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 substantial burden of symptoms experienced by people with non-dialysis chronic kidney disease (ND-CKD), but informative large-scale studies are scarce. We aimed to assess 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: 4430 patients with ND-CKD stages 3-5 enrolled into the CKDopps Study in Brazil, France, and the US between 2013 and 2021. EXPOSURES: 13 individual patient-reported symptoms from the KDQOL-SF questionnaire and an overall symptom burden score (low, intermediate, and high). OUTCOMES: Physical and mental component summary scores (PCS, MCS) of the KDQOL-SF. ANALYTICAL APPROACH: Adjusted prevalence ratios and generalized estimating equations. RESULTS: Patients (mean age: 68 years; 40% women; mean baseline eGFR: 30 mL/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, except for "sex life", in women. 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. PCS and MCS scores were 13.4 and 7.7 points lower, respectively, for high vs. 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 three diverse countries and its strong association with poorer HRQOL should inform clinical management of and clinical research in CKD.

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.

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.

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.

Sex and the Risk of Atheromatous and Non-Atheromatous 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 (ACVD) and non-atheromatous (N-ACVD) CVD is unknown. Assessing this interaction was the principal goal of this study. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: Adults enrolled in the CKD-Renal Epidemiology and Information Network (CKD-REIN) cohort from from 2013 to 2020, a nationally representative sample of 40 nephrology clinics in France. EXPOSURE: Sex. OUTCOMES: Fatal and non-fatal composite ACVD events (ischaemic coronary, cerebral, and peripheral artery disease) and composite N-ACVD events (heart failure, haemorrhagic 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. 69; mean estimated glomerular filtration rate [eGFR], 32±12 vs. 33±12 mL/min/1.73m2) were studied. Over a median follow-up of 5.0 (interquartile range, 4.8;5.2) years, the ACVD rate (per 100 patient-years) was significantly lower in women than men: 2.1 (95% confidence interval: 1.6-2.5) vs 3.6 (3.2-4.0) (P<0.01), while the N-ACVD rate was not: 5.7 (5.0-6.5) vs 6.4 (5.8-7.0) (P=0.55). N-ACVD 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 hazard ratio for women compared to men was 0.42 (0.25;0.71) at 45 mL/min/1.73m2 and gradually attenuated at lower levels of eGFR, reaching 1.00 (0.62;1.63) at 16 mL/min/1.73m2. In contrast, the N-ACVD hazard did not differ between the sexes across the eGFR range studied. LIMITATIONS: Cardiovascular biomarkers and sex hormones were not assessed. CONCLUSION: This study shows how the lower risk of ACVD among women compared to men attenuates fully with kidney disease progression. The equal risk of N-ACVD between sexes across CKD stages and its steeper association with eGFR suggest an important contribution of CKD to the development of this CVD type.

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.

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.

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.

Characteristics of patients and facility of peritoneal dialysis in Korea: Results from the Peritoneal Dialysis Outcomes and Practice Patterns Study (PDOPPS) Korea.

BACKGROUND: Varying peritoneal dialysis (PD)-related clinical outcomes have been reported in different countries. As a participant of the Peritoneal Dialysis Outcomes and Practice Patterns Study (PDOPPS), this study investigated the characteristics of Korean PD patients, PD facilities and the incidence rates of clinical outcomes including mortality and PD-related outcomes. METHODS: From July 2019 to December 2021, a total of 766 Korean PD patients were included for analysis. Poisson regression analysis was used to explore the incidence rates of various clinical events including mortality, modality transfer, exit site or catheter tunnel infection and peritonitis. RESULTS: Among the 766 patients (median age 55.5 years, males 59.5%), 276 were incident and 490 were prevalent PD patients. The incidence rates of events were as follows: all-cause mortality (0.048), modality transfer (0.051), exit site or catheter tunnel infection (0.054) and peritonitis (0.136) events per person year. The most common causative organism for exit site or tunnel infection was staphylococcus species (47%) and that for peritonitis was streptococcus (28%) followed by staphylococcus (27%) species. CONCLUSIONS: Up to now, PDOPPS Korea has recruited 766 Korean PD patients and started documentation of major PD-related outcomes which occurred during the follow-up period. The overall incidence rates of clinical outcomes in Korean PD patients were relatively favourable. There was no statistically significant difference in the incidence rates of clinical outcomes according to both facility and patient factors.

