the study. They were part of the university teaching hospital herd and were acclimated to being handled. Age ranged from 9 to 17 years old and body weight ranged from 62.6 to 88.7 kg. Alpacas were determined to be healthy based on normal findings on clinical examination and complete blood count and serum chemistry panel prior to the study. The study was approved by Auburn University Institutional Animal Care and Use Committee (protocol #2019–3523). At the conclusion of the study, all alpacas were returned to the teaching herd.T) of 15 ml/kg and a rate of 8 breaths per minute to maintain end tidal CO2 between 34–45 mm Hg. Alpacas were instrumented with a dedicated patient monitor  and electrocardiogram, pulse oximetry, and end-tidal gas analysis were monitored. A 20-gauge, 2-inch catheter  was placed in a caudal branch of the right femoral artery at the midpoint of the medial aspect of the thigh just caudal to the femur. Three way stop-cocks were placed on the arterial and jugular catheters and pressure transducers  were attached to one limb of each stopcock with non-compliant, 36 inch, saline filled tubing manufactured specifically for pressure monitoring . The pressure transducers were connected to the patient monitor, zeroed to atmospheric pressure, and positioned at the level of the manubrium to approximate the right atrium to measure arterial blood pressure and central venous pressure. New pressure transducers were used for each alpaca and were guaranteed by the manufacturer to have an accuracy of ± 1 mmHg plus 1% of reading from -50 to +50 mmHg and ± 2.5% of reading from +50 to +300 mmHg . Vital variables and end tidal concentration of isoflurane were recorded at five minutes intervals during general anesthesia. The gas analyzer component of the patient monitor was checked for accuracy at weekly intervals against a standard calibration gas per the manufacturer’s recommendation . Mechanical ventilation was kept constant throughout the data collection period.Food but not water was withheld for 12 hours prior to administration of any medications. The day before general anesthesia, alpacas were acclimated in pairs for 24 hours in a stall in a dedicated food animal medical barn to minimize stress. On the day of the study, a 14-gauge 5.5-inch polyurethane catheter  was aseptically placed in the left jugular vein under minimal physical restraint. Prior to insertion of the catheter, the thoracic inlet was identified via manual palpation and the insertion point into the jugular vein was determined so that the tip of the catheter would be at least two inches into the thoracic cavity . Anesthesia was induced with propofol  at 6 mg/kg IV to effect. Animals were placed in sternal recumbency for orotracheal intubation with a 12 mm internal diameter cuffed orotracheal tube. Animals were then positioned in right lateral recumbency and the endotracheal tube was attached to a rebreathing circuit attached to an anesthesia machine . Maintenance of anesthesia was performed with isoflurane  delivered in oxygen at 4 L per minute. Alpacas’ lungs were mechanically ventilated with a tidal volume . For each alpaca, the arterial catheter was connected with the central jugular catheter through an extracorporeal arteriovenous (AV) loop. This AV loop was connected to a peristaltic pump that kept blood flow constant during measurements. Two ultrasound velocity sensors were attached to this circuit, a venous sensor was placed just upstream from the venous catheter and the arterial sensor just downstream from the arterial catheter. The sensor on the venous side measured the amount of the injected volume and the quality of the injection. The sensor on the arterial side measured a dilution curve. The dilution curve was created by a change in protein concentration of blood after injection of an isotonic saline indicator bolus as it circulates through the cardiovascular system . The bolVblood−UVsaline is the difference between the ultrasound velocities in blood and saline measured by the venous sensor, Vinj is the volume of isotonic saline injected (ml) measured by the venous sensor, UVa is the change in arterial blood ultrasound velocity measured by the arterial sensor; Ca(t) is the concentration of injected saline in arterial blood, and ∫Ca(t)dt is the area under the dilution curve of the saline concentration in arterial blood [Where al blood ,21.0.67):Other Hemodynamic variables determined by calculation were cardiac index (CI), systemic vascular resistance (SVR), stroke volume (SV), and total ejection fraction (TEF). Cardiac index was calculated as CO normalized to body weight  and central venous pressure (CVP).Where Stroke volume was calculated as:Where HR is heart rate.Total ejection fraction was calculated as:Where SV is stroke volume and TEDV is total end diastolic volume and the number 4 is used to account for all chambers of the heart.3 and LVESD3. Cardiac output was calculated as the product of stroke volume (SV) and heart rate (HR). In addition, the interventricular septum at end-diastole (IVSd) and end-systole (IVSs) and LV free wall thickness at end-diastole (LVFWd) and end-systole (LVFWs) were measured, obtained from a right short axis view during systole and diastole. Fractional shortening (FS), expressed as percentage, was also obtained for each blood pressure treatment. The left ventricular ejection time (LVET) was measured from the spectral tracing of the aortic valve.Transthoracic echocardiography was performed with a GE Vivid E9 ultrasound machine with a phase array transducer . A right thoracic window was used to obtain a two-dimensional view (2-D) of the short axis of the left ventricle (LV) with M-mode guidance. The specific imaging plane used for measurements was based on what the examiner regarded as the most accurate and representative view of the LV. From M-Mode, a LV internal diameter at end-diastole (LVIDd) and at end-systole (LVIDs) was measured and used to determine the left ventricular volume at systole and diastole. Total stroke volume indexed to body weight (TOT SV:BW) was derived from the difference of left ventricle (LV) end-diastolic and end-systolic volumes calculated respectively as LVEDDEach alpaca underwent UDCO and ECHO measurements during three cardiovascular phases, treatment NORMO, treatment HYPO, and treatment HYPER. During each phase, measurement with UDCO was performed simultaneously with ECHO. Each measure was taken in triplicate and averaged for each time point. The ECHO examinations were performed by the same board-certified veterinary radiologist (MH) with extensive experience with ECHO. Prior to the first measurements, alpacas were allowed a period of at least 15 minutes to achieve anesthetic equilibration  that resulted in a steady mean arterial blood pressure between 65 and 75 mm Hg (NORMO). After achieving normotension, UDCO and ECHO were performed for treatment NORMO. Next, hypotension was induced by increasing the inspired concentration of isoflurane until MAP was between 45 and 55 mmHg. Once the desired hypotension was achieved, the vaporizer setting was maintained for a period of at least 15 minutes to allow for anesthetic equilibration and UDCO and ECHO were performed for treatment HYPO. The vaporizer setting was not altered until after all measurement were performed. Finally, the isoflurane concentration was returned to baseline and an IV phenylephrine infusion was initiated for treatment HYPER. The initial phenylephrine infusion rate was 0.5 mcg/kg/min for the first five minutes. Afterwards, the rate was increased by 0.5 mcg increments at two minute intervals until a MAP greater than 85 mmHg was achieved. The infusion was maintained for a minimum of 15 minutes was allowed for anesthetic and phenylephrine equilibration and then UDCO and ECHO were performed. Phenylephrine and isoflurane administration were then discontinued and alpacas were allowed to recover from anesthesia.post hoc Dunn’s test when significant. A p value < 0.05 was used for significance.A sample size calculation was performed to detect a difference of 1 L/min in CO between blood pressure states with a sigma of 0.58 , an alphhttps://www.stat.ubc.ca/~rollin/stats/ssize/). All other statistics were performed with a commercially available statistics program .Sample size calculation was performed with an online sample size calculator . Cardiac output increased 48%, CI increased 73%, SVRI increased 61%, and TEF increased 33% from HYPO to HYPER. There were no significant difference in CO, CI, SVRI, SVI, or TEF between HYPER and NORMO or between NORMO and HYPO.Results for CO, CI, SVRI, SVI, and TEF obtained via UDCO for each blood pressure treatment are summarized in p < 0.05). Cardiac output increased 118%, LVIDd increased 22%, and TOT SV:BS increased 156%. There was no significant difference in CO between HYPER and NORMO or between NORMO and HYPO. There was no significant differences in LVIDd between HYPER and NORMO or between NORMO and HYPO. Left ventricular ejection time was significantly longer (34%) for HYPER compared to NORMO (p < 0.05). There were no significant differences in LVET between HYPER and HYPO or NORMO and HYPO. There were no significant differences in TOT SV:BW between HYPER and NORMO or between NORMO and HYPO. There was no significant difference among treatments for IVSd, IVSs, LVIDs, LVFWd, LVFWs, or FS.Results for CO, IVSd, IVSs, LVIDd, LVIDs, LVFWd, LVFWs, FS, LVET, and TOT SV:BW obtained via ECHO for each blood pressure treatment are summarized in Results for comparison of CO measurements between UDCO and ECHO for each treatment are summarized in To the authors’ knowledge, this is the first report of CO and other hemodynamic variables measured with UDCO and ECHO in mature, anesthetized alpacas during different blood pressure states. Contrary to our hypothesis, when compared to treatment NORMO, neither HYPO induced by isoflurane nor HYPER induced by phenylephrine resulted in significant reductions in CO when measured by either UDCO or ECHO. Cardiac output measurement with UDCO and ECHO were not significantly different between modalities within treatments.Phenylephrine was chosen to be used as a means to increase blood pressure for evaluation of UDCO and ECHO performance in this study because its use for manipulation of blood pressure for evaluation of cardiovascular measurement devices in other species ,19,23–25Cardiac output can be decreased by an increase in SVR through impedance of ejection of blood or the force that resists ventricular muscle contraction . This phAlpha adrenergic receptors are mainly located within pre and postsynaptic regions of the sympathetic nerve endings on smooth muscle cells . HoweverA second explanation for the increase in CO could be due to an increase in preload secondary to phenylephrine induced constriction of capillaries, peripheral veins, and central veins with a subsequent