Acute cardiorenal syndrome (cardiorenal syndrome type 1, CRS1) is a common complication of the most common cause of death, cardiovascular disease, and therefore is of considerable importance. Foundational research over the last 100 years detailed the elegant interplay between cardiovascular function and tubuloglomerular feedback that underpins the classic description of CRS1. However, as research into acute kidney injury has elucidated important modifying factors in sex difference, immune regulation, and proximal tubule function, these areas are ripe for investigation in CRS1. Here, we briefly review the nascent state of knowledge regarding CRS1 in women and sex differences, immune contributions, and proximal tubule transport function.

Acute kidney injury (AKI) and chronic kidney disease (CKD) are increasingly recognized as interconnected syndromes with overlapping pathophysiological mechanisms. A growing body of evidence suggests that macrophages are central regulators of the AKI-to-CKD transition, influencing both injury and repair through dynamic, microenvironment-dependent phenotypic shifts. M1-like macrophages dominate early injury responses in AKI, while M2-like macrophages can adopt a pro-fibrotic phenotype potentially contributing to the progression of CKD. Beyond this classical dichotomy, single-cell and spatial transcriptomic studies reveal a complex spectrum of macrophage states shaped by origin, tissue niche, temporal dynamics, and intercellular signaling. This review summarizes the current understanding of macrophage ontogeny, heterogeneity, and functional specialization in AKI and progression to CKD. We highlight how macrophages respond to local cues, engage in crosstalk with other cell types, and mediate phase-specific effects on inflammation and tissue remodeling. We also evaluate the consequences of macrophage depletion in AKI and the progression of AKI to CKD, highlighting divergent outcomes. Advancing our understanding of macrophage complexity is essential for developing precise immunomodulatory strategies for treating AKI and preventing CKD progression. By disentangling the context-specific roles of macrophages, future therapies can be tailored to attenuate pathogenic responses without compromising essential reparative functions, ultimately improving long-term renal outcomes. Semin Nephrol 36:x-xx © 20XX Elsevier Inc. All rights reserved.

The global health impact of sepsis is difficult to understate. As a complication of sepsis, the development of sepsis-associated acute kidney injury (SA-AKI) significantly increases the risk of mortality. Although several epidemiological risk factors for SA-AKI are known, the heterogeneity of this syndrome-across patients, pathogens, and treatment responses-has hindered therapeutic innovation and contributed to persistently poor outcomes. Precision medicine offers a promising framework to address this complexity, yet a substantial translational gap remains between mechanistic insights from preclinical models and the therapeutic strategies used in clinical practice. To bridge this gap, researchers should consider aligning preclinical models with human sepsis and embrace SA-AKI heterogeneity to identify treatable, mechanistically informed subtypes (endotypes). These efforts could enable the development of personalized therapies aimed at reducing the burden of SA-AKI.

Chronic kidney disease of unknown etiology has been reported in Mesoamerican regions and other parts of the world, with increasing evidence pointing to heat stress as a central contributing factor. The incidence of acute kidney injury appears to correlate strongly with heat exposure, as demonstrated in both human and animal studies. The underlying mechanisms of heat-induced kidney injury are likely multifactorial, involving hemodynamic changes, immune responses, and possibly coagulopathies. However, the precise pathways remain unclear, highlighting the urgent need for a deeper understanding of the mechanisms and for developing strategies to prevent or mitigate renal damage. This is particularly important not only for heat-exposed occupational groups, such as agricultural workers, military personnel, and athletes, but also for the general population, who are increasingly vulnerable to extreme heat events every year.

