Soon after haemodialysis was introduced into clinical practice, a high risk of cardiac death was noted in end-stage renal disease. However, only in the last decade has it become clear that any renal injury, acute or chronic, is associated with high overall and cardiovascular lethality. The need for early recognition of kidney damage in cardiovascular pathology to assess risk and develop tactics for patient management contributed to the emergence of the concept of the “cardiorenal syndrome” (CRS). CRS is a pathophysiological disorder of the heart and kidneys in which acute or chronic dysfunction of one of these organs leads to acute or chronic dysfunction of the other. The beneficial effect of ultrafiltration as a component of renal replacement therapy (RRT) is due to the elimination of hyperhydration, which ultimately affects the improvement in cardiac contractile function. This review considers the theoretical background, current status of CRS, and future potential of RRT, focusing on the benefits of ultrafiltration as a therapeutic option. The relationship between heart and kidney disease has been studied by both cardiologists and nephrologists. Cardiorenal syndrome (CRS) appears to be an interference of heart and kidney diseases. Acute heart failure (AHF) is a syndrome defined as new onset (de novo) heart failure (HF) or worsening symptoms and signs from HF, primarily associated with systemic congestion . In the ADHF is one of the most common causes of hospitalization and represents a significant burden to the health care system. ADHF is associated with medication nonadherence, comorbidities, diet, modifiable risk factors, disease progression, and/or treatment failure, and all of these factors lead to high hospitalization rates. The data on annual hospitalizations due to HF exceed 1 million in the United States of America (USA) and Europe ,4. More Because of multimorbidity, patients with ADHF invariably present with multiple comorbidities that often lead to urgent hospitalization. Demographic studies in ADHF patients have shown that cardiac comorbidities are common and can negatively impact treatment outcomes. Typical cardiac comorbidities include atrial fibrillation/flutter 30–46%), valvular heart disease (44%), and dilated cardiomyopathy (25%) %, valvul.Soon after the introduction of haemodialysis, a high risk of cardiac death was found in end-stage renal disease , but it Standard treatment is usually conservative, mainly with intravenous loop diuretics. Resistance to diuretics often develops beyond heart failure (HF). One of the most effective methods of treating severe, drug-resistant CRS is the use of renal replacement therapy (RRT). The beneficial effect of ultrafiltration (UF) as a component of RRT is based on the elimination of hyperhydration, a reduction in the load on the heart due to the reduction in venous return, which ultimately has an effect on improving the contractile function of the heart. Here we aimed to present an analysis of the clinical data supporting the use of UF in CRS, with a particular focus on identifying clinical situations where such treatment options are beneficial.Cardiorenal communication is important for controlling blood pressure, regulating the excretion of sodium and water by the kidneys, and ensuring adequate blood flow and oxygenation of tissues. Acute or chronic disease of one organ can lead to acute or chronic dysfunction of the other, and vice versa . In HF pAn uncontrolled increase in urine output during diuretic therapy can lead to hypovolaemia and a decrease in preload, and the use of vasodilators can cause hypotension. In addition, non-steroidal anti-inflammatory drugs, cyclosporine, angiotensin converting enzyme inhibitors (ACE), and angiotensin II receptor blockers (ARA II) can also cause a decrease in renal blood flow.Diuretic resistance is the absence of effective decongestion  despite adequate or increasing doses of diuretics. At the same time, a reduction in blood flow through the afferent artery and a reduction in sodium and chlorine concentrations in the distal nephron contribute to several pathophysiological effects that increase renin and angiotensin II production. Angiotensin II stimulates the adrenal cortex to produce aldosterone (ALDO). ALDO maintains fluid balance by supporting active sodium reabsorption in the kidney and colon, leading to fluid retention. On the contrary, an increase in sodium concentration in the distal nephron reduces the release of renin, angiotensin II, and ALDO. The increase in circulating blood volume (BCV) and LV pressure activate natriuretic peptide (NUP) synthesis. Normally, the main source of these peptides is the atrial tissue. When preload is increased, the synthesis of B-type atrial NUP (BNP) is initially accelerated; with sustained volume overload and remodelling of the ventricles, the synthesis of BNP increases markedly. NUPs have several effects on the nephron, including dilating afferent arterioles and constricting efferent arterioles, increasing intraglomerular pressure, decreasing mesangial tone, and improving effective renal filtration. In addition, ALDO production decreases due to inhibition of renin secretion secondary to a decrease in sodium reabsorption in the distal (convoluted) tubule of the kidney. Overall, the NUPs have an antagonistic effect on the RAAS. Volume overload or congestion in HF occurs due to increased filling pressures in the left and/or right ventricle. The role of the kidneys in the development of fluid overload and congestion is crucial even in the early stages of HF ,19. In HNevertheless, the effects of the RAAS remain without adequate countermeasures beyond sustained increased activity of vasopressor systems. As a result, excessive sodium and water retention, vasoconstriction, and volume overload occur .Conventionally, two periods are distinguished in the development of stagnation: the haemodynamic period and the clinical manifestation period . In the It is important to identify acute fluid diversion to detect general hyperhydration due to fluid retention in patients with the manifestation of ADHF, as this may influence the management of these patients.Resistance to diuretics seems to indicate a worse prognosis in patients with HF. It is characterised by a decrease or absence of response to diuretics before improvement in symptoms associated with congestion . It can A Cochrane review compared a number of scientific papers on continuous and concurrent infusions of loop diuretics in patients with chronic heart failure (CHF): a better diuretic effect and shorter hospital stay were found in cases with prolonged administration . In a suAggressive diuretic therapy in this group of patients may lead to diuretic-induced hypovolaemia provoking renal failure, as has been reported in patients with acute CRS. Therefore, gradual achievement of a diuretic effect is preferable .When congestion symptoms and the amount of circulating fluid increase, they are difficult to control with conventional therapeutic treatments. In patients resistant to diuretics, the UF method is used to reduce hypervolaemia with significant WRF and electrolyte disturbances ,44.Recently, due to the increase in the prevalence of cardiovascular pathologies, longer life expectancy of cardiac patients, and the use of interventional examination and treatment methods, the incidence of acute renal failure (ARF) has also increased . The AcuCRS of the first type is a sudden, acute deterioration of the heart leading to acute kidney injury (AKI). It occurs in approximately 25% to 33% of patients admitted with acute decompensated HF . Type 1 CRS of the second type is characterised by the presence of CHF in a patient leading to the development and progression of CKD over time. The incidence of CKD in patients with CHF can be 45–63.6% and is a poor predictor of cardiovascular death . TherapeCRS of the third type or acute kidney syndrome includes primary and acute renal dysfunction due to acute glomerulonephritis, pyelonephritis, or acute tubular necrosis. AKI, in turn, causes HF, cardiac arrhythmias, and myocardial ischaemia. AKI occurs most frequently in ICU patients (35%) . Timely CRS of the fourth type is characterised by CKD leading to CHF. The incidence of CKD has recently increased worldwide, reaching 10–15% . One of Currently, the main causes of CKD are diabetes mellitus, arterial hypertension, atherosclerosis, and obesity, diseases that are most prevalent in developed countries. The risk of dying from cardiovascular disease is increased 10–20-fold in patients with CKD compared to patients without CKD . The extCRS of the fifth type is a combination of cardiac and renal pathology as a result of acute injury, in which the dysfunction of one organ affects the function of another. Type 5 CRS occurs in septic patients or other critical conditions ; CKD andIn addition, a new definition was announced in 2022, renal tamponade or renal compression, to explain congestive nephropathy caused by limited space for renal expansion . This coRRT methods, especially UF, haemodialysis (HD), haemofiltration (HF), and haemodiafiltration (HDF), are widely used in nephrology practice and in the management of critical conditions. One of the components of HD, HF, and HDF is UF, i.e., mechanical fluid removal, which ultimately leads to elimination of overhydration and more effective recovery of sensitivity to drug therapies. A number of studies have established the efficacy of UF as the method of choice in the treatment of severe CRS. Recently, a “hybrid” RRT technique has emerged in clinical practice, called sustained low-efficiency dialysis (SLED). SLED differs from intermittent HD in that it uses a lower blood flow rate, dialysate, and a longer duration of sessions. Sparse modes of this technique allow the maintenance of haemodynamic stability while performing clearance of low-molecular-weight, water-soluble substances. Because numerous studies have shown an association between fluid overload and morbidity and mortality, prevention of iatrogenic fluid overload through fluid restriction, avoidance of unnecessary fluid intake, and prudent use of diuretics is critical. However, many patients with oliguria and fluid overload respond only moderately to diuretics, especially if the renal impairment is severe or rapidly progressive. For patients who are not helped by conservative fluid management strategies, strategies that prevent fluid overload and shorten the duration of fluid overload are needed.However, current guidelines mainly recommend UF in refractory HF when either high-dose intravenous loop diuretics or a combination of different diuretics are used.The recommendations of the European Society of Cardiology Working Group (ESC), and the Heart Failure Association (HFA) on the diagnosis and management of acute and chronic HF, state that “there is no evidence that UF is preferred over loop diuretics as first-line therapy in