Vitamin Supplement Use in Patients With CKD: Worth the Pill Burden?

All vitamins play essential roles in various aspects of body function and systems. Patients with chronic kidney disease (CKD), including those receiving dialysis, may be at increased risk of developing vitamin deficiencies due to anorexia, poor dietary intake, protein energy wasting, restricted diet, dialysis loss, or inadequate sun exposure for vitamin D. However, clinical manifestations of most vitamin deficiencies are usually subtle or undetected in this population. Testing for circulating levels is not undertaken for most vitamins except folate, B12, and 25-hydroxyvitamin D because assays may not be available or may be costly to perform and do not always correlate with body stores. The last systematic review through 2016 was performed for the Kidney Disease Outcome Quality Initiative (KDOQI) 2020 Nutrition Guideline update, so this article summarizes the more recent evidence. We review the use of vitamins supplementation in the CKD population. To date there have been no randomized trials to support the benefits of any vitamin supplementation for kidney, cardiovascular, or patient-centered outcomes. The decision to supplement water-soluble vitamins should be individualized, taking account the patient's dietary intake, nutritional status, risk of vitamins deficiency/insufficiency, CKD stage, comorbid status, and dialysis loss. Nutritional vitamin D deficiency should be corrected, but the supplementation dose and formulation need to be personalized, taking into consideration the degree of 25-hydroxyvitamin D deficiency, parathyroid hormone levels, CKD stage, and local formulation. Routine supplementation of vitamins A and E is not supported due to potential toxicity. Although more trial data are required to elucidate the roles of vitamin supplementation, all patients with CKD should undergo periodic assessment of dietary intake and aim to receive various vitamins through natural food sources and a healthy eating pattern that includes vitamin-dense foods.

DC ENaC-Dependent Inflammasome Activation Contributes to Salt-Sensitive Hypertension.

BACKGROUND: Salt sensitivity of blood pressure is an independent predictor of cardiovascular morbidity and mortality. The exact mechanism by which salt intake increases blood pressure and cardiovascular risk is unknown. We previously found that sodium entry into antigen-presenting cells (APCs) via the amiloride-sensitive epithelial sodium channel EnaC (epithelial sodium channel) leads to the formation of IsoLGs (isolevuglandins) and release of proinflammatory cytokines to activate T cells and modulate salt-sensitive hypertension. In the current study, we hypothesized that ENaC-dependent entry of sodium into APCs activates the NLRP3 (NOD [nucleotide-binding and oligomerization domain]-like receptor family pyrin domain containing 3) inflammasome via IsoLG formation leading to salt-sensitive hypertension. METHODS: We performed RNA sequencing on human monocytes treated with elevated sodium in vitro and Cellular Indexing of Transcriptomes and Epitopes by Sequencing analysis of peripheral blood mononuclear cells from participants rigorously phenotyped for salt sensitivity of blood pressure using an established inpatient protocol. To determine mechanisms, we analyzed inflammasome activation in mouse models of deoxycorticosterone acetate salt-induced hypertension as well as salt-sensitive mice with ENaC inhibition or expression, IsoLG scavenging, and adoptive transfer of wild-type dendritic cells into NLRP3 deficient mice. RESULTS: We found that high levels of salt exposure upregulates the NLRP3 inflammasome, pyroptotic and apoptotic caspases, and IL (interleukin)-1ß transcription in human monocytes. Cellular Indexing of Transcriptomes and Epitopes by Sequencing revealed that components of the NLRP3 inflammasome and activation marker IL-1ß dynamically vary with changes in salt loading/depletion. Mechanistically, we found that sodium-induced activation of the NLRP3 inflammasome is ENaC and IsoLG dependent. NLRP3 deficient mice develop a blunted hypertensive response to elevated sodium, and this is restored by the adoptive transfer of NLRP3 replete APCs. CONCLUSIONS: These findings reveal a mechanistic link between ENaC, inflammation, and salt-sensitive hypertension involving NLRP3 inflammasome activation in APCs. APC activation via the NLRP3 inflammasome can serve as a potential diagnostic biomarker for salt sensitivity of blood pressure.

Genome-Wide Association Study of CKD Progression.

