Women With a History of Preeclampsia Exhibit Accelerated Aging and Unfavorable Profiles of Senescence Markers.

BACKGROUND: Senescence, a mechanism of cellular aging, which is characterized by irreversible proliferation arrest and a proinflammatory secretory phenotype, has been documented in women with preeclampsia. As cellular senescence can persist and progress, we postulated that it is associated with accelerated aging phenotype and accumulation of comorbidities in women with a history of preeclampsia. METHODS: We included a cohort of women with a history of preeclampsia (n=40) age- and parity-matched to a group of referent women with normotensive pregnancies (n=40). Women with prior major cardiovascular events, neurological, or autoimmune conditions were excluded. We collected urine and blood samples to study markers of aging, data on multimorbidity at the time of enrollment, and prospectively followed them for events over the course of 6 years, on average. RESULTS: Women with a history of preeclampsia exhibited unfavorable aging profiles compared with referent women, including decreased urinary α-Klotho (P=0.018); increased leptin (P=0.016) and leptin/adiponectin ratio (P=0.027), and increased extracellular vesicles positive for tissue factor (P=0.025). Women with a history of preeclampsia likewise had a higher rate of comorbidities at the time of enrollment (P=0.003) and had a 4× higher risk of developing major cardiovascular events compared with referent women (P=0.003). CONCLUSIONS: Our data suggest that a history of preeclampsia is associated with accelerated aging as indicated by senescence marker differences and the accumulation of multimorbidity later in life. Targeting cellular senescence may offer novel, mechanism-based approaches for the diagnosis and treatment of adverse health outcomes in women with a history of preeclampsia.

State of the Science and Ethical Considerations for Preimplantation Genetic Testing for Monogenic Cystic Kidney Diseases and Ciliopathies.

There is a broad phenotypic spectrum of monogenic polycystic kidney diseases (PKDs). These disorders often involve cilia-related genes and lead to the development of fluid-filled cysts and eventual kidney function decline and failure. Preimplantation genetic testing for monogenic (PGT-M) disorders has moved into the clinical realm. It allows prospective parents to avoid passing on heritable diseases to their children, including monogenic PKD. The PGT-M process involves embryo generation through in vitro fertilization, with subsequent testing of embryos and selective transfer of those that do not harbor the specific disease-causing variant(s). There is a growing body of literature supporting the success of PGT-M for autosomal-dominant and autosomal-recessive PKD, although with important technical limitations in some cases. This technology can be applied to many other types of monogenic PKD and ciliopathies despite the lack of existing reports in the literature. PGT-M for monogenic PKD, like other forms of assisted reproductive technology, raises important ethical questions. When considering PGT-M for kidney diseases, as well as the potential to avoid disease in future generations, there are regulatory and ethical considerations. These include limited government regulation and unstandardized consent processes, potential technical errors, high cost and equity concerns, risks associated with pregnancy for mothers with kidney disease, and the impact on all involved in the process, including the children who were made possible with this technology.

Kidney function in patients with adrenal adenomas: A single-center retrospective cohort study.

OBJECTIVE: Patients with nonfunctioning adrenal adenomas (NFA) and mild autonomous cortisol secretion (MACS) demonstrate an increased risk of chronic kidney disease (CKD), however factors associated with CKD are unknown. We aimed to identify the factors associated with CKD and assess the impact of adrenalectomy on kidney function in patients with NFA or MACS. DESIGN: Single-center cohort study of patients with NFA and MACS, 1999-2020. METHODS: MACS was diagnosed based on post-dexamethasone cortisol (DST) ≥ 1.8 mcg/dL. Age, sex, dysglycemia, hypertension, therapy with statin, angiotensin converting enzyme inhibitor, or angiotensin II receptor blocker were included in the multivariable analysis. Outcomes included estimated glomerular filtration rate (eGFR) at the time of diagnosis with MACS or NFA and post-adrenalectomy delta eGFR. RESULTS: Of 972 patients, 429 (44%) had MACS and 543 (56%) had NFA. At the time of diagnosis, patients with MACS had lower eGFR (median 79.6 vs 83.8 ml/min/1.73m2, p < 0.001) than patients with NFA. In a multivariable analysis, factors associated with lower eGFR were older age, hypertension, and higher DST. In 204 patients (MACS: 155, 76% and NFA: 49, 24%) treated with adrenalectomy, post adrenalectomy eGFR improved in both groups starting at 18 months up to 3.5 years of follow up. Factors associated with increased eGFR were younger age, lower pre-adrenalectomy eGFR and longer follow-up period. CONCLUSION: DST cortisol is an independent risk factor for lower eGFR in patients with adrenal adenomas. Both patients with MACS and NFA demonstrate an increase in eGFR post-adrenalectomy, especially younger patients with lower eGFR pre-adrenalectomy.

