Current Opinion in Nephrology and Hypertension最新文献

Purpose of review: Chronic kidney disease-mineral bone disorder (CKD-MBD) is associated with several adverse outcomes, including bone fragility and sarcopenia. Identification of new agents mitigating systemic damage related to uremia is critical and needed to unveil pathways implicated in CKD-MBD.

Recent findings: Osteopontin (OPN) is involved in different physiological and pathological processes and works as a bridge connecting several systems. It may serve as a biomarker for many diseases, including human cancers, neurodegenerative disorders and autoimmune diseases. OPN has been implicated in disturbances of bone mineralization and remodeling, and has an interplay with parathyroid hormone and FGF23 in experimental models. In patients with CKD and severe hyperparathyroidism, OPN expression in muscle tissue has been linked to worse functionality and local inflammation, which is partially reverted after parathyroidectomy.

Summary: Future studies could confirm the role of OPN as a biomarker in nephrology. Greater understanding of its role in CKD-MBD will help us define a better therapeutic strategy in patients with CKD.

Purpose of review: Aging and chronic kidney disease mineral and bone disorder (CKD-MBD) interact to worsen bone health, vascular calcification, and frailty in older patients. The altered FGF23-Klotho axis and disrupted mineral homeostasis emphasize the need for early interventions to mitigate fractures and cardiovascular complications in this vulnerable population. This review provides an updated overview of the current knowledge on CKD-MBD in older patients.

Recent findings: CKD-MBD exacerbates bone fragility and vascular calcification in older populations. Early vascular aging and cognitive decline are associated with increased mortality. Disruptions in calcium, phosphate, and vitamin D homeostasis accelerate bone loss and fracture risk, whereas secondary hyperparathyroidism worsens cardiovascular outcomes. Additionally, polypharmacy, sarcopenia, and cognitive impairment further intensified the clinical burden in aging CKD patients.

Summary: Aging potentially worsens CKD-MBD, vascular calcification, and cardiovascular disease in older patients. This growing field offers promising opportunities for further research to enhance understanding, improve bone health outcomes, and reduce fracture risk.

Purpose of review: This review highlights studies published in the last 18 months focusing on sex dimorphism in clinical and preclinical areas related to chronic kidney disease (CKD).

Recent findings: Hypertension, cardiorenal disease, hormone exposure, heat stress and dietary intake are all risk factors with sexually dimorphic effects thus contributing differentially to the development of chronic kidney disease. In CKD, GFR decline and cardiovascular mortality are more pronounced in males. Females have higher STEMI related in hospital mortality. When on dialysis, females have higher cardiovascular events rate. Males develop anemia and hyperparathyroidism earlier. Hyperphosphatemia is more prevalent in males. Vitamin D deficiency is associated with CKD in males only. Males are more likely to develop severe sarcopenia. The renoprotective effects of estrogen or estrogen agonists are mediated in part through GPER. ET-1 dual antagonism offset the action of GPER. ET-1 dual antagonism abolished the sex differences in acclimation to high salt. Sodium transport and oxygen consumption across the different renal segments is sexually dimorphic. Sexually dimorphic gene expression is mostly seen in the proximal tubules and is under androgen control.

Summary: The above findings emphasize the need to systematically include female models in preclinical and clinical research which will improve clinical management and allow for development and implementation of precision medicine tailored to sex.

Purpose of review: The kidneys control systemic phosphate balance by regulating phosphate transporters mediating the reabsorption of inorganic phosphate (Pi). At least three different Na + -driven Pi cotransporters are located in the brush border membrane (BBM) of proximal tubule cells, NaPi-IIa (SLC34A1), NaPi-IIc (SLC34A3) and PiT-2 (SLC20A2). This review will discuss novel aspects of their regulation, pharmacology, and genetics.