SIGNIFICANCE STATEMENT: Rapid progression of CKD is associated with poor clinical outcomes. Most previous studies looking for genetic factors associated with low eGFR have used cross-sectional data. The authors conducted a meta-analysis of genome-wide association studies of eGFR decline among 116,870 participants with CKD, focusing on longitudinal data. They identified three loci (two of them novel) associated with longitudinal eGFR decline. In addition to the known UMOD/PDILT locus, variants within BICC1 were associated with significant differences in longitudinal eGFR slope. Variants within HEATR4 also were associated with differences in eGFR decline, but only among Black/African American individuals without diabetes. These findings help characterize molecular mechanisms of eGFR decline in CKD and may inform new therapeutic approaches for progressive kidney disease. BACKGROUND: Rapid progression of CKD is associated with poor clinical outcomes. Despite extensive study of the genetics of cross-sectional eGFR, only a few loci associated with eGFR decline over time have been identified. METHODS: We performed a meta-analysis of genome-wide association studies of eGFR decline among 116,870 participants with CKD-defined by two outpatient eGFR measurements of <60 ml/min per 1.73 m 2 , obtained 90-365 days apart-from the Million Veteran Program and Vanderbilt University Medical Center's DNA biobank. The primary outcome was the annualized relative slope in outpatient eGFR. Analyses were stratified by ethnicity and diabetes status and meta-analyzed thereafter. RESULTS: In cross-ancestry meta-analysis, the strongest association was rs77924615, near UMOD / PDILT ; each copy of the G allele was associated with a 0.30%/yr faster eGFR decline ( P = 4.9×10 -27 ). We also observed an association within BICC1 (rs11592748), where every additional minor allele was associated with a 0.13%/yr slower eGFR decline ( P = 5.6×10 -9 ). Among participants without diabetes, the strongest association was the UMOD/PDILT variant rs36060036, associated with a 0.27%/yr faster eGFR decline per copy of the C allele ( P = 1.9×10 -17 ). Among Black participants, a significantly faster eGFR decline was associated with variant rs16996674 near APOL1 (R 2 =0.29 with the G1 high-risk genotype); among Black participants with diabetes, lead variant rs11624911 near HEATR4 also was associated with a significantly faster eGFR decline. We also nominally replicated loci with known associations with eGFR decline, near PRKAG2, FGF5, and C15ORF54. CONCLUSIONS: Three loci were significantly associated with longitudinal eGFR change at genome-wide significance. These findings help characterize molecular mechanisms of eGFR decline and may contribute to the development of new therapeutic approaches for progressive CKD.

Fluid management protocols in hemodialysis patients using bioimpedance validation: time to look elsewhere?

The management of volume status in dialysis patients is an important determinant of the rate of decline of residual kidney function. The implementation of clinical protocols to guide volume management in the in-center hemodialysis unit resulted in comparable rates of development of anuria and decline in residual kidney function when compared with bioimpedance spectroscopy-guided volume management. Clinical judgment and experience are important drivers of patient outcomes. The importance and applicability of bioimpedance spectroscopy in other clinical settings, such as units without clear volume management protocols or in home dialysis units, remain to be seen.

The ASSESS-AKI Study found urinary epidermal growth factor is associated with reduced risk of major adverse kidney events.

Biomarkers of tubular function such as epidermal growth factor (EGF) may improve prognostication of participants at highest risk for chronic kidney disease (CKD) after hospitalization. To examine this, we measured urinary EGF (uEGF) from samples collected in the Assessment, Serial Evaluation, and Subsequent Sequelae of Acute Kidney Injury (ASSESS-AKI) Study, a multi-center, prospective, observational cohort of hospitalized participants with and without AKI. Cox proportional hazards regression was used to investigate the association of uEGF/Cr at hospitalization, three months post-discharge, and the change between these time points with major adverse kidney events (MAKE): CKD incidence, progression, or development of kidney failure. Clinical findings were paired with mechanistic studies comparing relative Egf expression in mouse models of kidney atrophy or repair after ischemia-reperfusion injury. MAKE was observed in 20% of 1,509 participants over 4.3 years of follow-up. Each 2-fold higher level of uEGF/Cr at three months was associated with decreased risk of MAKE (adjusted hazards ratio 0.46, 95% confidence interval: 0.39-0.55). Participants with the highest increase in uEGF/Cr from hospitalization to three-month follow-up had a lower risk of MAKE (adjusted hazards ratio 0.52; 95% confidence interval: 0.36-0.74) compared to those with the least change in uEGF/Cr. A model using uEGF/Cr at three months combined with clinical variables yielded moderate discrimination for MAKE (area under the curve 0.73; 95% confidence interval: 0.69-0.77) and strong discrimination for kidney failure at four years (area under the curve 0.96; 95% confidence interval: 0.92-1.00). Accelerated restoration of Egf expression in mice was seen in the model of adaptive repair after injury, compared to a model of progressive atrophy. Thus, urinary EGF/Cr may be a biomarker of distal tubular health, with higher concentrations and increased uEGF/Cr post-discharge independently associated with reduced risk of MAKE in hospitalized patients.

