Perirenal fat plays a key role in sustaining pathological high blood pressure. We aim to investigate the efficacy of intervention for perirenal fat mediated by focused power ultrasound (FPU) on primary hypertension.A multicenter, randomized, sham-controlled, double-blinded trial will be implemented in 200 participants with mild to moderate hypertension. All enrolled participants will be randomly allocated to perirenal fat modification (PFM) intervention using FPU or sham-procedure at a ratio of 1:1 and will be followed up at 24 h, 14 days, 30 days, and 90 days after the intervention. The primary endpoint is changes in office systolic blood pressure (SBP) at 30 days compared with baseline. The secondary endpoints include the changes in office SBP from baseline to 90 days, changes in 24-h mean SBP from baseline to 30 days and 90 days, and changes in heart rate from baseline to 30 days. Safety endpoint is defined as any severe adverse events related to the intervention.The present study is the first to use noninvasive FPU to intervene in perirenal fat to achieve the goal of reducing blood pressure for patients with essential hypertension. Our study is expected to provide a new treatment strategy to control high blood pressure.ClinicalTrials.gov. NCT05049096. Registered on September 7, 2021.Protocol version: Version 1.3.1, data 23 August 2021.Sponsor: Prof. Xiangqing Kong is the principal investigator of this trial. Hypertension is one of the most common cardiovascular diseases, whose prevalence exceeds 30% adult population worldwide, and has become the leading cause of global health issues and economic burden , 2. BlooAlthough pharmacological antihypertensive therapies are the main measures to reduce BP, the percentage of hypertensive patients whose BP attain the target guideline recommendation is unacceptably poor. Exploration of other options to reduce BP is urgent. Visceral fat is closely related to the occurrence of hypertension. Notably, perirenal fat is a unique connected tissue that is well vascularized and innervated . CumulatFocused ultrasound is increasingly used in the broad area of medicine, especially in the ablation of solid tissue, such as tumors . This prHerein, we conducted a multicenter, randomized, sham-controlled, double-blinded study using focused ultrasound to modify the PRAT to explore the efficacy of this kind of modification for the treatment of essential hypertension.This study is mainly to assess the efficacy of perirenal fat modification (PFM) therapy with focused ultrasound for hypertensive patients with uncontrolled blood pressure. In addition, the occurrence of adverse events  will be recorded to assess the safety outcomes.This is an investigator-initiated, multicentered, randomized, sham-controlled, double-blinded, and exploratory clinical trial with a 3-month duration, which primarily aims to assess whether PFM therapy can reduce blood pressure in patients with grade one to two hypertension.Eligible participants will be randomized at a ratio of 1:1 into an intervention group and a control group. The participants in the intervention group will receive PFM therapy with focused ultrasound, while a sham procedure will be performed for the participants assigned to the control group. All participants will be assessed for efficacy and safety at 24 h, 2 weeks, 1 month, and 3 months after PFM or sham procedure. The main indicators to evaluate efficacy are the changes in office BP and 24-h ambulatory BP. Adverse events will be recorded at each visit. Blood samples and urine samples will be collected, and imaging examinations will be performed at baseline, 24 h, 1 month, and 3 months. Participants are required to measure their office BP at a 2-week visit. Except for the operator who is responsible for focused ultrasound, all staff, including researchers, statisticians, and participants, are blinded to the groups of randomizations.This protocol report follows the SPIRIT reporting guidelines .This trial is initiated by the Cardiology Department, The First Affiliated Hospital of Nanjing Medical University. Eligible participants with uncontrolled BP will be recruited at three implementation sites, including the First Affiliated Hospital of Nanjing Medical University (Jiangsu Province), Nanjing Jiangning Hospital (Jiangsu Province), and Suzhou Municipal Hospital (Jiangsu Province).• Individuals aged 18–65 years old• Individuals have uncontrolled BP when receiving a medication regimen of one, two, or three antihypertensive medication classes for at least 4 weeks; and uncontrolled BP is defined as office systolic blood pressure (SBP) ≥ 140 mmHg and < 180 mmHg, and 24-h ambulatory BP monitoring (ABPM) average SBP ≥ 135 mmHg, regardless of diastolic BP• Individuals have at least 20 mm in the anteroposterior, transverse, and axial diameters of inferior perirenal fat measured by ultrasound• Individuals are willing to sign the informed consent of the studyThe inclusive criteria are as follows:• Individuals are diagnosed with secondary hypertension • Individuals have a history of kidney and or kidney surrounding tissue surgery• Individuals have impairment of liver or kidney function • Individuals have a myocardial infarction, unstable angina pectoris, cerebrovascular accident, or transient ischemic attack within 6 months before enrollment• Individuals have type 1 diabetes or poorly-controlled type 2 diabetes• Individuals have uncontrolled thyroid dysfunction• Individuals have urinary calculi and/or hematuria• Individuals have atrial fibrillation• Individuals have severe structural heart disease • Individuals have second-degree and above atrioventricular block• Individuals have abnormal coagulation function• Individuals have infected waist skin• Individuals have a malignant tumor• Individuals are pregnant, nursing, or planning to be pregnant• Individuals are unwilling to sign informed consent• Individuals fail to complete the screening periodThe exclusive criteria are as follows:Eligible patients will undergo either PFM with focused ultrasound or a sham procedure. It is expected that their prescribed antihypertensive medications should be unchanged in the 3 months follow-up period after the intervention.Patients who are assigned to the PFM group will be placed in a lateral position on the treatment bed. Firstly, an ultrasonic probe is used to locate the rough position of inferior perirenal fat and the location needs to be marked on the waist skin. Secondly, a focused power ultrasonic probe is applied to determine the precise target area of perirenal fat. Sequentially, automatic physique measurement starts to calculate the optimal output power for individuals. Lastly, treatment initiates. Bilateral inferior perirenal fat shares the same procedure. The training sessions including recognition of inferior perirenal fat from ultrasonic images and operation of the equipment have been conducted at each study site by only one designated operator.Patients who are assigned to the sham control group share the same procedure as PFM does except that the focused ultrasound will not transmit energy.• They may choose to withdraw for any reason• They have severe side effects that require unmarking to get cured• Their blood pressure is within “escape criteria,” defined as office SBP ≥ 180mmHg or < 90 mmHg• They have a significant deviation from the study algorithm, e.g., changing the established antihypertensive drugs scheme• Any other rational reasons to withdraw from the studyParticipants may discontinue this trial for any of the following reasons:Before enrollment, we repeatedly confirm the participants’ willingness and compliance with the study’s requirements, especially drug numbers and doses, and being able to follow up within the next 3 months. We make efforts to monitor the adherence to drug use which is prescribed before allocation for at least 4 weeks. Blood and urine samples will be collected to measure the concentration of the antihypertensive drugs , angiotensin-converting enzyme inhibitors (ACEI)/angiotensin receptor blocker (ARB), beta-blocker, and alpha-blocker) at baseline, 1 month, and 3 months.Though lifestyle modification should be recommended for all hypertensive patients according to the hypertension guidelines, we asked recruited participants to maintain their current lifestyle, including physical activities, diet, and regular rest habits. In order to assess the changes in lifestyle, weight, waist circumference, or hip circumference will be recorded at each follow-up time.We speculate that PFM will have a significant blood pressure lowering effects compared with the sham-control group. The endpoints in the present study include primary endpoints, secondary endpoints, and safety endpoints.• Changes in office systolic blood pressure at 1-month compared with baselinePrimary endpoint measure:• Changes in office blood pressure at 3 months compared with baseline• Changes in mean systolic blood pressure measured by 24-h ambulatory blood pressure monitoring at 1 month compared with baseline• Changes in mean systolic blood pressure measured by 24-h ambulatory blood pressure monitoring at 3 months compared with baseline• Changes in the heart rate at 1 month compared with baseline• Changes in the mean heart rate measured by 24-h ambulatory blood pressure monitoring at 1 month compared with baselineSecondary outcome measures:• Any severe adverse events (SAE) related to the intervention. The SAE was defined as acute renal failure, acute intestinal perforation, and thromboembolic events, etc.Safety endpoint measures:The participant timeline is shown in Table The PASS software (version 2011) was used to calculate the sample size. This study is a parallel group design, whose primary endpoint is the difference in office BP at 1 month compared with baseline. Our previous pilot study was a single-arm design recruiting 15 participants with mild-moderate hypertension for PFM therapy with results unpublished. Based on the outcome of the pilot study, the mean change in office SBP from baseline to 1 month was expected to 10 mmHg with a deviation of 13 mmHg in the PFM group. Meanwhile, we assumed that a mean difference of office SBP was 5 mmHg  with a dPotential eligible participants will be screened at the outpatient clinics of each study center. Advertisements of the trial introduction will be posted onsite at the hospital and on social media platforms.The randomized allocation sequence was generated at a 1:1 ratio in a completely random design among 200 participants by a statistician via the SAS 9.4 software  and integrated with a central computerized randomization system .The randomization codes were generated by a statistician and embedded in the computerized randomization system. The main investigators will not have permission to view the allocation except for the principal investigator of each study site and operators who are responsible for PFM operation. The principal investigators are only authorized for urgent unblinding when a serious complication related to the PFM procedure occurs.An independent randomization system account is created for investigators at each study site for the randomization implementation. Each investigator will log in to the system via a website to enter the randomization page, input the information of the participants, check the name and code of the study site, and confirm the randomization information. Then, the randomization code and allocated arm of the participant will be generated in the system background which is blinded for the investigators. Additionally, the operator at each study site will log in to the system using an independent account with the authority to view the allocated arms. At this time, the participants are successfully enrolled in this study.Study participants and all staff, including investigators, clinical care providers, statisticians, and personnel who recruit, follow-up with participants, and collect data are blinded to the randomizations. The operators will be unblinded to implement the PFM procedure and required to keep blinded to all other staff. After completing the procedure, we will ask about the participants’ feelings or any discomforts and if they can tell the real intervention and sham intervention. Once severe adverse events (SAE) that might be related to the PFM procedure occur, the principal investigators will be able to disclose the arm allocation. The disclosure reason, date, and location will be recorded in detail.The outcomes will be assessed at baseline, 1 day, 14 days, 30 days, and 90 days after the intervention. All staff involved in the collection of data were trained by the standard operating procedure of the study. The data will be recorded utilizing electronic CRFs and EDC systems.