KEY POINTS:Multidisciplinary kidney care eligibility changed from eGFR ≤33.4 ml/min per 1.73 m 2 to 2-year kidney failure risk ≥10% (includes eGFR and proteinuria). After the change, we found no difference in outcomes such as dialysis initiation, preparation for dialysis, and hospitalizations. The results of this study help guide decision making with respect to the care of patients with advanced CKD. BACKGROUND:We examined the effect of a change in the eligibility criteria for multidisciplinary kidney care implemented across Ontario, Canada, on April 1, 2016 (criteria moved from an eGFR ≤33.4 ml/min per 1.73 m 2 to 2-year kidney failure risk ≥10%, which incorporates assessment of proteinuria, or an eGFR <15). METHODS:Population-based, interrupted time series analysis using administrative health care databases that included adults with an outpatient eGFR ≤33.4 ml/min per 1.73 m 2 followed by a nephrologist ( N =97,299). We examined multidisciplinary clinic and nephrologist visits, dialysis-related outcomes, hospital encounters, and mortality by monthly interval between October 1, 2013, and February 1, 2020. Autoregressive integrated moving average models were tested for level (immediate) and slope (over time) changes in outcomes after the intervention and were fit on preintervention change data for projected trends. RESULTS:After intervention, there was a significant monthly decline in the multidisciplinary clinic visit rate of 1.49 visits per 100 person-years (95% confidence interval [CI], -2.83 to -0.14) and a significant monthly increase in the proportion of patients with a referral to multidisciplinary care within 1 year before starting dialysis ( i.e ., late referral; positive slope change, 0.67%; 95%, CI, 0.06 to 1.28). The intervention was not associated with significant changes in the proportion of patients initiating dialysis, initiating dialysis with a central venous catheter or during a hospitalization, using home dialysis, or in the rate of nephrologist visits. Immediately after intervention, there were small, significant increases in mortality and hospital encounters, but importantly, there was no monthly (slope) change in mortality and a significant negative monthly change in hospital encounters (-0.24 encounters per 100 person-years; 95% CI, -0.38 to -0.09). CONCLUSIONS:Changing the eligibility criteria for multidisciplinary kidney care from an eGFR ≤33.4 ml/min per 1.73 m 2 to a 2-year kidney failure risk ≥10% or an eGFR <15 ml/min per 1.73 m 2 resulted in significantly fewer patients receiving such care without negatively affecting important clinical outcomes.

Key PointsSuboptimal dialysis initiation is common and is associated with increased morbidity and mortality.Lower hemoglobin and higher comorbidity were risk factors for suboptimal dialysis initiation, but health literacy and kidney disease knowledge were not.Modifiable patient risk factors for suboptimal dialysis initiation were not found. Our study highlights the complexity of preventing this outcome.BackgroundSuboptimal dialysis initiation is common and is associated with increased morbidity and mortality. We sought to determine risk factors for suboptimal dialysis initiation among patients with advanced CKD.MethodsThis was a prospective cohort study that enrolled English-speaking patients without cognitive impairment followed in multidisciplinary kidney clinics across four regional kidney programs in Ontario, Canada. Patients completed a 6-month follow-up visit with further follow-up using health care administrative data. The primary outcome was suboptimal dialysis initiation defined by dialysis initiation with a central venous catheter, in patients younger than 75 years, or during a hospitalization. Adjusted cause-specific hazard models were used to examine the association of prespecified characteristics with suboptimal dialysis initiation.ResultsThree hundred and sixty-six patients were included; 122 (33%) patients had a suboptimal dialysis start (69% of dialysis starts) over a median follow-up of 1.9 (interquartile range, 0.7-2.5) years. Higher hemoglobin (time varying) was associated with a lower risk of suboptimal dialysis initiation (adjusted hazard ratio, 0.96; 95% confidence interval [CI], 0.95 to 0.98). The mean (SD) hemoglobin in those with suboptimal dialysis initiation was 10.7 (1.5) g/dl. Higher comorbidity index and greater number of nephrologist visits within the past 6 months were associated with a higher risk of suboptimal dialysis initiation (adjusted hazard ratio, 1.17 [95% CI, 1.01 to 1.35] and 1.70 [95% CI, 1.39 to 2.08]; respectively). Measures of health literacy, kidney disease knowledge, and influenza vaccination were not associated with suboptimal dialysis initiation. A secondary analysis defining suboptimal dialysis initiation by dialysis initiation during a hospitalization showed similar results.ConclusionsSuboptimal dialysis initiation was common despite established nephrology follow-up. Our study did not find readily modifiable patient-related risk factors for suboptimal dialysis initiation.