increase in stroke volume . In a stIt could be argued that the increase in CO seen in treatment HYPER compared to treatment HYPO was due to decreased concentration of isoflurane delivered to treatment HYPER. The isoflurane concentration in treatment HYPER was similar to treatment NORMO to return MAP to treatment NORMO values prior to initiation of the phenylephrine infusion. Isoflurane tends to have a dose dependent depressive effect on cardiovascular function. For example in dogs, CO decreases from a decrease in SV and SVR during isoflurane anesthesia . HoweverSimilar to CO, several other cardiac variables determined with UDCO increased in treatment HYPER compared to treatment HYPO. Cardiac index is simply CO normalized to body weight, and since CO increased in treatment HYPER compared to treatment HYPO, it would be expected that CI would be increased in treatment HYPER as well. An expected result was the increase in SVR in treatment HYPER compared to treatment HYPO. Phenylephrine, which causes a dose-dependent increase in SVR, was utilized in this study specifically to increase vascular tone and SVR in order to evaluate the effects of hypertension on CO. Stroke volume, the volume of blood pumped from the left ventricle during a single contraction, is one of the determinants of CO. Stroke volume was increased in treatment HYPER compared to treatment HYPO potentially indicating a positive inotropic effect from the administered phenylephrine. Total ejection fraction is the fraction of blood of the end-diastolic volume in the left ventricle ejected during contraction. This value, calculated by UDCO, is used as a measure of contractile strength of the ventricular myocardium. In treatment HYPER, TEF increased compared to treatments HYPO and NORMO again suggesting a positive inotropic effect from phenylephrine administration. Measured via ECHO, LVIDd increased in treatment HYPER compared to treatment HYPO. This finding supports the thought that phenylephrine induced vascular constriction results in a greater preload and thus an increase in CO. Left ventricular ejection time is the time interval from the aortic valve opening to aortic valve closure and directly correlated with SV. In this study LVET increased in treatment HYPER compared to treatments HYPO and NORMO and should be expected with the increase in SV resulting in the increase in CO. Finally, TOT SV:BW was increased in treatment HYPER compared to treatment HYPO. This is an expected finding given that SV and CO increased in that treatment as well.An additional outcome of this study was the comparison of CO measurement by UDCO and ECHO. Statistically, the measurements between the two methods were found not to be different within the treatment groups. However, further comparison should be made with greater numbers of animals to assess bias and limits of agreement. This study was likely underpowered to make a definitive statement on the agreement of UDCO with ECHO. However, the usefulness of the measurement methods of UDCO and ECHO for CO measurement is further supported by a systematic review and meta-analysis in humans that found CO measurement by ECHO or pulmonary artery catheterization were not different . FurtherThe main limitation of this study was the use of methods of CO measurement that have not been validated in alpacas. The practical gold standard method for measurement of cardiac output is thermodilution via pulmonary artery catheterization. However, this method has been associated with serious adverse events including pulmonary thrombosis, arrhythmias, and pulmonary artery rupture in humans . There hAnother limitation of this study included a small sample size  which may have affected the results, particularly for comparisons between treatments HYPO and NORMO. While the median values for CO between HYPO and NORMO treatments were similar, treatment NORMO was not statistically different from treatment HYPER even though treatments HYPO and HYPER were different. The lack of difference between treatments NORMO and HYPER was likely due to the wide variability among animals suggesting the number of animals used in the study may not have provided enough power. Enrolling additional alpacas in the study may have resulted in a statistical difference between treatments NORMO and HYPER. Additionally, there were no intact male alpacas used in this project. This was because the alpacas that were available for this study are part of a teaching herd and are housed together. Intact males are not permitted to prevent breeding and to minimize aggressive behavior. It is not known if the use of intact male alpacas would have impacted the results of this study.The use of intermittent positive pressure ventilation (IPPV) could have interfered with the CO measurements. During IPPV, elevated intrathoracic pressure is transmitted against the right atrial wall, reducing venous return. The reduction in right-sided preload, causes a reduction in right-sided cardiac output . AlpacasFinally, the order of the hemodynamic states during measurements was not randomized. This was done due to lack of information regarding the effect and duration of action of phenylephrine in alpacas. Concern was that if there was a prolonged effect from the phenylephrine, the alpacas would have needed to be maintained under anesthesia for an unacceptably long period of time. Therefore, the induced hypertension was the last state so as not to potentially interfere with the NORMO or HYPO treatments.Future studies in alpacas are warranted to support the use of UDCO and ECHO for monitoring hemodynamic variables. Additionally, investigation into the mechanism behind the increase in CO associated with phenylephrine administration as well as the effects of other inotropic or vasopressor agents would be of high clinical interest for the management of alpacas during anesthesia.In conclusion, in isoflurane anesthetized, healthy, mature alpacas, isoflurane induced hypotension can result from a decreasing in CO and other cardiovascular variables. In hypotensive isoflurane anesthetized, mature alpacas, a phenylephrine infusion along with reduction in isoflurane concentration may increase in CO, and other cardiovascular variables via increased ventricular performance and/or increased preload. Additionally, the results of this study, suggest that UDCO and ECHO may be viable methods for detecting changes in cardiovascular variables in anesthetized alpacas.S1 Dataset(XLSX)Click here for additional data file.


Continuous neuromonitoring in the neonatal intensive care unit allows for bedside assessment of brain oxygenation and perfusion as well as cerebral function and seizure identification. Near-infrared spectroscopy (NIRS) reflects the balance between oxygen delivery and consumption, and use of multisite monitoring of regional oxygenation provides organ-specific assessment of perfusion. With understanding of the underlying principles of NIRS as well as the physiologic factors which impact oxygenation and perfusion of the brain, kidneys and bowel, changes in neonatal physiology can be more easily recognized by bedside providers, allowing for appropriate, targeted interventions. Amplitude-integrated electroencephalography (aEEG) allows continuous bedside evaluation of cerebral background activity patterns indicative of the level of cerebral function as well as identification of seizure activity. Normal background patterns are reassuring while abnormal background patterns indicate abnormal brain function. Combining brain monitoring information together with continuous vital sign monitoring  at the bedside may be described as multi-modality monitoring and facilitates understanding of physiology. We describe 10 cases in critically ill neonates that demonstrate how comprehensive multimodal monitoring provided greater recognition of the hemodynamic status and its impact on cerebral oxygenation and cerebral function thereby informing treatment decisions. We anticipate that there are numerous other uses of NIRS as well as NIRS in conjunction with aEEG which are yet to be reported. Noninvasive neuromonitoring allows continuous screening and assessment of neurologic status at the bedside. With growing attention to the impact of brain injury on long-term neurodevelopmental outcomes, neuromonitoring has gained more attention as an essential element of neurocritical care in the neonatal intensive care unit (NICU) –3. Neuro2, reflect the balance between oxygen delivery and consumption at any cerebral or somatic site by reading a venous-weighted oxygen saturation  is most commonly monitored as the brain is a highly metabolic organ with tight autoregulatory mechanisms to maintain constant blood flow over a wide range of arterial pressures (2) is often the earliest indicator of alterations in systemic perfusion and oxygenation. Cardiac failure, low cardiac output, or decreased blood volume may be detected by a decrease in rSrO2 before any other clinical parameters are apparent  is useful in assessing gut oxygenation in neonates with bowel pathology, despite the frequent variability typical of this site , bowel ischemia, and other pathologies thus assisting in determining the optimal timing for a surgical intervention  has been increasingly used in neonatal intensive care units (NICU) and is most well-known for its use in babies with hypoxic-ischemic encephalopathy . aEEG moIn this manuscript, we describe 10 cases in critically ill neonates including cardiopulmonary disorders, circulatory disorders and abdominal disorders, in which comprehensive multimodal monitoring with multisite NIRS with and without simultaneous use of aEEG provided greater knowledge of the hemodynamic status and its impact on cerebral function and injury. These cases were obtained from Neuro-NICUs located at level III and IV NICUs in Brazil and the U.S., where NIRS and aEEG are routinely utilized in specific populations of neonates at risk for brain injury . The INV2 were implemented immediately, including increase of FiO2 to 100%. NIRS monitoring was then initiated and showed rScO2 ∼90% and rSrO2 ∼55%. The closest recorded SpO2 was 91%. Blood gas analysis showed PaCO2 99 mmHg, and the chest radiograph demonstrated bilateral pneumothorax (2 92%). The rScO2 decreased from 90% to 75%–77%, accompanied by a substantial increase in rSrO2 to 81% (2 to 56 mmHg.A late preterm infant was admitted to the NICU at 24 h of life due to respiratory distress and cyanosis requiring intubation. The infant experienced a sudden decompensation with a drop in mean blood pressure (MBP) to 32 mmHg and pulse oximetry to 75%. Measures to increase the SpOmothorax . Needle 2 to 81% . The rep2 patterns has been shown to provide information on hypercapnia-induced cerebral hyperperfusion. Dix et al.  on the day of life 3 due to persistent hypoxemia. An echocardiogram showed normal anatomy and suprasystemic