The impact of shortening patient-doctor contact duration on early peritoneal dialysis-related infections.

Early peritoneal dialysis (PD)-related infection is a severe complication. This study investigated the relationship between patient-doctor contact (PDC) duration and early PD-related infection. In the Peritoneal Dialysis Outcomes and Practice Patterns Study (PDOPPS) Korea, incident dialysis patients receiving PD were divided into two groups based on PDC duration (< 15 min versus ≥ 15 min), which was defined as the duration a nephrologist typically spends with a patient receiving PD during each visit according to the facility practice pattern. Early risks of PD-related infections, such as peritonitis and catheter-related infection (onset within 3 and 12 months of PD), were compared to the PDC duration using Cox regression. The study included 276 patients (184 [66.7%] in the shorter PDC group [< 15 min] and 92 [33.3%] in the longer PDC group [≥ 15 min]). The average age did not differ between the groups. The incidences of 3- and 12-month PD-related infections were significantly lower in the longer PDC group than in the shorter PDC group (3 months: 1.1% versus 9.8%, P = 0.007; 12 months: 9.8% versus 23.4%, P = 0.007). Longer PDC was independently associated with a lower risk of PD-related infections at 3 and 12 months (3 months: adjusted hazard ratio [aHR], 0.11; 95% confidence interval [CI], 0.02-0.85, P = 0.034; 12 months: aHR, 0.43; 95% CI 0.19-0.99, P = 0.048). Overall, a longer PDC duration was associated with a significantly lower risk of early PD-related infection.

Incorporation of Calcimimetics into ESRD Bundle: Changes in Etelcalcetide Utilization and PTH Control Following End of TDAPA Designation.

INTRODUCTION: Calcimimetics, including intravenous etelcalcetide and oral cinacalcet, are often prescribed to hemodialysis patients to prevent complications of elevated parathyroid hormone (PTH) levels. In January 2021, US dialysis reimbursement policy switched from the transitional drug add-on payment adjustment (TDAPA) to an increased bundled payment, with $10.09 per session added for all hemodialysis patients to cover the expense for calcimimetics, whether or not patients are administered etelcalcetide. We leveraged this natural experiment to investigate the impact of this policy change. METHODS: This analysis included 713 US in-center hemodialysis patients enrolled in the United States Dialysis Outcomes and Practice Patterns Study (US-DOPPS) who discontinued etelcalcetide during the TDAPA transition period (December 2020 - April 2021). Within a self-matched longitudinal design, within-patient changes in mean PTH, calcium, and phosphorus were assessed in the six months pre- vs. post- etelcalcetide discontinuation, using linear regression adjusted for potential confounders. RESULTS: Etelcalcetide use in US-DOPPS decreased 58%, from 12% to 5% from July 2020 to July 2021; 73% of etelcalcetide discontinuers switched to cinacalcet within six months. Comparing the six months pre- vs. post- etelcalcetide discontinuation, mean PTH levels increased by 107 (95% CI: 80, 133) pg/mL, and the prevalence of PTH >600 pg/mL increased by 15% (95% CI: 11%, 19%), from 28% to 43% overall, and increased from 26% to 49% among Black patients. Mean serum calcium and phosphorus levels increased by 0.42 and 0.16 mg/dL, respectively. CONCLUSION: Etelcalcetide use decreased substantially after TDAPA ended in January 2021, with most patients switching to cinacalcet. The subsequent increase in PTH levels was swift and sustained, and especially pronounced among Black patients, raising concerns about disparities and potential downstream impact on clinical outcomes. Despite the spirit of the policy change, the flat per-treatment increased payment may have inadvertently created a financial incentive to restrict patient access to a more effective therapy, and potentially stifle drug innovation.

Hypokalaemia in patients with type 2 diabetes and chronic kidney disease: the effect of finerenone - a FIDELITY analysis.