patients with acute HF. At this time, routine use of UF is not recommended and should be limited to patients who do not respond to diuretic strategies” .According to the National Institute for Health and Care Excellence clinical guideline on “Acute heart failure: diagnosis and management of acute heart failure in adults” , UF shouThe 2022 American Heart Association/American College of Cardiology/Heart Failure Society of America (AHA/ACC/HFSA) guideline on the management of HF is intended to provide patient-centred recommendations for clinicians and demonstrates that early initiation of UF after admission leads to a reduction in rehospitalizations. However, many aspects of UF, such as patient selection, fluid deprivation rate, venous access, avoidance of treatment-related complications, and cost, require further investigation .The heterogeneity in the selection of the study population and UF indications and protocols, as well as the large differences in the pharmacological therapy used in the control group, may contribute to the interpretation of some conflicting results. Indeed, it must be emphasized that a more selective approach is needed when deciding on the most effective treatment modality for a given patient .The co-dependency of heart and kidneys displayed in Several clinical trials have investigated the role of UF in the treatment of patients with ADHF. Fluid deprivation and weight change have generally been used to determine the efficacy of UF therapy, while effects on renal function have generally been considered a safety measure. A number of secondary end points, such as HF-related readmissions and length of hospital stay, were also assessed. The most relevant studies are summarized in A prospective randomized controlled trial (CARRESS-HF) enrolled patients with AHF and signs of CRS and persistent congestion. The study compared UF with diuretic therapy in patients with ADHF and WRF. It was found that the use of a graded pharmacological therapeutic approach was preferable to a UF strategy in terms of safety of renal function, with weight loss comparable with both approaches. Importantly, UF compared with pharmacologic therapy was associated with more effective dehydration , but also with increases in serum creatinine and neurohormonal activation; UF also was associated with a higher rate of adverse events ,77. HoweA meta-analysis of eight randomized controlled trials with 801 participants showed that UF increased fluid deprivation and weight loss and decreased rehospitalization and the risk of deterioration HF in congestive patients, making UF a safe and effective treatment option for volume overloaded patients with HF. UF was able to remove a greater net volume of fluid without increasing the risk of complications . The useA prospective randomized controlled clinical trial has shown that early UF is superior to diuretics in initiating treatment of volume overload in ADHF patients .In addition, UF has been reported to slightly reduce readmission rates up to 30 days after an acute episode of decompensated HF and to contribute to greater weight loss when an individualized rather than a fixed frequency of UF is applied. For example, in the CUORE trial , the UF A 2019 meta-analysis compared the effects of UF and diuretics on key clinical outcomes and showed that UF was associated with a significant reduction in rehospitalization rates. An increase in serum creatinine was observed in patients on high-dose diuretics. It is important to emphasize that WRF has been associated with greatly increased mortality HF .A recent evidence-based review of the management of type 1 CRS concluded that the management of CRS type 1 is often challenging due to a variety of mechanisms leading to WRF and the lack of new treatment approaches targeting renal dysfunction in HF patients. UF appears to be complex and associated with high costs, so it is still not justified for CRS patients .A multidisciplinary cardio-nephrology team approach has been recommended to achieve more effective treatment of patients with CRS ,80.Although UF is more effective in fluid removal compared with diuretics and reduces readmissions due to HF, it is not possible to prove that UF is superior to diuretics because of adverse events and mortality in the UF group. Treatment outcomes seem to vary because of the multiple causes and different aetiologies of patients .The Early Continuous Ultrafiltration in Chinese patients with Congestive Heart Failure (EUC-CHF) trial was designed to evaluate UF efficacy in clinical parameter improvement without adverse events. Also, the trial is expected to establish a scoring system based on a Chinese population to guide early UF treatment in appropriate patients. EUC-CHF is one of the first controlled trials tailored to determine the benefit of UF within 24 h of hospital admission. The results are pending .As is known, both renal function and renal filtration efficiency depend on the number of functionally active nephrons, as well as the permeability and surface area of the basement membrane of the glomeruli and Starling forces. The kidneys also possess an autoregulation mechanism by modulating vascular resistance, which helps to adjust blood flow. The studies demonstrate that measurements associated with vascular ageing  are associated with the development of CKD. CKD is associated with increased arterial stiffness (AS) and LVhypertrophy, two important risk factors for cardiovascular events. Conversely, AS and LV mass are interconnected and are associated with early signs of renal damage such as microalbuminuria ,82.Treatment of CRS aims to eliminate venous congestion and fluid retention, which could improve cardiorenal status. Diuretic agents appear to be the cornerstone of decongestive therapy in ADHF. In ADHF patients, the development of CRS during conventional treatment with decongestants impairs prognosis. Most studies confirm the efficacy and safety of UF in any type of CRS. UF is able to induce decongestion and remove a considerable volume of fluid; at the same time, the risk of side effects does not increase. The efficacy and safety of conventional therapies remain inadequate. Because of new, advanced insights into the pathophysiological mechanisms underlying ADHF, UF is becoming an attractive option for the treatment of ADHF and CRS.In the case of congestion with volume overload consider loop diuretics, i/v root is preferable .Assess efficacy of diuretics by monitoring urine output and/or weight control.If no decongestive effect within the next 6 h—consider doubling the IV diuretic dose.If no decongestive effect within the next 6 h—UF should be considered.The decision about UF application should be made according to the following stepped approach :In the Use of UF results in isosmotic volume loss without inducing electrolyte abnormalities. The efficacy and safety of conventional therapies remain inadequate, but UF is recommended to reduce volume overload in the case of diuretic resistance.Joint multidisciplinary meetings of the cardio-nephrology team would be constructive for CRS patients and public health systems. Although research in this context has generally shown positive results, there are still some unclear questions and concerns, especially regarding the effects of UF on renal function and rehospitalization rates. Further studies are needed to investigate the side effects associated with UF procedures, assess the potential benefits, and correctly identify the patient populations that might benefit most from early UF treatment.


Isolated nocturnal hypertension (INH) and masked nocturnal hypertension (MNH) increase cardiovascular risk. Their prevalence and characteristics are not clearly established and seem to differ among populations. We aimed to determine the prevalence and associated characteristics of INH and MNH in a tertiary hospital in the city of Buenos Aires. We included 958 hypertensive patients ≥ 18 years who underwent an ambulatory blood pressure monitoring (ABPM) between October and November 2022, as prescribed by their treating physician to diagnose or to assess hypertension control. INH was defined as nighttime BP ≥ 120 mmHg systolic or ≥70 diastolic in the presence of normal daytime BP . Variables associated with INH and MNH were analyzed. The prevalences of INH and MNH were 15.7% (95% CI 13.5–18.2%) and 9.7 (95% CI 7.9–11.8%), respectively. Age, male sex, and ambulatory heart rate were positively associated with INH, whereas office BP, total cholesterol, and smoking habits showed a negative association. In turn, diabetes and nighttime heart rate were positively associated with MNH. In conclusion, INH and MNH are frequent entities, and determination of clinical characteristics such as those detected in this study is critical since this might contribute to a more appropriate use of resources. Hypertension is currently considered the leading cause of death and disability in that as a risk factor, it underlies cardiovascular disease . For manOn the other hand, isolated nocturnal hypertension (INH) is defined as an abnormally elevated nocturnal BP in the presence of normal daytime ambulatory BP ,5,6. ThiOf note, masked nocturnal hypertension (MNH), i.e., controlled office BP with INH, is a subtype of masked hypertension , more diOffice BP does not allow the detection of any of these conditions, as they can only be diagnosed by ABPM or HBPM and especially the former since home BP monitors that can be programmed to perform measurements during sleep exist but are not very widely used ,13,14.Given that ABPM is expensive and not quite accessible ,16,17, iThis was a cross-sectional study that consecutively included patients aged 18 years or older who performed an ABPM between 1 October and 30 November 2022 in the Hypertension Section of Hospital Italiano de Buenos Aires. The patients underwent an ABPM as prescribed by their treating physician to diagnose hypertension or to assess its control. Therefore, subjects could have any BP level and be or not be under antihypertensive treatment. The study protocol was approved by the local ethics committee (Comité de Ética de Protocolos de Investigación (CEPI), approval #6464). The patients duly authorized the use of the information in their medical records under the protection of their confidentiality through informed consent. Duplicate ABPMs as well as ABPMs with less than 70% of attempted measurements were excluded from the analysis.Ambulatory BP was measured for 24 h at 15 min intervals during the day (6 a.m.–10 p.m.) and 20 min intervals during the night (10 p.m.