Selective clamping during robot-assisted partial nephrectomy (RAPN) may reduce ischemia-related functional impairment. The intraoperative use of 3D-virtual models (3DVMs) can improve surgical planning, resulting in a greater success rate for selective clamping. Our goal is to introduce a new generation of 3DVMs, which consider the perfusion volumes of the kidney. Patients listed for RAPN from 2021 to 2022 were recruited. A selective clamping strategy was designed and intraoperatively performed based on the specifically generated 3DVMs. The effectiveness of selective clamping was evaluated using near-infrared-fluorescence imaging (NIRF) and 3DVM. Perfusion areas extensions were compared, and relevant preoperative characteristics were analyzed. In 61 of 80 (76.25%) cases, selective clamping was performed. The concordance between the 3DVM areas and the NIRF-enhanced areas was verified (k = 0.91). According to the distribution of perfused areas crossing the tumor, there were one, two, three, four, and five crossing areas, with relative perfusion rates of 13.75%, 35%, 32.5%, 13.75%, and 5%, respectively. Lesion diameter and mesorenal location were the only factors related to a higher number (>3) of perfusion volumes crossing the lesion. The implementation of mathematical algorithms to 3DVMs allows for precise estimation of the perfusion zone of each arterial branch feeding the organ, leading to the performance of safe and effective pedicle management planning. Owing to the introduction of several new technologies and techniques in actual surgical practice, it is currently possible to perform more tailored and less invasive surgeries. Therefore, this evolution of surgical environment has been called “precision surgery” , and itsTo obtain a precise, tailored surgical procedure, the standard bidimensional imaging might sometimes be suboptimal since it requires a building-in-mind process by the surgeon to recreate the real aspects of the target organ in a three dimensional environment . TherefoAlthough it has shown promising results, 3DVM-based surgical planning sometimes the fails intraoperatively. Indeed, even if the planning is guided by 3DVMs, allowing the surgeon to simulate different selective clamping options and to perceive the relative areas of devascularization and consequent ischemia, the planned clamping strategy  can be insufficient during surgery to guarantee an appropriate avascular resection plane, forcing the surgeon to switch the strategy to main renal artery clamping. The modification of the intraoperative vascular management approach can be explained considering that, when we plan selective clamping, we consider only the direction of the arterial branches toward the kidney surface instead of the perfused parenchymal volumes fed by these vessels and their boundaries.To overcome this limit and precisely estimate the perfusion renal zones, we further implemented our models by introducing a mathematical algorithm able to identify the different perfusion volumes of the organ. The aim of the study was to test the accuracy of these new 3DVMs in guiding the clamping strategy and assessing whether there are factors influencing the tumor location relative to these perfusion volumes.We prospectively enrolled all patients with a radiological diagnosis of an organ-confined solitary renal tumor scheduled for robot-assisted partial nephrectomy (RAPN) with intraoperative imaging guidance at our center from January 2021 to May 2022.Informed consent was obtained, and the trial was performed in accordance with best clinical practice recommendations. According to Italian law, no formal institutional review board or ethical committee permission was required . Evidence of anatomical anomalies, such as a horseshoe-shaped or ectopic kidney, was used as an exclusion criterion. Patients who had preoperative imaging that was insufficient for producing a 3DVM  or who had imaging older than three months were also excluded.www.medics3d.com, Turin, Italy) developed the 3DVMs for the cases starting from CT scans [According to the previous description, Medics Srl ©  libraries . The 1D Precise artery segmentation is essential to accurately estimate kidney perfusion regions: the higher the detail of smaller branching, the greater the accuracy of perfusion zone subdivisions. This method allows for determining the final perfusion volumes related to the clampable blood vessels during surgery . All proBefore each case, the surgeon studied the 3DVMs and planned the surgical strategy accordingly. Moreover, he precisely defined its clamping strategy  based upon the information given by the 3DVMs. Intraoperatively, the model was available on demand electronically (using an tablet or a PC) or in an augmented reality fashion ,13,14,15After kidney exposure, under 3DVM guidance, the main renal artery was identified and dissected, isolating the segmental branches entering the renal sinus or some accessory and aberrant arteries eventually reported by the 3DVM. When possible, depending on the specific case anatomy, pedicle dissection was conducted in a centripetal fashion, from the sinusal rim toward the aorta, starting with isolation of the portion of the segmental arteries facing the sinusal orifice and often limiting the isolation to this order of vessels, following the information given by the 3DVM. Once the renal pedicle was dissected, the renal mass was exposed or marked on the kidney’s surface  under augmented reality (AR) guidance and ultrasound (US) confirmation . Then, tNIRF became the indicator of proper vascular control in those instances treated with selective clamping. The intravenous injection of a indocyanine green (ICG) solution (0.1–0.5 mg/mL/kg) allowed for the precise identification of the boundaries and the shapes of the different perfusion regions of the kidney, permitting visualization of portions still receiving blood flow as bright green areas, while clamped vessels were gray ,17 FiguA,B.We prospectively gathered demographic information for each patient, including age, body mass index (BMI), American Society of Anesthesiologists (ASA) score, and comorbidities as reported in the Charlson’s comorbidity index ; clinicaPer the study purpose, to demonstrate the concordance between virtual and real perfusion volumes, superimposition of the 3DVMs over the real anatomy was performed on bidimensional images recorded at the time of surgery. To superimpose the intraoperative ICG view with the 3D model, we used Mimics software, version 21.0 , uploading a screen extrapolated from the intraoperative video. The areas maintaining perfusion on the virtual model were selectively overlaid on the endoscopic image during the ICG injection to verify the concordance between the boundary lines A,B. MoreAfter evaluating each 3DVM, the total number of perfusion regions was recorded, as well as their relative volumes. Last, the position of each renal mass was assessed in proportion to the number of perfused regions it crossed.Using the Mann–Whitney test for continuous variables and Fisher’s exact test for categorical ones, patient characteristics were examined. Frequencies and proportions were given as percentages, and all results for continuous variables were expressed as medians (interquartile range).The extent of the vascularized areas calculated from the endoscopic NIRF video bidimensional frames and their virtual overlaid counterparts were compared via the k-Cohen test. Finally, a multivariate regression model (MLR) was fitted to assess tumor factors potentially related to the number of perfusion volumes crossed by the lesion. In particular we tested whether tumor variables, such as lesion size, PADUA score, tumor histology, stage, grade, sarcomatoid differentiation, necrosis, and microvascular invasion, were correlated with a number of tumor perfusion regions greater than three. All data were analyzed using Jamovi software, version 2.3.During the enrollment phase, 3DVM-assisted RAPN was performed on 80 patients. While 49 patients had cognitive intraoperative assistance, 31 patients underwent 3DVM-assisted RAPN with AR guidance.Selective clamping was used to manage the vascular pedicle in 61 (76.25%) patients, main artery clamping was performed in 12 (15%) patients, and clampless surgery was chosen in seven (8.75%) patients.For both global and selective clamping, the median (IQR) ischemia times were 17 (15–25) and 16 (12–20) minutes, respectively. In 28 cases (35%), pure enucleation was performed. In 18.75% of the procedures, we recorded a violation of the collecting system.Without varying depending on the hilar clamping technique, the median (IQR) operating time and estimated blood loss (EBL) were 95 min (80–130) and 265 mL (150–300), respectively.No conversions to radical nephrectomy occurred, and there was only one (1.25%) intraoperative complication . The overall postoperative complication rate was 11.25% (9/80), with a Clavien >2 complication rate of 2.5%. Two (2.5%) positive surgical margins (PSMs) were recorded.Based on 3DVMs, Eight perfusion volumes on average (IQR) per kidney (7–10) were recorded. According to 3DVMs, the distribution of perfused regions crossing the tumor was as follows: 13.75%, 35%, 32.5%, 13.75%, and 5% for one, two, three, four, and five crossing areas, respectively.3 (94.9–137.1), with a median volume of perfusion volumes contacting the tumor of 48.2 cm3 (33.4–74.1) and a median volume of regions not in contact with the renal mass of 65.6 cm3 (39.8–81.6).Moreover, the median (IQR) global volume of kidneys, given by the sum of all its perfusion zones was 113.8 cmConsidering the intraoperative assessment with ICG, the concordance between the bidimensional NIRF-enhanced areas and their corresponding 3DVM areas, automatically calculated on endoscopic video frames in cases that underwent selective clamping, was confirmed by the Cohen-k test, with a k = 0.91.p 0.048) and a mesorenal location  were the only two factors related to a higher number (>3) of perfusion volumes crossing the lesion, while the other biological variables  did not reach statistical significance.At MLR, larger tumor sizes , ranging between 30% and 50% of the total volume of the organ, considering the 25th and 