Current Opinion in Nephrology and Hypertension最新文献

Purpose of review: Autosomal dominant polycystic kidney disease (ADPKD) is a progressive genetic disorder characterized by cyst formation, kidney enlargement, and eventual kidney failure. While tolvaptan remains the only FDA-approved therapy targeting disease progression, there is a growing pipeline of novel therapies. This review explores emerging interventions aimed at modifying cystogenesis, metabolic reprogramming, and kidney function decline.

Recent findings: Recent preclinical and early clinical studies have identified promising therapeutic avenues including AMPK activators (e.g., metformin), SGLT2 inhibitors, GLP-1 receptor agonists, and bempedoic acid. Dietary interventions such as ketogenic diets and caloric restriction show potential for reducing cyst burden and preserving kidney function. RNA-based therapies targeting miR-17 and PC1-correcting agents like VX-407 offer genetically targeted treatment approaches. Several of these interventions are in ongoing phase 2 or 3 clinical trials evaluating their safety and efficacy and are discussed in this review.

Summary: The treatment landscape for ADPKD is rapidly evolving, with multiple innovative therapies advancing toward clinical implementation. Integration of pharmacologic, dietary, and genetic strategies represents a comprehensive approach to modifying disease trajectory. Further large-scale, long-term studies are essential to validate these approaches and optimize individualized patient care.

Purpose of review: The structures of the human sodium-chloride cotransporter (hNCC) and its complex with thiazide diuretics have been determined recently. This review summarizes key structural insights into NCC's transport and inhibition mechanisms.

Recent findings: Recent studies revealed the structures of hNCC and its complex with thiazide diuretics, in inward-facing and outward-facing conformations, respectively. The structures of hNCC in two major conformational states provided important insights into the transport and regulatory mechanisms. Thiazide-bound hNCC structures illuminated the molecular mechanisms of thiazide-mediated NCC inhibition and explained the structure-activity relationship of thiazide diuretics.

Summary: Structures of hNCC provide mechanistic insights into molecular mechanisms of loss-of-function NCC variants that cause Gitelman syndrome. The thiazide-bound hNCC structures provide a blueprint for further optimizing thiazide diuretics to reduce side effects. The novel interdomain interaction-mediated hNCC regulatory mechanisms revealed by structural studies lay the foundation for developing next-generation NCC modulators and NCC-rescuing therapeutics for treating NCC dysfunction.

Purpose of review: Antineutrophil cytoplasmic antibody (ANCA) vasculitides are complex, immune mediated conditions of significant morbidity and mortality. This review highlights the evolving therapeutic landscape and emerging sub-phenotypes of the disease group to support development of more personalised interventions for people living with ANCA vasculitides.

Recent findings: The advances in management include steroid-sparing strategies, with avacopan offering complement-based neutrophil inhibition. Rituximab has become central in induction and maintenance therapy, reducing cyclophosphamide use and replacing azathioprine. Cyclophosphamide is still used but often as an additional induction agent in the combination with rituximab to speed up disease control and to reduce glucocorticoid burden in severe kidney disease. Evidence gaps remain, particularly regarding long-term safety of newer agents, the optimal duration of maintenance therapy, and the benefits of plasma exchange in select populations. Recognition of distinct disease trajectories such as slowly sclerosing kidney disease in opposition to rapidly progressive glomerulonephritis highlight the need for more stratified treatment.

Summary: Early disease detection, shared decision-making and personalised care are keys to improving outcomes in ANCA vasculitis. Future directions are risk stratifications that incorporate biomarker and novel diagnostic techniques to guide treatment intensity. Identification of key service components associated with improved outcomes such as multidisciplinary care is essential to support equitable translation of medical advances into clinical practice, ensuring both efficacy and safety in this high-risk population.

Purpose of review: With No lysine (WNK) kinases participate in maintaining the homeostasis of water and electrolytes, by regulating the Cation Chloride Cotransporters (CCCs), which are implicated in the regulation of cell volume, neuronal intracellular [Cl-], and regulation of salt balance by the kidneys. Recently, the Nuclear Receptor Binding Proteins (NRBP) and the TGF-β-Stimulated Clone 22 Domain family (TSC22D) proteins were identified as WNK interactors that modulate WNK kinase activity. This review will summarize the findings of recent works that explore this previously unrecognized role of NRBP and TSC22D proteins.

Recent findings: Three groups independently described the interaction between components of the WNK/SPAK-OSR1 pathway and NRBP1 or the TSC22D proteins, which are known interactors of NRBP1. These proteins were shown to colocalize with WNK kinases in biomolecular condensates. It was described that NRBP1 and TSC22D proteins have an activating effect on WNK activity and that its deficiency leads to impaired cell volume regulation and impaired electrolyte transport regulation in the distal convoluted tubule.

Summary: These findings have implications extending beyond epithelial sodium transport, as they may be relevant for other fundamental processes modulated by WNKs, such as neuronal function, cellular volume regulation, and cell proliferation.

Purpose of review: Until recently, the underlying pathophysiology of diffuse podocytopathies associated with nephrotic syndrome was not understood. Since the discovery of antinephrin antibodies and antibodies against other slit diaphragm components in a subset of patients with minimal change disease and focal segmental glomerulosclerosis, there has been a transformation of our understanding of disease pathogenesis and treatment rationale.