AIMS: Hypokalaemia is associated with cardiovascular events and mortality in patients with chronic kidney disease (CKD). This exploratory FIDELITY analysis, a prespecified pooled patient-dataset from FIDELIO-DKD and FIGARO-DKD, investigated the incidence and effect of hypokalaemia in patients with CKD and type 2 diabetes (T2D) treated with finerenone vs. placebo. METHODS: Outcomes include the incidence of treatment-emergent hypokalaemia (serum potassium < 4.0 or < 3.5 mmol/L) and the effect of finerenone on cardiovascular composite outcome (cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, or hospitalization for heart failure) and arrhythmia composite outcome (new diagnosis of atrial fibrillation/atrial flutter, hospitalization due to arrhythmia, or sudden cardiac death) by baseline serum potassium subgroups. RESULTS: In the FIDELITY population, treatment-emergent hypokalaemia with serum potassium < 4.0 and < 3.5 mmol/L occurred in 41.1% and 7.5%, respectively. Hazards of cardiovascular and arrhythmia composite outcomes were higher in patients with baseline serum potassium < 4.0 vs. 4.0-4.5 mmol/L (hazard ratio [HR] 1.16; 95% confidence interval [CI] 1.02-1.32, P = 0.022 and HR 1.20; 95% CI 1.00-1.44, P = 0.055, respectively). Finerenone reduced the incidence of hypokalaemia with serum potassium < 4.0 mmol/L (HR 0.63; 95% CI 0.60-0.66) and < 3.5 mmol/L (HR 0.46; 95% CI 0.40-0.53) vs. placebo. Finerenone lessened the hazard of cardiovascular and arrhythmia events vs. placebo, irrespective of baseline serum potassium. CONCLUSION: A substantial proportion of patients with CKD and T2D experienced hypokalaemia, which was associated with an increased hazard of adverse cardiovascular outcomes. Finerenone reduced the incidence of hypokalaemia. Finerenone reduced the hazard of cardiovascular and arrhythmia outcomes irrespective of serum potassium subgroups. Clinical trials registration: FIDELIO-DKD and FIGARO-DKD are registered with ClinicalTrials.gov, numbers NCT02540993 and NCT02545049, respectively (funded by Bayer AG).

Hyperkalemia Incidence in Patients With Non-Dialysis Chronic Kidney Disease: A Large Retrospective Cohort Study From United States Clinical Care.

Rationale & Objective: Estimates of the incidence of hyperkalemia in patients with chronic kidney disease (CKD) vary widely. Our objective was to estimate hyperkalemia incidence in patients with CKD from routine clinical care, including by level of kidney damage or function and among important patient subgroups. Study Design: Retrospective cohort study. Setting & Participants: 1,771,900 patients with stage 1-4 CKD identified from the US Optum De-Identified electronic health records database. Exposures or Predictors: Impaired kidney damage or function level at baseline based on urinary albumin-creatinine ratio (UACR) and estimated glomerular filtration rate (eGFR), respectively, and selected patient subgroups. Outcomes: Hyperkalemia: 2 elevated serum potassium values (≥5.5 mmol/L) from the inpatient setting (2-24 hours apart) or outpatient setting (maximum 7 days apart), or 1 elevated serum potassium value plus pharmacotherapy initiation or hyperkalemia diagnosis (maximum 3 days apart). Analytical Approach: Incidence rates of hyperkalemia were calculated. Estimates were stratified by UACR and eGFR level at baseline and patient subgroups. Results: Over a mean follow-up of 3.9 years, the incidence of hyperkalemia was 3.37 events/100 person-years (95% confidence intervals, 3.36-3.38). Higher incidence rates were observed with increased UACR and lower eGFR. Highest rates were observed with UACR ≥3,500 (up to 19.1/100 person-years) irrespective of decreased eGFR level. High rates also occurred in patients with type 2 diabetes mellitus (T2DM, 5.43/100 person-years), heart failure (8.7/100 person-years), and those prescribed steroidal mineralocorticoid receptor antagonists (sMRAs, 7.7/100 person-years). Limitations: Potential misclassification of variables from possible medical coding errors; potential data incompleteness issues if patients received care at institutions not included in Optum. Conclusions: Hyperkalemia is a frequent occurrence in CKD, particularly in patients with T2DM, heart failure, or prescribed sMRAs, indicating the need for regular serum potassium and UACR monitoring in this patient population to help mitigate risk.