75th quartiles. This information needs to be taken in account when the surgeon plans the renal pedicle management strategy. If we want to gain a bloodless resection bed while maintaining as much as possible the vascularization of the kidney, we need to expose at least one-third of it to ischemia. Moreover, such a parenchymal zone will suffer not only due to the temporary ischemic injury given by the absence of blood flow but also due to the loss of renal units close to the tumor’s pseudocapsule due to the resection of the renal mass itself and to the ischemic damage caused by suturing of the resection bed. All these factors considered, the balance between the risks and the benefits of a selective clamping strategy can be more consciously assessed, especially in cases of patients with a solitary kidney or chronic kidney disease [Another aspect to be considered when examining our perfusion 3DVMs is the assessment of each kidney perfusion volume. As shown by our results, the median volume of the perfusion regions in contact with the tumor was 42% of the median of the whole kidney . This high rate of effective selective clamping, together with the adoption of a clampless strategy in some cases (8.75%), allowed for limiting as much as possible the use of global clamping (15%). Moreover, the use of these new virtual models in the intraoperative assistance of RAPN was safe, as demonstrated by the low rate of intra- and post-operative complications, as well as the rate of positive surgical margins. All these outcomes are in line with the concept of an adequate clamping strategy of the renal pedicle, not leading to uncontrolled bleeding potentially responsible for complications during or after the surgery or hiding the cleavage plane of the tumor potentially responsible for a positive surgical margin at the level of the resection bed ,29,30.The accuracy of the perfusion volumes-3DVMs was also demonstrated by their comparison with intraoperative evidence shown by ICG injection. The bidimensional images superimposed on the areas maintaining perfusion on the 3DVMs over the endoscopic image, recorded at the surgery time via ICG injection, demonstrated a high rate of concordance in terms of boundary lines and areas, with a Cohen-k coefficient of 0.91.Last, a multivariate regression model was created to evaluate the factors potentially related to the number of perfusion volumes contacting the tumor. This analysis was performed to consider the characteristics of the environment in which the lesion grows. Together with the anatomical features of the lesion and its location in the kidney , the histology and the grade of the tumor were also assessed. The multivariate analysis found a significant correlation between the higher number of tumors contacting perfusion volumes and the tumor size and mesorenal location. This evidence is explainable, considering that the larger the tumor is in size, the higher the probability is of having a wide resection bed intercepting different perfusion volumes. Similarly, mesorenal tumors more often grow in contact with a higher number of perfusion volumes. Interestingly, the kidney face on which the tumor is located was not a factor related to the number of perfusion volumes intercepted. This evidence confirms the previous finding, in contrast with the traditional anatomical principles of vascularization established by Graves ,24,25. INotwithstanding this interesting evidence, our study is not free of limitations. First, the real impact of our technology could be difficult to estimate considering the lack of a control group. Furthermore, all our surgeries were performed by a very experienced robotic surgeon, and therefore, the advantages of our technology might be overestimated, especially in terms of ischemia time, complications, and positive surgical margin rate, and could also limit the generalizability of our findings. Last, since this technology is new and rapidly evolving, its costs are difficult to define and might limit its diffusion in daily practice.To the best of our knowledge, this study is the first to demonstrate the accuracy and efficacy of this new generation of 3DVMs. With the implementation of a mathematical algorithm in the production of a virtual model, it is possible to have a virtual representation of the kidney composed of all its perfusion zones, pushing forward the limit of the information given by the human eye and making a significant contribution to the current anatomical principles of kidney vasculature. Its use in the intraoperative setting allows the surgeon to follow step by step the strategy set before the intervention with the consultation of the perfusion regions-3DVM, performing precise and unfailing selective clamping and giving the proper frame of mind to deal with the tumor resection and suture phases without distress due to the time spent under global ischemia of the kidney. In fact, considering the ischemia matter, we can argue that time and extension are inversely proportional for the postoperative global renal function: if the ischemic injury affects the whole kidney, it is necessary to reduce as much as possible the time of exposure, while if the portion of the organ injured is limited, the minimization of exposure time becomes less significant.This study emphasizes how technology, supported by the implementation of mathematical software, does not fail to enhance the lines traced by the anatomy. With these new virtual reconstructions, we are daily one step closer to connecting surgical anatomy to microscopy. All these innovations will lead to a super-tailored procedure, allowing us to spare the maximum functional tissue, minimizing the extension and duration of ischemia with the highest level of safety possible.


Major adverse cardiac events (MACE) are more likely to occur when abnormal heart rate recovery (HRR). This study aimed to assess the incremental predictive significance of HRR over exercise stress myocardial perfusion single-photon emission computed tomography (MPS) results for MACE in individuals with suspected coronary artery disease (CAD).2 min−1 min, were used to establish the slope of HRR. All patients were followed for a minimum of 4 years, with MACE as the follow-up goal. The associations between HRR and MACE were assessed using Cox proportional hazards analyses.Between January 2014 and December 2017, we continually gathered data on 595 patients with suspected CAD who received cycling exercise stress MPS. HRR at 1, 2, 3, and 4 min were used as study variables to obtain the optimal cut-off values of HRR for MACE. The difference between the peak heart rate achieved during exercise and the heart rate at 1, 2, 3, and 4 min was used to calculate the HRR, as shown in HRR3. Heart rate variations between two locations in time, such as HRRP = 0.001), and they also had higher rates of hypertension, dyslipidemia, diabetes, abnormal MPS findings (SSS ≥ 5%), medication history , and lower HRR values . Patients with and without MACE did not significantly vary in their HRR4 min−3 min. The optimal cut-off of HRR1, 2, and 3 combined with SSS can stratify the risk of MACE in people with suspected CAD . HRR 1, 2, and 3 and its slope were linked to MACE in multivariate analysis, where HRR3 was the most significant risk predictor. With a global X2 increase from 101 to 126 (P < 0.0001), HRR3 demonstrated the greatest improvement in the model's predictive capacity, incorporating clinical data and MPS outcomes.Patients with MACE were older (HRR at 3 min has a more excellent incremental prognostic value for predicting MACE in patients with suspected CAD following cycling exercise stress MPS. Therefore, incorporating HRR at 3 min into known predictive models may further improve the risk stratification of the patients. For theThere are no established standards for determining the best HRR time point for predicting MACE in individuals with suspected CAD, however. Additionally, it is uncertain whether HRR has additional predictive value for exercise stress MPS. To predict MACE in patients with suspected CAD undergoing exercise stress MPS, this research sought to retrospectively explore the predictive usefulness of HRR at various time points about other clinical factors and MPS outcomes.2.2.1.At the First Hospital of Shanxi Medical University (China), we analyzed 1,090 patients with known or suspected CAD who were referred for clinically indicated MPS with cycling exercise stress between January 2014 and December 2017. The following was taken into account as exclusion standards: (1) Patients with known CAD (known coronary stenosis ≥50%), a history of myocardial infarction (MI), percutaneous coronary intervention (PCI), or coronary artery bypass graft (CABG), early revascularization (coronary angioplasty or CABG surgery occurring <90 days after MPS), diagnosed heart failure (HF), significant cardiac valve disease, severe nonischemic cardiomyopathy, congenital heart disease, pacemaker patients, or any condition that could affect short-term prognosis. (2) those in whom ET duration was <6 min. (3) incomplete exercise stress testing or SPECT/CT data. We did not exclude but adjusted in the multivariable models with medications that affect HR, such as calcium channel blockers (including non-dihydropyridines) or β-blockers .Out of 650 patients who met all the requirements, 595  had their follow-ups completed. 2.2.Age, gender, body mass index (BMI), family history of CAD, hypertension, diabetes, hyperlipidemia, and medication history were the demographic and cardiovascular risk variables extracted from electronic medical records. Blood pressure >140/90 mmHg or using antihypertensive medication were both considered to be indicators of hypertension. Patients were deemed to have diabetes if they had previously been diagnosed with it or were using hypoglycemic drugs. Hyperlipidemia was defined as having a known history of the condition or being treated with a lipid-lowering drug. Prior or ongoing tobacco consumption was referred to as smoking history. A first-degree relative's diagnosis of CAD before or at the age of 55 was considered a diagnostic of early CAD .2.3.99mTc-sestamibi gated MPS using the symptom-limited Bruce Cycling protocol (According to the recommendations of the American Society of Nuclear Cardiology (ASNC), patients received stress protocol , 12. All99mTc-sestamibi (740 ± 74) MBq intravenously. The maximum heart rate attained while exercising was the peak heart rate. When calculating HRR, the difference between the peak heart rate and the heart rate during the recovery period was considered, as in HRR1. During the recovery phase, the measurement time was at least 4 min , or late (>90 days after SPECT imaging) coronary revascularization (PCI or CABG) . By chec2.6.