Background:The COVID-19 pandemic caused considerable disruption to health care services. Limited data exist on its impacts on clinical outcomes and health care utilization in patients with advanced chronic kidney disease (CKD). Objective:To compare the rates of all-cause mortality, cardiovascular-related hospitalizations, kidney-related outcomes, and health care utilization in patients with advanced CKD before and during the first 21 months of the COVID-19 pandemic. Design:Population-based, repeated cross-sectional study from March 15, 2017 to November 15, 2021, with follow-up until December 14, 2021 (preceding the Omicron variant). Setting:Linked administrative health care databases from Ontario, Canada. Participants:Adult patients with advanced CKD, defined as an estimated glomerular filtration rate <30 mL/min/1.73 m2 (excluding patients receiving maintenance dialysis). Measurements:The pre-COVID-19 period was from March 15, 2017 to March 14, 2020 and the COVID-19 period was from March 15, 2020 to December 14, 2021. Poisson generalized estimating equations were used to predict post-COVID-19 patient outcomes and health utilization based on pre-COVID trends, estimating relative changes between the observed and expected outcomes. The multivariable model incorporated age group-sex interaction terms, a continuous variable denoting time in months to capture general trends, and pre-COVID month indicators to adjust for seasonal changes. Methods:Our primary outcome was all-cause mortality. Secondary outcomes included all-cause hospitalizations, non-COVID-19-related deaths and hospitalizations, intensive care unit (ICU) admissions, mechanical ventilation, and emergency room visits. We also examined cardiovascular-related hospitalizations, kidney-related outcomes, and ambulatory visits. Results:We included 101 688 adults with advanced CKD. The incidence of all-cause mortality was 147.4 (95% confidence interval [CI] = 145.1, 149.7) per 1000 person-years in the pre-COVID-19 period compared to 150.8 (95% CI = 147.9, 153.7) per 1000 person-years in the COVID-19 period. After adjustment, there was an 8% higher rate of all-cause mortality during the COVID-19 (adjusted relative rate [aRR] = 1.08, 95% CI = 1.03, 1.12). Non-COVID-19-related deaths did not increase substantially (aRR = 1.02, 95% CI = 0.97, 1.07). The COVID-19 period was associated with a lower rate of all-cause hospitalizations, ICU admissions, and emergency room visits. There were declines in long-term care admissions and non-nephrology physician visits in the first 3 months of the pandemic. In contrast, nephrology visits remained stable throughout the study period, including the first 3 months of the pandemic. Similarly, the monthly rates of acute kidney injury requiring dialysis initiation showed little variation compared with pre-pandemic levels. Limitations:Due to data availability at the time of analysis, we did not examine the impact of the COVID-19 pandemic on patients with advanced CKD beyond December 2021. Conclusions:Non-COVID-19-related deaths did not increase during the first 21 months of the pandemic, despite reduced health care utilization. The study informs health service planning in future health care emergencies.

Background: Individuals receiving hemodialysis often experience concurrent symptoms during treatment and frequently report feeling unwell after dialysis. The degree to which intradialytic symptoms are related, and which specific symptoms may impair health-related quality of life (HRQoL) is uncertain. Objectives: To explore intradialytic symptoms clusters, and the relationship between intradialytic symptom clusters with dialysis treatment recovery time and HRQoL. Design/setting: We conducted a post hoc analysis of a prospective cohort study of 118 prevalent patients receiving hemodialysis in two centers in Calgary, Alberta and Hamilton, Ontario, Canada. Participants: Adults receiving hemodialysis treatment for at least 3 months, not scheduled for a modality change within 6 weeks of study commencement, who could provide informed consent and were able to complete English questionnaires independently or with assistance. Methods: Participants self-reported the presence (1 = none to 5 = very much ) of 10 symptoms during each dialysis treatment, the time it took to recover from each treatment, and weekly Kidney Disease Quality of Life 36-Item–Short Form (KDQoL-36) assessments. Principal component analysis identified clusters of intradialytic symptoms. Mixed-effects, ordinal and linear regression examined the association between symptom clusters and recovery time (categorized as 0, >0 to 2, >2 to 6, or >6 hours), and the physical component and mental component scores (PCS and MCS) of the KDQoL-36. Results: One hundred sixteen participants completed 901 intradialytic symptom questionnaires. The most common symptom was lack of energy (56% of treatments). Two intradialytic symptom clusters explained 39% of the total variance of available symptom data. The first cluster included bone or joint pain, muscle cramps, muscle soreness, feeling nervous, and lack of energy. The second cluster included nausea/vomiting, diarrhea and chest pain, and headache. The first cluster (median score: −0.56, 25th to 75th percentile: −1.18 to 0.55) was independently associated with longer recovery time (odds ratio [OR] 1.62 per unit difference in score, 95% confidence interval [CI]: 1.23-2.12) and decreased PCS (−0.72 per unit difference in score, 95% CI: −1.29 to −0.15) and MCS scores (−0.82 per unit difference in score, 95% CI: −1.48 to −0.16), whereas the second cluster was not (OR 1.24, 95% CI: 0.97-1.58; PCS 0.19, 95% CI −0.46 to 0.83; MCS −0.72, 95% CI: −1.50 to 0.06). Limitations: This was an exploratory analysis of a small data set from 2 centers. Further work is needed to externally validate these findings to confirm intradialytic symptom clusters and the generalizability of our findings. Conclusions: Intradialytic symptoms are correlated. The presence of select intradialytic symptoms may prolong the time it takes for a patient to recover from a dialysis treatment and impair HRQoL.

Background: In some jurisdictions, individuals become eligible or recommended for referral for different types of kidney care using criteria based on their estimated glomerular filtration rate (eGFR). Historically, GFR was estimated with an equation developed in 2009, which included a Black race term. An updated, race-free equation was developed in 2021. It is unclear how adoption of the 2021 equation will influence the number of individuals meeting referral criteria to receive different types of kidney care. Objective: To develop population-based estimates on how the number of individuals meeting the eGFR-based referral criteria to receive three different types of kidney care (nephrologist consultation, care in a multi-care specialty clinic, kidney transplant evaluation) changes when the 2021 versus 2009 equation is used to calculate eGFR. Design: Population-based, cross-sectional study. Setting: Ontario, Canada’s most populous province with 14.2 million residents as of 2021. Less than 5% of Ontario’s residents self-identify as being of Black race. Patients: Adults with at least one outpatient serum creatinine measurement in the 2 years prior to December 31, 2021. Measurements: Referral criteria to 3 different types of kidney care: nephrologist consultation, multi-care specialty clinic, and evaluation for a kidney transplant. The eGFR thresholds used to define referral eligibility or recommendation for these kidney health services were based on guidelines from Ontario’s provincial renal agency. Methods: The number of individuals meeting referral criteria for the 3 different healthcare services was compared between the 2009 and 2021 equations, restricted to individuals not yet receiving that level of care. As individual-level race data were not available, estimates were repeated, randomly assigning a Black race status to 1%, 5%, and 10% of the population. Results: We had an outpatient serum creatinine measurement available for 1 048 110 adults. Using the 2009 equation, 37 345 individuals met the criteria to be referred to a nephrologist, 10 019 met the criteria to receive care in a multi-care specialty clinic, and 10 178 met the criteria to be referred for kidney transplant evaluation. Corresponding numbers with the 2021 equation (and the percent relative to the 2009 equation) were 26 645 (71.3%), 9009 (89.9%), and 8615 (84.6%) individuals, respectively. These numbers were largely unchanged when Black race was assumed in up to 10% of the population. Limitations: Referral criteria based solely on urine albumin-to-creatinine ratio were not assessed. Self-reported race data were unavailable. Conclusions: For healthcare planning, in regions where a minority of the population is Black, a substantial number of individuals may no longer meet referral criteria for different types of kidney healthcare following adoption of the new 2021 eGFR equation.

