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.

Association of COVID-19 Versus COVID-19 Vaccination With Kidney Function and Disease Activity in Primary Glomerular Disease: A Report of the Cure Glomerulonephropathy Study.

RATIONALE & OBJECTIVE: Patients with glomerular disease (GN) may be at increased risk of severe COVID-19, yet concerns over vaccines causing disease relapse may lead to vaccine hesitancy. We examined the associations of COVID-19 with longitudinal kidney function and proteinuria and compared these with similar associations with COVID-19 vaccination. STUDY DESIGN: Observational cohort study from July 1, 2021, to January 1, 2023. SETTING & PARTICIPANTS: A prospective observational study network of 71 centers from North America and Europe (CureGN) with children and adults with primary minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, or IgA nephropathy. EXPOSURE: COVID-19 and COVID-19 vaccination. OUTCOME: Repeated measure of estimated glomerular filtration rate (eGFR); recurrent time-to-event outcome of GN disease worsening as defined by doubling of the urinary protein-creatinine ratio (UPCR) to at least 1.5g/g or increase in dipstick urine protein by 2 ordinal levels to 3+(300mg/dL) or above. ANALYTICAL APPROACH: Interrupted time series analysis for eGFR. Prognostic matched sequential stratification recurrent event analysis for GN disease worsening. RESULTS: Among 2,055 participants, 722 (35%) reported COVID-19 infection; of these, 92 (13%) were hospitalized, and 3 died (<1%). The eGFR slope before COVID-19 infection was-1.40mL/min/1.73m2 (± 0.29 SD); within 6 months after COVID-19 infection, the eGFR slope was-4.26mL/min/1.73m2 (± 3.02 SD), which was not significantly different (P=0.34). COVID-19 was associated with increased risk of worsening GN disease activity (HR, 1.35 [95% CI, 1.01-1.80]). Vaccination was not associated with a change in eGFR (-1.34mL/min/1.73m2±0.15 SD vs-2.16mL/min/1.73m2±1.74 SD; P=0.6) or subsequent GN disease worsening (HR 1.02 [95% CI, 0.79-1.33]) in this cohort. LIMITATIONS: Infrequent or short follow-up. CONCLUSIONS: Among patients with primary GN, COVID-19 infection was severe for 1 in 8 cases and was associated with subsequent worsening of GN disease activity, as defined by proteinuria. By contrast, vaccination against COVID-19 was not associated with change in disease activity or kidney function decline. These results support COVID-19 vaccination for patients with GN. PLAIN-LANGUAGE SUMMARY: In this cohort study of 2,055 patients with minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, or IgA nephropathy, COVID-19 resulted in hospitalization or death for 1 in 8 cases and was associated with a 35% increase in risk for worsening proteinuria. By contrast, vaccination did not appear to adversely affect kidney function or proteinuria. Our data support vaccination for COVID-19 in patients with glomerular disease.

Kidney Function Decline and Serious Adverse Drug Reactions in Patients With CKD.

RATIONALE & OBJECTIVE: Adverse drug reactions (ADRs) are common in patients with chronic kidney disease (CKD). The impact of kidney function decline on serious ADR risk has been poorly investigated. We comprehensively describe ADRs and assess the relationship between estimated glomerular filtration rate (eGFR) and serious ADR risk. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: 3,033 participants in French Chronic Kidney Disease-Renal Epidemiology and Information Network (CKD-REIN) cohort study, a nationwide sample of nephrology outpatients with moderate to advanced CKD. PREDICTORS: Demographic and biological data (including eGFR), medication prescriptions. OUTCOME: ADRs (preventable or not) were prospectively identified from hospital discharge reports, medical records, and patient interviews. Expert pharmacologists used validated tools to adjudicate ADRs. ANALYTICAL APPROACH: Restricted cubic splines in fully adjusted cause-specific Cox proportional hazard models were used to evaluate the relationship between eGFR and the risk of serious ADRs (overall and by subtype). RESULTS: During a median follow-up period of 4.7 years, 360 patients experienced 488 serious ADRs. Kidney and urinary disorders (n=170) and hemorrhage (n=170) accounted for 70% of serious ADRs. The most common medications classes were antithrombotics and renin-angiotensin system inhibitors. The majority of those serious ADRs were associated with hospitalization (n=467), with 32 directly or indirectly associated with death and 22 associated with a life-threatening event. More than 27% of the 488 serious ADRs were preventable or potentially preventable. The eGFR is a major risk factor for serious ADRs. The risk of acute kidney injury was 2.2% higher and risk of bleeding ADRs was 8% higher for each 1mL/min/1.73m2 lower baseline eGFR. LIMITATIONS: The results cannot be extrapolated to patients who are not being treated by a nephrologist. CONCLUSIONS: ADRs constitute a major cause of hospitalization in CKD patients for whom lower eGFR level is a major risk factor. PLAIN-LANGUAGE SUMMARY: Patients with chronic kidney disease (CKD) have complex clinical presentations, take multiple medications, and often receive inappropriate prescriptions. Using data from a large, prospective CKD cohort, we found a high incidence of serious adverse drug reactions (ADRs). The 2 most common serious ADRs were drug-induced acute kidney injury and bleeding. A large proportion of serious ADRs required hospital admission, and 11% led to death or were life threatening. Lower kidney function was a major risk factor for serious ADRs. Many of these serious ADRs were determined to be partly preventable through greater adherence to prescription guidelines. This report enhances our understanding of the potential toxicity of drugs taken by patients with moderate to advanced CKD. It emphasizes the importance of monitoring kidney function when prescribing drugs, particularly for high-risk medications such as antithrombotic agents.