–6 a.m.) using validated devices, i.e., Spacelabs 90207 and Spacelabs 90217  placed on the non-dominant arm. Patients were provided with a log where they had to register sleep and wake-up time, activities performed during the day, and the presence of symptoms. Sleep duration was then calculated, and daytime and nighttime were defined according to the diary. Office BP was measured with the same device prior to performing the ABPM. Measurements were made with the patient in a sitting position, with his/her back supported, and without crossing the legs; with the arm uncovered, supported, and at heart level; and without speaking.INH was defined as nighttime BP of ≥120 mmHg systolic and/or ≥70 mmHg diastolic in the presence of a normal daytime BP (<135 mmHg systolic and <85 mmHg diastolic) regardless of office BP . MNH was2 (kg/m2).The medical records of all patients were reviewed to gather data regarding risk factors (diabetes and smoking habits), a history of cardiovascular disease (coronary heart disease and cerebrovascular disease), and the use of antihypertensive drugs. Laboratory data (fasting plasma glucose (FPG), total cholesterol, and serum creatinine) from 12 months before ABPM were also gathered from the medical records. Weight and height were also extracted, and body mass index (BMI) was calculated as weight/heightSample size was estimated assuming a prevalence of INH of 12.9% and according to previous data from a similar population . For a pt-test for continuous variables and the chi-square test for categorical variables. A two-sided p-value of <0.05 was considered statistically significant. Statistical analyses were performed using STATA 14 .Results are reported as the percentage, mean ± standard deviation, or median and interquartile range, according to the data distribution. The characteristics of patients with INH, isolated diurnal hypertension, day-night hypertension, and normal day and nighttime BP were compared using one-way ANOVA test for continuous variables and the chi-square test for categorical variables. In turn, subjects with and without MNH were compared using the We included 958 patients in the study. After excluding duplicate ABPM and reports with less than 70% of attempted measurements, 917 participants remained for analysis .Mean age was 65.1 (±14.7) years, and 43.3% were men. A total of 73.9% of participants were taking antihypertensive drugs, with an average of two drugs per patient. Patient characteristics are depicted in The prevalence of masked hypertension, i.e., adequate office BP control (<140/90 mmHg) and elevated BP on ABPM , was 16.2% (95% CI 14–18.8%). The prevalences of INH and MNH were 15.7% (95% CI 13.5–18.2%) and 9.7 (95% CI 7.9–11.8%), respectively. When performing a sensitivity analysis and excluding subjects with a history of cardio or cerebrovascular disease, the results did not significantly change: the prevalence of INH was 15% (95% CI 12.7–17.6%), and the prevalence of MNH was 9.6% (95% CI 7.7–11.8%). There were 149 subjects with masked hypertension, i.e., patients with controlled office BP but elevated BP in the ABPM. Among this group, 89 patients had masked hypertension only at the expense of INH (59.7%).In turn, the prevalences of isolated diurnal hypertension and day-night hypertension are depicted in In bivariate analyses, patients with INH were significantly older, with a lower prevalence of smoking habits, a predominance of men, a higher prevalence of diabetes, a higher ambulatory heart rate, and a tendency to be more medicated for hypertension as compared with subjects with normal day and nighttime BP. They also had a lower cholesterol level and a lower office systolic and diastolic BP as compared with subjects with isolated diurnal hypertension and day and nighttime hypertension .In turn, patients with MNH tended to be more medicated for hypertension, had a higher prevalence of diabetes, and had a higher nighttime heart rate than subjects without MNH .n = 678) and untreated subjects (n = 239) separately, the prevalences of INH and MNH were 17.1% (95% CI 14.5–20.1%) and 10.8% (95% CI 8.6–13.3%), respectively, in the former and 11.7% (95% CI 8.2–16.5%) and 6.7% (95% CI 4.1–10.7%), respectively, in the latter. When analyzing treated ; and diabetes and nighttime heart rate remained associated with MNH. In our study, we found that both INH and MNH are frequent entities in Argentinean patients and that their associated characteristics are age, male sex, smoking habits, total cholesterol, ambulatory heart rate and office BP and nighttime heart rate, respectively, with a statistical tendency for being medicated for hypertension.Our prevalence of INH is consistent with other studies: Salazar et al. found a prevalence of 12.9% in a similar Argentinean population that was slightly younger than ours . In a muRegarding MNH, information is even scarcer. We found a study conducted by Rhee et al. in which the authors evaluated the prevalence and characteristics of patients with INH in the general population in Korea . Using tp = 0.045) and all cardiovascular events  [Several mechanisms may be responsible for nocturnal hypertension: increased sympathetic nervous system activity, hyperactivity of renin-angiotensin-aldosterone system, sodium retention, renal function impairment, etc. ,23,24. T= 0.037) . Of note= 0.037) . These rThe case of MNH is of particular interest since neither office BP nor usual HBPM are able to detect it. ABPM is not only a limited resource but is also underutilized by primary care physicians. In the MAMPA study, for example, the degree of knowledge and management of automated devices for office BP measurement, HBPM, and ABPM was examined in primary care in Spain . For thaWhen analyzing untreated and treated participants separately, the prevalences of INH and MNH were slightly higher in the latter, whereas the associated conditions were similar than when analyzing the whole population. Of course, given the reduced sample size in each subgroup, some of the variables lost statistical significance due to a loss of statistical power.Finally, our findings must be interpreted in the context of the study limitations: first, the cross-sectional nature of the study precludes cause–effect relationships. Second, patients affiliated with our health plan are mainly urban Argentinean middle-class individuals of European descent who may not represent other ethnicities living in South America. Third, the presence of obstructive sleep apnea, which is a possible cause of nocturnal hypertension, was not assessed. This is an important issue since this condition has been associated with nocturnal hypertension. Fourth, although we have data on sleep duration, we did not evaluate sleep quality, which may have influenced nocturnal BP level; and fifth, the time at which medicated patients took their antihypertensive drugs was not controlled. This may have also influenced nocturnal BP level.As in any other study, our findings raise questions that must be elucidated in future research: for instance, we only performed one baseline ABPM, and as a consequence, we do not know how reproducible INH and MNH are. Previous studies have suggested that although the reproducibility of nocturnal hypertension is higher than of nocturnal dipping , such reIn conclusion, INH and MNH are frequent entities that are usually overlooked unless properly screened. Since access to ABPM is expensive and limited, determination of clinical associated characteristics such as those detected in this study is critical and might contribute to a more appropriate use of resources.


Eighty percent of patients infected by SARS-CoV-2 report persistence of one symptom beyond the 4-week convalescent period. Those with orthostatic tachycardia and orthostatic symptoms mimicking postural tachycardia syndrome, they are defined as Long-COVID POTS [LCP]. This case-control study investigated potential differences in autonomic cardiovascular regulation between LCP patients and healthy controls.Thirteen LCP and 16 healthy controls, all female subjects, were studied without medications. Continuous blood pressure and ECG were recorded during orthostatic stress test, respiratory sinus arrhythmia, and Valsalva maneuver. Time domain and power spectral analysis of heart rate [HR] and systolic blood pressure [SBP] variability were computed characterizing cardiac autonomic control and sympathetic peripheral vasoconstriction.p = 0.004) and deltaSBP  upon standing; 47% had impaired Valsalva maneuver ratio compared with 6.2% in controls (p = 0.01). Spectral analysis revealed that LCP had lower RMSSD  and HFRRI, both in absolute  and normalized units . LFSBP was similar between groups.LCP had higher deltaHR (+ 40 ± 6 vs. + 21 ± 3 bpm, LCP have reduced cardiovagal modulation, but normal sympathetic cardiac and vasoconstrictive functions. Impaired parasympathetic function may contribute to the pathogenesis of Long-COVID POTS syndrome. The COVID-19 pandemic has caused unprecedented morbidity and mortality worldwide . AccordiUp to 80% of patients infected by SARS-CoV-2 develop chronic, disabling symptoms , includiPersistent tachycardia remains one of the most common and disabling symptoms, reported from 9% up to 62% of COVID-19 survivors –21. PosiAutonomic changes after SARS-CoV-2 infection are under investigation. Alterations in sympathovagal balance including increased cardiac sympathetic modulation have been described in PACS patients using Power Spectral Analysis techniques . ElevateOf note, a detailed characterization of autonomic functions of LCP is not yet available. The specific mechanisms underlying LCP remain unknown, and it is unclear whether the autonomic nervous system is compromised in these patients.The aim of the case-control study here presented was to determine differences in cardiac sympathovagal modulation and sympathetic peripheral vascular control between LCP patients and controls.LCP patients were identified from referrals to the Vanderbilt Autonomic Dysfunction Center from March to December 2021. Diagnosis was established after confirmation of all the following inclusion criteria: (1) previous real-time-PCR diagnosis of SARS-CoV-2 infection; (2) new onset of orthostatic intolerance after the infection and persistent symptoms for more than three months; and (3) orthostatic tachycardia > 30 beats-per-minute within 10 min of standing without concomitant orthostatic hypotension , 37. SubA population of healthy controls was enrolled for comparison. These subjects were recruited in pre-pandemic period, from August 2019 to March 2020, using flyers or massive email advertisements. They were young, non-obese female not affected by diabetes mellitus, chronic kidney disease, liver disease, neurodegenerative or cardiovascular disease and were not actively looking for a consult at the Autonomic Dysfunction Center clinic. Further, being studied in pre-pandemic period, they were not exposed to SARS-CoV-2.Subjects were asked to fast and abstain from exercise at least 12 hours before studies, and all pharmacological agents with antiarrhythmic and autonomic effects were withheld for at least 72 hours before the study session. All subjects had a medical history and physical exam performed by an autonomic specialist. This study was approved by an institutional review