Posthospital Multidisciplinary Care for AKI Survivors: A Feasibility Pilot.

Rationale & Objective: Innovative models are needed to address significant gaps in kidney care follow-up for acute kidney injury (AKI) survivors. Study Design: This quasi-experimental pilot study reports the feasibility of the AKI in Care Transitions (ACT) program, a multidisciplinary approach to AKI survivor care based in the primary care setting. Setting & Participants: The study included consenting adults with stage 3 AKI discharged home without dialysis. Interventions: The ACT intervention included predischarge education from nurses and coordinated postdischarge follow-up with a primary care provider and pharmacist within 14 days. ACT was implemented in phases (Usual Care, Education, ACT). Outcomes: The primary outcome was feasibility. Secondary outcomes included process and clinical outcomes. Results: In total, 46 of 110 eligible adults were enrolled. Education occurred in 18/18 and 14/15 participants in the Education and ACT groups, respectively. 30-day urine protein evaluation occurred in 15%, 28%, and 87% of the Usual Care, Education, and ACT groups, respectively (P < 0.001). Cumulative incidence of provider (primary care or nephrologist) and laboratory follow-up at 14 and 30 days was different across groups (14 days: Usual care 0%, Education 11%, ACT 73% [P < 0.01]; 30 days: 0%, 22%, and 73% [P < 0.01]). 30-day readmission rates were 23%, 44%, and 13% in the Usual Care, Education, and ACT groups, respectively (P = 0.13). Limitations: Patients were not randomly assigned to treatment groups. The sample size limited the ability to detect some differences or perform multivariable analysis. Conclusions: This study demonstrated the feasibility of multidisciplinary AKI survivor follow-up beginning in primary care. We observed a higher cumulative incidence of laboratory and provider follow-up in ACT participants. Trial Registration: ClinicalTrials.gov (NCT04505891). Plain-Language Summary: Abrupt loss of kidney function in hospitalized patients, acute kidney injury (AKI), increases the chances of long-term kidney disease and a worse health care experience for patients. One out of 3 people who experience AKI do not get the follow-up kidney care they need. We performed a pilot study to test whether a program that facilitates structured AKI follow-up in primary care called the AKI in Care Transitions (ACT) program was possible. ACT brings together the unique expertise of nurses, doctors, and pharmacists to look at the patient's kidney health plan from all angles. The study found that the ACT program was possible and led to more complete kidney care follow-up after discharge than the normal approach to care.

Impact of Aging and Cellular Senescence in the Pathophysiology of Preeclampsia.

The incidence of hypertensive disorders of pregnancy is increasing, which may be due to several factors, including an increased age at pregnancy and more comorbid health conditions during reproductive years. Preeclampsia, the most severe hypertensive disorder of pregnancy, has been associated with an increased risk of future disease, including cardiovascular and kidney diseases. Cellular senescence, the process of cell cycle arrest in response to many physiologic and maladaptive stimuli, may play an important role in the pathogenesis of preeclampsia and provide a mechanistic link to future disease. In this article, we will discuss the pathophysiology of preeclampsia, the many mechanisms of cellular senescence, evidence for the involvement of senescence in the development of preeclampsia, as well as evidence that cellular senescence may link preeclampsia to the risk of future disease. Lastly, we will explore how a better understanding of the role of cellular senescence in preeclampsia may lead to therapeutic trials. © 2023 American Physiological Society. Compr Physiol 13:5077-5114, 2023.

Development and Implementation of an Acute Kidney Injury Remote Patient Monitoring Program: Research Letter.