Rationale & Objective: To determine whether attendance at an acute kidney injury (AKI) follow-up clinic is associated with reduced major adverse kidney events.Study Design: Propensity-matched cohort study.Setting & Participants: Patients hospitalized with AKI in Ontario, Canada, from February 1, 2013, through September 30, 2017, at a single clinical center, who were not receiving dialysis when discharged.Exposure: Standardized assessment by a nephrologist.Outcomes: Time to a major adverse kidney event, defined as death, initiation of maintenance dialysis, or incident/progressive chronic kidney disease.Analytical Approach: Propensity scores were used to match each patient who attended an AKI follow-up clinic to 4 patients who received standard care. Cox proportional hazards models were fit to assess the association between the care within an AKI follow-up clinic and outcomes. To avoid immortal time bias, we randomly assigned index dates to the comparator group. Results: We matched 164 patients from the AKI follow-up clinic to 656 patients who received standard care. During a mean follow-up of 2.2 +/- 1.3 (SD) years, care in the AKI follow-up clinic was not associated with a reduction in major adverse kidney events relative to standard care (22.1 vs 24.7 events per 100 patient-years; HR, 0.91 [95% CI, 0.75-1.11]). The AKI follow-up clinic was associated with a lower risk of all-cause mortality (HR, 0.71 [95% CI, 0.55-0.91]). Patients aged at least 66 years who attended the AKI follow-up clinic were more likely to receive beta-blockers (HR, 1.34 [95% CI, 1.02-1.77]) and statins (HR, 1.35 [95% CI, 1.05-1.74]), but not angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (HR, 1.21 [95% CI, 0.94-1.5 6]).Limitations: Single-center study and residual confounding. Conclusions: Specialized postdischarge follow-up for AKI survivors was not associated with a lower risk of major adverse kidney events but was associated with a lower risk of death and increased prescriptions for some cardioprotective medications.

Background People with advanced CKD are at high risk of mortality and morbidity from coronavirus disease 2019 (COVID-19). We measured rates of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and severe outcomes in a large population attending advanced CKD clinics during the first 21 months of the pandemic. We examined risk factors for infection and case fatality, and we assessed vaccine effectiveness in this population. Methods In this retrospective cohort study, we analyzed data on demographics, diagnosed SARS-CoV-2 infection rates, outcomes, and associated risk factors, including vaccine effectiveness, for people attending a province-wide network of advanced CKD clinics during the first four waves of the pandemic in Ontario, Canada. Results In a population of 20,235 patients with advanced CKD, 607 were diagnosed with SARS-CoV-2 infection over 21 months. The case fatality rate at 30 days was 19% overall but declined from 29% in the first wave to 14% in the fourth. Hospitalization and intensive care unit (ICU) admission rates were 41% and 12%, respectively, and 4% started long-term dialysis within 90 days. Significant risk factors for diagnosed infection on multivariable analysis included lower eGFR, higher Charlson Comorbidity Index, attending advanced CKD clinics for more than 2 years, non-White ethnicity, lower income, living in the Greater Toronto Area, and long-term care home residency. Being doubly vaccinated was associated with lower 30-day case fatality rate (odds ratio [OR], 0.11; 95% confidence interval [CI], 0.03 to 0.52). Older age (OR, 1.06 per year; 95% CI, 1.04 to 1.08) and higher Charlson Comorbidity Index (OR, 1.11 per unit; 95% CI, 1.01 to 1.23) were associated with higher 30-day case fatality rate. Conclusions People attending advanced CKD clinics and diagnosed with SARS-CoV-2 infection in the first 21 months of the pandemic had high case fatality and hospitalization rates. Fatality rates were significantly lower in those who were doubly vaccinated. Podcast This article contains a podcast at https://dts.podtrac.com/redirect.mp3/www.asn-online.org/media/podcast/CJASN/2023_04_10_CJN0000000000000087.mp3

Background: Guidelines in Ontario, Canada, recommend timely referral for multidisciplinary kidney care to facilitate planned dialysis initiation. Many patients do not receive recommended multidisciplinary kidney care prior to dialysis. Objective: To better understand why this gap in pre-dialysis care exists, we conducted a study to describe the pathways by which patients initiate maintenance dialysis. Design: A retrospective cohort study. Setting: Population-based, using health care administrative databases from Ontario, Canada. Patients: Adults initiating maintenance dialysis from April 2016 to March 2019. Measurements and methods: Patients were grouped based on whether they received recommended multidisciplinary kidney care prior to dialysis initiation (at least 1 year of care with at least 2 visits). For those who did not receive recommended care, we grouped patients as having no identified care gap or into the following groups: (1) lack of timely chronic kidney disease (CKD) screening, (2) late nephrology referral (<1 year), or (3) late or no referral for multidisciplinary kidney care among patients followed by a nephrologist for at least 1 year. Results: A total of 9216 patients were included with a mean (standard deviation) age of 66 (15) years, and 61.5% were male. Of the total, 896 (9.7%) patients died, 7671 (83.2%) remained on dialysis at 90 days, and 649 (7.0%) had stopped dialysis due to kidney function recovery within 90 days. Of the 9216 patients, 5434 (59%) had not received recommended multidisciplinary kidney care. Among those without recommended care, there were 2251 (41.4%) patients with no identified care gaps, 1351 (24.9%) patients with a lack of timely CKD screening, 359 (6.6%) patients with late nephrology referral, and 1473 (27.1%) patients with late or no referral for multidisciplinary kidney care. Limitations: We could not determine if patients were referred but declined multidisciplinary kidney care. Conclusions: More than half of patients had not received recommended multidisciplinary kidney care. Many patients experienced an acute decline in kidney function, which may not be preventable, but in others, there were missed opportunities for CKD screening or early referral to nephrology, or at the level of nephrology practice for early referral for multidisciplinary care. This work could be used to inform policies aimed at improving increased uptake of multidisciplinary kidney care prior to dialysis.