board  and all participants gave written informed consent. This study was conducted under VUMC institutional guidelines and adhered to the principles of the Declaration of Helsinki and Title 45 of the US Code of Federal Regulations .All subjects underwent an initial orthostatic vital sign assessment, during which blood pressure and heart rate were obtained in different positions; once after lying supine for at least 5 min, once after 5 min of sitting with their feet on the floor and once after standing for 10 min, using an automated arm-cuff blood pressure device . Pulse pressure was calculated as previously described for supine and standing conditions . AutonomMAX and HRMIN of the specific time period were calculated. RSA ratio was computed by dividing median HRMAX/ median HRMIN. Distinguished phases of VM  were identified as previously described [RSA and VM were analyzed offline using analysis software . The RSA analysis took into account 90 s periods during a controlled 0.1 Hz breathing maneuver. The instantaneous maximal heart rate [HR] peaks and minimal HR valleys were automatically detected and the median HRescribed  and the Spectral analysis of continuous cardiovascular variables was performed offline using the BRS software  developed by one of the authors. R peaks and finger blood pressure waveform maxima were detected and displayed as R-R interval and SBP time series. The root mean square of standard deviations [RMSSD] and the standard deviations 1 and 2 [SD1 & SD2] were derived from Pointcare plots of consecutive R-R intervals . The appRRI and HFRRI] and SBP [LFSBP and HFSBP].Periods of spontaneous breathing while supine were analyzed. Time series of R-R intervals [RRI] were interpolated in order to obtain a continuous signal as a function of time, low-pass filtered (cut-off frequency 0.5 Hz) and resampled at 4 Hz . Linear RRI, which is considered a robust spectral marker of cardiac parasympathetic modulation . One of the authors was granted full access to all the data reported in this manuscript and takes responsibility for its integrity and the data analysis.A sample size calculation was performed taking into consideration expected modifications of the primary outcome using initial data of 7 LCP patients and 14 healthy controls , showing that it would be possible to detect a 200 ms2.15 females met diagnostic criteria for LCP and 16 healthy females without a history of COVID-19 infection were enrolled as controls. Past medical history and history of recent COVID-19-related illness are summarized in Table p = 0.004) and presented an orthostatic increase in SBP  that was not present in healthy controls. Also, pulse pressure was greater in the LCP population, both in supine  and standing condition .Demographic and hemodynamic parameters are presented in Table p = 0.07) and RSA ratio (1.29 ± 0.03 vs. 1.27 ± 0.03 p = 0.42); however, 46.7% of LCP had VM ratio < 1.6 compared with 6.2% in controls (p = 0.01).Cardiovagal assessment showed that LCP patients and healthy controls had similar VM ratio (1.67 ± 0.09 vs. 1.89 ± 0.07 p = 0.11), VM2l rise (+ 16.0 ± 2.9 vs. + 13.5 ± 3.4 mmHg p = 0.22) and VM4 overshoot (+ 21.0 ± 3.2 vs. + 18.6 ± 4.4 mmHg p = 0.21). A tendency towards reduced mean VM SBP recovery times was found in the LCP group compared with controls .VM hemodynamic changes during the four phases are presented in Fig. p = 0.29). LCP patients, however, had reduced RMSSD  and HFRRI, both in absolute value  and in normalized units . Accordingly, the LF/HF ratio was increased in LCP . The SBP variability indices, on the other hand, were similar between LCP patients and healthy controls .Data from HRV analysis of LCP and healthy controls are reported in Table Autonomic nervous system determinantion is traditionally complex and multimodal. A recent study from Novak et al.  used corRRI were decreased in LCP. Altogether these results suggest that impaired cardiac parasympathetic activation may contribute to the pathophysiology of this novel syndrome.Initial clinical evaluation revealed that our LCP population was characterized by greater orthostatic HR increment and SBP increment. While these findings may be explained by cardiac and vascular sympathetic overdrive, further analysis of cardiovascular reflexes did not provide evidence of that. Instead, we found higher incidence of vagal impairment as assessed by Valsalva Ratio compared to healthy controls. Further, HRV analysis using different methodologies showed that supine RMSSD and HFThe mechanisms by which SARS-CoV-2 infection may affect parasympathetic function is yet to be understood. Recent studies reported a neurotropic behavior in SARS-CoV-2, as the virus is known to replicate in neuronal cell cultures , and virRRI and improvement in orthostatic and gastrointestinal symptoms in POTS.It is possible that impaired parasympathetic function in these patients could be deleterious not only by affecting cardiac modulation but also by altering systemic inflammatory responses through attenuation of the cholinergic anti-inflammatory reflex arc , 52. PerThis study has some limitations. It is a single center study with a relatively small number of patients enrolled. While elevated pulse pressure suggests that these patients are not hypovolemic, we did not measure circulating blood volume, which can be an important contributor to the clinical manifestations of LCP. However, hypovolemia would tend to increase sympathetic activity through physiological baroreflex compensation. We accounted for deconditioning by excluding prolonged hospital stay and severe disease in our study design, but the quantity and type of daily physical exercise was not systematically assessed and may be a confounder. We were not able to demonstrate significant alterations in sympathetic drive compared to healthy controls using blood pressure variability indexes and blood pressure response during VM, but we also did not include in this study robust measurements of sympathetic activity, such as muscle sympathetic nerve activity recordings. Importantly, we did not include in this study dynamic determination of autonomic functions by performing HRV and blood pressure variability analysis during head-up tilt testing. Future larger studies that include a more systematic characterization of central and peripheral sympathetic activity in LCP may clarify autonomic alterations that we were not able to detect. Our sample size was small, yet we had enough power to detect differences in the primary outcome.In summary, LCP is a new orthostatic intolerance syndrome characterized by exaggerated orthostatic tachycardia, chronic orthostatic intolerance, exercise intolerance, and fatigue. The prevalence of this condition is expected to increase in parallel with new SARS-CoV-2 infections, likely increasing its burden on US healthcare system. The pathophysiology and optimal clinical management for this condition are still unknown. However, our results suggest that patients with LCP may have abnormalities in cardiac parasympathetic regulation. These findings, if borne out by much larger studies, support the hypothesis that LCP is a different condition from POTS unrelated to SARS-CoV-2 infection, although the manifestations may be similar. Further, if future larger studies will confirm these results, patients affected by LCP may especially benefit from the use of treatments aimed at restoring parasympathetic modulation, such as electrical Vagus nerve stimulation techniques.


Hypertension is the primary risk factor for cardiovascular disease and adequate blood pressure control is often elusive. The objective of this work was to conduct a meta-analysis of trial data of isometric resistance training (IRT) studies in people with hypertension, to establish if IRT produced an anti-hypertensive effect. A database search  identified randomised controlled and crossover trials of IRT versus a sedentary or sham control group in adults with hypertension.P < 0.01; diastolic blood pressure (DBP) MD − 3.17 mmHg , P < 0.01; and mean arterial blood pressure (MAP) MD − 7.19 mmHg , P < 0.0001. Office pulse pressure and resting heart rate was not significantly reduced, neither were 24-h or day-time ambulatory blood pressures . Night-time blood pressures, however, were significantly reduced with SBP MD − 4.28 mmHg , P = 0.02, and DBP MD − 2.22 mmHg , P < 0.01.We included 12 studies (14 intervention groups) in the meta-analyses, with an aggregate of 415 participants. IRT reduced systolic blood pressure (SBP), mean difference (MD) − 7.47 mmHg , IRT does lower SBP, DBP and MAP office and night-time ambulatory SBP and DBP, but not 24-h mean ambulatory blood pressures in people with hypertension.The online version contains supplementary material available at 10.1007/s11906-023-01232-w. Hypertension is the primary risk factor for cardiovascular disease (CVD) . AdequatIt is postulated that handgrip exercise either completely or partially occludes the brachial artery, and upon cessation of squeezing, the returning blood flow causes a rebound flow-mediated dilatation of the vessel. Progressive exposure to IRT may therefore enhance the vasodilatory response and in time may even increase the vessel diameter. In normotensive or pre-hypertensive participants the effect of IRT on blood pressure may be smaller due to a reduced potential for non-hypertensives to reduce their blood pressure. Ambulatory blood pressure monitoring (ABPM) over a 24-h period may be more accurate than office-based measurements due to the effects of ‘white coat hypertension’. ABPM is considered the ‘gold standard’ blood pressure measurement technique in some countries .Previous meta-analyses have examined the effectiveness of endurance , dynamicThis systematic review and meta-analysis followed the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines . The proWe conducted a systematic search of the literature using both electronic and hand searching methods for randomised controlled and crossover trials of IRT that reported change in blood pressure in adults with hypertension versus a sedentary or sham control group. We searched PubMed, CINAHL, and the Cochrane Central Register of Controlled Trials (CENTRAL) via (CRS-Web) and MEDLINE Ovid . The subject strategies for databases were modelled on the search strategy designed for MEDLINE (Supplementary Table We included RCTs and randomised cross-over studies comparing IRT with a sedentary or sham control group in adults (≥ 18 years of age), diagnosed with essential hypertension, with resting blood pressure greater than 140/90 mmHg, measured by manual auscultation or automated cuff inflation. We considered studies of IRT at above 10% MVC, versus non-IRT control or sham IRT at an intensity of 10% or less of MVC, delivered for a minimum of 2 weeks or six sessions.The exclusion criteria were as follows: (1) animal studies; (2) review papers; (3) acute exercise studies; (4) non-RCTs, except for