Acute kidney injury (AKI) survivors have a dynamic posthospital course which warrants close monitoring. Remote patient monitoring (RPM) could be used to improve quality and efficiency of AKI survivor care. Objective: The objective of this report was to describe the development and preliminary feasibility of an AKI RPM program launched in October 2021. Setting: Academic medical center. Patients: Patients enrolled in the AKI RPM program were those who experienced AKI during a hospitalization and underwent nephrology consultation. Measurements/Methods: At enrollment, patients were provided with home monitoring technology and underwent weekly laboratory assessments. Nurses evaluated the data daily and adhered to prespecified protocols for management and escalation of care if needed. Results: Twenty patients were enrolled in AKI RPM in the first 5 months. Median duration of program participation was 36 (31, 40) days. Eight patients (40%) experienced an unplanned readmission, or an emergency department visit, half (N = 4) of which were attributed to AKI and related circumstances. Of the 9 postgraduation survey respondents, all were satisfied with the RPM program and 89% would recommend RPM to other patients with similar health conditions. Limitations: Acute kidney injury RPM was made possible by the existing infrastructure in our integrated health system and the robust resources available in the Mayo Clinic Center for Digital Health. Such infrastructure may not be universally available which could limit scale and generalizability of such a program. Conclusions: Remote patient monitoring can offer a unique opportunity to bridge the care transition from hospital to home and increase access to quality care for the AKI survivors.

Les survivants d'un épisode d'insuffisance rénale aiguë (IRA) ont un parcours post-hospitalier dynamique qui justifie une surveillance étroite. La télésurveillance des patients (TSP) pourrait être employée pour améliorer la qualité et l'efficacité des soins pour les survivants de l'IRA. Objectif: L'objectif de ce rapport était de décrire le développement et la faisabilité préliminaire d'un programme de TSP-IRA (télésurveillance des patients atteints d'IRA) en octobre 2021. Cadre: Centre médical universitaire. Sujets: Les patients inscrits au programme de TSP-IRA étaient des patients qui avaient vécu un épisode d'IRA lors d'une hospitalisation et obtenu une consultation en néphrologie. Mesures et méthodologie: Au moment de l'inclusion, les patients ont reçu un dispositif de surveillance à domicile et se sont soumis à des évaluations de laboratoire hebdomadaires. Les infirmières ont évalué les données quotidiennement et ont respecté des protocoles prédéfinis pour la gestion et l'escalade des soins si nécessaire. Résultats: Vingt patients ont été inclus dans le programme de TSP-IRA au cours des cinq premiers mois. La durée médiane de participation au programme était de 36 (31, 40) jours. Huit patients (40%) ont dû être réadmis de façon non planifiée ou ont dû faire une visite aux urgences; pour la moitié d'entre eux (N = 4) en raison de l'IRA et de circonstances connexes. Parmi les neuf répondants qui ont répondu au sondage à la complétion du programme, tous se sont dits satisfaits du programme de TSP et 89% le recommanderaient à d'autres patients ayant des problèmes de santé similaires. Limites: Le programme de TSP-IRA a été rendu possible grâce à l'infrastructure existante dans notre système de santé intégré et aux ressources robustes disponibles au Mayo Clinic Center for Digital Health. Une telle infrastructure n'est peut-être pas universellement disponible, ce qui pourrait limiter l'ampleur et la généralisabilité d'un tel programme. Conclusion: La TSP peut offrir une occasion unique de faciliter la transition des soins entre l'hôpital et le domicile et d'accroître l'accès à des soins de qualité pour les survivants d'un épisode d'IRA.

Decreased Risk of Preeclampsia in Women with Inflammatory Bowel Disease on Anti-Tumor Necrosis Factor Therapy.

