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.
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.
Genetic testing in nephrology is evolving beyond diagnosis of kidney diseases to significantly influence broader patient care. This review evaluates the expanding role of genetic information in nephrology practice. We compare various testing technologies-including targeted gene panels, exome/genome sequencing, and single nucleotide polymorphism (SNP) arrays-highlighting their clinical utility and limitations in various medical specialties. We discuss existing tests where genetic results could impact the care of patients with chronic kidney disease (CKD): management of CKD-associated comorbidities, clinical implications of American Society of Medical Genetics and Genomics actionable genes, pharmacogenomic tests to optimize medication selection and dosing, and Human Leukocyte Antigen testing. As novel genetic tools emerge, such as polygenic risk scores and clonal hematopoiesis of indeterminate potential, we discuss how they may soon be reported in clinical settings. Given the complexity of interpreting diverse genetic data, we advocate for the integration of genetics professionals into nephrology care teams. This review concludes that genetic testing beyond kidney-specific genes holds immense promise for improving the care of patients with kidney diseases, but further research is necessary to establish guidelines for its integration into nephrology practice. Semin Nephrol 36:x-xx © 20XX Elsevier Inc. All rights reserved.
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.
Kidney fibrosis is a common cause of chronic kidney disease. Experimental studies have demonstrated a role for the epidermal growth factor receptor (EGFR) signaling pathway in mediating the development and progression of kidney fibrosis. Deletion of Rhbdf2 (iRhom2), a member of the rhomboid family that regulates A disintegrin and metalloproteinase domain 17-mediated release of membrane-anchored proteins, including EGFR ligands, inhibited kidney interstitial fibrosis, which was accompanied by decreased EGFR activation in interstitial fibroblasts/myofibroblasts. In addition, overexpression of another EGFR ligand, heparin-binding epidermal growth factor-like growth factor, induced interstitial fibrosis in kidneys. Although EGFR activation did not induce myofibroblast transformation, it was necessary for the initial pericyte/fibroblast migration and proliferation prior to subsequent myofibroblast transformation by transforming growth factor beta or other profibrotic factors. Therefore, EGFR activation in kidney fibroblasts and pericytes serves as a specific initiator of interstitial fibrosis in response to kidney injury by stimulating pericyte/fibroblast migration and proliferation. These findings may also provide insight into the development of fibrosis in other organs and in other conditions.
Genetic testing holds great potential to enhance the diagnosis and management of kidney disease, yet its integration into routine nephrology care remains limited and often delayed. Despite strong evidence supporting its clinical utility and cost effectiveness, significant barriers hinder its widespread adoption. This review examines care models designed to embed genetic testing into nephrology practice and proposes strategies to improve access for chronic kidney disease patients. Key approaches include enhancing clinical genetic services, establishing kidney genetics clinics, using technology such as virtual consultations, forming variant review boards and multidisciplinary teams, and mainstreaming genetic testing into nephrology care. For each model, the review identifies essential components for success and discusses barriers and facilitators to implementation. By focusing on practical, scalable, and patient-centered solutions, this review advocates for a paradigm shift in nephrology care. It envisions genetic testing as a standard component of kidney disease management, aiming to improve outcomes and promote equitable care for patients globally.
Severe malaria is associated with kidney and brain injury, yet potential mechanisms linking both complications remain understudied. We investigated the associations between kidney and brain injuries in a cohort of Indian adults and children with severe Plasmodium falciparum malaria. We found that acute kidney injury was prevalent in both adults (64.4%) and children (71.4%). We also found that plasma levels of the structural kidney injury biomarker neutrophil gelatinase-associated lipocalin (NGAL) were strongly associated with acute kidney injury severity (P < .0001) and negatively correlated with whole brain magnetic resonance imaging apparent diffusion coefficient values in cerebral malaria (r = -0.6, 95% confidence interval, -0.8 to -0.3). Low apparent diffusion coefficient values indicate cytotoxic edema, a form of hypoxic brain injury mediated by parasite sequestration and inflammation. Severe cytotoxic edema has been shown to be associated with increased mortality in severe malaria. In our cohort, there was a 5.5-fold greater risk of this form of brain injury (prevalence risk ratio, 5.5, 95% confidence interval, 2.3-13.2) in patients with high NGAL levels (>300 ng/mL). These results suggest that plasma NGAL may play a critical role in structural kidney injury and could serve as a predictive marker for hypoxic brain injury in the context of severe malaria.