Recent findings: Renal NaPi transporters are not only acutely regulated by the phosphaturic hormones parathyroid hormone (PTH) and Fibroblast Growth Factor 23 (FGF23) but possibly also by further mechanisms. A role of inositol hexakisphosphate (IP6) kinases has been found and their deletion from kidneys causes hypophosphatemia, hyperphosphaturia, and bone demineralization. Inhibitors of NaPis elicit phosphaturia and may reduce levels of PTH and FGF23 in chronic kidney disease (CKD) models. The relevance of renal NaPi transporters is highlighted by loss-of-function mutations in SLC34 transporters and analysis of patients provides new insights into diseases caused by variants. Major manifestations include nephrocalcinosis and -lithiasis, rickets, and variants may predispose to an accelerated decline in kidney function.

Summary: Renal Pi transporters are regulated, may provide novel drug targets for prevention or treatment of hyperphosphatemia, and contribute to the genetic risk to develop kidney stones and CKD.

Purpose of review: The recent widespread availability of genetic testing has resulted in the diagnosis of many more people with Alport syndrome. This increased recognition has been paralleled by advances in understanding clinical consequences, genotype-phenotype correlations and in the development of new therapies.

Recent findings: These include the international call for a change of name to 'Alport spectrum' which better reflects the diverse clinical features seen with autosomal dominant and X-linked Alport syndrome; the demonstration of how common Alport syndrome is in people with haematuria, proteinuria, or kidney failure; the inability of current genetic testing to detect all pathogenic variants in suspected Alport syndrome; the different genotype-phenotype correlations for autosomal dominant and X-linked disease; and the novel treatments that are available including SGLT2 inhibitors for persistent albuminuria despite renin-angiotensin-aldosterone blockade, as well as early studies of gene-modifying agents.

Summary: Autosomal dominant Alport syndrome is the commonest genetic kidney disease and X-linked Alport syndrome is the second commonest genetic cause of kidney failure. Both these diseases are frequently seen in the renal clinic, and clinicians should be aware of their likelihood in a person with persistent glomerular haematuria, proteinuria or kidney failure. Autosomal dominant Alport syndrome is so common that it also occurs coincidentally in other kidney diseases especially IgA nephropathy.

Purpose of review: Online hemodiafiltration (OL-HDF) is a type of outpatient intermittent dialysis therapy using purified online dialysis fluid sourced from the city water supply. OL-HDF has been widely practiced in Europe and Japan, and its clinical effects have been reported for prevention of dialysis amyloidosis, inflammation, and dialysis hypotension.

Recent findings: A randomized controlled trial of all-cause mortality in postdilution OL-HDF and high-flux hemodialysis groups with replacement fluid volumes >23 l/session (CONVINCE study) reported a lower risk of all-cause mortality with OL-HDF compared to conventional hemodialysis. Whereas USA had not previously adopted OL-HDF, in February 2024 Fresenius' 5008K received 510K FDA approval, Although efforts to purify dialysis water and systems using dialysis fluid for HDF, such as those from Aksys (2002) and Nephros (2012), had been made in the past in the USA, they did not gain widespread adoption. Neighboring Canada has been conducting OL-HDF using the Gambro AK200 (1999), Baxter Artis (2009), B. Braun Dialog+ (2010), B. Braun Dialog IQ (2021) and the Fresenius 5008 (2013), all of which have received Health Canada approval for OL-HDF.

Summary: OL-HDF's introduction to the USA represents both a challenge and an opportunity for patient care and the nephrology community. As a potentially superior treatment for ESRD patients, OL-HDF enables larger volumes of exchange, reduces costs by creating online solutions to replace expensive offline fluids, makes HDF therapy affordable for outpatient setting, and may improve survival and quality of life. However, significant barriers - ranging from regulatory and reimbursement hurdles to infrastructural inadequacies - must be addressed. Whether OL-HDF can finally emerge as a transformational renal replacement therapy after its entry to the US healthcare system remains to be determined.

Purpose of review: This review explores the variability in preimplantation kidney biopsy processing methods, emphasizing their impact on histological interpretation and allocation decisions driven by biopsy findings. With the increasing use of artificial intelligence (AI) in digital pathology, it is timely to evaluate whether these advancements can overcome current challenges and improve organ allocation amidst a growing organ shortage.