Rationale & Objective: Hypervolemia and vitamin D deficiency occur frequently in patients receiving peritoneal dialysis and may contribute to left ventricular (LV) hypertrophy. The effect of bioelectrical impedance analysis (BIA)-guided volume management or vitamin D supplementation on LV mass among those receiving peritoneal dialysis is uncertain. Study Design: Two-by-two factorial randomized controlled trial. Setting & Participants: Sixty-five patients receiving maintenance peritoneal dialysis. Intervention: BIA-guided volume management versus usual care and oral cholecalciferol 50,000 U weekly for 8 weeks followed by 10,000 U weekly for 44 weeks or matching placebo. Outcome: Change in LV mass at 1 year measured by cardiac magnetic resonance imaging. Results: Total body water decreased by 0.9 + 2.4 (SD) L in the BIA group compared with a 1.5 +/- 3.4 L increase in the usual care group (adjusted between-group difference: -2.4 [95% CI, -4.1 to -0.68] L, P = 0.01). LV mass increased by 1.3 +/- 14.3 g in the BIA group and decreased by 2.4 +/- 37.7 g in the usual care group (between-group difference: +2.2 [95% CI, -13.9 to 18.3] g, P = 0.8). Serum 25-hydroxyvitamin D concentration increased by a mean of 17.2 +/- 30.8 nmol/L in the cholecalciferol group and declined by 8.2 +/- 24.3 nmol/L in the placebo group (between-group difference: 28.3 [95% CI, 17.2-39.4] nmol/L, P < 0.001). LV mass decreased by 3.0 +/- 28.1 g in the cholecalciferol group and increased by 2.0 +/- 31.2 g in the placebo group (between-group difference: -4.5 [95% CI, -20.4 to 11.5] g, P = 0.6). Limitations: Relatively small sample size with larger than expected variation in change in LV mass. Conclusions: BIA-guided volume management had a modest impact on volume status with no effect on the change in LV mass. Vitamin D supplementation increased serum vitamin D concentration but had no effect on LV mass.

