Erythropoiesis-stimulating agent hyporesponsiveness was associated with worse survival of hemodialysis patients independent of the serum ferritin level.

INTRODUCTION: Ferritin level and erythropoiesis-stimulating agent (ESA) responsiveness are each associated with hemodialysis patient survival. We assessed interrelationships between these two vs. survival. METHODS: Patients in the Japan Dialysis Outcomes and Practice Patterns Study Phases 4-6 (2009-2018) were included. All-cause mortality associations were assessed with progressive adjustment to evaluate covariate influence. RESULTS: During follow-up (median 2.6 years), 773 of 5154 patients died. After covariate adjustment, the mortality hazard ratio (HR) was 0.99 (95% CI: 0.81, 1.20) for low serum ferritin and 1.12 (CI: 0.89, 1.41) for high serum ferritin. By contrast, mortality risk with elevated ESA resistance index (ERI) persisted after covariate adjustment (HR 1.44, CI [1.17-1.78]). The serum ferritin and ERI interaction was not significant; p > 0.96 across all models. CONCLUSIONS: Japanese hemodialysis patients with high ERI experienced worse survival independent of serum ferritin levels, highlighting the importance of identifying and mitigating ESA hyporesponsiveness among dialysis patients.

Frailty, multimorbidity and polypharmacy: exploratory analyses of the effects of empagliflozin from the EMPA-KIDNEY trial.

BACKGROUND: Sodium-glucose co-transporter-2 (SGLT2) inhibitors are recommended treatment for adults with chronic kidney disease (CKD), but uncertainty exists regarding their use in patients with frailty and/or multimorbidity, among whom polypharmacy is common. We derived a multivariable logistic regression model to predict hospitalization (reflecting frailty) and assessed empagliflozin's risk-benefit profile in a post-hoc analysis of the double-blind, placebo-controlled EMPA-KIDNEY trial. METHODS: The EMPA-KIDNEY trial randomized 6609 patients with CKD (estimated glomerular filtration rate [eGFR] ≥20<45 mL/min/1.73m2, or ≥45<90 mL/min/1.73m2 with urinary albumin-to-creatinine ratio ≥200 mg/g) to receive either empagliflozin 10 mg daily or matching placebo and followed for two years (median). Additional characteristics analysed in subgroups were multimorbidity, polypharmacy and health-related quality of life (HRQoL) at baseline. Cox regression analyses were performed with subgroups defined by approximate thirds of each variable. RESULTS: The strongest predictors of hospitalization were N-terminal prohormone of brain natriuretic peptide, poor mobility and diabetes; then eGFR and other comorbidities. Empagliflozin was generally well-tolerated independent of predicted risk of hospitalization. In relative terms, allocation to empagliflozin reduced the risk of the primary outcome of kidney disease progression or cardiovascular death by 28% (hazard ratio [HR] 0.72, 95% confidence interval [CI] 0.64-0.82); and all-cause hospitalization by 14% (HR 0.86, 95% CI 0.78-0.95); with broadly consistent effects across subgroups of predicted risk of hospitalization, multimorbidity, polypharmacy or HRQoL. In absolute terms, the estimated benefits of empagliflozin were greater in those at highest predicted risk of hospitalization (reflecting frailty) and outweighed potential serious harms. CONCLUSIONS: These findings support the use of SGLT2 inhibitors in CKD, irrespective of frailty, multimorbidity or polypharmacy.

Latent metabolic bone disease, skeletal dysplasia and other conditions related to low bone formation among 38 patients with subtrochanteric femoral fractures: a retrospective observational study.