Acute kidney injury (AKI) is a condition that is associated with increased mortality in the clinic and currently has no Food and Drug Administration-approved drug intervention that prevents progression to chronic kidney disease. To address the lack of therapy, it is imperative to use multiple model systems that can recapitulate the complex pathophysiology of AKI. Rodent AKI models are the gold standard and are widely used, but their genetic, metabolic, and circadian cycle divergence from humans can create hurdles in translational research. Similarly, well-established two-dimensional cell lines lack the complexity necessary to model heterogeneous injury occurring in multiple distinct renal cell types during AKI events. Advances in three-dimensional kidney organoids and microfluidic model systems are increasingly bridging the gap by improving structural and functional similarities to human renal tissue. Zebrafish and Drosophila models also provide functionally relevant systems that allow for high-content screening capabilities in whole organisms. In this review, we summarize three-dimensional in vitro and nonmammalian model systems and discuss how these systems have provided researchers with valuable platforms for furthering AKI drug discovery efforts.

Acute kidney injury (AKI) is a serious and common clinical condition characterized by a sudden decline in kidney function. Although kidney function decline is typically reversible, a certain subset of AKI patients eventually develop chronic kidney disease (CKD) and kidney failure. Immune cells are well-known mediators of injury sequelae. Myeloid cells such as neutrophils, dendritic cells, and macrophages drive the initial inflammatory response following AKI but can change their phenotype after resolution of the injury to promote repair. Failure to resolve the initial injury, or improper tubular repair, drives persistent myeloid cell accumulation that can result in the development of kidney fibrosis and CKD. In this review, we focus on the role of myeloid cells following AKI including the mechanisms through which they promote injury and repair.

Many patients with urinary obstruction have an accelerated decline in renal function despite early urologic interventions. They also have defects in urinary concentrating capacity that may predispose them to acute kidney injury and chronic kidney disease. Because urinary concentrating capacity depends on having intact solute concentrating mechanisms in the renal medulla, it is likely that this results from obstruction-induced abnormalities in renal medullary structure, function, or both. This review focuses on findings from a recent study characterizing the long-term effects of reversible unilateral ureteral obstruction in mice that address these questions. These findings show that there is delayed long-term growth of the inner medulla, which is initially shrunken, that results in complete restoration of inner medullary size and gross tissue architecture 3 months after reversal of the obstruction. More detailed analysis shows that despite relatively normal histologic appearances, there are permanent defects in the cellular organization and function of the medulla that account for the loss of urinary concentrating capacity. We discuss the extent to which regenerative versus nonregenerative repair mechanisms may contribute to the growth and functional recovery of the renal medulla and consider how these findings shed light on the mechanisms of tissue repair and dysfunction after reversal of urinary obstruction.

Despite intensive research efforts, acute kidney injury (AKI) is a common clinical syndrome that has limited treatment options apart from supportive care. The increasing availability of molecular interrogation data from patients with Acute Kidney Injury provides an unparalleled opportunity to leverage systems biology approaches. In this review, we discuss the challenges with AKI research, explain how systems biology approaches can link molecular data to clinical phenotypes, review available molecular interrogation tools and techniques, and provide examples where systems biology approaches have been successfully applied in nephrology.

Over the past 25 years, neuroimmune regulation has emerged as a compelling approach to the prevention and treatment of acute kidney injury. Vagus nerve stimulation through the cholinergic anti-inflammatory pathway can suppress inflammatory responses and demonstrate therapeutic potential in both animal disease models and a variety of human inflammatory conditions. The mechanisms underlying this neuroimmune-regulated protection are complex, but research undertaken since 2000 has significantly advanced our understanding of the key elements involved. This research has also yielded intriguing results and unexpected observations. In this review, we highlight current insights into vagus nerve-mediated neuroimmune regulation, areas of ongoing uncertainty, and promising directions for therapeutic modulation in AKI. Semin Nephrol 36:x-xx © 20XX Elsevier Inc. All rights reserved.

Maintaining kidney health throughout the human lifespan remains a significant global challenge. Worldwide, an estimated 850 million people have some level of kidney disease, with many unaware because of asymptomatic progression. Whether initiated by acute or chronic insults, renal injury and disease can have life-threatening consequences requiring interventions spanning the gamut of supportive care to kidney replacement therapies. Design of precision therapeutics is likely to benefit from understanding the heterogenous cell types and states that arise in the context of kidney injury and disease. Here we review an array of cellular states that have been detected following acute ischemic kidney injury, hypothesized to promote transition to chronic kidney disease. We focused on studies describing the cellular states of the proximal tubule (PT), a segment of the nephron most vulnerable to ischemic injury. PT cells have been shown in preclinical animal studies to have a heterogeneous response to ischemic injury, including repaired and failed-repair cellular states, inter alia. We end by discussing targeting these cellular states and/or pathological processes. Semin Nephrol 36:x-xx © 20XX Elsevier Inc. All rights reserved.