Pruritus in Hemodialysis Patients: Longitudinal Associations With Clinical and Patient-Reported Outcomes.

RATIONALE & OBJECTIVE: Cross-sectional studies have reported an association of chronic kidney disease-associated pruritus (CKD-aP) with adverse clinical events and patient-reported outcomes (PROs). We studied the longitudinal associations between changes in CKD-aP and clinical outcomes among patients receiving maintenance hemodialysis. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: 7,976 hemodialysis recipients across 21 countries in phases 4-6 (2009-2018) of the Dialysis Outcomes and Practice Patterns Study (DOPPS) who had 2 CKD-aP assessments approximately 12 months apart. EXPOSURES: Exposure status was based on the assessment of pruritis initially and again approximately 1 year later. Four groups were identified, including those with moderate or more severe pruritis only at the initial assessment (resolved), only at the second assessment (incident), at neither assessment (absent), or at both assessments (persistent). OUTCOMES: Laboratory values and PROs ascertained at the initial assessment of pruritis and 1 year later. ANALYTICAL APPROACH: Linear mixed model to investigate changes in laboratory values and PROs over the 1-year study period across the 4 exposure groups. RESULTS: 51% of patients had moderate to severe CKD-aP symptoms at either assessment (22% at both). The prevalences of depression, restless sleep, and feeling drained increased over the study period (+13%,+10%, and+14%, respectively) among patients with incident pruritus and decreased (-5%, -8%, and -12%, respectively) among patients with resolved pruritus. Minimal changes in PROs over time were observed for the absent and persistent groups. Changes over time in laboratory values (phosphorus, Kt/V) were not detected for either of these groups. Compared with patients with absent CKD-aP, the adjusted HRs for patients with persistent CKD-aP were 1.29 (95% CI, 1.09-1.53) for all-cause mortality, 1.17 (1.07-1.28) for all-cause hospitalization, and 1.48 (1.26-1.74) for cardiovascular events. LIMITATIONS: No interim evaluation of CKD-aP symptoms between the 2 assessments; potential selection bias from patients who died or were otherwise lost to follow-up before the second assessment. CONCLUSIONS: CKD-aP symptoms are chronic, and these findings highlight the potential value of repeated assessment of this symptom using standardized approaches. Future research should systematically investigate potential causes of CKD-aP and options for its effective treatment. PLAIN-LANGUAGE SUMMARY: Previous research has studied itching and its consequences in hemodialysis recipients only at a single time point. We surveyed 7,976 patients receiving maintenance hemodialysis to assess itching over a period of 1 year. We found that, among those experiencing itching at the initial assessment, more than half had persistent symptoms 1 year later. Those in whom itching developed during follow-up were more likely to experience depression, poor sleep, long recovery times after dialysis, and feeling faint or drained. These patients also rated their quality of life as poorer than those who did not experience itching. These findings emphasize the potential value of clinical detection of itching and the pursuit of effective treatments for patients receiving dialysis experiencing these symptoms.

Active Vitamin D Use and Fractures in Hemodialysis Patients: Results from the International DOPPS.