Introduction As of December 2021, 18.2 million have died globally from coronavirus disease 2019 (COVID-19) due to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and millions more suffer from longer-term consequences (1). Morbidity and mortality from COVID-19 is higher in patients who are immunocompromised, including those with advanced CKD (stages 4 and 5) and those with kidney failure. Even after propensity-score matching for the higher comorbid disease burden, a higher risk for hospitalization (risk ratio, 1.6; 95% confidence interval, 1.3 to 1.9) and mortality (risk ratio, 1.3; 95% confidence interval, 1.3 to 2.0) in severe CKD was reported (2). Although case fatality rates for patients on dialysis have fallen in recent waves and with vaccination, they remain markedly higher than those in the general population (3). While vaccines for COVID-19, particularly the mRNA vaccines, have reduced the severity and transmissibility of COVID-19, their effectiveness is attenuated in dialysis and transplant populations. Estimates of early antibody response in patients on dialysis were 89% relative to healthy controls, conferring incomplete protection that wanes over time (4). For kidney transplant recipients, antibody response was only 35% with small increments to repeat vaccination (4,5). For newer variants (such as omicron), higher antibody titers are required for viral neutralization, and vaccination alone will not provide sufficient protection against infection and severe outcomes in patients on dialysis and transplant patients (6). Patients with advanced CKD, patients receiving dialysis, and kidney transplant recipients are frequently excluded from clinical trials evaluating new drugs. This phenomenon, coined "renalism," recurred with COVID-19. A review of trial registries reported that 218 of 484 COVID-19 trials (45%) excluded patients with CKD (7). Studies evaluating nirmatrelvir/ritonavir have similarly excluded patients with advanced CKD, despite the relevance to this population. Nirmatrelvir/ritonavir, however, has pharmacology and toxicity data that can provide a basis for its use in advanced CKD (8). Nirmatrelvir/Ritonavir Efficacy Nirmatrelvir is an orally administered antiviral agent inhibiting the SARS-CoV-2 3-chymotrypsin–like cysteine protease enzyme (Mpro), also referred to as 3C-like protease or nsp5 protease, which renders the protein incapable of processing polyprotein precursors and prevents viral replication. The Evaluation of Protease Inhibition for COVID-19 in High-Risk Patients (EPIC-HR) trial evaluated the safety and efficacy of nirmatrelvir plus ritonavir in nonhospitalized adults with mild-to-moderate COVID-19 at high risk for progression to severe disease (9). Nirmatrelvir/ritonavir was initiated at a dose of 300 mg of nirmatrelvir plus 100 mg of ritonavir every 12 hours for 5 days within 5 days of symptom onset. The incidence of COVID-19–related hospitalization or death by day 28 was 89% lower in the nirmatrelvir group than in the placebo group. There were 13 deaths, all in the placebo group. On this basis, nirmatrelvir/ritonavir is indicated for the treatment of mild-to-moderate COVID-19 (i.e., for outpatient treatment) in adults with positive SARS-CoV-2 viral testing, and who are at high risk for progression to severe COVID-19, including hospitalization or death. Patients with advanced CKD are at such high risk, but were excluded from this trial, and there are theoretical concerns about drug accumulation and safety in these patients. For these reasons, the product monograph states that it is "not recommended" for those with an eGFR of <30 ml/min per 1.73 m2. Pharmacology of Nirmatrelvir/Ritonavir Nirmatrelvir is coadministered with a low dose (100 mg) of ritonavir, which acts as a pharmacokinetic enhancer. Ritonavir is a CYP3A4 inhibitor and enhances nirmatrelvir's bioavailability, allowing required therapeutic concentrations to be achieved. In preclinical studies, the concentration threshold that correlated with efficacy was 181 nM (292 ng/ml) (8). Hence, the desired dose of nirmatrelvir is that which maintains a trough level above this, and led to the 300-mg dose chosen in the EPIC-HR trial. Nirmatrelvir has a molecular mass of 499.5 D, 35% is approximately excreted by the kidneys, and it is 70% protein bound. Ritonavir is mostly hepatically metabolized and is 99% protein bound. Thus, nirmatrelvir is expected to accumulate with decreasing kidney function. In a phase 2 study (C4671005) of eight patients with serious kidney impairment (eGFR <30 ml/min per 1.73 m2, not on dialysis), the mean concentration at 24 hours was 694.2 ng/ml after a single dose of 100 mg nirmatrelvir (more than two times the required 292 ng/ml). Adverse Effects of Nirmatrelvir/Ritonavir From animal data, no adverse effects were observed at 1000 mg/kg per day, which correspond to an exposure approximately eight times higher than the recommended human dose (8). Nirmatrelvir-related adverse events after repeated dosing in monkeys at up to 600 mg/kg per day were limited to emesis, increased fibrinogen, and increased transaminases, which completely reversed within 2 weeks. In the EPIC-HR trial, serious adverse events were lower with nirmatrelvir/ritonavir (2%) compared with placebo (7%) (9). Adverse events reported by >1% of the participants were dysgeusia, nausea, vomiting, headache, diarrhea, and fever. In the phase 2 study with eGFR <30 ml/min per 1.73 m2, two of eight patients (25%) reported dysgeusia and dry mouth compared with none in the other arms with higher kidney function (8). Overall, nirmatrelvir/ritonavir has a favorable safety profile, with no evidence of dose-dependent toxicity. Rationale for Dosing in Patients with CKD and Those on Dialysis A single dose of 100 mg nirmatrelvir inhibited Mpro enzymatic activity at 24 hours in patients with an eGFR of <30 ml/min per 1.73 m2. Hemodialysis will clear a clinically insignificant amount of nirmatrelvir, on the basis of what is known about its molecular size, protein binding, and volume of distribution. The safety profile of nirmatrelvir is favorable, with few serious adverse effects, and the animal data are not indicative of dose-dependent toxicity. Nirmatrelvir is currently formulated as a 150-mg tablet and dosed at 300 mg along with 100 mg ritonavir twice a day for patients with normal kidney function, and at 150 mg with 100 mg ritonavir twice a day in those with an eGFR of 30–60 ml/min per 1.73 m2. A dose of 300 mg nirmatrelvir (with 100 mg ritonavir) on day 1, followed by 150 mg nirmatrelvir (with 100 mg ritonavir) administered daily, given after hemodialysis on dialysis days, should provide effective blood concentrations for enzyme inhibition (see Box 1). Minimal drug accumulation is expected on the basis of the short duration of therapy and single-dose pharmacokinetics. A lower dose of 150 mg every 48 hours could be considered for patients weighing <40 kg.Box 1.: Dosing guidance for nirmatrelvir/ritonavir in advanced CKD.Drug interactions are important because ritonavir is a potent CYP3A4 inhibitor and an inducer of other cytochrome p450 enzymes. Commonly used drugs in patients with CKD with important drug interactions include statins, calcium channel blockers, and direct-acting oral anticoagulants (see Box 1). These interactions are not always a contraindication to therapy and are mitigated by temporarily suspending or reducing the doses of CYP3A4-metabolized drugs. Support from pharmacists will help identify appropriate, temporary changes in treatments. A small case series using this modified lower dose of nirmatrelvir/ritonavir in 15 patients on dialysis who had COVID-19 reported rapid symptom resolution, with no safety signal, and highlighted the need to review drug interactions that were common in this population (P.A. Brown et al., unpublished observations). Rationale for Dosing in Kidney Transplant Recipients In patients with a kidney transplant, drug-drug interactions are an additional concern. The inhibition of drug metabolism due to ritonavir can result in extremely toxic levels (ten-fold higher) of calcineurin inhibitors (CNIs) and prolonged t1/2. To a lesser extent, levels of mycophenolic acid and sirolimus may also be affected. Even with an eGFR of >30 ml/min per 1.73 m2, CNIs must be held or decreased, and close monitoring of CNI levels is required after therapy is complete to also avoid low CNI levels. The American Society of Transplantation also provided guidance on use of nirmatrelvir/ritonavir in kidney transplant recipients with an eGFR of >30 ml/min per 1.73 m2 (see 10). Use in patients with an eGFR of <30 ml/min per 1.73 m2 should be considered cautiously in consultation with experienced teams, including infectious disease and pharmacy. Although not discussed separately here, similar considerations should also apply to patients with CKD due to glomerulonephritis receiving these immunosuppressive drugs. Conclusion The use of nirmatrelvir/ritonavir has been shown to be particularly effective in disarming SARS-CoV-2, especially in high-risk populations. Despite a relative dearth of data for the use and dosing of nirmatrelvir/ritonavir in patients with advanced CKD and those with a kidney transplant, these patients are at particularly high risk for COVID-19 morbidity and mortality and should not be excluded from therapy simply because of lack of data. We suggest patients with advanced CKD (eGFR <30 ml/min per 1.73 m2) and those receiving dialysis who contract COVID-19 be offered the low-dose nirmatrelvir/ritonavir regimens. This should be preceded by a discussion between the prescribing physician and the patient about the potential risks and benefits of the treatment, including alternative therapies. Special care must be taken with patients receiving immunosuppressive therapies, especially those with a kidney transplant, because drug-drug interactions can seriously affect the t1/2s of commonly used antirejection strategies. Disclosures C. Argyropoulos reports receiving research funding from Akebia and Alkahest, having consultancy agreements with Baxter, Bayer, Otsuka, and Quanta, and serving in an advisory or leadership role for Baxter Healthcare, Bayer, Health Services Advisory Group, and Quanta. P. Blake reports serving on the editorial board of American Journal of Nephrology, receiving honoraria from Baxter Global, and serving as medical director of Ontario Renal Network (this is a paid role). K.S. Brimble reports serving as provincial lead of Ontario Renal Network. P.A. Brown reports having consultancy agreements with Amgen Canada, AstraZeneca Canada, and Otsuka Canada, receiving honoraria from AstraZeneca Canada and Otsuka Canada, and receiving research funding from Otsuka Canada. Z. Chagla reports serving on a speakers bureau for Gilead and Pfizer, receiving research funding from Gilead and Roche, and having consultancy agreements with Pfizer. S. Hiremath receives research salary support from the Department of Medicine, University of Ottawa; reports serving on the editorial boards of American Journal of Hypertension, American Journal of Kidney Disease, and Canadian Journal of Cardiology; and serving on the board of directors for NephJC (not-for-profit educational entity). D. Juurlink reports receiving payment for lectures and medicolegal opinions regarding the safety and effectiveness of analgesics, including opioids, and serving as a member of Physicians for Responsible Opioid Prescribing (a volunteer organization that seeks to reduce opioid-related harm through more cautious prescribing practices). M. McGuinty reports receiving research funding from VBI. All remaining authors have nothing to disclose. Funding None.