• Written informed consent• Clinical questionnaire• Office BP and 24-h ambulatory BP• Anthropometric information including height, weight, waist circumference, and hip circumference• Electrocardiography and cardiac ultrasound• Arteries stiffness assessments (PWV)• Imaging examinations including ultrasonic examinations of renal and perirenal fat, carotid ultrasound, and magnetic resonance imaging for perirenal fat and hypothalamic function• Blood tests including routine blood tests, blood biochemical tests, and C-reactive protein• Urine tests including routine urine tests, urine biomarkers of acute renal injury • Hypertensive drug concentration detection (serum and urine)The following measures will be completed at baseline.• Office BP and 24-h ambulatory BP• Electrocardiography• Arteries stiffness assessments (PWV)• Imaging examinations including ultrasonic examinations of renal and perirenal fat and carotid ultrasound• Blood tests including routine blood tests, blood biochemical tests, and C-reactive protein• Urine tests including routine urine tests and urine biomarkers of acute renal injury • Office BP• Office BP and 24-h ambulatory BP• Anthropometric information including height, weight, waist circumference, and hip circumference• Electrocardiography• Arteries stiffness assessments (PWV)• Imaging examinations including ultrasonic examinations of renal and perirenal fat, carotid ultrasound, and magnetic resonance imaging for perirenal fat and hypothalamic function• Blood tests including routine blood tests, and biochemical blood tests• Urine tests including routine urine tests• Hypertensive drug concentration detection (serum and urine)• Office BP and 24-hour ambulatory BP• Anthropometric information including height, weight, waist circumference, and hip circumference• Electrocardiography• Arteries stiffness assessments (PWV)• Imaging examinations including ultrasonic examinations of renal and perirenal fat, carotid ultrasound, and magnetic resonance imaging for perirenal fat and hypothalamic function• Blood tests including routine blood tests, and biochemical blood tests• Urine tests including routine urine tests• Hypertensive drug concentration detection (serum and urine)All the eligible participants will have comprehensive health examinations and receive PFM therapy or sham-procedure for free. They will have close relationships with physicians who can provide professional consultations and medication guidance for their health problems. Traffic and accommodation subsidies will provide for all participants to promote participant retention and complete follow-up. If participants discontinue follow-up, the reasons will be recorded in detail, and their clinical treatment and other rights shall not be affected.Study data will be recorded via the Electronic Data Capture (EDC) system . Well-trained practitioners will log into the website and input data. The EDC system has the function of automatically checking data format, rules, and range so as to ensure the accuracy of data. Moreover, manual reconfirmation by a third staff is also required. Any change in data recording is permitted and tracked with reasons and dates in the EDC system. Additionally, data quality will be under the supervision of a third party. All documents and data will be stored at the institutional office of each study site.P < 0.05 will indicate significance in all statistical analyses used by the SAS software V.9.4 .For the primary endpoint, a mixed-effect model for repeated measures (MMRM) adjusted with baseline office SBP will be used to compare the group difference of the office SBP changes from baseline to 1 month. For the secondary endpoint, we will also use the MMRM method adjusted with mean SBP or heart rate to assess the changes in the mean SBP or heart rate from baseline to each visit point. And LS-means method adjusted with baseline SBP or heart rate will be used to estimate the changes in SBP or heart rate and 95% confidence intervals. Imputation for missing values of the main indicator will be conducted using the Markov chain Monte Carlo (MCMC) model which will be performed as the result of the sensitive analysis. We predefine an adverse event of laboratory index that is significantly abnormal at follow-up compared with baseline. Detailed presentation of adverse events will be described and explore the relationship with PFM products. The efficacy analyses will be carried out based on the full analysis set and the pre-protocol set. All baseline characteristics analysis will be conducted on the basis of the full analysis set. The safety evaluation will be analyzed from the safety analysis set. A two-sided P value is less than the boundary value of the interim analyzed α for the primary endpoint. And if the P value is greater than interim analyzed α with statistical power less than 60%, re-estimating the sample size is needed to make the final statistical power greater than 80%. In accordance with O’Brien-Fleming method, the interim analyzed α = 0.005, and final α = 0.048.An interim analysis is planned when 50 subjects  are enrolled in each group and completed 1 month follow-up, which will be conducted by an independent data monitoring committee (IDMC). The purposes of the interim analysis are as follows: (1) to evaluate the safety (a necessary disruption of the study is considered when there are serious or expected adverse events) and (2) to assess the efficacy. This trial will be expected to terminate in advance if the hypothesis test In order to monitor the trial process and participants’ safety, a trial steering committee (TSC) was established to make sure the trial run well. The members of this committee are experts from different professional fields, including hypertension management, cardiovascular disease, biostatistics and other fields. All personnel from the committee are absolutely independent from and have no competing interests with the funders and sponsor. We invited the staff from the Clinical Trial Institution of Jiangsu Province Hospital, and School of Public Health, Nanjing Medical University to regularly monitor the data and report to the committee. The TSC will meet onsite at each study site every three months to track the trial process and monitor the participant’s safety.In this study, potential risks of PFM therapy are the thermal damage of local skin, subcutaneous tissue, and organs adjacent to perirenal fat. Any discomforts or abnormal indicators changes through energy emission path including skin, muscles, renal area, and intestine will be identified as adverse events (AEs) and will be recorded in eCRF and EDC system with details of onset time, severity, and duration. The severity of AEs and their correlations with PFM therapy will be carefully evaluated in accordance with the Common Terminology Criteria for Adverse Events . Severe This study protocol was comprehensively considered and will not be amended easily without written permission from the Ethics Committee of the responsible unit. The revised protocol will be inspected by the local ethical boards again. The informed consent approved by local ethical boards will be presented to the potential participants and their authorized surrogates. Investigators is responsible for introducing the study design, procedure, potential harms, and benefits, and answering the participant’s questions. The participant can only be enrolled after signing their name on the page of the informed consent form. Additional sample collection is also noted on the pages of informed consent. For each visit, 5 ml blood samples and 2 ml urine samples will be collected and stored. To protect participants’ confidentiality, private information, including names, addresses, contact, and identified numbers will be kept within each investigation center. Access by any third party will be prohibited. All data used for analysis and report shall not have personal identifiers except for unique screening codes or randomization codes. Once the AEs occur, medical care will be provided for participants promptly. In addition, appropriate assistance and management will be presented according to the relevant laws and regulations.The study results will be published in peer-review journals, presented at scientific conferences, and shared with all participants. Access to all deidentified data will be permitted only for certificated researchers with written approval from the responsible investigators. Any data required to support the protocol can be supplied on reasonable request.Epidemiological studies have demonstrated that perirenal fat is closely associated with elevated blood pressure , 9. It iLong-term use of medical treatment is the essential method for hypertensive patients, which is bound to have increased risks of adverse events. Especially for those who are resistant to antihypertensive drugs, traditional medical therapy is of little help. Therefore, novel therapeutic methods are urgent for lowing blood pressure, notably the instrument treatment for hypertension. Renal denervation (RDN) is an intervention that uses an ablation catheter to destruct sympathetic nerves of renal arteries, which might be a promising way to reduce blood pressure for individuals with resistant hypertension. Several randomized clinical trials with unblinded designs showed remarkable effects of RDN on lowering blood pressure and few complications , 20. HowTraditional focused power ultrasound has limited use on adipose tissue in the abdominal cavity. In order to equip a focused power ultrasound dedicated to the intervention of perirenal fat, we designed and developed a novel machine that can be effectively and safely used for the modification of perirenal fat. This novel FPU machine has the strength of temperature monitoring of the target area and personalized output power according to the fat characteristics of the subjects to ensure that the target perirenal fat can be effectively and safely modified.To our knowledge, the present study is the first to use noninvasive FPU to intervene in perirenal fat to achieve the goal of reducing blood pressure for patients with essential hypertension. Our study is expected to provide a new treatment strategy to control high blood pressure. At the initial stage, we are exploring the efficacy of this new strategy for hypertensive patients on medication with mild to moderate elevated blood pressure. In the future, we will expand the population for adaption of this new therapy, such as new onset hypertensive patients, hypertensive patients without taking medications, and even refractory hypertensive patients.This paper is in accordance with the protocol . The study recruitment began on November 1, 2021, with 74 participants recruited by February 8, 2022, and is estimated to complete the study on September 30, 2023.