Subtrochanteric femoral fracture is rare and intractable due to the possible association with low bone formation. Retrospective analysis of 38 patients with subtrochanteric femoral fractures revealed that four patients suffered from disorders related to low bone formation and there were specific treatments for two of them. PURPOSE: The main aim of this study was to detect latent metabolic bone diseases and skeletal dysplasia associated with low bone formation among patients with morphologic atypical femoral fracture (AFF). A second aim was to evaluate the frequency of recognized risk factors, such as antiresorptive agents, glucocorticoids, and age. METHODS: Clinical information was retrospectively analyzed among 38 Japanese patients who were admitted to the Department of Orthopedic Surgery and Spinal Surgery and the Division of Emergency and Critical Care Medicine at the University of Tokyo Hospital with diagnoses of subtrochanteric fractures between February 2012 and March 2022. RESULTS: Among 38 patients (including 30 females), 21 patients were aged 75 and over. Ten patients had past oral glucocorticoid use, and 18 had past antiresorptive agent use. Two patients were diagnosed with hypophosphatemic osteomalacia after the development of fractures. One patient was suspected to be a carrier of a loss-of-function variant of alkaline phosphatase, biomineralization associated (ALPL), and one other patient had previously been genetically diagnosed with pycnodysostosis. Among four patients with a diagnosis or suspicion of these metabolic bone diseases and skeletal dysplasia, four had past clinical fractures, two had past subtrochanteric femoral fractures, and two had subtrochanteric femoral fractures on both sides. CONCLUSION: If clinicians encounter patients with morphologic AFF, latent diseases related to low bone formation should be carefully differentiated because appropriate treatment may prevent delayed union and recurrent fractures. Additionally, it may be desirable to exclude these bone diseases in advance before initiating long-term use of antiresorptive agents in osteoporotic patients by screening with serum alkaline phosphatase levels to reduce the risk of morphologic AFF.

Association between magnesium, erythropoietin resistance and mortality: the Japanese Dialysis Outcomes and Practice Patterns Study (J-DOPPS).

Background: Limited data are now available to evaluate the relationship between serum magnesium level, anemia and mortality in the dialysis population. Methods: Using data from the Japanese Dialysis Outcomes and Practice Patterns Study (J-DOPPS) phases 5 and 6, we analyzed the association between serum magnesium (s-Mg) levels and the erythropoiesis-stimulating agents resistance index (ERI) as the primary outcome. To estimate the longitudinal relationship, a mixed-effect model was used with ERI at each 4-month period as the dependent variable and quintiles of s-Mg at the previous 4-month period as the independent variable. We also examined incidence of infectious events, and the all-cause and cardiovascular disease (CVD)-related deaths as secondary outcomes by Cox regression with quintiles of s-Mg at baseline. Results: Of the 4776 participants in J-DOPPS, 1650 were included in the analysis. The median of s-Mg at baseline was 2.5 mg/dL. A significant linear association of s-Mg with ERI (P for trend <.001) was revealed. Low and high s-Mg levels were not associated with the clinical outcomes of interest, except for the highest quintile of s-Mg being significantly associated with lower incidence of all-cause mortality and CVD-related deaths compared with the middle (reference) quintile. Conclusions: We observed that lower s-Mg levels subsequently induced higher ERI and that mild higher s-Mg levels were possibly associated with good rather than poor outcomes in Japanese hemodialysis patients. Adjustment of s-Mg levels may be proposed as a new strategy at a low cost and risk to reduce the risk of premature mortality.

FGF-23, Left Ventricular Hypertrophy, and Mortality in Patients With CKD: A Revisit With Mediation Analysis.