People with chronic kidney disease (CKD) have a higher risk of illness, hospitalization, and death than those without CKD. Medicines that are commonly used to slow down CKD progression can sometimes lead to hyperkalemia, where levels of potassium in the blood are higher than normal and which can be potentially dangerous. Concerns about hyperkalemia have led some people with CKD to stop taking their medication. Our study of 1.7 million patients from the United States found that patients with severe kidney damage, as well as those with type 2 diabetes mellitus or heart failure, have a higher risk of hyperkalemia than other patients, indicating they are priority groups for having their potassium levels and level of kidney damage checked regularly.

Symptom Burden and Its Impact on Quality of Life in Patients With Moderate to Severe CKD: The International Chronic Kidney Disease Outcomes and Practice Patterns Study (CKDopps).

RATIONALE & OBJECTIVE: Recent evidence suggests people with nondialysis chronic kidney disease (ND-CKD) experience a substantial burden of symptoms, but informative large-scale studies have been scarce. We assessed the prevalence of symptoms and the association of overall symptom burden with quality of life in patients with moderate to severe CKD. STUDY DESIGN: Cross-sectional study. SETTING & PARTICIPANTS: 4,430 patients with ND-CKD stages 3-5 enrolled in the Chronic Kidney Disease Outcomes and Practice Patterns Study (CKDopps) in Brazil, France, and the United States between 2013 and 2021. EXPOSURE: 13 individual patient-reported symptoms from the Kidney Disease Quality of Life Short Form (KDQOL-SF) questionnaire and an overall symptom burden score (low, intermediate, and high). OUTCOME: Physical and mental component summary scores (PCS and MCS) of the KDQOL-SF. ANALYTICAL APPROACH: Adjusted prevalence ratios and generalized estimating equations. RESULTS: Patients (mean age, 68 years; 40% women; mean baseline estimated glomerular filtration rate [eGFR], 30mL/min/1.73m2) were very much to extremely bothered by numerous symptoms ("soreness in muscles," 23%; "washed out or drained," 21%; "cramps, shortness of breath, dry skin, diminished sex life, or numbness in hands or feet," 14%-17%). The adjusted prevalences of "cramps," "washed out or drained," "lack of appetite," "nausea/upset stomach," and "sex life" were greater with more severe CKD and in women (except for "sex life"). A high overall symptom burden was more common in women, in France, and in patients with severe albuminuria and various comorbidities, but not with lower eGFR. The PCS and MCS scores were 13.4 and 7.7 points lower, respectively, for high versus low overall symptom burden. LIMITATIONS: Generalizability limited to patients under nephrology care, residual confounding, and inaccurate Brazilian translation of some symptoms. CONCLUSIONS: The high symptom burden observed in this large cohort of ND-CKD patients across 3 diverse countries and its strong association with poorer health-related quality of life should inform clinical management of and clinical research in CKD. PLAIN-LANGUAGE SUMMARY: Little is known about symptoms in patients with non-dialysis-dependent chronic kidney disease (ND-CKD). In the Chronic Kidney Disease Outcomes and Practice Patterns Study, which enrolled 4,430 patients with CKD stages 3-5 in Brazil, France, and the United States, patients most often reported soreness in muscles, feeling washed out or drained, cramps, shortness of breath, dry skin, altered sex life, and numbness in hands or feet. Cramps, feeling washed out or drained, lack of appetite, and nausea were more often reported at lower levels of kidney function. The overall symptom burden was higher in women than men, in French than in Brazilian or US patients, and in those with severe albuminuria. The higher the symptom burden, the lower were the physical and mental health quality of life scores. The high symptom burden observed in this large cohort of ND-CKD patients across 3 diverse countries and its strong association with poorer health-related quality of life should inform clinical management of and clinical research in CKD.

