We aimed to evaluate the effect of hydration status and fluid distribution on pulmonary function in COPD patients. A cross-sectional study, 180 patients with a confirmed diagnosis of COPD were included. Patients with asthma, advanced renal or liver disease, acute HF, exacerbation of COPD, or pacemakers were excluded. Hydration status variables  and disturbance of fluid distribution [impedance ratio (IR) > 0.84 and phase angle (PhA)] were evaluated by BIA. Pulmonary function was assessed by spirometry. The mean population age was 71.55 ± 8.94 years; 55% were men. Subjects were divided into two groups according to the IR ≥ 0.84 or < 0.84. The group with higher IR ≥ 0.84 had lower FEV1, FVC, FEV1/FVC, DLCO and, PhA compared to those with IR < 0.84. After adjusting for confounding variables TBW, ECW, IR ≥ 0.84, PhA, and resistance/height increase were associated with decreased FEV1. In the same way, with IR ≥ 0.84, edema index ≥ 0.48, trunk and abdominal IR were negatively associated with FVC, and PhA had a positive association with FVC. Fluid distribution, especially IR and PhA, could be a useful parameter for predicting pulmonary function in COPD patients.Chronic Obstructive Pulmonary Disease (COPD) patients have alterations in body composition. Bioelectrical impedance analysis (BIA) evaluates body composition, hydration status, and fluid distribution. Subjects with fluid disturbances have been found to have lower FEV COPD has been considered a world health problem because it affects 600 million persons globally3 and is the 4th cause of global death; also, its mortality reached 30–48% in 4–7 years in persons 65–70 years old4.Chronic Obstructive Pulmonary Disease (COPD) is a common, preventable, and treatable disease characterized by airflow limitation due to airway and/or alveolar abnormalities, usually caused by significant exposure to noxious particles or gases10, in particular, the multifrequency modality (MF-BIA) allows evaluation of hydration status and fluid distribution. MF-BIA is considered more precise and accurate for the measurement of extracellular (ECW) and intracellular water (ICW) than single-frequency BIA11. Edema is not usually detectable until the interstitial fluid volume rises about 30% above average (4–5 kg of body weight). In contrast, the BIA can detect changes in tissue hydration status below 500 ml12.Bioelectrical impedance analysis (BIA) is easy-to-use, noninvasive, and safe method for evaluation of body composition widely used in COPD patients13. Low frequencies do not pass through the cell membrane and are conducted only through ECW, while high frequencies penetrate cell membranes and are used to estimate total body water (TBW).The impedance ratio (IR) evaluates the fluid distribution between ICW and ECW and membrane integrity. IR is obtained from the ratio of impedance (Z) at a higher frequency and Z at a lower frequency (200 kHz/Z at 5 kHz/Z)1, vital capacity, respiratory muscle strength, both maximum inspiratory pressure and maximum expiratory pressure, fat-free mass index, and handgrip strength7. Moreover, COPD patients with sarcopenia had increased ECW/ICW ratio evaluated by 250/5 kHz IR, and this increase was even higher in severe sarcopenia 8. IR is a strong and independent predictor of 2-year mortality  in COPD patients10. Likewise, the ECW/ICW ratio indicates the cellular hydration state. In COPD patients, the ECW/ICW ratio was inversely associated with Peak VO214.In COPD patients, Blasio et al. showed that patients with 5/250 kHz IR below the median had lower FEV10.Another important marker of hydric status is the phase angle (PhA), which provides information about water distribution between ICW and ECW spaces, cellular mass, cellular integrity, and prognosis15. However, few studies have evaluated the hydric alterations in COPD patients10 and its impact on pulmonary function. This study aimed to evaluate the impact of hydration status and fluid distribution on pulmonary function in COPD patients.In hemodialysis patients with end-stage renal disease, fluid overload, assessed by MF-BIA, is associated with restrictive and obstructive respiratory abnormalitiesA cross-sectional study was carried out in the Cardiology Service at Instituto Nacional de Enfermedades Respiratorias “Ismael Cosío Villegas” from August 1, 2019, to March 31, 2020.16 were included. Age > 40 years old, smoking record (tobacco index > 10), or wood smoke or biomass exposure (> 200 h/year), and spirometry with a post-bronchodilator FEV1/FVC ratio < 0.701 constituted inclusion criteria. Patients with asthma, advanced renal or liver disease, acute HF, exacerbation of COPD, pacemakers, acute coronary syndromes, percutaneous transluminal coronary angioplasty, or coronary artery bypass graft within the prior three months were excluded.Patients with a confirmed diagnosis of COPD according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) recommendationsThe study was conducted according to the Declaration of Helsinki and was approved by the Institutional Ethics and Research Committee of Biomedical Research in Humans of the Instituto Nacional de Enfermedades Respiratorias “Ismael Cosío Villegas” .Body composition, anthropometry, pulmonary function, clinical and demographic variables, which are part of the clinical management of the patients who come to our Institute, were evaluated.17; all subjects wore light clothing and were barefoot. Body mass index was calculated by dividing the total body weight (kilograms) by the squared height (meters).Weight and height were measured according to the manual reference of anthropometric standardization18: The measurements were conducted by the same operator, in the morning, in a comfortable area, free of drafts, with portable electric heaters. The area was cleaned before the study. The subjects were fasting and should not have exercised eight hours before or consumed alcohol 12 h before the study. During the entire study, the person was in a supine position with the arms separated from trunk by about 30° and the legs separated by about 45°. Electrodes were placed on the hand and ipsilateral foot. We registered the resistance, reactance, PhA, and IR.Total body composition and raw variables were measured with whole-body bioelectrical impedance analysis using four-pole multifrequency equipment BodyStat QuadScan 4000  by standard techniqueImpedance ratio (IR) was calculated as follows: the ratio of high (200 kHz) to low frequency (5 kHz) of multifrequency BIA. In our population, the 50-percentile value was 0.84.The segmental impedance ratio was performed in the same position as whole-body bioimpedance. Segmental IR was calculated as the ratio of high (200 kHz) to low frequency (5 kHz).Trunk impedance ratio: A pair of electrodes was placed on the midline at the interclavicular level, and the second pair was placed on the right upper ventral iliac spine.Thorax impedance ratio: A pair of electrodes was placed on the midline at the interclavicular level, second pair placed on the right costal border.Abdomen impedance ratio: A pair of electrodes was placed on the midline at the xiphoid process level, a second pair placed on the right upper ventral iliac spine.Edema index was calculated as follows: the ratio between ECW (lt) to TBW (lt). In our population, the 75-percentile value was 0.48.19.Handgrip strength was measured with a mechanical Smedley Hand Dynamometer  according to the technique described in Rodriguez et al.20. The spirometry variables analyzed were the Forced Expiratory Volume in the first second (FEV1) and the Forced Vital Capacity (FVC) after administration of a bronchodilator. After 15 min at rest, the participant performed a maximum forced inhalation and a powerful forced expiration using a nose clip. The reference values for spirometry were obtained for Mexican–American individuals21.Spirometry testing was conducted by an experienced respiratory medicine technician using a portable spirometer  according to the standards of the American Thoracic Society/European Respiratory Society2 for categorical variables and unpaired Student's t-test or Mann‐Whitney U tests for continuous variables.Analyses were performed using a commercially available STATA version 14 . Categorical variables were presented as frequencies and percentages; continuous variables with normal distribution were presented as mean and standard deviation. The Shapiro–Wilk test was used to test the normality of continuous variables. Normal continuous variables were presented as mean and standard deviation, while non-normal variables were presented as median and percentiles 25–75. A comparison among study groups was analyzed with X1% predicted and FVC % predicted) and hydration status and fluid distribution. The models were adjusted for sex, height, and age. A p < 0.05 was considered statistically significant.Linear regression analysis was performed to examine the association between pulmonary function , were older,  and had lower albumin levels . FEV1 was lower  as was FVC . The FEV1/FVC was lower  and the carbon monoxide lung diffusion capacity (DLCO) as well . The same was true of weight  handgrip strength , skeletal muscle mass index  and PhA  compared to those with IR < 0.84. The left atrial volume index was higher . Table One hundred and eighty patients with stable COPD were included. The mean population age was 71.55 ± 8.94 years; 55% were men. Subjects were divided in two groups according the IR ≥ 0.84 (n = 88) or < 0.84 n = 92). Table . Table pThe main finding in our study was the significance of the impact of hydration status and fluid distribution on pulmonary function in COPD patients.25, although the pathophysiology