right ventricular pressures. A chest radiograph demonstrated the arterial cannula tip at T3 and venous cannula tip at T10. After being on full ECLS support for 7 days, pump flow was gradually weaned due to improved lung expansion. While pump flow was weaned from 75 to 20 ml/kg/min, systemic oxygenation and perfusion as measured by SpOecrement . A pointNIRS is being used more frequently in ECLS patients due to their critical illness. In this setting, the primary focus is often on monitoring brain oxygenation. This case demonstrates the value of two site monitoring and how it provided an understanding of changes in perfusion to both the brain and kidneys. Despite a large pericardial effusion, there was no evidence of clinical instability based on vital signs and ECLS parameters. Monitoring of cerebral and renal NIRS easily detected the hemodynamic effect of the pericardial effusion, demonstrating a gradual decrease in perfusion to the cerebral and somatic tissue beds.2 100% and inhaled nitric oxide 20 ppm. Pre-ductal SpO2 was 90%–100% and post-ductal SpO2 20%–30%. Lactate was <2 and there was no evidence of acidosis. Echocardiogram demonstrated a dilated right ventricle (RV) with elevated RV pressures, right-to-left shunting across the patent ductus arteriosus, and mildly decreased function. Neuromonitoring was initiated in this critically ill infant with respiratory failure. rScO2 was 70%–80% and rSrO2 was 30%–45%. After initiation of pressor support to improve blood pressure, the rSrO2 increased to 55%–65%  was born by scheduled Cesarean section delivery. Fetal magnetic resonance imaging (MRI) showed half of the liver, stomach, and bowel in the chest with estimated lung volumes <25% of expected. The infant was intubated in the delivery room and despite a gentle ventilation and permissive hypercapnia approach, clinical support escalated quickly to include high frequency oscillatory ventilation with FiO 55%–65% . Simulta 55%–65% . Given tectively .2 and rSrO2 preceded an eventual decline in preductal SpO2 measures and acidosis, leading to the decision to place the infant on ECLS. As aEEG changes are typically also preceded by abnormal NIRS values  combined with reassuring brain function as measured by aEEG aided the initial clinical decision to avoid ECLS. However, a later decline in both rScOS values , initiatp < 0.001) with a sensitivity of 85% and specificity of 100%  measuring 2.9 mm. The infant had a prolonged desaturation to SpO on aEEG . Increase period . Even af2 ≤ 84%) for more than 30 s was associated with a significant reduction in systemic and regional oxygenation  in preterm infants. The intensity and prolongation of desaturation may compromise tissue oxygen utilization, leading to the risk of ischemic injury to the brain and kidney  was related with the presence of a hsPDA.Due to a low metabolic rate for oxygen, healthy neonates demonstrate considerable reserve capacity to deal with reduction of cerebral blood flow or decrease of oxygen content in arterial blood . Howeverd kidney . Alderlid kidney  conducted kidney –23. The t et al.  investigactivity  previous2 was ∼45% and rSrO2 ∼40%. Hemodynamic parameters were evaluated and blood pressure, peripheral perfusion, heart rate, systemic saturation and urine output all were within the normal range. Laboratory exams were performed and included PaCO2 37 mmHg, Hemoglobin 10.6 g/dl and Hematocrit 30.2%. The infant was transfused PRBCs with an increase in rScO2 to ∼55% and rSrO2 to ∼75% to 85% , but on the second week of life was diagnosed with late-onset sepsis with positive blood culture for oxacillin-resistant coagulase-negative staphylococcus. Lumbar puncture excluded associated meningitis. NIRS monitoring was initiated, and rScO% to 85% . A 10-po2 values from the second week of life through 36 weeks postmenstrual age. Worsening anemia was associated with a progressive decrease in rScO2 in preterm infants. The identified threshold hemoglobin was 9.5 g/dl below which rScO2 values decreased >2 SD below the mean. Two recent systematic reviews using NIRS to detect anemia reported a significant correlation between hemoglobin concentration and rScO2 values, even when hemoglobin level was within the normal range  and blood gas findings were normal. The infant received a PRBC transfusion due to a Hct of 27%. Sepsis screening was done, and a coagulase-negative staphylococcal infection was diagnosed and treated with antibiotics.A late preterm infant was born by cesarean section and admitted to the NICU with mild respiratory distress. On the 2nd day of life, the infant required inotropic support for poor peripheral perfusion and oliguria. Heart rate, blood pressure and systemic saturation were within the normal range . Blood gas noted . On the as noted . The infin rSrO2 . During The vein of Galen aneurysm is a malformation with multiple markedly dilated arteriovenous fistulas that can divert up to 60% of cardiac output, leading to heart failure. The diagnosis can be made through imaging in the fetal or neonatal period, and cerebral angiography is the gold standard to confirm the diagnosis . NIRS pr2 was trending very closely with rScO2 measuring ∼70% to 80%, but on day 3 of life over an 8-hour period there was a steady decrease in the rSrO2 to 30%–40%  decreased from 42% to 33% over a 24-hour period, and he developed a metabolic acidosis. He was transfused with 10 ml/kg of packed red blood cells (PRBCs) with a transient increase in his rSrO2 to 50%, but his rSrO2 decreased further to 20%–30%. The persistent decrease in renal saturation despite multiple transfusions prompted an exploratory laparotomy. The infant was found to have a subcapsular liver hematoma causing abdominal compartment syndrome. After bleeding was controlled and the bowel exteriorized to relieve pressure, the rSrO2 stabilized at 60%.A term infant with prenatal diagnosis of gastroschisis was admitted to the NICU with multiple loops of bowel outside of the abdomen. After elective intubation and sedation, the pediatric surgery team placed the bowel into a silo bag for gradual reduction. NIRS monitoring of cerebral and renal saturation was initiated following the surgical procedure. Initially the rSrO 30%–40% . The SpO2 levels, the cerebral saturation in this case was maintained for a longer time period. However, anemia from blood loss combined with abdominal compartment syndrome impacting perfusion to both intestines and kidneys likely contributed to the significant decrease seen in renal saturation. Stienstra et al.  moderately preterm infant was having frequent apnea and bradycardic episodes in the third week of life. CPAP support was initiated. Hematocrit was 25% and PRBCs were transfused. Over the next 12-hour period, the infant developed significant abdominal distention. NIRS tracing demonstrated a notable decrease in mesenteric saturation from the 55%–65% range down to 15%–20% . An abdo2 measures in preterm infants with subsequent feeding intolerance or NEC  may help to identify infants with NEC earlier or provide reassurance during episodes of feeding intolerance in a preterm infant. Several authors have reported a decrease in abdominal rSOe or NEC –41. Incre or NEC  and lowee or NEC  has alsosymptoms , 45. Dis2 values (These ten neonatal neuromonitoring cases demonstrate new uses of NIRS and aEEG in the neonatal population and how these neuromonitoring techniques can provide valuable information regarding hemodynamics as well as brain function. While the use of NIRS in specific clinical scenarios has been well documented for several neonatal diagnoses such as HIE, congenital heart disease, and PDA , 46–52, 2 values . Limitat2 values . The mai2 values .With understanding of the underlying principles of NIRS as well as the physiologic factors which impact oxygenation and perfusion of end organs, changes in neonatal physiology can be more easily recognized by bedside providers and diagnostic and therapeutic interventions can be undertaken. aEEG used in conjunction with NIRS provides an enhanced understanding of brain function in settings where brain injury is suspected. Normal background patterns are reassuring while abnormal background patterns confirm concerns regarding abnormal brain function. Considering the clinical benefit of better understanding physiology in critically ill neonates, we anticipate that there are a myriad of uses of NIRS and multimodality monitoring in populations at risk of hemodynamic disturbances which will continue to be reported.


This result was confirmed in a multiple Cox model adjusted for age, gender, diabetes, systolic arterial pressure, and dialysis adequacy . Similar results were obtained considering the combined event death–CV events as an outcome. Home pulse pressure represents, in part, arterial stiffness, and it is strongly related to all-cause mortality in peritoneal patients. In these high cardiovascular risk populations, it is important to maintain optimal blood pressure control, but it is fundamental to consider all the other cardiovascular risk indicators, such as pulse pressure. Home pulse pressure measurement is easy and feasible and can add important information for the identification and management of high-risk patients.Increased arterial hypertension represents a prevalent condition in peritoneal dialysis patients that is often related to volume expansion. Pulse pressure is a robust predictor of mortality in dialysis patients, but its association with mortality is unknown in peritoneal patients. We investigated the relationship between home pulse pressure and survival in 140 PD patients. During a mean follow-up of 35 months, 62 patients died, and 66 experienced the combined event death/CV events. In a crude COX regression analysis, a five-unit increase in HPP was associated with a 17% increase in the hazard ratio of mortality (HR: 1.17, 95% CI 1.08–1.26  Chronic kidney disease (CKD) is a global health issue. The disease burden has noticeably risen in recent years, with an estimated increase in CKD-related years of life lost equal to 82% . Among tDifferent from peri-dialysis measurements, out-of-dialysis BP is more efficient in diagnosing hypertension  and in pAmong the out-of-dialysis measurements, 44 h ambulatory blood pressure measurement (ABPM) is the gold standard for the diagnosis of hypertension in dialysis patients; however, its applicability and tolerability are still a matter of debate ,39. For Home BP monitoring represents the election choice for peritoneal dialysis (PD) patients who, due to the home-based treatment, routinely measure BP at home. However, information about the diagnostic accuracy of this measurement in these patients is scarce and in contrast with findings in HD patients. Among the studies published so far, most of them with limited sample size suggest an overestimation of daytime ambulatory BP and a worse performance in