The Lived Experience of Patients with Chronic Kidney Disease: Insights From DISCOVER CKD.

INTRODUCTION: Chronic kidney disease (CKD) can have a profound impact on patients' lives. However, multinational data on patients' lived experience with CKD are scarce. METHODS: Individuals from the prospective cohort of DISCOVER CKD (NCT04034992), an observational cohort study, were recruited to participate in one-to-one telephone interviews to explore their lived experience with CKD. A target of 100 participant interviews was planned across four countries (Japan, Spain, the UK, and the USA). These qualitative interviews, lasting ∼60-90 min, were conducted in the local language by trained interviewers with specific experience in CKD, between January and June 2023. Transcribed interviews were translated into English for coding and analysis. Data were coded using qualitative research software. RESULTS: Of the 105 participants interviewed, 103 were included in the final analysis. The average time since CKD diagnosis was 9.5 years, and at least half (50.5%) of participants had CKD stage 3A or 3B. CKD diagnosis was an emotional experience, driven by worry (n = 29/103; 28.2%) and shock (n = 26/103; 25.2%), and participants often reported feeling inadequately informed. Additional information was frequently sought, either online or via other healthcare providers. The proportion of participants reporting no impacts of CKD on their lives was highest in those with CKD stage 1 and 2 (64.3%). Conversely, every participant in the CKD stage 5 on dialysis group reported some impact of CKD on their lives. Across all participants, the most reported impacts were anxiety or depression (37.9%) or ability to sleep (37.9%). The frequency of the reported impacts appeared to increase with disease severity, with the highest rates observed in the dialysis group. In that group, the most frequently reported impact was on the ability to work (80.0%). CONCLUSION: Findings from this multinational qualitative study suggest that patients may experience symptoms and signs of disease prior to diagnosis; however, these are often nonspecific and may not be directly associated with CKD. Once diagnosed, the burden of CKD can have a diverse, negative impact on various aspects of patients' lives. This highlights the need for early identification of at-risk individuals, and the importance of early CKD diagnosis and management with guideline-directed therapies to either prevent further deterioration of CKD or slow its progression, thus reducing symptom burden and improving quality of life.

Suboptimal monitoring and management in patients with unrecorded stage 3 chronic kidney disease in real-world settings: Insights from REVEAL-CKD.

BACKGROUND: Clinical practice guidelines for patients with chronic kidney disease (CKD) recommend regular monitoring and management of kidney function and CKD risk factors. However, the majority of patients with stage 3 CKD lack a diagnosis code, and data on the implementation of these recommendations in the real world are limited. AIM: To assess the implementation of guideline-directed monitoring and management practices in the real world in patients with stage 3 CKD without a recorded diagnosis code. METHODS: REVEAL-CKD (NCT04847531) is a multinational, observational study of patients with stage 3 CKD. Eligible patients had ≥2 consecutive estimated glomerular filtration rate (eGFR) measurements indicative of stage 3 CKD recorded >90 and ≤730 days apart, lacked an International Classification of Diseases 9/10 diagnosis code corresponding to CKD any time before and up to 6 months after the second eGFR measurement. Testing of key measures of care quality were assessed. RESULTS: The study included 435,971 patients from 9 countries. In all countries, the prevalence of urinary albumin-creatinine ratio and albuminuria testing was low. Angiotensin-converting enzyme inhibitor, angiotensin receptor blocker and statin prescriptions were highly variable, and sodium-glucose cotransporter-2 inhibitor prescriptions remained below 21%. Blood pressure measurements were recorded in 20.2%-89.9% of patients. CONCLUSIONS: Overall, a large proportion of patients with evidence of stage 3 CKD did not receive recommended, guideline-directed monitoring and management. The variability in standard of care among countries demonstrates a clear opportunity to improve monitoring and management of these patients, most likely improving long-term outcomes.