of impaired pulmonary function has not been completely elucidated. In some cases, respiratory symptoms are either underestimated or overlooked in clinical practice22. However, the methods for estimating body composition like imaging technique and isotope dilution to evaluate hydration status are relatively invasive, expensive, and not suitable in clinical practice23. The BIA is a non-invasive, inexpensive, and easily reproducible procedure that detects fluid overload and fluid distribution24. This method has already been validated in several pathologies, demonstrating that an IR higher than 0.80 is associated with fluid overload25 and is an independent predictor of mortality in hemodialysis and COPD patients26.Several studies have found that weight increase is frequently associated with functional class decreases and pulmonary congestion in the absence of clinical edema10. In this study, we observed that IR ≥ 0.84 was an independent predictor for FEV1  and FVC  adjusted for age, sex and height. The subjects with IR ≥ 0.84 had a 13.14% lower FEV1 and 9.26% lower FVC than subjects with IR < 0.84 in this population.Lower values of IR and higher values of PhA provide information about the fluid distribution between ICW and ECW compartments. Moreover, they are considered indicators of greater cellularity, cell membrane integrity, and nutritional status. IR disturbance is associated with diminished pulmonary function, lower peripheral and respiratory muscle strength, fat-free mass index, physical function, and poor prognosis in COPD patients1, low skeletal muscle mass, diminished physical function, increased disease severity, malnutrition, poor quality of life, longer hospital stay, exacerbations, and poor prognosis10. Our results showed that the PhA is a strong independent predictor of FEV1  and FVC  adjusted by age, sex, and height. That is, for every 1 degree that PhA increases, there is an increment of 7.76% for FEV1 and 3.25% in FVC in this population.In COPD patients, low PhA was associated with low FEVp = 0.04)27. Also, Androne et al., found that blood volume increase was associated with higher pulmonary wedge pressure and mortality risk in heart failure patients with no visible edema (39% in a year)28. These data suggest that the mechanism of fluid overload may relate to redistribution rather than volume overload30.Our study also showed a negative association between FEV1, with TBW, ECW, IR > 0.84, and resistance adjusted by height. And a negative association of FVC with edema index > 0.47. Similar results have been observed in different studies Lui et al., found that the edema index evaluated by ECW/TBW was > 0.39 by multifrequency BIA in acute heart failure patients (20–80 years old) hospitalized in cardiogenic shock. These patients had an elevated risk of re-hospitalization related to HF ”34.On the other hand, with exercise chronic heart failure patients increase their ventricular filling pressures and decompensation periods due to volume overload or redistribution, raise pulmonary capillary wedge pressure, and allow fluid transudation into the interstitial space with the formation of edema35, and 50% die from cardiovascular causes, more than from respiratory distress36. Moreover, pulmonary congestion during COPD exacerbations increases the risk of dying, possibly due to heart failure37. The interstitial fluid or intravascular volumes depend on many factors, including HF etiology39. One of them, hypoalbuminemia, is partly responsible for the peripheral congestive state common in heart failure41 when capillary membrane stabilization capacity through colloid osmotic properties is severely compromised42.In COPD patients, heart failure is not always recognized, even though up to 23% of them are hospitalized43. Accumulation of pulmonary blood volume has been associated, as in our cases, with reduced spirometric parameters and a reduced DLCO. This increase of extravascular lung water is the main pathogenic factor of diminished functional capacity44. Our findings correlate with these pathophysiological mechanisms; the IR ≥ 0.84 with a significant FEV1 reduction was similar for FVC. Moreover, in patients with an IR ≥ 0.84, the DLCO was significantly reduced compared to decreased skeletal muscle mass index, handgrip strength, albumin, and worse functional spirometric parameters. However, when the left atrial volume index was higher, meaning left ventricular filling pressures were increased, a pathophysiological scenario of pulmonary fluid overload or local redistribution would be the outcome. The decrease in DLCO levels can be multifactorial and can lead to a greater number of exacerbations and a reduction in the quality of life as well as an increase in dyspnea.dditionally, there is an interaction between albumin levels with the hydrostatic pressure factors and the fluid redistribution that affect lung function and pulmonary gas exchange independent of heart failure phenotypesOur first limitation is the small sample size and the fact that it is a cross-sectional study. On the other hand, important previous studies have observed that subjects with hydration status and fluid distribution disturbances assessed by BIA have a worse pulmonary function. However, these studies performance a bivariate analysis that does not evaluate whether there is an independent association between the study variables. Among the strengths of our study, this is the first study in COPD patients that evaluates the association hydration status and fluid distribution on pulmonary function performance a multivariate prediction model adjusted for confounding variables in COPD patients, which allows us to assess the effect size of water status variables on FEV1 and FVC.Hydration status and fluid distribution have a significant impact on pulmonary function. Early detection of these disturbances in BIA, especially by IR and PhA, enables the early application of therapeutic strategies to improve pulmonary function in COPD patients.


Introduction: The effects of sodium-glucose cotransporter-2 (SGLT2) inhibitors on renal outcomes in patients with chronic kidney disease (CKD) were initially demonstrated in recent trials. However, the magnitude of renal benefits for CKD patients with different baseline features and underlying diseases remains unclear.Method: We systematically searched the Embase, PubMed, Web of Science, and Cochrane library databases from inception to April 15, 2021 to identify eligible trials. The primary outcome was a composite of worsening kidney function, end-stage kidney disease (ESKD), or renal death. Efficacy and safety outcomes were stratified by baseline features, such as type 2 diabetes, heart failure, atherosclerotic cardiovascular disease, proteinuria, and renal function.Results: A total of nine studies were included. These studies included 25,749 patients with estimated glomerular filtration rate (eGFR)<60 mL/min/1.73 m2 and 12,863 patients with urine albumin-to-creatinine ratio (UACR) >300 mg/g. SGLT2 inhibitors reduced the risk of the primary renal outcome by 30% in patients with eGFR<60 mL/min/1.73 m2  and by 43% in patients with UACR > 300 mg/g . A similar benefit was observed in CKD patients with type 2 diabetes. SGLT2 inhibitors had no clear effects on renal outcomes in patients with eGFR<60 mL/min/1.73 m2 combined with atherosclerotic cardiovascular disease . However, they reduced the risk of major renal outcomes by 46%  in patients with atherosclerotic cardiovascular disease and macroalbuminuria (defined as UACR > 300 mg/g). SGLT2 inhibitors did not significantly reduce the risk of major renal outcomes in CKD patients with heart failure . SGLT2 inhibitors showed consistent renal benefits across different levels of eGFR (P interaction = 0.48).Conclusion: SGLT2 inhibitors significantly reduced the risk of the primary outcome in CKD patients. However, for patients with different features and underlying diseases, there exists differences in the renal protective effect. Chronic kidney disease (CKD) has become a major global public health problem that imposes a heavy burden on families and society. Currently, about 700 million individuals worldwide suffer from CKD, and the incidence will continue to increase . DetermiSGLT2 inhibitors, a new class of glucose-lowering drugs, have been proven to reduce blood glucose, blood pressure, and body mass index . Within Over the last 2 years, two large studies , 11 thatThis systematic review and meta-analysis was designed and guided according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement . Moreovehttp://www.clinicaltrials.gov) from their inception to April 15, 2021.Without language or publication time restrictions, two authors searched for relevant randomized controlled trials that investigated the efficacy of SGLT2 inhibitors in CKD. The following electronic databases were searched: PubMed, Web of Science, Sciencedirect, Embase, and Clinical trials  incorporated with free text terms. The following terms were searched:  AND “Randomized controlled trial”. Any terms related to “SGLT2i” were searched to prevent leakages.Meanwhile, we performed several exhaustive searches of major international conference proceedings, grey literature  and clinical trials that may be ongoing or not yet published to minimize loss or omission of suitable articles that met our inclusion criterion. Additionally, the references in each study and meta-analysis of SGLT2 inhibitors were searched for potentially eligible studies. Details on the databases and search strategies are presented in the search strategies supplement. A check was indispensable for the integrity and veracity of studies. All records from