The Impact of a Wearable Activity Tracker and Structured Feedback Program on Physical Activity in Hemodialysis Patients: The Step4Life Pilot Randomized Controlled Trial.

RATIONALE & OBJECTIVE: People with end-stage kidney disease (ESKD) have very low physical activity, and the degree of inactivity is strongly associated with morbidity and mortality. We assessed the feasibility and effectiveness of a 12-week intervention coupling a wearable activity tracker (FitBit) and structured feedback coaching versus wearable activity tracker alone on changes in physical activity in hemodialysis patients. STUDY DESIGN: Randomized controlled trial. SETTING & PARTICIPANTS: 55 participants with ESKD receiving hemodialysis who were able to walk with or without assistive devices recruited from a single academic hemodialysis unit between January 2019 and April 2020. INTERVENTIONS: All participants wore a Fitbit Charge 2 tracker for a minimum of 12 weeks. Participants were randomly assigned 1:1 to a wearable activity tracker plus a structured feedback intervention versus the wearable activity tracker alone. The structured feedback group was counseled weekly on steps achieved after randomization. OUTCOME: The outcome was step count, and the main parameter of interest was the absolute change in daily step count, averaged per week, from baseline to completion of 12 weeks intervention. In the intention-to-treat analysis, mixed-effect linear regression analysis was used to evaluate change in daily step count from baseline to 12-weeks in both arms. RESULTS: Out of 55 participants, 46 participants completed the 12-week intervention (23 per arm). The mean age was 62 (± 14 SD) years; 44% were Black, and 36% were Hispanic. At baseline, step count (structured feedback intervention: 3,704 [1,594] vs wearable activity tracker alone: 3,808 [1,890]) and other participant characteristics were balanced between the arms. We observed a larger change in daily step count in the structured feedback arm at 12 weeks relative to use of the wearable activity tracker alone arm (Δ 920 [±580 SD] versus Δ 281 [±186 SD] steps; between-group difference Δ 639 [±538 SD] steps; P<0.05). LIMITATIONS: Single-center study and small sample size. CONCLUSION: This pilot randomized controlled trial demonstrated that structured feedback coupled with a wearable activity tracker led to a greater daily step count that was sustained over 12 weeks relative to a wearable activity tracker alone. Future studies are required to determine longer-term sustainability of the intervention and potential health benefits in hemodialysis patients. FUNDING: Grants from industry (Satellite Healthcare) and government (National Institute for Diabetes and Digestive and Kidney Diseases (NIDDK). TRIAL REGISTRATION: Registered at ClinicalTrials.gov with study number NCT05241171.

Integrated Analysis of Blood and Urine Biomarkers to Identify Acute Kidney Injury Subphenotypes and Associations With Long-term Outcomes.

RATIONALE & OBJECTIVE: Acute kidney injury (AKI) is a heterogeneous clinical syndrome with varying causes, pathophysiology, and outcomes. We incorporated plasma and urine biomarker measurements to identify AKI subgroups (subphenotypes) more tightly linked to underlying pathophysiology and long-term clinical outcomes. STUDY DESIGN: Multicenter cohort study. SETTING & PARTICIPANTS: 769 hospitalized adults with AKI matched with 769 without AKI, enrolled from December 2009 to February 2015 in the ASSESS-AKI Study. PREDICTORS: 29 clinical, plasma, and urinary biomarker parameters used to identify AKI subphenotypes. OUTCOME: Composite of major adverse kidney events (MAKE) with a median follow-up period of 4.7 years. ANALYTICAL APPROACH: Latent class analysis (LCA) and k-means clustering were applied to 29 clinical, plasma, and urinary biomarker parameters. Associations between AKI subphenotypes and MAKE were analyzed using Kaplan-Meier curves and Cox proportional hazard models. RESULTS: Among 769 AKI patients both LCA and k-means identified 2 distinct AKI subphenotypes (classes 1 and 2). The long-term risk for MAKE was higher with class 2 (adjusted HR, 1.41 [95% CI, 1.08-1.84]; P=0.01) compared with class 1, adjusting for demographics, hospital level factors, and KDIGO stage of AKI. The higher risk of MAKE among class 2 was explained by a higher risk of long-term chronic kidney disease progression and dialysis. The top variables that were different between classes 1 and 2 included plasma and urinary biomarkers of inflammation and epithelial cell injury; serum creatinine ranked 20th out of the 29 variables for differentiating classes. LIMITATIONS: A replication cohort with simultaneously collected blood and urine sampling in hospitalized adults with AKI and long-term outcomes was unavailable. CONCLUSIONS: We identify 2 molecularly distinct AKI subphenotypes with differing risk of long-term outcomes, independent of the current criteria to risk stratify AKI. Future identification of AKI subphenotypes may facilitate linking therapies to underlying pathophysiology to prevent long-term sequalae after AKI. PLAIN-LANGUAGE SUMMARY: Acute kidney injury (AKI) occurs commonly in hospitalized patients and is associated with high morbidity and mortality. The AKI definition lumps many different types of AKI together, but subgroups of AKI may be more tightly linked to the underlying biology and clinical outcomes. We used 29 different clinical, blood, and urinary biomarkers and applied 2 different statistical algorithms to identify AKI subtypes and their association with long-term outcomes. Both clustering algorithms identified 2 AKI subtypes with different risk of chronic kidney disease, independent of the serum creatinine concentrations (the current gold standard to determine severity of AKI). Identification of AKI subtypes may facilitate linking therapies to underlying biology to prevent long-term consequences after AKI.