randomised crossover studies; (5) studies that did not report any of the desired outcome measures; or (6) studies that did not have a sedentary or sham control group.Primary outcomes were change in blood pressure from baseline or after intervention, systolic, diastolic, and mean arterial pressure , 24-h blood pressure (measured by automated 24-h ambulatory monitoring), and day-time and night-time ambulatory blood pressures. Secondary outcomes were change in pulse pressure and resting heart rate.Two review authors  independently assessed all identified articles and consulted a third review author (NAS) to resolve disagreements. Review authors  extracted data using an approved data extraction sheet and a review author (GD) resolved any disagreements. We recorded information on outcome measures and archived these in a database. We recorded the following outcome measures: office and ambulatory systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), and pulse pressure and heart rate (beats/min). If MAP was not reported, it was not calculated because of potential error in calculating pre-post change in standard deviation. In addition to the primary and secondary outcome data, we extracted the following baseline clinical data for IRT and control or sham groups: age, gender, body mass, body mass index, medication use, smoking status, and co-morbid disease. We included data from randomised cross-over trials identified, if the wash-out period was considered long enough to reduce carry-over, no irreversible events such as mortality have occurred, and appropriate statistical approaches were used. We contacted investigators to verify and obtain missing outcome data where possible.P values for pre-post intervention change for each group. If only the level of statistical significance is available, we used precise P values , where it was possible for us to obtain these from study authors. Where we were unable to obtain these data, we calculated the change SD from pre- and post- standard deviation data, conservatively assuming a correlation coefficient R = 0.5 [We undertook meta-analyses only where this is meaningful, i.e., if the treatments, participants, and the underlying clinical question are similar enough for pooling to make sense. Continuous data were analysed and reported using mean difference (MD) with 95%CI, calculated from the change in the mean and SD of outcome measures. We calculated change in pre- versus post-intervention mean by subtracting baseline values from post-intervention values. We calculated change in SD between pre- and post-intervention outcomes using either 95% confidence interval (CI) data for pre-post intervention change for each group or where this was unavailable, actual  R = 0.5 .P value > 0.10, I2 < 50%) as this provided a more conservative statistical comparison of the difference between intervention and control groups. We completed the data synthesis and analyses using STATA version 16 SE . We intended to conduct the following sub-analyses when the primary analysis was significant (i) arm versus leg training (because arm exercise is likely to elicit greater blood pressure responses due to lower active muscle mass), (ii) unilateral verus bilateral limb IRT, (iii) number of weeks for IRT program duration, and (iv) medicated versus unmedicated participants.We pooled data from each study when four or more studies provided data. We used a random-effects model, even when substantial heterogeneity was absent  classification; two studies had participants of normal BMI; one study had borderline normal/overweight participants; one study had overweight participants; three studies used borderline overweight/obese participants; two studies had obese participants; and three studies provided no BMI data. With respect to participant gender, two studies provided no information , 29, whiAll but one study used handgrip IRT at 30% of MVC . This stP ≤ 0.01, I2 = 57% , IRT significantly reduced SBP with a mean difference (MD) of − 7.47 mmHg , All sub-analyses for SBP can be seen in Fig. P < 0.001.When the one study that used lower limb IRT was removed, the change in SBP for handgrip only IRT was MD − 6.45 mmHg , and the single study that used leg IRT produced a mean SBP reduction of − 12.6 mmHg , both IRT for 4, 8, 10, and 12 weeks showed significant reductions in SBP, although the one study of 6 weeks, with only 11 participants, was not significant.P < 0.001, and unilateral IRT participants MD − 7.11 mmHg , P = 0.001.Both these sub-analyses produced significant and similar reductions in SBP with bilateral IRT participants demonstrating a MD − 7.86 mmHg , P < 0.001.Both these sub-analyses produced significant, but similar, reductions in SBP with unmedicated participants showing a MD − 12.82 mmHg  and medicated participants MD − 6.1 mmHg , both P = 0.12, I2 = 92%, in a pooled analysis of 4 studies (5 comparison groups), with an aggregate of 147 participants , P = 0.19 , P < 0.01, I2 = 64% , IRT significantly reduced DBP with MD − 3.17 mmHg , All sub-analyses for DBP can be seen in Fig. P = 0.016, and the single study that used leg IRT produced a DBP reduction of MD − 6.00 mmHg , P = 0.001.When the one study that used lower limb IRT was removed, the change in DBP for handgrip only IRT was significantly lower with MD − 2.80 mmHg (95%CI − 5.08 to − 0.52), P = 0.001, and 8 weeks MD − 5.21 mmHg , P = 0.004, showed significant reductions in DBP. Program durations of 6, 10, and 12 weeks were not significant.IRT for 4 weeks MD − 6.00 mmHg , P = 0.003, whereas in unilateral IRT participants, the DBP reduction MD − 1.79 mmHg , P = 0.57, was not significant.Bilateral IRT participants demonstrated a significant DBP reduction of MD − 2.99 mmHg , P < 0.001, and medicated participants also showed a significant DBP reduction MD − 2.51 mmHg , P = 0.04.Unmedicated participants produced a significant reduction in DBP MD − 6.20 mmHg , P = 0.13, I2 = 70%, in a pooled analysis of 4 studies (5 comparisons), with 147 participants , P = 0.31, I2 = 48% , P < 0.0001, I2 = 0% , IRT significantly reduced MAP with MD − 7.19 mmHg , Only two studies provided this data, and a pooled analysis was not possible.P = 0.08, I2 = 0% , IRT did not significantly reduce pulse pressure; MD − 1.15 mmHg , P = 0.11, I2 = 36% , There were no major adverse events reported.Median TESTEX score was 10 (range 9–13); see Table The risk of bias for randomisation was considered low as most groups were matched for key participants characteristics at baseline. As blinding of participants to exercise therapy is not possible, the risk of bias on a possible placebo effect is not possible. As eight of the 12 studies failed to blind investigators to group allocations, there is a possibility of measurement bias.Heterogeneity was moderate to high for most analyses, but no reasons were identified for this. A possible explanations are study size, manual blood pressure measurement, medication status, and IRT study duration.The GRADE assessment can be seen in Table This review is the first meta-analysis to provide a pooled analysis of the effects of IRT on blood pressure, in people with hypertension, in only randomised controlled trials. Our analyses demonstrate that IRT can reduce office, but not mean 24-h or day-time ambulatory, systolic, diastolic, and mean arterial blood pressures in people with hypertension compared to sedentary control. Of note was that night-time systolic and diastolic blood pressures were significanly reduced following IRT.IRT significantly reduced office systolic, diastolic, and mean arterial blood pressures in people with hypertension by 7.5, 3.2, and 7.2 mmHg, respectively. A program of IRT did not, however, significantly reduce brachial pulse pressure or heart rate, nor 24-h mean ambulatory systolic and diastolic blood pressures. A sub-group analysis of handgrip versus lower limb IRT suggested the latter may produce larger systolic blood pressure reductions, although only 48 participants (1 study) undertook lower limb IRT. These findings are consistent with previous analyses ••, 33 thMedicated participants significantly reduced their SBP by about 6.1 mmHg and those unmedicated by almost 13 mmHg. A similar finding was observed for DBP as medicated and unmedicated participants significantly reduced their DBP by 2.5 and 6.2 mmHg, respectively. One might expect that people with hypertension have greater potential to lower their blood pressure compared to those who are normotensive. In contrast, those with hypertension may be medicated, and therefore the potential to further lower blood pressure may be attenuated by medication. It may be possible that IRT works via a physiological mechanism shared by some antihypertensive medications, but again, this concept must be investigated to further ascertain validity.Aside from the single study of 6 weeks IRT, all other program durations yielded a significant reduction in SBP of between 6.5 and 12.6 mmHg. Participants with IRT intervention duration > 8 weeks did not significantly reduce DBP, while those using IRT for 8 weeks or fewer reduced DBP by about 5 mmHg. These finding are counterintuitive and contrast the work of Inder et al.  One possn = 33) is noted. These findings are consistent with the individual patient data meta-analysis by Smart et al. [Participants using bilateral IRT decreased SBP and DBP by 7.9 mmHg and 3 mmHg, respectively, and unilateral IRT participants showed a decrease of 7.1 mmHg and nearly 2 mmHg, respectively, although the small sample of unilateral participants , from one study, means this finding must be investigated further in a much larger number of participants.A subgroup analysis of handgrip versus lower limb IRT suggested the latter may produce larger SBP reductions, although only 48 participants from one study undertook lower limb IRT. Handgrip only IRT was significant for DBP change as was lower limb IRT. The small sample of lower limb participants  identifying the physiological mechanism of adaptation changes in (a) the renin–angiotensin–aldosterone system or (b) the vascular endothelium; (ii) possible therapeutic uses of IRT in other patient groups beyond hypertension, for example peripheral arterial disease; (iii) identifying, and eliminating from the study design, factors leading to the discrepancy between reductions in resting versus 24-h ambulatory blood pressure measurements; and (iv) investigating the causal link between IRT-elicted reductions in night-time blood pressures and target organ damage and associated cardiac events.This review confirms that isometric resistance training produced significant reductions in office systolic, diastolic, and mean arterial blood pressures , but not mean 24-h or day-time ambulatory blood pressures. Night-time ambulatory SBP and DBP were reduced and may lower the risk of target organ injury in people with hypertension.Supplementary file1 (DOCX 1733 KB)Below is the link to the electronic supplementary material.