the initial search were imported into NoteExpress v3.2.0.7535 to manage and confirm the above information, and was performed concurrently by two independent authors . Discrepancies during this process were resolved through discussion or mediated by a third author (LZ).2 or urine albumin-to-creatinine ratio (UACR) > 300 mg/g. There were no race or sex restrictions.The included population was patients ≥18 years old with CKD, defined as estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 mThe included trials required the intervention group to take an SGLT2 inhibitor, and there were no limits on specific doses. Trials of SGLT2 inhibitors in combination with other basic therapeutic agents (such as those for controlling blood pressure or blood sugar) were also permitted.Control groups without treatment or treated only with placebos were included. Control groups provided basic treatment were also included.2) or renal death. If the study reported both doubling of serum creatinine and sustained 40% decline in eGFR, we prioritized sustained 40% decline in eGFR as the definition of worsening kidney function. The secondary renal outcome was a composite outcome including worsening kidney function, ESKD, renal death or cardiovascular death, other secondary outcomes including MACE , annualized eGFR slope , and the percentage of reduction in UACR compared with placebo. The safety outcomes included acute kidney injury, amputation, bone fracture, and volume depletion.The primary outcomes of this study included: worsening kidney function (defined as doubling of serum creatinine or sustained 40% decline in eGFR), end-stage kidney disease (ESKD)  with use of a standardized data form. If we encountered problems during the data extraction process, we consulted two experts in this field (LZ and DZ) for resolution through discussion. For data not available in the original text or appendices, we obtained the relevant secondary analyses by contacting the authors.The Cochrane quality assessment tool provided by RevMan was used to evaluate the risk of bias in each trial . Three a2 statistics. Values of 25% or less, 25–50%, and 75% and more represented mild, moderate, and high heterogeneity, respectively  values, we pooled HRs with 95% confidence intervals (CIs) to evaluate the effect of each trial. If the study only provided the number of events, we used the risk ratio (RR) for the calculation . For continuous variables, weighted mean differences (WMD) were used for analysis. Additionally, we used a random-effects models with application of the DerSimonian–Laird estimator. We assessed heterogeneity between studies using the Iectively . If the ectively . For dif2 and 12,863 had macroalbuminuria (defined as UACR > 300 mg/g). The lowest eGFR value was 20 mL/min/1.73 m2. Mean age among the trials ranged from 61.9 to 69 years. Median follow-up time ranged from 16 to 42 months. Features of the included studies are shown in A total of 3,286 studies were retrieved by searching the various databases. After screening abstracts and removing duplicates, 76 studies were retrieved. We performed full-text analyses of the studies, and a total of nine were ultimately included according to our strict criteria . Among tThere was a certain risk of bias in some of the included studies. Sufficient generation of random sequence was observed in eight trials, while this was unspecified in one trial . Adequat2, SGLT2 inhibitors reduced the risk of primary renal outcomes by 30%  compared with placebo (2 = 16.59%). Sensitivity analysis showed that different definitions of worsening kidney function did not alter the risk reduction of primary renal outcomes  and by 29% in patients with eGFR of 30–45 mL/min/1.73 m2 . SGLT2 inhibitors also significantly reduced the risk of primary outcomes among patients with eGFR <30 mL/min/1.73 m2 (2 = 0.00%). The effect of reduction in primary outcomes appeared to be consistent with eGFR ≥30 mL/min/1.73 m2 (P interaction = 0.37).SGLT2 inhibitors reduced the risk of the primary outcome across different subgroups of eGFR . For pat/1.73 m2  compared2 (2 = 0.00%) and by 44% in those with UACR > 300 mg/g (2 = 30.47%).For patients with type 2 diabetes, SGLT2 inhibitors reduced the primary outcomes by 36% in those with eGFR < 60 mL/min/1.73 m2 (2 = 0.00%), or UACR > 300 mg/g (2 = 0.00%).For patients with heart failure, there was no significant benefit in primary outcome compared with placebo in those with eGFR <60 mL/min/1.73 m2 = 0.00%), SGLT2 inhibitors did not significantly reduce the risk in those with eGFR <60 mL/min/1.73 m2 combined with ASCVD (2 = 0.00%).Although the risk of major renal outcomes was reduced by 46% in patients with macroalbuminuria with ASCVD  and by 35% in patients with macroalbuminuria . The HR for MACE was also significantly reduced  and 23% in those with UACR > 300 mg/g . The eGFR slope of the SGLT2 inhibitors group appeared to be more stable than that of the control group  and UACR > 300 mg/g . However, there was high heterogeneity among the different studies. The percentage of UACR (2 = 78.75%) in patients with eGFR <60 mL/min/1.73 m2 compared with placebo and by 31.1%  in patients with UACR > 300 mg/g. High heterogeneity was observed in patients with eGFR <60 mL/min/1.73 m2 (I2 = 78.75%).SGLT2 inhibitors reduced the risk of the secondary renal outcome  by 33%  in patie reduced  by 16% iol group  and this of UACR  was redu2 = 0.00%; amputation: HR 1.49, [95% CI 0.72–3.07], I2 = 67.61; fracture: HR 0.99, [95% CI 0.74–1.34], I2 = 0.00%; volume depletion: HR 1.24, [95% CI 0.98–1.58], I2 = 0.00%), or eGFR <60 mL/min/1.73 m2 .According to our results, there were no significant differences in adverse outcomes including amputation, fracture, volume depletion, or acute renal failure between patients with macroalbuminuria receiving SGLT2 inhibitors or placebo (https://gradepro.org/). The outcomes of Annualized eGFR slope (Both UACR and eGFR group) and The percentage of reduction in UACR (eGFR group) were low quality, while other outcomes were moderate or high quality , the use of SGLT2 inhibitors was associated with significant renal benefits, and this result is consistent with those from two previous meta-studies . The results from a prespecified analysis of dapagliflozin are similar . This may be explained by the following factors: first, heart failure aggravates the progression of CKD. Therefore, the beneficial effects may be attenuated in patients with CKD complicated with heart failure; second, one study . However, patients with macroalbuminuria were associated with reduced risk of major renal outcomes . Combined with the results in patients with CKD complicated with heart failure, we propose that SGLT2 inhibitors may not provide clinically relevant renal benefits in patients with CKD complicated with CVD, especially those with eGFR <60 mL/min/1.73 m2. However, given that the data in this population were primarily from subgroup analysis, and that most of the primary outcomes of these studies were not renal outcomes, the credibility of the results are diminished accordingly.For CKD patients with different underlying diseases, we found that there were corresponding differences in the magnitude of renal benefits from SGLT2 inhibitors. First, primary renal outcomes were reduced in patients with type 2 diabetes mellitus combined with CKD. This has been confirmed in previous meta-analyses . HoweverRegarding renal function, previously, a meta-analysis  which inRegarding safety outcomes, the results of our study showed that SGLT2 inhibitors did not increase the risk of fracture, amputation, acute kidney injury, or volume depletion. Previously, there were concerns that SGLT2 inhibitors could cause acute kidney injury by regulating hemodynamic mechanisms. Several large studies also demonstrated a significant decrease in eGFR during the early stage of use of SGLT2 inhibitors compared with placebo , 9. HoweOur meta-analysis had limitations. First, we used combined data rather than individual participant data. Second, there were differences in definitions of endpoints in some studies, which may have had an impact on our results. However, after sensitivity analysis, it was proven there was no substantial impact on our results. Third, the primary outcome of most of the studies was cardiovascular outcomes. In addition, most of the data came from subgroup analyses of major trials, which may reduce the credibility of the results of this study.2. In view of the limitations of our study, in the future, additional high-quality studies are needed to confirm the renal benefits of SGLT2 inhibitors in CKD patients with different baseline features and underlying diseases.In conclusion, SGLT2 inhibitors significantly reduced the risk of primary renal outcomes in patients with CKD, and this benefit was consistent across the spectrum of different levels of eGFR. Additionally, consistent benefits were observed in patients with type 2 diabetes. However, no significant renal benefit was observed in patients with CKD associated with heart failure. In the population with ASCVD, renal benefits were only observed in CKD patients with macroalbuminuria, whereas no significant benefits were observed in those with eGFR <60 mL/min/1.73 mThe original contributions presented in the study are included in the article/NL, DL, and LZ contributed to the concept and design of this study. NL, DL, XZ, and PW contributed to the literature search. NL, DL, and YG contributed to the data extraction and risk-of-bias assessment, LZ and DZ acted as consultants for data extraction and literature screening. NL responsible for statistical analysis and writing of the report. MZ assisted in statistical analysis. DL assisted with the writing of the report. EZ reviewed the article and provided critical feedback to shape the report. NL and DL contributed equally to this work and should be considered as co-first authors. All authors read and approved the final manuscript.This study was supported by Special Project of National Clinical Research Base of Traditional Chinese Medicine (No. JDZX2015094).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


