Nature Reviews Nephrology最新文献

Understanding the relationship between reproductive health and kidney function is important to provide holistic care for people living with kidney disease. Chronic kidney disease (CKD) has negative impacts on both male and female fertility owing to factors including inflammation, hormonal dysregulation, reduced ovarian reserve, reduced sperm quality and sexual dysfunction. However, pregnancy is achievable for most cisgender women with kidney disease, including kidney transplant recipients and patients on dialysis. CKD in pregnancy is associated with health risks to the mother and child, including increased risk of progression of kidney disease, hypertensive complications of pregnancy, and neonatal complications including fetal growth restriction, preterm birth and stillbirth. However, with appropriate pre-pregnancy counselling, fertility assessment and support, health optimization, and evidence-based antenatal care, the majority of patients will achieve a good outcome. Medication safety should be reviewed before and during pregnancy and lactation, weighing the risk of disease flare against potential adverse effects on the offspring. Important areas for further research include the optimal timing of delivery and the short- and long-term cardiovascular and renal impacts of pregnancy in patients with CKD, as well as long-term kidney and cardiovascular outcomes in their offspring.

Fibrosis results from the continuous deposition of extracellular matrix (ECM) by fibroblasts in response to injurious stimuli; however, the exact roles of fibroblasts in this process are unclear. New findings demonstrate a key role for the protease ADAMTS12 in driving fibrosis through the remodelling of ECM and activation of profibrotic fibroblasts. “On the basis of these observations, we hypothesize that ADAMTS12 serves as an autocrine switch that controls the initiation of fibroblast activation, including [their] detachment and migration from the perivascular niche,” say the researchers.

Using unbiased gene expression analyses, Konrad Hoeft, Lars Koch and colleagues observed upregulated expression of ADAMTS12 in fibroblasts after injury in mouse and human kidneys. Mice with deletion of Adamts12 were protected from kidney and cardiac fibrosis, characterized by the limited upregulation of ECM proteins and restricted expansion of profibrotic mesenchymal cells, indicating a regulatory role in the fibrotic process. In line with these findings, deletion of ADAMTS12 in immortalized PDGFRβ⁺ human mesenchymal kidney cells attenuated expression of the ECM component gene COL1A1 in response to TGFβ, associated with downregulation of JAK–STAT signalling and of pathways related to cell adhesion, cell migration and locomotion. Live cell imaging over a period of 24 h confirmed that the knockout cells exhibited a blunted migratory response to TGFβ, which was rescued by the expression of active ADAMTS12, along with upregulation of JAK–STAT signalling. Mechanistically, the researchers determined that active ADAMTS12 acts to cleave the fibulin HMCN1 — a component of basement membranes that tethers cells to membranes. Knockdown of HMCN1 in ADAMTS12-overexpressing cells inhibited their migration, which indicates that cleaved HMCN1 peptides (which are produced in the presence of activated ADAMTS12) promote mesenchymal cell migration, activation and perpetuation of fibrosis.

The use of next-generation sequencing technologies such as exome and genome sequencing in research and clinical care has transformed our understanding of the molecular architecture of genetic kidney diseases. Although the capability to identify and rigorously assess genetic variants and their relationship to disease has advanced considerably in the past decade, the curation of clinically relevant relationships between genes and specific phenotypes has received less attention, despite it underpinning accurate interpretation of genomic tests. Here, we discuss the need to accurately define gene–disease relationships in nephrology and provide a framework for appraising genetic and experimental evidence critically. We describe existing international programmes that provide expert curation of gene–disease relationships and discuss sources of discrepancy as well as efforts at harmonization. Further, we highlight the need for alignment of disease and phenotype terminology to ensure robust and reproducible curation of knowledge. These collective efforts to support evidence-based translation of genomic sequencing into practice across clinical, diagnostic and research settings are crucial for delivering the promise of precision medicine in nephrology, providing more patients with timely diagnoses, accurate prognostic information and access to targeted treatments.