Although asthmatics may present reduced exercise capacity, data on their cardiovascular responses during exercise testing have been scarcely investigated. The aim of this pilot case-control study is to test: a) whether double product (DP), an index of cardiovascular reserve, differs among patients with severe and mild-moderate asthma, and b) whether DP is associated with asthma control level, physical activity (PA) and exercise capacity, in asthmatics population.A group of patients with severe asthma (group S) and a matched group of patients with mild-moderate asthma (group M) was studied. All participants completed asthma control and physical activity (IPAC) questionnaires, lung function measurements and six-minute walk test. The exercise capacity  and corresponding work), the Borg Dyspnea, the rating of perceived excursion and the average PA METS were recorded.vs. 18594.8±3984.4 mmHgXbpm; p=0.041) and was moderately associated with % predicted 6MWD . Group S patients were also presented with lower moderate intensity PA, compared to group M, while exercise capacity was similar between the groups. Asthma control level had no impact on exercise capacity nor PA parameters.A total of 18 patients were studied. DP at exercise end was significantly lower in group S, compared to group M (16412.2±4732.1 Patients with severe asthma may have impaired cardiovascular reserve as established by DP, even when exercise capacity is indifferent from patients with milder disease. As an easy-to-assess parameter, DP may offer further information in the functional evaluation of these patients. CharThe 6-minute walking test (6MWT) is a simple, easy to perform, well-tolerated and widely utilized test for evaluating physical capacity among patients with chronic respiratory or other disorders , 5. The Based on the aforementioned, the current study aims to investigate, for the first time: a) whether DP assessed at the end of 6MWT differs between patients with severe and mild/moderate asthma, and b) whether levels of asthma control, physical activity and exercise capacity are associated with exercise DP in asthmatic patients.22.1e.g., low dose ICS / long-acting beta agonist (LABA) and severe asthma was defined as asthma that required Step 4 or Step 5 treatment  to prevent it from becoming “uncontrolled, or asthma that remained “uncontrolled”, despite this treatment  depending on the normality of distribution, while categorical variables as % percentages. The predicted 6MWD was also calculated based on the equation: predicted 6MWD= 1.250 X height – 2.816 X age -39.07 X gender + 518.853  . The %pr33.11. Patients’ regular treatment were as follow: ICS/LABA (33.3%), ICS/LABA + long-acting muscarinic agonist (LAMA) (33.3%), ICS/LABA + monoclonal antibody (16.7%), ICS/LABA + leukotriene antagonist (11.1%) and leukotriene antagonist (5.6%). No patient received extra short-acting beta agonist (SABA) before visiting the clinic.Eighteen subjects  were included in the study. Ten subjects (age range 39-72 years old) presented with severe asthma (Group S) and the rest 8 gender- age- and BMI- matched patients (age range 40-78 years old) presented with mild-moderate asthma (Group M). The baseline characteristics of the study population are presented in Table 3.21, normal FVC and normal FEV1/FVC).Based on ACT, 61.1% of patients had good and 38.9% had poor asthma control. Of those with good asthma control, 63.6% had mild-moderate, while 36.4% had severe asthma, while among those with poor asthma control, 14.3% had mild-moderate, while 85.7% had severe asthma (p=0.04). Based on ACQ, 44.4% had good, 27.8% had poor asthma control, while another 27.8% were in an intermediate condition. Among patients with mild-moderate asthma most had well-controlled asthma (87.5% based on ACT and 62.5% based on ACQ) and normal spirometry (75%). In the S group, 40% according to ACT or 30% according to ACQ had controlled asthma, while no patient had normal spirometry  were complied to physical activity levels, as suggested by WHO for subjects >18 years old. Only three subjects presented high PA, 12 (66.7%) moderate PA and the rest 16.7% PA. Exercise capacity, Borg dyspnea, RPE score and double product are presented in Table 3.4vs. 16412.2±4732.1 mmHgXbpm; p=0.041), while BorgD was significantly higher (Table 3). Although total METs were similar between the groups, group S had significantly lower moderate intensity physical activity, compared to Group M. However, 6MWD (both absolute and %predicted), 6MWWork, ACT score, ACQ and RPE were similar between the groups (Table 2). Moreover, the values of HR during the 1st, 2nd and 3rd minutes of recovery between the groups were also similar. Table 3 presents the absolute and the %predicted values of HR at the end of 6MWT for each patient. In M group the HR% predicted was 62.7±11.3%, while in the S group it was 66.8±10.9% (p>0.05), indicating similar exercise intensity between the groups.Double-product at exercise end was significantly lower in Group S, compared to Group M .3.51).Double product at the end of 6MWT was significantly and positively correlated to 6MWD %predicted   and overall physical activity (assessed by IPAQ), were similar between the groups. To the author’s knowledge, this is the first study indicating that cardiovascular reserve may be decreased in subjects with severe disease, without evident impairment of exercise capacity.et al. indicated that Chronic Obstructive Pulmonary Disease (COPD) patients with dynamic hyperinflation have a poor cardiovascular response to exercise, compared to patients without dynamic hyperinflation, as indicated by lower DP [Both the variables that compose a double product, systolic blood pressure and heart rate, are predictors of disability in the general population , 22. Thelower DP . Reducedlower DP , has beelower DP . Reducedlower DP . In our et al. where exercise capacity and physical activity were separately assessed, these two measures were concomitantly decreased only in one-third of asthmatics; in most of the rest, there was a significant deviation between exercise tolerance as assessed by 6-minute walking distance (“can do”) and daily step count, as assessed by an accelerometer (“do do”) [et al., less than half of asthmatic male and female patients reached physical activity recommendations [Although exercise capacity assessed by 6-minute walking distance was similar between the groups, certain differences were noted in physical activity intensity, indicating that these two assessments cannot be used indiscriminately in asthmatics. In the study of Janssen “do do”) . Moreovendations , confirmndations , 33, in 1 values. Moreover, no minimum clinical important difference is reported for DP in literature, while no study power calculation was conducted; however, no outlier was noted regarding DP, and its measured values had a similar trend, so it is highly unlikely results regarding DP to have been different with a bigger sample size. Currently, the majority of published studies refer either to patients with cardiovascular disorders, or to healthy population; the only study that has been conducted in patients with a respiratory disorder, and can be compared to our study, is the one of Tzani et al. [vs IPAQ; however, this tool has been repeatedly used for the assessment of physical activity among subjects with chronic respiratory disorders [The current report has certain strengths and limitations. The overall number of patients is quite small, and this may be the reason why no group differences were noted in FVC and FEVi et al. , which iisorders , 35.In conclusion, these preliminary results indicate that patients with severe asthma may have impaired cardiovascular reserve as established by DP at the end of 6-minute walking test, for the first time. As DP is an easy to calculate index, its routine assessment in patients with respiratory disorders may provide further information regarding their functional capacity. Future studies are necessary to investigate the association between DP and maximum exercise capacity, as assessed by cardiopulmonary exercise testing and to reveal the potential impact of asthma severity and level of control on its values.


Progression was evaluated by estimating GFR (eGFR) and height-adjusted total kidney volume (htTKV). Fresh morning urine was collected to determine cAMP by the competitive radioligand assay. Urine EVs were isolated using an adapted centrifugation method and characterized by electron microscopy, dynamic light scanning, flow cytometry with FITC CD63 labeling, protein and RNA content, and AQP2 and GAPDH mRNA detection. Total and EV cAMP was measurable in both control and patient urine samples. Total cAMP was significantly correlated with eGFR and its annual change but inversely correlated with htTKV. The cAMP-EVs showed a bimodal pattern with htTKV, increasing to ~1 L/m and falling at larger sizes. Our results demonstrate that urine cAMP correlates with ADPKD progression markers, and that its extracellular delivery by EVs could reflect the architectural disturbances of the organ.ADPKD is the most common genetic renal disease, characterized by the presence of multiple cysts which, through slow and gradual growth, lead to glomerular filtration rate (GFR) decline and end-stage renal disease. Cystic growth is associated with increased intracellular levels of 3′,5′-cyclic adenosine monophosphate (cAMP). Extracellular vesicles (EVs) are proposed to participate in “remote sensing” by transporting different cargoes, but their relevance to ADPKD progression is poorly understood. This study aimed to determine whether cAMP is contained in urinary EVs and, if so, how total and/or EV cAMP contents participate in disease progression. Fourteen ADPKD patients, naïve for V Polycystic kidney disease (PKD) is characterized by fluid-filled cysts that compress the surrounding renal parenchyma and compromise renal function. Autosomal dominant PKD (ADPKD) is one of the most common genetic diseases, affecting 1 in 1000 adults worldwide and being the first genetic cause of kidney disease and the fourth of end-stage renal disease (ESRD). This pathology is characterized by multiple epithelial cysts that, through slow and gradual growth, lead to a large expansion of the total kidney volume (TKV). Fluid accumulation within the cysts and the proliferation of cystic cells are the two main mechanisms for this expansion. The primary sources of the fluid are both non-reabsorbed glomerular filtrate and transepithelial secretion across the monolayer cystic cell membrane, which result in net fluid and solute secretion into the cyst. The proliferation rate of cystic cells is only slightly higher than that of normal tubular cells but is sufficient to increase the organ size by ~5% per year . ConsidePKD1 or PKD2 genes reduced basal intracellular calcium levels. PKD1 encodes polycystin-1, a transmembrane mechano-sensor receptor, whereas PKD2 encodes polycystin-2, a non-selective cationic channel permeable to calcium. In the primary cilium, the polycystin-1 and -2 complex regulates cell calcium influx. Then, the complex disruption due to mutated proteins disturbs the calcium cellular homeostasis cAMP for PKA. The assay allows cAMP to be measured within a standard curve in the range of 0.05–25 pmol/mL within a quantitation limit of 0.1 pmol/mL. The cAMP content was expressed as nmol/g creatinine.The cAMP content was determined by a competitive binding assay to specific protein kinase (PKA) as described previously . Brieflyp-value below 0.05 was considered significantly different.The GraphPad Prism version 8.0.2 software package  was used for statistical procedures. The normality was tested by the Shapiro–Wilk test. As most of the quantitative variables were normally distributed, ANOVA or unpaired Student’s t-test (with Welch corrections if necessary) was used to assess the differences between the groups. The Pearson regression test was used to analyze the associations between urinary cAMP and progression parameters . A 2), enlarged kidneys (1.6 ± 0.3 L of TKV), and normal blood pressure , mostly (10/14 patients) due to renin–angiotensin–aldosterone system (RAAS) antagonism treatment. The main progression markers were related, and they represented the cohort’s disease evolution landscape. TKV grew exponentially as eGFR declined  were moderate CKD  or microalbuminuria (3.55 ± 2.25 mg/mmol Cr) were found.