When the mean arterial pressure exceeded 65 mmHg after NE administration (T1), the measurement was repeated. Twenty-four patients  with septic shock were examined in this study. Before (T0) and after (T1) NE administration, the PSV  changed from 85.3 (21.1) cm/s to 83.5 (23.5) cm/s (p = 0.417); this change was not significant. However, the diameter and blood flow of the CCA increased significantly from 0.6 (0.09) cm and 0.75 (0.27) L/min to 0.66 (0.09) cm and 0.85 (0.27) L/min, respectively (p < 0.001). The diameter of the left ventricular outflow tract (LVOT) remained unchanged, but the velocity time integral of the LVOT increased significantly from 21.7 (4.39) cm to 23.6 (5.14) cm. There was no significant correlation between changes in blood flow of the CCA and changes in cardiac output . In conclusion, NE increased the diameter and blood flow of the CCA significantly, without changing the PSV in patients with septic shock.This study was designed to evaluate the hemodynamic effect of norepinephrine (NE) on the peak systolic velocity (PSV), diameter, and blood flow of the common carotid artery (CCA) using the point-of-care ultrasound (POCUS) in patients with septic shock. The study involved patients above 18 years old with septic shock. Arterial monitoring, carotid ultrasonography, and transthoracic echocardiography were performed before NE administration (T Norepinephrine (NE) is a first-line agent for the correction of hypotension, and its early administration is recommended for patients with septic shock. NE has α- and β1-adrenergic properties; therefore, it causes an increase in the mean arterial pressure (MAP), and small increases (10–15%) in the stroke volume and cardiac output (CO)9. Assessment of the hemodynamic status of patients with shock receiving NE is essential for an appropriate management of these patients. In recent decades, invasive hemodynamic monitoring has been replaced by the use of a non-invasive monitoring device or bedside ultrasonography10. However, using comprehensive echography proficiently to measure the cardiac output (CO) in emergency settings is not easy for physicians.The incidence of septic shock, defined as sepsis with concurrent hypotension requiring vasopressor therapy, have been increased worldwide11. Blood flow changes of the CCA by preload challenges in shock patient had already been reported in several15. A recent study by Marik et al. showed that the CCA blood flow rate increased by 60% after passive leg elevation, and predicted the volume response with 94% sensitivity and 86% specificity16. However, the hemodynamic effects of NE on the CCA blood flow in patients with septic shock have not been investigated. In addition, the correlation between CCA blood flow changes using the point-of-care ultrasound (POCUS) and CO changes using echocardiography according to NE administration is unclear.Carotid measurement is a much simpler technique, which can be performed with more accessibility on unstable patients with limited change of position. The blood flow of the common carotid artery (CCA) has been known to represent CO indirectly, showing moderate agreement with echocardiographyTherefore, the aim of this study was to evaluate the hemodynamic effect of NE on the peak systolic velocity (PSV), diameter, and blood flow of the CCA using the POCUS in patients with septic shock. In addition, we investigated whether CCA measurements can be used as a method compared to echocardiography in evaluating the response to NE in patients with septic shock.This prospective observational study was conducted from December 2019 to February 2020 at the emergency department of an academic tertiary hospital in an urban area. The study was conducted in accordance with the Declaration of Helsinki. The study was approved by the institutional review board committee of Samsung Medical Center (IRB File Number: 2019-09-102-003) and clinical research information service . Informed consent was provided by all patients or guardians if the patient was unconscious, disoriented, above 65 years old, or had dementia.20.We screened patients aged over 18 years with identified or developed sepsis-induced hypotension after visiting the emergency department (systolic blood pressure < 90 mmHg or MAP < 70 mmHg with a heart rate [HR] > 100 rates/min). Patients with persistent hypotension requiring vasopressor use for the maintenance of an MAP above 65 mmHg despite adequate fluid resuscitation (> 2000 mL or 30 mL/kg within 3 h) were enrolled22. Patients who were unable to undergo follow-up ultrasonography and who did not give consent to the use of their data were also excluded.Pregnant patients, trauma patients, patients with a do-not-resuscitate status, and patients with cardiac arrest were excluded. Additionally, patients who were receiving or had received a vasopressor within 24 h prior to the study were excluded. Patients with a CCA stenosis degree of ≥ 50% on carotid ultrasonography (PSV > 150 cm/s with post stenotic turbulence) and those with a medical history of CCA stenosis were excluded19. They underwent close monitoring via the arterial line at the radial artery, and POCUS was initially performed for cause assessment and patient management. Patients who required NE for the maintenance of an MAP above 65 mmHg even after initial resuscitative treatment were enrolled . When the MAP reached a level above 65 mmHg for 10 min after NE administration (T1), a re-measurement was performed. Additionally, the patients’ demographic, laboratory, and hemodynamic data were collected through arterial line monitoring at T0 and T1.All patients suspected of septic shock received initial diagnostic evaluations: these included laboratory and imaging work-up, concurrently with therapeutic interventions such as fluid administration and antibiotic therapy, according to Survival Sepsis Campaign guidelinesAll sonographic examinations were performed by a single operator experienced in emergency medicine POCUS, with convenient sampling according to the protocol. Bedside ultrasonography was performed with vivid ™ S70 . Two-dimensional (2D) image mode and Pulsed Wave (PW) Doppler image mode with linear probe (11L) on vascular preset were used for CCA identification and estimation. TTE was performed with a cardiac probe (M5Sc) for the measurement of the diameter and VTI of the LVOT on cardiac preset.25. The carotid and cardiac measurements were repeated three times if possible, and then averaged for the minimization of random errors.Ultrasonography was performed within 5 min, and the obtained images were saved as video files, and then reviewed by two attending emergency physicians who served as ultrasonography instructors. When the measurements were reviewed using six indicators, a score of ≥ 4 was considered clinically interpretable and included in the analysis; otherwise, it was excluded 23. The CCA was identified in the short-axis and the long-axis view. PW Doppler ultrasonography was performed at the center of the vessel with angle correction settings of 60° at 1–2 cm below the carotid bulb. The additional color Doppler mode was used for post-stenotic turbulence distinction. The CCA diameter was measured from opposite points of the vessel’s intimal wall. The PSV and VTI were determined automatically from the sample obtained from the center of the artery using PW Doppler 24. The CCA blood flow per minute was calculated using the equation: π × (CCA diameter)2/4 × CCA VTI × HR. This parameter was measured both before and after NE administration for the determination of CCA blood flow changes.To increase the accuracy of the repeat measurements, a pillow was used to ensure uniformity in the patients’ neck positions. We marked the center and edge of the probe on the patient’s neck for easy re-measurement at the same location 25. LV stroke volume was estimated after obtaining the VTI of the PW measurement at the LVOT. The CO per minute was calculated using the equation π × (LVOT diameter)2/4 × LVOT VTI × HR.The patients were maintained in a supine position for image acquisition in the parasternal and apical windows. The edge of the probe on the patient’s chest was marked for easy re-measurements at the same location. The diameter of the LVOT was considered as the inner distance between the bases of the aortic valve cusp during systole, as observed from the parasternal long-axis view. PW Doppler samples were then obtained at the center of the LVOT from the apical view, with the aim of obtaining a Doppler signal to aortic blood flow angle close to 0°0) and after the achievement of an MAP above 65 mmHg after NE administration (T1). The secondary outcome was the CCA diameter and blood flow change between T0 and T1. In addition, we measured the diameter, VTI of the LVOT, and CO changes by TTE according to the NE administration status. We also assessed the correlation between CCA flow changes via POCUS and CO changes via TTE. We analyzed the factors affecting the CCA blood flow change according to the NE status. For reliability evaluation, the intra-operator repeatability value was also calculated.The primary outcome was the PSV change in the CCA observed before NE administration  in the CCA was