Transition between peritoneal dialysis modalities: Impact on blood pressure levels and drug prescription in a national multicentric cohort.

BACKGROUND: Hypertension is a leading cause of kidney failure, affects most dialysis patients and associates with adverse outcomes. Hypertension can be difficult to control with dialysis modalities having differential effects on sodium and water removal. There are two main types of peritoneal dialysis (PD), automated peritoneal dialysis (APD) and continuous ambulatory peritoneal dialysis (CAPD). It is unknown whether one is superior to the other in controlling blood pressure (BP). Therefore, the aim of our study was to analyse the impact of switching between these two PD modalities on BP levels in a nationally representative cohort. METHODS: This was a cohort study of patients on PD from 122 dialysis centres in Brazil (BRAZPD II study). Clinical and laboratory data were collected monthly throughout the study duration. We selected all patients who remained on PD at least 6 months and 3 months on each modality at minimum. We compared the changes in mean systolic/diastolic blood pressures (SBP/DBP) before and after modality transition using a multilevel mixed-model where patients were at first level and their clinics at the second level. RESULTS: We analysed data of 848 patients (814 starting on CAPD and 34 starting on APD). The SBP decreased by 4 (SD 22) mmHg when transitioning from CAPD to APD (p < 0.001) and increased by 4 (SD 21) mmHg when transitioning from APD to CAPD (p = 0.38); consistent findings were seen for DBP. There was no significant change in the number of antihypertensive drugs prescribed before and after transition. CONCLUSIONS: Transition between PD modalities seems to directly impact on BP levels. Further studies are needed to confirm if switching to APD could be an effective treatment for uncontrolled hypertension among CAPD patients.

International variations in serum PTH and calcium levels and their mortality associations in peritoneal dialysis patients: Results from PDOPPS.

BACKGROUND: Mineral bone disorder (MBD) in chronic kidney disease (CKD) is associated with high symptom burden, fractures, vascular calcification, cardiovascular disease and increased morbidity and mortality. CKD-MBD studies have been limited in peritoneal dialysis (PD) patients. Here, we describe calcium and parathyroid hormone (PTH) control, related treatments and mortality associations in PD patients. METHODS: We used data from eight countries (Australia and New Zealand (A/NZ), Canada, Japan, Thailand, South Korea, United Kingdom, United States (US)) participating in the prospective cohort Peritoneal Dialysis Outcomes and Practice Patterns Study (2014-2022) among patients receiving PD for >3 months. We analysed the association of baseline PTH and albumin-adjusted calcium (calciumAlb) with all-cause mortality using Cox regression, adjusted for potential confounders, including serum phosphorus and alkaline phosphatase. RESULTS: Mean age ranged from 54.6 years in South Korea to 63.5 years in Japan. PTH and serum calciumAlb were measured at baseline in 12,642 and 14,244 patients, respectively. Median PTH ranged from 161 (Japan) to 363 pg/mL (US); mean calciumAlb ranged from 9.1 (South Korea, US) to 9.8 mg/dL (A/NZ). The PTH/mortality relationship was U-shaped, with the lowest risk at PTH 300-599 pg/mL. Mortality was nearly 20% higher at serum calciumAlb 9.6+ mg/dL versus 8.4-<9.6 mg/dL. MBD therapy prescriptions varied substantially across countries. CONCLUSIONS: A large proportion of PD patients in this multi-national study have calcium and/or PTH levels in ranges associated with substantially higher mortality. These observations point to the need to substantially improve MBD management in PD to optimise patient outcomes. LAY SUMMARY: Chronic kidney disease-mineral bone disorder (MBD) is a systemic condition, common in dialysis patients, that results in abnormalities in parathyroid hormone (PTH), calcium, phosphorus and vitamin D metabolism. A large proportion of peritoneal dialysis (PD) patients in this current multi-national study had calcium and/or PTH levels in ranges associated with substantially higher risks of death. Our observational study design limits our ability to determine whether these abnormal calcium and PTH levels cause more death due to possible confounding that was not accounted for in our analysis. However, our findings, along with other recent work showing 48-75% higher risk of death for the one-third of PD patients having high phosphorus levels (>5.5 mg/dL), should raise strong concerns for a greater focus on improving MBD management in PD patients.