Tubulointerstitial lesions play a pivotal role in the progression of IgA nephropathy (IgAN). Elevated N-acetyl-beta-D-glucosaminidase (NAG) in urine is released from damaged proximal tubular epithelial cells (PTEC) and may serve as a biomarker of renal progression in diseases with tubulointerstitial involvement.We evaluated the predictive value of urinary NAG (uNAG) for disease progression in 213 biopsy-proven primary IgAN patients from January 2018 to December 2019 at Zhongshan Hospital, Fudan University. We compared the results with those of serum cystatin C (sCysC).2, area under the curve [AUC] 0.760).Increased uNAG and sCysC levels were associated with worse clinical and histological manifestations. Only uNAG level was independently associated with remission status after adjustment. Patients with high uNAG levels (> 22.32 U/g Cr) had a 4.32-fold greater risk of disease progression. The combination of baseline uNAG and clinical data may achieve satisfactory risk prediction in IgAN patients with relatively preserved renal function (eGFR ≥ 60 ml/min/1.73 mOur results suggest that uNAG is a promising biomarker for predicting IgAN remission status.The online version contains supplementary material available at 10.1186/s12882-023-03262-7. Immunoglobulin A nephropathy (IgAN) is the most prevalent form of primary glomerulonephritis worldwide . IgAN rePrognostication based on baseline clinical data alone is unreliable. Risk models that use clinical parameters from follow-up studies for at least 2 years may accurately predict risk; however, the time frame required limits the utility of such models in clinical settings . The comN-acetyl-beta-D-glucosaminidase (NAG) is a lysosomal enzyme abundant in proximal tubular epithelial cells (PTEC). It is typically excreted into the urine in very small amounts due to physiological exocytosis . Its relIn the present study, we investigated the relationship between uNAG and the clinical and histologic findings, and the remission status of patients with primary IgAN, in parallel with serum cystatin C (sCysC), a widely accepted and highly sensitive indicator of renal function . We inco2 on admission (n = 10), or glomeruli count fewer than eight per biopsy section (n = 8) were not admitted. Patients were also excluded when they had a secondary cause of IgA deposition  (n = 17), urinary infection or septicemia at present (n = 2), and used steroids or immunosuppressants within 3 months before renal biopsy (n = 4). Patients with acute kidney injury  or liver disease  (n = 21) were not enrolled in this study. After excluding those whose baseline clinical data were incomplete (n = 55), 213 patients were finally enrolled in our study , eGFR lower than 15 ml/min/1.73 mThe following clinical data were collected at the time of renal biopsy: age, sex, body mass index (BMI), mean arterial pressure (MAP), comorbidity (hypertension and diabetes mellitus), blood information, 24-hour proteinuria, urine creatinine and NAG levels. Hypertension was defined as systolic blood pressure (SBP) ≥ 140 mmHg and/or diastolic blood pressure (DBP) ≥ 90 mmHg or using of antihypertensive drugs at the time of renal biopsy. Estimated glomerular filtration rate (eGFR) was calculated using the creatinine-based CKD Epidemiology Collaboration (CKD-EPI) equation. The level of uNAG was measured by rate method using assay kits from Wako. The level of sCysC was measured using enzyme-linked immunosorbent assay (ELISA) kits from Roche. The levels of urinary β2-MG and UTRF were detected by immunity transmission turbidity test using assay kits from Shanghai Kehua Bio-Engineering Co., Ltd. and DiaSys Diagnostic Systems respectively. Urinary levels of biomarkers were all tested in midstream morning urine samples and normalized for urine creatinine.The histological findings were assessed according to the Oxford classification of IgAN proposed in 2016 . Mesangi2 or requirement for dialysis or transplantation defined ESKD.Remission status was categorized as complete remission (CR), partial remission (PR) or remission failure (RF), based on the comparison between data recorded at the time of renal biopsy and at the end of six-month follow-up. 24-hour proteinuria and eGFR were used for the evaluation of patients’ outcome. CR was defined as absence of proteinuria (proteinuria ≤ 0.3 g/24 h) and lack of worsening of kidney function (< 30% reduction in eGFR from baseline). PR was defined as proteinuria ≤ 1 g/24 h and lack of worsening of kidney function (< 30% reduction in eGFR from baseline). Proteinuria > 1 g/24 h, reduction ≥ 30% in eGFR over baseline or ESKD indicated RF. eGFR < 15 ml/min per 1.73 mIBM SPSS Statistics version 23.0 was used for statistical analysis. Continuous variables were expressed as mean ± standard deviation (SD). Between-group differences were determined using independent sample t test or one-way analysis of variance (ANOVA) when appropriate. Categorical variables were expressed as numbers with percentages in parentheses and compared using the chi-square test. Correlations between parameters were performed by Pearson analysis, while Spearman analysis was used to test the correlation between expression level of biomarkers and the pathological grades. We examined the association between biomarkers and risk stratification of IgAN progression using binary logistic regression analysis in both univariable and multivariable models, in which biomarkers were treated as categorical variables. Covariates included in the model were age, sex, BMI, MAP, 24-hour urine protein, eGFR, MEST-C score and use of renin-angiotensin system inhibition or immunosuppression during follow-up. Adjusted odds ratio (OR) and 95% confidence interval (CI) were obtained for each model. Analyses of receiver operating characteristic curve (ROC) were performed by MedCalc version 20.100. Area Under Curve (AUC) was calculated for quantitative comparison of predictive power between different models. Significant difference between AUC was determined by Delong test. All tests were two-tailed and differences of p value less than 0.05 were considered statistically significant.2, and mean proteinuria was 1.48 ± 1.21 g/24 h. Patients were categorized into tertiles of uNAG levels . Tables The detailed clinical and histological data of the 213 patients enrolled are summarized in Table We first explored the relationship between uNAG levels and several clinical features. The results showed that uNAG levels were significantly positively correlated with serum creatinine , 24-hour proteinuria , serum cholesterol  and serum triglyceride , but negatively correlated with eGFR  and serum albumin at baseline . However, for patients with baseline eGFR < 60 ml/min/1.73 m2, uNAG was no longer independently associated with remission status in Model 2, suggesting that uNAG may be more useful for patients with a relatively early stage of IgAN  and MEST-C score in Model 2. In contrast, uNAG outperformed sCysC in each model and was still strongly associated with a higher risk of IgAN progression after further adjusting for using renin-angiotensin system inhibition or immunosuppression during follow-up in Model 3, showing a 4.32-fold greater risk of IgAN progression in patients with uNAG levels > 22.32 U/g Cr over those whose biomarker did not reach this threshold  showed much stronger predictive power than sCysC . We also tested whether combining uNAG levels with clinical parameters at biopsy  improved predictive ability over clinical data alone. As shown in Fig. 2, the combination of uNAG level and clinical data resulted in an AUC of 0.760 , demonstrating strongly better predictive performance than clinical data alone . It was also more accurate than the model further integrated with MEST-C score  than those of whole cohort and subgroup with eGFR ≥ 60 ml/min/1.73 m2, however, addition of uNAG level did not exhibit satisfactory predictive value compared with mere clinical data  or the model further integrated with MEST-C score  in this subgroup . ROC analysis revealed that adding uNAG to clinical data at biopsy resulted in the greatest improvement in risk prediction. However, in patients with eGFR < 60 ml/min/1.73 m2, the predictive power of uNAG disappeared. These results may be attributed to uNAG mainly originating from damaged PTECs and rapidly increasing approximately 12 h after tubular injury [2 proved adding renal tubular injury markers to the clinical model including serum creatinine-based eGFR and urinary albumin/creatinine ratio did not improve risk prediction, in which kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), liver fatty acid binding protein (L-FABP) and NAG were examined [Furthermore, we found that uNAG exhibited a much stronger predictive power in patients with early stage of IgAN  may limit the generalizability of our findings; therefore, our results require validation in larger and independent IgAN cohorts. Second, the follow-up time was inadequate. As such, we could not investigate the association between uNAG and long-term renal outcomes. In this study we combined 24-hour proteinuria at the end of six-month follow-up, reduction of eGFR and occurence of ESKD to determine remission status. 24-hour proteinuria is a traditional adverse prognostic factor in IgAN. A study revealed that proteinuria during follow-up was the most important predictor of the rate of GFR decline and remission of proteinuria improved prognosis in IgAN . Both 24 may limiIn conclusion, our study revealed that uNAG level was an independent and strong predictor of IgAN remission status. Adding uNAG levels to baseline clinical data produced a promising prediction model of disease progression among IgAN patients at a relatively early stage.Below is the link to the electronic supplementary material.Supplementary Material 1Supplementary Material 2


Despite significant improvements of renal and obstetrical management, pregnancies in women with glomerular diseases and with lupus nephritis continue to be associated with increased complications both for the mother and the fetus as compared to those of pregnancies in healthy women. To reduce the risk of these complications, planning pregnancy in a phase of stable remission of the underlining disease is necessary. A kidney biopsy is an important event in any phase of pregnancy. A kidney biopsy can be of help during counselling before pregnancy in cases of incomplete remission of the renal manifestations. In these situations, histological data may differentiate active lesions that require the reinforcement of therapy from chronic irreversible lesions that may increase the risk of complications. In pregnant women, a kidney biopsy can identify new-onset systemic lupus erythematous (SLE) and necrotizing or primitive glomerular diseases and distinguish them from other, more common complications. Increasing proteinuria, hypertension, and the deterioration of kidney function during pregnancy may be either due to a reactivation of the underlying disease or to pre-eclampsia. The results of the kidney biopsy suggest the need to initiate an appropriate treatment, allowing the progression of the pregnancy and the fetal viability or the anticipation of delivery. Data from the literature suggest avoiding a kidney biopsy beyond 28 weeks of gestation to minimize the risks associated with the procedure vs. the risk of preterm delivery. In case of the persistence of renal manifestations after delivery in women with a diagnosis of pre-eclampsia, a renal kidney assessment allows the final diagnosis and guides the therapy. Pregnancy is no longer considered to be a contraindication in women with glomerular diseases. However, the risk for maternal and fetal complications is increased, particularly in patients with renal insufficiency, severe hypertension, proteinuria, lupus nephritis, or a type of glomerular disease ,2,3,4. OIn this invited mini review, we discuss the role of the kidney biopsy in clarifying the diagnosis and evaluating the prognosis and management of pregnant women with glomerular diseases, with a focus on lupus nephritis.We conducted a literature search from the 1990s to the present day in PubMed, Embase, and Medline and from a reference list of retrieved articles. During searching, we used these terms and keywords: pregnancy, glomerular diseases, chronic kidney disease, and kidney biopsy. The study quality and recommendations were assessed based on importance of the published studies.A kidney biopsy before planning a pregnancy may be indicated in women with an undiagnosed decline of kidney function, proteinuria, hypertension, or hematuria. An accurate histopathologic diagnosis may provide important prognostic and therapeutic information to facilitate appropriate counseling to prevent the risks of an unplanned pregnancy.Pregnancy in women with autoimmune diseases, such as SLE, may present several issues. SLE may influence the pregnancy outcome, being associated with a higher than expected rate of pre-eclampsia, miscarriage, and/or pre-term delivery ,11. PregAdditionally, among patients with primary glomerular disease, a quiescent disease and good kidney function are recommended before planning a pregnancy. In a retrospective study that included 360 patients with different histological forms of primary glomerulonephritis and normal renal function, the long-term end-stage kidney disease (ESKD)-free survival was not significantly different between patients who did and those who did not conceive after the diagnosis glomerulonephritis . The samDuring pregnancy, there are hemodynamic changes characterized by an increase in the blood flow in the kidney with a consequent increase in the vascular and interstitial size up to 30%. The mean arterial pressure and systemic vascular resistance are lower during pregnancy, resulting in an increased cardiac output, renal plasma flow (RPF), and glomerular filtration rate (GFR). These changes may continue after delivery and resolve 1-month post-partum. Tubular function is also altered, leading to mild increases in the proteinuria and glycosuria levels ,29 that Particularly difficult to recognize and differentiate from other complications are the rare cases of new-onset SLE, necrotizing or primitive glomerular diseases during pregnancy which usually develop in the first trimester ,32,33,34More frequently, pregnant women with a diagnosis of LN or of primary glomerular diseases may exhibit increasing proteinuria, hypertension, and the deterioration of kidney function during pregnancy. These complications may be due either to a reactivation of the underlying disease (more frequently in patients with LN) or to pre-eclampsia. From a clinical point of view, a flare of lupus nephritis is usually associated with a rapid increase in proteinuria (proteinuric flares) and/or of serum creatinine (nephritic flares) . In flarOld and recent reports outlined fair maternal and fetal outcomes in pregnant women with glomerular diseases when hypertension was controlled and GFR was stable ,57,58,59Many women who develop de novo proteinuria, exacerbation of the urinary findings, or hemolytic uremic syndrome do not receive a kidney biopsy during pregnancy either because of the fear of hemorrhagic complications or because of formal contraindications related to severe hypertension or coagulation disorders. If the clinical manifestations persist after delivery, a kidney biopsy should be conducted within few months. By definition, the manifestations of pre-eclampsia completely reverse within 12 weeks after delivery. The persistence of proteinuria or of hypertension after this period require careful evaluation . SeveralPregnancy is regarded by many clinicians as a relative contraindication for a kidney biopsy because of the underlying risk of major complications, such as perirenal hematomas requiring blood transfusions, perirenal abscess, and even sepsis ,78. HoweIn conclusion, pregnancy is associated with an increased risk of complications in patients with glomerular diseases, and often the differential diagnosis between the reactivation or onset of the glomerular disease and pregnancy complications, such as pre-eclampsia, may be difficult. A correct diagnosis is crucial for the outcome of both the mother and fetus. In this setting, a kidney biopsy is very helpful to obtain a prompt diagnosis to decide the management of these patients. According to the available literature data and our personal experience, performing a kidney biopsy in patients with urinary abnormalities or alteration of the renal function before planning a pregnancy can be useful to establish the ideal timing for conception. Pre-conception counselling and a planning pregnancy in patients with a quiescent disease, stable kidney function, and normal blood pressure may prevent complications. During pregnancy, we suggest that clinicians consider a kidney biopsy possibly before 25 weeks of gestational age to reduce the risk of complications in patients with active urinary sediment, significant proteinuria (>500 mg/day), or a reduction of GFR, in whom less invasive diagnostic tests have failed to elucidate the disease etiology. In addition, we recommend post-partum renal check-ups, including a kidney biopsy, in patients with alterations of the renal function or persistent proteinuria after delivery .