Background: In patients with chronic kidney disease (CKD), fibroblast growth factor (FGF)-23 is suspected to cause death or cardiovascular disease by inducing left ventricular hypertrophy (LVH). Objectives: This study aims to quantify the mediational effect of LVH in the hypothetical causal pathway from FGF-23 to long-term adverse outcomes. Methods: From 3,939 adults with CKD stages 2 to 4 enrolled in the CRIC (Chronic Renal Insufficiency Cohort) study, 2,368 participants with available data of FGF-23, left ventricular mass index at 1 year, and covariates were included. We employed linear and Cox proportional hazards regression models to investigate the association between FGF-23 and LVH, all-cause mortality, atrial fibrillation (AF), or congestive heart failure (CHF). Mediation analysis was used within a counterfactual framework to decompose the effect of FGF-23 into natural direct and indirect effects. Results: Among 2,368 participants (mean age: 57.7 years, 1,252 males, median FGF-23 level: 138.8 RU/mL), left ventricular mass index was positively correlated with FGF-23. During a median of 12.0, 11.1, and 11.1 years, FGF-23 was associated with all-cause mortality (HR: 1.62, 95% CI: 1.24-2.12), AF (HR: 1.58, 95% CI: 1.12-2.24), and CHF (HR: 1.32, 95% CI: 0.95-1.84) when the highest quartile was compared to the lowest quartile. LVH mediated 7.4%, 11.2%, and 21.9% of the effect of FGF-23 on all-cause mortality, AF, and CHF, respectively. Conclusions: In CKD patients, FGF-23 had a minor effect on the development of long-term adverse outcomes through LVH. Other potential mediators and the validity of negative effect of FGF-23 should be explored.

Significance of eGFR and proteinuria for cardiovascular disease in individuals beyond 85 years.

BACKGROUND: There are limited data on how advancing age influences prediction of CVD risk based on the estimated glomerular filtration rate (eGFR) and proteinuria, especially in older adults, including those aged ≥ 85 years. This study aimed to clarify the association of eGFR and proteinuria with CVD outcomes and the impact of age on this association. METHODS: The distribution of eGFR and urine protein in Japan was assessed retrospectively using real-world administrative claims and health checkup data collected between April 2014 and November 2022. We investigated the associations of these two parameters with the incidence of CVD, with an emphasis on the impact of aging. RESULTS: We assessed 1 829 020 individuals for distribution of eGFR and proteinuria; after excluding those with known CVD, their association with CVD risk was examined in 1 040 101 individuals aged ≥ 40 years. The prevalence of impaired kidney function (eGFR <60 mL/min/1.73 m2) increased with age, being 0.7%, 9.2%, 21.9%, 40.2%, and 60.2% at the ages of 18-39, 40-64, 65-74, 75-84, and ≥ 85 years (P for trend < 0.001); similarly, the proportion with positive proteinuria increased with age, being 2.7%, 4.3%, 5.6%, 9.2%, and 15.8%, respectively (P for trend < 0.001). Both eGFR and urine protein were identified to be independent risk factors for CVD. Hazard ratios for CVD increased significantly when eGFR was <45 mL/min/1.73 m2 at the ages of 40-64, 65-74, and 75-84 and <30 mL/min/1.73 m2 at ≥ 85 years, while proteinuria remained significantly associated with a high CVD risk regardless of age. These findings were consistent even when analyzed separately by sex. CONCLUSIONS: This study identified eGFR and urine dipstick proteinuria to be independent risk factors for CVD, even among individuals aged ≥ 85 years. However, the contribution of eGFR to the CVD risk was attenuated by aging, whereas proteinuria remained less affected by advancing age.

Chronic Tonsillitis and IgA Nephropathy: Findings From a Nationwide Japanese Cohort Study.

RATIONALE & OBJECTIVE: Little is known regarding the association between chronic tonsillitis and the onset of IgA nephropathy (IgAN). In the present study, we examined the potential relationship between chronic tonsillitis and a subsequent risk of developing IgAN. STUDY DESIGN: Observational cohort study. SETTING: & Participants: 4,311,393 individuals without a history of IgAN identified between January 2005 to May 2022 within a Japanese nationwide epidemiological database, the JMDC Claims Database, representing health claims to over 60 insurers. EXPOSURE: Comorbid chronic tonsillitis based on diagnosis codes. OUTCOME: IgAN occurrence. ANALYTICAL APPROACH: Cause-specific Cox proportional hazards analysis adjusting for potential confounding factors were employed to estimate hazard ratios (HRs). RESULTS: Comorbid chronic tonsillitis was identified in 12,842 individuals, constituting 0.3% of the cohort. The cohort had a median age of 44 years (interquartile range: 36-53), and males accounted for 57.9%, with a follow-up of 1,089 days (interquartile range: 532-1,797), during which 2,653 cases of IgAN developed. Cumulative incidence curve showed a higher cumulative incidence of IgAN in individuals with chronic tonsillitis compared to their counterparts without this condition. Multivariable cause-specific analysis further demonstrated that individuals with chronic tonsillitis had an elevated risk of developing IgAN, with a HR of 2.72 (95% confidence interval: 1.79-4.14). LIMITATIONS: Potential residual confounders, and lack of consideration for ethnic distinctions. CONCLUSIONS: Using a largescale epidemiological dataset, these findings suggest a relationship between chronic tonsillitis and an elevated risk of IgAN development in the general Japanese population.