Nephrologists' perspectives on communication and decision-making regarding technique survival in peritoneal dialysis: an international qualitative interview study.

OBJECTIVES: Peritoneal dialysis (PD) allows patients increased autonomy and flexibility; however, both infectious and non-infectious complications may lead to technique failure, which shortens treatment longevity. Maintaining patients on PD remains a major challenge for nephrologists. This study aims to describe nephrologists' perspectives on technique survival in PD. DESIGN: Qualitative semistructured interview study. Transcripts were thematically analysed. SETTING AND PARTICIPANTS: 30 nephrologists across 11 countries including Australia, the USA, the UK, Hong Kong, Canada, Singapore, Japan, New Zealand, Thailand, Colombia and Uruguay were interviewed from April 2017 to November 2019. RESULTS: We identified four themes: defining patient suitability (confidence in capacity for self-management, ensuring clinical stability and expected resilience), building endurance (facilitating access to practical support, improving mental well-being, optimising quality of care and training to reduce risk of complications), establishing rapport through effective communications (managing expectations to enhance trust, individualising care and harnessing a multidisciplinary approach) and confronting fear and acknowledging barriers to haemodialysis (preventing crash landing to haemodialysis, facing concerns of losing independence and positive framing of haemodialysis). CONCLUSION: Nephrologists reported that technique survival in PD is influenced by patients' medical circumstances, psychological motivation and positively influenced by the education and support provided by treating clinicians and families. Strategies to enhance patients' knowledge on PD and communication with patients about technique survival in PD are needed to build trust, set patient expectations of treatment and improve the process of transition off PD.

Dapagliflozin and Blood Pressure in Patients with Chronic Kidney Disease and Albuminuria.

BACKGROUND AND AIMS: Sodium-glucose cotransporter 2 inhibitors decrease blood pressure in patients with type 2 diabetes, but the consistency and magnitude of blood pressure lowering with dapagliflozin in patients with chronic kidney disease (CKD) is unknown. We conducted a prespecified analysis of the DAPA-CKD trial to investigate the effect of dapagliflozin on systolic blood pressure (SBP) in patients with CKD, with and without type 2 diabetes. METHODS: A total of 4304 adults with baseline estimated glomerular filtration rate (eGFR) 25-75 mL/min/1.73m2 and urinary albumin-to-creatinine ratio (UACR) 200-5000 mg/g were randomized to either dapagliflozin 10 mg or placebo once daily; median follow-up was 2.4 years. The primary endpoint was a composite of sustained ≥50% eGFR decline, end-stage kidney disease, or death from a kidney or cardiovascular cause. Change in SBP was a prespecified outcome. RESULTS: Baseline mean (SD) SBP was 137.1 mmHg (17.4). By Week 2, dapagliflozin compared to placebo reduced SBP by 3.6 mmHg (95% CI 2.8-4.4 mmHg), an effect maintained over the duration of the trial (2.9 mmHg, 2.3-3.6 mmHg). Time-averaged reductions in SBP were 3.2 mmHg (2.5-4.0 mmHg) in patients with diabetes and 2.3 mmHg (1.2-3.4 mmHg) in patients without diabetes. The time-averaged effect of dapagliflozin on diastolic blood pressure (DBP) was 1.0 mmHg (0.6-1.4 mmHg); 0.8 mmHg (0.4-1.3 mmHg) in patients with diabetes and 1.4 mmHg (0.7-2.1 mmHg) in patients without diabetes. Benefits of dapagliflozin on the primary composite and secondary endpoints were evident across the spectrum of baseline SBP and DBP. CONCLUSION: In patients with CKD and albuminuria, randomization to dapagliflozin was associated with modest reductions in systolic and diastolic BP.