Difelikefalin in Black/African American Hemodialysis Patients with Moderate-to-Severe Pruritus: Post hoc Analysis of KALM-1 and KALM-2.

INTRODUCTION: Black and African American (AA) people are over-represented in the kidney failure population; therefore, the safety and efficacy of difelikefalin in Black/AA patients was evaluated. METHODS: This was a post hoc, pooled exploratory subgroup analysis of the Phase 3 KALM-1 and -2 studies. Patients undergoing hemodialysis (HD) who had moderate-to-severe chronic kidney disease-associated pruritus (CKD-aP) at enrollment were stratified into self-reported Black/AA or White subgroups. Patients were randomized (1:1) to receive intravenous (IV) difelikefalin 0.5 µg/kg or placebo for 12 weeks. Difelikefalin efficacy was assessed with validated patient-reported outcome questionnaires: 24-h Worst Itch Numerical Rating Scale (WI-NRS), 5-D itch, and Skindex­10. RESULTS: There were 249 (29.3%) patients from the KALM studies that self-identified as Black/AA (n = 135 difelikefalin; n = 114 placebo). Clinically meaningful (≥3-point) reduction in WI-NRS score was achieved by 47.9% of Black/AA patients with difelikefalin versus 24.6% with placebo (p < 0.001). More Black/AA patients achieved a ≥5-point 5-D itch total improvement (54.9% vs. 35.7%; p = 0.013) and a ≥15-point Skindex-10 score improvement with difelikefalin versus placebo (49.0% vs. 28.9%; p = 0.006) compared with White patients. Incidence of treatment-emergent adverse events (TEAEs) was higher for Black/AA patients (difelikefalin: 78.5%; placebo: 70.8%) versus White patients (difelikefalin: 64.8%; placebo: 61.8%). CONCLUSION: In this post hoc analysis, difelikefalin was efficacious in the Black/AA population and had an acceptable safety profile.

A New Understanding of Potassium's Influence Upon Human Health and Renal Physiology.

Potassium channels are expressed in virtually all cell types, and their activity is the dominant determinant of cellular membrane potential. As such, potassium flux is a key regulator of many cellular processes including the regulation of action potentials in excitable cells. Subtle changes in extracellular potassium can initiate signaling processes vital for survival (insulin signaling) while more extreme and chronic changes may lead to pathological states (acid-base disturbances and cardiac arrhythmia). While many factors acutely influence extracellular potassium levels, it is principally the role of the kidneys to maintain potassium balance by matching urinary excretion with dietary intake. When this balance is disrupted, human health is negatively impacted. In this review, we discuss evolving views of dietary potassium intake as means of preventing and mitigating diseases. We also provide an update on a molecular pathway called the potassium switch, a mechanism by which extracellular potassium regulates distal nephron sodium reabsorption. Finally, we review recent literature describing how several popular therapeutics influence potassium homeostasis.

Osmotic Demyelination Syndrome in Patients Hospitalized with Hyponatremia.

BACKGROUND: Osmotic demyelination syndrome (ODS) is a rare but potentially devastating neurologic complication of hyponatremia. The primary objective of this study was to identify the proportion of patients who developed ODS in a large, contemporary, multicenter cohort of patients admitted to the hospital with hyponatremia. METHODS: We conducted a multicenter cohort study of patients admitted with hyponatremia at five academic hospitals in Toronto, Ontario, Canada, between April 1, 2010, and December 31, 2020. All adult patients presenting with hyponatremia (serum sodium level 8 mmol/l in any 24-hour period). RESULTS: Our cohort included 22,858 hospitalizations with hyponatremia. Approximately 50% were women, the average age was 68 years, and mean initial serum sodium was 125 mmol/l (standard deviation, 4.6), including 11.9% with serum sodium from 110 to 119 mmol/l and 1.2% with serum sodium less than 110 mmol/l. Overall, rapid correction of serum sodium occurred in 3632 (17.7%) admissions. Twelve patients developed ODS (0.05%). Seven (58%) patients who developed ODS did not have rapid correction of serum sodium. CONCLUSIONS: In this large multicenter study of patients with hyponatremia, rapid correction of serum sodium was common (n=3632 [17.7%]), but ODS was rare (n=12 [0.05%]). Future studies with a higher number of patients with ODS are needed to better understand potential causal factors for ODS.