diagnosing hypertension compared with standardized BP ,43. MoreThis study was conducted in accordance with the Declaration of Helsinki, and the protocol was approved by the Ethical Committee of our institution . Each participant provided written informed consent before enrolment.n = 140). All the enrolled subjects were of Caucasian descent and came from the same geographic area . After the baseline visit, patients were followed up for a median time of 33 months (range: 20–58 months). One-hundred and six patients were treated with various anti-hypertensive drugs . The main demographic, somatometric, clinical, and biochemical characteristics of the study population are detailed in We included in this analysis all patients who started peritoneal dialysis at the Nephrology, Dialysis and Transplantation Unit of the Grande Ospedale Metropolitano “Bianchi-Melacrino-Morelli”, Italy, between August 1991 and December 2018  was calculated by subtracting diastolic BP from systolic BP. For this analysis, monthly average of all HPP values taken at home was considered. HPP variability was computed via the sample standard deviation (SD) of all HPP values. Dialysis adequacy was expressed by weekly Kt/V. Blood sampling was performed at baseline in the early morning after an overnight fast. Cholesterol, hemoglobin, PTH, calcium, phosphate, and C-reactive protein (CRP) were measured using standard methods in the routine clinical laboratory.As HPP was measured in a month period, follow-up started the day of the last measurement. All-cause mortality and a combination of mortality and fatal and non-fatal cardiovascular events were the study end-points. Cardiovascular events were classified as follows: stroke (ischemic or hemorrhagic), documented by computed tomography, magnetic resonance imaging, and/or clinical and neurological evaluation; transient ischemic attacks (TIA); myocardial infarction confirmed by serial changes of ECG and cardiac biomarkers; ECG-documented angina episodes; heart failure, diagnosed on the basis of clinical and instrumental evidence, as reported before; ECG documented arrhythmia; peripheral ischemia or amputations; unexpected, sudden death highly suspected as of cardiac origin. Each cause of death was assessed by three independent physicians. In doubtful cases, diagnosis was attributed by consensus. During the review process, involved physician used all available medical information, including hospitalization forms and medical records. In case of death at home, family members and/or general practitioners were interviewed to better understand the circumstances which led to death.Data were expressed as mean ± standard deviation , median and inter-quartile range , or as percent frequency .Pearson’s correlation coefficient was used to evaluate the association between HPP and the main demographic, somatometric, and clinical variables . The relationship between blood pressure values  and cardiovascular comorbidities was tested by univariate and multivariate logistic regression analysis, adjusted for traditional and non-traditional confounding factors . Univariate and multivariate Cox regression analyses, adjusted for age, gender, diabetes, systolic or diastolic arterial pressure, and dialysis adequacy, were used to assess the association between blood pressure values and mortality or the combined outcome. The effect of age and sex on the association between BP values and mortality/combined outcome was verified, including in the Cox model blood pressure values , age or sex, and their multiplicative term. Statistical analysis was performed via standard statistical packages .2. Overall, 10% of the patients were current smokers. Regarding the most important comorbidities, 36.4% of patients were diabetic, while 47.1% had previous cardiovascular events. The list of the main correlates of HPP is reported in p < 0.001), male gender , and previous cardiovascular events   .p = 0.001). This association was confirmed after adjustment for potential confounders such as age, gender, diabetes, and dialysis adequacy . This association was no longer significant after introducing the same model systolic arterial pressure .The association between HPP and previous cardiovascular comorbidities was confirmed at univariate logistic regression analysis, where for each 5-unit increase in HPP, a 4% increase in the odds of cardiovascular disease was observed  or multivariate analysis .Differently from HPP, pulse pressure variability was not associated with previous cardiovascular comorbidities, neither at univariate . Conversely, the inverse relationship between DBP and cardiovascular comorbidities was not significant .The same analysis performed on the two components of HPP reported a positive, significant association between SBP and cardiovascular comorbidities  (p = 0.001) (p = 0.001).During a mean follow-up of 35 months, 62 patients died. In a crude COX regression analysis, a five-unit increase in HPP was associated with a 17% increase in the hazard ratio of mortality  . This re= 0.001) . Forcingp = 0.33) and multivariate analysis . Adding previous cardiovascular comorbidities in the model did not change the result .The predictive power of HPP overcomes that of SBP and pulse pressure variability for all-cause mortality. As a result of our analysis, the association between these BP values and the considered outcome was not significant both at univariate .As expected, DBP was protective for all-cause mortality .Finally, no association was found between pulse pressure variability and all-cause mortality  (p > 0.05).No effect modification by age or sex was found on the link between HPP and mortality (n >0.22) A or on tp < 0.001) (p = 0.001) (p = 0.003). DBP confirmed the protective role for the combined outcome both at univariate and multivariate analysis .During the follow-up of 35 months, 66 patients experienced the combined event of death/CV events. Survival analyses considering the combined event death-CV events as outcome showed similar results. In a crude Cox regression analysis, HPP was directly and strongly related to the combined outcome  . In stri= 0.001) . By alsop = 0.19; multivariate analysis: HR for the 5-unit increase: 1.06, 95% CI: 0.97–1.17, p = 0.22; multivariate analysis + previous cardiovascular comorbidities: HR for the 5-unit increase: 1.05, 95% CI: 0.95–1.15, p = 0.34) and pulse pressure variability and the combined outcome .No association was found between SBP .No effect modification by age or sex was found on the link between HPP and the combined outcome , and these associations held true after adjustment for systolic blood pressure and previous cardiovascular comorbidities. HPP was also shown to be a better predictor of clinical outcomes than SBP and pulse pressure variability, whereas DBP confirmed its predictive role for the same outcomes.Pulse pressure, an index of the pulsatile component of the cardiac cycle , has beeIn PD patients, the increase in PP was significantly associated with all-cause mortality ,47,52,62In contrast with the other studies, we focused our analysis on BP measurements taken at home, thus without a standardized protocol, within the period of a month.p < 0.01). The association between HPP and previous cardiovascular comorbidities was independent of a list of potential confounders. This association was no longer significant after introducing the same model of systolic arterial pressure. In survival analysis, a five-unit increase in HPP was associated with a significant 17%  or 31%  increase in the hazard ratio of mortality. Similar results were obtained considering the combined death-CV events as an outcome. The predictive power of HPP overcame that of SBP or PP variability, as both failed to predict the considered outcomes. Different from the other BP measurements and in line with the literature, DBP was associated with a reduction of 30% of the risk of mortality and 26% of the risk of death and CV events in this population. Systolic, diastolic, and pulse pressure, though depending on vascular resistance and central artery stiffness, are variously affected by these components. DBP is raised by high peripheral vascular resistance and lowered by high arterial stiffness, so its values and, as a consequence, those of pulse pressure depend on the relative contribution of these factors. In contrast, pulse and systolic pressure are strongly interrelated because both rise with increases in vascular resistance and arterial stiffness [Unsurprisingly, we found a strong positive association between HPP and age, male gender, and previous cardiovascular events (r from 0.21 to 0.44, tiffness .The strong correlation between pulse pressure and arterial stiffness origins from age-related vascular calcification. This process translates into arterial stiffening, which in turn causes larger forward wave amplitude, earlier reflected wave arrival, and greater pulse pressure ,65. For The same dependence of SBP and PP from vascular resistance and arterial stiffness may explain why, when put together in our models, they remain both significantly associated with all-cause mortality and with the combined event mortality/CV events.The main limitation of our study is the small sample size. However, with a follow up of about 3 years and almost half of the patients experiencing the event of interest, our cohort can be considered satisfactory. Secondly, enrolled patients were followed up in a single dialysis center, and this prevented our results from being generalized. Third, the overall number of the events collected was relatively small, thus limiting the number of potential confounders to be included in the models. Furthermore, smoking habits were available only in a limited number of subjects. As a further limitation, data about aortic regurgitation was not available in our dataset, so we were not able to exclude from the analysis patients affected by this comorbidity.In spite of these limitations, our study is the first to show that home blood pressure, measured within a period of a month, is linearly associated with death and cardiovascular events in clinical outcomes and that this association is independent of SBP.In conclusion, home BP monitoring is considered a more suitable option for the management of hypertension in dialysis patients, and home pulse pressure represents, in part, arterial stiffness, and it is strongly related to all-cause mortality in peritoneal patients. In these high cardiovascular risk populations, multiple approaches, drug therapy associated with a better volume status control, lifestyle, and sodium and water intake are important to maintain optimal blood pressure control, but it is fundamental to consider all other cardiovascular risk indicators, such as pulse pressure. Home pulse pressure measurement is easy and feasible and can add important information to identify and manage high-risk patients.