Active vitamin D is commonly used to control secondary hyperparathyroidism in dialysis patients, but it is unknown whether active vitamin D directly improves bone strength, independently of its ability to suppress parathyroid hormone (PTH). We analyzed the association between the prescription of active vitamin D and incidence of any fracture and hip fracture in 41,677 in-center hemodialysis patients from 21 countries in phases 3 to 6 (2005 to 2018) of the Dialysis Outcomes and Practice Patterns Study (DOPPS). We used Cox regression, adjusted for PTH and other potential confounders, and used a per-protocol approach to censor patients at treatment switch during follow-up. We also used a facility preference approach to minimize confounding by indication. Overall, 55% of patients were prescribed active vitamin D at study enrollment. Event rates (per patient-year) were 0.024 for any fracture and 0.010 for hip fracture. The adjusted hazard ratio (95% confidence interval) comparing patients prescribed versus not prescribed active vitamin D was 1.02 (0.90 to 1.17) for any fracture and 1.00 (0.81 to 1.23) for hip fracture. In the facility preference approach, there was no difference in fracture rate between facilities with higher versus lower active vitamin D prescriptions. Thus, our results do not suggest a PTH-independent benefit of active vitamin D in fracture prevention and support the current KDIGO guideline suggesting the use of active vitamin D only in subjects with elevated or rising PTH. Further research is needed to determine the role of active vitamin D beyond PTH control. © 2023 American Society for Bone and Mineral Research (ASBMR).

Utility of the Kidney Failure Risk Equation and Estimated GFR for Estimating Time to Kidney Failure in Advanced CKD.

RATIONALE & OBJECTIVE: The Kidney Failure Risk Equation (KFRE) predicts the 2-year risk of kidney failure for patients with chronic kidney disease (CKD). Translating KFRE-predicted risk or estimated glomerular filtration rate (eGFR) into time to kidney failure could inform decision making for patients approaching kidney failure. STUDY DESIGN: Retrospective cohort. SETTING & PARTICIPANTS: CKD Outcomes and Practice Patterns Study (CKDOPPS) cohort of patients with an eGFR<60mL/min/1.73m2 from 34 US nephrology practices (2013-2021). EXPOSURE: 2-year KFRE risk or eGFR. OUTCOME: Kidney failure defined as initiation of dialysis or kidney transplantation. ANALYTICAL APPROACH: Accelerated failure time (Weibull) models used to estimate the median, 25th, and 75th percentile times to kidney failure starting from KFRE values of 20%, 40%, and 50%, and from eGFR values of 20, 15, and 10mL/min/1.73m2. We examined variability in time to kidney failure by age, sex, race, diabetes status, albuminuria, and blood pressure. RESULTS: Overall, 1,641 participants were included (mean age 69±13 years; median eGFR of 28mL/min/1.73m2 [IQR 20-37mL/min/1.73 m2]). Over a median follow-up period of 19 months (IQR, 12-30 months), 268 participants developed kidney failure, and 180 died before reaching kidney failure. The median estimated time to kidney failure was widely variable across patient characteristics from an eGFR of 20mL/min/1.73m2 and was shorter for younger age, male sex, Black (versus non-Black), diabetes (vs no diabetes), higher albuminuria, and higher blood pressure. Estimated times to kidney failure were comparably less variable across these characteristics for KFRE thresholds and eGFR of 15 or 10mL/min/1.73m2. LIMITATIONS: Inability to account for competing risks when estimating time to kidney failure. CONCLUSIONS: Among those with eGFR<15mL/min/1.73m2 or KFRE risk>40%), both KFRE risk and eGFR showed similar relationships with time to kidney failure. Our results demonstrate that estimating time to kidney failure in advanced CKD can inform clinical decisions and patient counseling on prognosis, regardless of whether estimates are based on eGFR or the KFRE. PLAIN-LANGUAGE SUMMARY: Clinicians often talk to patients with advanced chronic kidney disease about the level of kidney function expressed as the estimated glomerular filtration rate (eGFR) and about the risk of developing kidney failure, which can be estimated using the Kidney Failure Risk Equation (KFRE). In a cohort of patients with advanced chronic kidney disease, we examined how eGFR and KFRE risk predictions corresponded to the time patients had until reaching kidney failure. Among those with eGFR<15mL/min/1.73m2 or KFRE risk > 40%), both KFRE risk and eGFR showed similar relationships with time to kidney failure. Estimating time to kidney failure in advanced CKD using either eGFR or KFRE can inform clinical decisions and patient counseling on prognosis.

Patiromer utilization in patients with advanced chronic kidney disease under nephrology care in Germany.