Efficacy of Difelikefalin for the Treatment of Moderate to Severe Pruritus in Hemodialysis Patients: Pooled Analysis of KALM-1 and KALM-2 Phase 3 Studies.

Rationale & Objective: Chronic kidney disease-associated pruritus (CKD-aP) in patients treated by hemodialysis (HD) impairs quality of life (QoL). Difelikefalin, a selective κ-opioid receptor agonist, decreased the intensity of CKD-aP in patients undergoing HD. This pooled analysis evaluated difelikefalin's efficacy and the itch-related QoL overall and in subgroups defined by demographics or disease characteristics. Study Design: In KALM-1 and KALM-2, participants were randomized (1:1) to receive intravenous difelikefalin or placebo 3 times/wk for 12 weeks, followed by a 52-week open-label extension. Setting & Participants: Adults with moderate to severe CKD-aP treated by HD in North America, Europe, and the Asia-Pacific region. Intervention: Intravenous difelikefalin at 0.5 mcg/kg or placebo. Outcomes: Itch intensity (Worst Itching Intensity Numerical Rating Scale [WI-NRS]) and itch-related QoL (Skindex-10 and 5-D Itch questionnaires). Results: 851 participants were randomized (difelikefalin, n = 426; placebo, n = 425). This pooled analysis demonstrated early     (week 1), sustained difelikefalin efficacy, with significantly greater achievement of ≥3-point WI-NRS reduction with difelikefalin (51.1%) versus placebo (35.2%; P < 0.001). Achievement of a ≥4-point WI-NRS reduction was significantly greater with difelikefalin (38.7%) versus placebo (23.4%; P < 0.001). Difelikefalin reduced itch intensity in subgroups based on age, sex, anti-itch medication use, the presence of specific medical conditions, and gabapentin or pregabalin use. More participants receiving difelikefalin versus placebo achieved clinically meaningful decreases of ≥15 points on the Skindex-10 scale (55.5% vs 40.5%, respectively; P < 0.001) and ≥5 points on the 5-D Itch scale (52.1% vs 42.3%, respectively; P = 0.01), with sustained 5-D Itch effects up to 64 weeks. Limitations: Subgroup samples were small. The WI-NRS, Skindex-10, and 5-D Itch are not used in routine clinical care of dialysis patients; therefore, findings may not reflect the real-world effectiveness of difelikefalin. Conclusions: Difelikefalin demonstrated rapid, sustained efficacy, with consistent results in diverse populations of patients treated by HD. Funding: Cara Therapeutics, Inc. Trial Registration: The KALM-1 trial is registered as NCT03422653 and the KALM-2 trial is registered as NCT03636269.

Sodium-Glucose Co-transporter 2 Inhibitor-Associated Euglycemic Diabetic Ketoacidosis After Bariatric Surgery: A Case and Literature Review.

Sodium-glucose cotransporter-2 inhibitors (SGLT2i) reduce cardiovascular, kidney, and overall mortality. SGLT2i are also associated with a rare adverse event, euglycemic diabetic ketoacidosis (EDKA). This report describes a case of EDKA one day after bariatric surgery in a 51-year-old female with type 2 diabetes mellitus managed with the SGLT2i, canagliflozin. She was following a ketogenic diet for three weeks prior to surgery. The patient made a steady recovery with rapid anion gap closure followed by prolonged non-anion gap metabolic acidosis. Her medical record was tagged with a life-threatening reaction to SGLT2i. The risk of EDKA from SGLT2i may be increased by a low carbohydrate diet or postoperative status. Our case was complicated by hypokalemia, exemplifying the need for aggressive electrolyte management. Further guidance is needed to manage risk factors provoking EDKA and the use of SGLT2i therapy after an episode of EDKA.

Review of Early Immune Response to SARS-CoV-2 Vaccination Among Patients With CKD.