Evaluating the safety and efficacy of vadadustat for the treatment of anemia associated with chronic kidney disease.

INTRODUCTION: The breakthrough in erythropoietin-stimulating agents in the 1990s improved the prognosis and treatment of complications in chronic kidney disease patients and renal anemia. Discovery of the novel molecular mechanisms for hypoxia-inducible factor (HIF) transcription factor under hypoxic conditions has led to the development of oral drugs, HIF-Prolyl Hydroxylase inhibitors (HIF-PHIs), that constantly activate erythropoietin by inhibiting prolyl hydroxylase. HIF-PHIs have gained rapid approval in Asian countries, including Japan, with six distinct types entering clinical application. AREAS COVERED: This article provides a comprehensive review of the latest literature, with a particular focus on the effectiveness and safety of vadadustat. EXPERT OPINION: A phase 3, randomized, open-label, clinical trial (PRO2TECT) demonstrated that vadadustat had the prespecified non-inferiority for hematologic efficacy as compared with darbepoetin alfa in non-dialysis-dependent patients not previously treated with ESA. However, vadadustat did not show non-inferiority in major adverse cardiovascular events in the non-US/non-Europe patients. It may partly because of imbalances of the baseline eGFR level in those countries. In dialysis-dependent patients, a phase 3 clinical trial (INNO2VATE) showed vadadustat was non-inferior to darbepoetin alfa in cardiovascular safety and maintenance of hemoglobin levels. Adverse events including cancer, retinopathy, thrombosis, and vascular calcification should be evaluated in future clinical studies.

Bexarotene-induced hypothyroidism and dyslipidemia; a nation-wide study.

Central hypothyroidism and dyslipidemia are well-known adverse events (AEs) of bexarotene therapy. Although hypothyroidism is known to cause dyslipidemia, no study has examined the association between hypothyroidism and dyslipidemia in patients undergoing bexarotene therapy. The aim of this study is to examine this association. A retrospective observational study was performed among 294 patients who initiated bexarotene therapy in Japan (nation-wide postmarketing complete surveillance). Jonckheere-Terpstra (one sided) test was performed to evaluate the effect of the bexarotene dose on lipid metabolisms, and regression analyses were performed to evaluate associations of bexarotene dose, free thyroxine (FT4), body mass index (BMI), and lipid metabolisms. Most patients developed hypothyroidism. Two-third of patients showed FT4 values below the lower limit at 1 week. Triglycerides (TG) increased in a bexarotene dose-dependent manner, and grade ≥3 AEs on hypertriglyceridemia was observed in 39% of the patients. Additionally, one-third of grade ≥3 AEs on hypertriglyceridemia occurred within 1 week. The delta_FT4 (difference in FT4 from baseline) negatively correlated with TG increase at 1 week (p = 0.012) but not with low density lipoprotein cholesterol (LDL-C) increase at any week. Bexarotene-induced hypothyroidism is almost inevitable and occurred quickly. Bexarotene-induced hypertriglyceridemia showed positive bexarotene dose dependency and negative delta_FT4 dependency. Prophylactic and appropriate thyroid hormone compensation therapy and starting bexarotene at low doses with subsequent titration while managing dyslipidemia may have a beneficial effect for the successful continuation of bexarotene therapy without severe endocrine and metabolic AEs.