Background: Hyperkalemia (HK) is a frequent condition in patients with chronic kidney disease (CKD) that is associated with high morbidity and mortality. Patiromer has recently been introduced as a potassium binder. Data on patiromer use in patients with CKD in the real-world setting in Europe are lacking. We describe time to discontinuation and changes in serum potassium levels among German CKD stage 3-5 patients starting patiromer. Methods: Duration of patiromer use was estimated by Kaplan-Meier curve, starting at patiromer initiation and censoring for death, dialysis, transplant or loss to follow-up. Serum potassium levels and renin-angiotensin-aldosterone system inhibitor (RAASi) use are described at baseline and during follow-up, restricted to patients remaining on patiromer. Results: We identified 140 patiromer users within our analysis sample [81% CKD stage 4/5, 83% receiving RAASi, and median K+ 5.7 (5.4, 6.3) mmol/L]. Thirty percent of patiromer users had prior history of polystyrene sulfonate use. Overall, 95% of patiromer users stayed on treatment past 1 month, with 53% continuing for over a year. Mean serum potassium levels decreased after patiromer initiation and remained stable under treatment during follow-up (up to 180 days). Among these patients, 73%-82% used RAASis during the time periods before and after patiromer initiation, with no obvious trend indicating discontinuation. Conclusion: Real-world evidence of patiromer use in Germany shows that, in line with what has been observed in clinical trials, patients on patiromer have a reduction in serum potassium when used long-term. Moreover, most patients on patiromer do not discontinue treatment prior to 1 year after initiation.

Hemoglobin and Clinical Outcomes in Hemodialysis: An Analysis of US Medicare Data From 2018 to 2020.

Rationale & Objective: Anemia management in patients treated with maintenance dialysis remains a challenge. We sought to update information in this area by evaluating the association between hemoglobin and various outcome and utilization measures using data-rich Medicare sources. Study Design: Observational cohort study using data from the Consolidated Renal Operations in a Web-enabled Network and Medicare claims. Setting & Participants: We studied 371,250 prevalent patients treated with hemodialysis, covering 3,326,072 patient-months in 2019. Exposure: Monthly patient hemoglobin concentrations. Outcomes: We examined several outcomes, including mortality, all-cause hospitalization, cause-specific hospitalization, and emergency department utilization in the month following the exposure measurement. Analytical Approach: For each monthly observation period, we calculated unadjusted and adjusted (for demographics and comorbid condition) hazard ratios using Cox regression. Results: The hemoglobin concentration was <10.5 g/dL for 40% of observations. We found an inverse association between mortality and hemoglobin measured over a range from <9 g/dL (HR, 2.53; 95% CI, 2.45-2.61; P < 0.0001, reference = 10.5-11 g/dL) to 11-11.5 g/dL (HR, 0.92; 95% CI, 0.89-0.96; P < 0.0001). Mortality risk started to increase at hemoglobin levels >11.5 g/dL. All-cause hospitalization, cause-specific hospitalization (including cardiovascular, infection, and several subcategories including coronavirus disease 2019 hospitalization), and emergency department utilization were inversely associated with hemoglobin concentration, with risk reduction stabilizing at hemoglobin levels of approximately 11.5-12 g/dL and higher. Limitations: As with prior observational studies, the observed associations are not necessarily causal. Conclusions: In a large US hemodialysis population, there were better clinical outcomes at higher hemoglobin concentrations over short exposure and follow-up periods, consistent with other observational studies that generally used longer exposure and follow-up times. Mortality risk increased at hemoglobin concentrations >11.5 g/dL, consistent with findings from erythropoiesis-stimulating agent clinical trials. The apparently beneficial short-term effects associated with higher hemoglobin concentrations suggest that hemoglobin measurements capture unmeasured elements of patient risk.

Serum Phosphorus Level Rises in US Hemodialysis Patients Over the Past Decade: A DOPPS Special Report.

Mineral bone disorder (MBD) is a frequent consequence of chronic kidney disease, more so in patients with kidney failure treated by kidney replacement therapy. Despite the wide availability of interventions to control serum phosphate and parathyroid hormone levels, unmet gaps remain on optimal targets and best practices, leading to international practice pattern variations over time. In this Special Report, we describe international trends from the Dialysis Outcomes and Practice Patterns Study (DOPPS) for MBD biomarkers and treatments from 2002-2021, including data from a group of 7 European countries (Belgium, France, Germany, Italy, Spain, Sweden, United Kingdom), Japan, and the United States. From 2002-2012, mean phosphate levels declined in Japan (5.6 to 5.2 mg/dL), Europe (5.5 to 4.9 mg/dL), and the United States (5.7 to 5.0 mg/dL). Since then, levels rose in the United States (to mean 5.6 mg/dL, 2021), were stable in Japan (5.3 mg/dL), and declined in Europe (4.8 mg/dL). In 2021, 52% (United States), 27% (Europe), and 39% (Japan) had phosphate >5.5 mg/dL. In the United States, overall phosphate binder use was stable (80%-84% over 2015-2021), and parathyroid hormone levels rose only modestly. Although these results potentially stem from pervasive knowledge gaps in clinical practice, the noteworthy steady increase in serum phosphate in the United States over the past decades may be consequential to patient outcomes, an uncertainty that hopefully will soon be addressed by ongoing clinical trials. The DOPPS will continue to monitor international trends as new interventions and strategies ensue for MBD management in chronic kidney disease.