Diuretic prescriptions in the first year of haemodialysis: international practice patterns and associations with outcomes.

Background: The use of diuretics in patients on haemodialysis (HD) is thought to maintain diuresis. However, this assumption and the optimal dose are based on little scientific evidence, and associations with clinical outcomes are unclear. Methods: We reported international variations in diuretic use and loop diuretic dose across 27 759 HD patients with dialysis vintage <1 year in the Dialysis Outcomes and Practice Patterns Study phases 2-5 (2002-2015), a prospective cohort study. Doses of torsemide (4:1) and bumetanide (80:1) were converted to oral furosemide-equivalent doses. Adjusted Cox, logistic and linear regressions were used to investigate the association of diuretic use and dose with outcomes. Results: Diuretic utilization varied widely by country at vintage <3 months, ranging from >80% in Germany and Sweden to <35% in the USA, at a median dose ranging from 400-500 mg/day in Germany and Sweden to <100 mg/day in Japan and the USA. Neither diuretic use nor higher doses were associated with a lower risk of all-cause mortality, a higher risk of hospitalization for fracture or elevated parathyroid hormone levels, but the prescription of higher doses (>200 mg/day) was associated with a higher risk of all-cause hospitalization. Conclusions: Substantial international differences exist in diuretic prescriptions, with use and doses much higher in some European countries than the USA. The prescription and higher doses of loop diuretics was not associated with improved outcomes.

Clinical Outcomes in Patients with CKD and Rapid or Non-rapid eGFR Decline: A Report from the DISCOVER CKD Retrospective Cohort.

INTRODUCTION: This analysis examined the baseline characteristics and clinical outcomes of patients with chronic kidney disease (CKD) and rapid or non-rapid estimated glomerular filtration rate (eGFR) decline, using retrospective data from DISCOVER CKD (ClinicalTrials.gov, NCT04034992). METHODS: Data (2008-2020) were extracted from UK Clinical Practice Research Datalink, US TriNetX, US Limited Claims and Electronic Health Record Dataset, and Japan Medical Data Vision. Patients with CKD (two consecutive eGFR measures < 75 mL/min/1.73 m2 recorded 90-730 days apart) were included. Rapid eGFR decline was defined as an annual decline of > 4 mL/min/1.73 m2 at 2 years post-index; non-rapid eGFR decline was defined as an annual decline of ≤ 4 mL/min/1.73 m2. Clinical outcomes assessed included all-cause mortality, kidney outcomes (composite risk of kidney failure [progression to CKD stage 5] or > 50% eGFR decline, and kidney failure alone), cardiovascular events-including major adverse cardiovascular events (MACE; non-fatal myocardial infarction/stroke and cardiovascular death)-and all-cause hospitalization. RESULTS: Across databases, rapid eGFR decline occurred in 13.7% of 804,237 eligible patients. Mean annual eGFR decline ranged between - 6.21 and - 6.86 mL/min/1.73 m2 in patients with rapid eGFR decline versus between - 0.11 and - 0.77 mL/min/1.73 m2 in patients with non-rapid eGFR decline. Rapid eGFR decline was associated with increased comorbidity burden and medication prescriptions. Across databases, the composite risk of kidney failure or > 50% decline in eGFR was significantly greater in patients with rapid versus non-rapid eGFR decline (P < 0.01); all-cause mortality, kidney failure alone, MACE, and all-cause hospitalization each significantly increased in two databases (P < 0.01-0.05). CONCLUSION: Understanding patient factors associated with rapid eGFR decline in patients with CKD may help identify individuals who would benefit from proactive management to minimize the risk of adverse outcomes. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT04034992.