[Clinical application and future perspectives of HIF-PH inhibitors].

Anemia in chronic kidney disease (CKD) occurs due to insufficient production of erythropoietin to compensate for the decrease in hemoglobin. Anemia in CKD has traditionally been treated with periodic injections of erythropoiesis-stimulating agents (ESAs), which are recombinant human erythropoietin preparations. Although ESA improved anemia in CKD and dramatically improved the quality of life of patients, there are some patients who are hyporesponsive to ESA, and the use of large doses of ESA in these patients may have a negative impact on patient prognosis. Currently, HIF prolyl hydroxylase (HIF-PH) inhibitors have been approved in Japan as a new treatment for anemia in CKD. HIF-PH inhibitors activate HIF and promote the production of endogenous erythropoietin. The 2019 Nobel Prize in Physiology or Medicine was awarded for groundbreaking research that uncovered the HIF pathway. Because HIF-PH inhibitors improve both erythropoietin production and iron metabolism, they are expected to be effective in treating ESA hyporesponsiveness and solve the inconvenience of injectable preparations. On the other hand, its effects are systemic and multifaceted, and long-term effects must be closely monitored.

Eculizumab for adult patients with atypical haemolytic-uraemic syndrome: full dataset analysis of Japanese post-marketing surveillance.

BACKGROUND: Eculizumab has been approved for atypical haemolytic-uraemic syndrome (aHUS) in Japan since 2013. Post-marketing surveillance enrolled patients with aHUS who received ≥ 1 dose of eculizumab to assess eculizumab safety and effectiveness. METHODS: We evaluated serious adverse events and effectiveness endpoints, i.e., haematologic normalization, a decrease of ≥ 25% in serum creatinine (sCr) levels, and complete thrombotic microangiopathy (TMA) response in adult patients with aHUS without other underlying diseases. In addition, the difference of baseline characteristics between patients who did and did not meet effectiveness endpoints was examined. RESULTS: In this safety and effectiveness analysis, 79 adult patients were included; median age was 54.0 years, median treatment duration was 30 weeks. Total exposure time of eculizumab was 75.51 patient-years, and 94 serious adverse events were reported in 39 patients. No unexpected safety signals were identified in this population. Mean platelet count, lactate dehydrogenase and estimated glomerular filtration rate significantly improved after 7 days of treatment. Complete TMA response, haematologic normalization and the improvement of sCr levels were met by 35.3%, 40.4% and 51.3% of patients, respectively. Median treatment duration was shorter in patients who did not achieve complete TMA response (6 weeks) than in patients who did (114 weeks). Multivariate analysis suggested that the time from the most recent TMA episode to start of eculizumab treatment was negatively associated with kidney function improvement. CONCLUSIONS: No unexpected safety signals of eculizumab were identified in Japanese patients with aHUS in a real-world setting. Renal outcomes were negatively associated with the time from the most recent TMA episode to the initiation of eculizumab treatment.

Evaluating the associations between compliance with CKD guideline component metrics and renal outcomes.

Understanding the association between compliance to the Chronic Kidney Disease (CKD) guidelines in real-world clinical settings and renal outcomes remains a critical gap in knowledge. A comprehensive analysis was conducted using data from a national, multicenter CKD registry. This study included 4,455 patients with an estimated glomerular filtration rate (eGFR) measurement on the index date and eight additional metrics recorded within six months. These metrics comprised serum electrolyte levels, low-density lipoprotein cholesterol, hemoglobin, and the use of renin-angiotensin system inhibitors. The primary outcome was a composite of renal events, defined by a decline in eGFR to < 15 mL/min/1.73 m2 or a reduction of ≥ 30% in eGFR, confirmed by follow-up tests. Over a median follow-up of 513 days, 838 renal events were observed. High serum potassium levels (> 5.4 mmol/L) were associated with increased event rates compared to lower levels. Similarly, low serum sodium-chloride levels (< 33) correlated with higher event rates. Usage of renin-angiotensin system inhibitors, low serum calcium (< 8.4 mg/dL), and high uric acid levels (> 7.0 mg/dL) were also linked to increased events. Conversely, higher hemoglobin levels (≥ 13 g/dL) were associated with lower event rates. Compliance to guidelines, categorized into quartiles based on the number of met metrics, revealed a significantly reduced risk of events in the highest compliance group (meeting 8 metrics) compared to the lowest (0-5 metrics). Compliance to CKD guidelines in clinical practice is significantly associated with improved renal outcomes, emphasizing the need for guideline-concordant care in the management of CKD.

