Safety and infectious outcomes in pediatric kidney transplant recipients after COVID-19 vaccination: A pediatric nephrology research consortium study.

BACKGROUND: Adult kidney transplant recipients (KTRs) fully vaccinated against COVID-19 have substantial morbidity and mortality related to SARS-CoV-2 infection compared with the general population. However, little is known regarding the safety and efficacy of the COVID-19 vaccination series in pediatric KTRs. METHODS: A multicenter, retrospective observational study was performed across nine pediatric transplantation centers. Eligible KTRs fully vaccinated against COVID-19 were enrolled and data were collected pertaining to SARS-CoV-2 infection incidence and severity, graft outcomes and post-vaccination safety profile, as well as overall patient survival. RESULTS: A total of 247 patients were included in this investigation with a median age at transplantation of 11 years (IQR 5-15). SARS-CoV-2 infection was observed in 30/110 (27.27%) of fully vaccinated patients, tested post-transplant, within the defined follow-up period. Of these patients, 6/30 (18.18%) required hospitalization and 3/30 (12.12%) required reduction in immunosuppression, with no reported deaths. De novo donor-specific antibodies (DSAs) were found in 8/86 (9.30%) of DSA-tested patients with two experiencing rejection and subsequent graft loss. The overall incidence of rejection and graft loss among the total cohort was 11/247 (4.45%) and 6/247 (3.64%), respectively. A 100% patient survival was observed. CONCLUSIONS: Observationally, infectious outcomes of SARS-CoV-2 in fully vaccinated pediatric KTRs are excellent, with a low incidence of infection requiring hospitalization and no associated deaths. Though de novo DSAs were observed, there was minimal graft rejection and graft loss reported in the total cohort.

Applications of cardiac biomarkers in chronic kidney disease.

PURPOSE OF REVIEW: Cardiovascular disease is the leading cause of death in individuals with chronic kidney disease (CKD). The mechanisms connecting CKD and cardiovascular disease are complex, and serum biomarkers can help improve our understanding. Nt-proBNP and troponin have documented success as biomarkers to diagnose and provide mechanistic insights in non-CKD populations. The purpose of this review is to summarize evidence suggesting efficacy and potential for clinical application of Nt-proBNP and troponin in individuals with CKD. RECENT FINDINGS: Our understanding of how Nt-proBNP and Troponin should be interpreted in those with CKD is evolving. Although both biomarkers are in part cleared by the kidney, elevated levels predominantly reflect cardiovascular disease. Both Nt-proBNP and troponin are associated with risk for future cardiovascular events in CKD. Determining CKD-specific cutoffs and using biomarkers to guide therapy remains under active investigation. SUMMARY: Of the many serum biomarkers under investigation, Nt-proBNP and troponin best meet the criteria for effective biomarkers in CKD. Assays are widely available and proven to be accurate in CKD populations. Nt-proBNP and troponin deserve special focus in ongoing research of cardiovascular risk reduction in CKD, especially to identify patients at the highest risk, suggest targetable mechanisms and assess treatment efficacy.

Considerations and possibilities for sodium-glucose cotransporter 2 inhibitors in pediatric CKD.

Sodium-glucose cotransporter 2 inhibitors (SGLT2is) were originally developed as glucose-lowering agents. These medications function by inhibiting glucose and sodium reabsorption in the S1 segment of the proximal tubule. Early clinical trials in adults with type 2 diabetes mellitus (T2DM) suggested a significant improvement in kidney and cardiovascular outcomes with SGLT2i therapy. Since then, SGLT2is have become a mainstay treatment for adult patients with CKD. A growing body of research has explored deploying these medications in new clinical contexts and investigated the mechanisms underlying their physiologic effects. However, patients under the age of 18 years have been largely excluded from all major trials of SGLT2i. This review aims to summarize the available clinical evidence, physiology, and mechanisms relating to SGLT2is to inform discussions about their implementation in pediatrics.

Major adverse kidney events after acute kidney injury in the pediatric intensive care unit: a propensity score-matched cohort study.