Recent findings: Antinephrin antibodies are common in patients with acquired diffuse podocytopathy and are most reliably detected among those patients with treatment-naive nephrotic syndrome. Circulating antibodies correlate with disease activity and may be useful for monitoring patients with podocytopathies. Rituximab represents an effective treatment inducing remission in a majority of patients and reducing the frequency of relapses. Optimal dosing and frequency remain unclear, and randomized trials in this space are ongoing.

Summary: Our understanding of immune-mediated podocytopathy is rapidly evolving, and changes in treatment paradigms are likely to continue to change, with emphasis on targeted therapies addressing disease pathogenesis. Future prospective studies are required to understand the optimal use of antinephrin antibodies for diagnosis and monitoring and how to tailor therapy to individual patients.

Purpose of review: Fracture risk is significantly elevated in patients with chronic kidney disease (CKD), yet the diagnosis and treatment of CKD-associated osteoporosis remain complex. This review addresses the current gaps in managing bone health in CKD and highlights emerging strategies in this high-risk population.

Recent findings: Diagnosis of CKD-associated osteoporosis requires integration of imaging, bone turnover markers, and occasionally bone biopsy. Correction of mineral metabolism disturbances is foundational, while bone-targeted therapies must be carefully selected. Treatment strategies are informed by bone turnover status. Antiresorptives such as bisphosphonates and denosumab are used in high-turnover disease, and osteoanabolic agents such as teriparatide and romosozumab are promising for low-turnover disease.

Summary: Management of osteoporosis in CKD requires individualized approaches based on bone turnover and mineral metabolism status. While several pharmacologic options exist, evidence from randomized trials in CKD populations is limited. Further research is needed to guide treatment selection, define well tolerated therapeutic targets, and improve skeletal outcomes in this vulnerable group.

Purpose of review: The regulation of renal tubular transport is essential for maintaining electrolyte balance and blood pressure. Calcium-binding protein 39 (Cab39), also known as mouse protein-25 (MO25), plays a pivotal role in modulating this process through its interaction with WNK (with no lysine) kinases and Ste20-like kinases, including STE20/SPS1-related proline-alanine-rich kinase (SPAK) and oxidative stress response 1 (OSR1). By stabilizing and facilitating the activation of these kinases, Cab39 plays a crucial role in the regulation of key ion transporters, such as the sodium-chloride cotransporter (NCC) and the sodium-potassium-chloride cotransporters (NKCC1 and NKCC2). This review provides a comprehensive analysis of Cab39 structural properties, molecular interactions, and functional roles in renal physiology, emphasizing its significance in ion homeostasis.

Recent findings: Studies reveal that Cab39 enhances SPAK activity up to 100-fold. Importantly, the role of Cab39 extends beyond simple kinase activation, as it supports kinase complex assembly and localization, enabling precise control over transporter regulation. Evidence also suggests that Cab39 may influence the regulation of NCC and NKCC2 through similar mechanisms, making it a promising target for therapeutic interventions in disorders such as hypertension and salt-wasting syndromes.

Summary: The discovery of a small-molecule Cab39 inhibitor highlights its potential as a pharmacological target. Understanding the multifaceted functions of Cab39 may unlock novel strategies for managing renal and cardiovascular disorders.

Purpose of review: This review will provide an overview of the current understanding of mechanisms which drive IgA nephropathy (IgAN), and explore new therapies (those approved or being evaluated in phase 3 studies) which modulate these mechanisms to improve outcomes.

Recent findings: IgAN remains the most reported primary glomerular disease worldwide. It is now clear that the majority of those diagnosed with IgAN are likely to progress to kidney failure over their lifetime, unless stringent disease control is achieved early. For decades, therapeutic options have been limited to interventions generic to chronic kidney disease (CKD), which could not alone rescue patients with IgAN from the risk of kidney failure. Recent advances in our understanding of the mechanisms driving IgAN, coupled with regulatory shifts in approvable clinical trial endpoints, have led to a surge in the development and evaluation of targeted therapies.

Summary: As of early 2025, four agents have already received regulatory approval, and many more are expected. New treatments act on IgAN-specific disease pathways and modify disease pathways generic to CKD. For the first time, it is now possible to initiate well tolerated, effective, truly disease-modifying interventions early to meaningfully reduce the lifetime risk of kidney failure among those living with IgAN.

Purpose of review: Acute kidney injury (AKI) often progresses to chronic kidney disease (CKD), yet standardized clinical guidelines for managing this transition remain lacking. Recent studies suggest that sodium-glucose cotransporter 2 inhibitors (SGLT2i) or flozins improve AKI outcomes. Studies on patients living with diabetes post-AKI show flozins reduce mortality, CKD progression, and recurrent AKI, highlighting their potential in mitigating maladaptive kidney repair. We discuss recent preclinical evidence supporting a role of SGLT2i during AKI repair and subsequent CKD.

Recent findings: AKI is characterized by endothelial and tubular injury, hypoperfusion, metabolic dysfunction, inflammation, and cell death. SGLT2i restore renal hemodynamics, mitochondrial dysfunction, and reduce oxidative stress, improving recovery following AKI. Additionally, SGLT2i mitigate cell death by counteracting apoptosis and ferroptosis while reducing inflammation through suppression of pro-inflammatory cytokines and inflammasome activation. Beyond AKI, flozins exhibit long-term antifibrotic effects, reducing extracellular matrix deposition even after treatment discontinuation. Preclinical studies demonstrate a sustained protective effect on kidney integrity months after short-term treatment.

Summary: These inhibitors hold promise for broad nephroprotection, with robust biological rationale in maladaptive repair. Further research is needed to optimize their use and establish clinical guidelines for AKI management in both diabetic and nondiabetic populations.