Congenital nephrogenic diabetes insipidus (NDI; also known as arginine vasopressin resistance) is a rare inherited disorder of water homeostasis, caused by insensitivity of the distal nephron to arginine vasopressin. Consequently, the kidney loses its ability to concentrate urine, which leads to polyuria, polydipsia and the risk of hypertonic dehydration. The diagnosis and management of NDI are very challenging and require an integrated, multidisciplinary approach. Here, we present 36 recommendations for diagnosis, treatment and follow-up in both children and adults, as well as emergency management, genetic counselling and family planning, for patients with NDI. These recommendations were formulated and graded by an international group of experts in NDI from paediatric and adult nephrology, urology and clinical genetics from the European Rare Kidney Disease Reference Network and the European Society of Paediatric Nephrology, as well as patient advocates, and were validated by a voting panel in a Delphi process. The goal of these recommendations is to provide guidance to health care professionals who care for patients with NDI and to patients and their families. In addition, we emphasize the need for further research on different aspects of this potentially life-threatening disorder to support the development of evidence-based guidelines in the future.

Glucocorticoids are currently used to induce remission in patients with antineutrophil cytoplasmic antibody glomerulonephritis (ANCA-GN), but these drugs carry a high risk of adverse effects and infection. Targeting T cells through cytokine inhibition might represent an alternative therapeutic approach, according to a new study by Christian Krebs, Ulf Panzer and colleagues.

A digital pharmacology analysis identified the monoclonal antibody ustekinumab, which targets IL-12 and IL-23, as a candidate treatment for targeting T_H1 and T_H17 cells. These T cell subsets were confirmed to be enriched in inflamed areas of the kidney in an additional cohort of patients with ANCA-GN using flow cytometry. From this cohort, four patients with relapsing disease were treated with ustekinumab, in addition to standard-of-care cyclophosphamide and steroids. Over 26 weeks, treatment led to a positive clinical and serological response without causing serious adverse effects.

Several mechanisms prevent the ascent of uropathogenic bacteria from the bladder to the kidney, which can lead to pyelonephritis. A new study by Menna Clatworthy and colleagues clarifies the role of neutrophil extracellular traps (NETs) in this protection.

Noting the presence of neutrophils in urine from individuals with a negative leukocyte esterase urine dipstick test (which is typically thought to detect neutrophils in urine as a UTI marker), the researchers also demonstrated that the test was positive only in the presence of NETosing, and not intact, neutrophils.

The human genome is tightly packed into the 3D environment of the cell nucleus. Rapidly evolving and sophisticated methods of mapping 3D genome architecture have shed light on fundamental principles of genome organization and gene regulation. The genome is physically organized on different scales, from individual genes to entire chromosomes. Nuclear landmarks such as the nuclear envelope and nucleoli have important roles in compartmentalizing the genome within the nucleus. Genome activity (for example, gene transcription) is also functionally partitioned within this 3D organization. Rather than being static, the 3D organization of the genome is tightly regulated over various time scales. These dynamic changes in genome structure over time represent the fourth dimension of the genome. Innovative methods have been used to map the dynamic regulation of genome structure during important cellular processes including organism development, responses to stimuli, cell division and senescence. Furthermore, disruptions to the 4D genome have been linked to various diseases, including of the kidney. As tools and approaches to studying the 4D genome become more readily available, future studies that apply these methods to study kidney biology will provide insights into kidney function in health and disease.

Sympathetic efferent renal nerves have key roles in the regulation of kidney function and blood pressure. Increased renal sympathetic nerve activity is thought to contribute to hypertension by promoting renal sodium retention, renin release and renal vasoconstriction. This hypothesis led to the development of catheter-based renal denervation (RDN) for the treatment of hypertension. Two RDN devices that ablate both efferent and afferent renal nerves received FDA approval for this indication in 2023. However, in animal models, selective ablation of afferent renal nerves resulted in comparable anti-hypertensive effects to ablation of efferent and afferent renal nerves and was associated with a reduction in sympathetic nerve activity. Selective afferent RDN also improved kidney function in a chronic kidney disease model. Notably, the beneficial effects of RDN extend beyond hypertension and chronic kidney disease to other clinical conditions that are associated with elevated sympathetic nerve activity, including heart failure and arrhythmia. These findings suggest that the kidney is an interoceptive organ, as increased renal sensory nerve activity modulates sympathetic activity to other organs. Future studies are needed to translate this knowledge into novel therapies for the treatment of hypertension and other cardiorenal diseases.