BACKGROUND: Acute kidney injury (AKI) in patients admitted to the pediatric intensive care unit (PICU) is associated with poor short-term and long-term outcomes. Greater awareness of long-term AKI-associated outcomes is needed to optimally plan follow-up and management after ICU discharge. We used propensity score methods to study associations between pediatric AKI and major adverse kidney outcomes, including mortality. METHODS: We included all children 6 months-18 years admitted to PICU at Seattle Children's Hospital from 7/1/2009 to 12/31/2018. Our primary outcome measure was Major Adverse Kidney Events at 30 days (MAKE30): creatinine > 200% of baseline, eGFR < 60 mL/min/1.73 m2, dialysis dependence, or mortality. Propensity scores for AKI development in PICU were generated using demographic, medical history, admission, and PICU hospitalization variables. Patients with AKI were matched to control patients without AKI. Logistic regression was used to test association between AKI status and MAKE30. RESULTS: In the unmatched cohort (n = 878), patients with AKI had lower platelet count (160 vs. 222) and higher PRISM III score (11 vs. 3.5). After propensity score matching, those with AKI vs. no AKI had similar PRISM III scores (9 vs. 10) and platelet count (163 vs. 159). AKI was significantly associated with MAKE30 after propensity score matching (OR: 2.97; 95% CI 1.82-4.84). CONCLUSIONS: Propensity score matching significantly reduced imbalance in baseline characteristics between those with and without AKI. After matching, AKI remained significantly associated with MAKE30. Patients who developed AKI were more likely to have abnormal kidney function at 30 and 90 days after ICU admission and may be at high risk for developing CKD in the future. A higher resolution version of the Graphical abstract is available as Supplementary information.

BP in Young Adults with CKD and Associations with Cardiovascular Events and Decline in Kidney Function.

BACKGROUND: BP is an important modifiable risk factor for cardiovascular events and CKD progression in middle-aged or older adults with CKD. However, studies describing the relationship between BP with outcomes in young adults with CKD are limited. METHODS: In an observational study, we focused on 317 young adults (aged 21-40 years) with mild to moderate CKD enrolled in the Chronic Renal Insufficiency Cohort (CRIC) Study. Exposures included baseline systolic BP evaluated continuously (per 10 mm Hg increase) and in categories (<120, 120-129, and ≥130 mm Hg). Primary outcomes included cardiovascular events (heart failure, myocardial infarction, stroke, or all-cause death) and CKD progression (50% decline of eGFR or ESKD). We used Cox proportional hazard models to test associations between baseline systolic BP with cardiovascular events and CKD progression. RESULTS: Cardiovascular events occurred in 52 participants and 161 had CKD progression during median follow-up times of 11.3 years and 4.1 years, respectively. Among those with baseline systolic BP ≥130 mm Hg, 3%/yr developed heart failure, 20%/yr had CKD progression, and 2%/yr died. In fully adjusted models, baseline systolic BP ≥130 mm Hg (versus systolic BP<120 mm Hg) was significantly associated with cardiovascular events or death (hazard ratio [HR], 2.13; 95% confidence interval [95% CI], 1.05 to 4.32) and CKD progression (HR, 1.68; 95% CI, 1.10 to 2.58). CONCLUSIONS: Among young adults with CKD, higher systolic BP is significantly associated with a greater risk of cardiovascular events and CKD progression. Trials of BP management are needed to test targets and treatment strategies specifically in young adults with CKD.

Association of circulating cardiac biomarkers with electrocardiographic abnormalities in chronic kidney disease.

BACKGROUND: Among patients with chronic kidney disease (CKD), the circulating cardiac biomarkers soluble ST2 (SST2), galectin-3, growth differentiation factor-15 (GDF-15), N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high-sensitivity troponin-T (hsTnT) possibly reflect pathophysiologic processes and are associated with clinical cardiovascular disease. Whether these biomarkers are associated with electrocardiographic findings is not known. The aim of this study was to test the association between serum cardiac biomarkers and the presence of electrocardiographic changes potentially indicative of subclinical myocardial disease in patients with CKD. METHODS: We performed a cross-sectional analysis using 3048 participants from the Chronic Renal Insufficiency Cohort (CRIC) without atrial fibrillation, atrioventricular block, bundle branch block or a pacemaker at the baseline visit. Using logistic regression, we tested the association of each of the five cardiac biomarkers with baseline electrocardiogram (ECG) findings: PR interval >200 ms, QRS interval >100 ms and a prolonged QTc interval. Models were adjusted for demographic variables, measures of kidney function, prevalent cardiovascular disease and cardiovascular risk factors. RESULTS: In adjusted models, hsTnT levels associated with prolonged PR {odds ratio [OR] 1.23 [95% confidence interval (CI) 1.08-1.40]}, QRS [OR 1.28 (95% CI 1.16-1.42)] and QTc [OR 1.94 (95% CI 1.50-2.51)] intervals. NT-proBNP levels were associated with prolonged QRS [OR 1.11 (95% CI 1.06-1.16)] and QTc [OR 1.82 (95% CI 1.58-2.10)] intervals. SST2, galectin-3 and GDF-15 were not significantly associated with any of the ECG parameters. CONCLUSIONS: hsTnT and NT-proBNP were associated with ECG measures indicative of subclinical myocardial dysfunction. These results may support future research investigating the significance of myocardial ischemia and volume overload in the pathogenesis of dysfunctional myocardial conduction in CKD.