+ particles in two and four control and ADPKD samples, respectively (GAPDH and AQP2 genes was performed in control and ADPKD pooled (n = 2 each) samples of urine. As shown in AQP2 mRNA was detected, at least in control samples. Taken together, these results show that the pellets obtained in both control and ADPKD urine specimens could be considered EVs.The morphology and size characterization of FPCM from three control and four patient urine samples showed lipid-bilayer spheroids of 30–150 nm by EM and DLS A,B, wherectively C. ProteiTotal cAMP urinary content was measured by the radioligand method, and no differences were found between the control (n = 7) and patient (n = 14) groups A. Moreovp = 0.012 and 0.007; respectively)  A,B. In actively) C. = 0.998; p = NS). Kidney growth, expressed as a percentage of initial volume or mL/year, showed no relation to total cAMP, EV cAMP, and EV/total cAMP levels.Urine total cAMP was also related to htTKV since it decreased as the kidney grew A. Moreovp = 0.030), but treated patients showed a more advanced stage of the disease with lower eGFR  and higher htTKV .Blood pressure, albuminuria, and proteinuria showed no relationship with cAMP urine excretion. EV cAMP was higher in the RAAS antagonist-treated patients (angiotensin-converting enzyme inhibitors in eight and type 1 angiotensin receptor antagonists in two) than in untreated patients (4.98 ± 1.62 vs. 0.24 ± 0.13 nmol/g Cr, The present results demonstrate that cAMP urine excretion correlates with the main progression markers of ADPKD and indicate that the extracellular delivery of the second messenger by EVs could reflect the architectural disturbance of the organ. In ADPKD, intracellular cAMP has been implicated in all aspects of the disease, since stimulating mural epithelial cell proliferation and transepithelial fluid secretion promotes cyst enlargement ,25. The 2/AQP2 axis response to osmolality changes in CKD [Glomerular filtration rate and renal deterioration have already been associated with urine cAMP, mostly associated with concentration capacity alteration and/or vasopressin-receptor Vs in CKD ,29 and As in CKD ,31. Valus in CKD . DIPAK cs in CKD . On the s in CKD . This stThe correlation among eGFR, htTKV, and urinary cAMP may be related to the concept already described by other authors : althougAQP2 renal-specific mRNA content of isolated particles fulfill the current EV criteria [2 antagonist treatment-naïve patients and healthy subjects. It is well-recognized that microvesicles and exosomes have overlapping sizes but different origins and functions [An emerging body of evidence indicates that EVs—a common term used to describe exosomes, microvesicles, and apoptotic bodies—are promising candidates for non-invasive and accessible tools for diagnosis, monitoring, and even therapeutic purposes, but some concerns have been raised about the accessibility of the multiple available methods for clinical laboratories . Thus, wcriteria . Then, tunctions . The EVsNo data about cAMP in EVs from human or animal models of ADPKD were available, but an interesting study by Fonseca et al. showed that cAMP was found at higher levels in cystic than non-cystic mice , agreeinOn the assumption that the urine total amount is the sum of freely excreted and EV-vehiculized content, the latter could be related to the structural burden, since it increases with kidney volume, at least up to a certain level. It is well known that cystic endowment is the driving force of kidney growth ; hence, Overall, evidence stresses the key role of EVs as a mediator of these processes . Our resThis proposed process seems very attractive to explain and extend the current knowledge about the role of cAMP in ADPKD evolution, but the main results need confirmation in larger studies, and several uncertainties and questions need to be further addressed. It is mandatory to determine whether the observed cAMP-EV variations imply differences in the numbers of excreted EVs or are attributable to particle cAMP concentration, and to determine how total content continues decreasing at larger volumes. Some insight into the latter is available since direct efflux and influx of cyclic nucleotide transporters have been documented in the kidney ,45,46 an


Resistant hypertension, defined as blood pressure that remains above goal despite using three or more antihypertensive medications, including a diuretic, affects a significant proportion of the hypertensive population and is associated with increased cardiovascular morbidity and mortality. Despite the availability of a wide range of pharmacological therapies, achieving optimal blood pressure control in patients with resistant hypertension remains a significant challenge. However, recent advances in the field have identified several promising treatment options, including spironolactone, mineralocorticoid receptor antagonists, and renal denervation. In addition, personalized management approaches based on genetic and other biomarkers may offer new opportunities to tailor therapy and improve outcomes. This review aims to provide an overview of the current state of knowledge regarding managing resistant hypertension, including the epidemiology, pathophysiology, and clinical implications of the condition, as well as the latest developments in therapeutic strategies and future prospects. A coThe global burden of resistant hypertension is substantial, with an estimated 100–500 million people affected worldwide . The preAdditionally, certain racial and ethnic groups, such as African Americans and Hispanics, have a higher prevalence of resistant hypertension than others . ResistaThe economic burden of resistant hypertension is also substantial, with increased healthcare utilization and costs associated with this condition . IndividA recent systematic review found that 14.7% of individuals with high blood pressure experience apparent treatment-resistant hypertension, while only 10.3% have been diagnosed with actual resistant hypertension . Moreove2.2.1.Pseudo-resistant hypertension occurs when the blood pressure is elevated due to factors other than hypertension . This in2.2.True-resistant hypertension occurs when elevated blood pressure is due to a combination of factors, including genetic predisposition, lifestyle factors, medication nonadherence, and underlying medical conditions . True-re2.3.Refractory hypertension occurs when the blood pressure remains elevated despite optimal treatment with multiple antihypertensive medications and lifestyle modifications . Refract3.3.1.One of the primary causes of RH is nonadherence to medications. Compliance with medication schedules is essential for hypertension management, as it has been demonstrated to enhance clinical outcomes and decrease the likelihood of cardiovascular incidents . It can 3.2.Patients with hypertension often require multiple medications to manage their blood pressure effectively. The complexity of medication regimens can make it challenging for patients to adhere to their treatment plans. Patients may have difficulty keeping track of which medications they need to take and when, which can lead to missed doses and inconsistent blood pressure control. In addition, patients may experience confusion and frustration when they are prescribed multiple medications with different dosing schedules and instructions.A study conducted a study to investigate the association between medication regimen complexity and medication adherence in hypertensive patients, which revealed that patients prescribed more than three antihypertensive medications had lower adherence rates compared to those prescribed fewer medications . Poor meAntihypertensive medications can cause a range of side effects, including dizziness, fatigue, and sexual dysfunction. These side effects can impact patients' quality of life and lead to medication nonadherence. Patients may also experience side effects that they perceive as intolerable or unacceptable, which can cause them to discontinue their medication without consulting their healthcare provider. Another study found that side effects were the primary reason for medication nonadherence in up to 30% of patients. The authors recommended that healthcare providers discuss potential side effects with patients when prescribing antihypertensive medications and work with patients to manage any side effects that may occur . The cosPsychological factors such as depression, anxiety, and stress can also contribute to poor medication adherence in patients with hypertension , 33. Hea3.3.The renin-angiotensin-aldosterone system (RAAS) regulates blood pressure and fluid balance in the body. In hypertension, the RAAS can become dysregulated, leading to increased levels of angiotensin II (Ang II) and aldosterone, which can contribute to the development of resistant hypertension , 40. TheAnother factor that can contribute to RAAS activation in resistant hypertension is decreased nitric oxide availability . The dec3.4.Stress is a complex environmental factor that can have both acute and chronic effects on blood pressure regulation. Acute stressors, such as mental or physical stress, can lead to transient increases in blood pressure levels, while chronic stress can lead to sustained increases in blood pressure and the development of hypertension . Stress Air pollution, a growing environmental concern that has been shown to be associated with an increased risk of hypertension and cardiovascular disease –61. Air Sleep is a crucial component of overall health, and disruptions in sleep patterns have been linked to a variety of health issues, including hypertension. Chronic sleep deprivation and poor sleep quality have been shown to be associated with increased blood pressure levels and an increased risk of developing hypertension . Short sSleep disturbances can lead to increased sympathetic nervous system activity, which can increase blood pressure and contribute to the development of hypertension . Hyperte3.5.Genetic polymorphisms in the renin-angiotensin system have been associated with an increased risk of hypertension and resistance to antihypertensive medications , 68. OneStudies have found that the SLC4A5 gene, responsible for encoding a sodium bicarbonate transporter in the kidney, is associated with hypertension and salt sensitivity . CertainGenetic variants in the renin gene have been associated with increased renin activity and elevated blood pressure levels , 76. A mIn addition to specific genetic variants, epigenetic modifications can also affect the RAAS system and contribute to the development of resistant hypertension . Epigene3.6.The sympathetic nervous system plays a crucial role in regulating blood pressure and cardiovascular function through its effects on the vasculature, the heart, and the kidneys. Within the brain, the renin-angiotensin system (RAS) is viewed as the primary regulator of the sympathetic nervous system (SNS) . The sym3.7.Obesity is a common comorbidity in patients with resistant hypertension, and it is estimated that approximately 8% of individuals with resistant hypertension are obese . ObesityAcute hyperinsulinemia can cause blood vessel dilation by releasing nitric oxide, but this process is impaired in insulin-resistant individuals with obesity or hypertension . Also, iA cross-sectional study of 5,065 patients with hypertension, found that obesity was independently associated with the presence of resistant hypertension . Patient3.8.Most of the suggested theories for salt-induced high blood pressure involve impaired function in either the kidneys or the endocrine system, with a particular focus on the renin-angiotensin-aldosterone system (RAAS) , 102. AnSalt consumption is recognized to trigger an expansion in extracellular fluid volume, culminating in augmented blood volume and cardiac output, leading to elevated blood pressure and increased peripheral vascular resistance , 105.To reduce the risk of hypertension and resistant hypertension, American Heart Association recommends limiting salt intake to no more than 2,300 milligrams per day, and even lower  for individuals who are at higher risk of hypertension, such as those with diabetes, chronic kidney disease, or a family history of hypertension .3.9.Sleep apnea is a common condition characterized by recurrent episodes of partial or complete cessation of breathing during sleep. Sleep apnea is characterized by repetitive cessation of breathing during sleep, leading to intermittent hypoxia, sympathetic activation, and oxidative stress, which can contribute to the development and maintenance of hypertension .Several studies have shown