χ2 test, while continuous variables were compared using the appropriate Mann–Whitney U or student t-test. The Youden index was used to determine the HRR cutoff values that were most effective in forecasting MACE. The main result of MACE was evaluated using log-rank tests on Kaplan–Meier survival curves stratified by SSS and HRR factors.Numbers and percentages are used to represent categorical variables. The mean ± standard deviation (SD) or median values for continuous variables are shown (interquartile range). Categorical data were compared using the P < 0.05) or clinical significance. Separate Cox proportional hazard models were used to determine the hazard ratios (HRs) and 95% confidence intervals (CIs) for each HRR. Using the Schoenfeld residuals test, the proportional hazard assumption was put to the test. None of the Cox model's included variables resulted in the proportionate hazard assumption being rejected. Based on the likelihood ratio test, we further looked for possible statistically significant interactions. To assess the additional value of MPS findings in comparison to clinical features alone and HRR in comparison to clinical characteristics plus MPS results, global χ2 analyses were performed using Cox models and a likelihood ratios test. Statistical significance was defined as a 2-sided P < 0.05. All analyses were carried out using R version 4.1.1 and SPSS v25.0 .To comprehensively investigate the predictive power of HRR on MACE at various time points, univariable and multivariable Cox regression models were used. The multivariable model considered variables that have been shown to have statistical significance in univariable analysis (3.3.1.P = 0.001) and lower Phase SD than patients without MACE. They also had larger percentages of combined hypertension, dyslipidemia, diabetes, SSS ≥ 5%, maximum heart rate, maximal systolic blood pressure, and medication history . It took an average of 5.4 ± 1.2 years to follow up. During follow-up, 54 (9.1%) patients had MACE, which included the initial incident of 8 fatalities, 4 nonfatal MI, 29 UA hospitalizations, and 13 late revascularizations.595 patients made up the final research population. 2 min−1 min and HRR3 min−2 min values for the patients with MACE were substantially lower , but HRR4 min−3 min did not differ between MACE and without MACE (P = 0.576). The correlation of HRR is presented in r2 = 0.51 for HRR1 and HRR2, r2 = 0.76 for HRR2 and HRR3, r2 = 0.83 for HRR3 and HRR4). Taking into account the fact that patients with and without MACE did not have any discernible changes in HRR4 min−3 min and the fact that HRR3 and HRR4 have a high association (P > 0.05).ociation , this st3.2.P < 0.0001; For HRR1, HRR2, and HRR3, the ideal cutoff values were defined as 22 bpm, 34 bpm, and 35 bpm, respectively. The appropriate cutoff value of HRR1, 2, and 3 and the SSS abnormalities were used to build the Kaplan-Meier survival curves for MACE . MACE wa3.3.2 min−1 min, and HRR3 min−2 min were associated with MACE in univariate and multivariable Cox regression analyses. In 3 min−2 min in a multivariate model. The results showed that both HRR2  and HRR3 min−2 min  were significantly associated with MACE. This result confirms that HRR2 and HRR3 min−2 min contribute to the predictive value of HRR3 for MACE. Interactions of HRR3 with β-blockers, CCBs and statins are shown in P-value for interaction =0.013), whereas there was no interaction when treated as a continuous variable. There was no significant interaction between CCBs and statins, regardless of whether HRR3 was considered a continuous or dichotomous variable. Therefore, continuous HRR3 was included in the model to assess its incremental value.We investigated whether HRR2 could explain the link between HRR3 and MACE by fitting HRR2 and HRR3.4.χ2 findings for the MACE prediction are shown in P = 0.009), the global χ2 for model 2  dramatically increased. Additionally, global χ2 for the models that included clinal data, SSS, and HRR variables  were significantly higher than those for model 2  Different patient demographics and endpoint events were examined in the previous research; the study endpoints were all-cause and cardiac mortality, while MACE was used as the follow-up endpoint in our investigation, which included all patients with suspected CAD. (2) The different ET protocols and recovery positions; The ET protocol described in the former is Treadmill testing with a supine recovery position, whereas our ET protocol is Cycling testing with a half-supine recovery position. Previous studies have found that HRR in the seated position is significantly slower than in the supine or elevated leg position . (3) TheAlthough some previous studies have reported that β-blockers, CCBs, and statins affect HRR , our stu5.1.Consider some of our study's shortcomings. First, this is a single-center retrospective study, which makes it challenging to obtain a comprehensive set of biomarker data. Second, the low proportion of patients using β-blockers in our milder cohort without severe CAD may have influenced the relationship between such drugs and the prognostic value of HRR, and prospective and large cohort studies are needed to elucidate the possible implications. Third, resting MPS was not included in this study, but current guidelines  state th6.We provide unique data that links HRR at various time points during cycling exercise testing to MACE in patients with suspected CAD and demonstrate that HRR at 3 min has a stronger incremental value in predicting MACE in patients with suspected CAD compared to HRR at 1 and 2 min for exercise stress MPS. Therefore, assessing such parameters could further improve the risk stratification of patients during the MPS scan.


Purpose: This study aimed to evaluate the relationship between intra-abdominal pressure (IAP), renal perfusion indices, and postoperative acute kidney injury (AKI) in cardiac patients.Methods: In a prospective cohort study conducted at a single academic institution, we collected data from adult patients undergoing open-heart operations with cardiopulmonary bypass (CPB) at our institution from February 2022 to April 2022 using the Accuryn SmartFoley system® . Patients on mechanical support devices, pregnant patients, and patients on hemodialysis were excluded. Demographics, hemodynamics, and mean airway pressure (mAir) were measured at the beginning of the cardiac operations and during the first four hours of ICU. Renal perfusion indices were then calculated (mean perfusion pressure (MPP) = mean arterial pressure (MAP) - central venous pressure (CVP); abdominal perfusion pressure (APP) = MAP - IAP; and effective renal perfusion pressure (eRPP) = MAP - (CVP + mAir + IAP)). Length of stay (LOS) was measured from the day of surgery to ICU discharge (ICU LOS) and hospital discharge .Results: During the first four hours of ICU stay, the non-AKI group had lower IAP and higher renal perfusion indices . Logistic regression showed high perfusion pressures correlated with lower postoperative AKI . The postoperative AKI group also had significantly longer ICU LOS (7.33 vs. 4.57 days) and hospital LOS (17.0 vs. 10.2 days).Conclusion: Renal perfusion indices are a promising tool to predict postoperative AKI in cardiac surgery patients. Acute kidney injury (AKI) is one of the major complications following cardiac surgery. While the Society of Thoracic Surgeons National Cardiac Surgery Database reported a postoperative AKI rate of 4%, multiple studies have shown a postoperative AKI rate as high as 81% based on the Kidney Disease Improving Global Outcomes (KDIGO) criteria . Most imElevation of intra-abdominal pressure (IAP) has been increasingly recognized as an important cause of major morbidities and mortality such as AKI in patients during their ICU stay . UndergoMeasurement of IAP using a Foley catheter has been previously described. Recently, an FDA-approved foley catheter with the capability of continuously monitoring and measuring IAP, urinary output, and core body temperature has been introduced: Accuryn SmartFoley system® . The device measures bladder pressure through a balloon containing a pressure sensor at the tip of a Foley catheter and thereby calculates bladder pressure and IAP. Incidences of intra-abdominal hypertension (IAH) in patients undergoing cardiac surgery have been previously reported using this device , but theStudy design and populationWe conducted a prospective cohort study of patients undergoing open-heart operations with CPB at our institution from February 2022 to April 2022 using the Accuryn SmartFoley system®, which was capable of continuously monitoring IAP. We obtained approval from the Institutional Review Board at our institution (IRB Protocol#1294) with a waiver of written informed consent. The primary outcome was postoperative AKI, defined by the 2012 KDIGO criteria as at least 0.3 mg/dL increase of serum creatinine level from baseline within 48 hours . The secData collectionDemographic information including age, gender, BMI, MAP, CVP, mAir measured by the ventilators, CPB time, and IAP before CPB and during the ICU stay were collected. IAP was collected up to the discontinuation of the Foley catheter. Intraoperative mAir was not available due to the limitation of our anesthesia machine. To assess critical care acuity, EuroSCORE II was calculated for all patients. Since most of our patients underwent fast-track extubation after cardiac surgery, only the first four hours of renal perfusion pressure indices were analyzed. IAP, MPP, APP, and eRPP were collected at baseline (ICU admission) and in one-hour increments. Serum creatinine level and glomerular filtration