IgA nephropathy (IgAN), the world's most common form of primary glomerulonephritis (GN), has a variable clinical and pathologic presentation. While all cases of IgAN show dominant or codominant glomerular IgA deposits, their histologic appearance can range from essentially normal to severe crescentic GN. Oxford (MEST-C) scoring is widely used to classify IgAN on kidney biopsies and has been validated to correlate with clinical presentation and as an independent predictor of kidney outcomes in multiple studies. Components of MEST-C, most notably endocapillary hypercellularity (E score) and crescents (C score), have also been shown to correlate with response to immunosuppressive therapy. Furthermore, immunohistologic evidence of complement activation by the alternative pathway and sometimes the lectin pathway correlates with histologic lesions, proteinuria, and kidney survival, suggesting the complement cascade as a potential therapeutic target. Recent clinical trials have demonstrated the potential of newer classes of immunosuppressive agents as well as complement inhibitors to reduce proteinuria, a marker associated with disease progression, in patients with IgAN. While pathologic studies of kidney biopsies have generally not been part of these trials, this review presents an algorithm by which kidney biopsy findings can be used to guide the choice of therapeutic agents in patients with IgAN.

IgA nephropathy (IgAN) is the most prevalent primary glomerular disease and has been recognized to carry a poor prognosis. It is therefore critical to identify the patients that will progress to ESKD and start treatments early. The current gold standard for diagnosis remains kidney biopsy. Histopathologic findings along with proteinuria, glomerular filtration rate, and hypertension remain the best-validated biomarkers for prognosis but do not provide enough granularity to guide treatment decisions. The current understanding of the pathophysiology of IgAN with the four-hit hypothesis has helped identify potential additional biomarkers that could become available in the foreseeable future. In this review we detail the existing data for the most promising biomarkers including galactose-deficient IgA1 and its corresponding autoantibody, markers of complement activation, as well as more nascent assays such as MicroRNAs, genomic, and microbiome biomarkers.

IgA nephropathy (IgAN) presents with different expressions and natural histories across ages. The direct comparison of incidence and progression of IgAN in children and adults is difficult due to different policies for performing kidney biopsy in different ages and countries. In the past decade the focus has been on assessing the individual risk profile at kidney biopsy or after 1 year of follow-up in children and adults. This would help avoid overtreatment and unnecessary drug exposure in benign cases of IgAN, and promptly initiate an aggressive therapy in progressive ones. This issue is particularly relevant in children. This review addresses some recent insights into the similarities and differences of IgAN across the age spectrum, with a particular focus on the prognostic predictors of progression in children and in adults, aiming at offering some critical elements useful for treatment choices for IgAN across ages.

Immunoglobulin A (IgA) is a key actor in the mucosal immune system, which moderates interactions between the host and environmental factors such as food antigens and commensal microorganisms. The pathogenesis of IgA nephropathy (IgAN) involves a multistep process starting with deglycosylation of mucosally derived, polymeric IgA1 (dg-IgA1) that reaches the circulation. Modified O-glycans on dg-IgA1 are targeted by IgG-autoantibodies, leading to the formation of circulating immune complexes that deposit in the glomerular mesangium. Infections of mucosal surfaces trigger flares of primary IgAN, while inflammatory bowel disease and liver cirrhosis are important causes of secondary IgAN, supporting a mucosal source of nephritogenic IgA1. In the presence of microbial pathogens or food antigens, activated dendritic cells in the gut mucosa induce T-cell-dependent or T-cell-independent B-cell differentiation into IgA-secreting plasma cells. Herein we review the literature concerning mucosal immune function and how it is altered in this disease. We discuss recent evidence supporting a causal role of gut microbiota dysbiosis in IgAN pathogenesis.