The Impact of Donor and Recipient Renal Dysfunction on Cardiac Allograft Survival: Insights Into Reno-Cardiac Interactions.

BACKGROUND: Renal dysfunction (RD) is a potent risk factor for death in patients with cardiovascular disease. This relationship may be causal; experimentally induced RD produces findings such as myocardial necrosis and apoptosis in animals. Cardiac transplantation provides an opportunity to investigate this hypothesis in humans. METHODS AND RESULTS: Cardiac transplantations from the United Network for Organ Sharing registry were studied (n = 23,056). RD was defined as an estimated glomerular filtration rate <60 mL/min/1.73 m(2). RD was present in 17.9% of donors and 39.4% of recipients. Unlike multiple donor characteristics, such as older age, hypertension, or diabetes, donor RD was not associated with recipient death or retransplantation (age-adjusted hazard ratio [HR] = 1.00, 95% confidence interval [CI] 0.94-1.07, P = .92). Moreover, in recipients with RD the highest risk for death or retransplantation occurred immediately posttransplant (0-30 day HR = 1.8, 95% CI 1.54-2.02, P < .001) with subsequent attenuation of the risk over time (30-365 day HR = 0.92, 95% CI 0.77-1.09, P = .33). CONCLUSIONS: The risk for adverse recipient outcomes associated with RD does not appear to be transferrable from donor to recipient via the cardiac allograft, and the risk associated with recipient RD is greatest immediately following transplant. These observations suggest that the risk for adverse outcomes associated with RD is likely primarily driven by nonmyocardial factors.

A combined-biomarker approach to clinical phenotyping renal dysfunction in heart failure.

BACKGROUND: Differentiating heart failure (HF) induced renal dysfunction (RD) from intrinsic kidney disease is challenging. It has been demonstrated that biomarkers such as B-type natriuretic peptide (BNP) or the blood urea nitrogen to creatinine ratio (BUN/creat) can identify high- vs low-risk RD. Our objective was to determine if combining these biomarkers could further improve risk stratification and clinical phenotyping of patients with RD and HF. METHODS AND RESULTS: A total of 908 patients with a discharge diagnosis of HF were included. Median values were used to define elevated BNP (>1296 pg/mL) and BUN/creat (>17). In the group without RD, survival was similar regardless of BNP and BUN/creat (n = 430, adjusted P = .52). Similarly, in patients with both a low BNP and BUN/creat, RD was not associated with mortality (n = 250, adjusted hazard ratio [HR] = 1.0, 95% confidence interval [CI] 0.6-1.6, P = .99). However, in patients with both an elevated BNP and BUN/creat those with RD had a cardiorenal profile characterized by venous congestion, diuretic resistance, hypotension, hyponatremia, longer length of stay, greater inotrope use, and substantially worse survival compared with patients without RD (n = 249, adjusted HR = 1.8, 95% CI 1.2-2.7, P = .008, P interaction = .005). CONCLUSIONS: In the setting of decompensated HF, the combined use of BNP and BUN/creat stratifies patients with RD into groups with significantly different clinical phenotypes and prognosis.

Evidence of Lactobacillus strains shared between the female urinary and vaginal microbiota.

Lactobacillus species are common inhabitants of the 'healthy' female urinary and vaginal communities, often associated with a lack of symptoms in both anatomical sites. Given identification by prior studies of similar bacterial species in both communities, it has been hypothesized that the two microbiotas are in fact connected. Here, we carried out whole-genome sequencing of 49 Lactobacillus strains, including 16 paired urogenital samples from the same participant. These strains represent five different Lactobacillus species: L. crispatus, L. gasseri, L. iners, L. jensenii, and L. paragasseri. Average nucleotide identity (ANI), alignment, single-nucleotide polymorphism (SNP), and CRISPR comparisons between strains from the same participant were performed. We conducted simulations of genome assemblies and ANI comparisons and present a statistical method to distinguish between unrelated, related, and identical strains. We found that 50 % of the paired samples have identical strains, evidence that the urinary and vaginal communities are connected. Additionally, we found evidence of strains sharing a common ancestor. These results establish that microbial sharing between the urinary tract and vagina is not limited to uropathogens. Knowledge that these two anatomical sites can share lactobacilli in females can inform future clinical approaches.

Pharmacological management of youth with type 2 diabetes and diabetic kidney disease: a comprehensive review of current treatments and future directions.