that sleep apnea is associated with resistant hypertension. For example, a study found that 83% of patients with resistant hypertension had moderate to severe sleep apnea . AnotherIn obstructive sleep apnea (OSA) patients, cyclic intermittent hypoxia can trigger endothelial dysfunction and activate the renin-angiotensin and sympathetic systems . The rel4.The diagnosis of resistant hypertension requires careful evaluation to exclude secondary causes of hypertension and to optimize medication therapy. Recent research indicates that applying principles of chaos theory can provide new perspectives on this issue , 116. ThClinical inertia refers to the healthcare provider's inaction to escalate treatment when the desired blood pressure target is not achieved leading to inadequate medical treatment, resulting in uncontrolled hypertension . ClinicaWhite coat hypertension is another diagnostic challenge that clinicians may encounter when evaluating patients with resistant hypertension. White coat hypertension is defined as elevated BP in the clinic or office setting and normal BP on ambulatory or home monitoring –124. AccPseudo-resistant hypertension is a rare condition characterized by elevated BP despite the use of multiple antihypertensive medications, but it is not due to inadequate medication therapy or medication nonadherence . InsteadThe diagnosis of resistant hypertension requires a comprehensive evaluation to exclude secondary causes of hypertension and to optimize medication therapy. The American Heart Association (AHA). recommends a stepwise approach to the evaluation and treatment of patients with resistant hypertension .The AHA recommends the use of ambulatory monitoring or home BP monitoring to confirm the diagnosis of resistant hypertension and to monitor BP control . AmbulatThe appropriate diagnostic tests, such as polysomnography, aldosterone-renin ratio, or renal artery imaging, should be used to confirm the diagnosis and to guide treatment .5.5.1.Resistant hypertension is a challenging condition to manage, and it often requires a combination of pharmacological and lifestyle interventions. While pharmacological treatments are effective in controlling blood pressure in most patients, some patients may not achieve adequate blood pressure control despite multiple medications. Lifestyle changes, such as adopting a healthy diet, increasing physical activity, and reducing stress, can play a critical role in managing resistant hypertension . The AHAAccording to the TRIUMPH trial, lifestyle modifications, including weight loss, physical activity, and dietary changes, were associated with a significant reduction in blood pressure among patients with resistant hypertension . The stuThere is a growing body of evidence supporting the role of lifestyle changes in managing resistant hypertension. For example, a meta-analysis found that lifestyle interventions, including weight loss, reduced sodium intake, and increased physical activity, were effective in reducing blood pressure levels in patients with resistant hypertension. The study also highlighted the importance of individualized lifestyle interventions tailored to each patient's unique needs and circumstances .Regular physical activity can improve cardiovascular health by reducing inflammation and improving lipid profiles . A healtRegular physical activity has been found to have a beneficial effect on blood pressure control and can be an effective non-pharmacological intervention in managing resistant hypertension. Several studies have shown that exercise, both aerobic and resistance training, can lead to reductions in both systolic and diastolic blood pressure in patients with resistant hypertension , 141.One study found that a combination of aerobic and resistance exercise performed three times per week for 12 weeks resulted in significant reductions in systolic and diastolic blood pressure by possibly changing the vascular responses in patients with resistant hypertension .5.2.Pharmacological interventions for resistant hypertension have been the subject of intense research, with several classes of drugs showing promise in lowering blood pressure in these patients. One class of drugs that has garnered considerable attention in recent years is mineralocorticoid receptor antagonists (MRAs). MRAs, such as spironolactone and eplerenone, have been shown to reduce blood pressure in patients with resistant hypertension, with spironolactone being the most extensively studied in this population. MRAs have been found to reduce mortality in patients with heart failure with reduced ejection fraction (HFrEF)  and are A sequential monotherapy approach that targets multiple physiological pathways is utilized for optimizing blood pressure control by identifying the most effective antihypertensive agents for individual patients . This ap5.3.Although non-pharmacological and pharmacological interventions are the mainstay of treatment, some patients may not achieve adequate blood pressure control despite these interventions. In such cases, surgical intervention may be considered. Renal denervation (RDN) is a minimally invasive surgical intervention that has emerged as a potential treatment option for resistant hypertension. The procedure involves the use of radiofrequency energy to disrupt the renal sympathetic nerve fibers, leading to a reduction in sympathetic nervous system activity and subsequent blood pressure reduction . SeveralDespite these conflicting results, a recent meta-analysis has suggested that RDN may be effective in reducing blood pressure in patients with resistant hypertension. The meta-analysis of 11 controlled studies on renal denervation (RDN) in resistant hypertension found that RDN significantly reduced systolic and diastolic blood pressure respectively . The anaTranscranial direct current stimulation (tDCS)  is an emTranscranial magnetic stimulation (TMS) utilizes electromagnetic induction to produce a magnetic field capable of traversing the skull and accessing the brain . Consequ6.Resistant hypertension is a serious condition that can lead to various complications, including organ damage. The failure to control blood pressure can lead to various complications and hazards, including increased risk of cardiovascular disease, stroke, kidney damage, and other related health issues , 174.6.1.Resistant hypertension is associated with an increased risk of cardiovascular disease, including stroke, heart attack, and heart failure. Patients with resistant hypertension have a significantly higher risk of stroke compared to patients with controlled hypertension which may be due to the increased risk of stroke may be due to the greater severity of hypertension and the presence of other cardiovascular risk factors in patients with resistant hypertension , 175.6.2.2 and proteinuria, are significant predictors of resistant hypertension (RHT)  below 60 ml/min/1.73 mon (RHT) , 173. Thon (RHT) .6.3.Adverse drug events (ADEs) may occur in patients with resistant hypertension who are on multiple antihypertensive medications, ranging from mild symptoms such as dizziness and fatigue to more severe complications such as hypotension, electrolyte imbalances like hyperkalemia, renal dysfunction, acute kidney injury (AKI), and orthostatic or diastolic hypotension . The ris6.4.Resistant hypertension can have a significant impact on a patient's quality of life. The need for multiple medications and frequent adjustments can lead to medication side effects, increased healthcare costs, and reduced ability to engage in physical activity. Patients may also experience increased anxiety and depression related to the difficulty of managing their condition. Additionally, the burden of monitoring and managing their blood pressure can lead to decreased social interactions and a reduced sense of control over their health. A study found that patients with hypertension had lower health-related quality of life (HrQoL) compared to those without hypertension . Reducti7.This review has examined the current state of knowledge regarding resistant hypertension, with a focus on the epidemiology, pathophysiology, diagnosis, and management of this condition. We have discussed the various definitions of resistant hypertension and the prevalence and risk factors associated with this condition. We have also explored the underlying mechanisms involved in resistant hypertension, including alterations in the renin-angiotensin-aldosterone system, sympathetic nervous system activation, and endothelial dysfunction. Diagnosis of resistant hypertension involves careful evaluation of patients’ medication regimens, as well as identification and management of contributing factors such as obesity, sleep apnea, and secondary causes of hypertension. We have also reviewed the various pharmacological and non-pharmacological interventions that can be used to manage resistant hypertension, including lifestyle modifications, medication adjustments, renal denervation, and other emerging therapies.Resistant hypertension remains a significant clinical challenge, and research efforts should continue to explore new approaches to its management. One potential avenue for future research is the use of novel pharmacologic agents or combinations of existing drugs to improve blood pressure control. For example, new classes of drugs targeting the renin-angiotensin-aldosterone system or the sympathetic nervous system are currently in development and may prove effective in treating resistant hypertension.Another area of potential investigation is the use of non-invasive neuromodulation techniques, such as transcranial magnetic stimulation (TMS) or transcranial direct current stimulation (tDCS). These approaches have shown promise in animal studies as well as small sample human studies and may provide a non-pharmacologic alternative with fewer complications like infections and reduced recovery time, for patients with resistant hypertension. When traditional treatments fail to achieve desired results, non-invasive techniques such as transcranial direct current stimulation (tDCS) and transcranial magnetic stimulation (TMS) provide an alternative course of action by selectively modulating the autonomic nervous system to regulate and reduce blood pressure. By taking advantage of TMS' ability to inhibit sympathetic outflow from distinct parts of the brain—resulting in minimal systemic side effects commonly seen with conventional anti-hypertension medications—it might be possible to lower patients' blood pressures more effectively. These minimally invasive techniques offers a more cost-effective and safer option compared to other invasive interventions available today since it does not require any medication or surgery. Incorporating these techniques into clinical practice necessitates the development of consistent protocols, the selection of suitable patients, and the identification of biomarkers or neuroimaging techniques to anticipate treatment response. Precision medicine approaches could aid in customizing minimally invasive interventions for individual patients, resulting in improved outcomes. The use of innovative approaches, such as machine learning and artificial intelligence, may also offer new opportunities for improving the diagnosis and management of resistant hypertension.Finally, advances in precision medicine may also offer new opportunities for personalized management of resistant hypertension. By using genetic and other biomarkers to identify patients who are most likely to respond to specific treatments, clinicians may be able to tailor therapy and achieve better outcomes. Another potential application of precision medicine in resistant hypertension is the use of digital health technologies to monitor blood pressure and other physiological parameters in real time. Wearable devices and mobile applications could be used to collect data on blood pressure, heart rate, physical activity, and other relevant factors, which could then be analyzed to identify patterns and predict the risk of complications . This inMeanwhile, healthcare providers must remain vigilant in identifying patients with resistant hypertension and implementing appropriate interventions to reduce cardiovascular risk. Further research is needed to advance our understanding of this condition and to identify new and innovative approaches for its management. Through continued research and collaboration, we can work towards improved outcomes and better health for patients with resistant hypertension.