High tissue-sodium associates with systemic inflammation and insulin resistance in obese individuals.

BACKGROUND AND AIMS: High sodium intake is associated with obesity and insulin resistance, and high extracellular sodium content may induce systemic inflammation, leading to cardiovascular disease. In this study, we aim to investigate whether high tissue sodium accumulation relates with obesity-related insulin resistance and whether the pro-inflammatory effects of excess tissue sodium accumulation may contribute to such association. METHODS AND RESULTS: In a cross-sectional study of 30 obese and 53 non-obese subjects, we measured insulin sensitivity determined as glucose disposal rate (GDR) using hyperinsulinemic euglycemic clamp, and tissue sodium content using 23Na magnetic resonance imaging. Median age was 48 years, 68% were female and 41% were African American. Median (interquartile range) BMI was 33 (31.5, 36.3) and 25 (23.5, 27.2) kg/m2 in the obese and non-obese individuals, respectively. In obese individuals, insulin sensitivity negatively correlated with muscle (r = -0.45, p = 0.01) and skin sodium (r = -0.46, p = 0.01). In interaction analysis among obese individuals, tissue sodium had a greater effect on insulin sensitivity at higher levels of high-sensitivity C-reactive protein (p-interaction = 0.03 and 0.01 for muscle and skin Na+, respectively) and interleukin-6 (p-interaction = 0.024 and 0.003 for muscle and skin Na+, respectively). In interaction analysis of the entire cohort, the association between muscle sodium and insulin sensitivity was stronger with increasing levels of serum leptin (p-interaction = 0.01). CONCLUSIONS: Higher muscle and skin sodium are associated with insulin resistance in obese patients. Whether high tissue sodium accumulation has a mechanistic role in the development of obesity-related insulin resistance through systemic inflammation and leptin dysregulation remains to be examined in future studies. CLINICALTRIALS: gov registration: NCT02236520.

Bradykinin B2 receptor blockade and intradialytic hypotension.

INTRODUCTION: Intradialytic hypotension (IDH) is a common clinical complication and is associated with increased morbidity and mortality in patients undergoing maintenance hemodialysis (MHD). The pathogenesis of IDH has been attributed to the rapid reduction of plasma volume during hemodialysis and the inadequate compensatory mechanisms in response to hypovolemia, such as the lack of vasoconstriction. This may be due to the increased production of vasodilators, such as bradykinin. In this study we test the hypothesis that bradykinin B2 receptor blockade prevents intradialytic hypotension. METHODS: We performed a post-hoc analysis of a double-blind, placebo-controlled, randomized, 2 × 2 crossover clinical trial comparing the continuous infusion of icatibant, a bradykinin B2 receptor blocker, and placebo during hemodialysis. Icatibant or placebo was infused for 30 min before and during hemodialysis in 11 patients on MHD. RESULTS: Seven of the patients had IDH, defined as a reduction of systolic blood pressure equal to or greater than 20 mmHg during hemodialysis. Stratified analysis, based on the presence of IDH, revealed that icatibant prevented the decrease in blood pressure compared to placebo in patients with IDH [blood pressure at average nadir (2.5 h after hemodialysis): Placebo,114.3 ± 8.9 vs. icatibant, 125.6 ± 9.1 mmHg, mean ± S.E.M]. Icatibant did not affect blood pressure in the group of patients without IDH. CONCLUSION: Bradykinin B2 receptor blocker may prevent the occurrence of IDH. Further studies should evaluate the hemodynamic effects of icatibant during hemodialysis and the symptomatology associated with IDH.