Acute kidney injury (AKI) is a relatively common complication of trauma and is associated with significant morbidity and mortality in clinical studies. Given logistical and cost constraints, the majority of animal research on trauma-induced AKI is done in small animal models. However, large animal models have significant advantages from a scientific standpoint compared to small animal models because their size and anatomy are more analogous to humans. This review discusses a variety of trauma models in dogs, sheep, pigs, and nonhuman primates and the impact on AKI in several settings: hemorrhagic shock, ischemia-reperfusion injury, rhabdomyolysis, extracorporeal therapies, burns, and polytrauma.

Image analysis has played a critical role in our understanding of kidney morphology, function, and disease. This analysis has been historically limited to visualizing defined regions within the kidney in two dimensions. However, in recent years, significant advancements in microscopy have facilitated three-dimensional imaging and analysis of large tissue specimens and, in some cases, whole organs or organism. The use of these microscopy techniques combined with tissue-clearing strategies has resulted in detailed, multidimensional views of complex structures and processes within the kidney. This review discusses advanced light microscopy applications and optical clearing protocols that have been successfully modified for use in the kidney. Furthermore, this review will highlight how quantification of three-dimensional images has been applied in the kidney and thus contributed to novel spatiotemporal insights. Semin Nephrol 36:x-xx © 20XX Elsevier Inc. All rights reserved.

Acute kidney injury (AKI), a drop in kidney function with multiple etiologies, is a common complication in hospitalized patients and is associated with poorer patient outcomes. With the advent of electronic health records, machine learning algorithms have been developed that can predict the incidence and severity of AKI, AKI persistence, as well as patient outcomes like mortality and the need for kidney replacement therapies. Furthermore, it can risk-stratify patients based on early presentations to aid with clinical management. Newer technologies like natural language processing and generative artificial intelligence (AI) (e.g., ChatGPT) also show promise in the realm of AKI prediction and management. This review provides an overview of the role of AI in adults with AKI, as well as explores some limitations and ethical considerations that need to be addressed as we move forward. Semin Nephrol 36:x-xx © 20XX Elsevier Inc. All rights reserved.

Advances in genomic diagnostics have enabled earlier and more precise identification of genetic kidney disease, but the translation of these insights into trial methodology and therapeutic development has lagged. This review examines the current challenges in nephrology trials-including disease heterogeneity, slow progression, and limited industry engagement-and explores how genomic information can address these barriers. Examples from trials in autosomal dominant polycystic kidney disease and other genetic kidney diseases demonstrate the feasibility and value of genomics-informed approaches, including genotype-based recruitment, post hoc genetic stratification, and drug repurposing. The emergence of genotype stratification, artificial intelligence tools, and gene-based therapies presents further opportunities to refine trial design and personalize treatment. However, incorporating genomics into clinical research also raises complex ethical and regulatory issues, including consent processes, data governance, and equitable access to testing and trial participation. As genomic testing becomes embedded in standard clinical practice, its alignment with clinical research infrastructure offers the potential to create a learning health system in nephrology. Realizing this potential will require cross-disciplinary coordination, international collaboration, and co-design with patients and communities. Integrating genetic nephrology into clinical trial conduct is not only feasible but essential to advancing precision medicine and improving outcomes for patients with kidney disease.