Perioperative acute kidney injury (AKI) has been one of the leading causes of morbidity and mortality for surgical patients. Pheochromocytoma is a rare, catecholamine-secreting neuroendocrine neoplasm characterized by typical long-term hypertension that needs surgical resection. Our objective was to determine whether intraoperative mean arterial pressures (MAPs) less than 65 mmHg are associated with postoperative AKI after elective adrenalectomy in patients with pheochromocytoma.We performed a retrospective review of patients undergoing adrenalectomy for pheochromocytoma between 1991 and 2019 at Peking Union Medical College Hospital, Beijing, China. Two intraoperative phases, before and after tumor resection, were recognized based on distinctly different hemodynamic characteristics. The authors evaluated the association between AKI and each blood pressure exposure in these two phases. The association between the time spent under different absolute and relative MAP thresholds and AKI was then evaluated adjusting for potential confounding variables. P = 0.087) and before tumor resection phase , both time-weighted MAP and time-weighted percentage changes from baseline were strongly associated with postoperative AKI after tumor resection, with OR 3.50, 95% CI  and 2.03, 95% CI  in the univariable logistic analysis respectively, and with OR 2.36, 95% CI  and 1.63, 95% CI  after adjusting sex, surgical type (open vs. laparoscopic) and estimated blood loss in the multiple logistic analysis. At any thresholds of MAP less than 85, 80, 75, 70, and 65 mmHg, prolonged exposure was associated with increased odds of AKI.We enrolled 560 cases with 48 patients who developed AKI postoperatively. The baseline and intraoperative characteristics were similar in both groups. Though time-weighted average MAP was not associated with postoperative AKI during the whole operation (OR 1.38; 95% CI, 0.95–2.00;We found a significant association between hypotension and postoperative AKI in patients with pheochromocytoma undergoing adrenalectomy in the period after tumor resection. Optimizing hemodynamics, especially blood pressure after the adrenal vessel ligation and tumor is resected, is crucial for the prevention of postoperative AKI in patient with pheochromocytoma, which could be different from general populations. Perioperative morbidity and mortality continue to be a major health burden in current medical practice  patients aged ≤ 16 years old, (3) patients with partial or unilateral nephrectomy simultaneously, (4) patients with missing information for preoperative or postoperative serum creatinine, and (5) patients with invalid or unavailable intraoperative hemodynamic data for more than 10 consecutive minutes. If patients with bilateral pheochromocytoma had multiple surgeries, only the first surgery was kept. A patient inclusion/exclusion flow diagram is presented in Fig. The study included patients undergoing adrenalectomy with a diagnosis of pheochromocytoma between 1991 and 2019 at Peking Union Medical College Hospital, Beijing, China. All patients were diagnosed with pheochromocytoma based on postoperative pathological reports. The exclusion criteria include (1) patients with chronic kidney disease defined as a preoperative estimated glomerular filtration rate (eGFR) less than 60 mL·minAll patients diagnosed with pheochromocytoma via biochemical tests and imaging examinations were treated with nonselective α-adrenergic blockade (phenoxybenzamine) or selective α-adrenergic blockade  at least 2 weeks before the operation. The target blood pressure was lower than 120/80 mmHg when sitting, with systolic blood pressure (SBP) no less than 90 mmHg while standing. Metoprolol was added to control episodes of tachycardia if necessary with a heart rate (HR) goal of 60 to 80 beats/min. When blood pressure control was inadequate or in patients with intolerable side effects, calcium channel blockers or angiotensin-converting enzyme (ACE) inhibitors were added. All patients underwent surgery with general anesthesia and used arterial catheter to monitor blood pressure continuously. During the operation, substantial rises in blood pressure were controlled by bolus or continuous infusion of phentolamine, sodium nitroprusside, or urapidil, and the hypotension after tumor resection was treated by continuous infusion of vasopressors  and fluid infusion. All treatments were decided at the discretion of the anesthesiologist to keep blood pressure and heart rate stable. Patients were transferred to the intensive care unit after surgery and would be transferred back to floor wards when mechanical ventilation and vasopressors were no longer needed.The study was approved by the Institutional Review Board of Peking Union Medical College Hospital prior to data extraction. Given the retrospective nature of the study, the requirement of written informed consent was waived. Encounter-level patient data (demographics), comprehensive time-stamped medication orders, medication records, laboratory results, admission and discharge diagnoses , and procedures performed were extracted from the hospital information system  between 2013 and 2019, or collected by the study team via retrospective chart review between 1991 and 2012.Preoperative serum creatinine was defined as the serum creatinine obtained in closest proximity to the date of surgery. Peak postoperative serum creatinine was defined as the highest creatinine level obtained during the 7 days after surgery. Internal auditing was performed to ensure data accuracy. Preoperative kidney function was characterized according to the patient’s estimated glomerular filtration rate (eGFR) using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation , and MAP, which were recorded twice throughout the 24 h before the surgery, were collected by the study team via retrospective chart review using the mean of the two measurements. Intraoperative hemodynamic variables were extracted from anesthesia information management system  between 2013 and 2019, which cannot be modified by clinicians, but can be identified as artifactual. Invasive pressures were recorded at 5-min intervals. We removed artifacts using the following rules, in order: (1) blood pressures documented as artifacts; (2) pressures out-of-range defined by (a) SBP greater than or equal to 300 or SBP less than or equal to 20 mmHg, (b) SBP less than or equal to DBP + 5 mmHg, or (c) DBP less than or equal to 5 mmHg or DBP greater than or equal to 225 mmHg. Between 1991 and 2012, intraoperative hemodynamic variables were collected by the study team via retrospective chart review and were recorded at 5-min intervals. Pressures between measurements were linearly interpolated.The primary outcome measure of the study was postoperative AKI. We defined AKI according to the KDIGO clinical practice guidelines Khwaja . In our Univariable logistic regression model was used to examine the association between relevant patient demographic data, previous medical history, cardiac medication history, perioperative creatinine, baseline eGFR, intraoperative characteristics, and postoperative AKI. Univariable logistic regression model was also conducted to examine the association between intraoperative hemodynamic variables  under different threshold) and postoperative AKI.Multivariable logistic regression model was constructed to examine the adjusted association between intraoperative hemodynamic variables and postoperative AKI, while accounting for the effects of confounding factors. As adrenalectomy for pheochromocytoma, hypertensive episodes are common before tumor resection because of the excessive catecholamine secretion , while hypotensive episodes often occur after resection of the pheochromocytoma, intraoperative hemodynamic variables were both calculated during the whole procedure and in 2 separate phases (before tumor resection and after tumor resection). Given the particularity that patients with pheochromocytoma usually suffered from chronic hypertension, the incidence of AKI under different absolute MAP thresholds, including MAP < 65 mmHg and higher MAPs , as well as different relative decrease from baseline  was then using multivariable logistic regression respectively for further study, aiming to find a more sensitive absolute and relative MAP threshold in patients with pheochromocytoma for postoperative AKI. For each absolute and relative MAP thresholds, we divided the total time duration under this threshold into three values , and constructed an independent multivariable logistic regression model for this specific threshold. Since pheochromocytoma is a rare disease, the sample size of AKI patients included in this study is limited, then the use of Bonferroni correction may lead to a false-negative result. Therefore, we did not apply Bonferroni correction for multiple statistical comparisons, and our result was interpreted in an initial exploratory manner.All statistical tests were two-tailed at a significance level of 0.05. We used R version 4.0.2 for all statistical analyses.−1·1.73 m−2 in the AKI group and 100.0 ± 16.2 mL ·min−1·1.73 m−2 in the non-AKI group. The previous medical history, cardiac medication history, year of surgery, preoperative creatinine, preoperative and postoperative hemoglobin, and baseline hemodynamic variables  were balanced in the postoperative AKI and non-AKI groups.In a total of 677 patients who underwent adrenalectomy with pheochromocytoma between 1991 and 2019, the analysis included 560 patients who met our inclusion and exclusion criteria  and before tumor resection phase . However, after tumor resection, patients who developed postoperative AKI had lower MAP, greater % MAP decreases from baseline, and more cumulated minutes under all thresholds  compared to those with no evidence of AKI  and % MAP decreases from baseline  were associated with a statistically significant increase in postoperative AKI. The AUC for MAP < 85, 80, 75, 70, and 65 mmHg were also associated with statistically significant increase in postoperative AKI  according to the pathophysiological and intraoperative hemodynamic characteristics of pheochromocytoma. We found that pre-resection hypotension is less relevant with postoperative AKI than post-resection hypotension which could be explained by the pathophysiological mechanism that hypotension is considered a relatively rare situation before tumor resection than after resection. That is, for the prevention of AKI, anesthesiologists should pay more attention to the timely and effective treatment of post-resection hypotension.In our study, the AKI group had double the proportion of patients receiving vasodilators (14.6% vs 7.4%) after tumor resection; however, most of the patients who received vasodilators maintained an MAP greater than 65 mmHg. As all treatments were decided by the anesthesiologist to keep blood pressure and heart rate stable, this may be due to the target blood pressure varies in different anesthesiologists  compared to those with no evidence of AKI. Optimizing hemodynamics, especially blood pressure after the adrenal vessel ligation and tumor is resected, is crucial for the prevention of postoperative AKI in patient with pheochromocytoma, which could be different from general populations.


Accumulated evidence has shown that CKD increases the risk of cardiovascular diseases (CVD) such as myocardial infarction, stroke, and heart failure (HF), as well as death , and CKD should be an important target for primary CVD prevention such as heart failure (6).Chronic kidney disease (CKD) is a clinical diagnostic definition that comprehensively expresses pathological conditions where kidney damage or decreased kidney function persists (8). In addition, a large-scale cohort study of patients with CKD in Japan has reported that HF is more frequent than myocardial infarction and cerebrovascular disease as complications among patients with CKD (4); complications with a risk of acute kidney injury and cardiovascular-kidney comorbidity  are recent pathological features (6).Recent large-scale analysis of a Japanese real-world hospital database has shown that the presence of CKD or HF, in addition to type 2 diabetes, significantly increased mortality (9). It is issued by the Ministry, encouraging the conduction of awareness-raising activities regarding the importance of early detection and treatment of CKD (9).Therefore, the report of the study group on Measures against Kidney Disease, which was created in close cooperation with academic societies such as the Japanese Society of Nephrology, Japanese Circulation Society, Japan Diabetes Society, Japan Medical Association, local governments, and patient groups, was published by Health, Labor, and Welfare Association in July 2018 (2). Subsequently, the aging of patients with chronic dialysis has been noticeable in recent years, and the statistical analysis survey results by the Japanese Society for Dialysis Medicine [the annual report of The Japanese Society for Dialysis Therapy (JSDT) Renal Data Registry (JRDR)] also revealed that the number of patients with chronic dialysis would reach approximately 350,000 by the end of 2021, with an increasing trend in patients aged ≥70 years (11). Particularly, patients undergoing chronic dialysis are reported to have high mortality and hospitalization rates. Functional dependence is clinically recognized as a contributing factor to subsequent disability, recurrent hospitalization, and increased mortality (12). An increasing burden of functional dependence has been observed in several studies with progressive deterioration of kidney function; functional dependence may contribute to morbidity and mortality in patients with chronic dialysis, suggesting a problem from the socio-medical viewpoint in Japan and other countries (13).Moreover, the number of Japanese patients with CKD is estimated to be approximately 13.3 million, of which approximately 1 in 8 adults has CKD, and the prevalence of CKD is high among the elderly (2). Kidney function is assessed using glomerular filtration rate (GFR) and is calculated using the Japanese GFR estimation formula (eGFR-Cr) from serum creatinine level, gender, and age in daily clinical practice(14); additionally, the Japanese GFR estimation formula (eGFR-cysC) based on serum cystatin C levels can be used (15). If more accurate renal function is required, measured GFR is used using inulin clearance. Creatinine is produced by muscle, and serum creatinine levels are affected by muscle mass, so eGFR-Cr is estimated to be high in patients with decreased muscle mass due to sarcopenia  in elderly people, muscle disease, or limb loss (2). Conversely, eGFR-Cr is estimated to be low in cases such as athletes who have a habit of exercising and a large amount of muscle mass (2). Serum creatinine levels are also affected by diet, exercise, and renal tubular secretion (2). Cystatin C is produced by cells throughout the body, and serum cystatin C levels are not affected by muscle mass but are influenced by thyroid function, smoking, inflammation, fat mass, pregnancy, and immunosuppressants．Although CKD often presents a few subjective symptoms, it can be easily diagnosed by blood and urine tests. Therefore, the prevention of severity and suppression of CVD onset through early diagnosis, via health checkups, tests at medical institutions, and providing appropriate treatment, is important (16). Uemura et al described the accuracy of eGFR-cysC, when compared with eGFR-Cr, in patients with SMID. In their study, the authors measured 24h-Ccr in 18 patients with SMID and converted it into inulin clearance (Cin), which is the gold standard for measuring GFR, by an equation developed from children (16). The authors reported that eGFR-Cr does not reliably estimate kidney function in adult patients with SMID and alternatively recommended using cystatin C (cysC)-based eGFR (eGFR-cysC) in the Japanese population of severe motor and intellectual disabilities (16). This study was well performed and the results were important and interesting, especially for practitioners and researchers in the fields of kidney medicine and gerontology (16).Calculating eGFR in patients with severe motor and intellectual disabilities (SMID) using serum creatinine overestimates kidney function due to low muscle mass. Thus, in this issue of JMA Journal, Uemura O et al aimed to evaluate and compare the efficacy of eGFR formulae in patients with SMID by evaluating the efficacy of three eGFR equations, creatinine clearance (Ccr)-based eGFR (eGFR-Cr), serum cystacin C (cysC)-based eGFR (eGFR-cysC), and serum beta-2 microglobulin (β2MG)-based eGFR (eGFR-β2MG), in 18 patients with SMID NoneKouichi Tamura is one of the Editors of JMA Journal and on the journal’s Editorial Staff. He was not involved in the editorial evaluation or decision to accept this article for publication at all.


