Seminars in nephrology最新文献

Advances in genetic testing have attributed many cases of clinically unexplained kidney disease (UKD) to monogenic disorders with such reclarified diagnoses optimizing and individualizing patient care. Patients affected by UKD despite reasonable nephrological workup can benefit from genetic testing because it can reveal etiology, end protracted diagnostic odysseys, inform prognosis, guide management, avoid unnecessary treatments, confer broader implications for family members including transplantation, enable genetic counseling, and guide reproductive care. Recent studies have found diagnostic yield of genetic testing in UKD is between 11% and 32%, even in those without family history of kidney disease, with variants most frequently identified in COL4A3-5. Given the broad spectrum of patients with UKD, considering testing in all patients would ensure such clarifying diagnoses are not missed. However, genetic testing in UKD carries complexity for patients, clinicians and health care systems and thus requires education and support frameworks to overcome these barriers. A patient-centered discussion and shared decision-making around the merits and potential harms in all patients with UKD ensure potential genetic diagnoses are not missed, with a focus on patient autonomy and benefit.

Atypical hemolytic uremic syndrome (aHUS) or complement-mediated thrombotic microangiopathy (CM-TMA) and C3 glomerulopathy are two prototypical diseases of complement dysregulation occurring due to genetic variants in complement proteins or acquired factors such as autoantibodies. Despite the presence of an underlying genetic etiology, an environmental trigger is often necessary to manifest disease, a phenomenon known as incomplete penetrance. These triggers could include infections, pregnancy, medication, cancers, or ischemia-reperfusion injury and antibody-mediated rejection in the setting of transplantation and highlight the complex interplay between genetic etiology and environmental factors. Other diseases in which complement activation may also be a part of the underlying pathophysiology and where the gene-environment interaction also plays out are IgA nephropathy, lupus nephritis, ANCA-associated vasculitis, and membranous nephropathy. Genetic polymorphisms and haplotypes may further skew the balance between complement over activation and control. In this article, we discuss the activation and regulation of the complement system and the role of complement in various kidney diseases. We also attempt to provide an in-depth understanding of the genetic drivers and environmental triggers associated with complement activation using aHUS as a key example. 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.

Kidney transplantation is the best treatment for kidney failure in eligible patients, significantly improving survival and quality of life. While short-term post-transplant survival has improved, long-term outcomes remain limited. Advances in genetic research have the potential to transform kidney transplantation. The shortage of donor organs underscores the need for improved organ availability, optimized immunosuppression, and enhanced monitoring to minimize repeat transplants. Improved understanding of monogenic kidney diseases and availability of genetic testing are increasingly informing the evaluation of transplant candidates and living donors. Expanding genetic testing to include pharmacogenomics and improved immunologic matching between transplant recipients and donors can improve post-transplant outcomes. Living kidney donors have perioperative risks and a 5-10 times higher likelihood of developing kidney failure, particularly if biologically related to the recipient. Some of this risk may be attributable to genetic factors that should be ascertained during donor evaluation. Polygenic risk scores offer promise for early risk identification, personalized interventions, and better long-term outcomes, though further validation is needed across diverse populations. Additionally, gene-editing technologies and personalized genomics may enhance donor-recipient compatibility, reduce graft rejection, and improve transplant success. These advancements in precision medicine are set to transform kidney transplantation by improving patient care and allograft longevity. 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.

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.

This article explores the role of genetics in kidney stones and kidney cancer predisposition, focusing on monogenic genetic causes that can be identified through genetic testing. We provide a comprehensive review of monogenic causes of kidney stones and kidney cancer as well as the current treatment options. A curated list of 64 monogenic causes of kidney stones, including 11 provisional genes, and 50 genes for kidney cancer predisposition, also including 11 provisional genes, is presented. Selected genes are discussed in detail, highlighting their clinical presentations, underlying genetic mechanisms, and available treatment options. These include gene-specific therapies, such as drugs targeting AGXT for primary hyperoxaluria type 1 and VHL for renal cell carcinoma, alongside nonspecific treatments for conditions such as Bartter syndrome and Lynch syndrome. As gene discovery continues to progress, it holds the potential to inform future preventive guidelines, novel therapeutic approaches, and precision medicine strategies, ultimately advancing the field of nephrology and improving patient outcomes. Semin Nephrol 36:x-xx © 20XX Elsevier Inc. All rights reserved.