rate (GFR) were collected preoperatively as well as postoperative day (POD) 1, 2, 3, and on the day of discharge. ICU and hospital LOS were counted from the day of surgery to the day of discharge from either the ICU or the hospital. Multiple renal perfusion pressures and cutoff for high perfusion pressure values as reported by Kopitkó et al. ,11 were Statistical analysisDescriptive statistics are presented as number (%) for categorical variables or mean ± standard deviation (SD) for continuous variables. Two-sample Student’s t-test with the assumption of unequal variance (Satterthwaite’s degrees of freedom) was used to assess differences for continuous parametric variables, Mann-Whitney U test for non-parametric variables, and chi-square test for categorical variables as appropriate. We estimated the required sample size to be 20. The sample size was calculated to detect the difference in mean eRPP between 45 mmHg and 30 mmHg with an SD of 10 mmHg to achieve a power of 0.9 with a two-sided alpha level of 0.05. Logistic regression analysis was performed to evaluate the protective effect of high MPP, APP, and eRPP on the odds of developing postoperative AKI as defined by KDIGO criteria. To adjust for possible confounding, Euroscore II  and BMI were included in the analysis. All p-values were two-sided, and statistical significance was defined as a p-value of <0.05. All statistical analyses were performed with STATA 18.0 .A total of 23 patients were included in the study. From this, 88 renal perfusion pressure data points were collected. Nine patients 39.1%) had postoperative AKI based on the KDIGO criteria. Most of the patients in the AKI group experienced stage 1 AKI  vs. 8.17 mmHg , respectively). Furthermore, IAP and kidney perfusion indices  were not significantly different at ICU admission  . In addi2 mmHg . We posit renal injury in cardiac surgery to be a multifactorial process (intraoperative “hit” and postoperative “hit”), similar to the Knudson two-hit theory for cancer genetics . The iniOur study was limited by the observational nature of the study design. Therefore, the results can only infer correlation and not causation. In addition, since eRPP includes mAir, we were not able to monitor this once the patient was extubated. For this reason, since most of our patients underwent fast-track extubation postoperatively, we only analyzed renal perfusion pressure indices up to four hours after ICU admission. A small subset of patients experienced prolonged intubation due to hemodynamic instability or coagulopathy. However, a comparison between this subset of patients and the early extubated patients after four hours would not be inappropriate. Despite this limitation, we still observed a positive correlation between low renal perfusion pressure and the development of AKI. These findings persisted after adjusting for potential confounders using logistic regression analysis. Although AKI and non-AKI groups did not differ in renal perfusion pressure at the time of ICU admission, we were not able to measure renal perfusion pressure indices during surgery. Therefore, we cannot assess the influence of intraoperative renal perfusion pressure on postoperative AKI development. Further research into AKI prevention using composite renal perfusion indices encompassing a wider time span would be beneficial for this patient population.Composite renal perfusion indices such as eRPP, starting from the first four hours after surgery, had a significant relationship with postoperative AKI development for patients undergoing fast-track postoperative care after routine cardiac surgery. Future studies using a randomized control design with a longer time span can help establish the causation between renal perfusion pressure and the development of postoperative AKI.


For patients older than 70 years, beneficial changes were only observed for MEP, which increased by 9.3 cmH2O (for p < 0.05). Speleotherapy combined with pulmonary rehabilitation improves respiratory muscle function in older adults with chronic respiratory diseases, mainly in terms of MEP. Therefore, a greater emphasis on inspiratory muscle training in the rehabilitation program should be considered.Training the respiratory muscles is a crucial aspect of pulmonary rehabilitation. The purpose of this study was to assess the function of respiratory muscles in older adults both before and after a period of pulmonary rehabilitation and treatment stay within the underground chambers of a salt mine. A total of 50 patients aged 65 years and older with chronic respiratory conditions was enrolled in the study. These participants underwent a 3-week subterranean pulmonary rehabilitation (PR) program in the “Wieliczka” Salt Mine. Levels of sniff nasal inspiratory pressure (SNIP), maximum inspiratory pressure (MIP), and maximum expiratory pressure (MEP) were measured using the MicroRPM both before and after the outpatient PR program conducted 135 m underground. A total of 44 patients with a mean age of 68.8 ± 2.9 years who completed the PR program and tests were included in the analysis. The average changes in the parameters of pulmonary function before and after the PR were: MIP 8.8 cmH Respiratory muscles play a key role in respiratory function by generating the intrathoracic pressures that allow airflow, and they affect the shape and mobility of the chest, posture, and body balance. In addition, the diaphragm contributes to maintaining postural stability; its activity is important for the proper functioning of the heart and circulation in the lymphatic system and reduces the risk of developing chronic pain in the spine. Fatigue in the breathing muscles leads to an increase in the respiratory rate, which in turn limits exercise performance ,2,3. AloNumerous studies have shown that respiratory muscle training (defined as repetitive and controlled exercises of moderate-to-high intensity) can improve the structural and functional properties of these muscles, in both healthy older individuals and COPD patients of a similar age ,8,9,10. In this context, speleotherapy emerges as a potential adjunctive treatment. Speleotherapy (subterranean therapy) is a unique form of climatotherapy that utilizes mine  or cave environments for the treatment of chronic respiratory diseases . The envMaximal inspiratory pressure (MIP) and maximal expiratory pressure (MEP) are straightforward, user-friendly, and non-invasive measurements of respiratory muscle strength at the mouth. However, definitive standards for these indices have not yet been firmly established . The valFrom the literature review, it seems that there is a scarcity of research on the use of speleotherapy in pulmonary rehabilitation for older adults. In our previous article regarding this project, which involved participants aged 65 and older with chronic respiratory conditions, we described the impact of combining speleotherapy with pulmonary rehabilitation on the dynamic balance and chest mobility of older adults . Given tThe goal of the study was to assess the respiratory muscle function of older adults before and after their rehabilitation and treatment stay in the underground salt mine chambers. This was a prospective study of chronic respiratory diseases conducted at the “Wieliczka” Salt Mine Health Resort in Wieliczka, Poland from June 2017 to December 2019. Active cancer or cancer that has not been in remission for at least five yearsPrimary or secondary immunodeficienciesInfectious diseases during their active clinical, acute, and chronic phases (being a carrier is not a contraindication)Serious musculoskeletal damage that prevents independent movementSevere respiratory and circulatory failure limiting life activity to a resting lifestyleIncreased intracranial pressure, for example due to infectious diseases or traumaRecent (up to 6 months) surgical procedures or trauma to the chest, abdominal cavity, craniomaxillofacial region, brain, or eye areaRecent (up to 6 months) heart attack or strokeAneurysms of cerebral vessels and aortaSevere heart valve defectsDiagnosed arrhythmias that threaten loss of consciousnessUncontrolled hypertension, hemorrhagic disordersMental disordersClaustrophobiaRheumatic diseases involving the skeletal systemEpilepsy presenting as focal seizures with consciousness disturbances and focal seizures evolving to bilateral tonic–clonic seizuresPregnancyThe exclusion criteria for treatment in the underground salt chambers were medical contraindications to subterraneotherapy and speleotherapy, such as:No contraindications for speleotherapy, as confirmed by a doctor during qualification.A minimum score of 10 points on the short physical performance battery test, which assesses the risk of disability in older individuals ,23.A medical indication for pulmonary rehabilitation using subterraneotherapy methods (for chronic respiratory disease), confirmed by a doctor during qualification.Written, informed consent to participate in the project.The participants were all aged 65 years or older with chronic respiratory conditions. The inclusion criteria also included:Information forms about the project were distributed among patients who were consulted by the medical staff about participating in the underground rehabilitation and treatment stay. The study was explained to the volunteer participants, and they were enrolled in the study after their written consent was obtained. The study was conducted in accordance with the Declaration of Helsinki and was approved by the Regional Medical Ethics Board of Physicians in Krakow, Poland (pol. Okręgowa Izba Lekarska w Krakowie) No. 40/KBL/OIL/2018.Outpatient PR was conducted for a period of 3 weeks  135 m underground at the “Wieliczka” Salt Mine Health Resort in Wieliczka, Poland. The daily schedule of the rehabilitation and treatment program included a supervised descent into the mine by medical staff  using a shaft and a 700 m march on the uneven surface of the miners’ route. The program also included one session of group endurance training supervised by a physiotherapist using aerobic or resistance exercises for 30 min, one session of breathing exercises including posture control and respiratory muscle training with or without tools