Background: Asthma rehabilitation at high altitude is common. Little is known about the acute and subacute cardiopulmonary acclimatization to high altitude in middle-aged asthmatics without other comorbidities.Methods: In this prospective study in lowlander subjects with mostly mild asthma who revealed an asthma control questionnaire score >0.75 and participated in a three-week rehabilitation program, we assessed systolic pulmonary artery pressure (sPAP), cardiac function, and extravascular lung water (EVLW) at 760 m (baseline) by Doppler-echocardiography and on the second (acute) and last day (subacute) at a high altitude clinic in Kyrgyzstan (3100 m).Results: The study included 22 patients  with a mean age of 44.3 ± 12.4 years, body mass index of 25.8 ± 4.7 kg/m2, a forced expiratory volume in 1 s of 92% ± 19% predicted (post-bronchodilator), and partially uncontrolled asthma. sPAP increased from 21.8 mmHg by mean difference by 7.5 [95% confidence interval 3.9 to 10.5] mmHg (p < 0.001) during acute exposure and by 4.8 [1.0 to 8.6] mmHg (p = 0.014) during subacute exposure. The right-ventricular-to-pulmonary-artery coupling expressed by TAPSE/sPAP decreased from 1.1 by −0.2 [−0.3 to −0.1] mm/mmHg (p < 0.001) during acute exposure and by −0.2 [−0.3 to −0.1] mm/mmHg (p = 0.002) during subacute exposure, accordingly. EVLW significantly increased from baseline (1.3 ± 1.8) to acute hypoxia  but showed no difference after 3 weeks (2.0 ± 1.8).Conclusion: In otherwise healthy asthmatics, acute exposure to hypoxia at high altitude increases pulmonary artery pressure (PAP) and EVLW. During subacute exposure, PAP remains increased, but EVLW returns to baseline values, suggesting compensatory mechanisms that contribute to EVLW homeostasis during acclimatization. The resulting elevated pulmonary artery pressure (PAP) while traveling to high altitude has been associated with right-sided cardiac dysfunction and may predispose the patient to high-altitude pulmonary edema (HAPE), which is a life-threatening condition associated with increasing extravascular lung water   . When thB-lines) .Previous studies on the PAP and right heart function at high altitude have focused mainly either on acute short-term exposure in healthy younger travelers or highlanders permanently living at high altitude . HoweverTherefore, the purpose of the current study was to describe the cardiac function and hemodynamics and perform sonographic assessments of EVLW in otherwise healthy asthmatic lowlanders staying for 3 weeks at a high altitude (3100 m) while participating in a comprehensive rehabilitation program.This prospective study was embedded in a randomized controlled trial investigating the effect of 3 weeks of asthma rehabilitation at a high altitude . We condThe patients participated in a rehabilitation program during the high-altitude stay, including patient education, endurance training, muscle strength training, breathing exercises, and guided walks. A detailed description of the intervention can be found in the previous publication .The study was performed between June and July 2016 and was approved by the Ethics Committee of the National Center of Cardiology and Internal Medicine, Bishkek, Kyrgyzstan (No. 01-8/151). All patients provided written informed consent.Patients with mild to moderate, atopic, or non-atopic asthma that was not optimally controlled were included in this current trial. All patients had lived in or near Bishkek below 1,000 m for the last 3 months. Patients with an underlying cardiac pathology, assessed by taking a history and echocardiography, were excluded; for details, see ®, Bothell, United States of America), using a 5 to 1 MHz sector array transducer, and analyzed after the examination on the same system by the same physicians. A standard echocardiographic investigation was performed according to guidelines . The images were obtained with a CX 50 Ultrasound System (Philipsidelines .The tricuspid regurgitation pressure gradient (TRPG) was derived from the maximal tricuspid regurgitation jet velocity (TRVmax) using the modified Bernoulli equation. The systolic PAP (sPAP) was calculated by adding the maximal TRPG to the right atrial pressure (RAP), which was rated as 3, 8, or 15 mmHg, depending on the diameter and collapsibility of the inferior vena cava . The meaThe left ventricular systolic function was assessed by the ejection fraction (EF) according to the modified Simpson’s rule. Stroke volume (SV) was calculated using the velocity time integral and the diameter of the left ventricular outflow tract (LVOT). Cardiac output (CO) was derived by multiplying the SV by the heart rate (HR). Stroke volume index (SVI) and cardiac index (CI) were obtained by dividing SV and CO by the body surface area (BSA). The assessment of the right ventricular function included the following parameters: tricuspid annular plane systolic excursion (TAPSE), tricuspid annular systolic velocity (TASV), RV end-diastolic area (RV-EDA), RV end-systolic area (RV-ESA), right ventricular fractional area change (RV-FAC), diastolic right and left ventricular internal diameters and their ratios (RVIDd/LVIDd) from an apical four-chamber view, and right atrial end-systolic area (RA-ESA). The total pulmonary resistance was calculated with mPAP/CO, the right ventricular arterial coupling was calculated with TAPSE/sPAP , the pulAfter the echocardiographic examination, all patients were assessed for EVLW by looking for the number of B-lines in a supine position with the same ultrasound machine and transducer described previously . A B-lin2) spirometry, and a 6-min walk test (6 MWT) were obtained in the same time frame , heart rate (HR) and pulse oximetry .Data are presented as mean and ± SD. EVLW (B-lines) and echocardiographic and physiological parameters were analyzed in linear mixed models with different time points . The average marginal effects (mean difference) induced by time were extracted from these regression models and expressed as mean change with 95% confidence intervals. Model assumptions were tested by visual inspection of the homogeneity and normality of the residuals and the random effects (Kentucky–Ascombe and Q–Q plots). A Of 25 patients in the high altitude asthma rehabilitation study, 22 were included in this per-protocol study. Three patients were not available due to personal reasons ; see Characteristics of the 22 patients (14 women), aged between 24 and 66 years, all non-smokers with no relevant cardiac comorbidity, are displayed in p < 0.001) with a subsequent reduction over the course of the high-altitude stay and did not show a significant difference to the baseline . Oxygen saturation significantly decreased at altitude in the acute phase and only slightly recovered in the subacute phase .p > 0.05).There was no significant change in systolic and diastolic blood pressure .The echocardiographic results are shown in sPAP increased from 21.8 mmHg by 7.5 [3.9 to 10.5] mmHg in the acute exposure and by 4.8 [1.0 to 8.6] mmHg in the subacute exposure compared to baseline. Pulmonary vascular resistance increased from 1.5 WU at baseline by 1.5 [0.9 to 2.1] WU in the acute exposure and 0.8 [0.1 to 1.5] WU in the subacute exposure, and the right ventricular coupling expressed by TAPSE/sPAP decreased from 1.1 at baseline by −0.2 [−0.3 to −0.1] mm/mmHg in the acute exposure and −0.2 [−0.3 to −0.1] mm/mmHg in the subacute exposure; all values are statistically significant.The FAC of the right ventricle was significantly reduced in the subacute phase, and the size of the right ventricle was significantly larger than the baseline.Most patients tolerated the high altitude very well; only one patient suffered from asthma exacerbation, defined as a decline in PEF of >12%, and one patient, who suffered from AMS during the high-altitude stay, was treated with acetazolamide .2 and an increase in HR with altitude and were maintained after 17 nights at high altitude. All changes, with the exception of the PVR, remained below a level considered pathological at low altitude. EVLW was assessed as B-lines increased upon acute exposure to the high altitude but returned to low altitude baseline values after 17 days, suggesting compensatory mechanisms that contribute to EVLW homeostasis during acclimatization.In this study, we showed for the first time the acute and subacute effects of exposure to the hypobaric hypoxic environment on PAP, heart function, and EVLW in patients with mostly mild but partly uncontrolled asthma who participated in a three-week asthma rehabilitation program at high altitude (3100 m). We could show that in accordance with healthy subjects, sPAP increased with acute exposure to high altitude, albeit remaining below a level that would define pulmonary hypertension (PH), along with an increased PVR and a slightly lower TAPSE/sPAP ratio at high compared to low altitude but still within normal range. These changes went along with a decrease in SpO2 decreased from 95% to 89% upon acute exposure to the high altitude and slightly rose during subacute exposure but remained decreased compared to the low altitude. Mean systemic blood pressure did not change with acute or subacute exposure to the high altitude. Previous studies have shown that blood pressure tends to be elevated only in the first 10–24 h and then normalizes over the next days at a moderate altitude (∼2500 m), but several weeks of acclimatization are needed to normalize the blood pressure at higher altitudes  but did not take baseline measurements at the low altitude. In contrast to the Chinese study, the Turkish study showed that RV diastolic function is altered upon long-term exposure to moderate altitudes, whereas systolic function was preserved .2. This is consistent with compensatory mechanisms that assure adequate homeostasis of lung water during prolonged exposure to hypobaric hypoxia.B-lines can be used to measure extravascular lung water. High-altitude exposure can lead to acute mountain sickness and HAPE . The incBecause all patients underwent an asthma rehabilitation program during the high-altitude stay, a distinction between training and altitude effects cannot be made. However, it seems unlikely that asthma rehabilitation would have had a significant effect on PAP and heart function. Furthermore, with the background knowledge of similar changes found in acclimatization studies of healthy lowlanders without rehabilitation programs, it is well conceivable that changes seen here are due to the high-altitude exposure and subsequent acclimatization and not due to the asthma rehabilitation program, albeit the 3 weeks of asthma rehabilitation were associated with a significant increase in exercise capacity measured by the 6-minute walk distance and the 1 min sit-to-stand test and better asthma control. In addition to forced expiratory volume in 1 s, exhaled nitric oxide and hemoglobin were also significantly increased after the rehabilitation at the high altitude compared to the rehabilitation at the low altitude .All but two patients in this study had mild asthma but initially revealed an asthma control questionnaire score >0.75, which improved with the rehabilitation program, and all were otherwise healthy . High-alThere were many missing values of the TRPG at the last assessment in subacute hypoxia; whereas TRPG was assessable in 82% of subjects at baseline and even in 86% of subjects at acute high altitude measures, it was only present in 59% of subjects after 17 nights at the high altitude. The reason for the failing presence of the TRPG during subacute exposure to the high altitude is unclear but may be explained by hitherto unexplained acclimatization mechanisms. Echocardiography is associated with a potentially relevant intra- and interobserver variability, which was reduced by using the same echocardiographers throughout the study and double-checking the measurements. Because no blood gas analysis was carried out, we were not able to determine arterial oxygen content and oxygen delivery.In this first comprehensive assessment of the PAP, heart function, and EVLW upon acute and subacute exposure to a high altitude during asthma rehabilitation, we showed that in patients with mostly mild asthma, in accordance with findings in healthy subjects, PAP increases with altitude and remains elevated for up to 3 weeks, albeit with all changes being below pathological values proposed at a low altitude.