Advancements in chronic kidney disease (CKD) genetic research and next-generation sequencing have improved CKD diagnosis and personalized treatment. Broad gene panel testing or whole exome/genome sequencing has greatly improved understanding of the genetic etiology of kidney disease but has also increased the complexity of interpretation. Standardized variant classification guidelines help, but challenges remain due to subjective evidence and limited functional and phenotypic data. Careful consideration of genetic and clinical evidence, along with collaboration between clinicians, genetics experts, and laboratories, is essential for accurate interpretation and patient care. This article examines nephrology genetic testing, focusing on the complexities of variant analysis, classification, and interpretation. Variant classification in monogenic kidney diseases is crucial for accurate diagnosis and patient management. We outline the classification methods highlighting several variant examples using the ACMG/AMP framework and quantitative approaches for pathogenicity assessment. We highlight challenges in integrating genetic findings into nephrology and emphasize the clinical impact of accurate genetic diagnoses for precision medicine in CKD.

Acute kidney injury (AKI) continues to pose a significant clinical burden, characterized by high morbidity and mortality rates. Emerging evidence has established mitochondrial dysfunction as a central driver in the pathogenesis of AKI, encompassing deficits in bioenergetics, excessive production of reactive oxygen species, and disruption of mitochondrial dynamics. Therapeutic interventions targeting mitochondrial pathways-most notably peptide-based agents such as SS-31-have demonstrated promising results in preclinical models. Recent discoveries have identified phospholipid scramblase 3 (PLSCR3) as an essential mediator of SS-31's mitochondrial protective effects, positioning it as a novel therapeutic target. This review synthesizes current mitochondrial-directed approaches for AKI, with a particular emphasis on the mechanistic role of PLSCR3 in maintaining mitochondrial homeostasis and injury responses. Despite encouraging data, mitochondrial therapies face several translational hurdles, including limited bioavailability, challenges in establishing effective dosing regimens, incomplete mechanistic understanding, and variability in efficacy across different experimental models. Moreover, concerns regarding cost, accessibility, and long-term safety remain unresolved, contributing to inconsistent outcomes in clinical trials. Herein we evaluate the emerging role of PLSCR3 as a potentially druggable mitochondrial target, supported by recent genetic, biochemical, and in vivo evidence, and discuss translational strategies that may bridge the gap between experimental promise and clinical application. Semin Nephrol 36:x-xx © 20XX Elsevier Inc. All rights reserved.

Suspecting that a patient has an inherited renal tubular disorder usually involves a mixture of listening to their story, asking the right questions, looking at the whole patient and their context, examining components of blood and urine, and assessing relevant imaging. Usually, inherited tubulopathies are rare, and they may include extrarenal features. Genetic testing has become widely available and can be used to establish a firm diagnosis in many situations, but this should not replace attempts to work out the diagnosis biochemically. Patients with tubular disorders often wait a long time for a diagnosis because many such conditions are very rare; genetic confirmation may well improve their quality of life. Semin Nephrol 36:x-xx © 20XX Elsevier Inc. All rights reserved.

Effective communication of genetic risk alleles, particularly APOL1 renal risk variants, is essential for enhancing patient comprehension, guiding clinical decision-making, and ensuring equitable health care. This review explores the communication and implications of risk alleles in kidney-related genes, emphasizing the need for genetic training for nephrologists, expanded genetic counseling services, and multidisciplinary collaboration to optimize test interpretation and patient-centered care. Increasing ancestral diversity in genetic databases remains critical for refining risk assessments and minimizing uncertainty in result interpretation. Additionally, addressing concerns regarding genetic discrimination through legal protections is necessary to promote ethical use of genetic information. Collaborating with experts in risk communication and engaging community members, as exemplified by the APOLLO Consortium's Community Advisory Council, will aid in integrating genetic and nongenetic risk factors to improve health outcomes. Moving forward, research efforts must focus on elucidating APOL1-associated disease mechanisms, refining risk stratification, and developing targeted therapeutics. Implementing innovative communication strategies, including culturally competent counseling, digital education tools, and standardized decision aids, will be vital in making genetic information both accessible and actionable. By addressing these challenges, the medical community can fully leverage genetic testing to advance personalized medicine, improve patient outcomes, and reduce disparities in kidney disease care.