that give resistance during exhalation such as paper tubes, pinwheels, artificial feathers or purse-lip breathing for 30 min, and one session of specialized training using resistance tools including strength exercises or relaxation methods for 30 min. An educational panel was held three times a week, discussing methods of dyspnea control and behaviors during disease exacerbations, coping with chronic fatigue, sleep hygiene, healthy diet, and health-promoting behaviors. The panel was run by medical staff. The day concluded with a 700 m group walk to the shaft and ascent to the surface along the uneven surface of the miners’ route .2O), with the measuring range being between −300 cmH2O and +300 cmH2O. Tests were carried out three times in a sitting position to establish the best value, according to the manufacturer’s instructions. MIP and MEP were measured after calibrating the measuring device, through the mouth, with a mouthpiece applied to the mouth and teeth. In order to assess MEP, the patient was asked to take the deepest possible breath, near total lung capacity (TLC) level, and then exhale maximally into the gauge for at least 2 s. The result displayed on the LCD screen represented the MEP averaged for 1 s. To properly perform the examination, it was checked whether there were any leaks in the connection system during the measurement, with the exception of the one in the gauge that prevents the generation of erroneous, high results by closing the glottis and compressing the air in the oral cavity using cheek muscles. In order to evaluate MIP, the patient was asked to exhale completely until the lungs were emptied to reach residual volume (RV), and then inhale as hard as possible through the mouthpiece for at least 2 s. The result displayed on the screen represented the maximum inspiratory pressure averaged for 1 s  was performed with the Student’s t-test for dependent samples, as the normal distribution of variables was confirmed by the Shapiro–Wilk test. The analyses were carried out using Statistica 13.3. A p-value ≤ 0.05 was considered significant.The Student’s n = 1), and absence in post-treatment tests due to personal problems (n = 5). A total of 26 patients (59% of the study group) had conditions of the lower respiratory tract such as bronchial asthma, COPD, and bronchiectasis, and 18 people (41% of the study group) had conditions of the upper respiratory tract such as sinusitis, pharyngitis, and laryngitis  and treatment stay within the underground chambers of a salt mine. The combination of speleotherapy and PR led to an increase in respiratory muscle function, most notably in terms of maximal expiratory pressure (MEP). Physical inactivity is a primary cause of most chronic diseases. The elderly in particular experience involutionary changes in skeletal muscles, including decreases in respiratory muscle strength. Therefore, it is advisable for them to participate in regular physical training that is adapted to their needs, preferably in a natural, pollution-free environment.Pulmonary rehabilitation in the unique underground bioclimate of the “Wieliczka” Salt Mine Health Resort allows seniors with chronic respiratory diseases to participate in a physical exercise program. The program is supervised by a physiotherapist and is in line with the American Thoracic Society/European Respiratory Society recommendations. The types of activities include endurance training like walking, resistance exercises, and exercises that improve neuromuscular coordination, such as balance, coordination, and flexibility tasks. The program also features upper and lower limb training, relaxation exercises, and conscious efforts to improve posture and breathing quality . In the The pulmonary rehabilitation program implemented in the undergrounds of the Wieliczka mine includes education on postural control during breathing, flexibility exercises, and maintaining the alignment of body segments. The diaphragm, as the primary inspiratory muscle, is responsible for 70–80% of ventilation in healthy individuals. It utilizes the pressure disparities between the thoracic and abdominal cavities for both respiration and maintaining postural stability, and it interacts with the other human body diaphragms: cranial, cervical, and pelvic floor. Additionally, it impacts fluid dynamics and posture ,28,29. CA critical component of any rehabilitation program is evaluating the effectiveness of the therapeutic procedure. For patients with chronic respiratory diseases, in addition to conducting a functional assessment of the respiratory system (spirometry), it is beneficial to examine respiratory pressures . Respira2O) and final (82.7 cmH2O) fell within the normal range for the patients’ age group . Participation in the pulmonary rehabilitation program at the underground health resort in Wieliczka seemed to shift the result towards the upper limit of this range. Given the involutionary nature of changes in MIP over time, this increase in the mean MIP value in women can be deemed a favorable outcome. On the other hand, after the pulmonary rehabilitation program in the “Wieliczka” Salt Mine Health Resort, the average MIP value for men showed a slight increase from 110.9 cmH2O to 117.2 cmH2O. However, this difference was statistically insignificant. When juxtaposed with the established norms , it becomes apparent that the male participants in the study already exceeded the average MIP values during the initial measurement. This factor likely impeded the attainment of statistical significance due to the limited growth potential or the insufficient inclusion of inspiratory muscle training (IMT) in the rehabilitation program. The results demonstrated a significant improvement in maximum expiratory pressure (MEP) across all analyses conducted in the study. This could likely be attributed to the extensive utilization of expiratory muscle training (EMT) in the therapeutic procedures that were part of the pulmonary rehabilitation program implemented in the subterranean atmosphere of the “Wieliczka” Salt Mine. Our objective was to determine how the combined approach of pulmonary rehabilitation and subterraneotherapy influences the strength of respiratory muscles. In this study, we observed individuals aged 65 and above during a rehabilitation and treatment program conducted within the “Wieliczka” Salt Chambers. Our findings revealed a significant increase in the mean values of all measured respiratory pressures, as assessed by the MicroRPM meter. The least beneficial changes were found within the maximum inspiratory pressure (MIP) range. Further stratification by gender facilitated a comparison of our results with normative values established for healthy adults, as found in a systematic review with meta-analyses conducted by Sclauser Pessoa et al. . We obsePatients with lower respiratory tract disease are typically known to exhibit lower respiratory muscle strength . However2O for elderly men and 75.5 cm H2O for elderly women. They concluded that SNIP was inversely correlated with age. However, Huang et al. [2O and for men at 39.3 cmH2O before the rehabilitation and treatment stay, as well as after its completion, with values for women at 47 cmH2O and for men at 57.2 cmH2O, were below the aforementioned reference values established for older individuals by Uldry et al. [The sniff maneuver (SNIP) and maximum inspiratory pressure (MIP) are not interchangeable; rather, they are complementary. When both tests are performed, they can reduce the risk of false positives, thereby decreasing the incidence of inaccurately diagnosed respiratory muscle weakness by approximately 20% . Uldry eg et al. , who stuy et al. .The beneficial and significant effect of inspiratory muscle training (IMT) using specialized equipment was observed in individuals with chronic lower respiratory tract diseases. In a randomized trial by Chung et al. , involviIt is known that a decline in MIP and MEP correlates with increased mortality and morbidity in older individuals. Furthermore, the activity of the diaphragm, which is the primary inspiratory muscle, may influence the symptomatic manifestation of chronic disease. Stimulating the limbic system impacts the motivation system, which is crucial for maintaining the willingness of the elderly population to engage in consistent breathing training. The deep and rhythmic nasal breaths used in inspiratory muscle training have been shown to produce rhythmic oscillations that reach the limbic area, which is responsible for emotional processing . In a meThe limitations of our study include the absence of a control group that would perform the same pulmonary rehabilitation program above ground and the lack of a follow-up study to assess the long-term effects of the pulmonary rehabilitation. Furthermore, while maximum inspiratory pressure (MIP), maximum expiratory pressure (MEP), and sniff nasal inspiratory pressure (SNIP) are non-invasive and volitional tests, it is challenging to discern which specific respiratory muscles are weakened during their performance—whether it is the diaphragm, which actively participates in posture stabilization and body balance, or the inspiratory intercostals, scalenes, or accessory muscles such as the sternocleidomastoid. Nevertheless, this is the first study to assess respiratory muscle strength in elderly individuals with chronic respiratory diseases who underwent treatment in underground salt chambers where pulmonary rehabilitation was conducted. Speleotherapy, when combined with pulmonary rehabilitation conducted at the “Wieliczka” Salt Mine Health Resort, has been shown to enhance respiratory muscle function in older patients with chronic respiratory diseases. This improvement, measured using the MicroRPM device to assess respiratory pressures, was reflected in the increased maximal inspiratory pressure (MIP) and sniff nasal inspiratory pressure (SNIP), but was particularly evident in the maximum expiratory pressure (MEP). As a result of these findings, we suggest that incorporating increased inspiratory muscle training (IMT) into rehabilitation programs, with careful attention to postural alignment and control to activate the diaphragmatic system, could be beneficial.