Angiopoietins as Prognostic Markers for Future Kidney Disease and Heart Failure Events after Acute Kidney Injury.

BACKGROUND: The mechanisms underlying long-term sequelae after AKI remain unclear. Vessel instability, an early response to endothelial injury, may reflect a shared mechanism and early trigger for CKD and heart failure. METHODS: To investigate whether plasma angiopoietins, markers of vessel homeostasis, are associated with CKD progression and heart failure admissions after hospitalization in patients with and without AKI, we conducted a prospective cohort study to analyze the balance between angiopoietin-1 (Angpt-1), which maintains vessel stability, and angiopoietin-2 (Angpt-2), which increases vessel destabilization. Three months after discharge, we evaluated the associations between angiopoietins and development of the primary outcomes of CKD progression and heart failure and the secondary outcome of all-cause mortality 3 months after discharge or later. RESULTS: Median age for the 1503 participants was 65.8 years; 746 (50%) had AKI. Compared with the lowest quartile, the highest quartile of the Angpt-1:Angpt-2 ratio was associated with 72% lower risk of CKD progression (adjusted hazard ratio [aHR], 0.28; 95% confidence interval [CI], 0.15 to 0.51), 94% lower risk of heart failure (aHR, 0.06; 95% CI, 0.02 to 0.15), and 82% lower risk of mortality (aHR, 0.18; 95% CI, 0.09 to 0.35) for those with AKI. Among those without AKI, the highest quartile of Angpt-1:Angpt-2 ratio was associated with 71% lower risk of heart failure (aHR, 0.29; 95% CI, 0.12 to 0.69) and 68% less mortality (aHR, 0.32; 95% CI, 0.15 to 0.68). There were no associations with CKD progression. CONCLUSIONS: A higher Angpt-1:Angpt-2 ratio was strongly associated with less CKD progression, heart failure, and mortality in the setting of AKI.

Effects of caloric restriction and aerobic exercise on circulating cell-free mitochondrial DNA in patients with moderate to severe chronic kidney disease.

Circulating cell-free mitochondrial DNA (ccf-mtDNA) may induce systemic inflammation, a common condition in chronic kidney disease (CKD), by acting as a damage-associated molecular pattern. We hypothesized that in patients with moderate to severe CKD, aerobic exercise would reduce ccf-mtDNA levels. We performed a post hoc analysis of a multicenter randomized trial (NCT01150851) measuring plasma concentrations of ccf-mtDNA at baseline and 2 and 4 mo after aerobic exercise and caloric restriction. A total of 99 participants had baseline ccf-mtDNA, and 92 participants completed the study. The median age of the participants was 57 yr, 44% were female and 55% were male, 23% had diabetes, and 92% had hypertension. After adjusting for demographics, blood pressure, body mass index, diabetes, and estimated glomerular filtration rate, median ccf-mtDNA concentrations at baseline, 2 mo, and 4 mo were 3.62, 3.08, and 2.78 pM for the usual activity group and 2.01, 2.20, and 2.67 pM for the aerobic exercise group, respectively. A 16.1% greater increase per month in ccf-mtDNA was seen in aerobic exercise versus usual activity (P = 0.024), which was more pronounced with the combination of aerobic exercise and caloric restriction (29.5% greater increase per month). After 4 mo of intervention, ccf-mtDNA increased in the aerobic exercise group by 81.6% (95% confidence interval: 8.2-204.8, P = 0.024) compared with the usual activity group and was more marked in the aerobic exercise and caloric restriction group (181.7% increase, 95% confidence interval: 41.1-462.2, P = 0.003). There was no statistically significant correlation between markers of oxidative stress and inflammation with ccf-mtDNA. Our data indicate that aerobic exercise increased ccf-mtDNA levels in patients with moderate to severe CKD.NEW & NOTEWORTHY The effects of prolonged exercise on circulating cell-free mitochondrial DNA (ccf-mtDNA) have not been explored in patients with chronic kidney disease (CKD). We showed that 4-mo aerobic exercise is associated with an increase in plasma ccf-mtDNA levels in patients with stages 3 or 4 CKD. These changes were not associated with markers of systemic inflammation. Future studies should determine the mechanisms by which healthy lifestyle interventions influence biomarkers of inflammation and oxidative stress in patients with CKD.

A randomized controlled pilot trial of anakinra for hemodialysis inflammation.