INTRODUCTION: Diabetic kidney disease (DKD) is a leading cause of mortality in people with type 2 diabetes (T2D), and over 50% of individuals with youth-onset T2D will develop DKD as a young adult. Diagnosis of early-onset DKD remains a challenge in young persons with T2D secondary to a lack of available biomarkers for early DKD, while the injuries may still be reversible. Furthermore, multiple barriers exist to initiate timely prevention and treatment strategies for DKD, including a lack of Food and Drug Administration approval of medications in pediatrics; provider comfort with medication prescription, titration, and monitoring; and medication adherence. AREAS COVERED: Therapies that have promise for slowing DKD progression in youth with T2D include metformin, renin-angiotensin-aldosterone system inhibitors, glucagon-like peptide-1 receptor agonists, sodium glucose co-transporter 2 inhibitors, thiazolidinediones, sulfonylureas, endothelin receptor agonists, and mineralocorticoid antagonists. Novel agents are also in development to act synergistically on the kidneys with the aforementioned medications. We comprehensively review the available pharmacologic strategies for DKD in youth-onset T2D including mechanisms of action, potential adverse effects, and kidney-specific effects, with an emphasis on published pediatric and adult trials. EXPERT OPINION: Large clinical trials evaluating pharmacologic interventions targeting the treatment of DKD in youth-onset T2D are strongly needed.

Rates of Cardiovascular Disease and CKD Progression in Young Adults with CKD across Racial and Ethnic Groups.

Background: Significant racial and ethnic disparities in cardiovascular (CV) and kidney function outcomes in older adults with chronic kidney disease (CKD) have been reported. However, little is known about the extent to which these disparities exist in patients with CKD during the foundational period of young adulthood. The objective of this study was to determine risk factors and rates of CV disease and CKD progression in young adults with CKD across racial and ethnic groups. Methods: We studied all participants aged 21-40 years of age enrolled in the Chronic Renal Insufficiency Cohort (CRIC) Study (n=317). Baseline CV risk factors were described across racial and ethnic groups. Results: Outcomes included CV events or death (first incidence of heart failure, myocardial infarction, and stroke or death) and CKD progression (>50% decline in eGFR from baseline or end stage kidney disease [ESKD]). Incidence rate ratios (IRRs) were compared as a secondary analysis for participants identifying as Black or Hispanic with those identifying as White or another race and ethnicity. Adjusted models included age, sex, and per APOL1 high-risk allele. CV risk factors were higher in Black and Hispanic participants, including mean SBP, BMI, median UACr, and LDL. Black and Hispanic participants had higher incidence rates of HF (17.5 versus 5.1/1000 person-years), all-cause mortality (15.2 versus 7.1/1000 person-years), and CKD progression (125 versus 59/1000 person-years). Conclusions: In conclusion, we found a higher prevalence of CV risk factors, some modifiable, in young adults with CKD who identify as Black or Hispanic. Future strategies to ameliorate the racial and ethnic inequality in health outcomes earlier in life for patients with CKD should be prioritized.

The impact of increased awareness of acute kidney injury in the Neonatal Intensive Care Unit on acute kidney injury incidence and reporting: results of a retrospective cohort study.

OBJECTIVE: To evaluate the impact of nephrology integration in the NICU on acute kidney injury (AKI) incidence, provider reporting, and nephrology referral. STUDY DESIGN: Cohort study in a single-center NICU from January 2012 to December 2017 (n = 1464). We assessed the impact of clinical practice changes including neonatal-nephrology rounds on the incidence of AKI. RESULTS: AKI occurred in 318 neonates (22%). AKI occurred less frequently in those admitted after clinical practice changes (P < 0.001). After multivariable adjustment, clinical practice changes were associated with reduced odds of AKI (adjusted odds ratio, 0.31; 95% CI 0.22-0.44, P < 0.001). Provider reporting of AKI improved (P < 0.001) and more neonates were referred for nephrology follow-up (P < 0.001). CONCLUSIONS: Increased nephrology integration in the NICU was associated with decreased AKI incidence. While recognition of AKI improved, AKI remained poorly reported and nephrology AKI follow-up did not routinely occur. This study supports the importance of increased nephrology involvement in the NICU.

The Evolution of Molecular Compatibility between Bacteriophage ΦX174 and its Host.

Viruses rely upon their hosts for biosynthesis of viral RNA, DNA and protein. This dependency frequently engenders strong selection for virus genome compatibility with potential hosts, appropriate gene regulation and expression necessary for a successful infection. While bioinformatic studies have shown strong correlations between codon usage in viral and host genomes, the selective factors by which this compatibility evolves remain a matter of conjecture. Engineered to include codons with a lesser usage and/or tRNA abundance within the host, three different attenuated strains of the bacterial virus ФX174 were created and propagated via serial transfers. Molecular sequence data indicate that biosynthetic compatibility was recovered rapidly. Extensive computational simulations were performed to assess the role of mutational biases as well as selection for translational efficiency in the engineered phage. Using bacteriophage as a model system, we can begin to unravel the evolutionary processes shaping codon compatibility between viruses and their host.