Global variations in funding and use of hemodialysis accesses: an international report using the ISN Global Kidney Health Atlas.

BACKGROUND: There is a lack of contemporary data describing global variations in vascular access for hemodialysis (HD). We used the third iteration of the International Society of Nephrology Global Kidney Health Atlas (ISN-GKHA) to highlight differences in funding and availability of hemodialysis accesses used for initiating HD across world regions. METHODS: Survey questions were directed at understanding the funding modules for obtaining vascular access and types of accesses used to initiate dialysis. An electronic survey was sent to national and regional key stakeholders affiliated with the ISN between June and September 2022. Countries that participated in the survey were categorized based on World Bank Income Classification (low-, lower-middle, upper-middle, and high-income) and by their regional affiliation with the ISN. RESULTS: Data on types of vascular access were available from 160 countries. Respondents from 35 countries (22% of surveyed countries) reported that > 50% of patients started HD with an arteriovenous fistula or graft (AVF or AVG). These rates were higher in Western Europe (n = 14; 64%), North & East Asia (n = 4; 67%), and among high-income countries (n = 24; 38%). The rates of > 50% of patients starting HD with a tunneled dialysis catheter were highest in North America & Caribbean region (n = 7; 58%) and lowest in South Asia and Newly Independent States and Russia (n = 0 in both regions). Respondents from 50% (n = 9) of low-income countries reported that > 75% of patients started HD using a temporary catheter, with the highest rates in Africa (n = 30; 75%) and Latin America (n = 14; 67%). Funding for the creation of vascular access was often through public funding and free at the point of delivery in high-income countries (n = 42; 67% for AVF/AVG, n = 44; 70% for central venous catheters). In low-income countries, private and out of pocket funding was reported as being more common (n = 8; 40% for AVF/AVG, n = 5; 25% for central venous catheters). CONCLUSIONS: High income countries exhibit variation in the use of AVF/AVG and tunneled catheters. In low-income countries, there is a higher use of temporary dialysis catheters and private funding models for access creation.

Factors affecting the sodium-glucose cotransporter 2 inhibitors-related initial decline in glomerular filtration rate and its possible effect on kidney outcome in chronic kidney disease with type 2 diabetes: The Japan Chronic Kidney Disease Database.

AIM: Sodium-glucose cotransporter 2 (SGLT2) inhibitors often cause a transient decrease in glomerular filtration rate (GFR) shortly after the initiation, referred to as the 'initial drop'. However, the clinical significance of this initial drop in real-world practice remains unclear. MATERIALS AND METHODS: Using the nationwide Japan Chronic Kidney Disease Database, we examined factors that affected the initial drop, in patients with chronic kidney disease (CKD) and type 2 diabetes mellitus (T2DM). We also evaluated the effects of the initial drop on a composite kidney outcome (a decline in GFR of ≥50% or progression to end-stage kidney disease). RESULTS: Data from 2053 patients with CKD and T2DM newly prescribed an SGLT2 inhibitor were analysed. The follow-up period after SGLT2 inhibitor administration was 1015 days (interquartile range: 532, 1678). Multivariate linear regression models revealed that the concomitant use of the renin-angiotensin system inhibitors and diuretics, urinary protein levels ≥2+, and changes in GFR before the initiation of the SGLT2 inhibitor were associated with a larger initial GFR decline (ß = -0.609, p = .039; ß = -2.298, p < .001; ß = -0.936, p = .048; ß = -0.079, p < .001, respectively). Patients in the quartile with the largest initial GFR decline experienced a higher incidence of the subsequent composite kidney outcome than those in the other quartiles (p < .001). CONCLUSIONS: The concomitant use of renin-angiotensin system inhibitors and diuretics, higher urine protein levels and pre-treatment GFR changes were associated with a larger initial GFR decline. Of these factors, the use of a diuretic had the largest effect. Furthermore, patients with CKD and T2DM experiencing an excessive initial GFR drop might be at a higher risk of adverse kidney outcomes.