Chronic inflammation is highly prevalent among patients receiving maintenance hemodialysis and is associated with morbidity and mortality. Inhibiting inflammation with anti-cytokine therapy has been proposed but not well studied in this population. Therefore, we conducted the ACTION trial, a pilot, multicenter, randomized, placebo-controlled trial of an IL-1 receptor antagonist, anakinra, to evaluate safety, tolerability, and feasibility, and explore efficacy. Eighty hemodialysis patients with plasma concentrations of high sensitivity C-reactive protein (hsCRP) 2 mg/L and above were randomized 1:1 to placebo or anakinra 100 mg, three times per week via the hemodialysis circuit for 24 weeks, with an additional 24 weeks of post-treatment safety monitoring. Efficacy outcomes included changes in hsCRP (primary), cytokines, and patient-reported outcomes. Rates of serious adverse events and deaths were similar with anakinra and placebo (serious adverse events: 2.71 vs 2.74 events/patient-year; deaths: 0.12 vs 0.22 events/patient-year). The rate of adverse events of interest (including infections and cytopenias) was significantly lower with anakinra than placebo (0.48 vs 1.40 events/patient-year). Feasibility was demonstrated by attaining the enrollment target, a retention rate of 80%, and administration of 72% of doses. The median decrease in hsCRP from baseline to Week 24 was 41% in the anakinra group and 6% in the placebo group, a between-group difference that was not statistically significant. For IL-6, the median decreases were significant: 25% and 0% in the anakinra and placebo groups, respectively. An effect of anakinra on patient-reported outcomes was not evident. Thus, anakinra was well tolerated and did not increase infections or cytopenias. The promising safety data and potential efficacy on CRP and IL-6 provide support for conducting definitive trials of IL-1 inhibition to improve outcomes in hemodialysis patients.

Nutrition in Kidney Disease: Core Curriculum 2022.

As chronic kidney disease (CKD) progresses, the requirements and utilization of different nutrients change substantially. These changes are accompanied by multiple nutritional and metabolic abnormalities that are observed in the continuum of kidney disease. To provide optimal care to patients with CKD, it is essential to have an understanding of the applicable nutritional principles: methods to assess nutritional status, establish patient-specific dietary needs, and prevent or treat potential or ongoing nutritional deficiencies and derangements. This installment of AJKD's Core Curriculum in Nephrology provides current information on these issues for the practicing clinician and allied health care workers and features basic, practical information on epidemiology, assessment, etiology, and prevention and management of nutritional considerations in patients with kidney disease. Specific emphasis is made on dietary intake and recommendations for dietary patterns, and macro- and micronutrients. In addition, special conditions such as acute kidney injury and approaches to obesity treatment are reviewed.

Immune response to SARS-CoV-2 infection and vaccination in patients receiving kidney replacement therapy.

In this issue of Kidney International, the initial experience regarding the immunogenicity of prior coronavirus disease 2019 (COVID-19) infection and the response to the COVID-19 vaccines among patients on maintenance dialysis and kidney transplant recipients is summarized. Preliminary data suggest that there is durability of immune response after COVID-19 infection. Although immune response to the first dose of vaccine is less in infection-naïve patients than healthy individuals in both groups, after the second vaccine dose a significant portion of patients receiving maintenance dialysis develop robust antibody titers, whereas kidney transplant recipients show a less-strong immune response.

Renin-angiotensin aldosterone inhibitor use at hospital discharge among patients with moderate to severe acute kidney injury and its association with recurrent acute kidney injury and mortality.

Recurrent episodes of acute kidney injury (AKI) are common among AKI survivors. Renin-angiotensin aldosterone inhibitors (RAASi) are often indicated for these patients but may increase the risk for recurrent AKI. Here, we examined whether RAASi associates with a higher risk for recurrent AKI and mortality among survivors of moderate to severe AKI in a retrospective cohort of Veterans who survived Stage II or III AKI. The primary exposure was RAASi at hospital discharge and the primary endpoint was recurrent AKI within 12 months. Cox proportional hazards models were fit on a propensity score-weighted cohort to compare time to recurrent AKI and mortality by RAASi exposure. Among 96,983 patients, 40% were on RAASi at discharge. Compared to patients who continued RAASi use, those discontinuing use experienced no difference in risk for recurrent AKI but had a significantly higher risk of mortality [hazard ratio 1.33 (95% confidence interval1.26-1.41)]. No differences in recurrent AKI risk was observed for non-users started or not on RAASi compared to prevalent users who continued RAASi. Subgroup analyses among those with diabetes, chronic kidney disease, heart failure, and malignancy were similar with exception of a modest reduction in recurrent AKI risk among RAASi discontinuers with chronic kidney disease. Thus, RAASi use among survivors of moderate to severe AKI was associated with little to no difference in risk for recurrent AKI but was associated with improved survival. Reinitiating or starting RAASi among patients with strong indications is warranted but should be balanced with individual overall risk for recurrent AKI and with adequate monitoring.