used26. We assumed a drop-out rate of 10%. A total of 22 patients was deemed required.The sample size was calculated relative to the primary outcome achievement; we assumed an α value of 0.05 for two-sided hypothesis testing and a β error of 0.20 (power = 80%). A 15% increase in the CCA PSV following NE administration was considered clinically significantStandard descriptive statistics are used to present all data. Continuous variables are presented as mean (standard deviation [SD]) or median (interquartile range [IQR]). Categorical data are presented as numbers with percentages. Paired t-tests or Wilcoxon signed-rank tests were used for mean comparisons between the two groups. Univariate and multivariate regression analyses were performed to determine the factors affecting CCA blood flow changes. Variables for which analyses resulted in p values lower than 0.2 were incorporated into the multivariate regression analysis. The relationship between CCA flow changes and CO changes was assessed using Pearson’s correlation analysis. Intra-operator repeatability was evaluated by comparing the three variable measurements for the calculation of intra-class correlation coefficients (ICCs) with their 95% confidence intervals (CIs). All statistical analyses were performed using STATA ver. 15.0 software .0, 1.9 ± 0.69 L of fluid was administered. The mean (SD) NE dose was 0.11 (0.05) mcg/kg/min  to 94 (19) beats/min. The median blood lactate level (IQR) at T1 was 1.8 (1.3–2.8) mmol/L, which was significantly lower than 2.85 (2.5–5.5) mmol/L at T0 .There was no significant change in HR  from T0) and after (T1) NE administration, the mean (SD) of the PSV and CCA diameter were 85.3 (21.1) cm/s, 0.6 (0.09) cm and 83.5 (23.5) cm/s, 0.66 (0.09) cm, respectively. The CCA PSV remained unchanged, but the CCA diameter increased significantly. The CCA blood flow also increased significantly from 0.75 (0.27) L/min to 0.85 (0.27) L/min after NE administration (p < 0.001). The change was approximately 16 (SD 20) %  and after (T1) NE administration, the VTI and diameter of the LVOT were 21.7 (4.39) cm/s, 1.96 (0.2) cm and 23.6 (5.14) cm/s, 1.95 (0.18) cm, respectively  L/min in seven patients at T1. The carotid blood flow changes in the seven patients with decreased CO was 0.17 L/min (SD 0.07), which was significantly greater than the change of 0.06 L/min (SD 0.11) in 17 patients with increased CO at T1. (p = 0.023) (Table  L/min in0), HR (T0), and pH (T0). CCA blood flow change (L/min) decreased in association with high MAP values at T0  and increased in association with high HR values at T0  .A multivariate regression analysis to evaluate the factors influencing CCA blood flow changes was performed after adjusting for C-reactive protein (CRP), NE dose, MAP . The ICC of the carotid measurements (92–94%) performed using POCUS was excellent and superior to that of the cardiac measurement (80–88%) conducted using TTE.28. Several previous studies have examined the correlation between CA blood flow and CO16. Gassner M. et al. showed that the reliability of carotid POCUS, compared to that of invasive measurements such as pulmonary artery catheterization or arterial waveform pulse contour analysis, was 74–84%, showing more than a substantial degree of agreement12. In the study by Peng et al., the overall ICC between the carotid and echocardiographic CO was 0.537, but a subgroup analysis of 14 patients with septic shock showed a weak correlation with an ICC of 0.241. In addition, vasopressor use was not considered11. In this study, the mean value of CCA blood flow increased significantly by approximately 16 (SD 20) % when MAP increased after NE administration  conducted by Bonyhay et al. also showed similar results in six volunteers with normal blood pressure values31. Our findings suggest that when NE is administered to patients with septic shock, the passive dilatory forces resulting from the increased carotid blood flow are likely to dominate the active tension developed by smooth muscle contraction in the CCA. Also, since CCA blood flow reflects intracranial blood flow, this is thought to be related to cerebral autoregulation to maintain constant blood flow in the brain of patients with septic shock32.As NE exerts α- and β1-adrenergic agonist effects34. However, Hamzaou et al. suggested that NE may increase cardiac contractility through both an indirect α-adrenergic effect by improving coronary perfusion according to the increase in diastolic arterial pressure and a direct effect on cardiomyocytes via β1-adrenergic stimulation, mainly in the early phase of septic shock6. In this study, the CO value was increased by approximately 9 (SD 24) % from 5.83 (IQR 4.46–7.89) L/min to 6.50 (IQR 4.99–7.49) L/min after NE application. Whereas, in seven patients, the CO decreased at T1. This may be related to a negative effect of NE on cardiac function through an increase in left ventricular afterload35. The carotid blood flow change in the seven patients with decreased CO was 0.17 (SD 0.07) L, which was significantly greater than the change in patients with increased CO at T1 by about three-fold. (p = 0.023)  or the initial HR is high . However, these findings are thought to be related to the study design, and its generalizability is limited due to the small sample size.We analyzed several factors that affect CCA blood flow changes, according to the NE status, using univariate and multivariate analyses . MAP and HR at T37. In this study, the ICC of the CCA measurement ranged between 92 (95% CI 86–96)% in the CCA diameter and 94 (95% CI 88–97)% in the CCA PSV, indicating that carotid measurements performed using POCUS have an excellent reliability and are higher than the cardiac measurements (80–88%) . Since most emergency physicians are not professional sonographers, they often find it difficult to measure the level of CO by flow velocity through the LVOT, especially when dealing with suboptimal cardiac windows due to positioning difficulties in patients with shock. However, carotid POCUS is easier to approach superficially and insonate at the bedside than accessing the LVOT. In addition, carotid POCUS can be serially repeated in the same patient, allowing clinicians to adequately assess the response to volume-loading maneuvers or NE application. It can be particularly helpful in the monitoring of patients with septic shock in time-critical clinical situations, in resource-limited environments, or those with no other available options. Therefore, further studies are needed to assess patients with septic shock in several settings using carotid POCUS.The reliability of Doppler velocity measurements is severely affected by their intrinsic operator and machine dependency, with the beam-to-flow angle exerting the strongest effectThis study has several limitations. First, although it had a prospective design, it was limited by the observational nature of the research and the lack of a control group. In addition, it was performed in a single center and involved few patients; as such, the results not be generalizable to other settings. Hence, further studies in other settings are needed.0 and T1; i.e., during NE administration, these may have influenced preload dependence to a certain extent, in addition to the NE effect. Furthermore, a relatively small amount of NE  was administered in this study, and the effect on patients with refractory septic shock who required a high dose of NE could not be evaluated. Therefore, additional studies are needed on the effect of hypovolemia and NE dose on carotid and cardiac measurements following NE administration.Second, the patients’ comorbidities and drug use history, including use of antihypertensive drugs, may have affected the effectiveness of NE. In addition, since many patients had a hypovolemic component and the volume was administered between TThird, this study design did not include blinding the operator. Also, ultrasonography is operator-dependent. Even if PW Doppler is performed at the center of the vessel with an angle correction of 60°, a small difference in the angle and degree parallel to the vessel can cause the measurements to differ. Moreover, the arterial blood pressure of some patients changed dynamically, even during ultrasonography. Therefore, there may be some discrepancies between the MAP when measuring the PSV and the actual value. In addition, although we took the measurements at the same location, there may be differences in the values according to the change in the patient’s position and measurement site.Lastly, we measured both carotid and cardiac values non-invasively using ultrasonography, and none of these could be compared to exact baseline values when assessing their relationship. In addition, we could not provide other cardiac measurements to evaluate the cardiac functions except for CO measurements. Therefore, it was not possible to explain in more detail the changes of cardiac functions after NE administration. Moreover, since we did not measure outcomes serially after NE administration, changes such as compensation or desensitization of the effects of NE over time are not known.In summary, NE use leads to increases in the CCA diameter and blood flow rate without significant changes in the CCA PSV in patients with septic shock; these were observed using carotid POCUS. The measurements of CCA blood flow using carotid POCUS may have the potential of being used in the assessment of MAP increase in response to NE in patients with septic shock.Supplementary Information 1.Supplementary Information 2.Supplementary Information 3.Supplementary Information 4.Supplementary Information 5.Supplementary Information 6.