Effectiveness of DialBetesPlus, a self-management support system for diabetic kidney disease: Randomized controlled trial.

We evaluated the effectiveness of a mobile health (mHealth) intervention for diabetic kidney disease patients by conducting a 12-month randomized controlled trial among 126 type 2 diabetes mellitus patients with moderately increased albuminuria (urinary albumin-to-creatinine ratio (UACR): 30-299 mg/g creatinine) recruited from eight clinical sites in Japan. Using a Theory of Planned Behavior (TPB) behavior change theory framework, the intervention provides patients detailed information in order to improve patient control over exercise and dietary behaviors. In addition to standard care, the intervention group received DialBetesPlus, a self-management support system allowing patients to monitor exercise, blood glucose, diet, blood pressure, and body weight via a smartphone application. The primary outcome, change in UACR after 12 months (used as a surrogate measure of renal function), was 28.8% better than the control group's change (P = 0.029). Secondary outcomes also improved in the intervention group, including a 0.32-point better change in HbA1c percentage (P = 0.041). These improvements persisted when models were adjusted to account for the impacts of coadministration of drugs targeting albuminuria (GLP-1 receptor agonists, SGLT-2 inhibitors, ACE inhibitors, and ARBs) (UACR: -32.3% [95% CI: -49.2%, -9.8%] between-group difference in change, P = 0.008). Exploratory multivariate regression analysis suggests that the improvements were primarily due to levels of exercise. This is the first trial to show that a lifestyle intervention via mHealth achieved a clinically-significant improvement in moderately increased albuminuria.

Cardiovascular Outcomes of KCNJ5 Mutated Aldosterone-Producing Adenoma: A Systematic Review.

BACKGROUND: While clinical features of KCNJ5-mutated aldosterone-producing adenoma (APA) have been reported, evidence of its clinical outcomes is lacking. We aimed to synthesize available literature about the associations between KCNJ5 mutation with cardiovascular and metabolic outcomes among patients with APA. METHODS: In this systematic review of observational studies, MEDLINE and Embase were searched through August 2022. Two independent authors screened the search results and extracted data from eligible observational studies investigating cardiovascular or metabolic outcomes between KCNJ5-mutated APAs and KCNJ5-non-mutated APAs. Risk of Bias In Non-randomized Studies of Interventions was used to assess the quality of the included studies. RESULTS: A total of 573 titles/abstracts were screened and after the expert opinion of the literature, full text was read in 20 titles/abstracts, of which 12 studies were included. Across 3 studies comparing the baseline or change in the cardiac function between KCNJ5-mutated APAs and KCNJ5-non-mutated APAs, all studies reported the association between impaired cardiac functions and KCNJ5 mutation status. Among 6 studies evaluating the cure of hypertension after surgery, all studies showed that KCNJ5 mutation was significantly associated with the cure of hypertension. In quality assessment, 7 studies were at serious risk of bias, while the remaining studies were at moderate risk of bias. CONCLUSIONS: This systematic review provided evidence of the significant association between KCNJ5 mutation and unfavorable cardiovascular outcomes in patients with primary aldosteronism. Further research is needed to improve the quality of evidence on this topic and elucidate the underlying mechanisms of the potential burden of KCNJ5 mutation.