BACKGROUND: Evidence suggests that upregulation of tumor necrosis factor-alpha (TNF-α) plays a role in immune dysregulation in both preeclampsia and inflammatory bowel disease (IBD). AIMS: We aimed to investigate whether anti-TNF therapy during pregnancy decreases the risk of preeclampsia in women with IBD. METHODS: The study population included women with IBD and pregnancies who were followed at a tertiary care center from 2007 to 2021. Cases of preeclampsia were compared with controls with a normotensive pregnancy. Data on patient demographics, disease type and activity, pregnancy complications, and additional risk factors for preeclampsia were collected. The association between anti-TNF therapy and preeclampsia was analyzed using univariate analysis and multivariate logistic regression. RESULTS: Women with preeclampsia were more likely to have a preterm delivery (44% vs. 12%, p < 0.001). More women without preeclampsia were exposed to anti-TNF therapy during pregnancy than women with preeclampsia (55% vs. 30%, p = 0.029). The majority of women (32/44) on anti-TNF therapy, either adalimumab or infliximab, continued to have some degree of exposure during the third trimester. Though not significant, multivariate analysis showed a trend towards a protective effect of anti-TNF therapy against developing preeclampsia if exposed during the third trimester (OR 0.39; 95% CI 0.14-1.12, p = 0.08). CONCLUSIONS: In this study, anti-TNF therapy exposure was higher in IBD patients who did not develop preeclampsia than in those who did. While not significant, there was a trend towards a protective effect of anti-TNF therapy against preeclampsia if exposed during the third trimester.

Risk of Adult Hypertension in Offspring From Pregnancies Complicated by Hypertension: Population-Based Estimates.

BACKGROUND: Hypertensive disorders of pregnancy (HDP) have been associated with an increased risk of chronic hypertension for both mothers and offspring. We sought to quantify the incidence of chronic hypertension in offspring from HDP-affected pregnancies in a large, population-based cohort study. Furthermore, we evaluate the association of HDP exposure in utero and maternal chronic hypertension in offspring. METHODS: We performed a population-based cohort study of 8755 individuals born during 1976 to 1982 to 7544 women who all resided in the same community at the time of delivery. HDP were identified using a previously validated algorithm. Diagnosis of chronic hypertension in mothers and their offspring was determined using diagnostic codes. Cox proportional hazards regression was used to assess the association between HDP and chronic hypertension. RESULTS: HDP exposure (hazard ratio, 1.50 [95% CI, 1.18-1.90]) and maternal chronic hypertension (hazard ratio, 1.73 [95% CI, 1.48-2.02]) were both associated with a significant increased risk for chronic hypertension in offspring. Both risk factors remained significantly associated with increased risk of hypertension in offspring when included together in a multivariate model. Having both exposures was associated with a 2.4-fold increase in the risk of hypertension in offspring, suggesting a synergistic additive interaction. CONCLUSIONS: HDP exposure in gestation and maternal hypertension are both independently associated with an increased risk of chronic hypertension in offspring. Our results suggest that HDP exposure in utero, in addition to maternal chronic hypertension, may lead to a greater risk for the development of hypertension in offspring.

Comprehensive Acute Kidney Injury Survivor Care: Protocol for the Randomized Acute Kidney Injury in Care Transitions Pilot Trial.

BACKGROUND: Innovative care models are needed to address gaps in kidney care follow-up among acute kidney injury (AKI) survivors. We developed the multidisciplinary AKI in Care Transitions (ACT) program, which embeds post-AKI care in patients' primary care clinic. OBJECTIVE: The objective of this randomized pilot trial is to test the feasibility and acceptability of the ACT program and study protocol, including recruitment and retention, procedures, and outcome measures. METHODS: The study will be conducted at Mayo Clinic in Rochester, Minnesota, a tertiary care center with a local primary care practice. Individuals who are included have stage 3 AKI during their hospitalization, do not require dialysis at discharge, have a local primary care provider, and are discharged to their home. Patients unable or unwilling to provide informed consent and recipients of any transplant within 100 days of enrollment are excluded. Consented patients are randomized to receive the intervention (ie, ACT program) or usual care. The ACT program intervention includes predischarge kidney health education from nurses and coordinated postdischarge laboratory monitoring (serum creatinine and urine protein assessment) and follow-up with a primary care provider and pharmacist within 14 days. The usual care group receives no specific study-related intervention, and any aspects of AKI care are at the direction of the treating team. This study will examine the feasibility of the ACT program, including recruitment, randomization and retention in a trial setting, and intervention fidelity. The feasibility and acceptability of participating in the ACT program will also be examined in qualitative interviews with patients and staff and through surveys. Qualitative interviews will be deductively and inductively coded and themes compared across data types. Observations of clinical encounters will be examined for discussion and care plans related to kidney health. Descriptive analyses will summarize quantitative measures of the feasibility and acceptability of ACT. Participants' knowledge about kidney health, quality of life, and process outcomes (eg, type and timing of laboratory assessments) will be described for both groups. Clinical outcomes (eg, unplanned rehospitalization) up to 12 months will be compared with Cox proportional hazards models. RESULTS: This study received funding from the Agency for Health Care Research and Quality on April 21, 2021, and was approved by the Institutional Review Board on December 14, 2021. As of March 14, 2023, seventeen participants each have been enrolled in the intervention and usual care groups. CONCLUSIONS: Feasible and generalizable AKI survivor care delivery models are needed to improve care processes and health outcomes. This pilot trial will test the ACT program, which uses a multidisciplinary model focused on primary care to address this gap. TRIAL REGISTRATION: ClinicalTrials.gov NCT05184894; https://www.clinicaltrials.gov/ct2/show/NCT05184894. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/48109.