Despite decades of research, our knowledge of the global epidemiology of IgA nephropathy remains limited. Much of what we know about IgA nephropathy incidence comes from biopsy registry studies that are subject to bias related to differences in screening programs, referral patterns, and access to healthcare. Fewer epidemiologic studies used an appropriate data infrastructure that includes a well-defined source population. Nonetheless, all these studies show considerable geographic variation in disease incidence with an increase from west to east and south to north across Eurasia. This pattern is partly explained by the distribution of genetic risk alleles in individuals of European and East Asian ancestry. Although historically thought to be an indolent disease, recent long-term follow-up studies have demonstrated an exceptionally high lifetime risk of kidney failure. The International IgA Nephropathy Prediction Tool, derived and validated in multiple ethnically diverse cohorts, has improved our ability to identify patients at high risk of progression who may benefit from therapies being tested in clinical trials. The earlier identification of high-risk patients, evaluation of novel risk factors, and accurate assessment of global disease burden require high-quality regional data infrastructures and broad collaborative efforts to ensure the impact of new treatments is maximized.

Immunoglobulin A (IgA) nephropathy is the most common glomerulonephritis in many countries. Most patients progress to kidney failure for which kidney transplantation is the optimal therapy. Unfortunately, IgA nephropathy commonly recurs post transplant and shortens allograft survival. Multiple recipient and donor characteristics have been associated with the risk of recurrence, although these have varied between different cohorts. The clinical expression of post-transplant IgA nephropathy is modified by immunosuppression. Biomarkers have been identified and studied in native-kidney IgA nephropathy but need validation in transplantation. Treatment of recurrent IgA nephropathy hinges on supportive measures derived largely from evidence in native-kidney IgA nephropathy. The improved understanding of the autoimmune mechanisms of disease in native-kidney IgA nephropathy has led to promising new targets for treatment, which may in turn be deployed in post-transplant IgA nephropathy.

IgA nephropathy is a mesangioproliferative glomerular disease with significant morbidity and mortality. Most patients with IgA nephropathy develop kidney failure in their lifetime, reducing their life expectancy by a decade. Since its first description in 1968, it has been established that kidneys of IgA nephropathy patients are injured as "innocent bystanders" by nephritogenic IgA1-containing immune complexes. Results from clinical, biochemical, immunologic, and genetic studies suggest a multistep pathogenetic mechanism. In genetically predisposed individuals, this process results in formation of circulating immune complexes due to the binding of IgG/IgA autoantibodies to the polymeric IgA1 molecules with incomplete O-glycosylation. This event is followed by the addition of other proteins, such as complement C3, resulting in the formation of nephritogenic immune complexes. These complexes are not effectively removed from the circulation, and some of them pass through the fenestration of glomerular endothelial cells to enter the mesangial space and activate mesangial cells. It is thought that the process is initiated by soluble immune complexes and that their accumulation results in the formation of immunodeposits that further amplify glomerular injury. Here we summarize current understanding of the pathogenesis of IgA nephropathy and discuss experimental model systems that can inform development of new therapeutic strategies and targets.

IgA nephropathy (IgAN), the most prevalent primary glomerulonephritis worldwide, carries a considerable lifetime risk of kidney failure. The etiology of IgAN, however, remains incompletely understood, and effective treatment is lacking. Although the multihit model effectively identifies key steps in IgAN development and, to date, provides the best description of IgAN pathogenesis, it remains under development to fully capture the complexity of immune system dysregulation. Large-scale genome-wide association studies have revealed clues regarding the association between IgAN and genes in both innate and adaptive immune pathways. Hence, genetic investigations may shed light on the aberrant molecular mechanisms, thereby presenting new opportunities for therapeutic advancements. This review discusses the genetic associations that have been robustly connected with IgAN, placing them within the framework of disease mechanism. Altogether, these findings highlight numerous new possibilities for the development of treatments and the road to personalized medicine.

The past few years have heralded a sea change in the treatment landscape of IgA nephropathy (IgAN). An increasing understanding of its pathogenesis coupled with favorable changes in the regulatory approval pathway has led to an explosion of clinical drug development in this disease. This has directly resulted in the approval of three novel therapies specifically for the treatment of IgAN (nefecon, sparsentan, and iptacopan), and several others are in the late stages of clinical development. In this review, we outline the rationale for new therapies in development for IgAN and emerging clinical trial data and propose a new paradigm for the treatment of this condition.