Diabetes mellitus represents a growing concern, both for public economy and global health. In fact, it can lead to insidious macrovascular and microvascular complications, impacting negatively on patients’ quality of life. Diabetic patients often present diabetic kidney disease (DKD), a burdensome complication that can be silent for years. The average time of onset of kidney impairment in diabetic patients is about 7–10 years. The clinical impact of DKD is dangerous not only for the risk of progression to end-stage renal disease and therefore to renal replacement therapies, but also because of the associated increase in cardiovascular events. An early recognition of risk factors for DKD progression can be decisive in decreasing morbidity and mortality. DKD presents patient-related, clinician-related, and system-related issues. All these problems are translated into therapeutic inertia, which is defined as the failure to initiate or intensify therapy on time according to evidence-based clinical guidelines. Therapeutic inertia can be resolved by a multidisciplinary pool of healthcare experts. The timing of intensification of treatment, the transition to the best therapy, and dietetic strategies must be provided by a multidisciplinary team, driving the patients to the glycemic target and delaying or overcoming DKD-related complications. A timely nephrological evaluation can also guarantee adequate information to choose the right renal replacement therapy at the right time in case of renal impairment progression. Diabetes mellitus (DM) is a metabolic disease characterized by chronic hyperglycemia as a consequence of defects in insulin action, secretion, or both. DM currently affects more than 463 million people worldwide (9.3% of adults aged 20–79 years), and the number of patients with DM is estimated to rise up to 578 million by 2030, and 700 million by 2045 . The WorThe clinical and socio-economic impact of DKD is burdensome not only because of the risk of progression to end-stage renal disease (ESRD) and therefore to renal replacement therapies, but also because of the associated increase in cardiovascular (CV) risk ,5. A strBased on established vascular complications and comorbidities, it is necessary to identify treatment targets, and many trials ,9,10 sugThe failure to establish appropriate targets and escalate treatment to achieve treatment goals timely is termed “therapeutic inertia”. A broader concept of “clinical inertia” includes the delay of the escalation or deintensification of therapy and issues such as failure to screen, make appropriate referrals, and manage risk factors and complications . MoreoveThis narrative review aims to provide an overview of the pathophysiology and pharmacological management of DKD, highlighting evidence on therapeutic inertia from real-world settings and discussing barriers and potential strategies to optimize DKD management.2) ) and a reduced estimated GFR (GFR < 60 mL/min per 1.73 m2) .Traditionally, DKD can be identified by the presence of abnormal UACR  and defiDue to the differences in economic viability and governmental infrastructures between countries, there is a marked racial/ethnic difference besides the international difference in the epidemiology of diabetic nephropathy . DKD is The Institute for Alternative Futures (IAF) calculated that the number of DM patients in the United States would increase by 54%, between 2015 and 2030, with a rise of diabetes-related mortality of 38% ,25,26. DAn analysis of the United States Renal Data System reported that DKD-related deaths has been increasing, while other causes of CKD have been relatively stable . Gender-T2DM also presents a heritable polygenic component with specific susceptibility loci ,32,33, wBoth genetic and environmental variabilities represent risk factors of disease progression. Besides the non-modifiable risk factors, such as family history, genetics, gender, age at diagnosis, and DM duration, lifestyle can be improved promoting healthy habits. It is important to maintain a proper glycemic control, blood pressure, avoid or quit smoking, reduce alcohol consumption, practice physical activity, follow a balanced diet and maintain a healthy lipidic profile .Several epidemiological studies indicated obesity as one of the main risk factors for insulin resistance development and T2DM progression . AccordiIt is of paramount importance to guarantee a structured education for patients and health care professionals to raise awareness to the role of DM and DKD prevention. Self-management knowledge should be used as an adjunct therapeutic option, especially in high-risk patients.The pathophysiology of DKD is multifactorial and characterized by a critical metabolic impairment; the upstream influence of hyperglycemia leads to a dysregulated intracellular metabolism, inflammatory lesions, increased apoptosis processes and tissue fibrosis . At the Different intracellular pathways demonstrated a driving role in the DKD process, stimulated by hyperglycemia. High blood glucose stimulates protein kinase C beta type (PKC-beta) and protein kinase C delta type (PKC-delta) activation in the renal cortex. This mechanism triggers the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and the release of both interleukin (IL)-6 and the tumor necrosis factor (TNF)-α by endothelial and mesangial cells ,44. The In addition to PKC and AGEs-guided mechanisms, more intracellular pathways seem to be implicated in the DKD insult. NF-κB, inducible nitric oxide synthase, JAK/STAT, and transforming growth factor-beta1/SMAD pathways are all leading to the production of proinflammatory molecules inducing extracellular matrix deposition and the differentiation/proliferation of myofibroblast in DKD patients ,52,53,54DKD is an insidious complication of diabetes, often silent for years. The average time of onset of kidney impairment in diabetic patients is about 7–10 years . A timelSeveral wake-up calls should alarm diabetic patients regarding their kidneys’ health, and patients should be referred to a nephrologist earlier if they present rapid renal reduction, resistant hypertension, hyperkalemia, UACR exceeding 300 mg/g, or other urinary abnormalities .Some real-world experiences, such as that of Martínez-Castelao et al., report a late referral of patients to specialist nephrology clinics when the kidney mass is already reduced by 70% . An on-tA proper remodeling of lowering glucose therapy is one of the main points that should be evaluated in the evolution from DKD to ESRD. Diabetic patients with ESRD present high levels of blood urea nitrogen, leading to carbamylated hemoglobin production; these molecules are not distinguishable from glycosylated hemoglobin by electrophoresis, causing incorrect elevated levels of hemoglobin A1C . MoreoveMost oral diabetes drugs are contraindicated in ESRD and the pharmacological therapy should be balanced to avoid over- and undertreatment. Individuals with impaired renal function have a higher risk of lactic acidosis related to metformin use, which should be used cautiously in patients with a progressive decrement of renal function . Moreove2 , I2 = 79.8%), which was more evident in subjects with GFR 45–60 mL/min/1.73 m2 than with 30–45 mL/min/1.73 m2. However, this review offers a low level of evidence [2, because no evidence of adverse effects have been reported on allografts in mild CKD up to now.No RCTs are currently available evaluating metformin CV protection in CKD patients. A systematic review of six observational studies conducted on patients affected by moderate to severe CKD showed a 22% lower risk of all-cause mortality in the metformin cohorts than in other antihyperglycemic drugs ; vs. other drugs, −0.06% . SGLT2i lower glucose blood levels by inhibiting the renal tubular reabsorption of glucose, causing osmotic diuresis. Moreover, they appear to reduce the intraglomerular pressure, thus correcting hyperfiltration, which is at the basis of DKD development and progression . On the 2 , CANagliflozin cardioVascular Assessment Study (CANVAS), and Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE)) or ≥60 mL/min/1.73 m2 (Dapagliflozin Effect on CardiovascuLAR Events (DECLARE-TIMI 58)) [2, SGLT2i reduced the risk of major adverse CV events . Interestingly, CKD progression reduction  and hospitalization for heart failure  varied according to the CKD stage at enrollment, with less beneficial effects in subjects with more severe kidney impairment.The first RCTs on T2DM also including patients with GFR ≥30 mL/min/1.73 mIMI 58)) ,84,85,862 [Overall, metformin and SGLT2i are contraindicated in patients with GFR <30 mL/min/1.73 m2 ,79,80. IGenerally, glucagon-like peptide-1 receptor agonists (GLP-1 RA) are recommended in these situations due to their CV and benefits on albuminuria . GLP-1 iDipeptidyl peptidase-4 inhibitors (DPP-4i) prolong the activity of GLP-1 by inhibiting its catabolism and should be used with adjusted dosage regimens in DKD patients. They demonstrated a favorable safety profile and a very low risk of hypoglycemia . DPP-4i Sulfonylureas induce insulin release by preventing potassium from exiting in pancreas beta-cells. The consequent cell depolarization causes the opening of calcium channels leading to an increased insulin release. First-generation sulfonylureas should be avoided in DKD patients. Concerning second-generation sulfonylureas, glipizide and gliclazide do not require dose adjustment, while glimepiride does; glyburide is contraindicated in DKD patients ,79,80.The use of acarbose, an alpha-glucosidase inhibitor, should be avoided in patients with DKD ,80.Thiazolidinediones are ligands of peroxisome proliferator-activated receptors γ (PPAR γ) and activate glycemic control and lipid homeostasis. They are not contraindicated in patients with DKD ,80 becauDue to its short duration of action and transformation into inactive metabolites excreted in the feces, repaglinide can be used in patients with DKD, without dose adjustment ,80.Concerning insulin, although there are no guidelines on what type of insulin should be used or avoided, insulin treatment is considered safe in patients with DKD ,80. Howe2, a dose adjustment is required [Elevated levels of triglycerides and low-density lipoprotein—cholesterol (LDL-c) are associated with an increased CV risk and the progression of CKD in patients with DKD. Thus, an evaluation of the lipid profile is indicated, and an appropriate pharmacological approach in patients with DKD is needed. Lipid-lowering therapy with statins was proven to have a protective effect on renal function by improving albuminuria and the estimated GFR . Howeverrequired  