Effects of SARS-CoV-2 vaccination on the severity of COVID-19 infection in patients on chronic dialysis.

BACKGROUND: COVID-19 is associated with increased morbidity and mortality in patients with end-stage kidney disease on dialysis. Efficacy of SARS-CoV-2 vaccination to prevent severe COVID-19 disease in end-stage kidney disease patients remains limited. We compared the incidence of COVID-19-related hospitalization and death in dialysis patients based on SARS-CoV-2 vaccine status. METHODS: Retrospective study of adults on chronic dialysis within Mayo Clinic Dialysis System in the Midwest (USA) between April 1st, 2020 and October 31st, 2022, who had a laboratory test positive for SARS-CoV-2 by PCR. Incidence of both COVID-19-related hospitalization and death were compared between vaccinated and unvaccinated patients. RESULTS: SARS-CoV-2 infection was identified in 309 patients, including 183 vaccinated and 126 unvaccinated. The incidence of death (11.1% vs 3.8%, p = 0.02) and hospitalization (55.6% vs 23.5%, p < 0.001) was significantly higher in unvaccinated compared to vaccinated patients. Age at infection, sex, Charlson comorbidity index, dialysis modality, and hospital stays did not differ between the two groups. The incidence of hospitalization was significantly higher in partially vaccinated (63.6% vs 20.9%, p = 0.004) and unboosted (32% vs 16.4%, p = 0.04) patients compared to fully vaccinated and boosted, respectively. Among the 21 patients who died in the whole cohort, 47.6% (n = 10) died during the pre-vaccine period. The composite risk of death or hospitalization was lower among vaccinated patients after adjusting for age, sex and Charlson comorbidity index (OR 0.24, 95% CI 0.15-0.40). CONCLUSIONS: This study supports the use of SARS-CoV-2 vaccination to improve COVID-19 outcomes in patients on chronic dialysis.

Preeclampsia and the Kidney: Pathophysiology and Clinical Implications.

Preeclampsia and other hypertensive disorders of pregnancy are major contributors to maternal morbidity and mortality worldwide. This group of disorders includes chronic hypertension, gestational hypertension, preeclampsia, preeclampsia superimposed on chronic hypertension, and eclampsia. The body undergoes important physiological changes during pregnancy to allow for normal placental and fetal development. Several mechanisms have been proposed that may lead to preeclampsia, including abnormal placentation and placental hypoxia, impaired angiogenesis, excessive pro-inflammatory response, immune system imbalance, abnormalities of cellular senescence, alterations in regulation and activity of angiotensin II, and oxidative stress, ultimately resulting in upregulation of multiple mediators of endothelial cell dysfunction leading to maternal disease. The clinical implications of preeclampsia are significant as there are important short-term and long-term health consequences for those affected. Preeclampsia leads to increased risk of preterm delivery and increased morbidity and mortality of both the developing fetus and mother. Preeclampsia also commonly leads to acute kidney injury, and women who experience preeclampsia or another hypertensive disorder of pregnancy are at increased lifetime risk of chronic kidney disease and cardiovascular disease. An understanding of normal pregnancy physiology and the pathophysiology of preeclampsia is essential to develop novel treatment approaches and manage patients with preeclampsia and hypertensive disorders of pregnancy. © 2023 American Physiological Society. Compr Physiol 13:4231-4267, 2023.

Pharmacist-provider collaborative visits after hospital discharge in a comprehensive acute kidney injury survivor model.