BACKGROUND:There is limited research of electronic tools for self-management for patients with chronic kidney disease (CKD). We sought to evaluate participant engagement, perceived self-efficacy and website usage in a preliminary evaluation of My Kidneys My Health, a patient-facing eHealth tool in Canada.METHODS:We conducted an explanatory sequential mixed-methods study of adults with CKD who were not on kidney replacement therapy and who had access to My Kidneys My Health for 8 weeks. Outcomes included acceptance (measured by the Technology Acceptance Model), self-efficacy (measured by the Chronic Disease Self-Efficacy Scale [CDSES]) and website usage patterns (captured using Google Analytics). We analyzed participant interviews using qualitative content analysis.RESULTS:Twenty-nine participants with CKD completed baseline questionnaires, of whom 22 completed end-of-study questionnaires; data saturation was achieved with 15 telephone interviews. Acceptance was high, with more than 70% of participants agreeing or strongly agreeing that the website was easy to use and useful. Of the 22 who completed end-of-study questionnaires, 18 (82%) indicated they would recommend its use to others and 16 (73%) stated they would use the website in the future. Average scores for website satisfaction and look and feel were 7.7 (standard deviation [SD] 2.0) and 8.2 (SD 2.0) out of 10, respectively. The CDSES indicated that participants gained an increase in CKD information. Interviewed participants reported that the website offered valuable information and interactive tools for patients with early or newly diagnosed CKD, or for those experiencing changes in health status. Popular website pages and interactive features included Food and Diet, What is CKD, My Question List and the Depression Screener.INTERPRETATION:Participants indicated that the My Kidneys My Health website provided accessible content and tools that may improve self-efficacy and support in CKD self-management. Further evaluation of the website's effectiveness in supporting self-management among a larger, more heterogenous population is warranted.

INTRODUCTION:Chronic kidney disease (CKD) is a global-health problem. A significant proportion of referrals to nephrologists for CKD management are early and guideline-discordant, which may lead to an excess number of referrals and increased wait-times. Various initiatives have been tested to increase the proportion of guideline-concordant referrals and decrease wait times. This paper describes the protocol for a systematic review to study the impacts of quality improvement initiatives aimed at decreasing the number of non-guideline concordant referrals, increasing the number of guideline-concordant referrals and decreasing wait times for patients to access a nephrologist.METHODS AND ANALYSIS:We developed this protocol by using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses for Protocols (2015). We will search the following empirical electronic databases: MEDLINE, Embase, Cochrane Library, CINAHL, Web of Science, PsycINFO and grey literature for studies designed to improve guideline-concordant referrals or to reduce unnecessary referrals of patients with CKD from primary care to nephrology. Our search will include all studies published from database inception to April 2021 with no language restrictions. The studies will be limited to referrals for adult patients to nephrologists. Referrals of patients with CKD from non-nephrology specialists (eg, general internal medicine) will be excluded.ETHICS AND DISSEMINATION:Ethics approval will not be required, as we will analyse data from studies that have already been published and are publicly accessible. We will share our findings using traditional approaches, including scientific presentations, open access peer-reviewed platforms, and appropriate government and public health agencies.PROSPERO REGISTRATION NUMBER:CRD42021247756.

BACKGROUND:The effect of hemodialysis on cardiac biomarkers is unclear. We sought to evaluate the degree and causes of intradialytic variability of high sensitivity troponin I (hs-TnI), galectin-3 (gal-3), and heart-type fatty acid binding protein (hFABP).METHODS:hs-TnI, gal-3, and hFABP were prospectively measured pre-dialysis and post-dialysis for 1 week every month for 6 months in 178 prevalent adult hemodialysis patients at a single center in Hamilton, Canada. The degree of change from pre-dialysis to post-dialysis for each cardiac biomarker was estimated with multilevel linear regression models.RESULTS:The median change in the concentration of hs-TnI during hemodialysis was -1 ng/L (interquartile range [IQR] -1 to 2 ng/L) while gal-3 and hFABP changed by -36.3 ng/mL (IQR -27.7 to -46.8 ng/mL) and -19.41 ng/mL (IQR -13.61 to -26.87 ng/mL), respectively. The median (IQR) percentage intradialytic changes for hs-TnI, gal-3, and hFABP were 2.6% (-4.4% to 12.5%), -59.8% (-54.7% to -64.8%) and -35.3% (-28.4% to -42.1%), respectively. Ultrafiltration was associated with an increase in concentration of hs-TnI, gal-3, and hFABP (mean 0.99 ng/L, 1.05 ng/mL, and 1.9 ng/mL per L ultrafiltration, respectively, P < 0.001). Both gal-3 and hFABP concentrations decreased in association with the volume of blood processed (P < 0.001) and with hemodialysis treatment time (P  = 0.02 and P  = 0.04) while hs-TnI concentration decreased only in association with hemodialysis treatment time (P  < 0.001).CONCLUSIONS:Ultrafiltration volume and hemodialysis treatment time influenced hs-TnI, gal-3, and hFABP concentrations during hemodialysis and should be considered when interpreting their measurement.