This multicenter cohort study retrospectively assessed the association between polar vasculosis and the progression of diabetic kidney disease (DKD) in type 2 diabetes.We enrolled 811 patients with type 2 diabetes, biopsy‐proven DKD, and proteinuria (≥0.15 g/g creatinine [g/day]). The association between polar vasculosis and other kidney lesions was explored. The outcome was DKD progression defined as a composite of renal replacement therapy initiation or 50% decline in estimated glomerular filtration rate (eGFR) from baseline.Of the 811 cases, 677 (83.5%) had polar vasculosis. In multivariate logistic regression analysis, subendothelial widening of the glomerular basement membrane, glomerulomegaly, glomerular class in the Renal Pathology Society classification ≥IIb, vascular lesions, age, eGFR, and hemoglobin A1c were positively associated with polar vasculosis, whereas interstitial fibrosis and tubular atrophy (IFTA) was negatively associated with polar vasculosis. During a median follow‐up of 5.2 years, progression of DKD occurred in 322 of 677 (7.4 events/100 person‐years) and 79 of 134 (11.4 events/100 person‐years) cases with and without polar vasculosis, respectively. Kaplan–Meier analysis showed that polar vasculosis was associated with lower cumulative incidences of DKD progression. Multivariate Cox regression analyses showed that polar vasculosis was associated with a lower risk of DKD progression, regardless of eGFR or proteinuria subgroups. These associations between polar vasculosis and better kidney outcome were unchanged considering all‐cause mortality before DKD progression as a competing event.This study showed that polar vasculosis of DKD was associated with less advanced IFTA and a better kidney outcome in type 2 diabetes with proteinuria. This multicenter cohort study retrospectively assessed 811 proteinuric patients with type 2 diabetes and biopsy‐proven diabetic kidney disease (DKD) in Japan to investigate the association between polar vasculosis and DKD progression. This study showed that polar vasculosis of DKD was associated with less advanced interstitial fibrosis and tubular atrophy and a better kidney outcome in type 2 diabetes patients with proteinuria. The clinical course and outcomes in diabetic kidney disease (DKD) are heterogeneous and various phenotypes of DKD exist, but DKD is the leading cause of end‐stage kidney disease globally, including JapanAbnormal angiogenesis is involved in the pathogenesis of DKD, and the development of extra vessels, termed polar vasculosis (perihilar neovascularization), is noted as an early kidney lesion in DKDAlthough the function of polar vasculosis is also unknown, it has been speculated that the formation of polar vasculosis may decrease the intraglomerular pressureThis is a retrospective study of patients who underwent clinical kidney biopsy after obtaining informed consent and had a pathological diagnosis of DKD between June 1981 and January 2020 at the following 14 hospitals in Japan: Kanazawa University Hospital , Kanazawa Medical University Hospital , Toranomon Hospital , Fujita Health University Hospital , National Hospital Organization Chiba‐East National Hospital , Tohoku University Hospital , St Marianna University School of Medicine Hospital , Niigata University Hospital , University of Tsukuba Hospital , Nara Medical University Hospital , Kobe University Hospital , Nagasaki University Hospital , Okayama University Hospital , and Nagoya University Hospital . Kidney biopsy was performed on patients with type 2 diabetes in whom it was necessary to confirm clinically precise pathological findings. The exclusion criterion was patients with other kidney diseases, except for nephrosclerosis coexisting with DKD. Among 1,050 patients with type 2 diabetes and biopsy‐proven DKD, 93, 30, 30, and 86 patients were excluded for lack of data on urinary protein excretion, lack of data on the presence or absence of polar vasculosis, lack of data on kidney outcome, and baseline proteinuria <0.15 g/g creatinine [g/day], respectively. Thus, 811 patients were included in the final analysis. This study was approved by the Kanazawa University Ethics Committee [No. 2016‐460 (1204)] and all participating institutions.2) and G3a–G5 (<60 mL/min/1.73 m2) for categorical analysesThe following parameters at the time of kidney biopsy (baseline) were collected by manual chart review: age, sex, serum creatinine, eGFR, urine protein‐to‐creatinine ratio, 24 h urinary protein excretion, hemoglobin A1c, systolic and diastolic blood pressure, total cholesterol, use of antihyperglycemic medications, use of RAAS inhibitors, use of calcium channel blockers, and use of lipid‐lowering agents. eGFR was calculated based on the equation established by the Japanese Society of NephrologyBiopsy samples were stained using periodic acid–Schiff, periodic acid methenamine–silver, hematoxylin–eosin, and Mallory–Azan (or Masson's trichrome), and subsequently examined under a light microscope. The definition and scoring of all pathological lesions were agreed upon after reviewing previous pathological studies on diabetic nephropathy and after more than 2 years of meetings among the authors. Furthermore, we published the “Manual for pathological diagnosis of diabetic nephropathy and hypertensive nephrosclerosis”, focusing on the characteristic lesions of diabetic nephropathy/DKD and the common lesions of diabetic nephropathy/DKD and hypertensive nephrosclerosis in 2014The outcome was the progression of DKD, defined as a composite of renal replacement therapy initiation or 50% decline in eGFR from baseline. Data were obtained from the medical records of all participating institutions. Cases that did not achieve these outcomes or were lost to follow‐up were censored at the last follow‐up visit.U test and Fisher's exact test, respectively. To determine the factors associated with the presence of polar vasculosis, univariate and multivariate logistic regression analyses were performed including 12 pathological variables in the Japanese classificationP <0.05 were considered statistically significant. All analyses were performed using Stata version 17.0 software  and R version 4.2.3.Data are expressed as median and interquartile ranges for continuous variables and percentages for categorical variables, which were compared using the Mann–Whitney 2, and 1.9 (0.6–4.5) g/g creatinine or g/day, respectively. The proportions of G1, G2, G3a, G3b, G4, and G5 in the GFR categories were 10.7% (87/811), 24.2% (196/811), 21.7% (176/811), 24.2% (196/811), 15.2% (123/811), and 4.1% (33/811), respectively. The proportions of 0.15–0.49 g/g creatinine (g/day) and ≥0.5 g/g creatinine (g/day) in proteinuria categories were 20.5% (166/811) and 79.5% (645/811), respectively.The baseline characteristics of the 811 patients included in this study are shown in Table Polar vasculosis was present in 677 (83.5%) patients. Table P < 0.001), nodular sclerosis , subendothelial widening of GBM , exudative lesion , mesangiolysis , glomerulomegaly , glomerular class by the RPS classification ≥IIb , arteriolar hyalinosis , and arteriosclerosis  were positively associated with the presence of polar vasculosis, whereas the use of RAAS inhibitors was negatively associated with the presence of polar vasculosis . In the multivariate analysis of pathological variables, subendothelial widening of GBM , glomerulomegaly , glomerular class by the RPS classification ≥IIb , arteriolar hyalinosis , and arteriosclerosis  were positively associated with the presence of polar vasculosis, whereas IFTA was negatively associated with the presence of polar vasculosis . In the multivariate analysis of clinical variables, age , eGFR , and hemoglobin A1c  were positively associated with the presence of polar vasculosis.To investigate the associations between polar vasculosis and other kidney lesions and baseline clinical variables, we used univariate and multivariate logistic regression analyses Table . In the P = 0.006).During the median follow‐up of 5.2 years , DKD progression occurred in 322 of 677  and 79 of 134  patients with and without polar vasculosis, respectively. The cumulative incidences of DKD progression stratified by polar vasculosis are shown in Figure P = 0.005).In the cumulative incidence functions for DKD progression by the presence of polar vasculosis in consideration of all‐cause mortality before DKD progression as a competing event, the cumulative incidence of DKD progression was lower than that of the Kaplan–Meier analysis Figure . There wP = 0.003) and G3a–G5 categories  and G3a–G5 categories  and G3a–G5 categories  and G3a–G5 categories  among the G1–G2 and G3a–G5 categories. In the Cox model including 13‐pathological variables in the Japanese classification, the presence of polar vasculosis was associated with a lower risk of DKD progression among the G1–G2  and urinary protein excretion ≥0.5 g/g creatinine (g/day) categories  and urinary protein excretion ≥0.5 g/g creatinine (g/day) categories  and urinary protein excretion ≥0.5 g/g creatinine (g/day) categories  and urinary protein excretion ≥0.5 g/g creatinine (g/day) categories  among urinary protein excretion 0.15–0.49 g/g creatinine (g/day) and ≥0.5 g/g creatinine (g/day) categories. In the Cox model including the 13 pathological variables in the Japanese classification, the presence of polar vasculosis was associated with a lower risk of DKD progression among urinary protein excretion 0.15–0.49 g/g creatinine (g/day)  categories Tables  and 4, sThis multicenter study investigated a large cohort of patients with type 2 diabetes and biopsy‐proven DKD and showed two findings: (i) the presence of polar vasculosis was related to less advanced IFTA in contrast to more advanced glomerular lesions  and vascular lesions, and (ii) the presence of polar