Blood pressure oscillations during different time scales, known as blood pressure variability (BPV), have become a focus of growing scientific interest. BPV can be measured at long-term , at mid-term (differences in consecutive days or weeks) or at short-term (day-night differences or changes induced by other daily activities and conditions). An increased BPV, either at long, mid or short-term is associated with a poor cardiovascular prognosis independently of the amount of blood pressure elevation. There is scarce evidence on the effect of different antihypertensive treatments on BPV, but some observational and interventional studies suggest that calcium channel blockers in general, and particularly amlodipine, either in monotherapy or combined with renin-angiotensin system blockers, can reduce BPV more efficiently than other antihypertensive drugs or combinations. Nevertheless, there are several aspects of the relationship between BPV, antihypertensive treatment, and clinical outcomes that are still unknown, and more work should be performed before considering BPV as a therapeutical target in clinical practice. High blood pressure (BP) is one of the most powerful determinants of cardiovascular risk . BP estiThe importance of BPV is that such fluctuations are related with the development of organ damage, cardiovascular events and mortality, independently of the absolute degree of BP elevation. Such circumstances have created a great interest in the understanding of mechanisms responsible for BPV, the different types of variability and the methods of assessment, as well as possible therapeutical interventions modifying several aspects of BPV.The types of BPV, their physiological regulation, and methods of assessment depend on the time scale contemplated. It ranges from very short periods of time, such as beat-to-beat or even intra-beat variability, short-term variability, usually defined as variations occurring in a 24 h period of time, day-to-day, week-to-week, or long-term variability, including variations occurring among visits, in different seasons of the year, or even through several years ,4.The physiological regulation of BP variations, as well as its derangements, are complex and poorly understood. They constitute a mixture of cardiovascular regulatory mechanisms, as well as behavioral and environmental factors . In addiThe assessment of very-short-term BPV requires continuous monitoring. This can be achieved by intra-arterial recording, or with the use of some non-invasive devices. Its use is usually restricted to monitor patients in intensive care units, emergencies or operation rooms. Continuous ambulatory non-invasive devices using finger plethysmography were developed several years ago, but were impractical for its use in ambulatory patients ,6. ShortThe standard deviation (SD) and the coefficient of variation  are the most commonly used indices for all types of BPV. Variability independent of the mean has been also proposed for the assessment of visit-to-visit variability, and it is calculated by dividing SD by the mean powered to a value obtained by non-linear regression analysis of population values .Several other indices are also commonly used for short-term BPV. Among them, the most important are weighted SD and average real variability (AVR). The first is obtained by the average of daytime and nighttime SD weighted for the duration of each period . Its maiThe first and most consistent data regarding the prognostic influence of BPV refers to long-term or visit-to-visit variability. A post hoc analysis of four large clinical trials, including a large cohort of patients with a history of transient ischemic attacks  and a large population of patients with hypertension and added risk factors (ASCOT-BPLA) demonstrated that intervisit BP variability and peak BP values were strong predictors of stroke independently of mean SBP and, albeit to a lesser extent, equally associated with coronary risk . Since tRegarding mid-term BPV and cardiovascular prognosis, two population studies have confirmed the prognostic value of BP variability in the medium term. In the Ohasama study , increasWith regard to short-term BPV, as measured through ABPM, the relationship has been established both with the standard deviation estimators, night pressure fall and with the morning surge. An increase in the standard deviation both during the day  and at nThe nocturnal fall in BP also has an important impact on cardiovascular prognosis. The first studies already suggested that a lack of nocturnal decrease in BP was associated with a worse cardiovascular prognosis . The datThe main problem in assessing the prognostic value of circadian pattern alterations is the association of both nocturnal BP fall with nocturnal BP levels, a very well known factor for a higher risk of mortality and cardiovascular events .Not only the nocturnal decrease in BP, but also the increase that occurs upon awakening may be important from the prognostic point of view. Thus, in the Japanese population or those of other Asian countries, an excessive increase in the morning has been associated with a greater risk of events, especially cerebral vascular accidents of hemorrhagic etiology . HoweverMeta-analyses of clinical trials in hypertension with different classes of antihypertensive drugs have strongly supported that mean BP reduction is essential to achieve cardiovascular protection . MoreoveWith respect to mid-term BPV, studies on the effect of antihypertensive treatment are few and quite inconsistent. Only one comparative study evaluating the effects of two types of antihypertensive combinations found that a combination of an angiotensin receptor antagonist with a calcium antagonist was more effective in reducing home SBP variability than the combination of the same receptor antagonist with a thiazide diuretic . FinallyWith respect to short-term BPV, again studies have shown a beneficial effect of calcium channel blockers, particularly amlodipine. The X-CELLENT study  showed aIn the Spanish ABPM Registry, we looked at short-term BPV in a very large number of patients under different types of antihypertensive therapies, including monotherapies and different combinations . A totalIn this latter group of patients treated with monotherapy, the comparison among the major drug classes revealed lower BPV indices in those treated with calcium channel blockers or diuretics, in comparison with beta blockers, ACE inhibitors or ARB. When looking at the different compounds inside each therapeutic class, there were no differences in BPV among diuretics , while in the calcium channel blocker group, amlodipine was associated with lower values of BPV, in comparison to other dihydropyridines, diltiazem or verapamil. Finally, this favorable effect of calcium channel blockers, particularly amlodipine, was also observed in patients treated with a two-drug or a three-drug combination, with those including a calcium channel blocker being associated with lower values of BPV indices.It has recently been suggested that new non-pharmacological treatments for resistant AHT, such as renal denervation, could have a beneficial effect on short-term variability. In this regard, in a clinical trial comparing treatment with spironolactone versus renal sympathetic denervation, the latter procedure had a greater effect on the short-term variability of diastolic pressure, measured by the 24 h weighted standard deviation or by the average real variability . A recenThere is considerable theoretical evidence that abnormalities in BPV are associated with the cardiovascular prognosis. However, BPV is a general term including several possible abnormalities, which in fact may have different pathogenetic mechanisms. It is difficult to admit that differences in BP among long-term visits or seasonal variations have any relation with day–night changes or other changes in shorter periods of time. They are all considered BPV, but mechanisms responsible are obviously different. Moreover, it is still a matter of debate if increased BPV is a true risk factor influencing the prognosis or merely a marker of other alterations. In addition, all the evidence regarding the impact of therapeutical maneuvers on BPV are based on post hoc analyses of clinical trials, in which the primary objective was the cardiovascular prevention through the achievement of an absolute BP reduction.Considering these limitations, it can be hypothesized that the impact of different antihypertensive treatments, in reducing BPV in addition to their effect on absolute BP, might be an advantage in terms of protection. Results from clinical observations suggest that long-acting calcium channel blockers have an advantage over other types of drugs. However, if this advantage is related to the mechanism of action or to their pharmacokinetic properties is still unknown. New drugs under development include some possible changes in the way antihypertensive treatment is currently administered. The possibility of using drugs administered once per month or even once or twice per year will open different perspective in the assessment and the role of BPV.Not only possible changes in antihypertensive treatment, but future changes in BP measurement and monitoring will also impact in the study of BPV. The growing use of wearable BP devices represents a unique opportunity, and may change the way BP is measured in the future. They have obvious advantages, as the possibility of monitoring BP very frequently, almost continuously, without interfering individual activities and without tolerability issues is clearly promising. These aspects are of particular relevance in the evaluation of BPV, and can serve for future studies. However, as it has been recently stated , the accIt is possible that the different classes of antihypertensives may have a different impact on blood pressure variability, at short, mid or long terms. If this could be translated to a greater cardiovascular protection, independently or added to the decrease in mean BP values will need specific clinical trials to be assessed. It is also possible that not only the antihypertensive drug class, through its mechanism of action, but also the pharmacokinetics of each compound would impact BPV, with drugs with longer duration of action reducing more efficiently BPV.