Understanding International Variations in Kidney Failure Incidence and Initiation of Replacement Therapy.

Introduction: Incidence of kidney replacement therapy (KRT) varies widely across countries. Its relations to individual characteristics, nephrology practices for slowing chronic kidney disease (CKD) progression, and KRT access remain unclear. Methods: We investigated intercountry differences in kidney failure (KF) rate, defined by a sustained estimated glomerular filtration rate (eGFR) <15 ml/min per 1.73 m2, and separately in KRT incidence, before and after adjusting for risk factors and blood pressure (BP) control or renin-angiotensin-aldosterone system inhibitor (RAASi) prescription practices in the CKD Outcomes and Practice Patterns Study (CKDopps) cohort study. Results: Among 7381 patients with CKD stage 3 to 4 at enrollment, 1297 progressed to KF and 947 initiated KRT over a 3-year follow-up period. Compared to the United States, demographic-adjusted and eGFR-adjusted hazard ratios (HRs) (HRs, 95% confidence intervals [CI]) for a sustained low eGFR were 0.77 (95% CI, 0.57-1.02) in Brazil, 0.90 (95% CI, 0.75-1.08) in France, and 1.03 (95% CI, 0.86-1.03) in Germany. Further adjustment for comorbidities, albuminuria, systolic BP, and RAASi prescription did not substantially change these HRs. In contrast, compared with the United States, the fully-adjusted HR for KRT remained significantly lower in Brazil (0.55, 95% CI 0.39-0.79), higher in Germany (95% CI, 1.36, 1.09-1.69), and similar in France (95% CI, 1.07, 0.81-1.39). Conclusion: Individual risk factors for CKD progression in nephrology patients appeared to explain most intercountry variations in KF but not KRT incidence. This suggests a prominent role for differences in practices related to KRT initiation or access, but not those for slowing disease progression. This study also shows that using KRT as a KF surrogate may bias estimates of associations with CKD progression risk factors.

Availability and prioritisation of COVID-19 vaccines among patients with advanced chronic kidney disease and kidney failure during the height of the pandemic: a global survey by the International Society of Nephrology.

OBJECTIVE: Patients with advanced chronic kidney disease (CKD) or kidney failure receiving replacement therapy (KFRT) are highly vulnerable to COVID-19 infection, morbidity and mortality. Vaccination is effective, but access differs around the world. We aimed to ascertain the availability, readiness and prioritisation of COVID-19 vaccines for this group of patients globally. SETTING AND PARTICIPANTS: Collaborators from the International Society of Nephrology (ISN), Dialysis Outcomes and Practice Patterns Study and ISN-Global Kidney Health Atlas developed an online survey that was administered electronically to key nephrology leaders in 174 countries between 2 July and 4 August 2021. RESULTS: Survey responses were received from 99 of 174 countries from all 10 ISN regions, among which 88/174 (50%) were complete. At least one vaccine was available in 96/99 (97%) countries. In 71% of the countries surveyed, patients on dialysis were prioritised for vaccination, followed by patients living with a kidney transplant (KT) (62%) and stage 4/5 CKD (51%). Healthcare workers were the most common high priority group for vaccination. At least 50% of patients receiving in-centre haemodialysis, peritoneal dialysis or KT were estimated to have completed vaccination at the time of the survey in 55%, 64% and 51% of countries, respectively. At least 50% of patients in all three patient groups had been vaccinated in >70% of high-income countries and in 100% of respondent countries in Western Europe.The most common barriers to vaccination of patients were vaccine hesitancy (74%), vaccine shortages (61%) and mass vaccine distribution challenges (48%). These were reported more in low-income and lower middle-income countries compared with high-income countries. CONCLUSION: Patients with advanced CKD or KFRT were prioritised in COVID-19 vaccination in most countries. Multiple barriers led to substantial variability in the successful achievement of COVID-19 vaccination across the world, with high-income countries achieving the most access and success.

Urea levels and cardiovascular disease in patients with chronic kidney disease.