Genomic sequencing technologies are used in diagnostic laboratories to identify genetic causes of disease in patients. Gene curation plays an integral role by determining which genes have sufficient evidence for inclusion in diagnostic panels and those that should be prioritized in genome and exome sequencing. As the precursor to variant curation, gene curation also establishes pathogenicity limits for variant classification. Evaluating the clinical validity of a gene-disease relationship requires assessment of genetic and experimental evidence from literature and databases. The Clinical Genome Resource (ClinGen) has a semiquantitative framework for gene curation that is used across its Gene Curation Expert Panels (GCEPs). The ClinGen Kidney Disease Clinical Domain Working Group oversees five GCEPs covering the glomerulopathies, tubulopathies, complement-mediated kidney diseases, congenital anomalies of the kidney and urinary tract, and renal ciliopathies. These panels use a multidisciplinary approach in their gene curations, which are published and accessible to the public via the ClinGen website. ClinGen's expert-informed curations and other resources outlined in this review will help nephrologists validate whether genetic findings in reports are clinically relevant to their patients. Empowering nephrologists with knowledge of gene curation principles is imperative for informed decision-making in patient care.
The "10 Recommendations for Global Kidney Health" developed at the Global Policy 2017 constitute a commitment by and challenge to all stakeholders. Achieving these goals in disadvantaged population such as the First Nation Peoples (FNP) is even more challenging. Qom and Wichi ethnics are isolated Argentine FNP with poor access to health care. Research on chronic kidney disease (CKD) in Qom FNP in the Chaco Province, Argentina showed high rates of proteinuria without a decrease of the glomerular filtration rate in a group of 385 persons in 2003. In 2018, a subsequent cross-sectional evaluation in those individuals still living in the area revealed that diabetes mellitus (DM) increased sixfold (from 2% to 14%) and obesity increased threefold (from 21% to 61%). Infections (tuberculosis) and cardiovascular disease were the main causes of mortality in the whole sample, whereas gynecologic cancer was the first cause of death in women and cardiovascular disease in men. In 2018, a new group of subjects (not those originally assessed in 2003) showed a remarkably high prevalence of renal risk factors despite being as young as those originally evaluated in 2003 but with a prevalence of renal risk factors as high as when the latter were assessed 15 years afterward. Wichi FNP, in 2020, showed lower proteinuria rates (14%) with virtually no presence of DM. FNP deserve the creation of public policies for CKD detection and treatment, but they must be based on local scientific evidence, with continuous monitoring and learning and scalable strategies.
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.
Cellular senescence, a key driver of kidney aging and functional decline, manifests in 2 primary forms: (1) replicative senescence, primarily caused by telomere shortening; and (2) stress-induced senescence, triggered by factors such as oxidative stress and DNA damage. Senescent cells are characterized by permanent cell cycle arrest, activation of senescence-associated secretory phenotype (SASP), and epigenetic alterations, among others. It is important to note that cellular senescence is not exclusively detrimental; it also serves necessary, programmed functions in physiologic tissue remodeling and tumor suppression. However, its chronic accumulation with age is a major driver of organ decline. Currently, specific treatments targeting senescent cells are lacking. Strategies to counteract senescent cells fall into 2 main categories: (1) senolytics, which eliminate senescent cells; and (2) senomorphics, which mitigate their detrimental paracrine effects, including SASP inhibitors. Traditional Chinese Medicine (TCM) has demonstrated potential in combating aging through both senolytic and senomorphic mechanisms. Current evidence suggests that several TCM-derived compounds and formulations may modulate renal senescence-related pathways, including BCL-2 family-dependent apoptosis resistance, NF-κB/JAK2-STAT3/NLRP3-mediated SASP, NOX4-ROS/Nrf2 oxidative stress signaling, AMPK/mTOR/SIRT1 nutrient-sensing pathways, Klotho expression, and the gut-kidney axis. This review explores the emerging role of TCM in addressing renal aging, highlighting its advantages as a multi-targeted, low-toxicity therapeutic strategy to mitigate aging-related kidney diseases.
The therapeutic advantage of angiotensin-converting enzyme inhibitors was first described more than 40 years ago by Brenner and colleagues. Since then, a number of clinical trials have demonstrated the utility of drugs that modify the renin-angiotensin system (RAS) to slow the rate of progression of kidney disease in patients with and without diabetes. However, despite the well-known benefits of these drugs in reducing cardiorenal events, most clinicians are not using them consistently in their practice. The lack of use is related to concerns about increases in serum creatinine and the development of hyperkalemia. With the advent of many newer drugs to delay the progression of kidney disease and reduce the likelihood of cardiovascular events which have lesser effects on increasing serum creatinine or potassium, clinicians may prefer to use these therapies. Although trials of the newer cardiorenal protective therapies were conducted on the background of RAS inhibition, only the highest tolerated dose of RAS inhibition was used, a dose not shown to provide cardiorenal protection in a clinical trial. As multimodal therapy for slowing the progression of chronic kidney disease and reducing cardiovascular events moves into prime time, one has to wonder whether RAS inhibition will remain a foundation therapy.