High volume online hemodiafiltration: a global perspective and the Brazilian experience / Hemodiafiltração on-line de alto volume: uma perspectiva global e a experiência brasileira

ABSTRACT Online hemodiafiltration (HDF) is a rapidly growing dialysis modality worldwide. In Brazil, the number of patients with private health insurance undergoing HDF has exceeded the number of patients on peritoneal dialysis. The achievement of a high convection volume was associated with better clinical imprand patient - reported outcomes confirming the benefits of HDF. The HDFit trial provided relevant practical information on the implementation of online HDF in dialysis centers in Brazil. This article aims to disseminate technical information to improve the quality and safety of this new dialysis modality.

RESUMO A hemodiafiltração (HDF) on-line é uma modalidade dialítica em rápido crescimento no mundo. No Brasil, o número de pacientes com planos de saúde privados tratados por HDF já ultrapassa aquele de pacientes em diálise peritoneal. O alcance de um alto volume convectivo associado à redução de desfechos clínicos e do risco de morte confirmam os benefícios da HDF. Dados nacionais do estudo HDFit forneceram informações práticas relevantes sobre a implementação da HDF on-line em clínicas de diálise no Brasil. O objetivo desta publicação é a disseminação de informações técnicas que possam auxiliar na utilização, com qualidade e segurança, dessa nova modalidade dialítica.

Sex and the Risk of Atheromatous and Nonatheromatous Cardiovascular Disease in CKD: Findings From the CKD-REIN Cohort Study.

RATIONALE & OBJECTIVE: Sex differences in cardiovascular disease (CVD) are well established, but whether chronic kidney disease (CKD) modifies these risk differences and whether they differ between atheromatous CVD (ACVD) and nonatheromatous CVD (NACVD) is unknown. Assessing this interaction was the principal goal of this study. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: Adults enrolled in the CKD-REIN (CKD-Renal Epidemiology and Information Network) cohort, a nationally representative sample of 40 nephrology clinics in France, from 2013 to 2020. EXPOSURE: Sex. OUTCOMES: Fatal and nonfatal composite ACVD events (ischemic coronary, cerebral, and peripheral artery disease) and composite NACVD events (heart failure, hemorrhagic stroke, and arrhythmias). ANALYTICAL APPROACH: Multivariable cause-specific Cox proportional hazards models. RESULTS: 1,044 women and 1,976 men with moderate to severe CKD (median age, 67 vs 69y; mean estimated glomerular filtration rate [eGFR], 32±12 vs 33±12mL/min/1.73m2) were studied. During a median follow-up of 5.0 (IQR, 4.8-5.2) years, the ACVD rate (per 100 patient-years) was significantly lower in women than in men, at 2.1 (95% CI, 1.6-2.5) versus 3.6 (3.2-4.0; P<0.01), whereas the NACVD rate was not, at 5.7 (5.0-6.5) versus 6.4 (5.8-7.0; P=0.55). NACVD had a steeper relationship with eGFR than did ACVD. There was an interaction (P<0.01) between sex and baseline eGFR and the ACVD hazard: the adjusted HR for women versus men was 0.42 (0.25-0.71) at 45mL/min/1.73m2 and gradually attenuated at lower levels of eGFR, reaching 1.00 (0.62-1.63) at 16mL/min/1.73m2. In contrast, the NACVD hazard did not differ between sexes across the eGFR range studied. LIMITATIONS: Cardiovascular biomarkers and sex hormones were not assessed. CONCLUSIONS: This study shows how the lower risk of ACVD among women versus men attenuates fully with kidney disease progression. The equal risk of NACVD between sexes across CKD stages and its steeper association with eGFR suggest an important contribution of CKD to the development of this CVD type. PLAIN-LANGUAGE SUMMARY: Sex differences in the risks of atheromatous and nonatheromatous cardiovascular disease (CVD) are well established in the general population. If or how chronic kidney disease (CKD) might modify these risks is unknown. In this large cohort of 3,010 patients with CKD, women had a lower risk than men of atheromatous CVDs such as coronary artery disease or stroke when they were at an early stage of CKD. This advantage, partly due to women's better cardiovascular risk profile, tended to attenuate as CKD progressed to kidney failure. In contrast, the risk of nonatheromatous CVDs such as heart failure for women with CKD appeared similar to that of men with CKD at all kidney function levels.