based onrequired   had a diagnosis of severe renal impairment  and were therefore not eligible for the treatment with metformin .Associazione Medici Diabetologi, involving more than 300 diabetes centers throughout Italy, showed that between 2011 and 2018 the proportion of subjects with glycated hemoglobin >9% not treated with insulin had fallen from 40.5% to 28.2%, while there was no significant change in the ratio of subjects not treated with statins despite elevated LDL cholesterol levels (from 57.5% to 52.4%). Similarly, a considerable proportion of patients did not receive anti-hypertensive medication despite blood pressure values ≥140/90 mmHg (30.2% in 2011 vs. 26.2% in 2018); moreover, among subjects receiving anti-hypertensive medication, almost one out of two continued to have blood pressure values ≥140/90 mmHg (56.8% in 2011 vs. 48.5% in 2018) [Along with glycemic control, the control of blood pressure and blood cholesterol levels is crucial to slow DKD progression and prevent its macrovascular and microvascular complications ,102. It in 2018) .Due to their complex clinical conditions, DKD patients generally take many drugs to slow the progression of their renal disease, prevent specific complications, and manage comorbidities , thus leSeveral factors may influence the need for the intensification of treatment, including ineffective diet and exercise initiatives, limited pharmacologic armamentarium, conservative management, adverse events, poor compliance, underlying physiopathology, limited resources, and suboptimal healthcare systems .Barriers to treatment intensification can be categorized into three levels :(a) patient level: difficulty in changing lifestyle and taking the medication is common and is a significant contributor to the challenge of meeting glycemic targets. Moreover, the term “psychological insulin resistance” was used to describe patients’ refusal to start insulin therapy when recommended by a clinician. Depression is very common among people with DM, with reported rates as high as 17.8% compared with 9.8% in those without DM, and patients with depression are more likely to have concerns related to starting the treatment with insulin ,116. Eld(b) clinician level: several provider-related factors can lead to therapeutic inertia: overestimating the quality of care, lack of materials, lack of time available to communicate with the patient, and training to escalate care to meet the recommended targets appropriately. The lack of knowledge and resources also delays treatment intensification, particularly insulin initiation. Studies comparing General Practitioners (GPs) to specialists have shown that the latter are more likely to initiate insulin and GLP-1 RA earlier in the course of therapy than GPs. Communication issues between health care providers and patients can also limit effective diabetes management and medication intensification. For instance, clinicians may have assume incorrectly that their patients are unable or reluctant to adapt to an increasingly complex regimen. For many patients, the fear of becoming dependent on insulin or a misunderstanding of the severity of the disease outweighs the physical fear of injections and injection discomfort that physicians perceive to be the most significant sources of concern . This pe(c) system level: Several health-system-level issues can also lead to difficulty in achieving therapy goals. A lack of knowledge about guidelines or a lack of clear guidelines, differences among societies’ recommendations , and chaAll these factors  can contribute to therapeutic inertia and, in turn, have a large impact on outcomes for patients with DKD. Mechanisms to improve the communication between clinicians and patients as well as understanding the barriers to patients’ willingness or ability to engage in therapy are therefore essential to preventing therapeutic inertia, improving outcomes, and increasing medication-taking.The management of DKD must be improved and is still far from perfect. The barriers for DKD treatment intensification must be crossed, and the common issues must be solved at all the three levels included in the intrinsic meaning of therapeutic inertia:(A) Patient level: Diabetic patients should be conscious of the care plans and target value for the best DKD management: glucose, creatinine, GFR, blood urea nitrogen, phosphorus, calcium, PTH, Vitamin D, albumin, lipid, potassium, and hemoglobin targets. A proper management of blood pressure control and pulse pressure targets is essential. The patient should be motivated to follow a balanced dietary intake and know the best nutrients to choose to reach the desirable glucose values: the subject should use a pre-established meal plan and timing plan for glycemic control medication. Educational interventions should be performed for both the patient and family members, utilizing reading, virtual, and interactive educational materials.(B) Clinician level: High-quality diabetes care requires creating a multi-specialist team that can gain a complete vision of the patient’s status and study the best strategies for implementing cures. Bridging fundamental approaches to care optimization for general practitioners, diabetologists, dieticians, nephrologists, and pharmacologists is critical. The team must perform a “treat to success” management approach rather than a “treat to failure” strategy . SpecialA pharmacological consult should be considered in patients with complex multidrug therapy or in case of any possible doubt on the part of the clinician. Pharmacotherapy expertise can solve insidious drug-related problems in patients with a rapid decline of kidney function with many comorbidities . A nephrAn adequate educational training should also be performed for the clinicians, who must test their own performance and be aware of medical updates. Clinical audits must also be an integral part of the educational programs for health care professionals. Finally, cost-benefit data on drug use must be clearly explained and presented to the patient, who must freely evaluate and understand all the therapeutic strategies.(C) System level: Specialized efforts to identify patients at high risk of DKD progression are of pivotal importance to program primary care strategies and to direct clinical resources. The health system must promote the necessary acts to improve the quality of care and establish clear guidelines among the different scientific societies to recognize subjects who may benefit from a closer control, intensive glucose-lowering treatment, or particular therapies. An implementation of data on therapeutic inertia should be performed globally: most of the studies were conducted in North America and in Europe, while in other Countries data are still scarce . For thiReal-world data use can also be helpful to assist physicians in making decisions about a patient’s care pathway.A summary of these suggestions can be found in Several studies are bringing evidence and suggestions to develop novel approaches to contrast therapeutic inertia in CKD and diabetic patients.A review performed by Wrzal et al.  showed hAs emerging from the observation by Reach et al. , the neeThe need for new strategies to address this problem has been recently highlighted in several randomized and cluster-randomized controlled studies or prospective cohort trials, aiming to establish appropriate strategies directed to either the patient, clinician and/or, system levels, with only 28% of studies contemporarily addressing several levels .ADA is currently conducting a 3-year initiative called Overcoming Therapeutic Inertia (OTI), to promote a better adherence to guideline indications in primary care settings. It is even developing user-friendly tools to support decision-making processes, in order to adopt therapeutic choices tailored to patients’ needs. Clinicians’ awareness of newer drugs and their positive effect on CV and renal outcomes, as well as a better knowledge of continuous glucose monitoring, represent a worldwide issue and are some of the practical steps to be addressed by the OTI initiative, as well as the identification of best practices with the constitution of a research team .p = 0.002), diabetes diet habits , and blood sugar testing , although the glycemic control and renal function indicators were similar for the intervention arms and the usual care.Health care system strategies should include the establishment of multidisciplinary care programs, as seen in other chronic diseases, such as CKD. These programs were shown to reduce medical costs and the need for RRT, slowing the progression to ESRD . DiabetiTelemedicine may represent a new strategy to improve patients’ education and compliance with treatment. The Simultaneous Risk Factor Control Using Telehealth to slow the Progression of Diabetic Kidney Disease   focused DKD subjects present patient-related, clinician-related, and system-related issues. All these problems are translated into therapeutic inertia and a lower quality of care.The health complexity of patients with many comorbidities makes a broader vision necessary, studying all their comorbidities. In turn, the patient should not be considered an isolated individual, but a component of a society that interacts with him. The clinician must consider not only the patient’s needs but also his limits. The clinician’s role is to find the best way to improve the quality of life of his patient, taking the time to communicate with him and to find the best strategies to reach the pharmacological targets appropriately. The third component of the therapeutic inertia, the “system”, must take into account the complexity of the interaction of the patient with his caregivers, medical specialists, and other figures that take care of his health.Therapeutic inertia can be resolved by an evaluation of an interprofessional pool of health care experts. The timing of the intensification of treatment, the transition to the best therapy, and dietetic strategies must be provided by a multidisciplinary team, driving the patients to the glycemic target and delaying or overcoming DKD-related complications. A timely nephrologist evaluation can also guarantee adequate information to choose the right renal replacement therapy at the right time in case of renal impairment progression. The pharmacology consultation can facilitate the drug choices, to avoid prescribing inappropriate and potentially dangerous pharmacological interactions.Future studies are necessary to improve the effective strategies to cross the therapeutic inertia barriers and to guarantee a patients-centered care with the best drug prescription at the right time.