Acute kidney injury (AKI) complicates non-falciparum malaria, particularly that from Plasmodium knowlesi. AKI (any KDIGO stage) is present in 20-30% of hospitalized patients with knowlesi malaria, with age >45 years having a sixfold risk of AKI. WHO-defined severe AKI (creatinine >265μmol/L) is found in ∼2.5% of adult knowlesi hospitalizations and 60% of deaths, with pathogenesis linked with intravascular hemolysis, endothelial activation, glycocalyx degradation and acute tubular necrosis (ATN). Paracetamol may have a renoprotective effect in severe knowlesi AKI, including reductions in medium-term proteinuria. WHO-severe AKI has been estimated by meta-analysis as occurring in 0.01% of combined hospital inpatient and outpatients with P. vivax malaria with unexplained geographic heterogeneity and incomplete systematic exclusion of comorbidities. Despite a paucity of community-based P. vivax KDIGO-defined AKI studies, one such study identified AKI in 10% of adults and children with vivax malaria, almost all KDIGO stage 1. AKI pathogenesis in vivax malaria is not well characterized; an exception is 8-aminoquinoline drug-induced acute hemolysis and ATN in patients with G6PD deficiency. AKI risk in malaria from P. malariae and P. ovale is poorly characterized and may be underrecognized. Long-term outcomes of AKI, including CKD and cardiovascular disease, are unknown in non-falciparum species, and longitudinal studies are needed.
I synthesize how systemic drivers (hypertension, diabetes, renin-angiotensin-aldosterone system activation) elevate glomerular capillary hydrostatic pressure and cyclic strain and how podocytes sense and respond to these loads via integrins, the slit diaphragm, and stretch-activated ion channels. When podocytes' normal adaptation mechanisms are overwhelmed by higher loads, inflammatory priming, genetic risk, or loss of cytoskeletal resilience, podocytes retract, detach, and are not meaningfully replaced, driving progressive glomerulosclerosis. Therapeutically, benefit follows two complementary strategies: lowering glomerular capillary hydrostatic pressure (angiotensin-converting enzyme inhibitor/angiotensin receptor blocker, sodium-glucose cotransporter 2 inhibitors, endothelin antagonism) and reinforcing podocyte mechanoadaptation (stabilizing actin/adhesion, modulating Ca²⁺ signaling, targeting load-sensing nodes). Taken together, progressive glomerulosclerosis is best explained by a model in which elevated single-nephron pressure loads exceed podocyte mechanoadaptive capacity. Durable protection will therefore require concurrent control of intraglomerular pressure and podocyte mechanotransduction. Semin Nephrol 36:x-xx © 20XX Elsevier Inc. All rights reserved.
Acute kidney injury (AKI) is a common clinical complication in malaria, with AKI reported across all species that cause severe disease, including Plasmodium falciparum, Plasmodium knowlesi, and Plasmodium vivax. AKI during malaria varies based on host and parasite factors, including the growth potential of the parasite within host red blood cells, the extent of red blood cell lysis, and the capacity of the parasite to sequester within the microvasculature. In this review, we focus primarily on P. falciparum pathogenesis and the role of intravascular hemolysis in AKI through the depletion of endogenous hemoglobin and heme scavengers, resulting in oxidative stress and tissue injury. We discuss the etiology of blackwater fever as a hemolytic complication in severe malaria that has been rising in incidence. All patients with severe malaria should have a high index of suspicion for AKI, particularly when hemolytic features are present. Finally, we review potential interventions to mitigate the impact of hemolysis on kidney injury in severe malaria. Given the high burden of malaria in Africa, the incidence of AKI in severe malaria, and the number of malaria episodes over a person's lifetime, the cumulative impact of malaria-associated AKI on chronic kidney disease needs to be considered. Semin Nephrol 36:x-xx © 20XX Elsevier Inc. All rights reserved.
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.