Patterns of kidney function and risk assessment in a nationwide laboratory database: the Brazilian CHECK-CKD study.

BACKGROUND: Chronic kidney disease (CKD) is a global health problem with rising prevalence, morbidity, mortality, and associated costs. Early identification and risk stratification are key to preventing progression to kidney failure. However, there is a paucity of data on practice patterns of kidney function assessment to guide the development of improvement strategies, particularly in lower-income countries. METHODS: A retrospective observational analysis was conducted in a nationwide laboratory database in Brazil. We included all adult patients with at least one serum creatinine assessment between June 2018 and May 2021. Our primary objective was to determine the proportion of patients with estimated glomerular filtration rate (eGFR) evaluations accompanied by predicted levels of urinary albumin-to-creatinine ratio (pACR) assessments within 12 months. RESULTS: Out of 4,5323,332 serum creatinine measurements, 42% lacked pACR measurements within 12 months. Approximately 10.8% of tests suggested CKD, mostly at stage 3a. The proportion of serum creatinine exams paired with pACR assessment varied according to the CKD stage. Internal Medicine, Cardiology, and Obstetrics/Gynecology were the specialties requesting most of the creatinine tests. Nephrology contributed with only 1.1% of serum creatinine requests for testing. CONCLUSION: Our findings reveal that a significant proportion of individuals with a creatinine test lack an accompanying urinary albuminuria measurement in Brazil, contrary to the recommendations of the international guidelines. Non-Nephrologists perform most kidney function evaluations, even among patients with presumable advanced CKD. This highlights the urge to incorporate in clinical practice the early detection of CKD and to encourage more collaborative multidisciplinary care to improve CKD management.

Inhibition of Interleukin-33 to Reduce Glomerular Endothelial Inflammation in Diabetic Kidney Disease.

Introduction: Inflammation is a significant contributor to cardiorenal morbidity and mortality in diabetic kidney disease (DKD). The pathophysiological mechanisms linking systemic, subacute inflammation and local, kidney injury-initiated immune maladaptation is partially understood. Methods: Here, we explored the expression of proinflammatory cytokines in patients with DKD; investigated mouse models of type 1 and type 2 diabetes (T2D); evaluated glomerular signaling in vitro; performed post hoc analyses of systemic and urinary markers of inflammation; and initiated a phase 2b clinical study (FRONTIER-1; NCT04170543). Results: Transcriptomic profiling of kidney biopsies from patients with DKD revealed significant glomerular upregulation of interleukin-33 (IL-33). Inhibition of IL-33 signaling reduced glomerular damage and albuminuria in the uninephrectomized db/db mouse model (T2D/DKD). On a cellular level, inhibiting IL-33 improved glomerular endothelial health by decreasing cellular inflammation and reducing release of proinflammatory cytokines. Therefore, FRONTIER-1 was designed to test the safety and efficacy of the IL-33-targeted monoclonal antibody tozorakimab in patients with DKD. So far, 578 patients are enrolled in FRONTIER-1. The baseline inflammation status of participants (N > 146) was assessed in blood and urine. Comparison to independent reference cohorts (N > 200) validated the distribution of urinary tumor necrosis factor receptor 1 (TNFR1) and C-C motif chemokine ligand 2 (CCL2). Treatment with dapagliflozin for 6 weeks did not alter these biomarkers significantly. Conclusion: We show that blocking the IL-33 pathway may mitigate glomerular endothelial inflammation in DKD. The findings from the FRONTIER-1 study will provide valuable insights into the therapeutic potential of IL-33 inhibition in DKD.