Chronic kidney disease (CKD) is a modern epidemic worldwide. Introducing renin–angiotensin system (RAS) inhibitors  not only as blood-pressure-lowering agents, but also as nephroprotective drugs with antiproteinuric potential was a milestone in the therapy of CKD. For decades, this treatment remained the only proven strategy to slow down CKD progression. This situation changed some years ago primarily due to the introduction of drugs designed to treat diabetes that turned into nephroprotective strategies not only in diabetic kidney disease, but also in CKD unrelated to diabetes. In addition, several drugs emerged that precisely target the pathogenetic mechanisms of particular kidney diseases. Finally, the role of metabolic acidosis in CKD progression (and not only the sequelae of CKD) came to light. In this review, we aim to comprehensively discuss all relevant therapies that slow down the progression of non-diabetic kidney disease, including the lowering of blood pressure, through the nephroprotective effects of ACEi/ARB and spironolactone independent from BP lowering, as well as the role of sodium–glucose co-transporter type 2 inhibitors, acidosis correction and disease-specific treatment strategies. We also briefly address the therapies that attempt to slow down the progression of CKD, which did not confirm this effect. We are convinced that our in-depth review with practical statements on multiple aspects of treatment offered to non-diabetic CKD fills the existing gap in the available literature. We believe that it may help clinicians who take care of CKD patients in their practice. Finally, we propose the strategy that should be implemented in most non-diabetic CKD patients to prevent disease progression. Chronic kidney disease (CKD) is defined as a reduced glomerular filtration rate (eGFR), increased urinary albumin excretion, or both, and is an increasing public health issue ,2. Its gCKD prevalence rates differ across regions. For example, the prevalence of CKD in the United States is approximately 14%; in Asia, it is estimated to be between 8% and 16%, while in Europe, about 12% . For exaIn Poland, it is estimated that 4.2 million individuals suffered from CKD in 2020, with 90% being unaware of their condition . At leasThese growing trends can be noticed in different countries. Based on an analysis of Medicare data in the United States, the prevalence of diagnosed CKD has steadily risen annually across all stages of CKD. Medicare spending on CKD and end-stage renal disease (ESRD) patients exceeded USD 120 billion in 2017 alone .The globalization of the CKD problem is inextricably linked to the epidemic of other lifestyle diseases, such as obesity, diabetes mellitus, cardiovascular diseases, and hypertension . Type 2 Additionally, sodium–glucose co-transporter type 2 inhibitors (SGLT2i) have recently emerged as promising new therapeutic options. These agents reduce the renal workload by decreasing sodium reabsorption, leading to a reduction in blood pressure and albuminuria, which are both associated with CKD progression. Nowadays, it is evident that the combination of RAA axis inhibitors and SGLT2i have additive and synergistic effects in reducing cardiovascular risk in CKD patients. Optimal blood pressure control and the correction of metabolic acidosis are crucial for preserving kidney function.In addition to these general strategies, other diseases/diagnosis-specific nephroprotection therapies are essential in conditions such as autosomal-dominant polycystic kidney disease (ADPKD) and Fabry disease. Nowadays, disease-modifying treatment, e.g., an arginine vasopressin V2 receptor antagonist or enzyme replacement therapy with recombinant alpha-galactosidase A, has also been available in daily nephrological practice.In the face of new nephroprotective therapies, the asymptomatic course of the early stages of CKD requires systemic actions towards mandatory preventive examinations, especially in risk groups. The benefits of this go beyond treatment, which can slow or even stop the progression of CKD. This could help to reduce cardiovascular risk and healthcare costs.To address the challenges of CKD management, it is essential to update and widely disseminate evidence-based recommendations for the diagnosis and treatment of CKD. Implementing these recommendations in clinical practice can help improve outcomes in CKD patients, reduce the burden of cardiovascular disease, and slow the progression of CKD. Faced with these objectives, the Polish Society of Nephrology has prepared a position statement for nephroprotection in non-diabetic CKD patients. The guidelines aim to provide optimal nephroprotection use and to emphasize the importance of the early detection and management of CKD. They will help clinicians make treatment decisions and ensure that patients receive the best care to prevent or delay the progression to ESRD. Although the precise definition of pharmacological nephroprotection is not universally accepted, in our opinion, these include the pharmacological interventions aimed at the preservation of or increase  in the glomerular filtration rate and at the attenuation of other indices of renal damage .Statement 2.1. We suggest that adults with CKD and high blood pressure (BP) should be treated at a target office BP like in the general population—at least 130–139/70–79 mmHg  and perhaps lower (120–129/70–79 mmHg) in most CKD patients  [expert opinion].Statement 2.2. Antihypertensive drugs should be started in most CKD patients with hypertension without unnecessary delay, together with lifestyle modifications [expert opinion].Statement 2.3. We suggest using renin–angiotensin system inhibitors (RASi) (angiotensin-converting enzyme inhibitor (ACEi) or angiotensin II receptor blocker (ARB)) as a first line of antihypertensive therapy in people with high BP and CKD [expert opinion], and recommend ACEi or ARB in those with increased albuminuria (A2 (2C) and A3 (1B)). We suggest monitoring serum potassium and creatinine concentrations during ACEi or ARB therapy .2, thiazide or thiazide-like diuretics should be used; in patients with eGFR ≤ 30 mL/min/1.73 m2, chlorthalidone or loop diuretics should be used (1B). We suggest monitoring serum sodium and potassium concentrations in patients treated with thiazide diuretics (including hydrochlorothiazide), thiazide-like diuretics , and loop diuretics (including furosemide and torsemide) [expert opinion].Statement 2.4. Combined antihypertensive therapy should be used in most hypertensive CKD patients. We suggest adding a dihydropyridine calcium channel blocker (CCB) and/or a diuretic (1B). In patients with eGFR > 30 mL/min/1.73 mStatement 2.5. We suggest adding steroid mineralocorticoid antagonist (MRA)—spironolactone in patients with resistant hypertension and no tendency to hyperkalemia . In patients treated with spironolactone, serum potassium concentrations should be monitored (2D). In patients with hyperkaliemia or other contraindications to spironolactone, other antihypertensive drugs should be added to achieve the target BP: doxazosin, post-synaptic α1-receptor antagonists, clonidine, central presynaptic α1-receptor agonists, moxonidin, I1-imidazoline receptor agonist, or β-adrenergic antagonist  [expert opinion].Comment on Statement 2.12, the prevalence of hypertension exceeds >80% and reaches almost 100% in advanced CKD  .Statement 3.1.5. If serum creatinine concentration increases less than 30% of the baseline after initiating ACEi or ARB or increasing their doses, we suggest continuing an ACEi or ARB. In the case of an increase of more than 30%, we suggest discontinuation of ACEi or ARB and evaluation for renal artery stenosis [expert opinion].Statement 3.1.6. In case of hyperkalemia (5.0–5.5 mmol/L) after initiating ACEi or ARB or increasing their doses, we suggest using methods that reduce the serum potassium level . In case of hyperkalemia (>5.5 mmol/L) after initiating ACEi or ARB or increasing their doses, we suggest the discontinuation of these agents, further monitoring of serum potassium, and the possible resumption of ACEi or ARB treatment at a lower dose in combination with measures to lower serum potassium [expert opinion].Statement 3.2. We suggest using a pharmacological blockade of the RAS (ACEi or ARB) (if not contraindicated) in patients with non-diabetic CKD  (2C) and CKD  (2D).Statement 3.3. We recommend not stopping ACEi or ARB in advanced CKD (G4–G5) to increase the glomerular filtration rate or slow its decline (1B).Statement 3.3.1. Dosing or discontinuing ACEi or ARB in symptomatic hypotension or uncontrolled hyperkalemia despite medical treatment should be considered [expert opinion].Statement 3.4. We recommend not using a combination of ACEi and ARB (1A).Statement 3.5. We suggest using a combination of ACEi or ARB and MRA—spironolactone  in patients with non-diabetic CKD (A2–A3) with persistent albuminuria despite the use of ACEi or ARB. Such treatment should be carried out with frequent monitoring of serum potassium concentration (2D).Comment on Statement 3.12 and proteinuria of 3 g/24 h (REIN-Stratum 2), the treatment was stopped early due to the efficacy of ramipril (5 mg daily) in slowing GFR decline. The monthly decrease in GFR was significantly lower in the ramipril group (0.53 mL/min) than in the placebo group . The composite of doubling of the serum creatinine or ESKD was reached in 18 versus 40 participants  . In some etiologies of CKD, the safety and efficacy of SGLT2i therapy remain unknown (1A).Statement 4.4. We recommend adding SGLT2i to ACEi or ARB as the first-line nephroprotective agent whenever possible, especially in patients with increased albuminuria (1A). In case of contraindications or intolerance to ACEi/ARB, using these drugs is not a prerequisite to starting SGLT2i therapy (2B).Statement 4.5. There is no clear evidence to recommend the additional measurements of serum creatinine concentration, eGFR, and serum sodium and potassium concentration after the commencement of treatment with SGLT2i; the monitoring of these parameters should follow standard guidelines [expert opinion].Comment on Statement 4.12, and only 11% had eGFR ≥ 60 mL/min/1.73 m2. Seventy-five percent were in CKD stage 3, and the remaining 14% were in CKD stage 4. Median UACR (965 and 934 mg/g) and the percentage of patients with UACR >1000 mg/h (48.7 and 47.9% in dapagliflozin-treated and placebo groups) pointed to a high risk of CKD progression. The DAPA-CKD trial investigators carefully analyzed the underlying etiology of CKD: in 16% of patients, CKD was attributed to ischemic/hypertensive nephropathy; in 6.3%, IgA nephropathy (IgAN); and in another 2.7%, focal/segmental glomerulosclerosis (FSGS). All glomerulopathies were confirmed based on the kidney biopsy results. Interestingly, although more than 67% of the trial patients had type 2 diabetes (T2D), only 58.3% of CKD was attributed to diabetic kidney disease (DKD) (leaving a relatively high number of T2D patients with other kidney diseases identified) .Statement 7.3. Based on the available information, no specific anti-oxidative and anti-inflammatory therapies are recommended for nephroprotection (2C).Comment on Statement 7.1Renal anemia caused by a relative deficiency of renal erythropoietin production and impairment of iron metabolism affects almost all patients reaching advanced and end-stage CKD . Anemia To better understand the potential nephroprotective effect of ESA in renal patients, a meta-analysis of 32 controlled clinical trials was performed . The autComment on Statement 7.2Chronic kidney disease–mineral bone disorder (CKD-MBD) is a term recommended by the KDIGO group of experts to define a broad range of systemic disorders of mineral and bone metabolism caused by CKD. Both the severity and rate of progression of CKD-MBD show a strong association with the increased risk for cardiovascular events, mortality, and progression of CKD to end-stage kidney disease . SeveralParathyroid hormone has been known as a non-classical uremic toxin, and its increased levels may be both cardio- and nephrotoxic ,179. PTHHyperphosphatemia is another common late consequence of CKD, and high serum phosphate levels were tightly linked to increased cardiovascular complications and mortality in cross-sectional