IgA vasculitis (IgAV) is considered a systemic form of IgA nephropathy (IgAN). The two diseases share similar geographic and ethnic distribution, along with common variants in genetic association studies. The pathophysiology of IgAN and IgA vasculitis nephritis (IgAVN) can be explained by the four-hit hypothesis. Key molecules involved at each step in both diseases were evaluated as diagnostic and prognostic biomarkers with many common factors, most prominently serum galactose-deficient IgA1. On kidney biopsy, the two diseases are indistinguishable, and the established histological Oxford classification for IgAN will soon be validated for IgAVN. Chronic lesions (segmental glomerulosclerosis and tubular atrophy / interstitial fibrosis) seem more frequent in IgAN, while proliferative lesions (endocapillary hypercellularity and crescents) are more frequent in IgAVN, which could explain the worse IgAN renal prognosis. Due to characteristic skin rash, IgAVN patients are diagnosed precociously. Conversely, the frequent absence of overt clinical signs in IgAN leads to a delayed diagnostic kidney biopsy in the disease evolution, which explains the chronic pathologic lesions. From a therapeutic perspective, while impressive advances have been made in recent years for IgAN, there is a glaring lack of evidence-based guidelines for the treatment of IgAVN. Large therapeutic clinical studies are required, and future IgAN trials should include IgAVN.

The IgA Nephropathy Foundation was established in 2004 by Bonnie and Ed Schneider, the concerned parents of a young boy diagnosed with IgA nephropathy (IgAN). At the time the Foundation was established, patients had trouble finding the most basic information about IgAN, and few nephrologists had experience with this rare disease. Celebrating its 20th anniversary this year, the Foundation has been instrumental in bringing the IgAN community together through research grants, advocating for patients and caregivers, offering patient support services, and becoming the go-to source for information and education. A big focus for the Foundation is communicating the "voice of the patient" to the medical community to help identify needs and provide insight into the lives of IgAN patients and caregivers. The Foundation is very active in getting the word out, attending the last two International Symposia on IgA Nephropathy, in Prague, Czech Republic, and Tokyo, Japan. The Foundation also sponsored the IgA Nephropathy Seminar Day at the 6th CKD Summit in Boston in spring 2024. This article chronicles some of the Foundation's key milestones, highlights patient-facing and point-of-care resources, and provides key insights into the patient experience as well as tips for how clinicians can best meet patients where they are, bridge gaps, and improve care. The unmet needs of the IgAN community continue to drive the IgA Nephropathy Foundation's purpose and steadfast commitment to finding a cure for this rare disease.

Congenital anomalies of the kidney and urinary tract (CAKUT) are the leading cause of kidney failure in children and adolescents. CAKUT describes a wide spectrum of structural disorders with a prenatal origin. The etiology of CAKUT is multifactorial, including environmental, nongenetic, and genetic causes that impact kidney development as well as upper and lower urinary tract development. Adult nephrologists who treat patients with CAKUT may be challenged by the underlying diseases they are not familiar with and the accumulation of chronic kidney disease complications in childhood. This article discusses CAKUT etiology and presentation, the course during childhood and adolescence, as well as adult issues in CAKUT patients including CKD complications, urologic interventions, and genetic counseling. A smooth transition of CAKUT patients from pediatric to adult care can be challenging. Semin Nephrol 43:x-xx © 2023 Elsevier Inc. All rights reserved.