vasculosis was associated with a better kidney outcome in patients with proteinuria regardless of the subgroups stratified by GFR and proteinuria categories. We have previously shown that polar vasculosis was associated with preserved eGFR for 3 years after kidney biopsyet al.First, we explored the association between polar vasculosis and other kidney lesions and clinical variables. In the multivariate logistic regression analysis, IFTA was negatively associated with polar vasculosis, whereas subendothelial widening of GBM, glomerulomegaly, glomerular class by the RPS classification ≥IIb, vascular lesions, age, eGFR, and hemoglobin A1c were positively associated with polar vasculosis. Previous several studies have shown the relationships between polar vasculosis and more advanced mesangial expansion, glomerulomegaly, and arteriolar hyalinosis in human DKD, consistent with this studyNext, we showed that the presence of polar vasculosis positively correlated with eGFR and was associated with a better kidney outcome of DKD in type 2 diabetes with proteinuria. Kaplan–Meier analyses showed that polar vasculosis was associated with lower cumulative incidences of DKD progression. Cox regression analyses showed that polar vasculosis was associated with a lower risk of DKD progression in multivariate analyses, regardless of subgroups stratified by GFR and proteinuria categories. When we conducted the cumulative incidence function and the multivariate Fine‐Gray regression model in consideration of all‐cause mortality before DKD progression as a competing event, these results were unchanged. As many studies have suggested, we also identified that more advanced IFTA was associated with a poor kidney outcome in type 2 diabetes with DKD in this studyet al.In this study, hemoglobin A1c was positively associated with the presence of polar vasculosis in multivariate logistic regression analysis. Nyumura Furthermore, vascular lesions and age were also positively associated with polar vasculosis by multivariate logistic regression analysis in this study. Pathologically, DKD can be complicated by nephrosclerosis as well as by traditional diabetic kidney lesionsThere are several limitations in this study. First, this retrospective study included only cases that underwent kidney biopsy, which may have resulted in bias. Particularly, we included patients who underwent kidney biopsy in clinical settings, rather than using research biopsies. Therefore, there is a possibility that biases in the indications for kidney biopsy existed among participating institutions. Second, patients without proteinuria were excluded from this study because the number of observed outcomes was insufficient to perform a survival analysis. Third, we did not quantitate polar vasculosis. To understand the importance of polar vasculosis in the progression of DKD, quantitative assessment  is also needed. Because the quantitative analysis of renal pathology is complex and time‐consuming, we were unable to investigate quantitative assessment in this study, which deals with a relatively large number of cases. Fourth, we have tried to reduce inter‐observer and inter‐institutional variability in the pathological diagnosis including polar vasculosis as a collaborative study, but the current study did not assess them in detail. Fifth, we used only baseline clinical variables in our analyses, although the changes in clinical variables and the use of RAAS inhibitors during follow‐up may affect kidney outcome. However, the study has several strengths, including biopsy‐proven DKD of a large sample collected from multiple institutions in Japan and long duration follow‐up of a maximum of approximately 30 years.In summary, this multicenter cohort study showed that polar vasculosis of DKD was associated with less advanced IFTA and a long‐term better kidney outcome in patients with type 2 diabetes and proteinuria.The authors declare no conflict of interest.Approval of the research protocol: This study was approved by the Kanazawa University Ethics Committee [No. 2016‐460 (1204)] and all participating institutions.Informed consent: Not required, because de‐identified data were used; patients could ‘opt out’ of participation.Registry and the registration no. of the study/trial: N/A.Animal studies: N/A.Table S1| Multivariate Cox and Fine‐Gray regression results for diabetic kidney disease progression including 6‐pathological variables among subgroups stratified by glomerular filtration rate categoriesTable S2 | Multivariate Cox and Fine‐Gray regression results for diabetic kidney disease progression including 6‐pathological variables among subgroups stratified by proteinuria categoriesClick here for additional data file.


Multimorbidity, the coexistence of multiple health conditions, is associated with functional decline, disability, and mortality. We aimed to investigate the effects of multimorbidity on hypertension treatment and control rates by analyzing data from the Korean National Health and Nutrition Examination Survey database, which is a cross-sectional, nationally representative survey conducted by the Korean government. Multimorbidity, defined as having two or more chronic diseases, was evaluated by blood pressure measurements, blood chemistry examinations, and questionnaires. We classified the participants according to the number of multimorbidities from 0 to ≥ 6. Association analysis was performed to identify the patterns of multimorbidity related to hypertension control. From 2016 to 2020, 30,271 adults (≥ 20 years) were included in the analysis , and 14,278 (47.2%) had multimorbidity. The number of chronic conditions was significantly higher in older adults, women, and hypertensive patients. Multimorbidity was associated with hypertension treatment. The number of chronic conditions was significantly higher in controlled compared to uncontrolled patients . But the control rate of hypertension among treated patients was lower in patients with multimorbidity . Multimorbidity patterns showed distinct features in treated and controlled hypertensive patients. In conclusion, multimorbidity has a beneficial effect on the treatment of hypertension, but the control rate of systolic blood pressure was lower among the patients with multimorbidity. More attention should be paid to the hypertensive patients with multimorbidity to improve the control rate of hypertension. Multimorbidity focuses on the characteristic clustering or patterns of multiple diseases in a single patient and the interactions between diseases and patients. Multimorbidity is more common in older adults than in younger individuals. The prevalence of multimorbidity is over 50% in the elderly, and certain clusters can be found for individual diseases in patients with multimorbidities3. Multimorbidity in older patients requires intensive diagnostic workups and is associated with unexpected in-hospital events. In addition, multimorbidity is significantly associated with higher mortality, increased disability, decline in functional status, and lower quality of life (QoL). Consequently, multimorbidity is the primary contributor to increased medical costs, leading to increased healthcare utilization6.Multimorbidity, defined as the coexistence of two or more chronic diseases in the same individual, is an emerging issue owing to an increase in population aging in developed countries8. However, data on the effects of multimorbidity on the treatment or control of hypertension are limited. In addition, current guidelines do not sufficiently address older patients with multimorbidity, who are commonly excluded from or underrepresented in major clinical trials; hence, there is little evidence on how to manage elevated blood pressure (BP) in hypertensive patients with multimorbidity.Hypertension is a common chronic condition associated with an increased risk of cardiovascular disease, disability, and impaired QoL. It frequently manifests with other chronic conditions such as diabetes mellitus, obesity, and depression. Accordingly, it is important to consider multimorbidity in the diagnosis and treatment of patients with hypertension9.Multimorbidity shows different patterns, and understanding these patterns is helpful in determining the optimal treatment of certain diseases. Thus, it is important to understand whether certain comorbidities can affect BP over time, which could justify individualized recommendations for BP treatment in such patientsFor this purpose, we analyzed data from the Korean National Health and Nutrition Examination Survey (KNHANES). We aimed to identify the association between multimorbidity and hypertension prevalence, treatment, and control rate, and to investigate the characteristic patterns of multimorbidity related to hypertension treatment or control among KNHANES participants.10. KNHANES has been conducted periodically since 1998 to assess the health and nutritional status of community-dwelling Koreans. The survey consists of a health interview survey, nutrition survey, and health examination survey. A stratified multistage probability sampling design was used to select household units.Data were derived from the KNHANES. The KNHANES is a cross-sectional and nationally representative survey conducted by the Division of Chronic Disease Surveillance of the Korea Disease Control and Prevention AgencyAmong the 31,811 participants older than 20 years who participated in the survey between 2016 and 2020, 1540 were excluded owing to a lack of data regarding BP or hypertension treatment. A total of 30,271 participants, including 13,334 males (44.0%) were included in the analysis. All study procedures were performed in accordance with relevant guidelines and regulations. All surveys were conducted with the written consent of the participants. This study was approved by the