Background: While home dialysis therapies are more cost effective and may offer improved health-related quality of life, uptake compared to in-center hemodialysis remains low. Objective: To test whether a web-based interactive health communication application (IHCA) compared to usual care would increase home dialysis use. Design: Randomized control trial Setting: Patients were recruited from 3 multidisciplinary kidney clinics across Ontario, Canada (Hamilton, Kingston, London). Patients: We included adults with advanced chronic kidney disease (CKD) followed in multidisciplinary kidney clinics. Patients who had not completed dialysis modality education, who did not have access to a home computer or the internet, who had significant hearing or vision impairment, who could not read/write/speak English, who had a medical contraindication for home dialysis, or who had selected conservative kidney care were excluded. Measurements: The primary outcome was any use of home dialysis (peritoneal dialysis or home hemodialysis) within 90 days of dialysis initiation. Secondary outcomes were social support, decision conflict and dialysis knowledge measured at baseline, 6 months and 1 year. Methods: Eligible patients were randomized to either usual care or the IHCA in addition to usual care in a 1:1 ratio. As part of usual care, all patients received education about dialysis modalities and kidney transplantation delivered by clinic nurses according to local practices. Randomization was performed using a computer-generated sequence in randomly permuted block sizes, stratified by site, and allocation occurred using sequentially numbered sealed, opaque envelopes. Participants, care providers, and outcome assessors were not blinded to the intervention. All analyses were performed blinded using an intention to treat approach. We estimated the effect of the ICHA on the odds of the primary outcome using unadjusted logistic regression models. Linear mixed models for repeated measures over time were used to analyze the impact of the IHCA on the secondary outcomes of interest. Results: We randomized 140 (usual care, n = 71; IHCA, n = 69) out of a planned 264 patients (mean [SD] age 61 [14.5] years, 65% men). Among patients randomized to the IHCA group that completed 6-month and 1-year follow-up visits, 56.8% and 71.4%, respectively, had not accessed the IHCA website within the past month. There were 23 (32.4%) and 26 (37.7%) patients in the usual care and IHCA groups who received a home dialysis therapy within 90 days of dialysis initiation (odds ratio, OR = 1.3, 95% CI = [0.6-2.5], P = .5). Among the 78 patients who initiated dialysis (n = 38 usual care, n = 40 IHCA), 60.5% and 65% in the usual care and IHCA groups received a home therapy within 90 days of dialysis initiation (OR = 1.2, 95% CI = [0.5-3.0], P = .7). Secondary outcomes did not differ by intervention group over time. Limitations: The trial was underpowered due to poor recruitment and use of the IHCA was low. Conclusions: We did not find evidence of a difference in home dialysis uptake with IHCA use, but our analyses were notably underpowered. The incorporation of greater patient engagement, qualitative research and design research, and pilot implementation may help future evaluations of strategies to improve home dialysis uptake. Trial Registration: ClinicalTrials.gov # NCT01403454, registration date: Jul 21, 2011 Keywords chronic kidney disease , trial , dialysis , education , home dialysis

Abstract Background Polypharmacy, often defined as the concomitant use of ≥ 5 medications, has been identified as a significant global public health threat. Aging and multimorbidity are key drivers of polypharmacy and have been linked to a broad range of adverse health outcomes and mortality. Patients with chronic kidney disease (CKD) are particularly at high risk of polypharmacy and use of potentially inappropriate medications given the numerous risk factors and complications associated with CKD. The aim of this systematic review will be to assess the prevalence of polypharmacy among adult patients with CKD, and the potential association between polypharmacy and adverse health outcomes within this population. Methods/design We will search empirical databases such as MEDLINE, Embase, Cochrane Library, CINAHL, Web of Science, and PsycINFO and grey literature from inception onwards (with no language restrictions) for observational studies (e.g., cross-sectional or cohort studies) reporting the prevalence of polypharmacy in adult patients with CKD (all stages including dialysis). Two reviewers will independently screen all citations, full-text articles, and extract data. Potential conflicts will be resolved through discussion. The study methodological quality will be appraised using an appropriate tool. The primary outcome will be the prevalence of polypharmacy. Secondary outcomes will include any adverse health outcomes (e.g., worsening kidney function) in association with polypharmacy. If appropriate, we will conduct random effects meta-analysis of observational data to summarize the pooled prevalence of polypharmacy and the associations between polypharmacy and adverse outcomes. Statistical heterogeneity will be estimated using Cochran’s Q and I2 index. Additional analyses will be conducted to explore the potential sources of heterogeneity (e.g., sex, kidney replacement therapy, multimorbidity). Discussion Given that polypharmacy is a major and a growing public health issue, our findings will highlight the prevalence of polypharmacy, hazards associated with it, and medication thresholds associated with adverse outcomes in patients with CKD. Our study will also draw attention to the prognostic importance of improving medication practices as a key priority area to help minimize the use of inappropriate medications in patients with CKD. Systematic review registration PROSPERO registration number: [ CRD42020206514 ].