BACKGROUND: Postdischarge follow-up in primary care is an opportunity for pharmacists to re-evaluate medication use in acute kidney injury (AKI) survivors. Of the emerging AKI survivor care models described in literature, only one involved a pharmacist with limited detail about the direct impact. OBJECTIVE: This study aimed to describe pharmacist contributions to a comprehensive postdischarge AKI survivorship program in primary care (the AKI in Care Transitions [ACT] program). METHODS: The ACT program was piloted from May to December of 2021 at Mayo Clinic as a bundled care strategy for patients who survived an episode of AKI and were discharged home without the need for hemodialysis. Patients received education and care coordination from nurses before discharge and later completed postdischarge laboratory assessment and clinician follow-up in primary care. During the follow-up encounter, patients completed a 30-minute comprehensive medication management visit with a pharmacist focusing on AKI survivorship considerations. Medication therapy recommendations were communicated to a collaborating primary care provider (PCP) before a separate 30-minute visit with the patient. PCPs had access to clinical decision support with evidence-based post-AKI care recommendations. Medication-related issues were summarized descriptively. RESULTS: Pharmacists made 28 medication therapy recommendations (median 3 per patient, interquartile range 2-3) and identified 14 medication discrepancies for the 11 patients who completed the pilot program, and 86% of the medication therapy recommendations were acted on by the PCP within 7 days. Six recommendations were made to initiate renoprotective medications, and 5 were acted on (83%). CONCLUSION: During the pilot phase of a multifaceted transitional care program for AKI survivors, pharmacists' successfully identified and addressed multiple medication therapy problems, including for renally active drugs. These results demonstrate the potential for pharmacist-provider collaborative visits in primary care to improve safe and effective medication use in AKI survivors.

Glomerular diseases in pregnancy: pragmatic recommendations for clinical management.

Our understanding of the various aspects of pregnancy in women with kidney diseases has significantly improved in the last decades. Nevertheless, little is known about specific kidney diseases. Glomerular diseases are not only a frequent cause of chronic kidney disease in young women, but combine many challenges in pregnancy: immunologic diseases, hypertension, proteinuria, and kidney tissue damage. An international working group undertook the review of available current literature and elicited expert opinions on glomerular diseases in pregnancy with the aim to provide pragmatic information for nephrologists according to the present state-of-the-art knowledge. This work also highlights areas of clinical uncertainty and emphasizes the need for further collaborative studies to improve maternal and fetal health.

Explainable Preoperative Automated Machine Learning Prediction Model for Cardiac Surgery-Associated Acute Kidney Injury.

BACKGROUND: We aimed to develop and validate an automated machine learning (autoML) prediction model for cardiac surgery-associated acute kidney injury (CSA-AKI). METHODS: Using 69 preoperative variables, we developed several models to predict post-operative AKI in adult patients undergoing cardiac surgery. Models included autoML and non-autoML types, including decision tree (DT), random forest (RF), extreme gradient boosting (XGBoost), and artificial neural network (ANN), as well as a logistic regression prediction model. We then compared model performance using area under the receiver operating characteristic curve (AUROC) and assessed model calibration using Brier score on the independent testing dataset. RESULTS: The incidence of CSA-AKI was 36%. Stacked ensemble autoML had the highest predictive performance among autoML models, and was chosen for comparison with other non-autoML and multivariable logistic regression models. The autoML had the highest AUROC (0.79), followed by RF (0.78), XGBoost (0.77), multivariable logistic regression (0.77), ANN (0.75), and DT (0.64). The autoML had comparable AUROC with RF and outperformed the other models. The autoML was well-calibrated. The Brier score for autoML, RF, DT, XGBoost, ANN, and multivariable logistic regression was 0.18, 0.18, 0.21, 0.19, 0.19, and 0.18, respectively. We applied SHAP and LIME algorithms to our autoML prediction model to extract an explanation of the variables that drive patient-specific predictions of CSA-AKI. CONCLUSION: We were able to present a preoperative autoML prediction model for CSA-AKI that provided high predictive performance that was comparable to RF and superior to other ML and multivariable logistic regression models. The novel approaches of the proposed explainable preoperative autoML prediction model for CSA-AKI may guide clinicians in advancing individualized medicine plans for patients under cardiac surgery.