and observational studies . TherefoComment on Statement 7.3Oxidative stress, which is defined as a pro-/antioxidant disbalance, is harmful to kidney cells, which are highly metabolically active. Increased oxidative stress has been well demonstrated in various kidney diseases due to a depletion of antioxidants and increased reactive oxygen species generation ,189. ThiChronic kidney disease (CKD) is a condition in which the kidneys are damaged and cannot filter blood as well as they should. CKD is recognized as a global health problem with a prevalence of one in six adults. CKD has a progressive course and is associated with a significantly increased risk of premature death, mainly due to cardiovascular events . Due to non-specific symptoms, more than nine out of ten people with chronic kidney disease are unaware of their kidney disease. Type 2 diabetes is the main risk factor for CKD, followed by arterial hypertension. Primary kidney diseases such as glomerulopathies or inherited diseases such as polycystic kidney disease are much less common causes of CKD. Although chronic kidney disease leads to irreversible kidney damage, it can be prevented by taking appropriate protective measures before kidney damage occurs or by slowing down its progression if the disease has already been diagnosed. These measures constitute so-called nephroprotection. Nephroprotective strategies include both lifestyle modification and pharmacotherapy. Lifestyle modification is a set of individually developed non-pharmacological activities aimed at introducing a healthy diet, weight control, increasing physical activity and avoiding alcohol abuse and smoking. Pharmacotherapy for nephroprotection mainly involves tight control of blood pressure, plasma lipids, and, in diabetic patients, the use of antidiabetic drugs. In addition to these general recommendations, some kidney diseases, such as autosomal-dominant polycystic kidney disease and Fabry disease, require specific nephroprotective measures, such as the use of an arginine vasopressin V2 receptor antagonist or a recombinant enzyme to replace its deficiency, respectively.Due to the very low awareness of the detrimental health consequences of CKD, it is important to intensively promote evidence-based recommendations for the diagnosis and treatment of CKD among both healthcare professionals and patients with CKD or those at increased risk of this disease. In particular, there is demand for clinical practice-oriented recommendations for renal diseases not caused by diabetes where new studies have recently brought significant progress in management strategies, adding new classes of drugs to nephroprotective regimens like sodium glucose cotransporter type 2 inhibitors, also known as flozins. This new class of previously solely oral antidiabetic drugs has already shown its nephroprotective efficacy and safety in non-diabetic kidney disease. Therefore, the Polish Society of Nephrology has prepared a position paper on nephroprotective therapy in patients with CKD without diabetes. These guidelines help select the optimal nephroprotection approach and also emphasize the importance of the early detection and treatment of CKD.We started working on this statement as there is a gap between current guidelines and practice. The authors of this statement follow the steps of colleagues, cardiologists, and diabetologists, who develop and frequently update their pivotal guidelines and recommendations. As has been stated in recent guidelines issued by the European Society of Hypertension, the European Society of Cardiology, and the joint initiative of the American Diabetes Association and European Association of the Study of Diabetes, patients with hypertension, heart failure, and diabetes should be treated aggressively immediately after their respective diagnoses have been established ,191,192.


Acute kidney injury (AKI) is a frequent complication of cardiac surgery that poses significant risks for both the development of chronic kidney diseases and mortality. Our previous study illustrated that heightened expression levels of faecal and plasma indole metabolites before the operation were associated with ischemic AKI. In this study, we aimed to validate the supposition that plasma indole-3-aldehyde (I3A) could serve as a predictive biomarker for AKI in patients undergoing cardiac surgery.This statistical reanalysis utilized AKI metabolomic data from patients scheduled for cardiac surgery between April 2022 and July 2022 in two tertiary hospitals. Faecal and blood samples were prospectively collected before surgery within 24 h, and variables related to the preoperative, intraoperative, and postoperative periods were recorded. AKI diagnosis was based on the Kidney Disease Improving Global Outcomes criteria.In this study, 55 patients who underwent cardiac surgery were analyzed, and 27 of them (49.1%) developed postoperative AKI. Before surgery, these patients had significantly higher levels of faecal indole metabolites, including skatole, trans-3-indoleacrylic acid, and 5-methoxyindoleacetic acid. The plasma I3A, clinical model that considered perioperative and intraoperative variables, and their combination had area under the receiver operating characteristic curve (ROC) values of 0.79 (95% CI 0.67–0.91), 0.78 (95% CI 0.66–0.90), and 0.84 (95% CI 0.74–0.94) for predicting AKI, respectively. Furthermore, by utilizing net reclassification improvement and integrated discrimination improvement, plasma I3A showed significant improvements in risk reclassification compared to the clinical model alone.The dysregulation of gut microbiota metabolism in patients scheduled for cardiac surgery can result in an increase in indoles from tryptophan metabolism, which may be associated with postoperative acute kidney injury (AKI). This suggests that indoles may serve as a predictive biomarker for AKI in patients undergoing cardiac surgery.The online version contains supplementary material available at 10.1186/s12871-023-02330-7. Millions of cardiac surgeries are performed annually throughout the world. The incidence of acute kidney injury (AKI) in patients undergoing cardiac surgery is high, ranging from 25 to 51% , the provia the gut microbiota, which play crucial roles in the kidney system by activating the aryl hydrocarbon receptor (AHR) signaling pathway [The gut microbiota plays an important role in the production of numerous compounds, influencing the host and the pathophysiological processes of a variety of diseases , 14, suc pathway . A recen pathway . HoweverIn our previous study , we emplThis prospective observational study was approved by the Ethics Committee of Maoming People’s Hospital (No. PJ2020MI-021-01) and conducted according to the Declaration of Helsinki at the Guangdong Provincial People’s Hospital and Maoming People’s Hospital. The study protocol complied faithfully with the Strengthening the Reporting of Observational Studies in Epidemiology . All parThe occurrence of AKI based on Kidney Disease Improving Global Outcomes (KDIGO) criteria within 1 week of the cardiac surgery was defined as the main outcome . As UO cOnce the patients were accepted to the cardiovascular surgical department, their clinical data were collected. Preoperative variables, including demographics , preexisting diseases , preoperative characteristics  were recorded. Moreover, the preoperative baseline sCr was considered a preoperative renal function. Intraoperative data containing cardiopulmonary bypass time, operation time and blood loss were noted. The postoperative Acute Physiology and Chronic Health Evaluation (APACHE) II score, which was used to estimate the overall condition of a patient, was evaluated immediately after recovery from anaesthesia. The prognosis variables were also documented, which comprised the length of ICU and hospital stay. For the baseline sCr, we used the sCr at the time of hospital admission, the last available sCr within the last 3 months, or an estimated sCr as per the KDIGO guideline in patients with no prior information about their prior kidney function .t-test was conducted for normally distributed data (presented as mean and standard deviation), while the Wilcoxon–Mann–Whitney U-test was used for skewed distributed data (presented as the median and interquartile range). Descriptive statistics for categorical variables were reported as frequency (percentage) and were compared using the Pearson χ2 test or Fisher’s exact test, as deemed appropriate. Using Fisher’s exact test or the Wilcoxon rank-sum test, the patient characteristics between AKI and Non-AKI were compared. The difference of the average of log2 peak areas concerning faecal indole metabolites or the concentrations of plasma I3A between the groups was calculated by Student’s t-test. Using simple logistic regression (SLR) models, the predictive performance of biomarkers was assessed. The SLR results were presented by the area under the receiver operating characteristic (ROC) curves (AUCs) and the corresponding 95% confidence intervals (CIs).The Shapiro–Wilk test was applied for continuous variables to determine the normal distribution. Student’s We calculated the C-index to assess the accuracy of predicting AKI and net reclassification improvement (NRI) and integrated discrimination improvement (IDI) to detect whether predicting accuracy could improve after the addition of plasma I3A into a baseline model with established risk factors. The established risk factors and clinical model were as follows: age, APACHE II score, haemoglobin and cardiopulmonary bypass time. The C-index was defined as the ROC between individual predictive probabilities for AKI and the incidence of AKI, and it was compared with both the baseline model (established risk factors only) and the enriched models (baseline model plus I3A). The NRI acted as a relative indicator of how many patients showed an improvement in the predicted probability of AKI, whereas the IDI indicated the average improvement in the predicted probability of AKI after adding the variables into the baseline model.The statistical analysis was conducted with Python 3.9 using the SciPy 1.9.3 module, fundamental algorithms for scientific computing in python , and visA total of 55 patients with cardiac surgery were enrolled in the study after obtaining their written informed consent before the cardiac surgery, which included 47 patients from the Guangdong Provincial People’s Hospital and 8 patients from the Maoming People’s Hospital. The faecal and plasma samples were collected before cardiac surgery. With reference to the 2012 KDIGO clinical practise guideline, 27 patients (49.1%) were defined as AKI patients based on sCr elevation, and the other 28 Non-AKI patients served as the control. The basic information of patients, including age, gender, preoperative indicators and intraoperative indicators, is presented in Table P = 0.6978).The faecal samples were analysed through untargeted metabolomics by high-resolution mass spectrometry, and all metabolites were annotated with five confidence levels as reported previously , 28. In P value of the boxplot was equal to 0.001  were upregulated in the AKI group vs. the Non-AKI group. Using the abovementioned 3 differential indole metabolites, the 001 Fig. A, and th001 Fig. B.The plasma samples were analysed by Metabolite Array using tandem mass spectrometry, which comprised amino acid, benzenoid, bile acid, carbohydrate, carnitine, fatty acid, indole, nucleoside, organic acid and phenylpropanoic acid. After univariate analysis, one indole metabolite I3A) was screened out between the AKI and Non-AKI groups. Using a boxplot, Fig. A was scrThis is the first study to demonstrate that the elevation of plasma I3A is an independent predictor for patients with cardiac surgery associated-AKI. The present results indicates that plasma I3A is a moderate predictor for AKI in patients undergoing cardiac surgery, which demonstrated almost a consistent performance (AUC = 0.79) with the clinical model (AUC = 0.78) in predicting AKI. The clinical model was developed using multivariable logistic regression analysis and ultimately incorporated age, APACHE II score, pre-surgery hemoglobin levels, and cardiopulmonary bypass time.P < 0.05). Thus, preoperative plasma I3A can be considered