This prospective study aimed to analyze the changes in these FDG-PET/CT features between young, middle-aged, and older adults, and investigate associations with arterial stiffness and blood pressure (BP).Young (< 40 years), middle-aged (40-to-60 years), and older (> 60 years) adults, who underwent an FDG-PET/CT, were prospectively recruited. FDG-PET/CT features of the proximal half of the thoracic aorta were analyzed relative to the age categories, BP and carotid-femoral pulse wave velocity (PWV), a reference indicator of aorta stiffness.3/m2 [interquartile range: 20–28 cm3/m2]), to middle-aged , and older  adults, and (ii) selected in the multivariate predictions of systolic, diastolic, and pulse BP. Indexed aorta volume was also a multivariate predictor of PWV but in association with SUV-SD and hypertension.We included 79 patients . An increase in age category was associated with increases in mean standardized uptake values (SUVs) of blood and aorta and most significantly in aorta SUV heterogeneity, represented by SUV standard deviation (SUV-SD), aorta calcification volume, and the aorta volume indexed to body surface area. However, this indexed aorta volume was the sole variable: (i) exhibiting a stepwise increase from young (median: 25 cmIn a population of patients referred to an FDG-PET/CT investigation, the indexed volume of the proximal and more elastic half of the thoracic aorta is the most comprehensive indicator of arterial aging. This imaging parameter exhibits a stepwise increase from young to middle-aged and older adults, is strongly linked to inter-individual changes in both arterial stiffness and BP, and thus, could help assess the early phases of arterial aging.Trial registration ClinicalTrial.gov, NCT03345290. Registered 17 November 2017, https://clinicaltrials.gov/ct2/show/NCT03345290?term=NCT03345290&draw=2&rank=1 Aorta function and stiffness are central to the increase in systolic and pulse blood pressure (BP) that occurs with advancing age. Aorta stiffness per se, is a strong indicator of the risk of cardiovascular events  positron emission tomography (PET) uptake in ascending aorta and aortic arch but only in small, selected study populations—i.e., diabetic, hypertensive, and primarily old patients  , 25 middle-aged adults (41-to-60 years), and 50 older adults (> 60 years) with the latter group providing a larger subgroup of individuals with increased arterial stiffness and BP.Baseline PWV and brachial BP were measured on the day of the FDG-PET/CT. A baseline PWV was not determined for atrial fibrillation patients.All the hemodynamic parameters were recorded on the day of the FDG-PET/CT, just before FDG injection. Resting brachial systolic, diastolic BP and heart rate were measured three times with an automatic monitor  and averaged for subsequent analyses. The pulse BP was computed as systolic BP minus diastolic BP.L.J. and P.S. measured the carotid-femoral PWV by applanation tonometry with the Pulspen DiaTecne® system  , starting 60 min after the intravenous injection of 3 MBq/kg of PET and CT images were analyzed on a MIM workstation . The volume of the first half of the thoracic aorta was segmented on CT slices from an axial plane placed just below the right pulmonary artery to a plane including the bisector between the aortic arch and the descending aorta segments. We used a semi-automatic segmentation method where the external aorta borders were drawn manually on a single CT slice, automatically expanded on the aorta volume and further corrected manually if necessary. This aorta volume of interest (VOI) was used to determine the aorta volume, expressed relative to body surface area , and the SUV standard deviations (SUV-SD), were extracted from aorta VOIs. Maximal and mean tissue-to-background ratios  were respectively computed as the ratios of SUVmax and SUVmean over the mean blood SUV obtained from a 2 cm diameter spherical VOI placed at the center of the right atrial cavity  the Chi-square or Fisher’s exact tests for categorical variables and (ii) a non-parametric Kruskal–Wallis test for continuous variables since most variables were not normally distributed. Associations between continuous variables were tested with the non-parametric Spearman’s rank correlation method. A p-value < 0.05 was considered to be significant.p-value < 0.025 considered to be significant to account for test multiplicity.Two-group comparisons obtained from the 3 age-groups were performed using the Mann–Whitney test for continuous variables, Chi-square or Fisher’s exact tests for categorical variables, and with a p < 0.15 from the univariate analysis were initially entered and a final model was selected using a stepwise backward approach which only retained variables with p < 0.05. Regression model fit was checked for distribution of residuals and with homoscedasticity tests. Linearity between outcome and continuous variables was ascertained using restricted cubic spline analyses.Multivariate linear regression models were used to analyze associations between individual hemodynamic parameters—i.e., PWV, systolic, diastolic, and pulse BP—and the clinical and PET/CT variables listed in Tables n = 16), known granulomatosis (n = 17) or other inflammatory diseases (n = 16), adenopathy of unknown origin (n = 11), infectious diseases (n = 6), and others (n = 13). None had any sign of vasculitis.We initially enrolled 100 participants with 21 participants subsequently excluded because of incomplete or unavailable data, known or suspected vasculitis, or tumor or adenopathy in close contact with the aorta. The remaining 79 participants: 38 women, 22 young adults (< 40 years), 19 middle-aged (40-to-60 years), and 38 older adults (> 60 years), were finally included in the analyses. We respectively obtained brachial BP and accurate PWV measurements from all and 68 participants. The main reasons for referral to FDG-PET were: an initial diagnostic workup for cancer , middle-aged , and older  adult groups  and this variable was also strongly correlated with all other hemodynamic variables , with Spearman coefficients ranging from 0.44 to 0.55. The other strong correlates of hemodynamic variables  were calcification volume, but also TBRmean, SUV-SD, blood SUV, hypertension and age , but not for PWV (p = 0.24), diastolic BP (p = 0.34) or pulse BP (p = 0.11).When age was forced into the models, the criteria of an indexed aorta volume exceeding the median value still provided a significant additional predictor for systolic BP  is a strong indicator of arterial aging. We provide supportive evidence of a clear stepwise increase in this indexed volume from young to middle-aged, and older adults, and identify this volume parameter as the most comprehensive FDG-PET/CT predictor of the inter-individual changes in both arterial stiffness and BP.We examined several hemodynamic variables, namely (i) PWV, a non-invasive gold standard for assessing aorta stiffness , contrary to FDG-PET and clinical variables, and to outperform the prediction provided by age for systolic BP, a key indicator of cardiovascular risk  needs to be confirmed at a larger scale, by longitudinal studies, and moreover, in other study populations than the present one—i.e., in patients without any suspected health disease. It is of note that some patients had a known or suspected inflammatory or infectious disease, but none had any known or suspected vasculitis.In a population of patients referred to an FDG-PET/CT investigation, the age-stratification into young, middle-aged, and older adult subgroups, and the analysis of associated changes in BP and arterial stiffness, identified a strong association with proximal aorta volume, which corresponds to the more elastic half of the thoracic aorta . This imaging parameter, which is very easy to record and analyze, is the most comprehensive FDG-PET/CT indicator of arterial aging during adulthood, including in young and middle-aged adults, and it could potentially help assessing and further preventing accelerated arterial aging, especially during the early phases.