A prospective cohort study of acute kidney injury and kidney outcomes, cardiovascular events, and death.

Acute kidney injury (AKI) has been reported to be associated with excess risks of death, kidney disease progression and cardiovascular events although previous studies have important limitations. To further examine this, we prospectively studied adults from four clinical centers surviving three months and more after hospitalization with or without AKI who were matched on center, pre-admission CKD status, and an integrated priority score based on age, prior cardiovascular disease or diabetes mellitus, preadmission estimated glomerular filtration rate (eGFR) and treatment in the intensive care unit during the index hospitalization between December 2009-February 2015, with follow-up through November 2018. All participants had assessments of kidney function before (eGFR) and at three months and annually (eGFR and proteinuria) after the index hospitalization. Associations of AKI with outcomes were examined after accounting for pre-admission and three-month post-discharge factors. Among 769 AKI (73% Stage 1, 14% Stage 2, 13% Stage 3) and 769 matched non-AKI adults, AKI was associated with higher adjusted rates of incident CKD (adjusted hazard ratio 3.98, 95% confidence interval 2.51-6.31), CKD progression (2.37,1.28-4.39), heart failure events (1.68, 1.22-2.31) and all-cause death (1.78, 1.24-2.56). AKI was not associated with major atherosclerotic cardiovascular events in multivariable analysis (0.95, 0.70-1.28). After accounting for degree of kidney function recovery and proteinuria at three months after discharge, the associations of AKI with heart failure (1.13, 0.80-1.61) and death (1.29, 0.84-1.98) were attenuated and no longer significant. Thus, assessing kidney function recovery and proteinuria status three months after AKI provides important prognostic information for long-term clinical outcomes.

Apolipoprotein-1 risk variants and associated kidney phenotypes in an adult HIV cohort in Nigeria.

HIV-positive adults are at risk for various kidney diseases, and apolipoprotein 1 (APOL1) high-risk genotypes increase this risk. This study aimed to determine the prevalence and ethnic distribution of APOL1 risk genotypes among a cohort of HIV-positive Nigerian adults and explore the relationship between APOL1 risk variant status with albuminuria and estimated glomerular filtration rate (eGFR). We conducted a cross-sectional study among 2 458 persons living with HIV who attended an HIV clinic in northern Nigeria and had received antiretroviral therapy for a minimum of six months. We collected two urine samples four-eight weeks apart to measure albumin excretion, and blood samples to measure eGFR and determine APOL1 genotype. The frequency of APOL1 high-risk genotype was 6.2%, which varied by ethnic group: Hausa/Fulani (2.1%), Igbo (49.1%), and Yoruba (14.5%). The prevalence of microalbuminuria (urine/albumin creatinine ratio 30- 300 mg/g) was 37%, and prevalence of macroalbuminuria (urine/albumin creatinine ratio over 300 mg/g) was 3%. The odds of microalbuminuria and macroalbuminuria were higher for participants with the APOL1 high-risk genotype compared to those carrying the low-risk genotype ([adjusted odds ratio 1.97, 95% confidence interval 1.37-2.82] and [3.96, 1.95-8.02] respectively). APOL1 high-risk genotype participants were at higher risk of having both an eGFR under 60 ml/min/1.73m2 and urine/albumin creatinine ratio over 300 mg/g (5.56, 1.57-19.69). Thus, we found a high proportion of HIV-positive, antiretroviral therapy-experienced, and largely virologically suppressed adults had microalbuminuria. Hence, although the high-risk APOL1 genotype was less prevalent than expected, it was strongly associated with some level of albuminuria.

Achieved blood pressure post-acute kidney injury and risk of adverse outcomes after AKI: A prospective parallel cohort study.