Institutional Research Committee of the Seoul National University Bundang Hospital (IRB No. X-2208-773-902).Trained nurses measured BP using a mercury sphygmomanometer  with an appropriately sized cuff after the participants sat for at least 5 min to stabilize BP. During the measurement period, the participants were seated, leaning against the back of a chair, with their feet flat on the floor. The participants’ right arm was positioned such that the middle of the cuff was at the heart level. Three BP readings were obtained from each participant after 5 min of rest. The mean of the second and third measured BP values were used in the analysis.11. Body mass index (BMI) was calculated as weight in kilograms divided by height in meters squared.Blood samples were obtained in the morning after at least 8 h of fasting. Blood samples were centrifuged, refrigerated at the examination site, and transferred to a central laboratory in ice boxes. Body weight and height was measured by trained medical staff at the mobile examination center12. Hypertension was defined as a BP ≥ 140/90 mmHg or current treatment with antihypertensive medication. Hypertension control was defined as having an average systolic and diastolic BP of < 140/90 mmHg. Control rate was defined as the proportion of participants with adequate BP control among those with hypertension or taking antihypertension medication. Hypertension treatment was defined if the participants were taking antihypertensive medications for ≥ 20 days/month.Among the many chronic conditions, we selected 26 conditions base on previous reports and availability of data in KNHANE213. Anemia was defined as a hemoglobin level < 13 g/dL in men and < 12 g/dL in women. Chronic kidney disease (CKD) was defined as estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2, which was measured using the chronic kidney disease-epidemiology collaboration (CKD-EPI) equation14. Hepatitis B infection was determined based on the serum hepatitis B viral surface antigen status using an electrochemiluminescence immunoassay. Hepatitis C infection was determined by anti-HCV antibody testing using a chemiluminescent microparticle immunoassay.Hypercholesterolemia was defined as cholesterol ≥ 240 mg/dL or current treatment with cholesterol-lowering agents. Diabetes mellitus was defined as a fasting glucose ≥ 126 mg/dL or treatment with an oral hypoglycemic agent or insulin. Obesity was defined as a BMI ≥ 25 kg/mThe presence of other diseases was assessed during the health interview, and participants responded to the following question: “Has a doctor ever told you that you have (or have had) stroke, ischemic heart disease, depression, osteoporosis, bronchial asthma, atopy, chronic sinusitis, liver cirrhosis, thyroid disease, rheumatoid or degenerative arthritis, or cancer ?”.Among the 26 conditions, we calculated the presence of conditions and classified the participants according to the number of multimorbidities from 0 to ≥ 6.Statistical analyses were performed using SAS 9.4 for Windows  using the survey procedure and R . To calculate the total population represented by the sample, stratified variables and sample weights designed by the Korean Centers for Disease Control and Prevention were used. All estimates were weighted, and the sample weights accounted for the unequal probabilities of selection resulting from the complex sample design, survey non-response, and planned oversampling of the selected population subgroups. Continuous variables were expressed as mean ± standard deviation and compared using the unpaired Student’s t-test. Qualitative variables were expressed as counts and percentages, and the Chi-square test was used to compare proportions. Uni- and multivariable logistic models were used to identify the factors affecting the hypertension control. We used association rule analysis to display the pattern of multimorbidity based on R packages “arules” and “arulesViz”. Multimorbidity patterns were visualized as pathways represented by nodes and edges. The size and color of the nodes represent the support and lift, respectively. All statistical analyses were two-tailed, and p-values < 0.05 were considered statistically significant.The mean age of the study population was 52.1 ± 16.8 years, and men represented 44.0% of the sample. The mean number of chronic diseases was 1.8 ± 1.7 (range 0–15).Among the 26 chronic conditions, obesity was the most common (35.1%), followed by hypertension (33.2%), hypercholesterolemia (22.7%), diabetes mellitus (12.7%), and arthritis (11.5%).The baseline clinical and laboratory characteristics according to the number of multimorbidities are presented in Table Compared with normotensive participants, hypertensive patients were older, male, obese, and less active. In addition, hypertensive patients had more chronic conditions; thus, the number of chronic conditions were significantly higher among the hypertensive patients  (Table The prevalence and treatment of hypertension were significantly higher among participants with multimorbidity. In addition, the hypertension control rate was significantly higher in patients with multimorbidity. However, the hypertension control rate among treated hypertensive patients was not significantly different according to the number of chronic conditions Fig. a. SpecifThe distributions of systolic and diastolic BPs according to age and hypertension treatment are presented in Fig. The pattern of multimorbidity in controlled hypertensive patients or uncontrolled hypertensive patients despite antihypertensive treatment are shown in Fig. We showed that multimorbidity was common among older adults and women. Interestingly, multimorbidity was associated with hypertension treatment, and patients with multimorbidity were more likely to be treated with antihypertensive medications. However, the control rate of systolic BP among the treated patients was lower in those with multimorbidities.15, suggesting that multimorbidity is a common problem in older adults.The prevalence of chronic diseases such as hypertension, diabetes mellitus, and dyslipidemia increases with age. Furthermore, complications of chronic medical conditions such as myocardial infarction, stroke, heart failure, chronic kidney disease, and dementia also increase steeply with age. Accordingly, the risk of multimorbidity was significantly higher in older patients. It has been reported that most older patients present with more than two chronic medical conditions16. Previous studies showed the importance of patients-centered care for the patients with multimorbidity18 However, this study showed that multimorbidity had a beneficial effect on the likelihood of receiving hypertension treatment. Having multiple medical conditions may increase the likelihood of visiting a hospital for disease care. Accordingly, we can assume that multimorbidity has a beneficial effect on the awareness or treatment of hypertension.Multimorbidity has a negative clinical impact; it reduces life expectancy, affects an individual’s QoL and ability to work, increases the risk of hospitalization, and leads to the excessive use of healthcare resources19. Drug resistance or impaired organ function may be associated with poor BP control in patients with multimorbidities.However, we observed that the control rate of systolic BP in patients with multimorbidity was lower than that in patients without multimorbidity. The hypertension control rate is reportedly lower among patients with multimorbidities20. However, patients with multimorbidity are commonly excluded from or underrepresented in major clinical trials, thus limiting the evidence on how best to manage elevated BP in patients with hypertension and multimorbidity. With the expected increase in the burden of multimorbidity and hypertension, it is important to understand how the presence of comorbidities affects BP to inform future policies and research. Additionally, multimorbidity is strongly associated with polypharmacy. Thus, it is necessary to consider the interactive effects of drug-drug or drug-disease interactions in patients with hypertension.In this study, we showed that age, sex, marital status, and multimorbidity were independently associated with hypertension control in patients with hypertension. Up to two-thirds of patients with hypertension have other comorbiditiesThe pattern of multimorbidity differed between patients with controlled and uncontrolled hypertension. Moreover, several principal chronic diseases had a larger impact on the control of hypertension. Thus, there is a need to focus on managing key diseases to improve BP control. In this study, we showed that hypertension control was strongly associated with other morbidities such as diabetes, anemia, and CKD.This study has several limitations. Because we used data from a nationally representative survey, the results can be generalized to the non-institutionalized Korean population. However, these results cannot be applied to other populations such as those from other countries or ethnic groups. Due to the study design, it is impossible to analyse cause and effect between multimorbidities and hypertension control. Finally, patients responded to a survey regarding their comorbidities instead of being tested, so some comorbidities may have gone unreported. Finally, KNHANES dataset do not provide information regarding medication or treatment, which may have an impact on the relationship between multimorbidity and hypertension management.In conclusion, multimorbidity has a positive effect on the treatment of hypertension; however, the control rate of systolic blood pressure is poor among patients with multiple chronic conditions. More attention should be paid to hypertensive patients with multimorbidities to improve the control rate of hypertension.Supplementary Tables.