Cardiovascular disease (CVD) remains the leading disability burden and cause of mortality worldwide. As emphasized by the cardiovascular-kidney-metabolic health construct, enhanced screening mechanisms are needed for the identification and prediction of subclinical endothelial injury and silent CVD. We hypothesized that urinary podocyte shedding (podocyturia), as a biomarker of ongoing glomerular endothelial injury, may be an earlier predictor of CVD than moderate albuminuria. Urinary podocin and nephrin messenger RNAs (podocyturia), as candidate biomarkers of endothelial/podocyte injury, were measured by quantitative polymerase chain reaction in type 2 diabetics with normal albumin excretion rates at baseline, at 3-4 years, and at 7 years. The development of CVD was collected as the outcome. On visit 1, podocyturia was significantly higher in individuals who subsequently developed CVD versus those who did not. We also found a significant association between podocyturia and obstructive coronary artery disease. Moreover, individuals with CVD risk factors that included male sex, metabolic syndrome, and type 2 diabetes were found to have significantly higher urinary podocin levels than individuals without these risk factors. Podocyturia may be an earlier predictor of cardiovascular events than moderate albuminuria. Semin Nephrol 36:x-xx © 20XX Elsevier Inc. All rights reserved.
Glomerular disease significantly contributes to chronic kidney disease worldwide, affecting both pediatric and adult patients. Traditionally, clinical evaluation and kidney biopsy have been the gold standards for accurately diagnosing glomerular disease. However, advancements in genomics have introduced genetic testing as a valuable tool to enhance clinical care by enabling timely and precise diagnoses. More than 100 genes have been implicated in glomerular diseases, with particular relevance to conditions such as focal segmental glomerulosclerosis, Alport syndrome, and thrombotic microangiopathy. This article outlines a systematic approach to suspecting and diagnosing genetic glomerular diseases, incorporating clinical history, physical examination, general laboratory findings, and kidney biopsy. It discusses strategies for selecting cases for genetic evaluation while also highlighting the importance of interpreting genetic findings in the context of the patient's clinical presentation and socioeconomic factors. Additionally, it emphasizes the potential impact of genetic testing on patient care. Given the increasing accessibility of genomic technology, nephrologists should integrate genetic testing into the routine clinical management of patients with glomerular diseases. Semin Nephrol 36:x-xx © 20XX Elsevier Inc. All rights reserved.
Chronic kidney disease (CKD) affects approximately 9% of the global population, leading to increased risks of end-stage kidney disease (ESKD), cardiovascular disease (CVD), and mortality. Patients with CKD are a huge burden on health care resources globally. CKD is a complex condition influenced by a combination of genetic, environmental, and traditional risk factors. Family studies have suggested heritability rates for CKD ranging from 30% to 75%, and large genomic biobank studies have proven essential in identifying genes with substantial effects on CKD risk and in capturing cumulative genetic risk through polygenic risk scores. These biobanks are crucial for discovering new genes associated with kidney health and disease, and their growing size enhances the power to detect novel genetic associations. Integrating multi-omics technologies such as transcriptomics, metabolomics, and proteomics further enriches our understanding of CKD, while advanced computational tools continue to expand our insights into genetic data. Polygenic risk scores, derived from hundreds of genetic variants with small effect sizes, can help identify individuals at high risk of CKD. Genomic biobanks offer valuable opportunities for early identification and personalized treatment of monogenic kidney disorders, such as autosomal dominant polycystic kidney disease and Alport syndrome. These biobanks help fill knowledge gaps, particularly in individuals with milder or asymptomatic presentations who are often underrepresented in traditional studies. Expanding genomic biobank efforts globally, especially in diverse populations, is vital to enhancing our understanding of the genetic underpinnings of kidney disease. This review highlights the significant contributions of genomic biobanks to advancing our comprehension of the genetics of CKD.
Kidney diseases, represented by chronic kidney disease (CKD) and acute kidney injury (AKI), pose significant global public health challenges due to their complex pathogenesis and limited therapeutic options. In recent years, epigenetic regulation-including DNA methylation, histone modifications, and non-coding RNAs-has been shown to play a crucial role in the progression of kidney diseases, offering new directions for therapeutic strategies. Natural herbal compounds have emerged as a research focus for modulating epigenetic mechanisms owing to their multi-target effects, low toxicity, and broad bioactivity. This review outlines the regulatory functions of epigenetic mechanisms across various kidney diseases and illustrates how natural herbal compounds can mitigate renal injury via multi-target epigenetic modulation. These compounds have been shown to reverse renal fibrosis, attenuate inflammatory responses, suppress oxidative stress, and protect podocytes and renal tubular epithelial cells by targeting DNA methyltransferases, histone-modifying enzymes, and non-coding RNAs, including microRNAs and long non-coding RNAs. However, challenges such as limited bioavailability and insufficiently elucidated in vivo mechanisms impede clinical translation. Future research should prioritize structural optimization, advanced delivery systems, and investigations into gut microbiome interactions to enhance therapeutic applicability. Overall, this review highlights the promise of epigenetics-based therapeutic strategies using herbal active ingredients for kidney disease intervention, though further validation and optimization are needed for clinical application.