CDKAL1 rs10946398, GCK rs1799884, GCKR rs780094 and DGKB/TMEM195 rs2191349, with the development of post-transplant diabetes in kidney transplant patients. This study included 201 Caucasian patients after kidney transplantation treated with tacrolimus. An association was observed between the CDKAL1 rs10946398 gene polymorphism and PTDM. Among patients with PTDM, there was an increased prevalence of the CC genotype in the PTDM group compared to the group without PTDM. The chance of PTDM in those with the CC genotype was 2.60 times higher compared to those with the AC + AA genotypes (CC vs. AC + AA OR (95% CI): 2.60 (1.02–6.61), p = 0.040). Multivariate logistic regression analysis showed that advanced age and the CC genotype (rare homozygote) of CDKAL1 rs10946398 were risk factors for the development of PTDM at 1 year after transplantation. There was no statistically significant association between GCK rs1799884, GCKR rs780094 or DGKB/TMEM195 rs2191349 polymorphisms and the development of post-transplant diabetes mellitus in kidney transplant patients. The results of this study suggest that the CDKAL1 rs10946398 CC genotype is associated with the increased risk of PTDM development in patients after kidney graft transplantation treated with tacrolimus.Post-transplant diabetes mellitus (PTDM) is a common complication that occurs in kidney transplant patients, increasing the risk of infection, cardiovascular disease and loss of graft function. Currently, factors that increase the risk of this complication are being sought, among them polymorphisms in genes that regulate carbohydrate metabolism and influence pancreatic β-cell function. The aim of this study was to evaluate the association of selected polymorphisms of genes affecting carbohydrate metabolism, such as  Kidney transplantation is the most effective treatment for kidney failure because it restores normal kidney function, resulting in a better quality of life and longer patient survival. Post-transplant diabetes mellitus (PTDM) is one of the most common complications of renal transplantation, worsening the prognosis of recipient survival and function of the transplanted organ. Patients with PTDM, compared to patients without PTDM, have a higher incidence of infection, episodes of acute rejection, a deterioration of graft function and faster graft loss, cardiovascular incidents , ischemic heart disease and death .PTDM is most often found in the first year, especially in the first three months, after kidney transplantation. Its pathomechanism is similar to that of type 2 diabetes mellitus, but the exact pathogenesis remains unknown. In PTDM, both decreased insulin secretion by pancreatic β-cells and tissue insulin resistance were observed . All of Due to the similar pathogenesis of PTDM and type 2 diabetes, risk factors are currently being sought among the genetic polymorphisms associated with the development of type 2 diabetes . Among tCDKAL1 gene, located on the short arm of chromosome 6, consisting of 65 amino acids. CDKAL1 is involved in the pathogenesis of diabetes type 2 through impaired β-cell function [Cyclin-dependent regulatory kinase subunit 5 (CDK5) regulatory subunit associated protein 1 like 1 (CDKAL1) is a protein encoded by the function .CDKAL1 gene have been shown to be associated with a decrease in insulin sensitivity of the body’s tissues and an increased risk of type 2 diabetes [CDKAL1 gene polymorphism rs10946398 was found to be associated with decreased insulin secretion by pancreatic β-cells [Certain polymorphisms in the diabetes . The CDK β-cells .Glucokinase (GCK) is an essential enzyme involved in glucose metabolism that belongs to the hexokinase family of isoenzymes. It is found in cells of the pancreas, liver, brain and gastrointestinal tract. It is encoded by the gene for glucokinase, which is located on chromosome 7. Glucokinase catalyses the phosphorylation reaction of glucose to glucose-6-phosphate in the cytoplasm. It is the first step in glucose metabolism . The gluGCKR consists of 19 exons and is located on the short arm of chromosome 2 (2p23) [The glucokinase regulator (GCKR), otherwise known as glucokinase regulatory protein, (GKRP), is a 68 kDa protein containing 626 amino acids, which is formed in hepatocytes and is responsible for the binding and translocation of glucokinase, thus controlling both its activity and intracellular localisation. The gene encoding 2 (2p23) . The rs72 (2p23) ,16,17.DGKB gene, located like the transmembrane protein 195 (TMEM195) gene on chromosome 7 (p21.2) [DGKB and TMEM195 intergenic region have been shown to influence the development of type 2 diabetes and obesity [Diacylglycerol kinase β (DGKB or DAGK2) belongs to a family of enzymes that catalyses the reaction to convert diacylglycerol (DAG) to phosphatidic acid (PA) by using ATP as a phosphate source. It is a very small 13–15 kDa integral membrane protein encoded by the  p21.2) . Polymor obesity ,21..2 . PolyCDKAL1 rs10946398, GCK rs1799884, GCKR rs780094 and DGKB/TMEM195 rs2191349 gene polymorphisms and the development of post-transplant diabetes in kidney transplant patients treated with tacrolimus.Due to the possible influence of genes that affect carbohydrate metabolism and are associated with an increased risk of type 2 diabetes as well as the diabetogenic effects of tacrolimus, the purpose of this study was to assess whether selected polymorphisms of these genes could affect the risk of PTDM in kidney transplant patients treated with tacrolimus ,10,22,23The study group consisted of 201 Caucasian patients  after kidney transplantation from a deceased donor. Patients in the whole group were treated with tacrolimus. Patients who had a diagnosis of diabetes mellitus (type 1 or type 2) before kidney transplantation (either as a cause of kidney disease or as a comorbidity) and patients with graft failure or death within the first month after transplantation were excluded from the study, and patients observed for less than 12 months were also excluded. Kidney transplants were performed at the Department of General and Transplant Surgery of Pomeranian Medical University. Immunosuppressive treatment of transplant patients included a standard three-drug therapeutic regimen with calcineurin inhibitors (tacrolimus (TAC), mycophenolate mofetil (MMF) and glucocorticosteroid (GCS). Tacrolimus dosing was started at 0.1 mg/kg body mass, with doses modified to maintain plasma concentrations between 10 and 12 ng/mL in the first month after transplantation and then between 8 and 10 ng/mL in subsequent months. Mycofenolate mofetil was administered at a dose of 2 g per day and prednisolone at a dose of 10–20 mg per day. Post-transplant diabetes was diagnosed in patients with glycated haemoglobin A1c levels above 6.5% and fasting glucose levels above 7.0 mmol/L, sustained for more than 3 months. The study was approved by the local ethics committee (BN-001/59/04), and written informed consent was obtained from all participants.® Pre-Designed SNP Genotyping Assays were used .Genomic DNA was extracted from 1 mL of peripheral blood samples using a Genomic Mini AX Blood 1000 Spin kit  following the manufacturer’s protocol. Prior to isolation, blood samples were stored at −80 °C. DNA was subsequently standardised to equal concentrations of 20 ng/µL, based on spectrophotometric absorbance measurements (260/280 nm)  . Testingp < 0.05 was used as the threshold for statistical significance.Statistical analysis of the obtained results was carried out using the statistical program STATISTICA 13. Compliance of the distributions of genotypes with the Hardy–Weinberg law (HWE) was evaluated using Fisher’s exact test. The chi-square test (χ2) was used to compare the distributions of genotypes and alleles between groups. Multivariate logistic regression analysis was used to evaluate independent factors associated with the risk of developing post-transplant diabetes during the year after kidney transplantation. 2 (±2.9), respectively. The follow-up period was 12 months after transplantation.In this study, we examined patients after kidney allograft transplantation . The mean age of the patients at the time of transplantation was 44.6 years (±13.2), and the mean body mass and BMI of the patients at the time of transplantation were 72.4 kg (±11.3) and 24.6 kg/mCDKAL1 rs10946398 gene polymorphism and PTDM. Among patients with PTDM, there was an increased prevalence of the CC genotype in the PTDM group compared to the group without PTDM. The risk of PTDM in individuals with the CC genotype was 2.60 times higher compared to those with the AC + AA genotypes (CC vs. AC + AA OR (95% CI): 2.60 (1.02–6.61), p = 0.040) (An association was observed between the = 0.040) . PTDM waCDKAL1 rs10946398 polymorphism as independent variables in a recessive model showed that advanced age and the CC genotype (rare homozygote) of CDKAL1 rs10946398 were risk factors for the development of PTDM at 1 year after transplantation in patients treated with tacrolimus  [The association between pulation . In a me= 0.006) . Helvaci= 0.006) .GCK rs1799884, GCKR rs780094 and DGKB/TMEM195 rs2191349 polymorphisms and the risk of PTDM developing in patients treated with tacrolimus. These genes affect pancreatic β-cell function and insulin secretion, and their polymorphisms have been shown to be associated with the development of type 2 diabetes. Our results may suggest that there is no interaction between the pathways modulated by these genes and the effects of tacrolimus, which could explain the lack of association of the polymorphisms studied with PTDM. Since our work was limited by the number of patients, it is also possible that the effect of these genes on PTDM risk is so small that its detection would require studies on a much larger group of subjects.We found no statistically significant association between the PTDM is a metabolic complication that occurs in organ transplant patients, especially those treated with calcineurin inhibitors. The pathogenesis of PTDM is very complex and includes both impaired insulin secretion and tissue insulin resistance. Underlying this complication are factors affecting carbohydrate metabolism and pancreatic function, including genetic conditions. To date, many studies have considered the role of genetic polymorphisms as risk factors for the development of PTDM . In partCDKAL1 gene rs10946398 polymorphism and post-transplant diabetes in kidney allograft recipients treated with tacrolimus. Patients with the CDKAL1 rs10946398 CC genotype treated with tacrolimus had an increased risk of developing PTDM. The lack of evidence on the association of polymorphisms of other analysed genes involved in glycaemic regulation  with the risk of post-transplant diabetes in kidney transplant recipients suggests that they do not play a key role in the development of this type of diabetes. Determining the exact role of genetic polymorphisms as risk factors for PTDM requires further multicentre studies.The results of this study suggest an association between