an independent predictor for cardiac surgery-associated-AKI, which may aid in the identification of patients in whom preventive treatment strategies can be effective [As demonstrated by the AUCs, the addition of plasma I3A to the clinical model could further increase the area of AUC from 0.78  to 0.87 . When measured by category-free NRI  and IDI , the risk reclassification was markedly improved by adding plasma I3A to the clinical model  were excluded. Another possible contributory factor could be the limitation of creatinine in accurately reflecting the true renal function reserve, as it is influenced by variables such as muscle mass and protein intake, which can impact its reliability as a measure of renal function. Moreover, the elevated creatinine in the AKI group may be attributed to older age, as also indicated in Table APACHE II score was also a predictor in the clinical model free of the collinearity with creatine prior to surgery, which can be attributed to several factors. Firstly, these variables serve different purposes and capture different aspects of evaluation. Secondly, the utilization of distinct measurement methods for APACHE II score and creatinine may have diminished their correlation. Lastly, rigorous data preprocessing techniques and consideration of sample characteristics likely mitigated the potential presence of collinearity. In addition, it should be noted that the relatively small sample size in our study may introduce some variability in blood creatine levels. To address this potential imbalance between the groups, we are planning to conduct a prospective study with a significantly larger sample size. This will allow for more robust and reliable conclusions by minimizing the effects of any observed discrepancies.Plasma I3A demonstrated the ability to discriminate subgroup, suggesting that it may detect kidney injury earlier than creatinine. It is worth noting that plasma indole metabolites have been shown to be correlated with CKD , 31 and P > 0.05), which indicated that we should continue to expand the samples and conduct a multi-centre prospective study to further verify the improvement of I3A to AUC.As for AUCs, both plasma I3A and clinical mode demonstrated fair prediction ability owing to their AUC values of 0.7–0.8, while the combination displayed good ability owing to the AUC value of 0.8–0.9 , 32. In via the gut microbiota [As an important metabolite of tryptophan, indole compounds are under the direct or indirect control of the gut microbiota, which is involved in microbiota-host crosstalk across health and disease sectors . I3A, prcrobiota , can actcrobiota . As molecrobiota . Therefocrobiota .Our study offers several strengths. First, we measured the performance of plasma I3A preoperatively in patients undergoing cardiac surgery. Consequently, as the time nodes of initial injury in the kidney were accurate, the variations among patients due to the individual differences in preexisting but unclear initial kidney injury and the underlying comorbidities could be reduced. Second, the samples were prospectively gathered at different centres; therefore, the accuracy of internal verifiability could be improved. Third, the early detection of plasma I3A can facilitate clinicians to recognise patients at a high risk of developing postoperative AKI for the initiation of efficient intervention in a timely manner. Indeed, the performance of plasma I3A was not satisfactory in AUC. However, this study was the pilot exploratory research. We plan to further improve the experimental design to increase AUC, NRI and IDI in the subsequent confirmatory experiments.Nevertheless, this study has several limitations. First, as UO was not used in the diagnosis of AKI, it may have led to the omission of a portion of the incidence of AKI . HoweverThe dysregulation of gut microbiota metabolism in patients scheduled for cardiac surgery can result in an increase in indoles from tryptophan metabolism, which may be associated with postoperative acute kidney injury (AKI). This suggests that indoles may serve as a predictive biomarker for AKI in patients undergoing cardiac surgery.Below is the link to the electronic supplementary material.Supplementary Material 1


Concerns about nephrotoxicity from chemotherapy play a key role in treatment selection for urothelial cancer.The link between kidney disease and cancer is complex. AKI and CKD are more common in patients with cancer, and kidney disease often affects treatment selection for patients with cancer.Kidney360, Cote et al., describe a single-center experience with the treatment of metastatic urothelial carcinoma (mUC). Cisplatin-based chemotherapy is considered the first-line treatment of mUC. Patients with kidney disease are frequently deemed ineligible for cisplatin because of kidney disease. In this retrospective study, the authors compared outcomes for patients with mUC treated with standard-dose gemcitabine-cisplatin, split-dose cisplatin, and a noncisplatin-based regimen.3 There was no difference in the occurrence of AKI among the three groups.3 When AKI occurred, it was most commonly mild . Patients who did not receive full-dose cisplatin had a lower eGFR than those who received standard therapy, and lower kidney function was a frequent reason for not receiving standard therapy. Unfortunately, patients who did not receive the standard regimen had significantly worse survival compared with those who did receive standard treatment.3 This study has various limitations as noted by the authors. It was a retrospective study, and there is a risk of selection bias, and the unaccounted confounders, such as patient comorbidities or poorer functional status, associated with CKD may have affected treatment selection and results. The overall sample size was small. Few patients had laboratory values available to assess long-term kidney function. There was no information available on concurrent exposure to other medications.In this issue of et al., to describe the systematic withholding of indicated, potentially beneficial studies and interventions from patients on the basis of coexisting kidney disease.4 This was initially described in the context of cardiovascular disease, specifically decreased rates of coronary angiography after myocardial infarction for elderly (age 65–89 years) patients with kidney disease compared with those with normal kidney function.4 Similarly, patients with kidney disease are less likely to receive cardioprotective medications than those with normal kidney function.5Even with the above limitations, the study does present the very important observation that many patients did not receive the best therapy for mUC because they had kidney disease. Limiting patient access to best treatment options solely because of the presence of kidney disease is a form of renalism. This term was first used almost two decades ago by Chertow 7 There are various reasons for reluctance to include kidney patients in cancer therapy trials.8 Many anticancer therapies are cleared by the kidney or may have nephrotoxicity.7 Excluding patients with kidney disease may reflect a desire to enhance the likelihood for a drug to move through the development, testing and approval process (by minimizing chances of adverse events), concern over contrast-based radiographic studies for disease monitoring, and safety concerns.8 Patients are frequently excluded with only very mild kidney disease, many times on the basis of a serum creatinine alone as measurement of kidney function, and often distinction is not made for drugs that do not rely on the kidney for metabolism or clearance.8 The impact of excluding patients with CKD from cancer therapy trials is further magnified in the aging population with higher risk for coexistent cancer and kidney disease.8 For some of these older patients, renalism and ageism, excluding patients from diagnostic and therapeutic interventions on the basis of chronologic age, combine to further limit access to care.Treatment of cancer for patients with kidney disease represents another example of renalism. Although CKD is highly prevalent among those receiving treatment for cancer, these patients are grossly underrepresented in clinical trials of cancer therapy with 85%–95% of major anticancer trials excluding a majority of patients with CKD and with very strict kidney function eligibility criteria.et al., provide such a clear example of renalism and its adverse effects on care for patients with mUC.As a result of the limited access of kidney patients to cancer therapy trials, there is limited information to guide clinicians on how to safely use these treatments for patients with kidney disease. Consequently, many patients with kidney disease are denied access to cancer treatments which may have led to improved outcomes. The findings reported by Cote 8 The American Society of Clinical Oncology has issued guidance to improve participation in clinical trials for patients with comorbid conditions, including kidney disease.9 The US Food and Drug Administration has also provided guidance meant to enhance inclusion of patients with CKD in randomized controlled drug trials.10What can be done to lessen the impact of renalism? The arena of drug development and clinical trials should be targets for improvement. Awareness of renalism exists, and efforts have been made for improved representation of multiple stakeholders in trial designs for patients with cancer and kidney disease. The input of patients, oncologists, nephrologists, and pharmacists working closely with professional societies, pharmaceutical companies, and regulatory agencies is key to design clinical trials that can inform the field.8 Large-scale observational studies across a larger spectrum of primary cancers can help to shed additional light on the problem and add to the planning of clinical trials and advance collection of valuable data. Other steps include leveraging data from electronic health records to reach larger pools of potential participants and trial designs.10 Continued and intensified advocacy for consideration of patients with CKD in cancer therapy trials is essential and has been successful in other fields. This is a proven and direct way to bring additional resources and support studies to allow advances and generate the evidence to guide treatment decisions.Important steps include reassessing kidney eligibility criteria for cancer trials with more precise determinations of kidney function and pharmacokinetic studies of anticancer drugs in kidney models.et al., is that a small but significant number of patients in the standard treatment arm received full-dose cisplatin despite an eGFR <60 ml/min per m2.3 This represents some deviation by some of the oncologists from conventional practice. Did these providers make the decision unilaterally? Did they seek input from nephrologists? This highlights the opportunity for nephrologists and other clinicians and investigators to make a day-to-day impact through simple communication and collaboration.An interesting observation from the study by Cote Health care professionals also have an opportunity to make an impact in medical education. It is likely that renalism has made its way into the larger curriculum of medical students, residents, fellows, scientists, and pharmacists. It is not difficult to envision learners accepting the premise that some indicated treatments are not available to kidney patients. In this context, there is an opportunity to role model patient advocacy.et al., ineligibility to access the best therapy for mUC on the basis of concerns about reduced kidney function was associated with higher risk of progressive disease and reduced patient survival.3 There is clearly a need to revisit cisplatin eligibility criteria and develop new strategies such as immunotherapy, targeted treatments, and other novel therapies for patients with mUC and kidney disease.11 Moreover, there is an opportunity to revise the broad restrictions on access to cancer therapies in general for patients with CKD. It is now time to collect the necessary data and develop an evidence-based approach to guide development of best care practices for patients with cancer and kidney disease.In conclusion, renalism is a real barrier to patient care. As reported by Cote