Recent findings: Significant inconsistencies exist in biopsy methodologies, including core versus wedge sampling, frozen versus paraffin-embedded processing, and variability in pathologist expertise. These differences complicate study comparisons and limit the reproducibility of histological assessments. Emerging AI-driven tools and digital pathology show potential for standardizing assessments, enhancing reproducibility, and reducing dependence on expert pathologists. However, few studies have validated their clinical utility or demonstrated their predictive performance for long-term outcomes.

Summary: Novel AI-driven tools hold promise for improving the standardization and accuracy of preimplantation kidney biopsy assessments. However, their clinical application remains limited due to a lack of proven associations with posttransplant outcomes and insufficient evaluation of predictive performance metrics. Future research should prioritize longitudinal studies using large-scale datasets, rigorous validation, and comprehensive assessments of predictive performance for both short- and long-term outcomes to fully establish their clinical utility.

Purpose of review: Proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID), is a disease defined by the presence of glomerulonephritis with nonorganized mono-isotypic immunoglobulin (Ig) deposits. This review will discuss the pathogenesis of PGNMID and address novel techniques for detection of monoclonal Ig and pathologic B-cell clones and for distinguishing monoclonal from oligoclonal Ig deposits.

Recent findings: Because of low detection rate of circulating monoclonal Ig and nephritogenic B-cell clones and emerging reports of PGNMID-IgG in children, it has been recently argued that many PGNMID-IgG3 cases may not be monoclonal lesions. A mass spectrometry-based method, serum matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry, has been shown to have superior sensitivity than immunofixation for detection of monoclonal Ig in PGNMID and other monoclonal gammopathy of renal significance (MGRS) lesions. Two novel sequencing techniques, RNA-based immunoglobulin repertoire sequencing and single-molecule real-time sequencing of monoclonal immunoglobulin, enable identification of the full-length variable sequence of monoclonal Ig, even in MGRS patients with low tumor burden and undetectable monoclonal Ig by conventional methods. Finally, staining of kidney biopsy for Ig light chain variable domain subgroups may allow for separation of true monoclonal from oligoclonal PGNMID.

Summary: Novel sequencing, mass spectrometry, and immunofluorescence techniques have the potential to increase the detection rate of nephritogenic monoclonal Ig/B-cell clone and distinguish monoclonal from oligoclonal deposits in PGNMID.

Purpose of review: The Banff schema uses combinations of pathological lesions at predefined thresholds to diagnose of T cell rejection (TCMR) and grade its severity. Constant definitional changes have caused confusion among clinicians and pathologists. This review describes the evolution of lesion definitions and the rationale for the minimal thresholds.

Recent findings: The minimal diagnostic threshold for borderline TCMR has been reset to original Banff i1/t1, where isolated tubulitis is now excluded. Arteritis can be mediated by either Grade II TCMR or caused by donor specific antibody as antibody-mediated vascular rejection. The conservative threshold for chronic active TCMR diagnosis uses moderate total and scarred inflammation with tubulitis has been challenged by recent longitudinal data to suggest lower thresholds including i-IFTA=1 as clinically relevant.

Summary: Minor changes in the threshold ruleset can cause substantial alterations in the final pathological diagnoses. While minimal thresholds for borderline and active TCMR have now stabilized, future changes are likely for chronic active TCMR pending confirmatory research.

Purpose of review: In this review, we highlight the importance of understanding the inherent biological variability in normal kidney, or healthy reference tissue, to establish an accurate reference point for biomedical research. We explore this and the advantages and limitations of various sources of healthy reference tissue suitable for structural and omics-level studies.

Recent findings: Several large consortia are employing omic technologies for diseased and normal kidney tissue, underscoring the importance of utilizing healthy reference tissue in these studies. Emerging approaches, such as artificial intelligence and multiomic analyses, are expanding our understanding of structural and molecular heterogeneity in healthy reference kidney tissue and uncovering new insights.

Summary: Biological variability in healthy reference tissue at the functional, structural, and molecular level is complex and remains an active area of study. Thoughtful selection of healthy reference tissue sources is critical, providing the greatest potential for producing high-quality research outcomes.