BACKGROUND: Elevated serum urea levels are common in moderate-to-advanced CKD. Several studies have shown that urea is a direct and indirect uremic toxin, especially with regard to cardiovascular disease. We sought to determine whether serum urea levels are associated with adverse cardiovascular events and death before renal replacement therapy (RRT) in patients with CKD. METHODS: CKD-REIN is a prospective cohort of CKD nephrology outpatients not receiving maintenance dialysis. The 2507 patients included in the analysis were divided into three groups according to the baseline serum urea level (T1 < 10.5, T2:10.5 to 15.1, and T3 ≥ 15.1 mmol/L). Cox proportional hazard models were used to estimate hazard ratios (HRs) for first atheromatous or nonatheromatous cardiovascular (CV) events, and all-cause mortality before RRT. The models were adjusted for baseline comorbidities, laboratory data, and medications. FINDINGS: Of the 2507 included patients (median [interquartile range (IQR)] age: 69[61-77]; mean (standard deviation) eGFR 33.5(11.6) mL/min/1.73 m²), 54% had a history of cardiovascular disease. After multiple adjustments for cardiovascular risk factors (including eGFR), patients in T3 had a higher risk of atheromatous and nonatheromatous cardiovascular events than patient in T1 (n events = 451, HR[95%CI]: 1.93[1.39-2.69]). The adjusted HRs for death before RRT (n events = 407) were 1.31[0.97; 1.76] and 1.73[1.22; 2.45] for patients T2 and those in T3, respectively. INTERPRETATION: Our data suggested that urea is a predictor of cardiovascular outcomes beyond CV risk factors including eGFR.

Diabetes Prevalence, Treatment, Control, and Outcomes Among Hemodialysis Patients in the Gulf Cooperation Council Countries.

Introduction: Diabetes mellitus (DM) is a leading cause of end-stage kidney disease (ESKD). We provide the first description of DM prevalence, related outcomes, and the hemoglobin A1c (HbA1c)/mortality relationship in national hemodialysis (HD) patient samples across the Gulf Cooperation Council (GCC) countries. Methods: We analyzed data from the prospective Dialysis Outcomes and Practice Patterns Study (DOPPS) in the GCC (2012-2018, N = 2274 HD patients ≥18 years old). Descriptive statistics were calculated, and all-cause mortality was analyzed for patients with DM versus without DM and by HbA1c levels in patients with DM by Cox regression with progressive confounder adjustments. Results: DM in the GCC ranged from 45% to 74% in patients with HD by country. Patients with DM were 13 years older (59.9 vs. 46.7 years) and had greater body mass index (BMI), shorter median years on dialysis (1.5 vs. 3.0 years), and higher comorbidity burden. In patients with DM, insulin use was 26% to 50% across countries, with variable oral antidiabetic drug use (2%-32%); median HbA1c levels were 6.1% to 7.5% across countries. Patients with DM (vs. without DM) had higher crude death rates (15.6 vs. 6.2 deaths per 100 patient-years, mean follow-up 1.3 years) and adjusted mortality (hazard ratio [HR] = 1.72 [95% CI 1.23-2.39]). In patients with DM, mortality was lowest at HbA1c 6.5% to 7.5%, with mortality particularly elevated at high HbA1c >9% (HR = 2.13 [95% CI 1.10-4.10]). Conclusion: Patients with DM in the GCC have high comorbidity burden and mortality rates despite a relatively young mean age. In GCC countries, a holistic strategy for improving diabetes care and outcomes for HD patients is needed at the primary, secondary, and tertiary levels.

Etelcalcetide Versus Cinacalcet in Hemodialysis Patients in the United States: A Facility Calcimimetic Approach to Assess Real-World Effectiveness.