The effects of the coronavirus disease-2019 (COVID-19) pandemic, particularly among those with chronic kidney disease (CKD), who commonly have defects in humoral and cellular immunity, and the efficacy of vaccinations against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) are uncertain. To inform public health and clinical practice, we synthesized published studies and preprints evaluating surrogate measures of immunity after SARS-CoV-2 vaccination in patients with CKD, including those receiving dialysis or with a kidney transplant. We found 35 studies (28 published, 7 preprints), with sample sizes ranging from 23 to 1140 participants and follow-up ranging from 1 week to 1 month after vaccination. Seventeen of these studies enrolled a control group. In the 22 studies of patients receiving dialysis, the development of antibodies was observed in 18% to 53% after 1 dose and in 70% to 96% after 2 doses of mRNA vaccine. In the 14 studies of transplant recipients, 3% to 59% mounted detectable humoral or cellular responses after 2 doses of mRNA vaccine. After vaccination, there were a few reported cases of relapse or de novo glomerulonephritis, and acute transplant rejection, suggesting a need for ongoing surveillance. Studies are needed to better evaluate the effectiveness of SARS-CoV-2 vaccination in these populations. Rigorous surveillance is necessary for detection of long-term adverse effects in patients with autoimmune disease and transplant recipients. For transplant recipients and those with suboptimal immune responses, alternate vaccination platforms and strategies should be considered. As additional data arise, the NephJC COVID-19 page will continue to be updated (http://www.nephjc.com/news/covid-vaccine).

COVID-19, Social Media, and the Role of the Public Physician.

The COVID-19 pandemic has resulted in an avalanche of information, much of it false or misleading. Social media posts with misleading or dangerous opinions and analyses are often amplified by celebrities and social media influencers; these posts have contributed substantially to this avalanche of information. An emerging force in this information infodemic is public physicians, doctors who view a public presence as a large segment of their mission. These physicians bring authority and real-world experience to the COVID-19 discussion. To investigate the role of public physicians, we interviewed a convenience cohort of physicians who have played a role in the infodemic. We asked the physicians about how their roles have changed, how their audience has changed, what role politics plays, and how they address misinformation. The physicians noted increased audience size with an increased focus on the pandemic. Most avoided confronting politics, but others found it unavoidable or that even if they tried to avoide it, it would be brought up by their audience. The physicians felt that confronting and correcting misinformation was a core part of their mission. Public physicians on social media are a new occurrence and are an important part of fighting online misinformation.

Proliferation of Papers and Preprints During the Coronavirus Disease 2019 Pandemic: Progress or Problems With Peer Review?

The coronavirus disease 2019 (COVID-19) pandemic has spread exponentially throughout the world in a short period, aided by our hyperconnected world including global trade and travel. Unlike previous pandemics, the pace of the spread of the virus has been matched by the pace of publications, not just in traditional journals, but also in preprint servers. Not all publication findings are true, and sifting through the firehose of data has been challenging to peer reviewers, editors, as well as to consumers of the literature, that is, scientists, healthcare workers, and the general public. There has been an equally exponential rise in the public discussion on social media. Rather than decry the pace of change, we suggest the nephrology community should embrace it, making deposition of research into preprint servers the default, encouraging prepublication peer review more widely of such preprint studies, and harnessing social media tools to make these actions easier and seamless.

A Picture Is Worth a Thousand Views: A Triple Crossover Trial of Visual Abstracts to Examine Their Impact on Research Dissemination.

BACKGROUND: A visual abstract is a graphic summary of a research article's question, methods, and major findings. Although they have a number of uses, visual abstracts are chiefly used to promote research articles on social media. OBJECTIVE: This study aimed to determine if the use of visual abstracts increases the visibility of nephrology research shared on Twitter. METHODS: A prospective case-control crossover study was conducted using 40 research articles published in the American Journal of Nephrology (AJN). Each article was shared by the AJN Twitter account in 3 formats: (1) the article citation, (2) the citation with a key figure from the article, and (3) the citation with a visual abstract. Tweets were spaced 2 weeks apart to allow washout of the previous tweet, and the order of the tweets was randomized. Dissemination was measured via retweets, views, number of link clicks, and Altmetric scores. RESULTS: Tweets that contained a visual abstract had more than twice as many views as citation-only tweets (1351, SD 1053 vs 639, SD 343) and nearly twice as many views as key figure tweets (1351, SD 1053 vs 732, SD 464). Visual abstract tweets had 5 times the engagements of citation-only tweets and more than 3.5 times the engagements of key figure tweets. Visual abstract tweets were also associated with greater increases in Altmetric scores as compared to citation-only tweets (2.20 vs 1.05). CONCLUSIONS: The use of visual abstracts increased visibility of research articles on Twitter, resulting in a greater number of views, engagements, and retweets. Visual abstracts were also associated with increased Altmetric scores as compared to citation-only tweets. These findings support the broader use of visual abstracts in the scientific community. Journals should consider visual abstracts as valuable tools for research dissemination.