Recent data reiterate low-protein diets (LPDs) as cornerstones in the conservative management of chronic kidney disease (CKD). The reduction in proteinuria, better blood pressure control and the reduction in the rate of decline in kidney function with LPDs were reported, both in non-diabetics and diabetics patients. Supplemented, vegetarian, very-low-protein diets  could postpone kidney replacement therapy (KRT) initiation, mainly through the better control of metabolic disorders of advanced CKD in non-diabetic patients. Plant-based diets could ameliorate gut microbiota and appear to be superior to mixed hypoproteic diets in treating advanced CKD: better control of nitrogen balance, acid-base metabolism and bone mineral disorders. Vegetarian diets generate fewer uremic toxins and reduce salt intake and acid overload. At the same time, they can improve lipid metabolism, providing a high ratio of unsaturated to saturated fatty acids, as well as insulin resistance. Chronic kidney disease (CKD) is a worldwide healthcare problem, both in the predialysis stages and during kidney replacement therapy (KRT). With a prevalence of 10% in the general population [Therefore, it is important to focus on the possibility of reducing the progression of CKD and postponing RRT through a multifactorial approach, including dietary protein restriction.The largest trial which examined the efficacy of nutritional intervention in CKD, the Modification of Diet in Renal Disease study group (the MDRD study), yielded controversial results . Upon a In recent years, there is increasing evidence that low-protein diets (LPDs) can favorably influence the decline in kidney function ,6,7.The recommended protein intake. The KDOQI Clinical Practice Guidelines for Nutrition in CKD recommends to patients with metabolically stable CKD stage 3+, under close monitoring, protein restriction and in some circumstances supplementation with ketoanalogues of essential amino acids. The effect of this type of dietary intervention seems to reduce the risk of mortality and progression to the final stage of CKD, with an improvement in patients quality of life [ of life . In this of life . Diabeti of life .Reducing protein intake may affect the nutritional status of patients at risk of protein-energy wasting. However, Western patients who consume processed red meat have a protein intake above the optimal level considered necessary to achieve a nutritional balance (1.35 g protein/kg-day versus 0.8 g/kg-day). Moreover, a further reduction in protein intake (0.3–0.4 g/kg-day) supplemented with ketoanalogues it can also provide the required daily dose of essential amino acids .The major concern when it comes to the LPDs, especially in vegetarians, is the risk of malnutrition, since very restrictive diets with limited food sources can struggle to reach the recommended daily dose of certain amino acids, vitamins or even energy intake. 2) and increased proteinuria [There are also effects on the kidney function. The dietary protein intake in CKD has been investigated in several recent studies, suggesting that Western diets, with an increased content of processed red meat, were associated with the accelerated progression of CKD, three times higher than normally expected  study, in 14,882 patients with a median estimated glomerular filtration rate (eGFR) above 60 mL/min/1.73 mfunction . In contfunction .A high-protein intake causes the vasodilation of the afferent arteriola, increasing the intraglomerular pressure, and thus the progression of glomerulosclerosis ; while lClinical studies showed the additional benefits of LPDs in CKD: the amelioration of nitrogen balance, metabolic acidosis, calcium-phosphorus metabolism, insulin resistance and of blood pressure control ,16,17.Kidney and patient survival. Several studies showed LPDs to be beneficial both for patient and kidney survival in adherent patients. In 1985, Rosman et al. demonstrated that patients who were compliant to LPD had a better survival rate compared to the patients who did not follow a dietary intervention (55 versus 40%) [sus 40%) . In thissus 40%) . The achsus 40%) . The patsus 40%) . HoweverLPDs in Diabetic Kidney Disease. Diabetic kidney disease is one of the most common etiologies of CKD, characterized by significantly higher proteinuria, and thus a more rapid decline in kidney function when compared to other kidney diseases [diseases . Persistdiseases . An impodiseases . LPDs sediseases ,25,26, bdiseases .The multifactorial approach is currently recommended in diabetic patients; therefore, there are limited data regarding the effects of a low-protein diet per se in a patient with diabetic kidney disease, but the few studies that address the role of the diet are in favor of low-protein diets, mostly vegetarian, primarily because of the hemodynamic effect of such a diet ,26. MoreMediterranean diets, rich in vegetables, fruits and cereals were associated with better survival in patients with CKD as compared to Western diets . PatientVegetarian and vegan diets are increasingly used in patients with chronic diseases, including CKD, especially to facilitate the integration of LPDs ,33. VegaIn addition, vegetarian and vegan diets are rich in vitamins.Diets based solely on plant proteins were considered for a long time nutritionally inadequate, mainly because of the potential deficit of essential amino acids found in animal proteins. In fact, all foods contain amino acids and vitamins in different proportions; an appropriately balanced vegetarian diet achieves the same amino acid and vitamins content as the animal-based proteins ,38,39.For the assessment of the nutritional value of food the Protein Digestibility Corrected Amino Acid Score (PDCAAS) can be used . This scThe largest study conducted to assess the effects of plant-based diets, Adventist Health Study 2, enrolled 96,335 participants grouped into five different dietary interventions: non-vegetarian (consuming non-fish meat more than once per month or any meat more than once per week), semi-vegetarian , pesco-vegetarian , lacto-ovo-vegetarian , and vegan  . VegetarNitrogen balance. Vegan and vegetarian diets appear to generate a smaller quantity of uremic toxins by changing the proteolytic intestinal bacteria into a Saccharolytic profile with the promotion of the production of short-chain fatty acids to form the intestinal barrier and reduce bacterial translocation and inflammation [ammation ,46.Acid-base and electrolytic abnormalities. Meat consumption is usually associated with increased protein intake; the meat itself, mainly in a highly processed form, accentuates metabolic acidosis in patients with CKD. Acidemia induces protein-energy malnutrition by promoting glucocorticoid secretion and insulin resistance, thus interfering with albumin synthesis [ynthesis . Vegetabynthesis . In addiynthesis ,49. Corrynthesis .Bone mineral disorders. Mineral and bone disorders in CKD are associated with increased cardiovascular and all-cause mortality and a more rapid decline in kidney function [function ,52,53. Pfunction . About tfunction ,51,55.Arterial hypertension. Some beneficial effects on blood pressure control, especially on diastolic blood pressure, were also observed [observed ,56. Moreobserved ,60,61,62The quality of amino acids appears to influence the blood pressure control. The elevated serum levels of methionine and alanine, found in patients who preferentially consumed animal proteins, were associated with a high arterial blood pressure. The increased serum levels of threonine and histidine, frequent among vegan and vegetarian patients, were associated with the optimal control of blood pressure .The benefits of vegetarian LPDs were also observed in diabetic patients. In this regard, it seems that the mean arterial blood pressure could be decreased by 13 mmHg with an optimal multifactorial approach, including a dietary intervention of mostly vegetarian LPD .Lipid metabolism. Patients with CKD were frequently associated with abnormalities in lipid metabolism, thus promoting atherosclerosis. Therefore, the control of lipid metabolism represents an important goal. The consumption of soya decreases serum LDL-cholesterol levels and wheat gluten lowers the levels of LDL-cholesterol, triglycerides and uric acid [ric acid ,64,65. Vric acid .The role of gut microbiota. In CKD patients, there is a dysbiotic gut microbiota, characterized by a decrease in commensal bacteria and an increase in uremic toxin-producing bacteria. It seems that gut-derived uremic toxins, such as p-cresol and indoxyl sulfate promote the acceleration of cardiovascular disease [ disease ,68. Othe disease . This im disease ,71. Comp disease .Although LPDs have positive effects on delaying KRT and on obtaining the control of different metabolisms, it should be taken in consideration that there are special patient populations in which LPD seems to be contraindicated . In thisSocio-economic and cultural barriers could be a hindrance to obtaining adherence to LPDs but can be overcome by individualizing the psychological approach, in addition to nutritional interventions.Patients with psychiatric disorders represent another challenge in obtaining compliance to nutritional intervention, but with a psychiatric intervention and closer follow-up, adherence to LPD could be achieved due to interdisciplinary communication.Old age is not a contraindication in adopting LPD, but the close monitoring of elderly patients (considered as over 80 years of age) should be taken into account due to the presence of possible frailty, as well as their frequent association with cognitive disorders. There are few studies that analyze the benefits and risks of LPDs in elderly patients, but the conclusion would be that prescribing a LPD regimen in the elderly also seems to delay KRT without consequences for patient survival .Low-protein diets are feasible and have beneficial effects in patients with chronic kidney disease, with and without diabetes, both in postponing kidney replacement therapy, but also for a better patient survival on the long term, as these diets are nutritionally safe. The vegetarian-supplemented, very-low-protein diets seem to have an additional positive effect on patient and kidney survival.Vegetarian and vegan diets seem to be superior to mixed diets and could improve some metabolic disturbances related to chronic kidney disease and optimize blood pressure control.Protein restriction, including the plant-based, low-protein diets (vegetarian or vegan diets), are nutritionally safe in chronic kidney disease patients, with or without diabetes mellitus, in patients who achieve the required energy intake.