Many people across the spectrum of chronic kidney disease (CKD) experience a large symptom burden. Measuring symptoms can be a way of responding to the concerns of patients and their priorities of care and may help to improve overall outcomes, including health-related quality of life. The objective of this article is to discuss approaches to measuring symptoms across the spectrum of CKD and to highlight strategies to facilitate the incorporation of routine symptom assessment into kidney care. Specifically, we discuss the use of validated patient-reported outcome measures in CKD as they relate to measuring symptoms, including their benefits and limitations, and describe commonly used patient-reported outcome measures. We discuss potential barriers that should be considered when contemplating the development of a program to routinely measure and address symptoms. Finally, we outline a systematic, stepwise approach to measuring symptoms with implementation strategies to address the common barriers. Although the principles outlined in this article can be applied to research and audit, the principal focus is on symptom measurement aimed at informing clinical practice and directly improving patient outcomes.

Social functioning is a key aspect of daily life and is important to patients living with chronic kidney disease (CKD) and their caregivers. Many patients with CKD experience debilitating symptoms and treatment burden that can diminish their social functioning and thereby overall social health, which is the aspect of a person's well-being relating to their interactions and connections with others. In patients with CKD, symptoms (e.g., fatigue and pain), burden of ongoing treatments (including kidney replacement therapies), and medication side effects can impair social functioning. Having to manage responsibilities of self-management, which can include time-consuming and invasive treatments such as dialysis, can severely limit social functioning in patients with CKD. This can lead to poor social connections at many levels, including with family, friends, peers, and colleagues, and can hinder the development of new relationships. Patients with CKD with poorer social functioning have been reported to have worse quality of life and impaired mental health. Many patients with CKD rely on an informal caregiver-usually a family member or friend-to assist with management of their disease. This can place strain on the caregiver, further limiting opportunities for social connections for both the patient and caregiver. Although social functioning is critical for the overall well-being of patients with CKD, it remains underaddressed clinically, and patient-reported outcome measures (PROMs) to assess social functioning are limited. The objective of this article is to define social functioning, discuss the impacts of social functioning in patients with CKD and their caregivers, outline PROMs that have included assessment of social functioning, and discuss considerations in developing an appropriate PROM to measure social functioning in patients with CKD. This may help to inform the evaluation of interventions and care regarding social functioning within the CKD population.

Risk, prevalence, management, and outcomes in chronic kidney disease (CKD) are influenced by social and broader determinants of health. Consequently, there are wide-ranging kidney health inequities. As patients are key stakeholders, their perspectives on the care they receive and on health status are central in guiding health system improvement, particularly to reduce the impact of disadvantage. Patient-reported experience measures (PREMs) and patient-reported outcome measures (PROMs) are important self-report tools in quality improvement, acting to guide initatives aimed at enhancing access to timely and relevant support. However, the extent to which PREMs and PROMs address the reduction of kidney health inequities is unclear. The aim of this review is to summarize how PREMs and PROMs are designed and implemented, highlighting key dimensions that are integral to health equity-oriented quality improvement in kidney care. There are several problems yet to be overcome so that such tools do not unintentionally reproduce kidney health gaps. Inclusive generation of the scope of tools, transparent reporting on attributes of patients who engage, and embedding PREMs and PROMs within a framework of value-based quality improvement is fundamental to their impact as part of equitable health system transformation.

The increasing burden of chronic kidney disease (CKD) on the health care system highlights the need to prioritize services and manage the use of resources efficiently. Amid these financial constraints, key decision makers must weigh the impact of an intervention or program on health care expenditure when determining the allocation of limited resources. Patient-reported outcome measures (PROMs) are relevant in health economic decision-making within nephrology. Health-related quality of life, a patient-reported outcome, can provide data that inform economic evaluations of treatments for patients with CKD. PROMs help determine the value of different therapies by assessing their impact on patients' daily lives beyond clinical outcomes and can help policymakers make decisions about funding and reimbursement that consider the priorities and preferences of patients. Economic evaluations often employ cost-utility analyses, which use quality-adjusted life years as a key metric. Quality-adjusted life years combine both the quality and quantity of life lived, allowing for comparison of the effectiveness of different interventions in a standardized manner. By integrating utilities derived from PROMs, these analyses quantify the benefits of CKD treatments in terms of how patients feel and function. Furthermore, PROMs contribute to quality improvement initiatives by identifying areas where patient care can be enhanced, guiding the implementation of programs that improve health-related quality of life while maintaining cost-effectiveness. In value-based financing environments, the integration of PROMs ensures that patient-centered outcomes are prioritized, leading to more effective and equitable health care delivery. In this article, we discuss the role of PROMs in economic evaluations in CKD and provide an overview of approaches for using PROMs in economic evaluations to inform decision-making in nephrology.