The hemodynamics of patients with cirrhosis and portal hypertension are complex and variable. We aimed to investigate differences in venous pressures determined by innovative angiography and conventional angiography using balloon occlusion of the hepatic veins in patients with alcoholic cirrhosis and portal hypertension.t-test and Pearson’s correlation coefficient were used for analysis.A total of 134 patients with alcoholic cirrhosis who fulfilled the inclusion criteria from June 2017 to June 2020 were included. During transjugular intrahepatic portosystemic shunt, conventional and innovative angiography were performed, and venous pressures were measured. A paired P < 0.001). Innovative angiography detected a total of 65 patients with lateral shunts, of whom 37 (56.9%) had initial shunts. The average wedged hepatic venous pressure and portal venous pressure of the initial lateral branches were 21.27 ± 6.66 and 35.84 ± 7.86 mmHg, respectively, with correlation and determination coefficients of 0.342 (P < 0.05) and 0.117, respectively. The mean hepatic venous pressure gradient and portal pressure gradient were 9.59 ± 7.64 and 26.86 ± 6.78 mmHg, respectively, with correlation and determination coefficients of 0.292 (P = 0.079) and 0.085, respectively.Conventional and innovative hepatic angiography detected lateral branches of the hepatic vein in 26 (19.4%) and 65 (48.5%) cases, respectively (Innovative angiography reveals collateral branches of the hepatic veins more effectively than conventional angiography. Hepatic vein collateral branches are the primary factors leading to underestimation of wedged hepatic venous pressures and hepatic venous pressure gradients, with the initial hepatic vein collateral branches resulting in the most severe underestimations. Hepatitis and alcoholism are common causes of cirrhotic portal hypertension , 2. HepaIn recent years, the measurement of hepatic vein pressure in lieu of portal vein pressure has been used clinically and in research. The hepatic venous pressure gradient (HVPG) can be used as the "gold standard" to indirectly reflect the portal pressure gradient (PPG) –7. NeverIn this study, 134 patients with alcoholic cirrhosis and portal hypertension who fulfilled the inclusion criteria from June 2017 to June 2020 were enrolled for transjugular intrahepatic portosystemic shunt (TIPS) and underwent innovative hepatic venous angiography based on conventional measurement of hepatic venous pressure and angiography. Subsequently, we analyzed the correlation between the hepatic vein anatomy and venous pressure.A total of 134  patients with alcoholic cirrhosis who fulfilled the inclusion criteria for portal hypertension underwent TIPS between January 2017 and June 2020. PPG and HVPG were obtained by measuring various pressures during the interventional surgery. There were 88 cases of gastrointestinal hemorrhage in patients with alcoholic cirrhosis and portal hypertension (65.7%), 35 cases of intractable ascites or pleural effusion combined with ascites (26.1%), and 11 cases of gastrointestinal bleeding with intractable ascites (8.2%). According to Child–Pugh classification, there were 36 grade A, 47 grade B, and 51 grade C cases. Fourteen cases of alcoholic cirrhosis with portal hypertension were complicated with liver cancer. The study protocol conforms to the ethical guidelines of the 1975 Declaration of Helsinki  and was approved by the Ethics Committee of Beijing Shijitan Hospital (2018(01)). Informed consent was obtained from each patient included in the study.The inclusion criteria were as follows: 1) TIPS indications, 2) age 18–75 years, 3) presence of TIPS and undergoing elective surgery, and 4) normal hepatic vein and inferior vena cava.: 1) portal vein carcinoma thrombus, 2) arterioportal venous fistula, 3) portal vein thrombosis affecting blood flow , 4) use of drugs affecting portal vein pressure within the preceding week, and 5) presence of factors that affect the accuracy of intraoperative pressure measurement, such as biliary-cardiac reflex and incomplete balloon occlusion.The exclusion criteria were as followsVarious examinations were conducted before the surgery, including routine blood examination, hepatorenal function, ICG-R15 , blood ammonia, blood type, electrocardiograph, coagulation function, portal vein ultrasound, and abdominal CT and/or magnetic resonance imaging. Coagulation function, platelet count, bilirubin, albumin, and hemoglobin levels should be adjusted according to the interventional surgery. The effects and risks of the surgery were explained to patients and their families, and consent for surgery was obtained. Medications affecting portal vein pressure were discontinued for at least one week preceding surgery.Pressure was measured by catheterization of the right internal jugular vein to the right atrium, inferior vena cava, and hepatic vein under routine disinfection and local anesthesia. A Fogarty balloon catheter  was inserted into the hepatic vein using an RUPS-100 outer sheath . The tip of the balloon catheter was placed 3–5 cm from the hepatic vein to the opening of the inferior vena cava. WHVP and FHVP were measured before and after hepatic vein occlusion by expanding the balloon (contrast agent (5 mL) was carefully injected). The pressure was recorded after stabilization; the pressure measurement was repeated three times, and the average value was recorded; the HVPG value was then calculated. The liver parenchyma and portal vein were punctured through the hepatic vein or inferior vena cava. After successful portal vein puncture, a porcine tail catheter was inserted into the splenic or superior mesenteric vein for angiography. Before the shunt, the main portal vein pressure was measured three times; the average value was recorded and the PPG value was then calculated.After completion of the standard measurement methods, the hepatic vein was blocked again by inserting a balloon at the same position as was done in the conventional method. The dose of contrast agent was increased , and pressure angiography was performed; the pressure was 200–300 psi, and continuous angiography was performed for more than 6 s. Subsequently, subtraction was performed. The WHVP and free hepatic venous pressure (FHVP) were measured again; the pressure was recorded after stabilization, and the measurement was repeated three times; the average value was used to calculate the HVPG value.To observe the occlusion of the balloon catheter after balloon dilatation, if the blockage was incomplete, the position was adjusted and retested; radiography of the balloon catheter was performed. The indwelling catheter in the portal vein was inserted for 24–48 h; the portal vein pressure was measured at least three times per day. The pressures of the inferior vena cava and right atrium were measured three times during extubation, and the average value was recorded.t-test was used to analyze the differences between WHVP and PVP, PPG and HVPG, and FHVP and IVCP. The Pearson correlation test was applied to analyze the correlation and determination coefficients. Blood pressures are expressed as means ± standard deviations. P < 0.05 was considered statistically significant.GraphPad Prism 8  was used for the statistical analysis. The paired P < 0.001)  and 65 (48.5%) cases, respectively. The difference was statistically significant (9.4% and P = 0.133) and 0.092, respectively  and 0.043, respectively  and 0.117, respectively (Table P = 0.079) and 0.085, respectively (Table P = 0.353) and 0.043, respectively (Table P = 0.236) and 0.069, respectively (Table P < 0.001) and 0.991, respectively (Table P = 0.068) and 0.607, respectively   and 0.135, respectively. The mean HVPG and PPG were 18.67 ± 9.05 and 24.44 ± 6.79 mmHg, respectively, with correlation and determination coefficients of 0.263 (P = 0.006) and 0.069, respectively.There were 108 patients (81.6%) without collateral branches on conventional hepatic venography Fig. B. The avP < 0.001) and 0.640, respectively  and 0.407, respectively  and 0.325, respectively  and 0.111, respectively  underwent innovative hepatic venography without detection of collaterals, including 45 patients 65.2%) Fig. A with po1.5% undeely Fig. B. The av% Fig. A Alcoholic cirrhosis is a common cause of portal hypertension. Hemodynamic changes in portal hypertension caused by pathological changes in alcoholic cirrhosis occur mainly in the hepatic sinus, resulting in portal vein resistance and increased blood volume , 13. NorHowever, it has rarely been reported whether the HVPG represents PPG. The basic principle of measuring WHVP is that after the hepatic vein is completely blocked by a balloon, hepatic vein pressure gradually increases until it achieves the pressure of the hepatic sinuses; this accurately represents the pressure of the hepatic sinuses , 23. HowP = 0.004) and 0.325, respectively. The mean HVPG (23.50 ± 9.30 mmHg) was higher than the PPG (20.83 ± 6.78 mmHg); the correlation and determination coefficients were 0.334 (P = 0.111), and 0.111, respectively. Since the hepatic vein was perfused with contrast medium, the hepatic venous pressure gradually increased, and the contrast medium could not enter the portal vein through the hepatic sinusoids (possibly the blood of the hepatic sinusoids is mainly supplied by the hepatic artery) because of the higher hepatic sinusoidal pressure. The contrast medium was retained in the hepatic vein and could not enter the portal vein or the hepatic venous collateral return. Therefore, the absence of collateral branches of the hepatic vein is an important reason for the overestimation of WHVP and HVPG. Studies [By using innovative hepatic venography in this study, we detected more collateral branches of the hepatic vein (48.5%) than those identified using the conventional method 19.4%). Furthermore, in patients with collateral branches of the hepatic vein, the WHVP was significantly lower than the PVP and HVPG was significantly lower than PPG. Hepatic vein collateral flow is the key factor causing underestimation of WHVP and HVPG. Moreover, our analysis revealed that hepatic vein collateral branches appeared at the three shunt levels, and this underestimation was more obvious the earlier the shunt appeared. In addition to identifying more cases with hepatic vein collaterals, 45 patients  underwent portal vein imaging in the innovative hepatic venography group in this study. The correlation between WHVP and PVP in these patients was good, and the same was true for the HVPG and PPG. This was because the pressure of the hepatic vein increased after it was filled with the contrast agent. When the pressure of the hepatic vein was balanced with that of the hepatic sinus, the contrast agent entered the portal vein through the hepatic sinus countercurrent, which enabled portal vein imaging, indicating that the hepatic sinus pressure was roughly equal to the portal vein pressure. Furthermore, 24 patients  had no hepatic vein collateral branches. The mean WHVP of these patients (35.49 ± 7.78 mmHg) was higher than the mean PVP (30.13 ± 6.01 mmHg), with correlation and determination coefficients of 0.570 , and injection pressure that are most appropriate for innovative angiography also deserve further investigation.