Rationale & Objective: Some US hemodialysis (HD) facilities switched from oral cinacalcet to intravenous etelcalcetide as the primary calcimimetic therapy to control parathyroid hormone (PTH) levels after the introduction of etelcalcetide in 2017. Although clinical trials have demonstrated the superior efficacy of etelcalcetide versus cinacalcet, evidence comparing real-world effectiveness is lacking. Study Design: Prospective cohort. Setting & Participants: Patients receiving HD enrolled in US Dialysis Outcomes and Practice Patterns Study facilities. Exposure: We classified HD facilities on the basis of whether >75% of calcimimetic users were prescribed etelcalcetide ("etelcalcetide-first") or cinacalcet ("cinacalcet-first") from March-August 2019. Outcomes: PTH, calcium, and phosphorus levels among calcimimetic users, all averaged in the 6 months after the exposure assessment period. Analytical Approach: We used adjusted linear regression to compare outcomes using 2 approaches: (1) cross-sectional comparison of etelcalcetide-first and cinacalcet-first HD facilities; (2) pre-post comparison of HD facilities that switched from cinacalcet-first to etelcalcetide-first using facilities that remained cinacalcet-first as a comparison group. Results: We identified 45 etelcalcetide-first and 67 cinacalcet-first HD facilities; etelcalcetide-first (vs cinacalcet-first) facilities were more likely to be from small or independent dialysis organizations (86% vs 22%) and had higher total calcimimetic use (43% vs 29%) and lower active vitamin D use (66% vs 82%). In the cross-sectional analysis comparing etelcalcetide-first and cinacalcet-first HD facilities, the adjusted mean difference in PTH levels was -115 pg/mL (95% CI, -196 to -34) and the prevalence of a PTH level of >600 pg/mL was lower (prevalence difference, -11.4%; 95% CI, -19.3% to -3.5%). Among facilities that switched to etelcalcetide-first, the mean PTH level decreased from 671 to 484 pg/mL and the prevalence of a PTH level of >600 pg/mL decreased from 39% to 21%. Among facilities that remained cinacalcet-first, the mean PTH level increased from 632 to 698 pg/mL and the prevalence of a PTH level of >600 pg/mL increased from 37% to 43%. The adjusted difference-in-difference between the switch to etelcalcetide-first and the continuation of cinacalcet-first was -169 pg/mL (-249 to -90 pg/mL) for the mean PTH and -14.4% (-22.0% to -6.8%) for a PTH level of >600 pg/mL. We also observed slightly lower serum calcium levels and minimal differences in serum phosphorus levels between the etelcalcetide-first and the cinacalcet-first facilities. Limitations: Residual confounding. Conclusions: We observed better PTH control in HD facilities that switched from using cinacalcet to etelcalcetide as the primary calcimimetic therapy. Further research is needed to investigate how the greater real-world effectiveness of intravenous etelcalcetide (vs oral cinacalcet) may affect clinical outcomes.

Variation in Peritoneal Dialysis Time on Therapy by Country: Results from the Peritoneal Dialysis Outcomes and Practice Patterns Study.

BACKGROUND AND OBJECTIVES: Quantifying contemporary peritoneal dialysis time on therapy is important for patients and providers. We describe time on peritoneal dialysis in the context of outcomes of hemodialysis transfer, death, and kidney transplantation on the basis of the multinational, observational Peritoneal Dialysis Outcomes and Practice Patterns Study (PDOPPS) from 2014 to 2017. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Among 218 randomly selected peritoneal dialysis facilities (7121 patients) in the PDOPPS from Australia/New Zealand, Canada, Japan, Thailand, the United Kingdom, and the United States, we calculated the cumulative incidence from peritoneal dialysis start to hemodialysis transfer, death, or kidney transplantation over 5 years and adjusted hazard ratios for patient and facility factors associated with death and hemodialysis transfer. RESULTS: Median time on peritoneal dialysis ranged from 1.7 (interquartile range, 0.8-2.9; the United Kingdom) to 3.2 (interquartile range, 1.5-6.0; Japan) years and was longer with lower kidney transplantation rates (range: 32% [the United Kingdom] to 2% [Japan and Thailand] over 3 years). Adjusted hemodialysis transfer risk was lowest in Thailand, but death risk was higher in Thailand and the United States compared with most countries. Infection was the leading cause of hemodialysis transfer, with higher hemodialysis transfer risks seen in patients having psychiatric disorder history or elevated body mass index. The proportion of patients with total weekly Kt/V ≥1.7 at a facility was not associated with death or hemodialysis transfer. CONCLUSIONS: Countries in the PDOPPS with higher rates of kidney transplantation tended to have shorter median times on peritoneal dialysis. Identification of infection as a leading cause of hemodialysis transfer and patient and facility factors associated with the risk of hemodialysis transfer can facilitate interventions to reduce these events. PODCAST: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2022_05_31_CJN16341221.mp3.

An investigation into possible sex differences in Association of Haemoglobin with survival among Haemodialysis patients in the J-DOPPS cohort.

AIMS: Lower haemoglobin levels are common among females without kidney diseases. However, little is known about the sex-specific management of anaemia in haemodialysis patients. METHODS: This prospective cohort study investigated the role of sex differences in the association between categorical baseline or time-varying haemoglobin levels and all-cause mortality via cox regression using data from 6890 patients in the Japan Dialysis Outcomes and Practice Patterns Study (J-DOPPS, 2005-2015). Likelihood ratio tests were used to evaluate the effect modification of sex on the relationship between haemoglobin and mortality. RESULTS: A total of 781 patients died during the median follow-up of 31 months. Mortality risk, adjusted for case mix, varied between five haemoglobin categories, with the highest category (≥12 g/dL) having a hazard ratio of 0.73 (0.41-1.29) for females and 2.02 (1.03-3.95) for males versus 10-10.9 g/dL. Despite this difference, the p-value comparing the overall among males versus females was.35. Similar associations were observed in models stratified by patient age (<75 years), time on dialysis (≤1 year), and models lagging the haemoglobin exposure. CONCLUSION: The results based on this sample of Japanese haemodialysis patients did not support the hypothesis that the association between haemoglobin and survival differed by sex. We also could not conclude that the association was identical, as the parameter estimates are consistent with male patients having a relatively greater mortality risk than female patients at higher haemoglobin levels. More detailed investigations into the effects of higher haemoglobin levels by sex might help better understand strategies for anaemia management.