Incorporating the patient's perspective into the entire product life cycle of medical device development is paramount for ensuring patient-centric evaluation. By prioritizing patient-centric evaluation, medical device developers can better address patient needs and enhance the quality and effectiveness of health care solutions. Patient-reported outcomes (PROs), patient preference information (PPI), and qualitative inquiry are methodologies to incorporate and amplify the patient's voice. In nephrology, unlike in other clinical domains, the utilization of PROs, PPI, and qualitative inquiry in medical device development has been notably sparse. Consequently, a glaring absence of patient involvement in the development of devices leaves the impact of these devices on patient well-being and functionality largely unexplored. Many forward-thinking programs as well as Food and Drug Administration guidance on the use of PROs and PPI are effectively bringing PROs into nephrology device development. Many resources exist to help researchers select high-quality PROs. There are unique considerations for using PROs and PPI to support regulatory decision-making, including fit-for-purpose, concepts of interest, context of use, and least burdensome selection. The rapid evolution of patient-centric initiatives in nephrology will serve to ensure that medical devices meet the needs of people with kidney disease and improve the quality of care.

Patient experience is considered a pillar of high-quality care, integral to patient-centered care, but despite significant policy focus on patient-reported experience measures (PREMs), little is published regarding their development, use, or impact on clinical practice. In nephrology, PREMs are increasingly used in research to capture and quantify patients' perceptions of their experiences with health care services. It has been shown that a negative patient experience impacts patients' physical and psychological health, and a small but significant proportion of patients across a selection of settings report their experiences of health care as poor or suboptimal. Evidence of whether PREMs improve quality of care or support person-centered care in the clinical setting remains largely theoretical. Extensive effort has been invested to develop various PREMs for kidney services. Although little evidence linking PREM collection to meaningful change in delivery of care currently exists, work is underway. Early indications are that with the right facilitators, implementing PREMs in routine practice can help providers recognize where change is needed and galvanize transformation. The journey toward understanding the connection between PREM data and modifiable provider characteristics to target and enable change has started, but further evidence is needed. This article outlines the history of PREMs in nephrology and details their current use alongside implementation challenges. The use and benefits of PREMs are discussed before considering the evidence base for their impact on renal health care. Possible next steps for PREMs are suggested and best practices highlighted.

The outcomes reported in trials across all stages of chronic kidney disease (CKD) are highly variable and often do not include outcomes that are directly relevant to patients and caregivers. Frequently, the outcomes reported in trials are often unvalidated surrogate biochemical end points. The omission of outcomes that are meaningful and important to patients can diminish the value of trials in supporting treatment decisions. In response, there have been increasing efforts across many health and medical disciplines to develop core outcome sets, defined as the minimum set of outcomes to be reported in all trials in a specific health area to improve the relevance and consistency of reporting trial outcomes. The international Standardized Outcomes in Nephrology (SONG) initiative was established in 2014 and has since developed seven core outcome sets for different diagnosis and treatment stages of CKD. The core outcomes were based on consensus among patients, caregivers, and health professionals. Each core outcome set includes at least one patient-reported outcome, including fatigue (hemodialysis), life participation (kidney transplantation, peritoneal dialysis, early CKD not yet requiring kidney replacement therapy, children and adolescents, and glomerular disease), and pain (polycystic kidney disease). This article outlines how patient-reported outcomes are currently reported in trials, discusses core patient-reported outcomes that have been established for trials in kidney disease, and outlines strategies for implementing core patient-reported outcomes in trials.