BACKGROUND:Supporting patients to self-manage their chronic kidney disease (CKD) has been identified as a research priority by patients with CKD and those who care for them. Self-management has been shown to slow CKD progression and improve the quality of life of individuals living with the disease. Previous work has identified a need for a person-centered, theory-informed, web-based tool for CKD self-management that can be individualized to a patient's unique situation, priorities, and preferences. We addressed this gap using an integrated knowledge translation method and patient engagement principles.OBJECTIVE:The aim of this study is to conduct systematic co-design and usability testing of a web-based self-management prototype for adults with CKD (nondialysis and nontransplant) and their caregivers to enhance self-management support.METHODS:A multistep, iterative system development cycle was used to co-design and test the My Kidneys My Health prototype. The 3-step process included creating website features and content using 2 sequential focus groups with patients with CKD and caregivers, heuristic testing using the 10 heuristic principles by Nielsen, and usability testing through in-person 60-minute interviews with patients with CKD and their caregivers. Patients with CKD, caregivers, clinicians, researchers, software developers, graphic designers, and policy makers were involved in all steps of this study.RESULTS:In step 1, 18 participants (14 patients and 4 caregivers) attended one of the 2 sequential focus groups. The participants provided specific suggestions for simplifying navigation as well as suggestions to incorporate video, text, audio, interactive components, and visuals to convey information. A total of 5 reviewers completed the heuristic analysis (step 2), identifying items mainly related to navigation and functionality. Furthermore, 5 participants completed usability testing (step 3) and provided feedback on video production, navigation, features and functionality, and branding. Participants reported visiting the website repeatedly for the following features: personalized food tool, my health care provider question list, symptom guidance based on CKD severity, and medication advice. Usability was high, with a mean system usability score of 90 out of 100.CONCLUSIONS:The My Kidneys My Health prototype is a systematically developed, multifaceted, web-based CKD self-management support tool guided by the theory and preferences of patients with CKD and their caregivers. The website is user friendly and provides features that improve user experience by tailoring the content and resources to their needs. A feasibility study will provide insights into the acceptability of and engagement with the prototype and identify preliminary patient-reported outcomes (eg, self-efficacy) as well as potential factors related to implementation. This work is relevant given the shift to virtual care during the current pandemic times and provides patients with support when in-person care is restricted.

Background:Patients with AKI may require interhospital transfer to receive RRT. Interhospital transfer may lead to delays in therapy, resulting in poor patient outcomes. There is minimal data comparing outcomes among patients undergoing transfer for RRT versus those who receive RRT at the hospital to which they first present.Methods:We conducted a population-based cohort study of all adult patients (≥19 years) who received acute dialysis within 14 days of admission to an acute-care hospital between April 1, 2004 and March 31, 2015. The transferred group included all patients who presented to a hospital without a dialysis program and underwent interhospital transfer (with the start of dialysis ≤3 days of transfer and within 14 days of initial admission). All other patients were considered nontransferred. The primary outcome was time to 90-day all-cause mortality, adjusting for demographics, comorbidities, and measures of acute illness severity. We also assessed chronic dialysis dependence as a secondary outcome, using the Fine and Gray proportional hazards model to account for the competing risks of death. In a secondary post hoc analysis, we assessed these outcomes in a propensity score-matched cohort, matching on age, sex, and prior CKD status.Results:We identified 27,270 individuals initiating acute RRT within 14 days of a hospital admission, of whom 2113 underwent interhospital transfer. Interhospital transfer was associated with lower rate of mortality (adjusted hazard ratio [aHR], 0.90; 95% CI, 0.84 to 0.97). Chronic dialysis dependence was not significantly different between groups (aHR, 0.98; 95% CI, 0.91 to 1.06). In the propensity score-matched analysis, interhospital transfer remained associated with a lower risk of death (HR, 0.88; 95% CI, 0.80 to 0.96).Conclusions:Interhospital transfer for receipt of RRT does not confer higher mortality or worse kidney outcomes.

Background: One of the key components of multidisciplinary CKD clinics is education; however, kidney disease knowledge among patients followed in these clinics is not routinely measured. Objective: The aim of this study was to determine objective and perceived kidney disease knowledge and patient characteristics associated with knowledge among patients followed in a multi-care kidney clinic. Design: This is a cross-sectional survey study. Setting: This study was conducted in a multi-care kidney clinic in Ontario, Canada. Patients: Patients who did not speak English, who were unable to read due to significant vision impairment, or who had a known history of dementia or significant cognitive impairment were excluded. Measurements: Perceived kidney disease knowledge was evaluated using a previously validated 9-item survey (PiKS). Each question on the perceived knowledge survey had 4 possible responses, ranging from “I don’t know anything” (1) to “I know a lot” (4). Objective kidney disease knowledge was evaluated using a previously validated survey (KiKS). Methods: The association between patient characteristics and perceived and objective kidney disease knowledge was determined using linear regression. Results: A total of 125 patients were included, 57% were male, the mean (SD) age and eGFR were 66 (13) years and 16 (5.9) mL/min/1.73 m2, respectively. The median (IQR) objective and perceived knowledge survey scores were 19 out of 27 (16, 21) and 2.9 out of 4 (2.4, 3.2), respectively. Only 25% of patients answered correctly that CKD can be associated with no symptoms, and 64% of patients identified correctly that the kidneys make urine. More than 60% of patients perceived themselves to know nothing or only a little about medications that help or hurt the kidney. Older age was independently associated with lower perceived and objective knowledge, but sex, income, and educational attainment were not. Limitations: This is a single-center study. Cognitive impairment was based on the treating team’s informal assessment or prior documentation in the chart; formal cognitive testing was not performed as part of this study. Conclusions: Despite resource-intensive care, CKD knowledge of patients followed in a multidisciplinary clinic was found to be modest. Whether enhanced educational strategies can improve knowledge and whether increasing knowledge improves patient outcomes warrants further study.