Potential Surrogate Outcomes for Kidney Failure in Advanced CKD: Evaluation of Power and Predictive Ability in CKDopps.

RATIONALE & OBJECTIVE: Potential surrogate end points for kidney failure have been proposed in chronic kidney disease (CKD); however, they must be evaluated to ensure accurate, powerful, and harmonized research, particularly among patients with advanced CKD. The aim of the current study was to investigate the power and predictive ability of surrogate kidney failure end points in a population with moderate-to-advanced CKD. STUDY DESIGN: Analysis of longitudinal data of a large multinational CKD observational study (Chronic Kidney Disease Outcomes and Practice Patterns Study). SETTING & PARTICIPANTS: CKD stage 3-5 patients from Brazil, France, Germany, and the United States. OUTCOMES: Reaching an estimated glomerular filtration rate (eGFR) < 15 mL/min/1.73 m2 or eGFR decline of ≥40%, and composite end points of these individual end points. ANALYTICAL APPROACH: Each end point was used as a time-varying indicator in the Cox model to predict the time to kidney replacement therapy (KRT; dialysis or transplant) and was compared by the number of events and prediction accuracy. RESULTS: 8,211 patients had a median baseline eGFR of 27 mL/min/1.73 m2 (interquartile range, 21-36 mL/min/1.73 m2) and 1,448 KRT events over a median follow-up of 2.7 years (interquartile range, 1.2-3.0 years). Among CKD stage 4 patients, the eGFR < 15 mL/min/1.73 m2 end point had higher prognostic ability than 40% eGFR decline, but the end points were similar for CKD stage 3 patients. The combination of eGFR < 15 mL/min/1.73 m2 and 40% eGFR decline had the highest prognostic ability for predicting KRT, regardless of the CKD stage. Including KRT in the composite can increase the number of events and, therefore, the power. LIMITATIONS: Variable visit frequency resulted in variable eGFR measurement frequency. CONCLUSIONS: The composite end point can be useful for CKD progression studies among patients with advanced CKD. Harmonized use of this approach has the potential to accelerate the translation of new discoveries to clinical practice by identifying risk factors and treatments for kidney failure.

Sex-Specific Differences in Mortality and Incident Dialysis in the Chronic Kidney Disease Outcomes and Practice Patterns Study.

Introduction: More men than women start kidney replacement therapy (KRT) although the prevalence of chronic kidney disease (CKD) is higher in women than men. We therefore aimed at analyzing sex-specific differences in clinical outcomes among 8237 individuals with CKD in stages 3 to 5 from Brazil, France, Germany, and the United States participating in the Chronic Kidney Disease Outcomes and Practice Patterns Study (CKDopps). Methods: Fine and Gray models, evaluating the effect of sex on time to events, were adjusted for age, Black race (model A); plus diabetes, cardiovascular disease, albuminuria (model B); plus estimated glomerular filtration rate (eGFR) slope during the first 12 months after enrollment and first eGFR after enrollment (model C). Results: There were more men than women at baseline (58% vs. 42%), men were younger than women, and men had higher eGFR (28.9 ± 11.5 vs. 27.0 ± 10.8 ml/min per 1.73 m2). Over a median follow-up of 2.7 and 2.5 years for men and women, respectively, the crude dialysis initiation and pre-emptive transplantation rates were higher in men whereas that of pre-KRT death was more similar. The adjusted subdistribution hazard ratios (SHRs) between men versus women for dialysis were 1.51 (1.27-1.80) (model A), 1.32 (1.10-1.59) (model B), and 1.50 (1.25-1.80) (model C); for pre-KRT death, were 1.25 (1.02-1.54) (model A), 1.14 (0.92-1.40) (model B), and 1.15 (0.93-1.42) (model C); for transplantation, were 1.31 (0.73-2.36) (model A), 1.44 (0.76-2.74) (model B), and 1.53 (0.79-2.94) (model C). Conclusion: Men had a higher probability of commencing dialysis before death, unexplained by CKD progression alone. Although the causal mechanisms are uncertain, this finding helps interpret the preponderance of men in the dialysis population.