BACKGROUND: There has recently been considerable interest in better understanding how blood pressure should be managed after an episode of hospitalized AKI, but there are scant data regarding the associations between blood pressure measured after AKI and subsequent adverse outcomes. We hypothesized that among AKI survivors, higher blood pressure measured three months after hospital discharge would be associated with worse outcomes. We also hypothesized these associations between blood pressure and outcomes would be similar among those who survived non-AKI hospitalizations. METHODS: We quantified how systolic blood pressure (SBP) observed three months after hospital discharge was associated with risks of subsequent hospitalized AKI, loss of kidney function, mortality, and heart failure events among 769 patients in the prospective ASSESS-AKI cohort study who had hospitalized AKI. We repeated this analysis among the 769 matched non-AKI ASSESS-AKI enrollees. We then formally tested for AKI interaction in the full cohort of 1538 patients to determine if these associations differed among those who did and did not experience AKI during the index hospitalization. RESULTS: Among 769 patients with AKI, 42 % had subsequent AKI, 13 % had loss of kidney function, 27 % died, and 18 % had heart failure events. SBP 3 months post-hospitalization did not have a stepwise association with the risk of subsequent AKI, loss of kidney function, mortality, or heart failure events. Among the 769 without AKI, there was also no stepwise association with these risks. In formal interaction testing using the full cohort of 1538 patients, hospitalized AKI did not modify the association between post-discharge SBP and subsequent risks of adverse clinical outcomes. CONCLUSIONS: Contrary to our first hypothesis, we did not observe that higher stepwise blood pressure measured three months after hospital discharge with AKI was associated with worse outcomes. Our data were consistent with our second hypothesis that the association between blood pressure measured three months after hospital discharge and outcomes among AKI survivors is similar to that observed among those who survived non-AKI hospitalizations.

Body mass index and chronic kidney disease outcomes after acute kidney injury: a prospective matched cohort study.

BACKGROUND: Acute kidney injury (AKI) and obesity are independent risk factors for chronic kidney disease (CKD). This study aimed to determine if obesity modifies risk for CKD outcomes after AKI. METHODS: This prospective multisite cohort study followed adult survivors after hospitalization, with or without AKI. The primary outcome was a combined CKD event of incident CKD, progression of CKD and kidney failure, examined using time-to-event Cox proportional hazards models, adjusted for diabetes status, age, pre-existing CKD, cardiovascular disease status and intensive care unit admission, and stratified by study center. Body mass index (BMI) was added as an interaction term to examine effect modification by body size. RESULTS: The cohort included 769 participants with AKI and 769 matched controls. After median follow-up of 4.3 years, among AKI survivors, the rate of the combined CKD outcome was 84.7 per1000-person-years with BMI ≥30 kg/m2, 56.4 per 1000-person-years with BMI 25-29.9 kg/m2, and 72.6 per 1000-person-years with BMI 20-24.9 kg/m2. AKI was associated with a higher risk of combined CKD outcomes; adjusted-HR 2.43 (95%CI 1.87-3.16), with no evidence that this was modified by BMI (p for interaction = 0.3). After adjustment for competing risk of death, AKI remained associated with a higher risk of the combined CKD outcome (subdistribution-HR 2.27, 95%CI 1.76-2.92) and similarly, there was no detectable effect of BMI modifying this risk. CONCLUSIONS: In this post-hospitalization cohort, we found no evidence for obesity modifying the association between AKI and development or progression of CKD.

Effects of long-term intradialytic oral nutrition and exercise on muscle protein homeostasis and markers of mitochondrial content in patients on hemodialysis.

Patients with end-stage kidney disease on maintenance hemodialysis commonly develop protein-energy wasting, a syndrome characterized by nutritional and metabolic abnormalities. Nutritional supplementation and exercise are recommended to prevent protein-energy wasting. In a 6-mo prospective randomized, open-label, clinical trial, we reported that the combination of resistance exercise and nutritional supplementation does not have an additive effect on lean body mass measured by dual-energy X-ray absorptiometry. To provide more mechanistic data, we performed a secondary analysis where we hypothesized that the combination of nutritional supplementation and resistance exercise would have additive effects on muscle protein accretion by stable isotope protein kinetic experiments, muscle mass by MRI, and mitochondrial content markers in muscle. We found that 6 mo of nutritional supplementation during hemodialysis increased muscle protein net balance [baseline: 2.5 (-17.8, 13.0) µg·100 mL-1·min-1 vs. 6 mo: 43.7 (13.0, 98.5) µg·100 mL-1·min-1, median (interquartile range), P = 0.04] and mid-thigh fat area [baseline: 162.3 (104.7, 226.6) cm2 vs. 6 mo: 181.9 (126.3, 279.2) cm2, median (interquartile range), P = 0.04]. Three months of nutritional supplementation also increased markers of mitochondrial content in muscle. Although the study is underpowered to detected differences, the combination of nutritional supplementation and exercise failed to show further benefit in protein accretion or muscle cross-sectional area. We conclude that long-term nutritional supplementation increases the skeletal muscle anabolic effect, the fat cross-sectional area of the thigh, and markers of mitochondrial content in skeletal muscle.